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The South African Society of Psychiatrists (SASOP) Treatment Guidelines for

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AUGUST 2013

South African Journal of Psychiatry

VOL. 19, NO. 3

PART 2

The South African Society

of Psychiatrists (SASOP)
Treatment Guidelines for
Psychiatric Disorders
Edited by Robin Emsley and Soraya Seedat

Editor: Prof Werdie van Staden Official Journal of the South African Society of Psychiatrists
www.sajp.org.za | ISSN 1608-9685
 Editor

South African Journal of Psychiatry

C W VAN STADEN (Pretoria)

Associate Editorial Board:

Psychiatry
Vol. 19 No. 3 August 2013
C W ALLWOOD (Johannesburg)(Past editor)

Contents
O ALONSO (Umtata)
F COLIN (Pretoria)
R EMSLEY (Stellenbosch)(Past editor)
D MKIZE (KZN)
Y MOOSA (Johannesburg)
The South African Society of Psychiatrists (SASOP) Treatment Guidelines J PRETORIUS (Bloemfontein)

for Psychiatric Disorders S RATEMANE (Limpopo)

L ROOS (Pretoria)
S SEEDAT (Stellenbosch)
D STEIN (Cape Town)

134 Introduction M VORSTER (Johannesburg)

O GUREJE (Nigeria)
F NJENGA (Kenya)
136 Attention deficit hyperactivity disorder in children and adolescents F KIGOZI (Uganda)
A J Flisher, S Hawkridge O ODEJIDE (Nigeria)
A ABDELRAHMAN (Sudan)
136 1. Introduction M ARAYA (Ethiopia)
S KAAYA (Tanzania)
136 2. Diagnosis and clinical characteristics M SEBIT (Zimbabwe)
2.1 Screening B LEONARD (Ireland)
2.2 Evaluation N SARTORIUS (Switzerland)
2.3 Clinical presentation A OKASHA (Egypt)
A JOUBERT (Denmark)
137 3. Assessment D MOUSSAOUI (Morocco)
3.1 Laboratory or neurological testing
PUBLISHED BY THE HEALTH &
3.2 Psychometric testing MEDICAL PUBLISHING GROUP (HMPG):
137 4. Treatment Editor-In-Chief
4.1 Treatment goals JANET SEGGIE
4.2 General aspects of treatment Managing Editor
4.3 Acute treatment JP DE V VAN NIEKERK

4.4 Maintenance treatment Deputy Editor

4.5 Pharmacological treatment BRIDGET FARHAM

4.6 Non-pharmacological treatment Editorial Systems Manager

4.7 Special populations MELISSA RAEMAEKERS

4.8 Managing partial and non-responders Scientific Editor

KERRY GORDON
140 5. Summary points Technical Editors
EMMA BUCHANAN

141 Dementia ROBERT MATZDORFF

TARYN SKIKNE
F C V Potocnik
PAULA VAN DER BIJL
141 1. Introduction News Editor
1.1 Prevalence and burden of disease CHRIS BATEMAN

1.2 Causes and types of dementia Head of Publishing

1.2.1 Alzheimer’s disease ROBERT ARENDSE

1.2.2 Vascular dementia – with or without stroke Production Assistant

1.2.3 Combination of Alzheimer’s disease and vascular dementia NEESHA HASSAN

1.2.4 Dementia with Lewy bodies Art Director

BRENT MEDER
1.2.5 Pick’s disease and frontotemporal dementia
1.2.6 Substance-induced persisting dementia DTP & Design
ANELIA DU PLESSIS
1.2.7 Huntington’s disease CARL SAMPSON
1.2.8 Parkinson’s disease
Online Manager
1.2.9 Creutzfeldt-Jakob’s disease GERTRUDE FANI
1.2.10 Dementia associated with normal pressure hydrocephalus Distribution Manager
EDWARD MACDONALD
Published by the Health and Medical Publishing Group Sales Director
(Pty) Ltd, Co. registration 2004/022032/07, a subsidiary of the South African Medical Association. DIANE SMITH
28 Main Road (Cnr Devonshire Hill Road), Rondebosch, 7700 (012) 481-2069
Tel. (021) 681-7200. E-mail: publishing@hmpg.co.za
All letters and articles for publication should be submitted online at www.sajp.org.za.
Use of editorial material is subject to the Creative Commons Attribution – Noncommercial Works License.
http://creativecommons.org/licenses/by-nc/3.0/
ISSN 1608-9685

SAJP is available open-access at www.sajp.org.za Printed by Creda Communications

CONTENTS

1.2.11 Dementia secondary to head injury

1.2.12 AIDS dementia complex/HIV dementia
1.2.13 Other less common causes of dementia
143 2. Diagnosis, clinical characteristics and course
2.1 Course
144 3. Assessment and differential diagnosis
3.1 Mild cognitive impairment
3.2 Depression and delirium
3.3 Assessment of neuropsychiatric symptoms
3.3.1 Cognitive assessment: the Mini Mental State Examination
3.3.2 Functional assessment: activities of daily living
3.3.2.1 Driving
3.3.2.2 Firearms
3.3.2.3 Financial affairs and wills
3.3.2.4 Social assessment
3.3.2.5 Elder abuse
3.4 Comorbid medical conditions
3.5 Investigations
145 4. Treatment
4.1 Treatment goals
4.2 General aspects of treatment
4.2.1 Imparting the diagnosis
4.2.2 Accommodation and level of supervision
4.3 Pharmacological treatment
4.3.1 Acetylcholinesterase inhibitors and memantine
4.3.1.1 Adverse effects
4.3.1.2 Recommended dosages
4.3.1.3 Follow up
4.3.1.4 Neuropsychiatric symptoms
4.3.2 Antidepressants
4.3.3 Antipsychotics
4.3.4 Other medication/strategies
4.3.4.1 Hypnotics
4.3.4.2 Mood stabilisers/anticonvulsants
4.3.4.3 Restless legs syndrome
4.3.4.4 Hypersexuality
4.3.4.5 Treatment-resistant psychoses and disruptive vocalisers
4.4 Non-pharmacological treatment
4.4.1 The patient
4.4.2 The caregiver
4.5 Preventative measures
150 5. Algorithm
151 6. Summary points

153 Schizophrenia
D Swingler
153 1. Introduction
153 2. Diagnosis and clinical characteristics
153 3. Assessment
3.1 Diagnostic
3.2 Pretreatment
153 4. Treatment
4.1 Treatment goals
4.2 General aspects of treatment
4.3 Acute pharmacological treatment
4.3.1 First episode
4.3.2 Multi-episode/relapse
4.3.3 Second-line treatment
4.3.4 Third-line treatment
4.4 Long-term maintenance
4.5 Non-pharmacological treatment

129 SAJP - August 2013 Vol. 19 No. 3

 CONTENTS

4.5.1 Psychological interventions

4.5.2 Social interventions
4.6 Special populations
4.6.1 First-episode patients
4.6.2 Electro-convulsive therapy
4.7 Managing partial and non-responders
4.7.1 Non/partial response
4.7.2 Treatment resistance
155 5. Summary points

157 Major depressive disorder

G Grobler
157 1. Introduction
1.1 Prevalence and risk factors
1.2 Comorbidity and consequences
157 2. Diagnosis and clinical characteristics
2.1 Course and prognosis
156 3. Assessment
159 4. Treatment
4.1 Treatment goals
4.2 General aspects of treatment
4.3 Acute treatment
4.4 Pharmacological treatment
4.5 Continuation and maintenance treatment
4.6 Non-pharmacological treatment
4.7 Special populations
4.7.1 Subtypes
4.7.2 Comorbidity
4.7.3 Suicidality
4.7.4 Pregnancy and lactation
4.8 Managing partial and non-response
162 5. Summary points

164 Bipolar disorder

F Colin
164 1. Introduction
1.1 Epidemiology of bipolar disorder pertinent to the treatment guideline
1.1.1 Epidemiological statistics
1.1.2 Illness characteristics
164 2. Diagnosis and clinical characteristics
165 3. Recommended baseline investigations for BD
165 4. Treatment
4.1 Pharmacological treatment
4.2 Acute treatment: bipolar mania
4.2.1 Monotherapy
4.2.2 Combination treatment
4.2.3 Psychotherapy for mania
4.3 Acute treatment: bipolar depression
4.3.1 Pharmacotherapy for bipolar depression
4.3.2 Psychotherapy for bipolar depression
4.4 Maintenance treatment
4.4.1 Psychological interventions as an adjunct to medication
4.4.2 Maintenance pharmacotherapy
4.4.3 How long to treat
4.5 Complex bipolar presentations
4.5.1 Rapid cycling
4.5.2 Mixed states
4.6 Partial or no treatment response
4.7 Algorithm
170 5. Summary points

August 2013 Vol. 19 No. 3 - SAJP 130

CONTENTS

172 Panic disorder

C P Szabo
172 1. Introduction
172 2. Diagnosis and clinical characteristics
172 3. Assessment
172 4. Treatment
4.1 Treatment goals
4.2 General aspects of treatment
4.3 Pharmacological treatment: Acute
4.4 Pharmacological treatment: Maintenance
4.5 Non-pharmacological treatment
4.6 Special populations
4.7 Partial and non-responders

174 5. Conclusion
174 6. Summary points

175 Generalised anxiety disorder

D J Stein

175 1. Introduction
175 2. Diagnosis and clinical characteristics
175 3. Assessment
176 4. Treatment
4.1 Treatment goals
4.2 General aspects of treatment
4.2.1 Geriatric patients
4.2.2 Alcohol and/or substance abuse
4.2.3 Other comorbid disorders
4.2.4 Pregnancy, lactation, menopause
4.2.5 Comorbid medical disorders and medications
4.3 Pharmacological treatment
4.4 Non-pharmacological treatment
4.5 Acute treatment
4.6 Maintenance treatment
4.7 Managing partial and non-responders
4.7.1 Comorbidity
4.7.2 Compliance
4.7.3 Comorbid substance use
4.7.4 Comorbid personality disorders
4.7.5 Underlying medical disorder
4.7.6 Pharmacokinetic issues
4.7.7 Psychosocial issues
178 5. Summary points

180 Obsessive-compulsive disorder

D J Stein

180 1. Introduction
180 2. Diagnosis and clinical characteristics
180 3. Assessment
180 4. Treatment
4.1 Treatment goals
4.2 General aspects of treatment
4.2.1 Severity
4.2.2 Melancholia
4.2.3 Tourette’s disorder
4.2.4 Pregnancy, lactation, menopause

131 SAJP - August 2013 Vol. 19 No. 3

 CONTENTS

4.2.5 Comorbid medical disorders and medications

4.3 Pharmacological treatment:
4.4 Non-pharmacological treatment
4.5 Acute treatment
4.6 Maintenance treatment
4.7 Managing partial and non-responders
4.7.1 Compliance
4.7.2 Comorbid substance use
4.7.3 Comorbid personality disorders
4.7.4 Underlying medical disorder
4.7.5 Pharmacokinetic issues
4.7.6 Psychosocial issues

185 5. Algorithm
185 6. Summary points

187 Post-traumatic stress disorder

S Seedat

187 1. Introduction
187 2. Diagnosis and clinical characteristics
187 3. Assessment
187 4. Treatment
4.1 Treatment goals in PTSD
4.2 General aspects of treatment
4.3 Acute treatment
4.4 Maintenance treatment
4.5 Pharmacological treatment
4.6 Non-pharmacological treatment
4.7 Special populations
4.7.1 Pregnancy and lactation
4.7.2 Children and adolescents
4.7.3 The elderly
4.8 Managing partial and non-responders
4.9 Algorithm
4.10 Early interventions for PTSD
190 5. Summary points

192 Social anxiety disorder (social phobia)

S Seedat

192 1. Introduction
192 2. Diagnosis and clinical characteristics
192 3. Assessment
192 4. Treatment
4.1 Treatment goals
4.2 General aspects of treatment
4.3 Acute treatment
4.4 Maintenance treatment
4.5 Pharmacological treatment
4.6 Non-pharmacological treatment
4.7 Special populations
4.7.1 Pregnancy and lactation
4.7.2 Children and adolescents
4.7.3 The elderly
4.8 Managing partial and non-responders
4.9 Algorithm

195 5. Summary points

August 2013 Vol. 19 No. 3 - SAJP 132

 GUIDELINE

The South African Society of Psychiatrists (SASOP) Treatment

Guidelines for Psychiatric Disorders
R Emsley,1 MB ChB, MMed (Psych), FCPsychSA, DMed, DSc; F Colin,2 MB ChB, MMed (Psych), FCPSA;
A J Flisher,3 (deceased), MSc (Clin Psychol), MMed (Psych), MPhil (Child and Adolescent Psychiatry), PhD., FCPsych(SA), DCH;
G Grobler,4 MB ChB, MMed (Psych); S Hawkridge,1 MB BCh, FFPsych(SA); F C Potocnik,1 MB BCh, Dip Mid COG (SA), FCPsych(SA);
S Seedat,1 MB ChB, FCPsych, MMed (Psych), PhD; D J Stein,3 BSc (Med), MB ChB, FRCPC, PhD, DPhil; D Swingler,5 MB ChB, FCPsych(SA);
C P Szabo,6 MB BCh, MMed, FCPsych, PhD, MSc Med (Bioethics & Health Law)

1
Department of Psychiatry, Stellenbosch University, Cape Town, South Africa
2
Private practice, Pretoria, South Africa
3
Department of Psychiatry and Mental Health, University of Cape Town, South Africa
4
Department of Psychiatry, University of Pretoria, South Africa
5
2 Military Hospital, Wynberg, Cape Town, South Africa
6
Division of Psychiatry, University of the Witwatersrand, Johannesburg, South Africa

Corresponding authors: R Emsley (rae@sun.ac.za), S Seedat (sseedat@sun.ac.za)

The South African Society of Psychiatrists (SASOP)
Treatment Guidelines for Psychiatric Disorders have
been developed in order to address the local need for
guidelines in our unique clinical setting. The need for
treatment guidelines has frequently been expressed by
South African psychiatrists and other medical practitioners, as well
as by other role players such as medical scheme and other funding
body advisors and the pharmaceutical industry. While several well-
developed international treatment guidelines are readily accessible
and are indeed extensively utilised in South Africa, they are not always
applicable to our own circumstances. There are often important
differences, not only regarding the availability of various psychotropic
medications, but also in healthcare settings and availability of
resources that need to be considered when selecting particular
medications. For example, prescribing compounds that require
regular monitoring such as lithium and clozapine may not always be
feasible in certain rural settings in South Africa.
It is important to point out that these Guidelines do not aim
to provide a comprehensive review of all the pertinent literature
comprising the evidence base, and as such, should be utilised in
conjunction with other guidelines that do provide that kind of
information. We advise readers to use these and other guidelines with a
great deal of caution. Prescribing medication for psychiatric disorders
comprises a major component of psychiatrists’, and indeed general
practitioners’ function. It is therefore necessary for practitioners
to maintain a high level of knowledge and expertise in clinical
psychopharmacology, and to keep up-to-date with the ever-evolving
‘evidence base’. However, it needs to be remembered that the evidence
base in psychiatry is often difficult to interpret. Results of clinical
trials are frequently difficult to generalise to clinical practice, and are
often inconclusive, inconsistent or even conflicting. Methodological
differences in aspects such as selection of patient samples, dosage and
duration of treatment administered and outcome measures all make
it difficult to interpret findings across studies. This means that ‘the
evidence’ may be interpreted in different ways and there is a real risk
that it can be selectively applied to support a particular point of view.
This has been a point of criticism against the use of guidelines and
evidence-based practice in psychiatry. At the end of the day it behoves
practitioners to maintain an open and flexible mind, and most of all to
apply sound clinical judgement and common sense when interpreting
the available evidence.
These Guidelines do not cover all of the psychiatric disorders at this
stage, although most of the important ones are covered. We envisage
an ongoing process of updating and expanding the Guidelines
regularly, as new drugs are introduced and as healthcare settings
evolve. The chapters comprise a collection of systematically developed
chapters in standardised format that attempt to provide evidence-
based recommendations for assessment and treatment of common
psychiatric disorders. The aim is to provide guidelines that are of
assistance to psychiatrists and other medical practitioners in clinical
decision making. It is hoped that policy makers and administrators
will also make use of them.
These SASOP Guidelines refer to the current private healthcare
setting in South Africa. There are two important considerations
here. First, the pending introduction of a National Health Insurance
(NHI) in South Africa is likely to have an impact on the Guidelines.
However, at present no details of the NHI are available and it has not
been possible to take this into account in the current version. Second,
a majority of the people in South Africa currently receive healthcare
in the public sector and do not have access to many of the medications
referred to in the SASOP Guidelines. This is clearly a shortcoming
and an issue that needs to be addressed if the NHI is not going to be
introduced in the near future. Nevertheless, we hope that the SASOP
Guidelines will have some application in the public healthcare sector,
and particularly that they may assist decision makers determine the
most appropriate and cost-effective treatments in the public sector.

August 2013 Vol. 19 No. 3 - SAJP 134

GUIDELINE

The process. In 2009 the SASOP National Executive appointed Prof
Robin Emsley to chair a Task-Team to develop the Guidelines. A team
of experts was selected and several teleconference meetings were held.
The experts were identified, based on both their academic and clinical
experience, and they were invited to write one or two chapters.
The authors were requested to write their chapters according to the
following brief:
• The Guidelines should be specific to South Africa.
• We should aim at what is appropriate in a private practice setting –
and what is realistic given our budgetary constraints.
• As far as possible decisions should be evidence-based, and key
references should be provided.
• The Guidelines should be clear, concise and user-friendly.
• Authors were encouraged to use the following documents as a point
of departure:
• Stein DJ, et al. Standard treatment guidelines for common mental
health conditions, 2nd ed. South African Psychiatry Review 2007;
10(2):106-119.
• The partly developed previous SASOP Guidelines, which were
available on the SASOP website.
Each of the chapters was subjected to anonymous peer review by at
least two reviewers, together with editorial review. Chapter drafts were
revised according to these reviews. Finally, the chapters were edited
and formatted according to a uniform style. These draft Guidelines
were posted on the SASOP website (http://www.sasop.co.za/) and
comment was invited. Finally, a SASOP workshop with national
representation from both state-employed and private psychiatrists was
held in George in April 2013 to finalise the document.
S Afr J Psych 2013;19(3):128-199. DOI:10.7196/SAJP.474
Conflict of interest disclosures
Prof. Emsley reports receiving research funding from Janssen,
Lundbeck, and AstraZeneca, participating in speakers/advisory
boards, and receiving honoraria from AstraZeneca, Bristol-Myers
Squibb, Janssen, Lilly, Lundbeck, Organon, Pfizer, Servier, Otsuka,
and Wyeth.
Dr Colin reports lecturing in continuing medical education
programmes of Eli Lilly, Lundbeck, BMS, Janssen, GSK, Cipla, Pfizer,
Servier, and Astra Zeneca and serving on advisory boards for Janssen,
Lundbeck, Lilly, Servier, Cipla, and Astra Zeneca. He has also received
sponsorships from many pharmaceutical companies for attendance of
overseas and local congresses.
Dr Grobler reports attending a Lilly Advisory Board meeting.
Drs Hawkridge and Potocnik declare no conflict of interest.
Prof. Seedat reports receiving research grants from Lundbeck,
GlaxoSmithKline, and Astra-Zeneca and speaking for Pfizer, Servier,
Dr. Reddy’s, Sanofi-Aventis and Lilly.
Prof. Stein reports receiving research grants and/or consultancy
honoraria from Abbott, AstraZeneca, Eli-Lilly, GlaxoSmithKline,
Jazz Pharmaceuticals, Johnson & Johnson, Lundbeck, Orion, Pfizer,
Pharmacia, Roche, Servier, Solvay, Sumitomo, Takeda, Tikvah and
Wyeth.
Dr Swingler reports receiving speaker and consultation fees from
Servier and GlaxoSmithKline and speaker fees for Janssen and
Lundbeck.
Prof. Szabo reports receiving speaker fees from Lilly, Sanofi, and
AspenGSK for continuing professional development meetings that
were not product related and participating in advisory board matters
for Servier and Lilly.
It is recommended that the guidelines for bipolar disorder and
major depressive disorder be considered in conjunction with the
annexures for these guidelines (‘The management of psychiatric
disorders; evidence-based and consensus treatment guidelines
(including protocols and algorithms) for major depression
and bipolar disorder; practice guideline for the private sector;
Psychiatry Management Group (PsychMg)) that will be posted on
the SASOP website (www.sasop.co.za).

Acknowledgements
We gratefully acknowledge the assistance of the following reviewers: André Venter, Anersha Pillay, Bernard Janse van Rensburg, Bonga
Chiliza, Dana Niehaus, Franco Colin, Francois Pretorius, Frans Korb, Gerhard Jordaan, Ian Westmore, Jan Chabalala, Janus Pretorius, John
Joska, Jonathan Burns, Laila Asmal, Liezl Koen, Louw Roos, Lynette Nel, Mike Ewart Smith, Orlando Betancourt, Piet Oosthuizen, Rene
Nassen, Sean Baumann, Sean Kaliski, Solly Rataemane, Soraya Seedat, Surita van Heerden, Thabo Rangaka, Ulla Botha, Willie Pienaar.

Prof. Dan Stein kindly provided permission for us to make liberal use of the publication ‘Standard treatment guidelines for common mental
health conditions’ 2nd edition. South African Psychiatry Review 2007;0(2):106-119) for several of the chapters.

Dr Karen Cloete provided extensive editorial assistance.

Permission to reproduce various Tables, Figures and text was obtained and these acknowledgements are included in the text.

135 SAJP - August 2013 Vol. 19 No. 3


Attention deficit hyperactivity disorder in children
and adolescents
A J Flisher, S Hawkridge
1. Introduction
Attention deficit hyperactivity disorder (ADHD), although
commonest in childhood and adolescence, can be diagnosed across
the age span. The Diagnostic and Statistical Manual of Mental
Disorders, Fourth Edition, Text Revision (DSM-IV-TR)[1] defines the
disorder using the core features of hyperactivity, impulsivity and/or
inattention which are inappropriate for developmental stage.
The major aetiological influence for ADHD is genetic, which
accounts for 80% of the variability of the disorder.[2,3] However,
the environment and environment-gene interactions are also
significant. Examples of social factors associated with ADHD are
low socioeconomic status, low parental education, family conflict
and non-intact nuclear families, parental mental disorder, substance
abuse, criminality, punitive parenting, severe early deprivation and
institutional upbringing.[4] Examples of pre-, peri- and postnatal
environmental insults that are associated with ADHD include low
birth weight, maternal prenatal smoking, stimulant and alcohol use,
obstetric complications, head injury, epilepsy, HIV/AIDS, iron and
zinc deficiency, lead exposure, and early and increased television
exposure.[4]
The treatment guidelines that follow draw on and are broadly
compatible with the following documents, which should be consulted
for further information:
• Practice Parameter for the Assessment and Treatment of Children
and Adolescents With Attention-Deficit Hyperactivity Disorder of
the American Academy of Child and Adolescent Psychiatry[5]
• Treatment guidelines of the National Institute for Health and
Clinical Excellence (NICE) on methylphenidate, atomoxetine
and dexamphetamine for attention deficit hyperactivity disorder
(ADHD) in children and adolescents[6]
• European Guidelines for hyperkinetic disorder[7,8]
• Flisher et al.[9] ‘Packages of care for attention deficit hyperactivity
disorder in low- and middle-income countries’.
2. Diagnosis and clinical characteristics
2.1 Screening
Screening for ADHD should be included in the psychiatric assessment
of every patient, regardless of the main complaint. Questions about
the core symptoms of ADHD should be asked to assess whether a
diagnosis of ADHD is possibly applicable. If it is, then a complete
assessment should be performed. The diagnosis is not appropriate
if the symptoms occur exclusively during the course of a pervasive
developmental disorder, schizophrenia, or another psychotic disorder,
or are better accounted for by another psychiatric disorder. The
diagnosis is also inappropriate if the symptoms are better accounted
for by a substance use disorder (e.g. intoxication) or a general medical
condition such as allergic conditions, sensory deficits, chronic
GUIDELINE
infections, etc. Collateral information is essential, particularly with
regard to performance at school.
There are two types of instrument available to detect (and
diagnose) ADHD: clinical diagnostic interviews and rating scales.
The Diagnostic Interview Schedule for Children (DISC-IV) has been
assessed for use in South Africa.[10] No specific rating scales for ADHD
have been assessed in South Africa, but the Conner’s Parent Rating
Scale - Revised (CPRS-R) and the Conner’s Teacher Rating Scale -
Revised (CTRS-R)[11] are often used. However, the AD/HD Rating
Scale-IV[12] may be a better choice since the symptoms correspond
directly to those in DSM-IV-TR.
2.2 Evaluation
Evaluation of the child or adolescent for ADHD should consist
of clinical interviews with the caregiver and patient, obtaining
information about the patient’s school or day-care functioning,
evaluation for comorbid psychiatric disorders, and review of the
patient’s medical, developmental, social and family history.
Clinical observation of the patient should occur more than once and
if possible in more than one setting. School visits are recommended
if there is a discrepancy between reports from home and school
or if there is uncertainty about the diagnosis. If possible, school
observations should be carried out by a clinician other than those
known to the child.
An important initial step is to determine whether the child
or adolescent fulfils the criteria for the diagnosis. This involves
establishing whether each of the 18 symptoms is present; confirming
that at least 6 of the inattentive or at least 6 of the hyperactivity/
impulsivity cluster are present more days than not; that there is a
chronic course; that onset was before the age of 7 years; and that
the symptoms are associated with functional impairment. There
is a significant risk of misdiagnosing other psychiatric disorders
as ADHD, particularly anxiety disorders, and it is important to
explore the child’s emotional symptoms (e.g. worry, anxiety, beliefs,
somatic symptoms, etc.). Oppositional defiant disorder can also be
misdiagnosed as ADHD, because of some overlap of symptoms.
It is equally necessary to establish whether comorbid disorders
are present, the most common of which are oppositional defiant
disorder and conduct disorder. Other important comorbid disorders
include intellectual disability, depression, mania, anxiety disorders, tic
disorders, substance abuse, and specific learning disability. In some
cases symptoms of inattention and hyperactivity may be attributable
to another disorder, and not ADHD. In other cases, a child may suffer
from symptoms that do meet criteria for a disorder and are a direct
consequence of ADHD. For example, a child may become depressed
owing to social isolation or academic difficulties that are caused by
ADHD. Finally, a child may satisfy the criteria for ADHD as well as
August 2013 Vol. 19 No. 3 - SAJP 136
GUIDELINE
another disorder. In such cases, treatment may be necessary for both
disorders.
It is generally helpful to use a symptom scale, which can be
completed by the clinician, teacher and parent, although a diagnosis
should never be made only on the basis of such a scale. However,
extreme scores should raise the index of suspicion. The main use of
symptom scales is to monitor response to treatment.
It is important to assess the patient’s family, as untreated ADHD in
family members is a common finding. Providing treatment for family
members can often have collateral benefits for the child or adolescent
who has been referred. Children or adolescents with ADHD function
better in structured environments, and an unstructured environment
may be the result of parental ADHD.
2.3 Clinical presentation
A thorough mental status and physical examination of the patient is
mandatory, during which particular care should be taken to assess
whether other psychiatric disorders are present. It is important to note
that at the first session, hyperactivity may not be particularly evident
as the child may initially be inhibited or making an extra effort to
behave well for the occasion, so it is useful to see the child more than
once before making a diagnosis of ADHD. Girls in particular may
present with predominantly inattentive symptoms and this may not be
obvious in the consulting room unless specifically sought.
3. Assessment
3.1 Laboratory or neurological testing
If there is a medical disorder that can account for the symptoms
of ADHD, this will almost always be evident from the history and
physical examination. Examples of such disorders include brain
injury, hyperthyroidism, encephalopathies, lead poisoning and
fetal alcohol syndrome. In the absence of any specific indications of
such pathology, laboratory or neurological testing is not indicated.
However, there is a significant comorbidity of epilepsy with ADHD,
and a high index of suspicion should be maintained, bearing in mind
that a normal electroencephalogram (EEG) is not necessarily proof of
the absence of a seizure disorder, and an evaluation by a neurologist
may be helpful.
3.2 Psychometric testing
Psychological and neuropsychological tests are not diagnostic for
ADHD, but should be performed if the patient’s history suggests
low general cognitive ability or low achievement in language or
mathematics relative to the patient’s intellectual ability. It is common
for those with ADHD to perform poorly on testing owing to poor
concentration and impulsivity. This should be taken into account
when interpreting results, and results should be regarded as conclusive
only once the child is being successfully treated for ADHD.
It is not uncommon for children and adolescents with ADHD to
have evidence of poor educational attainment. The clinician needs
to assess whether the low level of educational attainment is entirely
due to the ADHD; whether the symptoms attributable to ADHD are
in fact the result of other learning or language problems; or whether
ADHD and other problems are both present. In the South African
context, tests or norms may not be available for all language and
137 SAJP - August 2013 Vol. 19 No. 3
cultural groups, and interpretation of the findings should take this
into account.
4. Treatment
4.1 Treatment goals
The aim of treating ADHD is to optimise the child’s cognitive, social and
emotional functioning so as to prevent the development of secondary
emotional distress or psychiatric disorders, and allow the child to reach
his/her full developmental potential. Symptoms of inattentiveness and
hyperactivity/impulsivity should be targeted, but the child’s overall
functioning, including family and social relationships, leisure activities
and self-esteem must also receive attention.
4.2 General aspects of treatment
It is important to develop a treatment plan once the diagnosis has
been established. This plan can be changed in the light of responses
to treatment options, the emergence of other issues that need to be
addressed and changing family circumstances. The treatment plan
should always include psycho-education of the patient and their
caregivers and educators. It should include information about ADHD,
helping parents and teachers to anticipate developmental challenges
that are difficult for children and adolescents with ADHD, and
general advice to improve the child’s academic, social and behavioural
functioning.
4.3 Acute treatment
In recent years, much research attention has been focused on the
relative indications for various forms of management, from which a
considerable degree of consensus has emerged. Based on the existing
guidelines, we propose that behavioural treatments may be applicable
as first-line treatment if:
• The ADHD is mild or (perhaps) moderate, with minimal
impairment
• The diagnosis is uncertain
• The parents (or patient) reject medication as a treatment option
• There is disagreement between key stakeholders about the diagnosis
• There are no comorbid diagnoses or significant life stressors
• An urgent response is not required.
However, if the patient’s response to behavioural interventions is
suboptimal, in that there is still significant impairment, relationships
are still affected, or development is held back, then a trial of
medication should be instituted. For severe cases, or where the above
circumstances do not pertain, a trial of medication is appropriate as a
first line of intervention.
Further steps following the initiation of treatment are indicated in
the algorithm (Fig. 1).
Comorbid psychiatric conditions should be independently
addressed by an appropriate child and adolescent mental health
professional.
4.4 Maintenance treatment
Children who are taking stimulant medication require monthly
prescriptions (repeat prescriptions are not permitted for Schedule 6
drugs) and at least 6-monthly reviews by a psychiatrist. At each review
the following should be recorded:

• Symptoms are mild or moderate, with minimal impairment
• Diagnosis is uncertain
• Parents or patient reject medication as a treament option
• Urgent response is not required
Yes to any of the above
Commence behavioural
programme
No
Good response?
Yes
Continue with status quo
Residual impairment OR
No comorbid disorder OR
family stressor
Continue with status quo
Yes
Add psychosocial intervention
and address comorbid disorders if
present
No further improvment
Commence behavioural
programme and/or other
medication (e.g., TCAs or
clondine) in consultation with
child and adolescent psychiatrist
Fig. 1. Treatment algorithm (TCAs – tricyclic antidepressants).
• Weight and height (recorded on a
percentile chart)
• Reported adverse effects
• Efficacy (school and parent reports)
• Pulse rate and blood pressure.
Significant deviation from the child’s usual
percentile in terms of weight or height should
provoke a review of dosage as well as the
institution of a ‘drug holiday’ of at least 4
weeks, preferably during school holidays,
so that catch-up growth can occur. Should
this not happen, alternative medication or
non-pharmacological treatment should be
considered. Should failure to gain weight
continue, consultation with a paediatrician
should be requested.
No
Commence methylphenidate or
atomoxetine (see text for
medication choice and dosage)
and titrate to effective or
maximum dose
Good response?
No
Yes
Stop selected medication
and commence the other
one
Yes
Good response?
No
Review diagnosis
Diagnosis correct?
Yes
No
Re-assess and act on new
findings
Adverse effects include headaches and gastric
discomfort. These may be transitory, but
if they persist, dose reduction should be
implemented. If this does not relieve the
adverse effects, or if the ADHD symptoms
again become troublesome, then a change of
medication should be considered.
If efficacy is reduced, an increased dose
may be required according to the child’s
increasing weight. If this is already optimal or
does not improve the situation, examination
for developing comorbid conditions
(especially mood disorders or substance use
disorders) should be carried out.
Abnormalities of pulse rate and/or blood
pressure should be retested 10 minutes
GUIDELINE
later and if persistent, stimulant medication
should be withdrawn. Should the abnormal
cardiovascular parameters persist without
medication, a referral to a paediatrician or
physician is mandatory. If there is a return
to normal parameters, then alternative
medication or non-pharmacological
treatments should be instituted.
If a patient with ADHD has been
symptom-free for at least 1 year, the clinician
may consider stopping the medication. Clues
that this may be appropriate include: not
needing to adjust the dose despite an increase
in growth; the lack of obvious symptoms
when a dose is accidentally omitted; and
observations of adequate concentration
during drug holidays. Medication can be
tapered or stopped at a time when stressors
are absent or minimal, and once the school
term is under way. It is important to obtain
feedback from the patient, the parents and the
educators about the effect of this change. If
symptoms recur, it is necessary to reinstitute
treatment immediately.
4.5 Pharmacological treatment
Pharmacotherapy of ADHD with
psychostimulants is one of the best established
and most consistently demonstrated effective
treatments in psychiatric medicine. There
is consistent evidence of effect in domains
such as symptomatic improvement; enhanced
cognitive, social, family and academic
functioning; and improvement of non-
diagnostic symptoms frequently associated
with the condition such as irritability,
aggressive outbursts and difficulties with fine
motor co-ordination.[13-16] Significant and
clinically substantial effect sizes (0.8 – 1.1)
of methylphenidate have been reported from
analyses of clinical studies.[8] Results from
the most comprehensive study of ADHD
treatment (the Multimodal Treatment Study
of Children with ADHD (MTA)) strongly
support the use of methylphenidate as a
treatment for young people (school age into
adolescence) with ADHD.[17]
Dosing should be started as low as possible
(usually 5 - 10 mg) in a morning dose of a
short-acting formulation. The effect of short-
acting methylphenidate lasts approximately
3 hours, and the teacher should be able to
give a report as to the efficacy in the first few
hours of school. Should this be ineffective,
an increased dose (10 - 20 mg) should be
August 2013 Vol. 19 No. 3 - SAJP 138
GUIDELINE
considered. Initial dosing should not exceed 1 mg/kg/day. If a
response is obtained, the dose can be repeated at about 11h00, and
the outcome documented. Conversion to a long-acting formulation
should then be considered. Should insufficient response to an optimal
dose be seen, the protocol for partial and non-responders should
be followed. Doses greater than 1 mg/kg/day may occasionally be
necessary, but should only be considered in consultation with a child
and adolescent psychiatrist.
The preferred formulation of methylphenidate is long-acting and
removes the necessity for mid-morning doses, which are potentially
embarrassing for the child and have become difficult owing to the
paucity of school-based medical services and legislation prohibiting
the possession or dispensing of scheduled medication by unqualified
individuals. Long-acting formulations have the additional benefit
of maintaining blood levels of methylphenidate, giving more even
efficacy. Adverse effects tend to be less troublesome, and adherence to
medication is enhanced. Additional doses of short-acting formulation
may be required for specific times of the day, either before the morning
dose of long-acting formulation takes effect or to cover a possible
afternoon period of rebound hyperactivity as the effect wears off.
Adverse effects of methylphenidate include headache, insomnia,
gastric discomfort and decreased appetite (with concomitant weight
loss or failure to gain weight appropriately). Anxiety and depression
may be worsened by methylphenidate, prompting many clinicians to
choose alternative medications for children with comorbid anxiety
or mood disorders. Methylphenidate carries a Food and Drug
Administration black box warning in respect of a slightly increased
danger of sudden death. A family history of cardiovascular disease
or sudden death, or an individual history of unexplained fainting
or cardiovascular disorders, should cause the treating physician to
refer the child to a cardiologist for an opinion before instituting
psychostimulant therapy. In the absence of these risk factors, a
baseline electrocardiograph is not regarded as mandatory by most
authorities.
Children and adolescents with tic disorders may experience
worsening of tics on methylphenidate. Some will consider the
advantage of their improved school functioning worth the increase
in tics; others should be offered other treatment options. Patients
with mania or psychosis should not be given methylphenidate.
Methylphenidate has been shown to protect against substance use
disorders, but for patients with comorbid substance use disorders,
alternative medications should be considered, although physical
dependence is not a documented risk.
Other medications have also demonstrated positive therapeutic
effects in ADHD across the life span, from primary school age to
adulthood.[6] The most intensively studied of these is atomoxetine, a
noradrenergic reuptake inhibitor.[18-20] Even though treatment effect
sizes are less than for methylphenidate, it can be considered the agent
of first choice for patients with an active substance abuse problem,
comorbid anxiety, or tics; or if the patient experiences intolerable
side-effects to methylphenidate, or if the patient (or caregiver) prefers
this agent. Dosing of atomoxetine starts at 0.5 mg/kg/day and can
be titrated upwards at minimum 3-day intervals to 1.2 mg/kg/day.
Adverse effects tend to be mild but severe liver damage can occur,
and cardiovascular monitoring should be routine. Atomoxetine has
been included in the group of drugs potentially causing an increase
139 SAJP - August 2013 Vol. 19 No. 3
in suicidality in children and adolescents, so informed consent and
appropriate psycho-education of patient and caregivers is mandatory.
Less evidence exists for the tricyclic antidepressants (desipramine
and imipramine), buproprion and clonidine.[21] These medications
may be considered to be second-line pharmacotherapy alternatives
because of the proportionally smaller research data base, shorter
timeline of clinical experience, a potentially greater frequency of
medically significant side-effects and greater expense compared with
methylphenidate.[20]
4.6 Non-pharmacological treatment
Behavioural programmes are the first line of treatment in very
young children, and in those whose difficulties are mild and where
immediate relief is not required. Such programmes can be delivered by
non-medical personnel such as mental health nurses or psychologists,
provided adequate training has been done. Parent support groups for
ADHD may be helpful in the sourcing of such resources.
The successful behavioural programmes[22] consist of between
10 and 20 sessions of 1 - 2 hours each in which parents are given
information about the nature of ADHD and learn to:
• Attend more carefully to their child’s behaviour and to notice when
their child does or does not comply with requests
• Understand the principles and implementation of behaviour
management
• Use time out effectively
• Use a daily school report card
• Anticipate future difficulties.
A systematic literature review[23] and a meta-analysis investigating
174 ADHD treatment studies concluded that behavioural treatment
is highly effective.[24]
4.8 Special populations
Data from preschool-age populations are sparse, but those available
support use of psychostimulants for the treatment of ADHD[18]with the
caveat that psychosocial modalities, especially parent training, should be
the initial interventions of first choice.[25] Should consideration be given to
treating a preschool child with a stimulant drug, consultation with a child
and adolescent psychiatrist should be obtained where possible.
The treatment of adolescents with ADHD is the same as that for
children, but special attention must be given to the developmental
trajectory of adolescents. Increasing weight will usually require an
increased dose. Sporting activities at a high level (where drug testing
is carried out) may require a switch to non-stimulant medication,
and social changes make it imperative that substance use disorders
should be specifically asked about and managed appropriately. Some
adolescents may find themselves in a tertiary education environment
and others may be in the workplace before they turn 18. These
individuals should be managed as adults. Symptoms persist into
adulthood in at least one-third of children with ADHD, and ADHD is
increasingly diagnosed in adults. Diagnostic criteria and management
are modified for the different environment and obligations of adults,
and separate guidelines are required.
4.7 Managing partial and non-responders
Partial response may be dose-related, or there may be undiagnosed
comorbid conditions which are limiting response. Should there be no

response to therapeutic doses of pharmacological treatment or parent
training/behavioural programmes, the diagnosis should be reviewed.
Pervasive developmental disorders, mood disorders and anxiety
disorders are frequently misdiagnosed as ADHD, and require very
different management. An evaluation by, or at least consultation with,
a child and adolescent psychiatrist should be obtained.
In ADHD with severe behavioural difficulties, atypical antipsychotic
drugs are sometimes prescribed for impulsive aggression or temper
outbursts. This should not be done without a complete review of
the family and school environments, possible stressors, adequate
psychosocial intervention and a clear risk-benefit evaluation of the
potential adverse effects of the drug considered. The involvement of
child mental health professionals is advised prior to such a step being
taken.
5. Summary points
• The most important aspect of treating ADHD is an accurate
diagnosis. Making the incorrect diagnosis may render treatment
futile or even harmful.
• In mild to moderate ADHD, first-line treatment is a behavioural
programme with or without pharmacological modalities.
• In moderate to severe ADHD, first-line treatment is a
pharmacological agent plus a behavioural programme.
• Family education and intervention where necessary is mandatory.
References
1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders:
Fourth Edition, Text Revision (DSM-IV-TR). Washington DC: American Psychiatric
Association, 2000.
2. Biederman J. Attention-deficit/hyperactivity disorder: A selective overview. Biol Psychiatry
2005;57:1215-1220. [http://dx.doi.org/10.1016/j.biopsych.2004.10.020]
3. Biederman J, Faraone SV. Attention deficit hyperactivity disorder. Lancet 2005;366:237-248.
[http://dx.doi.org/10.1016/S0140-6736(05)66915-2]
4. Patel V, Lund C, Hatherill S, et al. Social determinants of mental disorders. In: Blas E,
Sivasankara Kurup A, eds. Priority Public Health Conditions: From Learning to Action on Social
Determinants of Health. Geneva: World Health Organization (in press).
5. American Academy of Child and Adolescent Psychiatry. Practice parameter for the assessment
and treatment of children and adolescents with attention-deficit/hyperactivity disorder. J Am
Acad Child Adolesc Psychiatry 2007;46:894-921.
6. National Institute for Health and Clinical Excellence (NICE). Methylphenidate, atomoxetine
and dexamphetamine for attention deficit hyperactivity disorder (AD/HD) in children and
adolescents. Technology appraisal 98. London: NICE, 2008.
GUIDELINE
7. Taylor E, Sergeant J, Doepfner M, et al. Clinical guidelines for hyperkinetic disorder. Eur
Child Adolesc Psychiatry 1998;7:184-200. [http://dx.doi.org/10.1007/s007870050067]
8. Taylor E, Dopfner M, Sergeant J, et al. European clinical guidelines for hyperkinetic disorder
– first upgrade. Eur Child Adolesc Psychiatry 2004;13:17-130. [http://dx.doi.org/10.1007/
s00787-004-1002-x]
9. Flisher AJ, Sorsdahl K, Hatherill S, Chehil S. Packages of care for attention-deficit
hyperactivity disorder in low- and middle-income countries. PLoS Medicine
2010;7:e1000235. [http://dx.doi.org/10.1371/journal.pmed.1000235]
10. Flisher AJ, Lund C, Sorsdahl K, Robertson B. Test-retest reliability of the Xhosa version of
the Diagnostic Interview Schedule for Children (abstract). Journal of Child and Adolescent
Mental Health 2009;21:88. [http://dx.doi.org/10.1111/j.1365-2214.2010.01195.x]
11. Conners CK. Conners Rating Scales - Revised: Technical Manual. Toronto: Multi-Health
Systems, 1997.
12. DuPaul GJ, Power TJ, Anastopoulos AD, Reid R. AD/HD rating scales - IV: Checklists,
Norms and Clinical Interpretation. New York: Guilford, 1998.
13. Vitiello B. Methylphenidate in the treatment of children with attention-deficit hyperactivity
disorder. CMAJ 2001;165:1505-1506.
14. Banaschewski T, Coghill D, Santosh P, et al. Long-acting medications for the hyperkinetic
disorders: A systematic review and European treatment guidelines. Eur Child Adolesc
Psychiatry 2006;15:476-495. [http://dx.doi.org/10.1007/s00787-006-0549-0]
15. Karande S. Attention deficit hyperactivity disorder – a review for family physicians. Indian J
Med Sci 2005;59:546-555. [http://dx.doi.org/10.4103/0019-5359.19200]
16. Kratochvil CJ, Egger HL, Greenhill LL, McGough JJ. Pharmacological management of
preschool AD/HD. J Am Acad Child Adolesc Psychiatry 2006;45:115-118. [http://dx.doi.
org/10.1097/01.chi.0000186451.49579.0a]
17. The MTA Cooperative Group. A 14-month randomized clinical trial of treatment strategies
for attention deficit/hyperactivity disorder (AD/HD). Arch Gen Psychiatry 1999;56:1073-
1086. [http://dx.doi.org/10.1001/archpsyc.56.12.1073]
18. Michelson D, Allen AJ, Busner J, et al. Once-daily atomoxetine treatment for children and
adolescents with attention deficit hyperactivity disorder: A randomized, placebo-controlled
study. Am J Psychiatry 2002;159:1896-1901. [http://dx.doi.org/10.1176/appi.ajp.159.11.1896]
19. Michelson D, Buitelaar JK, Danckaerts M, et al. Relapse prevention in pediatric patients
with AD/HD treated with atomoxetine: A randomized, double-blind, placebo-controlled
study. J Am Acad Child Adolesc Psychiatry 2004;43:896-904. [http://dx.doi.org/10.1097/01.
chi.0000125089.35109.81]
20. Michelson D, Faries D, Wernicke J, et al. Atomoxetine in the treatment of children
and adolescents with attention-deficit/hyperactivity disorder: A randomized, placebo-
controlled, dose-response study. Pediatrics 2001;108:1-9. [http://dx.doi.org/10.1542/
peds.108.5.e83]
21. Pliszka SR. Non-stimulant treatment of attention-deficit/hyperactivity disorder. CNS
Spectrums 2003;8:253-258.
22. Smith BH, Barkley RA, Shapiro CJ. Attention deficit hyperactivity disorder. In: Mash EJ,
Barkley RA, eds. Treatment of Childhood Disorders, 3rd ed. New York: Guilford Press, 2006.
23. Chronis AM, Jones HA, Raggi VL. Evidence-based psychosocial treatments for children and
adolescents with attention-deficit/hyperactivity disorder. Clin Psychol Rev 2006;26:486-502.
[http://dx.doi.org/10.1016/j.cpr.2006.01.002]
24. Fabiano G, Pelham WE, Coles EK, et al. A meta-analysis of behavioural treatments for
attention-deficit/hyperactivity disorder. Clin Psychol Rev 2009;29:129-140. [http://dx.doi.
org/10.1016/j.cpr.2008.11.001]
25. Taylor E, Döpfner M, Sergeant J, et al. European clinical guidelines for hyperkinetic disorder
– first upgrade. Eur Child Adolesc Psychiatry 2004;13:17-30. [http://dx.doi.org/10.1007/
s00787-004-1002-x]
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GUIDELINE
Dementia
F C V Potocnik
1. Introduction
By definition, dementia is an acquired global impairment in memory,
personality and intellect in an alert patient, that is sufficiently severe
to interfere with social and/or occupational functioning. In the
absence of a stroke or rapidly growing cerebral tumours (among
other causes), the onset is usually gradual and the cognitive decline
is always progressive. In the absence of a cure for the disease, non-
pharmacological inventions and the judicious use of pharmacotherapy
may not only help the patient and alleviate the stress on the caregiver,
but can also help in delaying institutionalisation.
1.1 Prevalence and burden of disease
The worldwide prevalence of dementia currently approximates
35.6 million people, a figure set to rise to 65.7 million by 2030 and (by
doubling every 20 years) to 115.4 million by 2050. Nearly two-thirds
of individuals with dementia live in developing countries, where the
sharpest increase in numbers is said to occur.[1] The prevalence of
dementia is approximately 5 - 7% of the elderly population. Starting at
1% for 60-year-olds, the prevalence doubles every 5.1 years, rising to
some 30 - 45% of those aged 85 and older[2,3] in developed countries,
while doubling every 7 years in developing countries.[4] Among
the South African elderly an estimate would place the number of
dementia sufferers at 250 000, with some 35 000 of these suffering
from Alzheimer’s disease (AD).
Twenty per cent of AD patients are alive after a 15-year period, the
mean duration of illness being some 10 - 12 years.[5] Of the people with
late-onset (65 years and older) dementia in developed countries, more
than half have AD, some 15% have vascular dementia (VaD), and
the remaining 30%, a variety of some 60 other forms of dementia. [6]
Many cases of AD exhibit a confluence with cerebrovascular disease
(CvD).[7] The total worldwide societal cost of dementia was estimated
at US$ 422 billion in 2009, which included US$142 billion (34%) for
informal care.[8] Americans estimate that dementia costs them some
US$100 billion per year,[1] and yet a delay in the onset of AD by
only 5 years would halve the prevalence of the disease, resulting in
enormous savings of human misery and cost to society.[5,9] In all cases
there are profound psychosocial effects on the caregiver, in whom
the rates of depression, substance abuse, hospitalisation and physical
illness are all increased.[9]
1.2 Causes and types of dementia
In the South African population, dementia due to the HIV/AIDS
complex (affecting mainly the younger age group) is the most
common. Among the elderly the most prevalent is VaD, followed by
AD, which is on the increase.[7]
1.2.1 Alzheimer’s disease
The neuropathological hallmarks of AD are amyloid plaques,
neurofibrillary tangles, and synaptic and neuronal loss with
141 SAJP - August 2013 Vol. 19 No. 3
subsequent brain atrophy. Macroscopically, and with neuro-imaging
(magnetic resonance imaging (MRI) and computed tomography
(CT) scan), this demonstrates as flattening of gyri, widening of sulci,
atrophied medial temporal lobes and enlarged ventricles. Pathology at
microvascular level has increasingly been implicated in the aetiology
of AD, blurring the boundaries with VaD in many cases. AD and
possibly most other dementias tend to follow a sinusoidal course
in that the initial slow, progressive deterioration accelerates rapidly
before flattening out towards the end – in keeping with the 3 stages of
mild, moderate and severe.[10]
The duration of illness may be as short as 6 months or as long
as 20 years, with an average of 12 years. Neurochemically there are
deficits in neurotransmitters including acetylcholine, noradrenaline,
serotonin, and somatostatin. Specific mutations on chromosomes
21, 14 and 1, inherited as familial autosomal dominant traits with
full penetrance, are found in some 1% of all AD patients. Here the
illness usually presents itself in the 40s or early 50s and is essentially
‘pre-senile’ in onset (i.e. before the age of 65 years). More than 90%
of cases of AD occur in individuals older than 60 years. Individuals
carrying one or both alleles coding for apolipoprotein E-4 (APOE4)
on chromosome 19 bear an elevated risk for late-onset AD, although
this gene is not itself a cause of the disorder.[11] Fig. 1 represents the
course of AD.
1.2.2 Vascular dementia – with or without stroke
Among the VaDs, multi-infarct dementia associated with multiple
areas of cortical infarction, patchy cognitive impairment, focal
neurological signs and a ‘stepwise’ rather than a steady, continuous
deterioration as in AD is more easily diagnosed than dementia due to
vascular damage of the deep white matter.
After each shower of ‘mini strokes’, which produce a sudden
deterioration in the individual’s functioning, there is a partial recovery
which stabilises within approximately 3 - 12 weeks until the next
stroke or ‘step’ occurs several weeks or months later. It is hypothesised
that in both vascular and alcohol-induced dementias, temporary
vascular spasms may result in intermittent or fluctuating intellectual
with memory enhancer
without memory enhancer
Function
Full
Nursing
Care
1 5 10
Time (Years)
Fig. 1. Course of Alzheimer’s disease (with/out memory enhancer).[10]

(a)
Function
Time
(b)
Function
Time
Fig. 2. Course of (a) Alzheimer’s disease and (b) vascular dementia.10
and personality changes, with unpredictable bouts of irritability and
mood swings. In all types of VaDs the risk factors for stroke such as
hypertension, arrhythmias, hypercholesterolaemia, diabetes, smoking
and alcohol need to be assessed. Fig. 2 represents the course of multi-
infarct dementia compared to AD.
1.2.3 Combination of Alzheimer’s disease and vascular dementia
This is referred to as AD with CvD.
1.2.4 Dementia with Lewy bodies
Dementia with Lewy bodies usually exhibits as fluctuations in
cognition (mimicking a sub-acute delirium) with pronounced
variation in attention and alertness, recurrent well-formed visual
hallucinations (especially sun-downing), and motor features
of Parkinsonism. The course of the illness tends to be rapidly
progressive, interspersed with repeated falls, syncope, transient loss of
consciousness, other hallucinations and congruent delusions. These
patients tend to be sensitive to the side-effects of neuroleptic agents
(requiring utilisation of drugs like clozapine or newer neuroleptic
agents). They may be responsive to cholinesterase inhibitors.
1.2.5 Pick’s disease and frontotemporal dementia
Pick’s disease (PD) is a progressive dementia that chiefly affects the
frontal cortex. PD most commonly manifests between the ages of 50
and 60 years and is distinguished from frontotemporal dementia by the
presence of characteristic intraneuronal argentophilic Pick inclusion
bodies found at autopsy. Patients present with prominent personality
changes and impaired executive function. In frontotemporal dementia
diagnostic criteria range across 4 domains:
1. Behavioural disorder: insidious onset and slow progression; early
loss of personal and social awareness; early signs of disinhibition;
mental rigidity and inflexibility; and hyperorality, stereotyped and
perseverative behaviour.
GUIDELINE
2. Affective symptoms: depression and anxiety; somatic preoccupation;
emotional unconcern.
3. Speech disorder: reduction and stereotypy of speech; echolalia and
perseveration.
4. Physical signs: early primitive reflexes and incontinence; late
akinesia, rigidity and tremor.
1.2.6 Substance-induced persisting dementia
Paramount are deep white-matter changes blurred with alcohol-
induced vasculopathy, clinically often indistinguishable from VaDs
and with the same risk factors as precipitating and perpetuating
causes. Note that both vascular and alcohol-induced dementia
patients have relatively well-preserved personalities, compared to
the degree of dementia present. Their excellent social skills or verbal
ability may be misleading unless one screens for dementia using the
Mini Mental State Examination (MMSE).
1.2.7 Huntington’s disease
Huntington’s disease is an inherited disease (autosomal dominant
gene on chromosome 4) characterised by degeneration of the basal
ganglia and cerebral cortex. Age of onset is between 15 and 50 years
,when choreiform movements and progressive dementia are noted.
The dementia initially presents as a sub-cortical dementia before
affecting the cortex as the illness progresses. No cure is currently
available and death results within 15 - 20 years. Psychiatric disorders,
especially depression, may be the presenting feature.
1.2.8 Parkinson’s disease
The primary features are tremor, muscular rigidity, hypokinesia and
postural abnormality. Although a movement disorder, cognitive
impairment occurs in 10 - 40% of patients during the course of the
disease, known as Parkinson’s disease dementia.
1.2.9 Creutzfeldt-Jakob’s disease
Creutzfeldt-Jakob’s disease is brought about by a virus-like infective
agent called a prion. It causes a rapid progressive dementia also
affecting the pyramidal and extrapyramidal systems. A new variant of
Creutzfeldt-Jakob’s disease, described in England in 1995, appears to
express itself under certain conditions in individuals under the age of
40 years, leading to death within a year. This variant is associated with
bovine spongiform encephalopathy or ‘mad cow disease’.
1.2.10 Dementia associated with normal pressure hydrocephalus
Normal pressure hydrocephalus occurs in the elderly and is
characterised by a triad of ataxia (wide-based, shuffling gait), urinary
incontinence and dementia. CT scans of the brain show prominent
enlargement of the ventricles out of keeping with the widening of the
sulci. Ventricular peritoneal shunts may improve cognitive functions
in 10 - 30% of patients. Usually a demented person only becomes
incontinent on attaining an MMSE score of 8 - 10/30.
1.2.11 Dementia secondary to head injury
This is lesion-location- and severity-specific, and diagnosed and
treated accordingly. It may manifest with 2 distinct symptom clusters,
namely cognitive impairment (i.e. decreased information processing
speed, decreased attention, increased distractibility) and behavioural
August 2013 Vol. 19 No. 3 - SAJP 142
GUIDELINE

disturbances. The behavioural disturbances may involve personality
changes, impulsivity and depression, all of which can be exacerbated
by substance misuse.
1.2.12 AIDS dementia complex/HIV dementia
HIV infection currently affects 5 million people in South Africa and is
set to reach a steady state of 32% within less than a decade. The course
of the illness may vary considerably but in general the patient converts
to AIDS after 9 years of illness and dies a year later from systemic
complications. Nearly 90% of AIDS brains are histopathologically
abnormal, more than half of them uniquely due to HIV infection.
Referred to as the AIDS dementia complex, this condition contributes
significantly to the morbidity of HIV patients, causing varying degrees
of cognitive, motor or behavioural impairment, known as HIV-
associated neurocognitive disorders (HAND).
1.2.13 Other less common causes of dementia
• Endocrine states (hypo- or hyperthyroidism, hyperparathyroidism)
• Deficiency states (B complex vitamins)
• Intracranial space-occupying lesions (subdural haematomas,
tumours)
• Post-irradiation dementia
• Demyelinating disorders
• Neurosyphilis
2. Diagnosis, clinical characteristics and course
The diagnostic criteria for AD are outlined in Table 1.[11]
Clinical features include the following:
• Memory impairment: Poor memory must interfere with daily
functioning. Initially, short-term memory is affected, with the later
involvement of long-term memory.
• Personality and behavioural changes: Emotions are shallow and
easily influenced by environmental factors; irritability and bouts
of anger are common. Usually premorbid traits become more
accentuated. There is a loss of initiative and the person becomes
increasingly apathetic and withdrawn. Emotional blunting ensues,
and may be mistaken for depression.
• Intellectual impairment: Thinking becomes more concrete. There
are word-finding and other language difficulties (dysphasia), the
person may no longer recognise familiar faces or objects (agnosia)
and may be unable to carry out simple manual tasks such as
fixing a plug or dressing themselves (apraxia). A key feature is the
instrumental impairment of activities of daily living (e.g. ability to
use telephone, shop, handle finances).
• Physical changes: As the disease progresses, the patient appears
unduly frail and weak, is stooped in posture with slow, shuffling
gait and mild tremor of the hands. There is weight loss, regardless
of appetite, increasing bouts of restlessness and confusion, and
reduced sphincter control.
2.1 Course
This may give an indication of aetiology. Patients with vascular
(especially multi-infarct) dementia and to some extent alcohol-
induced dementia will present with patchy memory loss and
fluctuating disturbances in language and behaviour with a relatively
well-preserved personality in the earlier phases, characterised by
appropriate social interaction.
• A step-wise deterioration rather than a steady even pattern
• A more abrupt deterioration rather than slow, insidious onset
• Attacks of dizziness, frequent falls and fainting spells, nocturnal
confusion
• Bouts of urinary urgency, particularly at night.

Table 1. Diagnostic criteria for dementia of the Alzheimer’s type[11]*

A. The development of multiple cognitive deficits manifested by both:
1. Memory impairment (impaired ability to learn new information or to recall previously learned information)
2. One (or more) of the following cognitive disturbances:
a. aphasia (language disturbance)
b. apraxia (impaired ability to carry out motor activities despite intact motor function)
c. agnosia (failure to recognise or identify objects despite intact sensory function)
d. disturbance in executive functioning (i.e., planning, organising, sequencing, abstracting)
B. The cognitive deficits in criteria A1 and A2 each cause significant impairment in social or occupational functioning and represent a significant decline
from a previous level of functioning.
C. The course is characterised by gradual onset and continuing cognitive decline.
D. The cognitive deficits in criteria A1 and A2 are not due to any of the following:
1 . Other central nervous system conditions that cause progressive deficits in memory and cognition (e.g. cerebrovascular disease, Parkinson’s disease,
Huntington’s disease, subdural hematoma, normal-pressure hydrocephalus, brain tumour)
2 . Systemic conditions that are known to cause dementia (e.g. hypothryoidism, vitamin B12 or folic acid deficiency, niacin deficiency, hypercalcaemia,
neurosyphyllis, HIV infection)
3. Substance-induced conditions
E. The deficits do not occur exclusively during the course of a delirium.
F. The disturbance is not better accounted for by another Axis I disorder (e.g. major depressive disorder, schizophrenia).

*Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, (Copyright © 2000). American Psychiatric Association. For educational purposes
only.

143 SAJP - August 2013 Vol. 19 No. 3


3. Assessment and differential diagnosis
3.1 Mild cognitive impairment
Of note is that up to one-quarter of elderly present as ‘doddery’, falling
into the realm of mild cognitive impairment (MCI), also known as
age-associated cognitive decline. Here the MMSE score is around
27/30. Cognitive function is not impaired to the point where it
interferes significantly with daily social or occupational functioning,
but may well do so over the next 2 - 5 years, when an estimated 30% of
this category are known to go on to exhibit dementia. These patients
need to be re-evaluated at regular intervals.
3.2 Depression and delirium
At this stage of diagnostic screening dementia must be distinguished
from depression (primarily a mood disorder with very little
disturbance in cognition), and delirium (a transient organic disorder
hallmarked by a global cognitive impairment as well as disturbance in
consciousness and attention/concentration deficit). In addition there
is a reversal of the sleep-wake cycle. In the elderly, depression and
delirium may frequently coexist with AD or herald its presence, and
both require management in their own right. Delirium constitutes
a medical emergency. Good collateral information from a reliable
family member, friend or caregiver is crucial. A detailed history and
thorough physical examination including blood (‘organic work-up’)
and urine tests not only distinguish AD from depression and delirium,
but also help to differentiate AD from other types of dementia. A
review of all current prescribed medications and over-the-counter
preparations, with particular emphasis on those impacting on central
nervous system functions, is essential.
3.3 Assessment of neuropsychiatric symptoms
This is discussed below.
3.3.1 Cognitive assessment: the Mini Mental State Examination
Ascertain the degree of cognitive impairment by administering
the MMSE,[12] which was designed to distinguish dementia from
depressive pseudodementia. While one or two mistakes are allowed,
the nature of these mistakes is of importance (e.g. an accountant
failing to do the serial sevens). An MMSE score of 27 generally
indicates MCI. In mild AD (MMSE range 21 - 26) there is short-term
memory impairment, often accompanied by symptoms of anxiety
and depression. Moderate AD (MMSE range 11 - 20) is characterised
by neuropsychiatric phenomena such as visual hallucinations, false
beliefs, restlessness and disturbed sleep patterns. Severe AD (MMSE
range 0 - 10) is characterised by prominent cognitive decline, motor
signs and the onset of loss of sphincter control.
While depressed patients will still obtain a high MMSE score, an
MMSE score of 26 or less out of 30 is strongly indicative of dementia,
where the patient has had at least 7 years of schooling. AD patients
lose on average some 2 - 3 points on the MMSE per year, and progress
can thus be tracked by re-administration of the test at 3 - 6-monthly
intervals. There is no time limit for the completion of the test.
Note that a person with dementia may achieve an MMSE score of
30 out of 30 with some difficulty, while still holding a high position in
working life. This function is support-staff dependent.
GUIDELINE
3.3.2 Functional assessment: activities of daily living
Cognition and behaviour also impact on the patient’s level of
function.[13] This determines whether patients can still perform more
complicated tasks such as taking their medication, difficult household
chores, shopping, cooking and finances (instrumental activities of
daily living (IADL)) or only wash, dress, feed and toilet themselves
(basic activities of daily living (BADL)).[14] The watershed between
IADL and BADL usually occurs at an MMSE of 16 out of 30,[15] while
urinary incontinence occurs at a score of around 8.
3.3.2.1 Driving
Driving a car relies on implicit memory, praxis and executive
functioning. In the early stages of the illness patients can still drive a car
because these abilities are still relatively intact. With time, however, they
are unable to pay attention to all aspects of driving and often become
impulsive or exercise the wrong options. Note that if the dementia
renders the person incapable of driving and controlling a vehicle safely,
he/she is medicolegally disqualified from driving. Doctors have a legal
obligation under the National Road Traffic Act 1996 (Act 93 of 1996) to
report such individuals to the traffic authorities.[16]
In general:
• Assess all cases on individual merit.
• Patients must drive in conditions affording good visibility and
then in day time only, on non-busy suburban roads and always
accompanied by a caregiver.
• Their MMSE should be at least 20-22/30 or above and they must
still be able to do the pentagon test (which tests for visuospatial
ability) or trail-making B.
• Re-assess at 3-monthly intervals.
3.3.2.2 Firearms
Similarly gun licenses should be revoked for the same reasons.
3.3.2.3 Financial affairs and wills
Should the patient be incapable of handling her/his own financial
affairs, urge a reliable and trustworthy member of the family to take
control of the situation. Transfer of authority by means of power
of attorney works well in early dementia where competency is still
preserved. Failing this, or where no family members are available,
curatorship should be sought. The forms are obtainable from the court
who will appoint a curator bonis to attend to the patient’s affairs based
on the recommendations of a psychiatrist and medical officer/general
practitioner. Social workers and occupational therapists who are well-
versed in these matters may have to be called in for advice and help
with these cases. A patient who has not yet written a will or testament
but now wishes to do so should be referred to a psychiatrist in order to
establish testamentary capacity.[16]
3.3.2.4 Social assessment
A thorough social evaluation is of the utmost importance when
assessing a dementia patient. The social assessment includes
information regarding where the person lives, living circumstances,
relevant family members and caregivers, and the extent of coping of
both patient and caregivers, employment (if relevant) and economic
August 2013 Vol. 19 No. 3 - SAJP 144
GUIDELINE
resources, and degree of additional social support, as well as
medicolegal matters.
3.3.2.5 Elder abuse
Awareness of abuse in the area of financial resources and the
administration of the patient’s affairs is of paramount importance.
It should be determined who draws, administers and dispenses the
patient’s financial resources and pension.
Elder abuse includes physical abuse as well as ‘acts of omission’
or negligence leading to the detriment of the health and well-being
of the person. This would include physical, psychological, financial
and material aspects. Examples would be the denial of food, visits,
medication, clothing and other essentials. Note that sexual abuse and
incest also occur.
Cases must be reported to Halt Elder Abuse Line (toll free 0800
003081) for investigation and management.
3.4 Comorbid medical conditions
Patients with dementia commonly have comorbid medical conditions
such as depression, cardiovascular and pulmonary diseases, infections,
arthritis, sleep disturbances, falls, incontinence and drug-related
adverse events, among others. There is a strong association between
medical conditions and impaired cognition in AD.[17]
People with dementia, particularly those who live alone, are at risk
of inadequate nutrition and dehydration. Both of these factors can
contribute to the development of neuropsychiatric symptoms (NPS).
The propensity to develop subsequent bronchopneumonia or urinary
tract infection is very high.
Comorbid medical conditions need to be optimally managed,
especially vascular risk factors which may be contributing to the
dementia by exacerbating any vascular disease. Regular medication
review is mandatory as is the supervision of medication by a
responsible caregiver.
3.5 Investigations
Cost restraints and other practicalities often dictate the number
of investigations that can be performed. Generally, in a typical or
advanced case of dementia, investigations have little to offer towards
treatment. A ‘positive’ result is more likely to be obtained when:
• The patient is less than 65 years of age
• Onset has been recent and the course rapid
• Course of disease fluctuates markedly
• Physical examination reveals a neurological deficit.
Special investigations help to improve or rule out treatable contributory
and exacerbating causes of dementia. The full ‘organic work-up’ entails
a full blood count, plasma viscosity, urea and electrolytes; thyroid,
liver and parathyroid function tests, random blood sugar, niacin,
vitamin B12, red cell folate and lipogram. C-reactive protein (CRP)
levels may be indicated. Additional tests include syphilis serology,
HIV and urine dipstick (this also helps to exclude a concurrent
urinary tract infection).
More specialised investigations encompass a CT or MRI scan (with
measurements of the medial temporal lobes) as well as psychometric
testing. Single photon-emission CT results often settle diagnostic
speculation.
145 SAJP - August 2013 Vol. 19 No. 3
Assessment by a trained neuropsychologist may be required when the
cognitive impairment is very mild or does not conform to an expected
pattern.
The trimmed-down version of the ‘organic work-up’ consists of the
following only: haemoglobin, mean cell volume, white cell count and
platelets; glucose; potassium, sodium and urea/creatinine; thyroid-
stimulating hormone; albumin and gamma-glutamyl transferase
(γGT); calcium; vitamin B12; total cholesterol; syphilis serology and
urine dipsticks.[10]
4. Treatment
Patients with dementia almost invariably display neuropsychiatric
symptoms (NPS), such as disturbances in mood with psychotic
and vegetative symptoms among other phenomena.[18] Hitherto the
focus with cognitive enhancers has been on cognitive improvement,
overlooking the fact that these medications will often improve the
NPS, especially in the early phases of the illness. Amelioration of these
symptoms may be insufficient later on, at which stage treatment with
more conventional psychotropic agents will be required.
4.1 Treatment goals
• Re-establishing the homeostasis, correcting for both internal and
external factors by correcting influences such as dehydration,
urinary tract infection, and disruptions in day/night rhythm.
• Stabilising the NPS to promote patient well-being and reduce
caregiver burden.
• Maintaining the quality of life and highest level of patient functioning
for as long as possible, in order to delay institutional care.
4.2 General aspects of treatment
As with the assessment process, treatment is holistic, by its nature
multifaceted and, more often than not, multidisciplinary. Of necessity,
the treatment involves caregivers and family. Team-work is essential
and should utilise as many members from the community (helpful
family members, religious groups) and medical resources (social
worker, occupational therapist, community nurse) as possible. Patient
target symptoms include declining cognition and impairment in
daily functioning, among various associated symptoms that manifest
during the course of the disorder. Treatment aims at maximising
functional performance and quality of life, while reducing the period
of disability.
4.2.1 Imparting the diagnosis
Ensure that key family members and caregivers are present. Be
compassionate, honest and leave sufficient time available for questions
and answers in order to contain the situation. Keep hope alive in
that there are treatments available for some dementias, and potential
benefits from psycho-education, social support and medication
trials. Apart from the diagnosis, include prognosis and management
strategies. Keep an open-door policy, link up with the family physician
and refer to the local support organisation.[19] Additional issues that
need to be addressed include genetics and other practical and medico-
legal decisions such as driving, firearms, power of attorney, financial
controls, curatorship and wills, and capacity assessments (discussed
above). Note that the detection of elder abuse, incapacity to drive and/
or ownership of a firearm is notifiable by law.[16]

4.2.2 Accommodation and level of supervision
The situation in South Africa mirrors the global move away from
residential institutions. Fewer beds are available at ever-rising cost.
Patients, their families and caregivers increasingly have to rely on
their own resources. To help them in this task are the primary-care
facilities, social clubs, seniors centres, daycare centres and respite-care
facilities. Welfare organisations and non-profit organisations (NPOs)
offering support, counselling and psycho-education are invaluable.
4.3 Pharmacological treatment
4.3.1 Acetylcholinesterase inhibitors and memantine
Based on the cholinergic hypothesis of AD, cognitive deterioration is
associated with progressive loss of cholinergic neurons and decreasing
levels of acetylcholine in the brain. Both acetylcholinesterase (AChE)
and butyrylcholinesterase (BuChE) have been found to play an
important role in the degradation of acetylcholine. Table 2 outlines
these medications.
The 3 acetylcholinesterase inhibitors (AChEIs) differ in their
pharmacological action: donepezil selectively inhibits AChE;
rivastigmine affects both AChE and BuChE; and galantamine
selectively inhibits AChE and also affects nicotinic receptors. To
date, these differences have not been shown to result in differences in
efficacy and tolerability.[20]
An alternative strategy is the inhibition of excitotoxic amino-
acid neurotransmitters (e.g. glutamate, aspartate, homocysteine)
which play an important role in the pathophysiology of dementia.
Memantine is an N-methyl-D-aspartate receptor antagonist which
regulates calcium flux across membranes and may protect against
neuronal death.
A combination of an AChEI with memantine appears to be more
effective than either agent on its own and is well tolerated, there being
no pharmacokinetic or pharmacodynamic interactions between the
two.[20,21]
Most indications for the above agents are AD-specific but may
also benefit those AD patients with cerebrovascular disease. Other
indications include MCI, diffuse Lewy body (DLB) dementia, and
Parkinson’s disease dementia. These indications are, however, country-
specific as is their range of applications for the mild, moderate and
severe stages of AD. The mode of administration (slow-release capsules,
transdermal patches) further impacts more positively on tolerability,
Table 2. Pharmacological treatment schedule for Alzheimer’s
disease[10]
1. One of the following acetylcholinesterase inhibitors:
Donepezil (Aricept) 5 - 10 mg at night
Rivastigmine (Exelon) 3 - 6 mg twice daily
Galantamine (Reminyl) 16 - 24 mg daily
and/or
2. NMDA receptor antagonist: Memantine (Ebixa) 10 - 20 mg daily.
3. Psychotropic agents for residual symptoms, i.e. mood (depression
and irritability) and behavioural disturbances (restlessness,
agitation, psychotic symptoms, insomnia).
4. Control of cardiovascular risk factors such as hypertension,
diabetes mellitus, dyslipidaemia and smoking.
NMDA - N-methyl-D-aspartate
GUIDELINE
compliance and efficacy; as do ease of titration, price of product and
familiarity with the medication. Under ideal circumstances, treatment
should start in the prodromal/symptomatic/MCI phase of AD, bearing
in mind that patients only tolerate the minimum effective dose in
the early stages. The earlier diagnosis would involve the testing of
cerebrospinal fluid biomarkers for AD, which is currently being
standardised.[22] Patients respond with both improved cognitive and
behavioural changes. Studies tend not to capture the more subtle
changes in the dementing patient, such as the return of personality,
spontaneity, insight and interest in their surroundings. The relief
in caregiver stress burden is observed immediately, and this in turn
enhances the well-being of the caregiver. Improvement in the mild to
moderate AD patient is usually above baseline for the first 9 months;
then it slowly declines as the illness relentlessly progresses. Data
obtained at the 3-year mark show that patients are still functioning at
above their expected level of deterioration when compared to untreated
patients observed over the past decades.[23,24] With positive results,
treatment may continue uninterrupted to an MMSE as low as 5/30,
after which continuing benefit becomes increasingly questionable and
difficult to evaluate in research;[17,25] or where the patient’s dementia
has progressed to a stage where there is no significant benefit from
continued therapy.[26] Furthermore, longer-term follow-up data of
AD patients on a previous generation AChE shows a cost-saving of
7.5% over the patient’s lifetime from diagnosis to death.[27,28] Though
the costs of medical and social services were reduced, most of the
savings were due to reduced time in nursing home placement (at least
14 months). New treatments that can both improve clinical outcomes
and save costs should be given serious consideration by clinicians and
administrators.[29]
The benefits of treatment with AChEIs are rapidly lost when drug
administration is interrupted for as little as 6 weeks and may not be
fully regained when drug treatment is reinstated.[30] Notwithstanding,
it may be necessary to check whether the medication is having
the desired effect by very occasionally withholding treatment for
approximately 2 weeks when the recurrence in severity of former
NPS/behavioural and psychological symptoms of dementia (BPSD)
target symptoms will act as an indicator for continued treatment.[26]
At least two-thirds of patients can be expected to derive modest
benefit from the above medications with regard to not only
improvement in cognition, but also to NPS/BPSD and activities of
daily living (ADL). Failure to benefit from one AChEI or memantine
does not necessarily mean that the patient will not respond to another
of these medications.[19,20]
4.3.1.1 Adverse effects
Excess cholinergic stimulation with the use of AChEIs may lead to
transitory nausea, vomiting, dizziness, insomnia and diarrhoea. A
lowering of dosage, short pause or even rechallenge (if treatment
is re-initiated after a prolonged period) is usually successful in
overcoming these events should they occur. Urinary incontinence,
abdominal muscle cramps and excessive sweating may occur and
usually indicate the need for a ‘switch’ to another agent. There appear
to be no important differences between drugs in respect of type or
frequency of adverse events.[20]
AChEIs may potentially have vagotonic effects on heart rate (i.e.
bradycardia), of importance in patients with ‘sick sinus syndrome’
August 2013 Vol. 19 No. 3 - SAJP 146
GUIDELINE
or other supraventricular cardiac conduction disturbances such
as sinoatrial or atrioventricular block. These medications should
therefore be used with caution in patients with cardiovascular
disease or those taking concurrent medicines that reduce heart rate.
Bradycardic drugs include beta-blockers, digoxin, amiodarone and
calcium channel antagonists. Recent reviews show that the incidence
of cardiovascular side-effects is low and that serious adverse effects
are rare. Interestingly, the value of pretreatment screening and routine
electrocardiograms (ECG) is questionable and these are not currently
recommended by the National Institute for Health and Clinical
Excellence.[20,31]
Common (usually transient) side-effects of memantine include
confusion, dizziness, headache and tiredness. Uncommon are anxiety,
hypertonia and vomiting. Note that, being an amantadine derivative
memantine may enhance the action of L-dopa and dopaminergic
agonists.[20]
Generally, all the above interact with anticholinergic drugs and
cholinomimetics to a variable extent.
4.3.1.2 Recommended dosages
It is also important to optimise the dose and duration of cholinesterase
inhibitor treatment. It is thought that the higher the dose tolerated by
the patient, the better the result. A minimal trial period of between 3
and 6 months is indicated.
AD patients are given a once-daily dose of 5 mg donepezil at
night, increasing to 10 mg after 4 weeks. Medication is given at
night to obviate side-effects which may occur 4 hours after ingestion
coinciding with peak plasma levels. The half-life of donepezil is 70
hours and steady state is usually obtained in 14 - 21 days. As with
the other medications, should side-effects become intolerable, one
skips the medication for a day or two.[20] Elimination of the drug is
through both renal excretion of intact drug and bio-transformation
via the cytochrome P450 system. The latter is only partially saturated
by the drug, and hence drug-drug interactions tend not to be a
problem. Rivastigmine is initiated at 1.5 mg twice daily, and increased
by 1.5 mg twice daily every 2 - 4 weeks to a maximum of 12 mg
daily. Rivastigmine has almost no potential for interaction since
it is metabolised at the site of action and does not affect hepatic
cytochromes. Galantamine is initiated at 8 mg daily, and the dose is
then increased by 8 mg every 4 weeks to a maximum of 24 mg daily.
Metabolism is via the cytochrome P450 system. Memantine is given in
the morning with a starting dose of 5 mg, then raised in increments of
5 mg on a weekly basis to a maximum of 20 mg per day. Metabolism
is primarily non-hepatic (Table 3).[10,20,32-34]
4.3.1.3 Follow up
It is important to determine the patient’s response to medication,
and as such it may be useful to complete a scale such as the MMSE or
ADL[15] or the Neuropsychiatric Inventory (NPI) for NPS[35] in order to
help quantify the treatment response.
4.3.1.4 Neuropsychiatric symptoms
NPS, also formally known as BPSD, rather than cognitive decline,
prompt entry into long-term care. Over 90% of subjects with dementia
will exhibit at least one NPS that needs specific management at some
point in the course of their illness.[18,36] These symptoms may wax and
147 SAJP - August 2013 Vol. 19 No. 3
wane over time while some symptoms (e.g. visual hallucinations in
DLB dementia) are more common in some dementias than in others.
Another frequent mistake made by both caregivers and physicians
alike is to assume that there are no hallucinations or delusions, since
patients may objectively not display these phenomena which are
only elicited on very careful mental state examination or behavioural
assessment. The behavioural domains are best assessed by using the
NPI.[35] The diffuse nature of the NPS means that each patient needs
an individual assessment and treatment strategy.[18,32,35-37]
In general, once treatable medical causes for NPS have been
addressed or eliminated, psychosocial intervention follows with or
without psychotropic medication. The latter consists of the use of
AChEIs or memantine on their own or in combination followed by
antidepressant, antipsychotic or other medication as indicated.
The general treatment principles follow those for younger adults.
Except that half to two-thirds of the adult dose is given. ‘Start low,
go slow, review frequently’ is the standard watchword, as the elderly
are more sensitive to medication side-effects than the younger adult.
Note that polypharmacy may be necessary in the form of a non-
sedating (high-potency) neuroleptic by day and a sedating (low-
potency) neuroleptic at night. Psycho-education about the illness and
supervision of medication is essential, keeping in mind that data on
medication are, in general, controversial (Table 4).[32,36]
4.3.2 Antidepressants
While symptoms of anxiety or depression are common in the
premonitory stages of dementia, e.g. their occurrence at 50 years of
age may herald dementia 10 - 20 years later, once the dementia is
established, apathy is the most common NPS (frequently misinterpreted
as ‘depression’).[18] Though major depression may precede the onset of
AD, it occurs less frequently as the disease progresses, while minor
depression, mild depressive symptoms or bouts of dysphoria become
much more common in the early course of AD. If in doubt about the
coexistence of depression with AD, a trial of antidepressant medication
should be given. Note that antidepressants also have anxiolytic, and
in the case of some newer-generation antidepressants, sedating if
not hypnotic qualities. Symptomatic treatment of neuropsychiatric
disturbances will afford both the patient and caregiver much relief. By
and large the elderly require smaller dosages (about half to two-thirds)
of antidepressant medication than that of the young adult population,
and in most cases the ‘sedating’ antidepressants are preferred. Higher
dosages may be required for more resistant cases where the diagnosis
of coexistent depression is certain. Exercise caution with regard to
side-effects and patient tolerance. AD patients with an MMSE of
below 20/30 tend not to benefit from an antidepressant in terms of
its antidepressant effect. AD patients on an AChEI, however, may
experience depressive symptoms in both the mild and moderate stages
of AD.[38] In these patients the depression appears in part to be coupled
to the renewed insight afforded the patient by the drug, and is usually
transient in nature. When it persists, treatment with an antidepressant
is indicated.[38]
Avoid tricyclics in therapeutic doses on account of anticholinergic
side-effects, and ECG QTc problems, especially when combined with
other medication, e.g. antipsychotics.
Dementia patients fare better on ‘sedating’ antidepressants such as
citalopram (20 mg), sertraline (50 - 150 mg), mirtazapine (15 - 30 mg)
 GUIDELINE

Table 3: Description of cognitive enhancers. Adapted from Taylor et al.,[32] Ihl et al.[33] and Rossiter[34]
Donepezil Rivastigmine Galantamin Memantine
Name (Aricept) (Exelon) (Reminyl) (Ebixa)
Derivative Piperidine Carbamate Tertiary alkaloid Amantidine
Therapeutic class Acetylcholinesterase Acetylcholinesterase inhibitors Acetylcholinesterase NMDA receptor antagonist
inhibitors inhibitors
Therapeutic dose 5 - 10 mg at night 3 - 6 mg 2 x daily 16 - 24 mg daily 5 - 10 mg 2 x daily
Starting dose 5 mg at night 1.5 mg 2 x daily 8 mg daily 5 mg daily
Presentation 5 mg, 10 mg tablets 1.5 mg, 3 mg, 4.5 mg, 6 mg capsules 8 mg, 16 mg, 24 mg CR 10 mg tablets/oral drops
capsules
Interval between dose 4 weeks 4 weeks 4 weeks 1 week weighted mornings
increases

Common adverse effects Nausea, vomiting, Nausea, vomiting, diarrhoea, Nausea, vomiting, Confusion, dizziness,
(often transient) diarrhoea, fatigue, dizziness, anorexia, confusion, diarrhoea, abdominal headache, tiredness,
insomnia, muscle headache, somnolence, muscle pain, anorexia, fatigue, constipation
cramps, anorexia, cramps dizziness, headache,
headache, vivid dreams somnolence
Half-life (h) 70 12 7-8 60 - 100
Metabolism CYP 2D6 Non-hepatic CYP 2D6 Primarily non-hepatic
CYP 3A4
Drug-drug interactions Yes Interaction unlikely Yes Yes

NMDA = N-methyl-D-aspartate; CR = controlled release; CYP = cytochrome P.

Table 4. Approach to neuropsychiatric symptoms/behavioural and psychological symptoms of dementia. Adapted from
Ames et al.[36] and Taylor et al.[34]
Take a routine history (patient and key informants) focusing on mental state (including MMSE) and assess interpersonal and environmental factors. Key
questions around symptoms exhibited, the circumstances under which they arose and management strategies utilised to date.
Exclude physical illness potentially precipitating NPS/BPSD, e.g. constipation, infection (e.g. urinary tract infections especially from dehydration) and pain.
Target the symptom requiring treatment.
Consider non-pharmacological methods.
Psycho-educate the patient (if they have the capacity) and family/caregiver.
Carry out a risk/benefit analysis prior to selecting medication. Ideally start with an AChEI or memantine prior to other psychotropic medication. Discuss
the use and side-effect profile fully with patient/family/caregiver.
Titrate medication from a low starting dose and maintain the lowest dose possible for the shortest period of time necessary.
Review medication regularly, monitoring for compliance, efficacy and adverse events.
Ensure support and ongoing psycho-education, monitoring and dealing with problems as they arise. Create awareness of local support group.
NPS = neuropsychiatric symptoms; BPSD = behavioural and psychological symptoms of dementia; AChEi = acetylcholinesterase inhibitors.

and agomelatine (25 - 50 mg) at night. Escitalopram (2.5 - 5 mg) and
venlafaxine (75 - 225 mg) are given in the mornings. The latter should
only be used as second-line treatment. Augmentation usually involves
neuroleptics, while electroconvulsive therapy may only be effective
during the prodromal phase of the disorder.
4.3.3 Antipsychotics
Table 5 outlines a treatment schedule for restlessness, psychotic
symptoms, agitation and insomnia. Note that haloperidol (a potent
antipsychotic, with little sedation, but prone to extrapyramidal
side-effects) acts synergistically with chlorpromazine (a less potent
antipsychotic, sedating, and prone to postural hypotension as side-
effect). The drugs in combination usually allow for a lower dose of
either agent, with fewer side-effects, affording better tolerability and
targeting of symptoms. Some caregivers prefer one drug only, an even
lower dosage of either agent, or different timing. Good caregivers will
experiment with different regimens, tell you what their AD patient
needs, and should be accommodated, for at the end of the day it is they
who have to live with the consequences.[10,38]
When aggression, psychosis, resistance to care or restlessness is
prominent, low-dose risperidone/haloperidol at 0.25/0.5 mg twice
daily is the drug of choice. Reinforce the day-night cycle by adding
a sedative antipsychotic such as quetiapine/chlorpromazine 25 - 50
mg at night (Table 5).[10] Titrate up as indicated. For acute sedation
1 - 2 mg lorazepam orally or intramuscularly is the drug of choice
(Table 6).[10]

August 2013 Vol. 19 No. 3 - SAJP 148

GUIDELINE
Ultimately, it is the treatment with which one is familiar and
comfortable that works best. First-generation antipsychotics (FGAs)
are probably as effective as second-generation antipsychotics (SGAs)
but owing to their side-effect profile less well tolerated. As a rule
of thumb, the ‘non-sedating’ antipsychotics have extrapyramidal
symptoms as side-effects, the sedating antipsychotics have
oversedation, hypotension and dizziness as their chief side-effect.
There is no significant difference between treatment groups.[32,36]
In 2004 increased mortality with antipsychotics in dementia raised
warnings for risperidone and olanzapine, which over the years were
extended to include all SGAs as well as FGAs. The risk of developing both
serious and non-serious cerebrovascular adverse events (CVAEs) such as
stroke and mortality increases threefold with the use of antipsychotics. To
date the mechanism by which the risk of such CVAEs is raised remains
obscure, and patients with poorly controlled cardiac arrhythmias,
hypertension, diabetes and previous stroke are more at risk.[32]
4.3.4 Other medications/strategies
4.3.4.1 Hypnotics
Avoid benzodiazepines on account of the frequent occurrences of
daytime somnolence, emotional lability, confusion, incoordination,
ataxia, memory impairment and incontinence. Implementation of
measures of sleep hygiene is a prerequisite.
If medication is required for insomnia (preferably short-term) the
following may be useful:
• Benzodiazepine-related: zolpidem 5 mg or zopiclone 3.75 – 7.5 mg
• Antidepressants: Sedating agents such as citalopram 10 - 20 mg,
trazodone 50 mg, mirtazapine 7.5 - 15 mg or agomelatine 25 mg at
night.
Table 5. Example of a neuroleptic regimen[10]
Haloperidol (Serenace)/risperidone (Risperdal) 0.5 mg/0.25 - 0.5 mg
respectively twice daily.
Increase the dose to 0.75 mg, 1.0 mg and 1.5 mg twice daily, if necessary,
for daytime control. Wait a day or two between increases.
Together with:
Chlorpromazine (Largactil)/quetiapine (Seroquel) 25 mg at night
I ncrease the dose to 50 mg, 75 mg and 100 mg at night, if
necessary, for nocturnal control.
Wait a day or two between increases.
Or:
Olanzapine (Zyprexa) 2.5 - 5 mg at 17h00
Table 6. Psychotropics for acute sedation[10]
One of the following agents:
Lorazepam (Ativan)
1 - 2 mg po/IMI
0.5 - 1.5 mg IVI
Do not exceed 8 mg over 24 hours
Haloperidol (Serenace)
2.5 mg IMI/IVI
Do not exceed 10 mg over 24 hours
149 SAJP - August 2013 Vol. 19 No. 3
• Neuroleptics: Sedating agents such as chlorpromazine 25 mg,
olanzapine 2.5 mg (given at 17h00) or quetiapine 25 mg at night.
4.3.4.2 Mood stabilisers/anticonvulsants
Trials with anticonvulsants (carbamazepine, sodium valproate,
lamotrigine, topiramate and gabapentin) have not produced
convincing evidence upon which to advocate their routine use.[32]
4.3.4.3 Restless legs syndrome
Clonazepam 0.5 mg may be taken at bedtime. Failing this, a dopamine
agonist may be indicated: pramipexole, 0.125 mg at night.
4.3.4.4 Hypersexuality
Cyproterone acetate 150 mg given every 2 - 4 weeks IMI is effective
in combating paraphilia in non-dementing patients and those with
dementia. Sexual disinhibition or hypersexuality will diminish within
a few days. The strategy is to administer the medication for 6 months,
then withhold treatment, and should symptoms re-emerge, another 3
months of treatment is indicated. Very occasionally a further 3-month
course may be necessary.[39]
4.3.4.5 Treatment-resistant psychoses and disruptive vocalisers
In these situations the clozapine/amisulpiride regimen (taking into
account white cell count measurements) may be useful:
Initiate: clozapine
• Start with 12.5 mg (in very frail patients, prone to extrapyramidal
side-effects)
• Increase in 12.5 mg increments
• Start with 25 mg (in more robust patients)
• Increase in 25 mg increments
• If response is good, continue to near-intolerance level
• Split dose with night-time weighting, then drop one level
• Total daily dose 125 - 300 mg
• Watch out for: sedation, hypotension, urinary incontinence and
drooling
Add: amisulpiride
• Start with 50 mg
• Increase in 50 mg increments
• Split dose with night-time weighting
• Total daily dose 150 - 200 mg
• Watch out for sedation and dystonia
4.4 Non-pharmacological treatment
4.4.1 The patient
A complex interaction of biological, psychosocial and environmental
factors contribute to the development of NPS in AD.[18] It is therefore
important to observe for environmental triggers that influence
behaviour, and get feedback from those around the patient,. This has
led to the A-B-C approach, whereby Antecedents to the behaviour are
noted, as well as details of the Behaviour (description, time, duration),
and the Consequences. A disruptive patient may thus get much
more attention from nursing staff than when they are quiet, which
inadvertently reinforces their disruptive behaviour.[18]
Environmental factors implicated in triggering NPS include excessive
noise and stimulation, lack of daily structure and routine, confusing
surroundings, excessive demands, loneliness and boredom.[18] Specific

non-pharmaceutical interventions that enjoy
success are validation therapy, positive
reinforcement, reminiscence therapy, reality
orientation and creative diversions, among
others.
4.4.2 The caregiver
A most vital link in the pharmacotherapy and
general care of AD is the caregiver. Caregivers
are estimated to spend an average of 70 - 100
hours per week on providing care. Caregivers
utilise 45% more physician visits and 70%
more prescription drugs than non-caregivers,
and are more likely to be hospitalised. More
than 50% of caregivers are at risk for clinical
depression.[40,41] A recent study[42] showed that,
in general, there was a six-fold risk of dementia
in spouses of patients with dementia. Where
husbands looked after spouses suffering from
dementia the risk was twelve-fold. Judicious
use of pharmacotherapy, therefore, not only
alleviates the stress on the caregiver but also
delays the institutionalisation of the AD patient.
All caregivers should be referred to NPOs
such as Dementia SA in the Western Cape
and Alzheimer’s South Africa, elsewhere.
Not only do these organisations assist in
supporting caregivers and monitoring their
well-being but they also explain how to care
for the patient, provide support services –
such as home help or respite care – wherever
possible, provide counselling and medicolegal
advice, and continually update the caregiver
by means of newsletters, meetings or
workshops, on the latest developments.
4.5 Preventative measures
It is estimated that the neurodegeneration
in AD starts some 20 - 30 years before the
appearance of the first clinical symptoms,[43]
reflecting the need for earlier intervention while
minimal brain damage has occurred.
Note that the preventative measures
mentioned below offer no benefit to people
whose preclinical AD pathology is sufficiently
advanced to produce dementia symptoms
within very few years and especially once the
dementia is clinically evident:
• Hormone replacement therapy (oestrogen
with or without progesterone) is only
effective if initiated at the time of menopause
where a deficiency in female sex hormones
has clearly been established.[44]
• Vitamin E (≤400 IU) and C (400 mg)
daily, preferably in combination.[45] Note
that high-dose vitamin E (+400 IU daily)
GUIDELINE
supplementation is associated with an fatty acids (fish) and low in high trans-fat
increased mortality risk.[46] (processed foods) reflects in beneficial blood
• Red wine (Bordeaux blend 250 - 500 ml nutrient biomarker patterns influencing both
daily). Ascribed to resveratrol and other cognitive function and brain volume.[54]
aliphatic compounds.[47] • Physical exercise
• Non-steroidal anti-inflammatory drugs • Weight reduction
(NSAIDs). Conventional NSAIDs such • Control of hypertension
as ibuprofen and voltaren[48] as well as • Control of hypercholesterolaemia
naproxen used for as little as 2 - 3 years[49] • Dietary antioxidants
may protect against AD. • Intellectual activity
• Coffee. Consuming 3 - 5 cups of coffee (not • Leisure activities and hobbies
decaffeinated or instant) a day decreases • Social networks
the risk of dementia/AD later in life.[50-52] • Red wine
• Fish and other sources of omega 3
Currently, there is interest in establishing • Folate-rich food or low-dose vitamin B
a ‘risk score’ as early as midlife, similar to supplementation
that of the risk of cardiovascular disease.
It is hoped that these lifestyle changes, 5. Algorithm
antioxidant supplementation and treatment Fig. 3 shows the treatment algorithm for
of medical conditions may then decrease the dementia.
risk of AD and other dementias in persons For further reading on the biological
at risk.53 A diet rich in vitamins B, C, D treatment of AD, please refer to Ihl et al.,[33]
and E (fruit and vegetables) and omega 3 Rossiter[34] and Daoud.[55]
Concerns about memory
Initial assessment
No memory Memory impairment
Delirium?
Look at reason for concern
depression, anxiety or family history
Yes No
Keep under review
Treat cause Depression or anxiety disorder?
Reassess memory on
recovery
Yes No
Confirm dementia
Treat depression/anxiety aggressively
Non-pharmacological and
Reassess memory on pharmacological (cognitive
recovery enhancers) interventions
Appropriate psychotropic or other
agent Stabilised
Residual
neuropsychiatric symptoms
Keeping under review
Fig. 3. Algorithm for therapy of dementia (adapted from Daoud[55]).
August 2013 Vol. 19 No. 3 - SAJP 150
GUIDELINE
6. Summary points
• Treatment with antidementia medication combined with non-
pharmacological measures provides the most benefits in patients
with dementia.
• Medication must be individualised taking into account the
constellation of symptoms, the stage of the disease, the side-effect
profile, and caregiver availability.
• Titrate medication from a low starting dose.
• Target daily doses of first-line antidementia medication are as
follows: donezepil 10 mg, rivastigmine 12 mg, galantamine 24 mg,
and memantine 20 mg. This should, however, be guided by response
and tolerability. These medications are effective in the symptomatic
treatment of AD, VaD, DLB dementia, dementia in Parkinson’s
disease and certain frontotemporal dementias.
• Patients should be closely monitored for the first month after
commencing treatment.
• The most promising approach to VaD is secondary prevention of
CvD by addressing its risk factors.
• Rule out underlying or coexisting medical conditions and
psychosocial environmental factors in patients with behavioural,
mood or anxiety symptoms.
• In patients with depression, consider antidepressants that have
more sedative effects, such as citalopram, sertraline, mirtazapine,
and agomelatine. In view of the potential for QT prolongation,
citalopram should not be used in doses greater than 20 mg per day
in adults older than 60 years.
• For hyperactivity or agitation, a low-dose first- or second-
generation antipsychotic medication may be used for a short period
of time.
References
1. Wimo A, Prince M. World Alzheimer Report 2010. London: Alzheimer’s Disease
International, 2010.
2. Jorm AF, Korten AE, Henderson AS. The prevalence of dementia: A quantitative integration of
the literature. Acta Psychiatr Scand 1987;76:465-479.
3. Cummings JL, Jeste DV. Alzheimer’s disease and its management in the year 2010. Psychiatr
Serv 1999;50:1173-1177.
4. Lobo A, Launer LJ, Fratiglioni L, et al. Prevalence of dementia and major subtypes in Europe:
A collaborative study of population-based cohorts. Neurologic diseases in the elderly research
group. Neurology 2000;54(11 Suppl 5):S4-9.
5. Breitner JCS, Haneuse SJPA, Walker R, et al. Risk of dementia and Alzheimer’s disease with
prior exposure to NSAIDs in an elderly community-based cohort. Neurology 2009;72:1899-
1905.
6. Kester MI, Scheltens P. Dementia: the bare essentials. Practical Neurology 2009;9:241-251.
7. Kalaria RN, Maestre GE, Arizaga R, et al. Alzheimer’s disease and vascular dementia in
developing countries: prevalence, management and risk factors. Lancet Neurology 2008;7:812-
826. [http://dx.doi.org/10.1016/S1474-4422(08)70169-8]
8. Wimo A, Winblad B, Jönsson L. The worldwide societal costs of dementia: Estimates for 2009.
Alzheimer’s and Dementia 2010;6:98-103. [http://dx.doi.org/10.1016/j.jalz.2010.01.010]
9. Brookmeyer R, Johnson E, Ziegler-Graham K, Arrighi HM. Forecasting the global burden of
Alzheimer’s disease. Alzheimer’s and Dementia 2007;3:186-191. [http://dx.doi.org/10.1016/j.
jalz.2007.04.381]
10. Potocnik F. Psychogeriatrics. In: Emsley RA, Pienaar WP, eds. Textbook of Psychiatry, EDS.
Tygerberg, Cape Town: Mental Health Information Centre of South Africa, 2005: 81-101.
11. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders,
Fourth Edition, Text Revision (DSM-IV-TR). Washington DC: American Psychiatric
Association, 2000.
12. Folstein MF, Folstein SE, McHugh PR. ‘Mini-Mental State’: A practical method for grading the
cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189-198.
13. Cummings JL. The Neuropsychiatry of Alzheimer’s Disease and Related Dementias. London:
Martin Dunitz, 2003.
14. Galasko D, Bennett D, Sano M, et al. An inventory to assess activities of daily living for clinical
trials in Alzheimer’s disease. The Alzheimer’s disease cooperative study. Alzheimer Dis Assoc
Disord 1997;11(Suppl 2):S33-39.
151 SAJP - August 2013 Vol. 19 No. 3
15. Feldman HH, van Baelen B, Kavanagh SM, Torfs KE. Cognition, function, and caregiving
time patterns in patients with mild-to-moderate Alzheimer disease: A 12-month analysis.
Alzheimer Dis Assoc Disord 2005;19:29-36.
16. Potocnik F, Pienaar W. The elderly. In: Kaliski S, ed. Psycholegal Assessment in South Africa.
Cape Town: Oxford University Press, 2006:271-286.
17. Hort J, O’Brien JT, Gainotti G, et al. on behalf of the European Federation of the Neurological
Societies (EFNS) Scientist Panel on Dementia. EFNS guidelines for the diagnosis and
management of Alzheimer’s disease. Eur J Neurol 2010;17:1236-1248. [http://dx.doi.
org/10.1111/j.1468-1331.2010.03040.x]
18. Gauthier S, Cummings J, Ballard C, et al. Management of behavioural problems in Alzheimer’s
disease. Int Psychogeriatr 2010;22:346-372. [http://dx.doi.org/10.1017/S1041610209991505]
19. Ames D, Cheu E, Lindesay J, Shulman KI. Guide to the Psychiatry of Old Age. Cambridge:
Cambridge University Press, 2010:31-47.
20. Taylor D, Paton C, Kapur S. Maudsley Prescribing Guidelines, 10th ed. London: Informa
Healthcare, 2009: 388-399.
21. Lopez OL, Becker JT, Wahed AS, et al. Long-term effects of the concomitant use of memantine
with cholinesterase inhibition in Alzheimer disease. J Neurol Neurosurg Psychiatry
2009;80:600-607. [http://dx.doi.org/10.1136/jnnp.2008.158964]
22. Vanderstichele H, Bibl M, Engelborghs S, et al. Standardization of preanalytical aspects of
cerebrospinal fluid biomarker testing for Alzheimer’s disease diagnosis: A consensus paper
from the Alzheimer’s Biomarkers Standardization Initiative. Alzheimer’s and Dementia
2012;8:65-73. [http://dx.doi.org/10.1016/j.jalz.2011.07.004]
23. Rogers SL, Doody RS, Pratt RD, Jeni JR. Long-term efficacy and safety of donepezil
in the treatment of Alzheimer’s disease: Final analysis of a US multicentre open-label
study. Eur Neuropsychopharmacol 2000;10:195-203. [http://dx.doi.org/10.1016/S0924-
977X(00)00067-5]
24. Winblad B, Wimo A, Engedal K, et al. for the Donepezil Nordic Study Group. 3-year study
of donepezil therapy in Alzheimer’s disease: Effects of early and continuous therapy. Dement
Geriatr Cogn Disord 2006;21:353-363. [http://dx.doi.org/10.1159/000091790]
25. Howard R, McShane R, Lindesay J, et al. Donepezil and memantine for moderate-to-
severe Alzheimer’s disease. New Engl J Med 2012;366:893-903. [http://dx.doi.org/10.1056/
NEJMoa1106668]
26. Hogan DB. Progress update: Pharmacological treatment of Alzheimer’s disease.
Neuropsychiatric Disease and Treatment 2007;3:569-578.
27. Knopman D, Schneider L, Davis K, et al. Long-term tacrine (Cognex) treatment: Effects on
nursing home placement and mortality. Neurology 1996;47:166-177.
28. Henke CJ, Burchmore MJ. The economic impact of tacrine in the treatment of Alzheimer’s
disease. Clin Ther 1997;19:330-345.
29. Stewart A, Phillips R, Dempsey G. Pharmacotherapy for people with Alzheimer’s disease: A Markov-
cycle evaluation of five years’ therapy using donepezil. Int J Geriatr Psychiatry 1998;13:445-453.
[http://dx.doi.org/10.1002/(SICI)1099-1166(199807)13:7<445::AID-GPS794>3.3.CO;2-5]
30. Doody RS, Geldmacher DS, Gordon B, et al. Open label, multicenter, phase 3 extension study
of the safely and efficacy of donepezil in patients with Alzheimer’s disease. Arch Neurol
2001;58:427-433.
31. National Institute for Clinical Excellence (NICE). Donepezil, galantamine, rivastigmine
(review) and memantine for the treatment of Alzheimer’s disease. Technology Appraisal No
111. http://www.nice.org.uk.2006 (accessed april 2013).
32. Taylor D, Paton C, Kapur S. Behavioural and Psychological Symptoms of Dementia. Maudsley
Prescribing Guidelines, 10th edition. London: Informa Healthcare, 2009:400-404.
33. Ihl R, Frölich L, Winblad B, et al. World Federation of Societies of Biological Psychiatry (WFSBP)
guidelines for the biological treatment of Alzheimer’s disease and other dementias. World Journal
of Biological Psychiatry 2011;12:2-32. [http://dx.doi.org/10.3109/15622975.2010.538083]
34. Rossiter D, ed. South African Medicines Formulary (SAMF), 10th ed. Cape Town: Health and
Medical Publishing Group of the South African Medical Association, 2012.
35. Cummings JL, Mega MS, Gray K, et al. The neuropsychiatric inventory: Comprehensive
assessment of psychopathology in dementia. Neurology 1994;44:2380-2314.
36. Ames D, Cheu E, Lindesay J, Shulman KI. Guide to the Psychiatry of Old Age. Cambridge, UK:
Cambridge University Press, 2010:49-56.
37. Okura T, Plassman BL, Steffens DC, et al. Prevalence of neuropsychiatric symptoms and
their association with functional limitations in older adults in the United States: The
aging, demographics, and memory study. J Am Geriatr Soc 2010;25:330-337. http://dx.doi.
org/10.1111/j.1532-5415.2009.02680.x
38. Potocnik F. Forgetfulness and other disturbances of cognitive function: The dementias. In:
Baumann SE, ed. Primary Health Care Psychiatry. A Practical Guide for Southern Africa. Cape
Town: Juta, 2007:494-508.
39. Potocnik F. Successful treatment of hypersexuality in AIDS dementia with cyproterone
acetate. S Afr Med J 1992;81:433-435.
40. Jones DA, Peters TJ. Caring for the elderly dependents: Effects on the carer’s quality of life. Age
Ageing 1992;21:421-428.
41. Eisdorfer C. Families in distress: Caring is more than loving. Psychiatr Ann 1996;26:285-288.
42. Norton MC, Smith KR, Ostbye T, et al. for the Cache County Investigators. Greater risk of
dementia when spouse has dementia? The Cache County study. J Am Geriatr Soc 2010;58:895-
900. [http://dx.doi.org/10.1111/j.1532-5415.2010.02806.x]
43. Goedert M, Spillantini MG. A century of Alzheimer’s disease. Science 2006;314:777-781.
[http://dx.doi.org/10.1126/science.1132814]
44. Breteler MMB, Hofman A, Launer LJ, et al. Pharmacologic agents associated with a preventive
effect on Alzheimer’s disease: A review of the epidemiologic evidence. Epidemiol Rev
2002;24:248-268.

45. Zandi PP, Anthony JC, Khachaturian AS, et al. Reduced risk of Alzheimer’s disease in users of
anti-oxidant vitamin supplements: The cache county study. Arch Neurol 2004;61:82-88.
46. Miller ER, Pastor-Barriuso R, Dalai D, et al. Meta-analysis: high-dosage vitamin E
supplementation may increase all-cause mortality. Ann Intern Med 2005;142:37-46. [http://
dx.doi.org/10.7326/0003-4819-142-1-200501040-00110]
47. Orgogozo JM, Dartigues JF, Lafont S, et al. Wine consumption and dementia in the elderly:
Aprospective community study in the Bodeaux area. Revue Neurologique. (Paris) 1997;153:185-
192.
48. t’Veld BA, Ruitenberg A, Hofman A, et al. Nonsteroidal anti-inflammatory drugs and the risk of
Alzheimer’s disease. New Engl J Med 2001;345:1515-1521.
49. Breitner JC, Baker LD, Montine TJ, et al. Extended results of the Alzheimer’s disease
anti-inflammatory prevention trial. Alzheimer’s & Dementia 2011;7:402-411.[http://dx.doi.
org/10.1016/j.jalz.2010.12.014]
GUIDELINE
50. Van Gelder BM, Buijsse B, Tijhuis M, et al. Coffee consumption is inversely associated with
cognitive decline in elderly European men: The FINE study. Eur J Clin Nutr 2007;61:226-232.
[http://dx.doi.org/10.1038/sj.ejcn.1602495]
51. Eskelinen MH, Ngandu T, Tuomilehto J, et al. Midlife coffee and tea drinking and the risk of late-
life dementia: A population-based CAIDE study. Journal of Alzheimer’s Disease 2009;16:85-91.
52. Cao C, Wang L, Lin X, et al. Caffeine synergizes with another coffee component to increase
plasma GCSF: linkage to cognitive benefits in Alzheimer’s mice. Journal of Alzheimer’s Disease
2011;25:323-335.
53. Vellas B, Gillette-Guzonnet S, Andries S. Memory health clinics - a first step to prevention.
Alzheimer’s & Dementia 2008;4(Suppl 1):S144-149. [http://dx.doi.org/10.1016/j.jalz.2007.11.001]
54. Bowman GL, Silbert LC, Howieson D, et al. Nutrient biomarker patterns, cognitive function, and
MRI measures of brain aging. Neurology 2012;78:241-249.
55. Daoud JB. Memory loss. Update 1998:40-45.
August 2013 Vol. 19 No. 3 - SAJP 152
ARTICLE
Schizophrenia
D Swingler
1. Introduction
Schizophrenia is a major mental disorder that imposes a significant
burden on the individual including poor quality of life[1] and increased
morbidity[2] and mortality;[3] it disrupts interpersonal relationships
and family structures, and has significant economic costs to society.
[4]
While there are substantial limitations to current treatments,[5] an
integrated package of biopsychosocial interventions is essential to
alleviate the negative impact of the disorder and enhance quality of
life.[6] Active early intervention, in particular, can improve long-term
outcomes.[4]
2. Diagnosis and clinical characteristics
Schizophrenia is a heterogeneous cluster of psychotic conditions
characterised by positive (delusions, hallucinations) and negative or
‘deficit’ (blunting of affect, avolition) symptoms, disorganised speech
and behaviour, as well as mood (depressive) and cognitive impairments.
Diagnosis in terms of the Diagnostic and Statistical Manual of
Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR)[7]
requires the presence for at least 1 month (or less if successfully
treated) of 2 or more of the following characteristic symptoms (in
the context of the disturbance persisting for at least 6 months which
includes 1 month of symptoms) (criterion A):
• Delusions
• Hallucinations
• Disorganised speech
• Grossly disorganised or catatonic behaviour
• Negative symptoms.
Further, the disorder must cause social and/or occupational
dysfunction, and cannot be better accounted for by:
• Schizoaffective or mood disorders
• Substance-related disorders
• General medical conditions.
3. Assessment
3.1 Diagnostic
A detailed clinical history, mental state and careful physical
examinations must inform a diagnosis made rigorously in terms of
the DSM-IV-TR, satisfying, in particular, criterion A of the disorder.[7]
Clinically indicated special investigations (bedside, serological and
drug screening) should support the exclusion of other biological
causes of psychosis, and screening for HIV, syphilis and psychoactive
substances is recommended in the South African context. Brain
imaging (computed tomography (CT) or magnetic resonance imaging
(MRI)) and electro-encephalography (EEG) are recommended in
first-episode patients, when the clinical picture is atypical, and when
there are abnormal findings on routine examination.[4]
3.2 Pre-treatment
Clinically indicated baseline investigations prior to initiating
antipsychotic treatment are directed by the clinical process and choice
153 SAJP - August 2013 Vol. 19 No. 3
of initial drug therapy, and include body mass index (BMI) and
waist:hip ratio (cardiovascular (CV) risk), fasting blood glucose and
lipogram (metabolic risk), and full blood count and liver function
tests (depending on drug selection).
A baseline electrocardiogram (ECG) is indicated before treatment if
required by the product’s package insert. If there is a personal history
of CV disease or evidence of CV risk on physical examination, an
ECG should be considered for inpatients.[6]
4. Treatment
4.1 Treatment goals
Therapeutic goals are to relieve symptoms, prevent relapse, promote
recovery and improve quality of life.[6] More specifically, this includes:
• Achieving and maintain symptom alleviation
• Achieving and maintain treatment adherence
• Minimising treatment side-effects
• Monitoring physical health and drug-specific adverse event risks, e.g.
• White cell count (WCC) (acute neutrophil count) with clozapine
• Metabolic syndrome risk factors with olanzapine
• Tardive dyskinesia with haloperidol
• Managing smoking and substance abuse
• Managing risk of harm to self and others.
4.2 General aspects of treatment
At the outset of management, an integrated treatment plan including
pharmacological, psychological and social interventions should be
formulated in terms of available resources. Pharmacological treatment
remains the mainstay of therapy, while psychosocial interventions are
crucial in promoting recovery and improving quality of life.[6]
While both the classification and relative efficacies of the so-called
‘typical’ first-generation antipsychotic (FGA) agents, such as
haloperidol and chlorpromazine, and ‘atypical’ second-generation
antipsychotic (SGA) compounds, such as risperidone and olanzapine,
remain controversial, current evidence supports the following:
• Drugs from both groups are equally effective in alleviating
psychosis[8]
• SGAs may have benefit in negative syndromes, and with mood and
cognitive impairments[4]
• Where differences exist, the effect sizes are small to modest, except
for clozapine which is more effective in treatment resistance and
reducing suicide risk[4]
• SGAs, largely because of less severe extrapyramidal side-effects
(EPS), are more tolerable[9]
• Each drug has a unique side-effect profile
• The choice of drug is informed by[6]
• Access and availability
• Shared patient-centred decision making
• Previous experience (efficacy and side-effects), if any
• Tailoring the side-effect profile to the individual patient
• Choice of mode of administration (oral or parenteral)

• Recommended dosage is in the range of 300 - 1 000 mg
chlorpromazine (CPZ) equivalents.[4]
Oral therapy is advised. Should parenteral therapy be considered
for maintenance on the basis of patient preference or convenience
or to manage non-adherence, this can be planned in the acute phase.
It is logical to convert from an effective oral agent to its parenteral
equivalent, and a test dose of the oral equivalent of the agent should
be used before administering a long-acting injectable antipsychotic
agent.
Monotherapy is recommended. There is no advantage to combining
antipsychotics, which should only be done for short periods when
switching agents, or in treatment-resistant settings.[4,6] Doses should
not exceed 1 000 mg CPZ equivalents and/or the manufacturer’s
instruction as there is no additional therapeutic benefit in doing so,
with added cost and side-effects.[4,6]
Loading doses or ‘rapid neuroleptisation’ is ill-advised as it confers
no therapeutic benefit with added risks.[6] Adjunctive benzodiazepines
(the evidence supports lorazepam[10]) can be used liberally to attenuate
disruptive behaviour in the acute setting.[4]
Continuous dosing is advised, as intermittent or targeted dosing
leads to increased risk of relapse.[4] A trial of 4 - 6 weeks is required
before considering another agent.[4,6,11]
4.3 Acute pharmacological treatment
4.3.1 First episode
A recent meta-analysis[12] found no differences between FGAs and
SGAs in efficacy in this population, but a clear difference in side-
effect profile. In view of the vulnerability of drug-naive first-episode
psychosis patients to develop EPS and tardive dyskinesia, the drug
of choice is an SGA other than clozapine. Risperidone, olanzapine,
quetiapine, aripiprazole, ziprasidone and amisulpride are supported
by the evidence base.[4,6,13] Dosing should start low with incremental
upward titration, with the target dosage at the lower end of the
therapeutic range for each agent according to the package insert.[6]
4.3.2 Multi-episode/relapse
The drug of choice will be influenced by any prior agents’ efficacy
and tolerability. If SGAs are available, they are generally preferred
and risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone and
amisulpride are supported by the evidence base.[13] Haloperidol and
chlorpromazine are FGA alternatives.
4.3.3 Second-line treatment
If response to the first-line agent above is unsatisfactory, then a second
trial should be considered after review of potential contributors to
non-response.[6]
This second-trial agent can be another SGA or an FGA, but should
be an SGA if there was a failed response to an FGA in the first trial.[4,6]
Switching strategies includes cross-titration, overlap-and-taper, and
abrupt change. Other than for switching to clozapine (see below), there
is no evidence of difference in efficacy or tolerability.[14]
Oral monotherapy at doses not exceeding 1 000 mg CPZ equivalents
and/or the manufacturer’s recommendation in a continuous dosing
strategy is advised for a further 4 - 6 weeks before considering the
third line of treatment.[4,6,11]
ARTICLE
4.3.4 Third-line treatment
Clozapine oral monotherapy is the next treatment of choice, at the
highest tolerable dose (≤900 mg daily) for 6 months.[11] Switching
requires tapering and stopping the extant agent prior to initiating
clozapine, to minimise haematological risk.
Because of a non-dose-dependent risk of agranulocytosis, WCCs –
absolute neutrophil counts in particular – should be monitored prior
to treatment, weekly for the first 18 weeks and monthly thereafter.
Considering the risk of dose-related seizures, caution and careful
monitoring should be exercised at doses above 450 mg daily.[15]
4.4 Long-term maintenance
Half of all patients stopping medication will relapse within 6 -
10 months, compared to one-fifth on treatment.[6] Long-term
antipsychotic treatment reduces the risk of relapse over several years
by two-thirds.[16]
Continuation of pharmacological treatment that was effective in the
acute and stabilisation phases is advised. While many practitioners
attempt dose reduction during maintenance, the evidence suggests
that even gradually decreasing doses increases the risk of relapse.[17]
Continuous dosing is advised as intermittent or targeted dosing leads
to increased risk of relapse.[4]
Oral therapy is usual, but long-acting intramuscular preparations
should be considered for maintenance on the basis of patient
preference or convenience, or to manage non-adherence.
The minimum duration of treatment for first-episode patients is
1 year symptom-free if the episode is of mild severity and responds
well to treatment, and 2 years symptom-free in severe cases or those
slow to respond initially.[17] Second-episode patients require at least
2 and up to 5 years symptom-free before drug withdrawal can be
considered. Indefinite treatment is advised after a third episode.[17]
4.5 Non-pharmacological treatment
4.5.1 Psychological interventions
These are focused on the individual (cognitive behaviour therapy,
psycho-education, supportive psychotherapy) and the family (psycho-
education, family therapy). These can be introduced during the acute
phase of illness, but are more usually commenced in the stabilisation
period.[6]
4.5.2 Social interventions
Long-term goals of treatment adherence and symptom reduction,
limitation of injurious behaviours (smoking, substance abuse, suicide
risk) and improved quality of life are supported by social interventions,
including assertive community programmes, social skills training,
appropriate housing, supported employment and adaptation to life
in the community. These may be required during the acute phase of
illness, but are more usually commenced in the stabilisation period.[6]
4.6 Special populations
4.6.1 First-episode psychosis
In view of the vulnerability of drug-naïve first-episode psychosis
patients to develop EPS and tardive dyskinesia, the drug of choice
is an SGA other than clozapine. Dosing should start low with
incremental upward titration, with the target dosage at the lower
August 2013 Vol. 19 No. 3 - SAJP 154
ARTICLE
end of the therapeutic range of each agent
according to package insert.[6] Oral therapy is
recommended.
4.6.2 Electro-convulsive therapy (ECT)
While ECT is considered a last-line treatment4
in uncomplicated schizophrenia, it has a role
in early acute treatment in the context of
extreme psychomotor agitation, catatonia,
pregnancy, or when life is at risk.
4.7 Managing partial and
non-responders
4.7.1 Non/partial response
If response to any line of treatment
is unsatisfactory, then a further line of
intervention should be considered after
review of potential contributors to non-
response.[6] This includes:
• Review of the diagnosis
• Review of treatment adherence
• Drug choice
• Dosage
• Duration
• Adequacy of psychosocial interventions
• Presence of comorbid:
• Substance abuse
• Psychiatric illness
• Physical illness
• Pharmacotherapy.
4.7.2 Treatment resistance
While there are many definitions of treatment-
resistant schizophrenia, for the purposes of
this guideline it is taken to mean ‘insufficient
improvement in target symptoms despite
treatment at the recommended dosage for
at least 6 weeks with at least 2 antipsychotic
agents, one of which was an SGA other than
clozapine’.[4]
In addition to a review of potential
contributors to non-response as above,[6] a
multidimensional assessment of positive,
negative, affective and cognitive symptoms,
as well as social and vocational function and
quality of life, is indicated.[4]
With ongoing insufficient response to
maximum dose clozapine, the options (for
which there is only limited evidence) are:
• Combining clozapine with another SGA
that does not compound its side-effects
• Augmentation with mood stabilisers
• Lamotrigine has some evidence for
utility[4]
• Valproate when hostility is a problem[18]
155 SAJP - August 2013 Vol. 19 No. 3
• Lithium when depression is trouble­ • A loading dose (‘rapid neuroleptisation’)
some[19] is ill-advised, as it confers no therapeutic
• Benzodiazepines can be added in cases of benefit with added risks.
agitation, for short-term use • Risperidone, olanzapine, quetiapine,
• ECT is a last-line treatment.[4] aripiprazole, ziprasidone and amisulpride are
Fig. 1 outlines the treatment algorithm. effective in first-episode psychosis patients.
• For multi-episode patients, consider
5. Summary points risperidone, olanzapine, quetiapine,
• Both typical FGA agents and atypical SGA aripiprazole, ziprasidone and amisulpride.
agents are effective in schizophrenia. Any Haloperidol and chlorpromazine may be
differences in efficacy between these agents considered as alternatives to FGAs.
are small to modest. There are, however, • A trial of 4 - 6 weeks is required before
clear differences in side-effect profiles. considering an alternative agent.
• Monotherapy is recommended as there is • A second trial agent may be another
no advantage to combining antipsychotics. SGA or an FGA, but should be an SGA if
Diagnosis: DSM-IV-TR
• History and examination
• Special investigations - bedside, serology, drug
screen
Multiple episodes/relapse
First episode
• Oral monotherapy
• Oral monotherapy
• SGA: RIS, OLA, QUE, ARI, ZIP, AMI •
•
SGA: RIS, OLA, QUE, ARI, ZIP, AMI
Or FGA: HAL, CPZ
• Lower dose range 300 - 1 000 mg
CPZ/E • Dose in range 300 - 1 000 mg
CPZ/E
• 4 - 6 weeks
• 4 - 6 weeks
• BZD as required
Response?
No
Yes
Poor response review
• Diagnosis correct?
• Drug trial of adequate dose and duraction?
• Adequate pschosocial interventions?
• Comorbidities assessed and managed?
Second line
• Oral monotherapy
•
•
Second SGA: RIS, OLA, QUE, ARI, ZIP, AMI
Or FGA: HAL, CPZ only if failed first line was SGA
• Dose in range 300 - 1 000 mg CPZ/E
• 4 - 6 weeks
Response?
Yes
Third line No
• Oral CLO up to 900 mg daily
• WCC monitoring
• Seizure caution >450 mg daily
Response?
No Yes
Fourth line
• Combine CLO with SGA
• Augment CLO with mood stabiliser (LAM, VAL, Li)
• ECT (earlier in certain clinical situations - see
text) Maintenance
Fig. 1. Treatment algorithm. FGA = first-generation antipsychotic; HPL = haloperidol; CPZ = chlorpromazine;
CPZ/E = chlorpromazine equivalents; SGA = second-generation antipsychotics; RIS = risperidone; OLA
= olanzapine; QUE = quetiapine; ARI = aripiprazole; AMI = amisulpride; CLO = clozapine; BZP =
benzodiazepines; LAM = lamotrigine; VAL = valproate; Li = lithium.

there was a failed response to an FGA in the first trial. Third-line
treatment is clozapine.
• Clozapine is more effective than other FGA and SGA agents in
treatment resistance and reduction of suicide risk.
• If there is an insufficient response to a maximum dose clozapine,
consider combining clozapine with another SGA, or augmenting
with a mood stabiliser, ECT, or adding a benzodiazepine in the
short-term to control agitation or disruptive behaviour.
• Half of all patients stopping medication will relapse within 6 - 10
months, compared to one-fifth on treatment.
• Minimum treatment duration for first episode patients is 1 year
symptom-free if the episode is of mild severity and responds well to
treatment, and 2 years symptom-free in severe cases or those slow
to respond initially.
• Second-episode patients require at least 2 - 5 years of medication
while symptom-free before discontinuation is considered, while
patients who have had 3 or more episodes should be treated
indefinitely.
References
1. Jones PB, Barnes TRE, Davies L, et al. Randomised control trial of the effect on quality of life
of second- vs first-generation antipsychotic drugs in schizophrenia: Cost utility of the latest
antipsychotic drugs in schizophrenia study (CUtLASS 1). Arch Gen Psychiatry 2006;63:1079-
1086. [http://dx.doi.org/10.1001/archpsyc.63.10.1079]
2. Murray CJ, Lopez AD. Global mortality, disability and the contribution of risk factors: Global
burden of disease study. Lancet 1997;349:1436-1442. [http://dx.doi.org/10.1016/S0140-
6736(96)07495-8]
3. Brown S, Inskip H, Barraclough B. Causes of excess mortality of schizophrenia. Br J Psychiatry
2000;177:212-217. [http://dx.doi.org/10.1192/bjp.177.3.212]
4. Falkai P, Wobrock T, Lieberman J, et al. World Federation of Societies of Biological Psychiatry
(WFSBP). Guidelines for biological treatment of schizophrenia, Part 1: acute treatment
of schizophrenia. World Journal of Biological Psychiatry 2005;6:132-191. [http://dx.doi.
org/10.1080/15622970510030090]
ARTICLE
5. Lieberman JA, Scott Stroup T, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients
with chronic schizophrenia. N Engl J Med 2005;353:1209-1223. [http://dx.doi.org/10.1056/
NEJMoa051688]
6. National Institute for Health and Clinical Excellence (NICE). Core interventions in the
treatment and management of schizophrenia in adults in primary and secondary care.
London: NICE, 2009: Clinical Guidance 82. (http://www.nice.org.uk/guidance/index.
isp?action=bvID&o=11786)
7. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders,
Fourth Edition, Text Revision (DSM-IV-TR). Washington, DC: American Psychiatric
Association, 2000.
8. Leucht S, Corves C, Arbter D, et al. Second-generation versus first-generation antipsychotic
drugs for schizophrenia: A meta-analysis. Lancet 2009;373:31-41. [http://dx.doi.org/10.1016/
S0140-6736(08)61764-X]
9. Fleischhacker WW. Second generation antipsychotics. Psychopharmacology 2002;162:90-91.
[http://dx.doi.org/10.1007/s00213-002-1064-8]
10. American Psychiatric Association. Practice guideline for the treatment of patients with
schizophrenia, 2nd edition. Am J Psychiatry 2004;161:1-114.
11. Kenneth O, Jobson MD. The International Psychopharmacology Algorithm Project (IPAP)
- Schizophrenia Algorithm, Schizophrenia Algorithm nodes. 2006. http://www.ipap.org/
(accessed July 2013).
12. Crossley NA, Constante M, MacGuire P, et al. Efficacy of atypical v. typical antipsychotics in
the treatment of early psychosis: Meta-analysis. Br J Psychiatry 2010;196:434-439. [http://
dx.doi.org/10.1192/bjp.bp.109.066217]
13. Leucht S, Komossa K, Rummel-Kluge C, et al. A meta-analysis of head-to-head comparisons
of second-generation antipsychotics in the treatment of schizophrenia. Am J Psychiatry
2009;166:152-163. [http://dx.doi.org/10.1176/appi.ajp.2008.08030368]
14. Kane JM, Leucht S, Carpenter D, et al. The Expert Consensus Guideline Series: Optimising
pharmacologic treatment of psychotic disorders. J Clin Psychiatry 2003;64:1-100.
15. Gibbon CJ, Blockman M. South African Medicines Formulary, 8th ed. Cape Town: Health and
Medical Publishing Group, South African Medical Association, 2008.
16. Kissling W. Guidelines for neuroleptic relapse prevention in schizophrenia. 1991. Berlin:
Springer, 1991.
17. Falkai P, Wobrock T, Lieberman J, et al. World Federation of Societies of Biological Psychiatry
(WFSBP) guidelines for biological treatment of schizophrenia, Part 2: Long-term treatment
of schizophrenia. World Journal of Biological Psychiatry 2006;7:5-40. [http://dx.doi.
org/10.1080/15622970500483177]
18. Citrome L, Casey DE, Daniel DG, et al. Adjunctive divalproex and hostility among patients
with schizophrenia receiving olanzapine or risperidone. Psychiatr Serv 2004;55:290-294.
[http://dx.doi.org/10.1176/appi.ps.55.3.290]
19. Leucht S, Kissling W, McGrath J. Lithium for schizophrenia revisited: A systematic review
and meta-analysis of randomized controlled trials. J Clin Psychiatry 2004;65:177-186. [http://
dx.doi.org/10.4088/JCP.v65n0206]
August 2013 Vol. 19 No. 3 - SAJP 156
GUIDELINE
Major depressive disorder
G Grobler
1. Introduction
This treatment guideline draws on several international guidelines: (i)
Practice Guidelines of the American Psychiatric Association (APA)
for the Treatment of Patients with Major Depressive Disorder, Second
Edition;[1] (ii) Clinical Guidelines for the Treatment of Depressive
Disorders by the Canadian Psychiatric Association and the Canadian
Network for Mood and Anxiety Treatments (CANMAT);[2] (iii)
National Institute for Clinical Excellence (NICE) guidelines;[3] (iv) Royal
Australian and New Zealand College of Psychiatrists Clinical Practice
Guidelines Team for Depression (RANZCAP);[4] (v) Texas Medication
Algorithm Project (TMAP) Guidelines;[5] (vi) World Federation of
Societies of Biological Psychiatry (WFSBP) Treatment Guideline for
Unipolar Depressive Disorder;[6] and (vii) British Association for
Psychopharmacology Guidelines.[7]
Major depressive disorder (MDD) is frequently associated with
comorbid psychiatric and medical conditions and carries with it a
high risk of morbidity and mortality. For many an initial episode
of depression evolves into a recurrent and debilitating chronic
illness with significant and pervasive impairments in psychosocial
functioning.[8-11] The recent Global Burden of Disease Study estimated
that unipolar major depression is the fourth largest contributor to the
global burden of disease (premature mortality and disability).[12] By
the year 2020, unipolar MDD is projected to be the second largest
contributor to the global burden of disease, after heart disease.[13]
1.1 Prevalence and risk factors
MDD has a median lifetime prevalence of 16.1% (range 4.4 - 18%). [14]
Twelve-month prevalence ranges from 5% to 10% in adults, with
women at higher risk than men (ratio is approximately 2:1).[15-17] In
South Africa, the lifetime prevalence of MDD documented in the
South African Stress and Health (SASH) survey, the first nationally
representative epidemiological survey of common mental disorders
in South Africa,[18] was 9.8% across all age groups, with the highest
prevalence (14.6%) in the Free State. The survey, conducted between
2003 and 2004 was a three-stage, area probability sample of 4 351
adults of all races and ethnic groups living in households and
single-sex migrant labourer group quarters in South Africa. The
12-month prevalence rate of MDD during this period was 4.9%. The
aforementioned SASH study found that females were 1.75 more likely
to develop MDD than males.
The age of onset of MDD is difficult to assess because the first
episode is frequently mild and untreated, and may be determined
retrospectively many years after first onset. MDD can begin at any
age, even in childhood and adolescence, but there are two peaks,
in the twenties and forties.[1,19] The mean age of onset of MDD has
been estimated around the age of 30.[14] Family and twin studies have
indicated that MDD is a complex genetic disorder being 1.5 - 3 times
more common among first-degree biological relatives of persons with
this disorder than among the general population.[20,21]
157 SAJP - August 2013 Vol. 19 No. 3
Female gender, a previous episode of major depression and a positive
first-degree family history of depression are the most consistently
described risk factors.
1.2 Comorbidity and consequences
Anxiety disorders are highly comorbid, occurring in about 58% of
patients with MDD.[22] In addition, anxiety symptoms are highly
prevalent in MDD, occurring in up to 80% of patients.[23] Studies
investigating the effects of depression on health-related quality of life
have demonstrated detrimental effects that equal or exceed those of
patients with chronic medical illnesses, such as ischaemic heart disease
or diabetes mellitus.[24-26] The most serious sequela of MDD is suicide. It
has been estimated that about 50% of depressed patients make at least
one suicide attempt during their lifetime.[27] It is well established that
patients with mood disorders suffer a higher risk of suicide relative to
the general population.[28] However, no risk factor or classification of
diagnostic subtype has been shown to reliably predict suicide.[29] In a
recent meta-analysis, the lifetime prevalence of suicide was estimated,
on the basis of the intensity of the treatment setting. The analysis
showed that clinically depressed patients who had been hospitalised
for suicidality had a lifetime risk of suicide of 8.6%. Patients with
affective disorders, who had been hospitalised without specification
of suicidality, had a lifetime suicide rate of 4.0%. The lifetime suicide
prevalence for mixed inpatient/outpatient populations was 2.2%, and
less than 0.5% for the non-affectively ill population.[29] Depression also
substantially increases the risk of death by cardiovascular disease.[30]
In addition to the personal suffering of individuals and their
families, depression imposes significant costs on society.[31] These
include both direct total healthcare costs and indirect costs (the latter
have been estimated to be much higher than direct costs). Direct
costs include mental health treatment costs and all other healthcare
costs. Indirect costs include such varied factors as lost productivity
associated with morbidity and mortality.[32] As depression is often
not properly diagnosed and/or undertreated,[33-36] and as it can affect
many individuals at a relatively early age, the impact on cost can be
cumulative over time.
2. Diagnosis and clinical characteristics
MDD is characterised by single or recurrent major depressive episodes.
The essential feature of a major depressive episode is a period of at
least 2 weeks of depressed mood with abnormalities of neurovegetative
functions (e.g. appetite, weight loss, sleep disturbances), psychomotor
activity (e.g. loss of energy and interests, agitation or retardation),
cognition (feelings of worthlessness, hopelessness or inappropriate
guilt), as well as anxiety and suicidal ideation.[1] Table 1 summarises the
diagnostic criteria according to the Diagnostic and Statistical Manual
of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR)[37] as
well as the International Statistical Classification of Diseases and Related
Health Problems, Tenth Revision (ICD-10).[38]

Depressive symptoms and pathology lie on a spectrum in terms of
duration, severity and comorbid pathology.
2.1 Course and prognosis
An untreated depressive episode typically lasts about 6 months or
longer.[1,19,39] Modern pharmacotherapy alleviates suffering during
acute episodes, and placebo-controlled trials show response and
remission occurring more quickly in actively treated groups. A 27-year
prospective study of 186 unipolar depressed patients meeting DSM-III
criteria for major depression found shorter episodes and cycles with
increasing episode number.[19] However, a 10-year prospective study
of 258 subjects treated for unipolar MDD showed that the duration of
recurrent mood episodes remained relatively uniform over time and
averaged approximately 20 weeks.[39]
MDD is typically a recurrent disorder and 50 - 85% of the patients
who have an episode will eventually have another episode.[40,41] There is
also increasing evidence that some who experience a major depressive
episode will have a lifelong course of illness characterised by recurrent
major depressive episodes or the development of chronicity, e.g.
recurrent MDD without full inter-episodic recovery, or a chronic
major depressive episode, or ‘double depression’ (concurrent major
depression and dysthymic disorder).[31,42-44] Between 9% and 24%
of patients with the initial diagnosis of a major depressive episode
will undergo a change in diagnosis over time, mostly to bipolar
disorder. [19,39]
Table 1. Criteria and classification of a depressive episode and major depressive disorder*
International Classification of Diseases, Tenth Revision code[38]
A. Depressive episode
Severe (F32.2): all 3 typical symptoms plus at least 4 other common
symptoms; some severe symptoms
Moderate (F32.1): at least 2 typical symptoms plus at least 3 common
symptoms; some marked symptoms
Mild (F32.0): at least 2 typical symptoms plus at least 2 other common
symptoms; no intense symptoms
B. Recurrent depressive disorder (F33): recurrent depressive episodes
Abridged criteria of depressive episode
Minimum duration of episode: about 2 weeks
Typical symptoms
Reduced energy, increased fatigability
Loss of interest and enjoyment
Depressed mood
Other common symptoms
Diminished appetite
Disturbed sleep
Ideas or acts of self-harm or suicide
Agitation or retardation
Ideas of guilt and unworthiness
Reduced self-esteem and self confidence
Reduced concentration and attention
*Reprinted with permission from Bauer M, Whybrow PC, Angst J, et al. World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Unipolar Depressive Disorders,
Part 1. Acute and continuation treatment of major depressive disorder. World Journal of Biological Psychiatry 2002;3:5-43. Informa Healthcare. For educational purposes only.
GUIDELINE
Although the prognosis for a depressive episode is good, with most
patients returning to normal functioning once the episode is over, in
20 - 30% of cases depressive symptoms will persist.[40,43,45-47]
3. Assessment
A thorough diagnostic evaluation to determine both the presence of
MDD and comorbid psychiatric or general medical conditions is key.
This should include a review of the history of the illness including
symptoms of current illness, past psychiatric and treatment history
(with attention to current treatment and response to past treatment);
general medical history; history of psychoactive substance abuse;
personal developmental history and response to life transitions
and major life events; social, occupational, and family history;
mental status examination; physical examination; and laboratory
investigations, as indicated.
Careful assessment of the patient’s suicidal as well as homicidal
risk is paramount. The APA guidelines[1] propose evaluation of the
following:
• Presence of suicidal or homicidal ideation, intent, or plans
• Access to means for suicide and the lethality of those means
• Presence of psychotic symptoms, command hallucinations in
particular, or severe anxiety
• Presence of alcohol or substance use disorder(s)
• History and seriousness of previous attempts
• Family history of, or recent exposure to, suicide.
American Psychiatric Association’s Diagnostic and Statistics Manual,
Fourth Revision, Text Revision[37]
Major depressive disorder
A. Single episode (296.2x)
B. Recurrent (296.3x)
Abridged criteria major depressive episode
A. O  ver the last 2 weeks, 5 of the following features should be present
most of the day or nearly every day (must include 1 or 2):
Depressed mood
Loss of interest/pleasure in almost all activities
Significant weight loss/gain (>5% change in 1 month) or an increase
or decrease in appetite nearly every day
Insomnia/hypersomnia
Psychomotor agitation or retardation (observable by others)
Fatigue or loss of energy
Feelings of worthlessness/excessive/inappropriate guilt (not merely
self-reproach about being sick)
Diminished ability to think/concentrate, indecisiveness (either by
subjective account or as observed by others)
Recurrent thoughts of death (not just fear of dying)/recurrent suicidal
ideation/a suicide attempt/a specific plan for committing suicide
B. The symptoms cause clinically significant distress or impairment in
social, occupational, or other important areas of functioning
C. Physical/organic factor or illness do not cause symptoms (e.g. drug
abuse, medication, a general medical condition)
D. The symptoms are not better explained by bereavement (although this
can be complicated by major depression)
August 2013 Vol. 19 No. 3 - SAJP 158
GUIDELINE
Measurement-based diagnostic tools can aid in the assessment of
depression severity, presence of co-occurring disorders, and suicide
risk, but should always be accompanied by a clinical diagnostic
assessment incorporating a differential diagnosis.[48] Conditions that
need to be excluded before making a definitive diagnosis of MDD
include bipolar disorder, an adjustment disorder with depressed
mood, mood disorder due to a general medical condition and a
substance-induced mood disorder.
The Structured Clinical Interview for DSM-IV Axis I Disorders
(SCID-I)[49] and the Mini-International Neuropsychiatric Interview
(MINI)[50] are clinician-rated diagnostic instruments, while the
9-item Patient Health Questionnaire (PHQ-9)[51] and the PRIME-
MD[52] are commonly used patient-rated tools. For monitoring of
depressive symptoms on treatment, the Hamilton Depression Rating
Scale (HAM-D)[53] and the Montgomery-Åsberg Depression Rating
Scale (MADRS)[54] are gold-standard clinician-rated scales. Other
measures include the Quick Inventory of Depressive Symptomatology
(QIDS) [55] which is available in both clinician-rated and patient-rated
formats and the patient-rated Beck Depression Inventory (BDI).[56]
Diagnostic assessment and evaluation of patient safety, as well as that
of others, should be followed by an evaluation of functional impairment
and determination of the treatment setting (inpatient or outpatient).
4. Treatment
4.1 Treatment goals
Definitions of response, remission, and recovery[2] are summarised
in Table 2.[57] In depression, full remission is defined as the virtual
elimination of symptoms which in most clinical trials refers to
depression scores within the normal range. This is most consistently
defined as a score of 7 or less on the 17-item Hamilton Depression
Rating Scale (HDRS-17). The term ‘response’ generally indicates a
50% reduction in depression score. Recovery from depression is often
equated with remission in the literature. It is also variably defined as
remission for an extended period of time or the complete absence of
symptoms and improved work and psychosocial functioning.
Evidence for the benefits of treating to remission in depression
is clear: remitted patients are more likely to regain full functional
recovery and to suffer fewer relapses and recurrences.[58] Remission
has become the accepted treatment goal in MDD, as seen in many
recent clinical trials. In the current National Institutes for Mental
Health Sequenced Treatment Alternatives to Relieve Depression
(STAR*D) trial, for example, anything less than remission was viewed
as treatment failure.[59,60]
Table 2. Response, remission, and recovery definitions[57]*
Outcome
Recovery
Remission
Residual symptoms
Response
Partial response
No response
*Reprinted with permission from O’Donovan C. Achieving and sustaining remission in depression and anxiety disorders: Introduction. Canadian Journal of Psychiatry 2004;49 (Suppl 1):5S-9S. Canadian
Psychiatric Association. For educational purposes only.
159 SAJP - August 2013 Vol. 19 No. 3
4.2 General aspects of treatment
Treatment consists of an acute phase (during which remission of all
symptoms is induced); a continuation phase, during which remission
is preserved; and a maintenance phase during which susceptible
patients are protected against the recurrence of subsequent major
depressive episodes.[1]
4.3 Acute treatment
Initial management of MDD should entail: the establishment and
maintenance of a therapeutic alliance; education of the patient and the
family about the disorder with provision of information about treatment
options; a review of the possible adverse effects of medications and
potential drug-drug interactions; emphasis of the importance of taking
medication as prescribed; and addressing the early signs of relapse.[61] The
appropriate treatment setting (inpatient or outpatient) should be selected
and the treatment plan should be individualised to the patient’s needs.[62]
Treatment decisions should also importantly take into account
depression severity. A mild depressive episode, according to the
DSM-IV-TR,[37] is characterised by 5 or 6 symptoms or less and
mild disability (social, occupational and other important areas of
functioning), a moderate depressive episode by 6 or more symptoms
and moderate disability, and a severe depressive episode by most of
the symptoms (as per the DSM-IV-TR symptom list) and observable
disability. According to the DSM-IV-TR, subthreshold depression
comprises fewer than 5 symptoms.[37]
Guidelines differ in their opinion on the management of mild
depression. The APA guidelines[1] advise psychotherapy or antidepressant
monotherapy based on patient preference. Similarly the CANMAT
guidelines[2] recommend either cognitive-behavioural therapy (CBT),
cognitive therapy, interpersonal therapy (IPT), or antidepressants as
a first-line treatment, while the BAP guidelines[63] recommend CBT,
behavioural therapy with activity scheduling, IPT or an antidepressant.
For moderate depression, all guidelines accept the use of an
antidepressant or evidence-based psychotherapy as a first-line choice,
with the exception of the NICE guideline which recommends
antidepressants as the only first-line choice.[3,64] In view of their
superior tolerability and safety, the selective serotonin reuptake
inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors
(SNRIs), or the norepinephrine-dopamine reuptake inhibitors
(NDRIs), and mirtazapine are encouraged over the use of the
tricyclic antidepressants (TCAs) and the monoamine oxidase
inhibitors (MAOIs). However, the following considerations apply
in deciding on the most appropriate medication: availability, safety
Definition based on Hamilton Depression Rating Scale [53]
Remission and return of function
Response plus score of ≤7
Response plus score of ≥8
≥50% reduction
21 - 49% reduction
≤20% reduction
 GUIDELINE

and tolerability, patient preference and patient needs, and cost.[65]

Table 3. Dosage ranges for antidepressant medications[1]*
Newer antidepressant classes such a melatonin agonist may also be
employed. Moderate depression may necessitate a combination of Starting dosage Usual dosage
Generic name (mg/day) (mg/day)
both an antidepressant and psychotherapy (either CBT or IPT). The
APA guidelines recommend a combination of antidepressants and Tricyclics and tetracyclics
psychotherapy for patients with significant psychosocial problems or Tertiary amine tricyclics
Axis II disorders and/or poor compliance.[1] Amitriptyline 25 - 50 100 - 300
For severe depression, the guidelines concur that the following first- Clomipramine 25 100 - 250
line treatment options apply: (i) a combination of an antidepressant Doxepin 25 - 50 100 - 300
and psychotherapy (either CBT or IPT); (ii) electroconvulsive therapy
Imipramine 25 - 50 100 - 300
(ECT) (6 to 10 treatments, maximum of 20, WFSBP guidelines
Trimipramine 25 - 50 100 - 300
recommend bilateral rather than unilateral ECT); or (iii) a combination
of an antidepressant with an antipsychotic agent for a major depressive Secondary amine tricyclics (not available in SA)
episode with psychotic features.[62] In addition to using SSRIs as first- Desipramine 25 - 50 100 - 300
line agents, the WFSBP guidelines[6] also recommend TCAs and Nortriptyline 25 50 - 150
SNRIs as first-line options for severe depression. The RANZCAP Protriptyline 10 15 - 60
guidelines[4] suggest a TCA or venlafaxine, an SNRI, as first-line
Tetracyclics
treatment with lesser evidence for use of the SSRIs as first-line
Amoxapine 50 100 - 400
therapy. The RANZCAP guidelines also recommend the use of
phenelzine or CBT for depression with atypical features. The BAP Maprotiline 50 100 - 225
guidelines[63] do not consider psychotherapy alone as adequate for Selective serotonin reuptake inhibitors (SSRIs)
acute severe depression and recommend the use of an antidepressant Citalopram 20 20 - 40
as a first line. The aforementioned guidelines do not consider Escitalopram 10 10 - 20
repetitive transcranial magnetic stimulation (rTMS), vagal nerve Fluoxetine 20 20 - 60
stimulation (VNS), hypericum extract (St John’s wort) or omega 3
Fluvoxamine 50 50 - 300
supplementation as first-line treatments for severe depression, but
Paroxetine 20 20 - 50
consider light therapy as first-line treatment for seasonal affective
disorder (SAD). Sertraline 50 50 - 200
Dopamine-norepinephrine reuptake inhibitors (NDRIs)
4.4 Pharmacological treatment Bupropion 150 150 - 300
Dosage ranges for antidepressant medications are summarised in Bupropion, sustained 150 150 - 300
Table 3.[1] In order to improve tolerability, it may be necessary to release
initiate the patient on a subtherapeutic dose of an antidepressant Bupropion, extended 150 150 - 300
release
(e.g. 10 mg fluoxetine) with gradual titration up to therapeutic dose
Serotonin-norepinephrine reuptake inhibitors (SNRIs)
levels. A medication trial should be of adequate dose and duration
(i.e. 8 - 12 weeks). Cognisance should be taken of pharmacodynamic Duloxetine 40 40 - 60
and pharmacokinetic properties of the selected antidepressant, and Venlafaxine 37.5 75 - 375
the expectation that efficacy may only be achieved following several Venlafaxine, extended 37.5 75 - 225
weeks of treatment. The principle of ‘what gets you well, keeps you release
well’ should be kept in mind. Serotonin modulators
The patient should be monitored at regular intervals (fortnightly) Trazodone 50 75 - 400
to assess clinical status, response, side-effects, and safety, including Norepinephrine-serotonin modulator (NaSSA)
worsening or emergence of suicidal ideation. Response can be Mirtazapine 15 15 - 45
assessed using a measurement-based tool such as the Clinical Global
Monoamine oxidase inhibitors (MAOIs)
Impressions Scale (CGI). In addition to monitoring response of
Irreversible, nonselective
depressive symptoms, overall change in functioning, disability and
subjective well-being should also be ascertained. If side-effects Phenelzine 15 15 - 90
are intolerable, the patient should be switched to an alternative. Tranylcypromine 10 30 - 60
Mirtazapine and bupropion, for example, may be useful in patients Isocarboxazid 20 30 - 60
who experience SSRI-induced sexual dysfunction. Reversible MAOI-A
In general benzodiazepines (which do not have specific antidepressant Moclobemide 300 300 - 600
effects) are not recommended as monotherapy and should be used
Melatonergic agonist
judiciously as short-term adjunctive therapy (i.e. not longer than 4
weeks) to manage symptoms of anxiety, insomnia, and agitation[66] Agomelatine 25 25 - 50
on an as-needed basis. Benzodiazepines should be avoided in patients *Reprinted with permission from APA Practice Guideline for the Treatment of Patients with Major
Depressive Disorder, 3rd ed, © 2010). American Psychiatric Association. For educational purposes only.
with comorbid substance-use disorders.

August 2013 Vol. 19 No. 3 - SAJP 160

GUIDELINE
4.5 Continuation and maintenance treatment
According to APA guidelines, the continuation phase is defined as the
16 - 20-week period that precedes sustained and complete remission
from the acute phase. To prevent relapse, antidepressant medication
should be continued at the same dose used during the acute phase.
The aforementioned guidelines recommend that the frequency
of visits be dictated to by the patient’s condition and the specific
treatment. Frequency can vary from once every 2 - 3 months to a few
times per week.
On average, 50 - 85% of patients with a single episode of MDD will
have at least one more episode. Therefore, following the continuation
phase, maintenance phase treatment should be considered to prevent
episodic recurrences. The following issues need to be borne in mind
when considering maintenance treatment:
• The risk of recurrence (based on the number of previous episodes,
presence of comorbid conditions, and residual symptoms between
active episodes)
• The severity of episode(s) (based on the presence of suicidality,
psychotic features, level of functional impairment)
• Side-effects associated with continuous treatment
• Patient preference.
The precise timing and methods of discontinuing psychotherapy
and pharmacotherapy for depression have not been systematically
evaluated. The decision to discontinue maintenance treatment
should be based on the same factors guiding the decision to initiate
maintenance treatment, including the probability of recurrence, the
frequency and severity of past episodes, the persistence of depressive
symptoms after recovery, the presence of comorbid disorders, and
patient preference.
4.6 Non-pharmacological treatment
Non-pharmacological alternatives include psychotherapy (e.g. CBT,
IPT) and newer alternatives that work on the basis of electric currents
or magnetic impulses such as ECT, rTMS, VNS, and deep brain
stimulation (DBS). Both CBT and IPT have been shown to be effective
in acute depression (as monotherapy in mild depression and as
augmentation in moderate and severe depression), and in preventing
relapse and recurrence.[65] ECT should be considered in patients with
severe depression, in patients with depression with psychotic features,
and in special circumstances or emergency situations.[67] rTMS, VNS
and DBS are not recommended as first- or second-line treatments in
MDD.
4.7 Special populations
4.7.1 Subtypes
MDD may present with melancholia, with psychotic features,
with atypical features, with catatonia, or as SAD. MDD with
melancholic features is characterised by anhedonia, lack of reactivity
to pleasurable stimuli and typical neurovegetative features such
as worsening of mood in the morning, early morning waking,
and marked weight loss.[1] Although data are inconsistent, there is
some evidence that venlafaxine and TCAs may be more effective
than SSRIs for this depressive subtype. As mentioned previously,
depression with psychotic features responds to the addition of an
antipsychotic; however ECT is also an effective first-line option.[67]
161 SAJP - August 2013 Vol. 19 No. 3
Atypical depression is characterised by mood reactivity, significantly
decreased energy or leaden feelings in the limbs (leaden paralysis),
heightened sensitivity to interpersonal rejection, and a reversal of
neurovegetative symptoms (increased sleep and appetite). SSRIs
are considered first-line agents but monoamine oxidase inhibitors
(MAOIs) are also effective (the latter have demonstrated superior
efficacy to the TCAs).[68] In these patients, it is important to consider
medication that has a lower propensity for sedation or weight gain
or a switch to mania. SAD, a subtype characterised by autumn/
winter depressive episodes and spring/summer hypomanic episodes,
responds to both antidepressants (e.g. SSRIs) and light therapy. Both
of the aforementioned treatments may be used as first-line, either
separately or in combination.[69] The extended release formulation
of bupropion is US Food and Drug Administration (FDA)-approved
for use in patients with this subtype (i.e. seasonal MDD). In patients
with catatonia, ECT has been shown to be effective. [70] Intravenous
administration with a benzodiazepine (e.g. lorazepam, diazepam)
may also induce rapid relief.[71]
4.7.2 Comorbidity
Patients with coexisting dysthymic disorder usually have a better
response to a combination of an antidepressant and psychotherapy
than to either treatment alone. In patients with comorbid anxiety
disorders, SSRIs or SNRIs are a good first choice.[72] In addition, short-
term augmentation with a benzodiazepine may be warranted and
may also assist in enhancing compliance. In patients with comorbid
panic disorder, it is prudent to start off with lower dose of an SSRI;
in patients with comorbid obsessive-compulsive disorder (OCD) a
serotonergic agent (SSRI or clomipramine) is advised; and in patients
with comorbid social anxiety disorder, an SSRI or venlafaxine but not
a TCA should be used.[73,74] Psychotherapies such as CBT, behavioural
therapy, and IPT may also be used to treat anxiety disorders and
symptoms in this setting. Substance use disorders are often comorbid
with MDD and in these patients an SSRI would be a good option
although it may be necessary to detoxify these patients and then treat
the substance use disorder first. For patients with comorbid borderline
personality disorder, an SSRI or SNRI, should be considered. The
behavioural impulsivity and dyscontrol can also be treated with a low-
dose antipsychotic, lithium, or an antiepileptic medication.[75]
In patients with comorbid medical disorders, the choice of
antidepressant medication and the potential for multiple interactions
with other medications need careful consideration; for example,
in patients with cardiac disease TCAs should be avoided while
in patients with stroke or epilepsy an SSRI is preferred.[76] In
HIV-infected patients, SSRIs are a preferred choice and are better
tolerated than TCAs. For those patients on antiretroviral treatment,
it is important to check for potential drug-drug interactions when
choosing an antidepressant.[77]
4.7.3 Suicidality
Debate about the risks of suicidal ideation and attempts following
the initiation of antidepressant treatment continues. It is well known
that as mood begins to improve on antidepressant treatment, so too
do neurovegetative symptoms, energy and psychomotor activity.
Patients may, therefore, act on pre-existing suicidal intent.[78] Recent
meta-analyses of data from clinical trials have shown a statistically

significant increase in suicidal thoughts or behaviours in depressed
individuals aged 25 years or younger treated with antidepressant
medications, compared with placebo, with a 1.5- to 2.5-fold increase
in the relative risk.[79,80] In contrast, no change in risk was detected for
adults aged 25 to 64 years, while older adults (aged 65 years or older)
on antidepressant treatment showed a decrease in the risk of suicidal
thinking or behaviours. All antidepressants, in accordance with an
FDA directive, carry a black-box warning that advises of the increased
risk of suicidal thinking and behaviour pertaining to children,
adolescents, and young adults.[81]
4.7.4 Pregnancy and lactation
Both antidepressant use and untreated depression in pregnancy
carry their own set of risks. Any decision to commence, continue, or
discontinue an antidepressant needs to weigh up the risks and the
benefits to mother and infant. Furthermore, it is important to bear
in mind that relapse rates for women with a history of MDD are high
during pregnancy, especially when antidepressants are discontinued.[82]
The risk of teratogenicity with antidepressants following first-
trimester exposure appears to be low overall. However, some rare
birth defects have been observed to occur at higher rates with the use
of specific SSRIs. For example first-trimester paroxetine exposure has
been associated with cardiac malformations, a finding that resulted
in changes in FDA labelling for paroxetine. Although most earlier
reports[83] suggested that SSRIs were not associated with a greater risk
of congenital malformation, Chambers et al.[84] have since shown that
SSRIs can adversely affect fetal development. Antidepressant use in
late pregnancy has been shown in some, but not all, studies to result
in medical complications such as prematurity and transient neonatal
withdrawal/adaptation syndrome.
ECT is both safe and effective during pregnancy and should be
considered in pregnant women with moderate to severe depression
who are unresponsive to, or unsuitable for, pharmacotherapy, for
pregnant patients with psychotic features, and for pregnant patients
who prefer this modality. MDD with postpartum onset is defined, in
the DSM-IV-TR, as a major depressive episode with onset within 4
weeks of delivery. Antidepressants can be prescribed for postpartum
depression, in accordance with the same treatment principles
delineated for other types of MDD.[85]
While long-term evidence on the risks and benefits of antidepressant
use during lactation are as yet not available, existing data suggest that
antidepressants are compatible with breastfeeding. There have been
case reports of adverse effects in breastfeeding infants exposed to
maternal antidepressants but most studies have indicated low levels
of exposure via breast milk with the SSRIs. The exception to this is
fluoxetine, which appears to have a dose-related risk for detectable
levels in infant sera.[86]
4.8 Managing partial and non-response
Medication response may take 6 - 8 weeks or longer. If a first-line
treatment has not worked after 8 weeks at an optimal dose (i.e.
there is no response), most guidelines recommend a re-evaluation
of symptoms and adverse effects before switching to another
antidepressant from another class; for example, if a patient has had a
trial of an SSRI then one should consider switching to an SNRI or to
mirtazapine or bupropion.[87]
GUIDELINE
If a first-line treatment has partially worked (i.e. there is a partial
response), then it is important to ensure that the patient is adherent
and not experiencing intolerable side-effects. In this instance, the dose
should be increased. If there is still no response after 4 - 6 weeks, it is
prudent to consider combining the existing antidepressant with another
antidepressant with a different mechanism of action (e.g. combining
bupropion or mirtazapine with an SSRI, combining an SSRI with a TCA,
combining venlafaxine with mirtazapine). Alternatively, augmentation
strategies can be tried. These include the addition of lithium, an atypical
antipsychotic, triiodothyronine (T3) or mianserin.[88]
5. Summary points
• First-line treatment for mild to moderate depression should consist
of psychotherapy (CBT or IPT) either alone or in combination with
an SSRI, an SNRI (e.g. venlafaxine), bupropion, mirtazapine or
agomelatine.
• For severe depression, always consider an antidepressant as first-
line (an SSRI, venlafaxine (SNRI), bupropion or mirtazapine) in
combination with CBT or IPT, or alternatively consider ECT.
• Severe major depression with psychotic features warrants a
combination of an antidepressant with an antipsychotic. ECT
should also be considered. Consider a combination of either a
tertiary amine tricyclic antidepressant with an antipsychotic agent
(either a first- or second-generation antipsychotic); an SSRI in
combination with an antipsychotic; or venlafaxine in combination
with an antipsychotic.
• Choice of medication should be based on patient profile, side-
effect profile, medication availability, nature of prior response to
medication, comorbid psychiatric and medical conditions, patient
preference, potential drug interactions and cost.
• If a patient presents without comorbidities and has had a previous
satisfactory response to an SSRI, consider initiating treatment with a
SSRI. If a patient presents with a comorbid anxiety or pain disorder,
consider initiating treatment with an SSRI, SNRI or mirtazapine.
• Monitor patients initially at least fortnightly and continue
medication treatment for 4 - 6 weeks.
• If remission is achieved, continuation treatment is warranted.
• With partial responders but not full remitters, increase the dose and
continue for a further 4 - 6 weeks and reassess.
• With no response, choose to: (i) switch to another first-line
medication from a different pharmaceutical class; (ii) augment
with any one of the following: lithium, triiodothyronine (T3), an
antipsychotic agent, an anticonvulsant/mood stabiliser; or (iii)
combine an SSRI with a TCA, an SSRI with bupropion, an SSRI with
mirtazapine, or venlafaxine with mirtazapine.
References
1. American Psychiatric Association. Practice Guideline for the Treatment of Patients With Major
Depressive Disorder, 2nd ed. Am J Psychiatry 2000;157:1-45.
2. Canadian Psychiatric Association. Canadian Network for Mood and Anxiety Treatments (CANMAT).
Clinical guidelines for the treatment of depressive disorders. Can J Psychiatry 2001;46(Suppl 1):5S-90S.
3. National Institute for Health and Clinical Excellence. Depression: the Treatment and Management of
Depression in Adults. 2009. http://www.nice.org.uk/CG90. (accessed 6 August 2013).
4. Royal Australian and New Zealand College of Psychiatrists, Clinical Practice Guidelines Team for
Depression. Australian and New Zealand Clinical Practice Guidelines for the Treatment of Depression.
Aust N Z J Psychiatry 2004;38:389-407.
5. Suehs BT, Argo TR, Bendele SD, et al. Texas Medication Algorithm Project Procedural Manual: Major
Depressive Disorder Algorithms. 2008. Austin: Texas Department of State Health Services http://www.
dshs.state.tx.us/mhprograms/disclaimer.shtm (accessed August 2013).
6. Bauer M, Bschor T, Pfennig A, et al, for the WFSBP Task Force on Unipolar Depressive Disorders. World
Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for biological treatment of unipolar
depressive disorders in primary care. World Journal of Biological Psychiatry 2007;8:67-104.
August 2013 Vol. 19 No. 3 - SAJP 162
GUIDELINE
7. Anderson IM, Ferrier IN, Baldwin RC, et al. Evidence-based guidelines for treating depressive disorders
with antidepressants: A revision of the 2000 British Association for Psychopharmacology guidelines. J
Psychopharmacol 2008;22:343-396.[http://dx.doi.org/1177/0269881107088441]
8. Klerman GL, Weissman MM. The course, morbidity, and costs of depression. Arch Gen Psychiatry
1992;49:831-834.
9. Mintz J, Mintz LI, Arruda MJ, Hwang SS. Treatments of depression and functional capacity to work.
Arch Gen Psychiatry 1992;49:761-768.
10. Judd LL, Akiskal HS, Zeller PJ, et al. Psychosocial disability during the long-term course of unipolar
major depressive disorder. Arch Gen Psychiatry 2000;57:375-380.
11. Hirschfeld RM, Montgomery SA, Keller MB, et al. Social functioning in depression: a review. J Clin
Psychiatry 2000;61:268-275.
12. Murray CJL, Lopez AD. Global mortality, disability, and the contribution of risk factors: Global Burden
of Disease Study. Lancet 1997;349:1436-1442.
13. Murray CJL, Lopez AD. Alternative projections of mortality and disability by cause 1990-2020: Global
Burden of Disease Study. Lancet 1997;349:1498-1504.
14. Wittchen HU. Epidemiology of affective disorders. In: Helmchen H, Henn F, Lauter H, Sartorius N, eds.
Contemporary Psychiatry, Vol. 3. Heidelberg: Springer, 2000:231-241.
15. Regier DA, Narrow WE, Rae DS, et al. The de facto US mental and addictive disorders service system.
Epidemiologic catchment area prospective 1-year prevalence rates of disorders and services. Arch Gen
Psychiatry 1993;50:85-94.
16. Kessler RC, McGonagle KA, Zhao S, et al. Lifetime and 12-month prevalence of DSM-III-R psychiatric
disorders in the United States. Arch Gen Psychiatry 1994;51:8-19.
17. Picinelli M, Gomez Homen F. Gender differences in the epidemiology of affective disorders and
schizophrenia. Geneva: World Health Organization, 1997.
18. Williams DR, Herman A, Stein DJ, et al. Twelve-month mental disorders in South Africa: prevalence,
service use and demographic correlates in the population-based South African Stress and Health Study.
Psychol Med 2008;38:211-220.
19. Angst J, Preisig M. Course of a clinical cohort of unipolar, bipolar and schizoaffective patients. Results of
a prospective study from 1959 to 1985. Schweizer Archiv fur Neurologie und Psychiatrie 1995;146:5-16.
20. Maier W, Gaensicke M, Freyberger HJ, et al. Generalized anxiety disorder (ICD-10) in primary care
from a cross-cultural perspective: A valid diagnostic entity? Acta Psychiatr Scand 2000;101:29-36.
21. Sullivan PF, Neale MC, Kendler KS. Genetic epidemiology of major depression: Review and meta-
analysis. Am J Psychiatry 2000;157:1552-1562.
22. Melartin T, Rytsala H, Leskela U, et al. Current comorbidity of psychiatric disorders among DSM-IV
major depressive disorder patients in psychiatric care in the Vantaa Depression Study. J Clin Psychiatry
2002;63:126-134.
23. Zimmerman M, Chelminski I, McDermut W. Major depressive disorder and axis I diagnostic
comorbidity. J Clin Psychiatry 2002;63:187-193.
24. Wells KB, Stewart A, Hays RD, et al. The functioning and well-being of depressed patients. Results from
the Medical Outcomes Study. JAMA 1989;262:914-919.
25. Agency for Health Care Policy and Research (AHCPR). Evidence Report on Treatment of Depression:
Newer Pharmacotherapies. San Antonio Evidence-Based Practice Center. Washington, DC: AHCPR,
Evidence-Based Practice Centers, 1999,AHCPR pub. No. 99-E014.
26. Unützer J, Patrick DL, Diehr P, et al. Quality adjusted life years in older adults with depressive symptoms
and chronic medical disorders. Int Psychogeriatr 2000;12:15-33.
27. Rihmer Z. Suicide and bipolar disorder. In: Zarate CA, Manji HK, eds. Bipolar Depression: Molecular
Neurobiology, Clinical Diagnosis and Pharmacotherapy. Basel: Birkhauser Verlag, 2009:47-56.
28. Angst J. Suicide risk in patients with major depressive disorder. J Clin Psychiatry 1999;60(Suppl 2):57-62.
29. Bostwick JM, Pankratz VS. Affective disorders and suicide risk: A reexamination. Am J Psychiatry
2000;157:1925-1932.
30. Wulsin LR, Vaillant GE, Wells VE. A systematic review of the mortality of depression. Psychosom Med
1999;61:6-17.
31. Brunello N, Burrows GD, Jönsson CPB, et al. Critical issues in the treatment of affective disorders.
Depression 1995;3:187-198.
32. Booth BM, Zang M, Rost KM, et al. Measuring outcomes and costs for major depression.
Psychopharmacology Bulletin 1997;33:653-658.
33. Wells KB, Hays RD, Burnam MA, et al. Detection of depressive disorder for patients receiving prepaid or
fee-for service care. Results from the Medical Outcomes Study. JAMA 1989;262:3298-3302.
34. Üstün TB, Sartorius N. Mental Illness in General Health Care: An International Study. Chichester:
Wiley, 1995.
35. Unützer J, Simon G, Belin TR, et al. Care for depression in HMO patients aged 65 and older. J Am
Geriatr Soc 2000;48:871-878.
36. Young AS, Klap R, Sherbourne CD, Wells KB. The quality of care for depressive and anxiety disorders in
the United States. Arch Gen Psychiatry 2001;58:55-61.
37. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth
Edition, Text Revision (DSM-IV-TR). Washington, DC: American Psychiatric Association, 2000.
38. World Health Organization. Manual of the International Statistical Classification of Diseases, Injuries,
and Causes of Death, Tenth Revision. Geneva: World Health Organization, 1992.
39. Solomon DA, Keller MB, Leon AC, et al. Recovery from major depression. A 10-year prospective follow-
up across multiple episodes. Arch Gen Psychiatry 1997;54:1001-1006.
40. Keller MB, Lavori PW, Rice J, et al. The persistent risk of chronicity in recurrent episodes of nonbipolar
major depressive disorder: A prospective follow up. Am J Psychiatry 1986;143:24-28.
41. Mueller TI, Leon AC, Keller MB, et al. Recurrence after recovery from major depressive disorder during
15 years of observational follow-up. Am J Psychiatry 1999;156:1000-1006.
42. Angst J. Major depression in 1998: Are we providing optimal therapy? J Clin Psychiatry 1999:60(Suppl
6):5-9.
43. Judd LL, Akiskal HS, Maser JD, et al. A prospective 12-year study of subsyndromal and syndromal
depressive symptoms in unipolar major depressive disorders. Arch Gen Psychiatry 1998;55:694-700.
44. Judd LL, Paulus MJ, Schettler PJ, et al. Does incomplete recovery from first lifetime major depressive
episode herald a chronic course of illness? Am J Psychiatry 2000;157:1501-1504.
45. Angst J. The course of affective disorders. Psychopathology 1986;19(Suppl 2):47-52.
46. Scott J. Chronic depression. Br J Psychiatry 1988;153:287-297.
47. Paykel ES. Epidemiology of refractory depression. In: Nolen WA, Zohar J, Roose SP, Amsterdam JD,
eds. Refractory Depression: Current Sstrategies and Future Directions. Chichester: Wiley,1994:3-17.
48. Gelenberg AJ. Using assessment tools to screen for, diagnose, and treat major depressive
disorder in clinical practice. J Clin Psychiatry 2010;71(Suppl E1):e01. [http://dx.doi.org/10.4088/
JCP.9058se1c.01gry]
163 SAJP - August 2013 Vol. 19 No. 3
49. First MB, Spitzer RL, Gibbon M, Williams JBW. Structured clinical interview for DSM-IV-TR
Axis I disorders, Research Version, Non-patient Edition (SCID-I/NP). New York: Biometrics
Research, New York State Psychiatric Institute, 2002.
50. Sheehan DV, Lecrubier Y, Sheehan KH, et al. The Mini-International Neuropsychiatric Interview
(M.I.N.I.): The development and validation of a structured diagnostic psychiatric interview for
DSM-IV and ICD-10. J Clin Psychiatry 1998;59(Suppl 20):22-33.
51. Kroenke K, Spitzer R, et al. The PHQ-9: Validity of a brief depression symptom severity measure.
J Gen Intern Med 2001;16:606-613.
52. Spitzer RL, Williams JBW, Kroenke K, et al. Utility of a new procedure for diagnosing mental
disorders in primary care: the PRIME-MD 1000 Study. JAMA 1994;272:1749-1756.
53. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;23:56-62.
54. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J
Psychiatry 1979;134:382-389.
55. Rush AJ, Trivedi MH, Ibrahim HM, et al. The 16-Item Quick Inventory of Depressive
Symptomatology (QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): A psychometric
evaluation in patients with chronic major depression. Biol Psychiatry 2003;54:573-583.
56. Beck AT, Ward CH, Mendelson M, et al. An inventory for measuring depression. Arch Gen
Psychiatry 1961;4:561-571.
57. O’Donovan C. Achieving and sustaining remission in depression and anxiety disorders:
Introduction. Can J Psychiatry 2004;49 (Suppl 1):5S-9S.
58. Judd L, Schettler P, Akiskal H. The prevalence, clinical relevance, and public health significance of
subthreshold depressions. Psychiatr Clin North Am 2002;25:685-698.
59. Parikh S, Lam R. Clinical guidelines for the treatment of depressive disorders, I. Definitions,
prevalence, and health burden. Can J Psychiatry 2001;46(Suppl 1):13S-20S.
60. National Institute of Mental Health. Sequenced Treatment Alternatives to Relieve Depression.
2002. Bethesda, MD: National Institute of Mental Health, 2002. http://www.edc.gsph.pitt.edu/
stard/public/index.html-ssi.
61. Nutt D. Treatment of depression and concomitant anxiety. Eur Neuropsychopharmacol
2000;10(Suppl 4):S433-437.
62. Davidson JRT. Major depressive disorder treatment guidelines in America and Europe. J Clin
Psychiatry 2010;71(Suppl E):e04.
63. Anderson IM, Nutt DJ, Deakin JF. Evidence-based guidelines for treating depressive disorders
with antidepressants: A revision of the 1993 British Association for Psychopharmacology
Guidelines. J Psychopharmacol 2000;14:3-20.
64. Baldwin R, Wild R. Management of depression in later life. Advances in Psychiatric Treatment
2004;10:131-139. [http://dx.doi.org/10.1192/apt.10.2.131]
65. Nutt DJ, Davidson JR, Gelenberg AJ, et al. International consensus statement on major depressive
disorder. J Clin Psychiatry 2010;71(Suppl E1):e08. [http://dx.doi.org/10.4088/JCP.9058se1c.08gry]
66. Birkenhager TK, Moleman P, Nolen WA. Benzodiazepines for depression? A review of the literature.
Int Clin Psychopharmacol 1995;10:181-195.
67. Nemeroff CB, Heim CM, Thase ME, et al. Differential responses to psychotherapy versus
pharmacotherapy in patients with chronic forms of major depression and childhood trauma.
Proc Natl Acad Sci U S A 2003;100:14293-14296.
68. Pae C-U, Tharwani H, Marks DM, et al. Atypical Depression: A Comprehensive Review. CNS
Drugs 2009;23:1023-1037.
69. Westrin A, Lam RW. Seasonal affective disorder: A clinical update. Ann Clin Psychiatry
2007;19:239-246.
70. Young JL, Rund D. Psychiatric considerations in patients with decreased levels of consciousness.
Emerg Med Clin North Am 2010;28:595-609.
71. Bush G, Fink M, Petrides G, et al. Catatonia II. Treatment with lorazepam and electroconvulsive
therapy. Acta Psychiatr Scand 1996;93:137-143.
72. Montgomery Sa, Judge R. Treatment of depression with associated anxiety: Comparisons of tricyclic
antidepressants and selective serotonin reuptake inhibitors. Acta Psychiatr Scand 2000;403:9-16.
73. Schneier FR, Blanco C, Campeas R, et al. Citalopram treatment of social anxiety disorder with
comorbid major depression. Depress Anxiety 2003;17:191-196.
74. Jefferson JW. Social Anxiety Disorder: More than just a little shyness. Primary Care Companion to
J Clin Psychiatry 2001;3:4-9.
75. American Psychiatric Association. Practice guideline for the treatment of patients with borderline
personality disorder. Am J Psychiatry 2001;158:1-52.
76. Levenson JL. Depression in the medically ill. Primary Psychiatry 2005;12:22-24.
77. Yanofski J, Croarkin P. Choosing antidepressants for HIV and AIDS patients: Insights on safety
and side effects. Psychiatry 2008;5:61-66.
78. Teicher MH, Glod CA, Cole JO.Antidepressant drugs and the emergence of suicidal tendencies.
Drug Safety 1993;8:186-212.
79. Hammad TA. Review and evaluation of clinical data. Washington, DC: Food and Drug
Administration, 2004. http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4065b1-10-
TAB08-Hammads-Review.pdf.
80. Hammad TA, Laughren T, Racoosin J. Suicidality in pediatric patients treated with antidepressant
drugs. Arch Gen Psychiatry 2006;63:332-339.
81. Gibbons RD, Brown CH, Hur K, et al. Relationship between antidepressants and suicide attempts:
An analysis of the veterans health administration data sets. Am J Psychiatry 2007;164:1044-1049.
82. Kalra S, Born L, Sarkar M, Einarson A. The safety of antidepressant use in pregnancy. Exp Opin
Drug Saf 2005;4:273-284.
83. Eberhard-Gran M, Eskild A, Opjordsmoen S. Treating mood disorders during pregnancy: Safety
considerations. Drug Saf 2005;28:695-706.
84. Chambers CD, Hernandez-Diaz S, Van Marter LJ, et al. Selective serotonin-reuptake inhibitors
and risk of persistent pulmonary hypertension of the newborn. New Engl J Med 2006;354:579-
587.
85. Wisner KL, Parry BL, Piontek CM. Postpartum depression. New Engl J Med 2002;347:194-199.
86. Kohen D. Psychotropic medication and breast-feeding. Advances in Psychiatric Treatment
2005;11:371-379.
87. Hirschfeld RMA, Montgomery SA, Aguglia E, et al. Partial response and nonresponse
to antidepressant therapy: Current approaches and treatment options. J Clin Psychiatry
2002;63:826-837.
88. Fava M, Rush AJ. Current status of augmentation and combination treatments for major
depressive disorder: A literature review and a proposal for a novel approach to improve practice.
Psychother Psychosom 2006;75:139-153.

Bipolar disorder
F Colin
1. Introduction
Bipolar disorder (BD) presents in different phases over time and is often
complicated by comorbid conditions such as substance-use disorders
and anxiety disorders. Treatment usually involves pharmacotherapy
with combinations of different classes of medications and frequent
medication revisions.
Since practice recommendations or treatment guidelines cannot
fully summarise the myriad of presentations, they need to be used
flexibly, taking into account the individual patient, the sociocultural
context and the availability of treatment resources. The Medicines
Control Council (MCC) in South Africa often lags behind other
international regulatory agencies regarding the registration of
medications with confirmed efficacy for indications in BD and
therefore clinicians have to prescribe certain drugs off-label in the
treatment of routine, difficult and treatment-resistant cases of BD.
In this guideline, levels of evidence derived from studies will be
explored.[1] Evidence criteria include:
• Level 1: meta-analysis or replicated double-blind (DB), randomised
controlled trial (RCT) with a placebo condition
• Level 2: at least one DB-RCT with active comparison condition or
placebo
• Level 3: prospective uncontrolled trial with at least ≥10 participants
• Level 4: anecdotal reports or expert opinion.
This guideline makes treatment recommendations:[1]
• First line: level 1 or level 2 evidence plus clinical support for safety
and efficacy
• Second line: level 3 evidence or higher plus clinical support for
safety and efficacy
• Third line: level 4 evidence or higher plus clinical support for safety
and efficacy
• Not recommended: level 1 or level 2 evidence for lack of efficacy.
1.1 Epidemiology of bipolar disorder pertinent to the
treatment guideline[2-5]
1.1.1 Epidemiological statistics
For bipolar I disorder, the mean reported age of the first mood
episode is 18.2 years, while the lifetime prevalence is 1%. For bipolar
II disorder, the mean reported age of first mood episode is 20.3 years,
while the lifetime prevalence is 1.1%. Bipolar I disorder affects men
and women equally, while bipolar II disorder is more common in
women.[3,4]
1.1.2 Illness characteristics
The first symptoms of BD often present at 15 - 19 years of age. The
most likely first episode, and also predominant phase in the later
stages of the illness, is depression. Suicide is 15 times more likely in BD
patients compared to the general population, with as many as 7 - 15%
of all bipolar sufferers committing suicide. Suicide is most likely to
occur during mixed or depressive episodes.[5]
GUIDELINE
2. Diagnosis and clinical characteristics
The diagnosis should be made with rigour. As the full spectrum of the
disorder does not present itself at one point in time only, the diagnosis
should be made over time. Table 1 summarises the Diagnostic and
Statistical Manual of Mental Disorders, Fourth Edition, Text Revision
(DSM-IV-TR)[6] classification of bipolar subtypes.[7,8]
The International Society for Bipolar Disorders (ISBD) Diagnostic
Guidelines Task Force made the following recommendations for the
DSM-V and International Classification of Diseases 11th Revision
(ICD-11) for BD.[1] For BD I, the DSM-V criteria for mania should
remain similar, but for bipolar depression, the criteria should
include a probabilistic approach acknowledging the presence of: (i)
atypical depressive symptoms (hyperphagia, hypersomnia, or leaden
paralysis); (ii) psychomotor disturbance; (iii) pathological guilt or
psychotic features; and (iv) a positive family history of BD. It was
suggested that the rapid-cycling specifier for BD I should be extended
to BD II and BD not otherwise specified (NOS)(now known as Other
Specified Bipolar and Related Disorder in the DSM-V. The Task Force
also suggested modifications to the diagnostic criteria for BD II and
BD NOS to improve the identification of bipolar spectrum disorders
to include the following: (i) subthreshold hypomanic episodes, and
(ii) other signs of bipolarity without manic or hypomanic episodes
(also known as bipolar spectrum disorder). These include:
• Family history (BD, alcohol and substance use, mental illnesses,
suicides)
• Depressive symptoms (atypical, psychomotor slowing, psychosis,
seasonal)
• Course of illness (early age of onset, short duration of episodes,
greater number of episodes).
Separating major depressive disorder (MDD) and BD, particularly
BD II, can be a challenge.[2] Several reports have found that BD, in
contrast to MDD, is associated with:
• A significantly earlier age of onset
• More recurrences
Table 1. Diagnostic and Statistical Manual of Mental
Disorders, Fourth Edition, Text Revision (DSM-IV-TR)
classification of bipolar subtypes[6,7,11]
Bipolar I disorder is characterised by one or more episodes of mania
with or without major depressive episodes.
Bipolar II disorder is characterised by one or more episode of
hypomania as well as at least one major depressive episode with no
psychotic features.
Cyclothymic disorder is characterised by a low grade cycling of mood
with the presence or history of hypomanic episodes and periods of
depression that do not meet the criteria for major depressive episodes.
Bipolar disorder not otherwise specified is characterised by bipolar
symptoms that do not meet the criteria for previous subtypes.
August 2013 Vol. 19 No. 3 - SAJP 164
GUIDELINE
• Atypical and mixed depressions
• A family history of BD or completed
suicide.
A BD diagnosis is highly predicted by
mixed states, especially BD II, which has
been linked with an increased lifetime risk for
comorbid psychiatric disorders, more mood
episodes, higher rates of treatment contacts,
and lower rates of full-time employment
compared to pure states.
Once a BD diagnosis has been made, the
diagnostic formulation should identify the
episode type and the longitudinal course of
illness. Valuable clinical tools that inform
assessment and assist in monitoring and
quantifying treatment response include the
following rating scales:
• Bipolar Inventory of Symptoms Scale
(BISS)
• Structured Clinical Interview for Mood
Spectrum (SCI-MOOD)
• Young Mania Rating Scale (YMRS) for
mania
• Bipolar Depression Rating Scale (BDRS)
for bipolar depression
• Mood Disorders questionnaire.
Once the diagnosis of BD has been
confirmed, a comprehensive risk assessment
should be completed on an ongoing basis
throughout treatment. Ensuring the safety
of patients with acute mania is essential,
since there is an increased risk of aggression,
excessive spending and disinhibited
behaviour, decreased judgement and
insight, and an increased risk of suicidal
thoughts immediately after admission to,
and immediately following discharge from,
hospital. The risk to others, including to
children or other family members, should
also be considered. The appropriate venue
for treatment, i.e. inpatient or outpatient,
voluntary or involuntary, should then be
determined.
3. Recommended baseline
investigations for BD[2]
The recommended investigations should
assist clinicians in management and are not
diagnostic in nature. The list below represents
a list of possibilities to be considered where
clinically appropriate and does not represent
an exhaustive list of tests to be performed in
every patient with suspected BD.
Baseline investigations:
• Extrapyramidal side-effects: clinical assess­
ment of abnormal involuntary movements
165 SAJP - August 2013 Vol. 19 No. 3
• Cataracts: ocular examination (quetiapine logical agents for BD treatment. As illustrated
only) in Fig. 1 these terms have been chosen based
• Metabolic syndrome: on the intended therapeutic action rather
• Waist circumference than on the traditional medication class.[2]
• Body mass index Medications efficacious in the treatment
• Blood pressure of mania or hypomania include antimanic
• Fasting lipid profile (triglycerides, high- agents. Maintenance agents include those
density lipoprotein (HDL), low-density administered in the euthymic phase of BD
lipoprotein (LDL)) with proven prophylactic efficacy. Bipolar
• Fasting blood sugar depression agents, which should not be
• Screen/test: confused or used interchangeably with the term
• Full blood count antidepressants, include effective medications
• Blood chemistry: for the treatment of bipolar depression.
(i) Electrolytes Some medications have indications for
(ii) Serum creatinine multiple phases of the illness. Since there
(iii) Thyroid-stimulating hormone are very few drugs that truly meet the full
(iv) Liver function tests definition of a mood stabiliser (i.e. effective
• Prolactin levels (if indicated) for all phases of the illness), the term mood
• Substance use: urine toxicology (if stabiliser has largely fallen into disfavour.
indicated) While some antibipolar agents are efficient in
• Polycystic ovarian syndrome: the acute phase, others are more efficient in
reproductive endocrine abnormalities (if the maintenance phase.
prescribing valproate to females of child- The treatment of BD can be divided into
bearing potential) the following components:
• Pregnancy test (if indicated, especially if • Acute treatment of mania and hypomania
prescribing valproate, or carbamazepine) • Acute treatment of depression
• Test for infectious diseases (if indicated) • Maintenance treatment
• Perform: • Bipolar II disorder
• Electrocardiogram (ECG) (if prescribing • Treatment of complex bipolar presentations
lithium and age >40 years) (i.e. rapid cycling and mixed states)
• Electro-encephalograph (EEG) (if • Partial or no treatment response
indicated) • Treatment of comorbidities (i.e. anxiety
• Magnetic resonance imaging (MRI) disorders and substance-use disorders (not
(preferred)/computed tomography included in this guideline)).
(CT) – indicated in suspected organic
aetiology. 4.2 Acute treatment: bipolar mania
For acute symptoms of mania, taper and
4. Treatment cease any antidepressants or agents with
4.1 Pharmacological treatment mood-elevating properties (e.g. stimulants)
Malhi and co-authors[2] have used spe­cific and introduce general measures where
terminology to categorise the pharmaco­ possible:
Psychosis
Antimanic
Mania
Mania
Agent
Hypomania
Euthymia
Maintenance
Euthymia Agent
Depression
Depression Bipolar
Depression
Agent
Psychosis
Fig. 1. Phases of bipolar illness with matching treatment terminology.[2]
 GUIDELINE

• Reduce stimulation Behavioural disturbance:[2]

• Lower activity level
• Delay individual from making important decisions
• Maintain a structured routine.
Commence treatment with an antimanic agent (level 1). When
selecting an agent, its antimanic efficacy and tolerability, as well as
the likelihood of continuing acute treatment into maintenance phase,
should be considered. Recommendations for the pharmacological
treatment of acute mania are summarised in Table 2.[3]
4.2.1 Monotherapy[2]
Antimanic agents with evidence for efficacy in acute mania include:
• Lithium
• Valproate – the speed of action for valproate can be accelerated
using dose-loading
• Olanzapine
• Aripiprazole
• Quetiapine
• Risperidone
• Ziprasidone
• Paliperidone
• Haloperidol – haloperidol is efficacious but longer-term use
carries an increased risk of extrapyramidal side-effects (e.g. tardive
dyskinesia). Haloperidol is not recommended unless other options
have failed, as it lacks efficacy in maintenance treatment.
• To a lesser extent, carbamazepine.
4.2.2 Combination treatment[2]
In comparison to monotherapy with either lithium or valproate alone,
recent studies have shown superior efficacy of lithium or valproate
in combination with the short-term administration of an atypical
antipsychotic. If symptoms and/or behavioural disturbances are severe
or protracted, electroconvulsive therapy (ECT) (level 3) should be
considered. During ECT, discontinue lithium and anticonvulsants.
Although recent studies have indicated that anticonvulsants may be
continued during ECT without losing therapeutic efficacy of ECT, it is
advisable to discontinue anticonvulsants during ECT.
Gabapentin, lamotrigine, topiramate, phenytoin and oxcarbamazepine
are not recommended for the treatment of acute mania.
• Acute behavioural disturbance can be managed by either the short-
term use of a benzodiazepine (e.g. lorazepam) or an antipsychotic;
the concurrent use of two antipsychotics is not recommended.
• Oral administration is preferable.
• It is advisable to use an injectable atypical or a combination
of an injectable typical antipsychotic and a benzodiazepine if
intramuscular (IM) administration is necessary. RCT data support
the use of IM aripiprazole or IM olanzapine (level 2) in the
treatment of acute agitation.[1]
• IM aripiprazole (9.75 mg and 15 mg) (not available in South Africa)
is superior to placebo and comparable with IM lorazepam (2 mg).[10]
In a DBRCT, IM olanzapine 10 mg was superior to placebo and has
shown a trend toward greater improvement than IM lorazepam
2 mg.[11]
• In view of the risk of respiratory failure, olanzapine should not be
used in combination with benzodiazepines.
Psychotic mania:
• Psychosis is common and occurs in approximately 60% of acute
manic episodes.
• For acute psychotic symptoms, an antipsychotic may be employed
as adjunctive treatment, if not already being administered as an
antimanic agent.
• Atypical antipsychotics are preferred to typical antipsychotics since
they have enhanced tolerability.
4.2.3 Psychotherapy for mania
Psycho-education (PE) and family-focused therapy (FFT) are
efficacious in the prevention of mania/hypomania (and possibly
depression).[11] To prevent bipolar episodes, interpersonal social
rhythm therapy (IPSRT) and cognitive-behavioural therapy (CBT) are
probably efficacious.[11]
4.3 Acute treatment: bipolar depression
4.3.1 Pharmacotherapy for bipolar depression
In patients with bipolar depression, any agents that could exacerbate
depressive symptomatology (e.g. typical antipsychotics such as
chlorpromazine, antihypertensive agents and corticosteroids) should
be ceased.[2]

Table 2. Recommendations for pharmacological treatment of acute bipolar II depression[1]

First line Quetiapine*
Second line Lithium
Lamotrigine
Divalproex*
Lithium or divalproex + antidepressants
Lithium + divalproex
Atypical antipsychotics + antidepressants
Third line Antidepressant monotherapy (particularly for those with infrequent hypomanias), switch to alternate antidepressant
Ziprasidone*
Not recommended Risk-benefit ratio for antidepressant use in BD II is still an unresolved issue
Switch rates with antidepressants are lower in patients with BD II compared with those with BD I

*New

August 2013 Vol. 19 No. 3 - SAJP 166

GUIDELINE
First-line monotherapy treatment options for bipolar depression
include:[2]
• Quetiapine 300 - 600 mg/day
• Lamotrigine 200 - 500 mg/day
• Olanzapine 5 - 15 mg/day
• Lithium
• Valproate.
Second-line options for bipolar depression include the following
adjunctive or combination therapies:
• Adjunctive risperidone 2 - 4 mg/day
• Lithium and antidepressant combinations
• Olanzapine and fluoxetine combination
• Valproate and lithium
• Lamotrigine as an add-on to lithium.
For concurrent psychotic symptoms, atypical antipsychotics can be
used as augmentation (level 2),[2] but combining two antipsychotic
medications should best be avoided.
The benefits of conventional antidepressants such as the tricyclic
antidepressants (TCAs), selective serotonin reuptake inhibitors
(SSRIs), and serotonin and noradrenaline reuptake inhibitors (SNRIs)
in the treatment of bipolar depression is currently unclear.[2] If a
conventional antidepressant is employed for bipolar depression, it
should be concurrently administered with an antimanic maintenance
agent to diminish the possibility of switching. The antidepressant
should then gradually be tapered after 2 - 3 months of sustained
recovery.[2] In addition, antidepressants should not be prescribed in
rapid-cycling BD. Also, venlafaxine (13 - 15%) and the TCAs (7 -
11%) are associated with a relatively higher risk of inducing a manic
switch than SSRIs (0 - 4%),[11] while other agents can also precipitate
switching (e.g. psychostimulants).[2]
ECT should be considered if the risk to self or others is high, if
psychotic features are present, or if there has been a previous response
to ECT (level 3).[2]
4.3.2 Psychotherapy for bipolar depression
As there is no definitive evidence for the efficacy of psychological
therapies as BD monotherapy, these therapies are best administered
as adjunctive treatments to pharmacotherapy. There is also limited
evidence for psychological treatments in acute bipolar depression
compared to evidence for their use as maintenance-phase treatments.
CBT and FFT are efficacious, with IPSRT possibly efficacious, as
adjuncts to medication, in the treatment of bipolar depression.[11]
If a patient has severe psychomotor impairment or psychotic
features, psychological treatments are not recommended during the
acute phase.[2]
4.4 Maintenance treatment
Maintenance treatment is important once a diagnosis of BD has been
made. Indications for maintenance treatment include:[2]
• A mood episode in the past 5 years
• Two previous mood episodes over any time period
• Severe acute episodes with psychotic features, or a suicide risk
• Ongoing functional disability (level 5).
The treatment plan should be re-evaluated and attention should
be paid to factors that may increase the risk of relapse, including
comorbid conditions and psychosocial stressors. A collaborative
167 SAJP - August 2013 Vol. 19 No. 3
approach to maintenance care should be adopted. Furthermore,
both pharmacological and psychological treatment strategies should
be used to eliminate subsyndromal depressive symptoms, since
disability is closely related to the depressive component of the
illness. Psychosocial stressors should be addressed; address problem-
solving skills and the development of social support networks
(especially with chronic depressive symptoms); encourage a
healthy lifestyle (good sleep hygiene, exercise, regular routine);
treat comorbidities, particularly substance misuse; monitor clinical
response to medications, adherence and side-effects; monitor social
and occupational functioning; provide PE for the family; and address
caregiver support.[2]
4.4.1 Psychological interventions as an adjunct to medication
These appear to have the greatest benefit in reducing the risk of relapse
and can improve functioning. By targeting euthymic patients in the
maintenance phase of illness, therapeutic effects can be optimised,
but are likely to be less effective in those with a high number of
prior mood episodes (>12 episodes). There is strong evidence for
interventions that focus on the recognition of early warning signs
(level 1) and this includes:
• CBT (level 2)
• FFT (level 2)
• IPSRT (level 2)
• Group PE (level 2)
4.4.2 Maintenance pharmacotherapy[2]
As a first step, any adjunctive agents that have been used to manage
behavioural disturbance associated with an acute mood episode
should be withdrawn. As little evidence currently exists for combining
treatments, monotherapy is preferred. Medications shown to be
effective maintenance agents include:
• Lithium (level 1), mainly for preventing manic episodes
• Lamotrigine (level 2), mainly for preventing depressive episodes
• Valproate (level 2)
• Atypical antipsychotics: olanzapine (level 2)
• Aripiprazole (level 2)
• Quetiapine adjunctive to lithium or valproate (level 2).
Other atypical antipsychotics that have a limited evidence base
(restricted to small trials or retrospective data) include:
• Ziprasidone (level 3)
• Risperidone (level 3)
• Adjunctive depot risperidone (level 3)
• Adjunctive clozapine (level 3).
Selection of maintenance agents should be based on their efficacy
and tolerability profiles. In addition, consideration needs to be given
to individual patient factors (preference, past response, safety). In this
regard and to maintain therapeutic blood levels, lithium needs to be
monitored regularly (0.6 - 1.2 mmol/l). The evidence for carbamazepine
as a maintenance treatment is mixed, while there is no evidence for the
efficacy of conventional antidepressants (e.g. TCAs, SSRIs and SNRIs)
in maintenance. That said, if depressive episodes are recurrent, an
antidepressant may be considered as an adjunctive to a maintenance
agent, after carefully weighing up the benefits of prevention versus the
risk of precipitating mania or rapid cycling.[2] The recommendations
for maintenance pharmacotherapy of BD are summarised in Table 3.
 GUIDELINE

Table 3. Recommendations for maintenance pharmacotherapy Table 4. Strength of evidence for monotherapy treatments of
of bipolar disorder[1] acute bipolar II depression[1]
First line Lithium Agent Level of evidence*
Lamotrigine monotherapy (limited efficacy in
Lithium 3
preventing mania)
Anticonvulsants
Divalproex
Divalproex 3
Olanzapine
Quetiapine* Lamotrigine 3

Lithium or divalproex + quetiapine* Gabapentin 3 (-ve)

Risperidone LAI* Atypical antipsychotics
Adjunctive risperidone LAI* Olanzapine No data
Aripiprazole (mainly for preventing mania)* Risperidone No data
Adjunctive ziprasidone* Quetiapine 1
Second line Carbamazepine Ziprasidone 3
Lithium + divalproex Aripiprazole No data
Lithium + carbamazepine Clozapine No data
Lithium or divalproex + olanzapine, lithium + Antidepressants
risperidone
Antidepressant monotherapy 4
Lithium + lamotrigine
Fluoxetine 3
Olanzapine + fluoxetine
Venlafaxine 3
Third line Adjunctive phenytoin
Tranylcypromine 2
Adjunctive clozapine
Combination therapy
Adjunctive ECT
Lithium or divalproex + pramipexole 2
Adjunctive topiramate
 ithium or divalproex + SSRI or
L 2 (-ve)
Adjunctive omega-3-fatty acids bupropion
Adjunctive oxcarbazepine Lithium or divalproex + topiramate Limited evidence
Adjunctive gabapentin Atypical antipsychotic + antidepressant 3
Not recommended Adjunctive flupenthixol Lamotrigine + bupropion 4
Monotherapy with:
* Level of evidence:
Gabapentin Level 1. Meta-analysis or replicated double-blind (DB), randomised controlled
trial (RCT) with a placebo condition.
Topiramate Level 2. At least one DB-RCT with active comparison condition or placebo.
Level 3. Prospective uncontrolled trial with at least ≥ 10 participants.
Antidepressants
Level 4. Anecdotal reports or expert opinion.
LAI = long acting injection; ECT = electroconvulsive therapy.
SSRI = selective serotonin reuptake inhibitor.
*New

4.4.3 How long to treat Treatment options for rapid cycling:[2]

Treatment of BD is often lifelong, and a minimum of 6-monthly • There is a limited evidence base of effective treatments for rapid
reviews is recommended. cycling.
The strength of evidence for monotherapy treatments for acute • Current treatments appear to be less effective in countering
bipolar II depression, and for maintenance of BD II are summarised depressive symptoms than manic symptoms.
in Tables 4 and 5, respectively. Pharmacological monotherapy:
• Consider valproate (level 2)
4.5 Complex bipolar presentations • Lithium (level 2)
4.5.1 Rapid cycling[2] • Olanzapine (level 2)
This presentation is associated with higher rates of morbidity, • Lamotrigine (level 2) (primarily for BD II patients)
increased suicide risk, and poorer long-term treatment response. • Quetiapine (level 3).
It is important to screen for and, where possible, exclude factors Combination therapies:
that may precipitate or exacerbate rapid cycling: • Consider adjunctive psychological interventions (level 5) as
• Antidepressants outlined under maintenance treatments.
• Substance misuse • There is limited evidence to support combination pharmacological
• Medications treatments and this should be decided according to clinical need, e.g.:
• Medical illness, e.g. hypothyroidism. • Lithium + valproate (level 3)

August 2013 Vol. 19 No. 3 - SAJP 168

GUIDELINE

4.6 Partial or no treatment response

Table 5. Strength of evidence for the maintenance therapy of Structured rating scales employed in combination with clinical
bipolar II disorder[1] assessment can be valuable in assessing treatment response and in
Agent Level of evidence* quantifying symptom change.
Lithium 2 • Re-evaluate the diagnosis. Reassess for psychosocial stressors that
Anticonvulsants may maintain symptoms and consider alternative causes (e.g.
Divalproex 3 organic causes).
• Reassess for medical comorbidities and psychiatric comorbidities
Lamotrigine 2
(e.g. anxiety disorders, drug and alcohol use disorders, personality
Carbamazepine 3
disorders).
Gabapentin 4 • Review adherence and dosage. Reassess adherence and satisfaction
Atypical antipsychotics with treatment plan. Ensure a therapeutic dose is prescribed and
Adjunctive risperidone 3 that adequate blood levels of medication are attained when taking
Antidepressants an antidepressant.
Fluoxetine 3 Therapeutic strategies for non-response in mania:[2]
• Optimise antimanic agent:
Imipramine 2 (-)
• Check levels
Combination therapy
• Adjust dose
Lithium + imipramine 2 (-) • And/or augment
Lithium + SSRI, venlafaxine or bupropion 4 • And/or combine with another antimanic agent.
Electroconvulsive therapy 4 • Consider combination therapy. This is often used in clinical
settings where response to monotherapy has been inadequate.
* Level of evidence:
Level 1. Meta-analysis or replicated double-blind (DB), randomised controlled Head-to-head comparison studies of different combinations are
trial (RCT) with a placebo condition. scant. Combinations that have been assessed in clinical trials
Level 2. At least one DB-RCT with active comparison condition or placebo.
Level 3. Prospective uncontrolled trial with at least ≥10 participants. include:[2]
Level 4. Anecdotal reports or expert opinion. • Lithium and valproate (level 2)
SSRI = selective serotonin reuptake inhibitor • Lithium and carbamazepine (level 2)
• Lithium or valproate and olanzapine (level 2)
• Adjunctive clozapine or risperidone (level 3).
• Lithium + carbamazepine (level 3) • Substitute antimanic agent with another and/or consider ECT
• Adjunctive lamotrigine (level 5). (level 3) if episode is very severe or there is a high suicide risk.[2]
• Physical treatments: ECT (level 3). Bipolar depression: non-response:[2]
• Optimise dose (check blood levels and/or adjust dose) of medication
4.5.2 Mixed states being used and/or
Distinguish mixed states from both mania and agitated depression.[2] • Switch to alternative bipolar depression agent and/or
Studies focusing on monotherapy and adjunctive treatment options • Augment and/or combine agents
for mixed states are scant, although patients with mixed states have • Consider adjunctive psychological therapy that will target depressive
been included in trials of acute mania and acute bipolar depression. symptoms (e.g. CBT, IPSRT, FFT).
As a start, it is important to taper and cease medications with mood- • Consider using conventional antidepressants, but closely monitor
elevating properties, especially those that may induce inter-episode for switch to mania.
switching.[2] Antidepressants can worsen or induce rapid cycling and • Consider ECT (level 3) if episode is very severe, or there is marked
are thus not recommended. Lithium may have reduced efficacy for or significant risk for treatment resistance.
treating mixed states.[2] Treatment options include:[2] Treatment non-adherence is common in BD.[2] Depot treatment of
• Olanzapine (level 2) either an injectable atypical antipsychotics (level 3) (e.g. risperidone)
• Quetiapine or valproate as monotherapy or an injectable first-generation antipsychotic (level 3) should be
• Olanzapine and fluoxetine in combination considered in cases of ongoing persistent non-compliance, and
• Valproate in combination with olanzapine (level 2). after failure of other appropriate interventions.[2] A first-generation
Lamotrigine may be a useful adjunctive treatment to an antimanic depot antipsychotic is not recommended where the course of BD is
agent for depressive symptoms in mixed states, although treatment characterised predominantly by depression. [2]
effect is likely to be delayed as this requires slow titration, especially
when used in conjunction with valproate.[2] 4.7 Algorithm
ECT (level 3) may be considered if symptoms and/or behavioural Fig. 2 outlines the treatment algorithm. Please refer to Appendix A for
disturbances are severe or protracted. other aspects of treatment and management.

169 SAJP - August 2013 Vol. 19 No. 3


5. Summary points
• For acute symptoms of mania, commence
treatment with an antimanic agent.
Antimanic agents with evidence for
efficacy in acute mania include lithium,
valproate, olanzapine, aripiprazole,
quetiapine, risperidone, ziprasidone,
paliperidone, haloperidol and to a lesser
extent carbamazepine.
• Recent studies have shown superior efficacy
of lithium or valproate in combination
with the short-term administration of an
atypical antipsychotic.
• Gabapentin, lamotrigine, topiramate,
phenytoin and oxcarbamazepine are not
recommended for the treatment of acute
mania.
• If IM administration is required for
acute agitiation/behavioural control, it
is advisable to use an injectable atypical
or a combination of an injectable typical
antipsychotic and a benzodiazepine. RCT
data support the use of IM aripiprazole or
IM olanzapine for acute agitation.
• First-line monotherapy treatment options
for bipolar depression include quetiapine,
lamotrigine, olanzapine, lithium, and
valproate.
• For concurrent psychotic symptoms, both
in bipolar mania and depression, atypical
antipsychotics can be used as augmentation.
• In bipolar depression, an antidepressant
should be administered concurrently with an
anti-manic maintenance agent to reduce the
possibility of switching. The antidepressant
should then gradually be tapered after 2 - 3
months of sustained recovery.
• Antidepressants should not be prescribed
in rapid-cycling BD.
• For rapid cycling, consider valproate,
lithium, olanzapine, lamotrigine (for BD II),
or quetiapine.
• Psychotherapies are best used as adjuncts
to medication in bipolar depression. CBT
(cognitive-behaviour therapy) and family-
focused therapy (FFT) are efficacious,
with interpersonal social rhythm therapy
(IPSRT) possibly efficacious, as adjuncts
to medication, in the treatment of bipolar
depression. Adjunctive psychotherapy can
reduce the risk of relapse and improve
functioning.
• Maintenance treatment must be considered
if there has been a mood episode in the past
5 years, if there have been 2 previous mood
GUIDELINE
DSM-IV-TR diagnosis
Acute phase
Depressive episode Manic episode
Cyclothymia • Mania or hypomania with
• Mild to moderate euphoric mood
• Severe • Rapid cycling
• Depression with psychosis • Mixed or dysphoric mood
• Mania with psychosis
• Lithium and/or valporate and /or
lamotrigine and/or antideressants and/or • Lithium and/or valporate and /or typical or
mood stabiliser as required. atypical antipsychotic as required.
• If IM olanzapine is given, no benzodiazepine
• Do not give antidepressant without mood
stabiliser. must be used within 2 hours
Remission Response Poor response within 4 to 6 weeks
Continuation phase
Remission Check adherence and/or
optimize medication
Remission Utilize all three mood
stabilisers in combination
Consider
Incomplete response
electroconvulsive
therapy
Add atypical antipsychotic
and/or another mood
Remission stabiliser
Review management and
diagnosis in accordance
Maintenance phase Incomplete response with public sector practice
To maintain the patient optimally, eliminate
treatment that might cause depression or relapse Continue maintenance Relapse
Fig. 2. Bipolar disorder algorithm.[1,2]
episodes over any time period, if acute • For non-response in bipolar mania,
episodes are severe with psychotic features consider combining 2 mood stabilisers
or is there is a suicide risk, or if there is (e.g. lithium + valproate, lithium +
ongoing functional disability. carbamazepine, lithium or valproate
• Medications shown to be effective + olanzapine) or combining a mood
maintenance agents include lithium (mainly stabiliser with an atypical antipsychotic;
for preventing manic episodes), lamotrigine for non-response in bipolar depression
(mainly for preventing depressive consider switching to another bipolar
episodes), valproate, atypical antipsychotics depression agent or augmenting with
(olanzapine, aripiprazole, and quetiapine another bipolar depression agent or with
adjunctive to lithium or valproate). psychotherapy.
August 2013 Vol. 19 No. 3 - SAJP 170
GUIDELINE

References
1. Yatham L, Kennedy S, Schaffer A, et al. Canadian Network for Mood and Anxiety Treatments
(CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of
CANMAT guidelines for the management of patients with bipolar disorder: Update 2009. Bipolar
Disorders 2009;11:225-255.
2. Malhi GS, Adams D, Lampe L, et al. Clinical practice recommendations for bipolar disorder. Acta
Psychiatr Scand 2009;119:27-46.
3. Merikangas KR, Akiskal HS, Angst J, et al. Lifetime and 12-month prevalence of bipolar spectrum
disorder in the National Comorbidity Survey replication. Arch Gen Psychiatry 2007;64:543-552.
4. Leibenluft E. Women with bipolar illness: Clinical and research issues. Am J Psychiatry
1996;153:163-173.
5. Goodwin FK, Jamison K. Manic-depressive illness: Bipolar disorders and recurrent depression,
second edition. New York: Oxford University Press, 2007.
6. Ghaemi SN, Bauer M, cassidy F, et al. Diagnostic guidelines for bipolar disorder: A
summary of the International Society for Bipolar Disorders Diagnostic
Guidelines Task Force Report. Bipolar Disorders 2008;10:117-128.
7. Zimbroff DL, Marcus RN, Manos G, et al. Management of acute agitation in patients with bipolar
disorder: Efficacy and safety of intramuscular aripiprazole. J Clin Psychopharmacol 2007;27:171-
176.
8. Meehan K, Zhang F, David S, et al. A double-blind, randomized comparison of the efficacy
and safety of intramuscular injections of olanzapine, lorazepam, or placebo in treating acutely
agitated patients diagnosed with bipolar mania. J Clin Psychopharmacol 2001;21:389-397.
9. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders,
Fourth Edition, Text Revision (DSM-IV-TR). Washington, DC: American Psychiatric
Association, 2000.
10. Hollon SD, Ponniah K. A review of empirically supported psychological therapies for mood
disorders in adults. Depress Anxiety 2010;27:891-932.
11. Chen J, Fang Y, Kemp DE, et al. Switching to hypomania and mania: Differential
neurochemical, neuropsychological, and pharmacologic triggers and their mechanisms. Curr
Psychiatry Rep 2010;12:512-521.

Appendix A: Other aspects of treatment and management

1. Definition of the bipolar disorder prescribed minimum benefit as defined in the Medical Schemes Act
The chronic disease list (CDL) specifies medication and treatment for the 25 chronic medical conditions that are covered in the section on
prescribed minimum benefits. Bipolar disorder (BD) is one of the 25 conditions. The section on these conditions stipulates the following:
‘To manage risk and ensure appropriate standards of healthcare, so-called treatment algorithms were developed for the CDL conditions.
The algorithms, which have been published in the Government Gazette, can be regarded as benchmarks, or minimum standards, for
treatment. This means that the treatment your medical scheme must provide for may not be inferior to the algorithms. If you have one of
the 25 listed chronic diseases, your medical scheme not only has to cover medication, but also doctors’ consultations and tests related to
your condition. The scheme may make use of protocols, formularies (lists of specified medicines) and designated service providers (DSPs)
to manage this benefit.’

2. Indications for hospital admission

Consider hospitalisation in patients who:
• Pose a serious threat of suicide or harm to others
• Are severely ill
• Are ill and lack social support outside of a hospital
• Demonstrate significantly impaired judgment
• Have complicating general medical or psychiatric conditions
• Have not responded adequately to outpatient psychiatric treatment
• Need urgent revisions of medication treatment requiring constant supervision in hospital.

3. Guidelines for intravenous treatment

Intravenous (IV) drug treatment is rarely appropriate in the treatment of BD and may only be indicated in the following cases:
• Where taking of oral medication is not possible, as in intensive care settings
• As part of treatment of secondary syndromes related to treatment side-effects, i.e. acute dystonia
• For IV sedation of acutely agitated/manic patients
• IIV sodium valproate has been described for the initial treatment of acute mania but is not deemed a routine treatment. It may be
considered when a manic presentation poses a life-threatening risk to patient or others.

171 SAJP - August 2013 Vol. 19 No. 3


Panic disorder
C P Szabo
1. Introduction
Panic disorder (PD) is a prevalent anxiety disorder with lifetime
prevalence rates ranging from 1.1% to 3.7% in the general population
and 3.0% to 8.3% in clinic settings.[1] The presence of agoraphobia in
patients with PD is associated with substantial severity, comorbidity
(e.g. major depression, other anxiety disorders, alcohol abuse) and
functional impairment.[1] The disorder is more common in women
than in men, with a 3:1 ratio in patients with agoraphobia and 2:1 in
patients without agoraphobia. While panic attacks are a core feature of
PD, panic attacks are also experienced by patients with post-traumatic
stress disorder, social anxiety disorder and specific phobias. However,
unlike in PD, these are typically cued by exposure to or anticipation of
specific anxiety-provoking situations.[2]
2. Diagnosis and clinical characteristics
PD is an anxiety disorder characterised by recurrent panic attacks
involving intense fear/discomfort and accompanied by at least 4 of 13
somatic or cognitive symptoms which develop abruptly and reach a
peak within 10 minutes (Diagnostic and Statistical Manual of Mental
Disorders, Fourth Edition, Text Revision (DSM-IV-TR)).[2] Attacks
should not be substance-induced, nor related to a medical condition
or as a consequence of another psychiatric disorder, and should be
spontaneous in nature. Panic attacks that occur with fewer than 4 of the
13 panic symptoms are termed limited symptom attacks.[2] To make the
diagnosis of PD, at least one of the attacks must be followed by a month
or more of persistent concern regarding the possibility of a subsequent
attack, worry about the implications of the attacks and/or behavioural
change, e.g. avoidant behaviours such as agoraphobia – anxiety about
being in places from which escape might be difficult or where help
may not be available in the event of a panic attack.[2] PD may occur
with or without agoraphobia.[2] The disorder has been described as a
‘common, persistent and disabling’ condition.[3] Notwithstanding such a
description, both pharmacological and psychotherapeutic interventions
have established efficacy.
3. Assessment
Based on the clinical characteristics, and awareness of the potential
diagnostic pitfalls, i.e. substance/medically/other related psychiatric
disorders, the assessment requires not only a careful history but also
the possibility of toxic screening and physical investigation to rule out
medically or substance-related presentations.
4. Treatment
4.1 Treatment goals
The initial goal of any intervention is symptom relief together with
maintenance of functioning, followed by ongoing alleviation of
symptoms accompanied by optimal functioning. PD represents a
specific challenge, given the experience of panic attacks as events
characterised by fear and accompanied by a range of somatic
GUIDELINE
symptoms.[2] Therefore the goal remains to reduce the severity
and intensity of panic attacks, avoidance, fearful anticipation, and
cognitive distortions. Of specific relevance is the unpredictability of
episodes and the need for clinicians to meaningfully reassure patients
of the planned intervention in terms of outcome, for both future
episodes and functioning.
4.2 General aspects of treatment
Two broad categories of intervention have demonstrable efficacy,
i.e. pharmacological and psychotherapeutic. Both interventions
may serve as first-line treatments, as meta-analytic reviews and
large-scale comparative trials have shown comparable efficacy, with
high remission rates (60 - 80%) and maintenance of gains over time
for both modalities.[4] Systematic reviews have also confirmed that
a combination of the two is most effective in the acute phase with
ongoing superior effectiveness following the acute-phase treatment.
This is compared to pharmacotherapy alone; however, combination
therapy may offer only limited benefits beyond that derived from
psychotherapy alone (viz. cognitive-behavioural therapy (CBT)).
Pharmacotherapy includes the use of both antidepressant agents
and benzodiazepines. Psychotherapeutic approaches include both
cognitive and behavioural components either individually or in
combination.[5]
4.3 Pharmacological treatment: Acute
The first-line pharmacotherapy of choice in this anxiety disorder is
the selective serotonin reuptake inhibitors (SSRIs, e.g. fluoxetine/
paroxetine/fluvoxamine/sertraline/citalopram/escitalopram), or the
serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine
(including the extended-release formulation), with multiple
randomised controlled trials (RCTs) showing their efficacy and
safety.[3] PD also responds to certain other antidepressants, such as
the tricyclic antidepressants (TCAs) (while of equivalent efficacy to
SSRIs, their use is limited by side-effects).[3] Very-low-dose treatment
should be initiated in PD (e.g. fluoxetine 5 mg/venlafaxine ER 75
mg) with gradual upward titration as required. At least 6 - 8 weeks
of adequate doses of medication are required to assess whether an
acute intervention is effective or not. While such an approach appears
reasonable, the use of antidepressants as stand-alone, first-line
intervention has, on the basis of systematic review, been cautioned
against.[4] Although there is less evidence available for children/
adolescents, SSRIs may again be useful.[6,7]
Given concerns about their side-effect profile (as well as tolerance
and dependency), the use of high-potency benzodiazepines should
generally be limited to short-term augmentation of antidepressant
medication to rapidly stabilise PD symptoms.[8] Certainly the use
of combination treatment (clonazepam/sertraline) has been found
to provide rapid – and safe – stabilisation of panic symptoms.[9]
Benzodiazepines (alprazolam, clonazepam and lorazepam) are effective
August 2013 Vol. 19 No. 3 - SAJP 172
GUIDELINE
and use patterns have demonstrated that this class of drug is the most
commonly used, notwithstanding guidelines recommending SSRIs as
the preferred treatment.[10] Data regarding the use of benzodiazepine
treatment combined with psychotherapy versus benzodiazepine
treatment alone suggest superiority of combined treatment; however,
there is a paucity of good-quality evidence, either supportive or non-
supportive.[11] Of note is a systematic review that failed to identify
quality studies comparing benzodiazepines to newer antidepressants
(now regarded as the first line of pharmacological intervention),
with the suggestion that the promoted move away from first-line and
maintenance treatment with benzodiazepines has occurred without
appropriate evidence to support this approach.[12] Most typically the
benzodiazepines are seen to have value as ‘rescue’ agents, specifically
alprazolam (including the extended-release formulation),[13] in spite
of a lack of evidence-based data supporting such use, notwithstanding
clinician and patient support and preference for such use.[14]
4.4 Pharmacological treatment: Maintenance
Maintenance treatment at the same dose on which improvement
occurred should be continued for at least 1 year. Relapse rates
following discontinuation have shown varying outcomes, with rates
ranging from 25% to 50%.[2] Of particular interest is that ongoing
psychotherapy (CBT) is as effective as combination treatment
(pharmacotherapy/psychotherapy), which suggests that this may be
the preferred option in the longer term.
4.5 Non-pharmacological treatment
CBT has been shown to be effective for the treatment of anxiety
disorders in multiple RCTs.[3] CBT for PD consists of components
of psycho-education, cognitive restructuring, and behavioural
interventions, with the combination of exposure therapy, relaxation
exercises and breathing retraining providing the most consistent
evidence for efficacy.[4] The typical duration of treatment is 12 - 15
sessions, but even briefer treatments have shown efficacy.[4] The
combination of pharmacotherapy and psychotherapy may have
particular advantages (e.g. preventing relapse after medication
discontinuation) and has been suggested as a first line of treatment
(together with psychotherapy alone).[5] In addition to these more
traditional non-pharmacological interventions, the role of education,
self-management and internet-based interventions have shown
benefit and appear worthy of further study for select patients
and situations.[3] Also, the use of virtual-reality exposure therapy
represents an interesting development, although it has not been clearly
demonstrated to be superior to CBT.[3]
4.6 Special populations
Comorbidity is common among psychiatric populations. Within the
context of PD, the impact of panic symptoms in relation to outcomes
of mood disorders is of relevance, because persistent panic symptoms
appear to negatively influence treatment outcomes of major
depression.[15] Further, PD comorbid with bipolar disorder confers
an increased risk for suicide.[16] This underscores data demonstrating
that PD is independently associated with risk for suicide attempts.[16 ]
The treatment of PD among patients with comorbid bipolar disorder
represents a challenge in so far as the use of antidepressant agents
173 SAJP - August 2013 Vol. 19 No. 3
may induce mania.[17] Further, the presence of mood instability in
PD patients may worsen the condition, as well as lead to resistance
to antidepressants.[18 ]A recently published trial of sodium valproate,
at doses of 600 - 700 mg daily (commencing at 300 mg daily),
co-administered with an antidepressant or as monotherapy in
PD patients with comorbid bipolar disorder, produced symptom
remission.[18] There are limited controlled data in this regard; hence
Perugi et al.[18] provide limited but objective evidence to support the
use of mood stabilisers as treatment for PD, in both ‘antidepressant-
resistant’ sufferers as well as those with comorbid bipolar disorder.
Another population of interest are those suffering from migraine
where PD is strongly associated, with either condition impacting
on the other bidirectionally.[19] It is clear that clinical assessment
regarding comorbidity covers a range of conditions and is critical
for outcome and optimal treatment of PD. Of specific interest are
those patients with anxiety disorders, including PD, who have
comorbid substance-related conditions, specifically in relation to
benzodiazepine use. It appears that the evidence does not preclude
the use of such agents in these patients.[20]
4.7 Partial and non-responders
Reviewing the studies for pharmacological management strategies,
the majority of patients treated with a range of antidepressant
agents achieve panic-free status during a trial of medication (with
no clear cut dose-response relationship) with generally high rates
of response and somewhat lower rates of remission.[3] It should be
noted that placebo response rates of up to 50% also occur,[3] and when
existing data have been subjected to systematic review, combination
treatment (pharmacotherapy plus psychotherapy) response rates
of just over 50% have been found.[5] Most patients do respond, to
varying degrees, to active treatment with a range of interventions
that include both pharmacotherapy and psychotherapy, either alone
or in combination. Obviously when either partial or non-response is
encountered, accurate diagnosis is paramount; careful reassessment
should occur. Multiple agents, at optimal doses for adequate duration
as well as combination treatment, are all considerations when
confronted with partial or non-response – specifically combinations
of antidepressant medication and benzodiazepines. It has been
suggested that benzodiazepine use be reserved for treatment-resistant
patients,[15,21] but it appears that actual clinical practice sees the use
of benzodiazepines far more routinely and in various ways.[22] While
there are limited data related to treatment resistance, the role of mood
instability has been postulated as a factor contributing to ‘resistance
to antidepressants’ with a study of sodium valproate demonstrating
improved outcomes where used as an adjunct or as monotherapy
(doses ranging from 300 to 700 mg daily).[18] Various other agents, i.e.
gabapentin, olanzapine and quetiapine, have demonstrated efficacy
in the treatment of PD and could potentially be considered under
circumstances of partial or non-response.[17] Within this context
there has been increasing interest in the use of natural remedies for
the treatment of anxiety disorders, of which inositol has been studied
with regard to PD.[23] In the most recent of such studies inositol (18 g/
day) was compared to fluvoxamine (150 mg/day) using a double-blind
crossover approach which demonstrated equivalent overall efficacy
in the treatment of PD with inositol demonstrating superiority with

regard to reduction in the number of panic attacks.[24] Such a study
would need to be replicated before a firm recommendation could
be made. In addition, the use of cognitive enhancers in the form of
D-cycloserine (a partial agonist at the N-methyl-d-aspartate receptor)
in conjunction with exposure therapy has shown promise but this
option cannot be recommended given the paucity of data.[3]
5. Conclusion
Based on the existing data, it would appear that combination
treatment (pharmacotherapy plus psychotherapy) is the intervention
of choice, and that the judicious use of benzodiazepines together
with an antidepressant will provide the most rapid initial response.
Further combination treatment may ultimately be adequate in the
longer term for maintenance of clinical improvement. However,
maintenance should include the consideration that psychotherapy
alone may be an option following longer term treatment and
stabilisation on combination treatment. The data for partial or
non-responders are limited, but there is a suggestion that sodium
valproate may be a consideration either as an adjunctive agent or as
monotherapy, specifically if there is mood instability or comorbid
bipolar disorder.
6. Summary points
• Both pharmacological therapies and CBT are considered first-line
treatments for PD.
• Antidepressant agents have proven efficacy in the treatment of PD.
• Agents from within the SSRIs and SNRIs are the preferred
options, namely the SSRIs citalopram, escitalopram, fluvoxamine,
fluoxetine, paroxetine, sertraline and the SNRI venlafaxine.
• Adjunctive benzodiazepines have a role in treatment.
• For acute treatment, a combination of pharmacological treatment
and CBT is likely to be more effective than either therapy alone.
• CBT and pharmacotherapy are not necessarily added concurrently
– there is some evidence that adding CBT to patients previously
treated with pharmacotherapy provides good benefits.
• Treatment with psychotherapy alone may be the preferred longer-
term option.
• Acute treatment: Combination treatment (pharmacotherapy +
psychotherapy or pharmacotherapy + pharmacotherapy (e.g.
antidepressant plus benzodiazepine/sodium valproate).
• Maintenance treatment: Combination treatment or psychotherapy
alone.
• In children and adolescents with PD, there are only non-
randomised, controlled studies to support the utility of the SSRIs.
• CBT is a good alternative for women with PD who plan to become
pregnant, and for pregnant women who need to discontinue
medication.
GUIDELINE
References
1. Kessler RC, Chiu WT, Jin R, et al. The epidemiology of panic attacks, panic disorder,
and agoraphobia in the National Comorbidity Survey Replication. Arch Gen Psychiatry
2006;63:415-24. [http://dx.doi.org/10.1001/archpsyc.63.4.415]
2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders,
Fourth Edition, Text Revision (DSM-IV-TR). Washington, DC: American Psychiatric
Association, 2000.
3. Pull CB, Damsa C. Pharmacotherapy of panic disorder. Neuropsychiatric Disease and
Treatment 2008;4:779-795.
4. McHugh RK, Smits JA, Otto MW. Empirically supported treatments for panic disorder.
Psychiatr Clin North Am 2009;32:593-610. [http//:dx.doi.org/10.1016/j.psc.2009.05.005.]
5. Furukawa TA, Watanabe N, Churchill R. Psychotherapy plus antidepressant for panic disorder
with or without agoraphobia. Br J Psychiatry 2006;188:305-312. [http://dx.doi.org/10.1192/
bjp.188.4.305]
6. American Academy of Child and Adolescent Psychiatry. Practice parameters for the
assessment and treatment of children and adolescents with posttraumatic stress disorder. J Am
Acad Child Adolesc Psychiatry 1998;37S:4-26.
7. Hawkridge S, Stein DJ. Risk-benefit assessment of drug therapies for anxiety disorders in
children and adolescents. Drug Safety 1998;19:283-297.
8. Ballenger JC, Davidson JRT, Lecrubier Y, et al. Consensus statement on panic disorder from
the International Consensus Group on Depression and Anxiety. J Clin Psychiatry 1998;59:47-
54.
9. Goddard AW, Brouette T, Almai A, et al. Early coadministration of clonazepam with sertraline
for panic disorder. Arch Gen Psychiatry 2001;58:681-686. [http://dx.doi.org/10.1001/
archpsyc.58.7.681]
10. Bruce SE, Vasile RG, Goisman RM, et al. Are benzodiazepines still the medication of choice
for patients with panic disorder with or without agoraphobia? Am J Psychiatry 2003;160:1432-
1438.
11. Watanabe N, Churchill R, Furukawa TA. Combination of psychotherapy and benzodiazepines
versus either therapy alone for panic disorder: a systematic review. BMC Psychiatry
2007;7:18.
12. Berney P, Halperin D, Tango R, et al. A major change of prescribing pattern in absence of
adequate evidence: benzodiazepines versus newer antidepressants in anxiety disorders.
Psychopharmacology Bulletin 2008;41:39-47.
13. Sheehan DV, Sheehan KH, Raj BA. The speed of onset of action of alprazolam-XR compared to
alprazolam-CT in panic disorder. Psychopharmacology Bulletin 2007;40;63-81.
14. Westra HA, Stewart SH. As-needed use of benzodiazepines in managing clinical anxiety:
incidence and Implications. Current Pharmaceutical Design 2002;8:59-74.
15. 15. DeVeaugh-Geiss AM, West SL, Miller WC, et al. Depression and comorbid panic in
primary care patients. J Affect Disord 2010;123:283-290. [http://dx.doi.org/10.1016/j.
jad.2009.09.013]
16. 16. Kilbane EJ, Gokbayrak NS, Galykner I, et al. A review of panic and suicide in bipolar
disorder: does comorbidity increase risk? J Affect Disord 2009;115:1-10. [http://dx.doi.
org/10.1016/j.jad.2008.09.014]
17. 17. El-Mallakh RS, Hollifield M. Comorbid anxiety in bipolar disorder alters treatment and
prognosis. Psychiatr Q 2008;79:139-150. [http://dx.doi.org/10.1007/s11126-008-9071-5]
18. 18. Perugi G, Frare F, Toni C, et al. Adjunctive valproate in panic disorder patients with
comorbid bipolar disorder or otherwise resistant to standard antidepressants: a 3 year
‘open’ follow-up study. Eur Arch Psychiatry ClinNeurosci 2010;260:553-560. [http://dx.doi.
org/10.1007/s00406-010-0109-y]
19. 19. Nepon J, Belik SL, Bolton J, Sareen J. The relationship between anxiety disorders and
suicide attempts: findings from the national epidemiological survey on alcohol and related
conditions. Depress Anxiety 2010;27:791-798. [http://dx.doi.org/10.1002/da.20674]
20. 20. Beghi E, Bussone G, D’Amico D, et al. Headache, anxiety and depressive disorders: the
HADAS study. Journal of Headache and Pain 2010;11:141-150.
21. 21. Lader M. Management of panic disorder. Expert Review of Neurotherapeutics 2005;5:259-
266. [http://dx.doi.org/10.1007/s10194-010-0187-2]
22. 22. Posternak MA, Mueller TI. Assessing the risks and benefits of benzodiazepines for
anxiety disorders in patients with a history of substance abuse or dependence. Am J Addict
2001;10:48-68.
23. 23. Kinrys G, Coleman E, Rothstein E. Natural remedies for anxiety disorders: potential use
and clinical applications. Depress Anxiety 2009;26:259-265.
24. [http://dx.doi.org/10.1002/da.20460]
25. 24. Palatnik A, Frolov K, Fux M, Benjamin J. Double-blind, controlled, crossover trial of
inositol versus fluvoxamine for the treatment of panic disorder. J Clin Psychopharmacol
2001;21:335-339.
August 2013 Vol. 19 No. 3 - SAJP 174
GUIDELINE
Generalised anxiety disorder
D J Stein
1. Introduction
Generalised anxiety disorder (GAD) is a common disorder with
a lifetime prevalence of 6.1% and a 1-year prevalence of 2.9% in
one large study.[1] It occurs most commonly in the 45 - 55-year
age group with women twice as likely as men to have GAD.[1]
Although symptoms typically wax and wane in intensity over time,
the disorder is characterised by chronicity and is associated with
high levels of psychiatric comorbidity (e.g. major depression and
other anxiety disorders), physical comorbidity (e.g. gastrointestinal,
respiratory, and thyroid disorders) and reduced quality of life.[2]
There have been important advances in the nosology and treatment
of this disorder. In particular, there is increasing evidence that
patients with GAD and mixed anxiety-depression frequently
present in primary care settings,[3] and the Diagnostic and Statistical
Manual of Mental Disorders, Fifth Edition [4] provides fairly
user-friendly criteria for the diagnosis of GAD. Table 1 lists the
diagnositic criteria.[5]
A few simple points can perhaps be made to help conceptualise
GAD. GAD can perhaps be viewed as a ‘tension disorder’. This is
a useful term in so far as it crosses the boundary between psychic
symptoms (worries, feeling ‘keyed up’, irritability) and somatic
complaints (muscle tension, restlessness, insomnia). While GAD
patients may not present with ‘worries’, they often describe themselves
as ‘worriers’ – worry may represent an avoidance behaviour that is
used to diminish tension (analogous to the way that agoraphobia may
develop after panic attacks).
The algorithm presented here (Fig. 1)[6] provides a step-by-step
approach to the pharmacotherapy of GAD, based on our reading of the
research literature. It is important to mention at the outset, however,
that psychotherapy approaches may be a first-line intervention in
some GAD patients and should be considered in all patients with this
disorder. In addition, psycho-education is of the utmost importance,
particularly in the initial stages of treatment, and should address the
direct effects of anxiety on the life of the patient, as well as possible
effects on family members.
2. Diagnosis and clinical characteristics
GAD is characterised by chronic, excessive, difficult-to-control
worry and a range of somatic symptoms. Making the correct
diagnosis is essential. Given that GAD often presents with somatic
symptoms and comorbid psychiatric disorders, the diagnosis is
frequently overlooked. It is therefore important to establish (i)
that persistent and excessive anxiety and worry about commonly
occurring events and activities – on more days than not for at least
6 months – is present; (ii) that difficulty in controlling the worries is
concomitant with physical and psychic symptoms; (iii) that the focus
of anxiety and worry is not part of another Axis I disorder or due to
the direct physiological effects of a substance or a general medical
condition; and (iv) that clinically significant distress or functional
impairment is evident.[4]
175 SAJP - August 2013 Vol. 19 No. 3
3. Assessment
Particular attention should be paid to the evaluation of symptoms that
are chosen as targets for pharmacotherapy and to symptoms that may
point to the presence of other psychiatric disorders. It is also useful
to determine the severity of GAD symptoms using a scale such as the
Hamilton Anxiety Scale. There are a number of other screening and
assessment scales that can be used, including the 7-item GAD scale[7]
for screening for GAD and assessing severity, the Generalized Anxiety
Disorder Severity Scale (DGSS) which consists of 8 DSM-IV-TR GAD
symptoms for the assessment of symptom frequency and intensity[8]
and the Daily Assessment of Symptoms-Anxiety (DAS-A) to assess
for symptom improvement.[9] It is possible that the situation in GAD
mirrors that in depression, where less severe forms of the disorder
respond equally well to pharmacotherapy and to psychotherapy.
It is also necessary to rule out the presence of comorbid psychiatric
and medical disorders. This includes a thorough physical examination,
appropriate laboratory investigation (with attention to thyroid and
glucose function), and assessment of current use of prescription or
over-the-counter medications. Mood disorders, such as depression and
dysthymia, other anxiety disorders, and alcohol and other substance
use disorders are common in patients with GAD. In addition, attention
Table 1. Criteria for generalised anxiety disorder[5]*
A. E
 xcessive anxiety and worry (apprehensive expectation), occurring
more days than not for at least six months, about a number of events or
activities (such as work or school performance)
B. The person finds it difficult to control the worry
C. The anxiety and worry are associated with three (or more) of the
following 6 symptoms (with at least some symptoms present for more
days than not for the past 6 months:
1. Restlessness or feeling keyed up or on edge
2. Being easily fatigued
3. Difficulty concentrating or mind going blank
4. Irritability
5. Muscle tension
6. Sleep disturbance (difficulty falling or staying asleep, or restless
unsatisfying sleep)
D. †The focus of the anxiety and worry is not confined to features of an
Axis I disorder
E. The anxiety, worry, or physical symptoms cause clinically significant
distress or impairment in social, occupational, or other important areas
of functioning
F. T
 he disturbance is not due to the direct physiological effects of a
substance (e.g. a drug of abuse, a medication) or a general medical
condition (e.g. hyperthyroidism) and does not occur exclusively during
a mood disorder, a psychotic disorder, or a pervasive developmental
disorder
* Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Fourth
Edition, Text Revision (Copyright © 2000). American Psychiatric Association. For educational
purposes only.
†
In the DSM-V[4] this criterion has been changed to: ‘The disturbance is not better explained by
another mental disorder
 GUIDELINE

should be used with caution in patients with a

Diagnosis of general anxiety history of substance abuse.[12]
disorder
4.2.3 Other comorbid disorders
Complicated? As noted earlier, there is a high rate of
comorbidity among GAD, other anxiety
Yes No
disorders and mood disorders. GAD will
often respond to the antidepressants that
Selective serotonin reuptake inhibitor or are used as first-line medication in these
selective norepinephrine reuptake inhibitor disorders, and these agents should therefore be
Appropiate Treat for 12 weeks at adequate dose considered initially. Similarly, in patients with
intervention (see chronic anxiety and comorbid personality
text) disorder (e.g. borderline personality disorder),
antidepressants may be a consideration.
Response?

4.2.4 Pregnancy, lactation, menopause

Remission?
Intolerable
response
No
Reassess
Switch
medication, then
reassess
response
Switch
medications or
augument
Fig. 1. Algorithm for pharmacotherapy of generalised anxiety disorder.[6]
should be paid to the possibility of comorbid
somatisation disorder. Children with pervasive
anxiety probably deserve specialist evaluation
before a diagnosis of GAD is made.
4. Treatment
4.1 Treatment goals
The goal of treatment of GAD is reduction
and ideally elimination of symptoms or
worry and anxiety, and restoration of normal
functioning.[10]
4.2 General aspects of treatment
The initial treatment of GAD can arguably be
either medication or psychotherapy as both
approaches are efficacious. Several factors may
complicate GAD, thus impacting on decisions
about the choice of pharmacotherapy and other
interventions. The most important factors,
along with their treatment implications, are
listed below. In addition, prior response to
treatment and patient preference are important
considerations.
No response
Evaluate for
significant
comorbidity
Switch or augument
Response
Optimise dose &
continue treatment
for at least 1 year
4.2.1 Geriatric patients
Research indicates that GAD in the elderly
is not uncommon and is often accompanied
by depression.[11] Given the possibility of
accumulation of the drug and consequent
adverse effects such as motor vehicle
accidents, falls and fractures, benzodiazepines
(particularly in high doses or those with
long half-lives) should be prescribed only
with great caution in this population. In
addition, dosages of many other psychotropic
medications require adjustment in the elderly.
4.2.2 Alcohol and/or substance use
When the diagnosis of GAD predates the
onset of substance abuse, treatment may be
initiated relatively soon after abstinence.
However, when symptoms of anxiety have
their onset during substance abuse or
withdrawal, it is likely that a longer period of
abstinence is indicated prior to re-evaluation
of the need for treatment. In addition, given
the risk of dependence, benzodiazepines
Pharmacotherapy should ideally be avoided
during pregnancy and lactation. Nevertheless,
where clinical considerations outweigh
the risk of medication, such intervention
should be considered after consultation
with a specialist. In particular, there is a
growing literature pointing toward relative
safety of fluoxetine in pregnancy.[13] Certain
benzodiazepines (e.g. chlordiazepoxide)
may be safer, while others (e.g. alprazolam)
should be avoided during pregnancy and
lactation; the lowest effective dose should be
prescribed for the shortest possible duration,
and high peak concentrations should be
avoided by dividing the daily dosage into two
or three doses.[14] Anxiety symptoms may be
exacerbated in susceptible patients during
menopause, and hormone replacement
therapy may be considered as an adjunct to
standard pharmacotherapy.
4.2.5 Comorbid medical disorders and
medications
Clinicians need to be aware of the multiple
interactions between medications used in
the treatment of GAD and the treatment of
other disorders, as well as of the impact of
the medication's adverse effects on medical
disorders.
4.3 Pharmacological treatment
The first-line treatment of uncomplicated
GAD is a selective serotonin reuptake
inhibitor (SSRI) or serotonin-norepinephrine
reuptake inhibitor (SNRI) drug. Given
the substantial comorbidity of GAD
with depression and other disorders for
which antidepressants are effective, expert
consensus favours the use of one of these
agents.[15,16] However, there is evidence for

August 2013 Vol. 19 No. 3 - SAJP 176

GUIDELINE
a range of other agents, including pregabalin, agomelatine, older
antidepressants such as tricylics (TCAs), benzodiazepines, the
azapirone buspirone, the antihistamine agent hydroxyzine, the first-
generation antipsychotic trifluoperazine and the second-generation
antipsychotic quetiapine.[2,17]
A recent meta-analysis and systematic review of the efficacy of
nine drug treatments for GAD notes advantages and disadvantages of
several of these agents.[18] For example, the TCAs (namely imipramine)
have been shown effective in GAD in several controlled trials, but are
currently considered a second-line option owing to their adverse event
burden and toxicity in overdose.[19] Similarly, given concerns about their
tolerability and side-effect profile, caution should be exercised in using
atypical and typical antipsychotic medications as monotherapy in GAD.
The benzodiazepines are best reserved for short-term use (2 - 4
weeks) in the early phase of treatment of GAD with an SSRI or SNRI
to provide some symptomatic relief until the antidepressant has
begun to work, to treat insomnia if it is a predominant symptom,
and to protect against occasional early worsening of anxiety seen
with the initiation of therapy.[19] The high comorbidity of symptoms
of depression in GAD, and the significant difficulties experienced by
many patients during benzodiazepine withdrawal, constitute a strong
argument against their long-term use. Benzodiazepines with longer
half-lives or slow-release preparations may, however, be associated
with fewer withdrawal problems.
Buspirone, a 5-HT1A agonist, takes 2 - 4 weeks or longer to begin
working, and appears to be experienced as less helpful in patients
recently treated with benzodiazepines.[20] Its advantage lies in its
benign side-effect profile, the lack of dependence, and its proven
efficacy in GAD. Disadvantages include a lack of efficacy against the
depressive symptoms often found in GAD, and a lack of efficacy in
some trials. Whereas some SSRIs have been shown useful in children
and adolescents with GAD, a controlled study of buspirone in this
population was negative.
Although beta-blockers (e.g. propranolol) are often prescribed
by general practitioners for anxiety symptoms, they have unproven
efficacy in GAD. Kava extract is a herbal that showed some promise
for the treatment of anxiety,[21] but it has not been studied rigorously
enough in GAD, and there are safety concerns, viz. hepatotoxicity.
4.4 Non-pharmacological treatment
Cognitive-behavioural treatment (CBT) has demonstrated efficacy
in GAD, where the benefits are maintained at 6 months to 2 years of
follow-up.[22] Treatment of GAD using CBT involves techniques of
cognitive restructuring, worry exposure, and behaviour modification.
There is currently little evidence that routinely initiating CBT together
with medication improves outcome in GAD.
4.5 Acute treatment
The response time to a first-line SSRI (e.g. fluoxetine, citalopram,
escitalopram, paroxetine, sertraline) or SNRI (e.g. venlafaxine,
duloxetine) is usually between 4 and 12 weeks in GAD, although with
adequate dosing a partial response may be evident by 4 - 6 weeks.[2,23]
TCAs and benzodiazepines are also efficacious in the treatment of
GAD, but are not considered first-line in view of their adverse event
profile (see below). Buspirone is another option in the treatment of
GAD (see below).
177 SAJP - August 2013 Vol. 19 No. 3
The first step after drug initiation is to determine response to the
medication. This is achieved by careful evaluation of change in
symptoms initially targeted for treatment. These are typically excessive
worry, various somatic symptoms, and consequent functional
impairment. Determining the side-effects of the medication is also
important, as these may influence compliance. Patients who are
intolerant of a particular medication can of course be switched to
another agent or to another class of agents. For example, within the
SSRIs, adverse effects may not be seen when an alternative SSRI is
used.
When there is a poor response to medication, the first course of
action is to optimise dose and duration of the treatment. For many of
the antidepressants, there is a relationship between dose and response
and also between dose and side-effects. Thus, optimal dosage is as
close to maximum recommended doses that the patient can tolerate.
Elderly patients generally require lower doses than younger adults.
Particularly in the case of the TCAs, clinicians often prescribe
suboptimal doses, rather than using doses of 150 mg or more of
medications such as imipramine. Even in the case of the SSRIs, some
patients may fail to respond to the standard initial starting dose, but
do better at higher doses.
Furthermore, there is increasing awareness that some patients may
be rapid metabolisers of antidepressant medication and, therefore,
require significantly higher doses than usual. When patients on TCAs
have little response and few anticholinergic side-effects on average
doses of medication (e.g. imipramine 150 mg), it may be useful to
further increase dosage with electrocardiogram and perhaps drug
level monitoring.
Although benzodiazepines are not recommended as first-line
treatments, when used, they should be prescribed in an optimal
fashion. In particular, it may be useful to replace short-acting
agents with slow-release compounds or long-acting agents. All too
frequently, patients on short-acting compounds have intermittent
increases of anxiety before the next dose of medication is to be taken.
Buspirone treatment usually begins at 5 mg three times daily. This
dose may be increased by 5 mg every 2 - 3 days. Therapeutic doses of
buspirone range from 30 mg to 60 mg daily, typically given in divided
doses. Buspirone has at least a 2 - 4-week time lag from initiation to
clinical onset; optimum duration of a trial of treatment should thus
be no less.
At the end of a clinical trial of optimal dose and duration, patients
should be thoroughly reassessed. There is growing recognition of
the importance of residual anxiety symptoms in causing disability
and predicting relapse, and of the consequent necessity of aiming for
remission of symptoms as the endpoint of treatment.[24]
4.6 Maintenance treatment
When the patient has a good response to medication, it is important to
reinforce the necessity for continuing the medication at the therapeutic
dose despite this improvement.[25] It is recommended that therapy be
continued for at least 1 year where there is a good response, given that the
disorder is chronic and randomised controlled trials have demonstrated
relapse with shorter-term maintenance. It is also important to regularly
monitor efficacy and tolerability during long-term treatment. Indeed,
guidelines for maintenance therapy of GAD emphasise the safety
of modern agents, the likelihood of additional episodes of illness in

patients with repeated past episodes, and the theoretical possibility that
appropriate treatment may prevent the onset of secondary disorders.
[15]
Such guidelines have become increasingly conservative, favouring
longer courses of medication. When a decision is made to discontinue
medication, a gradual taper is recommended (arguably with an even
slower taper in the elderly and in medically ill patients).
4.7 Managing partial and non-responders
When GAD does not respond to a clinical trial of adequate dose and
duration, it may be useful to reassess a number of important factors
that may influence choice of further interventions.
4.7.1 Comorbidity
It is important to establish whether comorbid mood or other
anxiety disorders are present. For example, comorbid dysthymia
may not respond to buspirone alone, comorbid social anxiety
disorder is unlikely to respond to a TCA (other than clomipramine),
and comorbid hypochondriasis may require high doses of SSRIs.
Excluding important comorbid psychiatric disorders is perhaps the
most important step in the evaluation and management of refractory
GAD.
4.7.2 Compliance
Many patients with GAD suffer from extreme anxiety and are in fact
compliant with their medication. Nevertheless, there is perhaps a
tendency for clinicians to overestimate patient compliance. Patients
are particularly likely to be concerned about physical or psychological
dependence on medication. It is well worth checking not only with the
patient, but perhaps also with the family, whether medication is in fact
taken as prescribed.
4.7.3 Comorbid substance use
In the presence of active alcohol or substance use, it may be necessary
to shift the emphasis of treatment towards a substance use disorder
as the primary diagnosis, with the anxiety as a secondary problem.
Detoxification is typically a first step in the management of these
patients.[26,27]
4.7.4 Comorbid personality disorders
Although antidepressants may be useful, additional interventions
such as psychotherapy may be helpful in patients with chronic
anxiety and comorbid personality disorder. While improvement in
anxiety symptoms may reduce maladaptive behaviour in patients with
comorbid personality disorder, there are other patients (e.g. those with
borderline personality disorder) in whom the personality disorder
itself may need to be a major target of treatment.
4.7.5 Underlying medical disorder
Patients with GAD who fail to show any noticeable response to
treatment should be thoroughly reassessed for the possibility of an
underlying medical condition. A range of different medical disorders
may lead to chronic anxiety, including endocrine disorders (e.g.
hyperthyroidism), respiratory disorders (e.g. chronic obstructive
pulmonary disorders), cardiac disorders (e.g. congestive heart failure),
and others. If present, such disorders naturally require specific
intervention. Note that when using a benzodiazepine in patients
GUIDELINE
with liver dysfunction, consider using those metabolised only by
conjugation (e.g. lorazepam, oxazepam).
4.7.6 Pharmacokinetic issues
Drug-drug interactions may result in a subtherapeutic dose of the
prescribed antidepressant.
4.7.7 Psychosocial issues
In some cases, a diagnosis of an adjustment disorder with
anxious features may be more accurate than that of GAD, and a
psychotherapeutic approach therefore indicated. This factor may
partially explain high rates of placebo response in some clinical trials
in GAD. In other cases of chronic anxiety, psychosocial factors may be
enduring and therefore continuously complicate treatment of GAD
until given independent attention.
Where there is only a partial response to an initial 12-week trial,
it is prudent to re-evaluate the patient and to consider switching to
another antidepressant within the same class or to a different class
(e.g. SSRI to SNRI or agomelatine, SNRI to SSRI or agomelatine),
or augmentation.[24] Neither augmentation nor switching strategies
in GAD have been well researched. Augmentation offers the
advantage of retaining any possible gains from the first agent, but
the potential disadvantages of polypharmacy (more side-effects,
drug interactions).[28] When insomnia is present, the use of an
appropriate agent (e.g. non-benzodiazepine gamma-amino-butyric
acid (GABA)-ergic hypnotics such as zolpidem, agomelatine, or
mirtazapine) may be considered.[24] If comorbid depression is
present, augmentation with bupropion, buspirone, or an atypical
antipsychotic may be considered. Similarly, if there is a comorbid
bipolar disorder, a mood stabiliser, anticonvulsant or an atypical
antipsychotic may be considered. Augmentation with psychotherapy
is another important consideration.
5. Summary points
• Both pharmacotherapy and psychotherapy are efficacious first-line
approaches for GAD.
• First-line pharmacotherapy of uncomplicated GAD comprises use
of an SSRI or SNRI drug.
• A range of other psychotropics are useful for the treatment of GAD.
• Response time to a first-line selective SSRI (e.g. fluoxetine,
citalopram, escitalopram, paroxetine, sertraline) or SNRI (e.g.
venlafaxine, duloxetine) is usually between 4 and 12 weeks in GAD.
• Benzodiazepines (e.g. lorazepam, alprazolam, diazepam) are best
reserved for short-term use (2 - 4 weeks) in the early phase of
treatment of GAD with an SSRI or SNRI to provide symptomatic
relief.
• Given concerns about their tolerability and side-effect profile,
caution should be exercised in using atypical and typical
antipsychotic medications as monotherapy in GAD.
• CBT for GAD involves techniques of cognitive restructuring, worry
exposure, and behaviour modification.
• Neither augmentation nor switching strategies have been well
researched in GAD. Where there is only a partial response to an
optimal 12-week trial, consider switching to another antidepressant
within the same class or to a different class (e.g. SSRI to SNRI or
agomelatine, SNRI to SSRI or agomelatine).
August 2013 Vol. 19 No. 3 - SAJP 178
GUIDELINE
References
1. Kessler RC, Chiu WT, Demler O, et al. Prevalence, severity, and comorbidity of 12-month
DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry
2005;62:617-627. [http://dx.doi.org/10.1001/archpsyc.62.6.617]
2. Bandelow B, Zohar J, Hollander E, et al. WFSBP Task Force on Treatment Guidelines for
Anxiety, Obsessive-Compulsive and Post-Traumatic Stress Disorders. World Federation
of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological
treatment of anxiety, obsessive-compulsive and post-traumatic stress disorders -
first revision. World Journal of Biological Psychiatry 2008;9:248-312. [http://dx.doi.
org/10.1080/15622970802465807]
3. Roy-Byrne PP, Katon W. Generalized anxiety disorder in primary care: The precursor/modifier
pathway to increased health care utilization. J Clin Psychiatry 1997;58S:34-38.
4. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth
Edition. 2013. Washington, DC: American Psychiatric Association, 2013.
5. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders,
Fourth Edition, Text Revision (DSM-IV-TR). Washington, DC: American Psychiatric
Association, 2000.
6. Stein DJ, Seedat S, Niehaus DJH, et al. Psychiatric medications in primary care: Algorithms
and guidelines. Tygerberg, Cape Town: University of Stellenbosch, Mental Health Information
Centre, 2005:91.
7. Spitzer R, Kroenke K, Williams J, Lowe B. A brief measure for assessing generalized anxiety
disorder. The GAD-7. Arch Intern Med 2006;166:1092-1097. [http://dx.doi.org/10.1001/
archinte.166.10.1092]
8. Stein DJ, Fincham D, Seedat S, et al. The DSM-IV-based Generalized Anxiety Disorder Severity
Scale: Preliminary validation using data from a trial of agomelatine versus placebo. J Nerv Ment
Dis 2009;197:391-394.
9. Feltner DE, Harness J, Brock J, et al. Clinical evaluation of the Daily Assessment of Symptoms-
Anxiety (DAS-A): A new instrument to assess the onset of symptomatic improvement in
generalized anxiety disorder. CNS Neuroscience and Therapeutics 2009;15:12-18.
10. Gorman JM. Treating generalized anxiety disorder. J Clin Psychiatry 2003; 64(Suppl 2):24-29.
11. Schneider F, Weiss U, Kessler C, et al. Subcortical correlates of differential classical conditioning
of aversive emotional reactions in social phobia. Biol Psychiatry 1999;45:863-871.
12. Posternak MA, Mueller TI. Assessing the risks and benefits of benzodiazepines for anxiety
disorders in patients with a history of substance abuse or dependence. Am J Addict
2000;10:48-68.
13. Nulman I, Rovet J, Stewart DE, et al. Neurodevelopment of children exposed in utero to
antidepressant drugs. New Engl J Med 1997;336:258-262.
179 SAJP - August 2013 Vol. 19 No. 3
14. Iqbal MM, Sobhan T, Ryals T. Effects of commonly used benzodiazepines on the fetus, the neonate,
and the nursing infant. Psychiatr Serv 2002;53:39-49. [http://dx.doi.org/10.1176/appi.ps.53.1.39]
15. Ballenger JC, Davidson JR, Lecrubier Y, et al. Consensus statement on generalized anxiety
disorder from the International Consensus Group on Depression and Anxiety. J Clin Psychiatry
2001;62S11:53-58.
16. Bandelow B, Zohar J, Hollander E, et al. World Federation of Societies of Biological Psychiatry
(WFSBP) guidelines for the pharmacological treatment of anxiety, obsessive-compulsive and
posttraumatic stress disorders. World Journal of Biological Psychiatry 2002;3:171-199.
17. Allgulander C. Novel approaches to treatment of generalized anxiety disorder. Curr Opin
Psychiatry 2010;23:37-42. [http://dx.doi.org/10.1097/YCO.0b013e328333d574]
18. Baldwin D, Woods R, Lawson R, Taylor D. Efficacy of drug treatments for generalised
anxiety disorder: Systematic review and meta-analysis. BMJ 2011;342:d1199. [http://dx.doi.
org/10.1136/bmj.d1199]
19. Davidson JR, Zhang W, Connor KM, et al. A psychopharmacological treatment algorithm for
generalised anxiety disorder (GAD). J Psychopharmacol 2010;24:3-26.
20. DeMartinis N, Rynn M, Rickels K, et al. Prior benzodiazepine use and buspirone response in
the treatment of generalized anxiety disorder. J Clin Psychiatry 2000;61:91-94. [http://dx.doi.
org/10.4088/JCP.v61n0203]
21. Sarris J, Kavanagh DJ. Kava and St. John's Wort: Current evidence for use in mood and anxiety
disorders. J Altern Complement Med 2009;15:827-836.
22. Hofmann SG, Smits JA. Cognitive-behavioural therapy for adult anxiety disorders: A meta-
analysis of randomized placebo-controlled trials. J Clin Psychiatry 2008;69:621-632. [http://
dx.doi.org/10.4088/JCP.v69n0415]
23. International Psychopharmacology Algorithm Project (IPAP). Algorithm for Generalized
Anxiety Disorder (GAD). 2006. www.ipap.org/gad/ (accessed June 2013).
24. Ballenger JC. Treatment of anxiety disorders to remission. J Clin Psychiatry 2001;62(S12):5-9.
25. Schweizer W, Rickels K, Uhlenhuth EH. Issues in the long-term treatment of anxiety disorder
psychopharmacology. In: Bloom FE, Kupfer DJ, eds. Psychopharmacology: The Fourth
Generation. New York: Raven Press, 1995..
26. Castenada R, Sussman N, Westreich L, et al. A review of the effects of moderate alcohol intake
on the treatment of anxiety and mood disorders. J Clin Psychiatry 1996;57:207-212.
27. Schadé A, Marquenie LA, van Balkom AJLM, et al. Do comorbid anxiety disorders in alcohol-
dependent patients need specific treatment to prevent relapse? Alcohol Alcohol 2003;38:255-
262. [http://dx.doi.org/ 10.1093/alcalc/agg062]
28. Fava M. Augmentation and combination strategies in treatment-resistant depression. J Clin
Psychiatry 2001;62(S18):4-11.

Obsessive compulsive disorder
D J Stein
1. Introduction
This guideline focuses on the pharmacotherapy of obsessive-
compulsive disorder (OCD). OCD is characterised by obsessions and
compulsions. A number of other disorders are also characterised by
repetitive thoughts and rituals and may also respond to modifications
of standard OCD treatment. These so-called OCD spectrum disorders
include body dysmorphic disorder (characterised by recurrent
concerns with imagined ugliness), hypochondriasis (characterised
by recurrent concerns with imagined illness), trichotillomania
(characterised by recurrent hair-pulling), and obsessive-compulsive
personality disorder.[1] The Diagnostic and Statistical Manual of Mental
Disorders, Fifth Edition[2] has a new chapter on obsessive-compulsive
and related disorders, which includes several of these conditions.
2. Diagnosis and clinical characteristics
Evidence indicates that OCD is commonly underdiagnosed and
undertreated.[3] There is also the converse possibility that various
disorders with intrusive symptoms, such as post-traumatic stress
disorder or generalised anxiety disorder, can be misdiagnosed as
OCD. Diagnostic criteria for OCD are provided in Table 1.[4]
3. Assessment
Most patients with OCD have both obsessions (which increase anxiety)
and compulsions (which aim to decrease anxiety), particularly given
that the Diagnostic and Statistical Manual of Mental Disorders, Fifth
Edition[2] definition of compulsion includes mental rituals. The most
common obsessions centre around concerns of contamination, harm,
hoarding, and sexual, somatic and religious preoccupations, while the
most common compulsions include washing, checking, repeating,
ordering, counting, and hoarding.[5] The disorder is highly comorbid
with obsessive-compulsive and related disorders, major depressive
disorder, anxiety disorders, alcohol dependence, eating disorders and
tic disorders.[6,7] Evaluation should include assessment of symptom
pattern, severity, and functional impairment. Comorbid Axis I and
II disorders, including tic disorders, as well as medical conditions
(including pregnancy) and disorders need to be accurately identified.
There is growing evidence that OCD and/or tics in some patients,
particularly children, are precipitated or exacerbated by streptococcal
or other infections.[8]
Evaluation of the OCD patient also requires attention to
psychosocial factors that may have precipitated or exacerbated
OCD symptoms. For example, are family members involved in the
patient’s rituals? What is the patient’s explanatory model of OCD -
does he or she regard it as a sign of weakness or as evidence of brain
dysfunction?
4. Treatment
4.1 Treatment goals
The goals of treatment of OCD are to reduce symptom frequency and
severity and to improve functioning and quality of life. Treatment
GUIDELINE
goals also encompass minimising medication adverse effects, helping
the patient develop coping strategies for their OCD and related
stressors, and educating the patient and family regarding the disorder
and its treatment.[7]
4.2 General aspects of treatment
In this discussion, we assume that the patient is an adult. Nevertheless,
there are increasing data on the pharmacotherapy of OCD in children.[9,10]
Indeed, the algorithm (see Fig. 1 below) can readily be adapted for
children, bearing in mind considerations such as differences in dosing
and differences in risk-benefit determination (e.g. clinicians are less
likely to use untested augmentation strategies in children). Consultation
with a child psychiatrist may well be indicated in such cases.
Table 1. Criteria for obsessive-compulsive disorder*
A. Either obsessions or compulsions:
Obsessions as defined by (1), (2), (3), and (4):
1. Recurrent and persistent thoughts, impulses, or images that are
experienced, at some time during the disturbance, as intrusive
and inappropriate and that cause marked anxiety or distress
2. †The thoughts, impulses, or images are not simply excessive
worries about real-life problems
3. The person attempts to ignore or suppress such thoughts,
impulses, or images, or to neutralise them with some other
thought or action
4. † The person recognises that the obsessional thoughts, impulses,
or images are a product of his or her own mind (not imposed
from without as in thought insertion)
Compulsions as defined by (1) and (2):
1. Repetitive behaviours (e.g. hand washing, ordering, checking)
or mental acts (e.g. praying, counting, repeating words silently)
that the person feels driven to perform in response to an
obsession, or according to rules that must be applied rigidly
2. The behaviours or mental acts are aimed at preventing
or reducing distress or preventing some dreaded event or
situation; however, these behaviours or mental acts either are
not connected in a realistic way with what they are designed to
neutralise or prevent or are clearly excessive
B. At some point during the course of the disorder, the person has
recognised that the obsessions or compulsions are excessive or
unreasonable
C. The obsessions or compulsions cause marked distress, are time
consuming (take more than 1 hour a day), or significantly interfere
with the person’s normal routine, occupational (or academic)
functioning, or usual social activities or relationships
D. ‡If another Axis I disorder is present, the content of the obsessions or
compulsions is not restricted to it
E. The disturbance is not due to the direct physiological effects of a
substance (e.g. a drug of abuse, a medication) or a general medical
condition.
* Adapted from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text
Revision; DSM-IV-TR.[4] For educational purposes only..
†
Omitted from the DSM-V[2]
‡
This has been changed in the DSM-V[2] ‘The disturbance is not better explained by the symptoms
of another mental disorder.’
August 2013 Vol. 19 No. 3 - SAJP 180
GUIDELINE
The initial treatment of OCD can arguably be either medication or
psychotherapy as both approaches are efficacious. Several factors
may complicate OCD, thus impacting on decisions about the choice
of pharmacotherapy and other interventions. The most important
factors, along with their treatment implications, are listed below.
In addition, prior response to treatment and patient preference are
important considerations.
4.2.1 Severity
Patients with severe symptoms may require brief hospitalisation
to help contain symptoms. In general, however, the principles of
behaviour therapy suggest that patients should attempt to continue
with their ordinary daily routines where possible.
4.2.2 Melancholia
There is some evidence that tricyclic antidepressants (TCAs) may be more
effective than selective serotionin reuptake inhibitors (SSRIs) in patients
with depression accompanied by melancholic features[11] and in possibly
related subgroups such as in-patients with depression,[11-13] although not
all evidence is consistent.[14] Melancholic features of depression include
loss of pleasure in activities, lack of reactivity to pleasurable stimuli, and
various neurovegetative symptoms such as exacerbation of depression in
the morning, early-morning awakening, and significant weight loss. The
only TCA that is effective in OCD is clomipramine.
4.2.3 Tourette’s disorder
This disorder is characterised by both motor and vocal tics. Many
patients with Tourette’s disorder have comorbid OCD. Although
this OCD may respond to standard OCD treatments, additional
medication that targets the tics (e.g. dopamine blockers such as
haloperidol, pimozide, or risperidone) may be necessary for resolution
of the range of symptoms that characterise the disorder.[15]
4.2.4 Pregnancy, lactation, menopause
Pharmacotherapy should ideally be avoided during pregnancy and
lactation. Nevertheless, where clinical considerations outweigh the
risk of medication, such intervention should be considered after
consultation with a specialist. In particular, there is growing literature
pointing toward the relative safety of fluoxetine in pregnancy.[16]
4.2.5 Comorbid medical disorders and medications
Clinicians need to be aware of the multiple interactions between
medications used in the treatment of OCD and other medications,
as well as the impact of a medication’s adverse effects on medical
disorders. Fortunately, certain SSRIs have relatively few interactions
with other medications, and the SSRIs as a class are well tolerated in
most medical disorders.
4.3 Pharmacological treatment
Refer to 4.5 and 4.6 below.
4.4 Non-pharmacological treatment
Psycho-education as part of the management of OCD is crucial.
Similarly, cognitive-behavioural therapy (CBT) is an important
aspect of OCD treatment, whether used alone or in combination with
medication.[17] CBT for OCD has been delivered in individual, group,
181 SAJP - August 2013 Vol. 19 No. 3
and family therapy formats. The number and length of treatment
sessions vary across different studies, but some guidelines recommend
13 - 20 weekly sessions for most patients.[7]
4.5 Acute treatment
Patient motivation and ability to comply with pharmacotherapy and/
or psychotherapy are important considerations in choosing a first-line
treatment approach. CBT and serotonin reuptake inhibitors (SRIs) are
both considered safe and effective first-line treatments for OCD.[5,7]
The decision of whether to commence CBT or an SRI will depend on
a number of factors including the nature and severity of symptoms,
presence of co-occurring psychiatric and medical comorbidity and
their treatments, patients’ access to CBT, past treatment history, and
patient preference.[5,7] CBT alone, consisting of exposure and response
prevention, is recommended as initial treatment for a patient who is not
too depressed, anxious, or severely ill to co-operate with this treatment
modality, or who prefers not to take medications and is willing to engage
with CBT. Initiating treatment with an SRI is recommended for a patient
who has previously responded well to an SRI or other drug, prefers
medication treatment or is not suited for CBT.[7]
The first line of medication in the treatment of OCD should
comprise an SRI. Consistent with growing evidence for the importance
of serotonin in OCD, both clomipramine and the SSRIs appear
to be more effective than the noradrenergic reuptake inhibitor,
desipramine, in the treatment of OCD.[18,19] The efficacy and safety
of clomipramine and the SSRIs in the treatment of OCD have been
well researched, with studies indicating that at least half of patients
will respond to one of these agents. The SRIs are also useful for
body dysmorphic disorder, hypochondriasis, obsessive-compulsive
symptoms in Tourette’s disorder, and possibly (albeit with relatively
less robust responses) in hair-pulling disorder (trichotillomania),
excoriation (skin-picking) disorder, so-called compulsive sexual
behaviour, and pathological gambling.[20,21] Note, however, that other
agents may be preferable as first-line options in some of these
conditions, e.g. given recent data that N-acetyl-cysteine is useful in
hair-pulling disorder, this is an important consideration.
An immediate question, however, is which SRI to use first. Given
the apparent lack of differences in efficacy between the SRIs, the side-
effect profile of these agents may be an important issue in considering
which agent to use first. Certainly, there are invariably fewer side-
effects during treatment with the SSRIs than during treatment
with clomipramine. Therefore, it seems reasonable to suggest that
treatment of OCD be initiated with an SSRI.
While all SSRIs appear to have similar efficacy, individual patients
may respond well to one medication and not to another. In choosing
among the SSRIs, it is important to consider the safety and acceptability
of particular side-effects for the patient, potential drug interactions,
past treatment response, and the presence of co-occurring general
medical conditions.[7] Low doses should initially be used in patients
with comorbid panic disorder.
Most patients will not experience substantial improvement until
4 - 6 weeks after initiating medication, and some patients who will
ultimately respond will experience little improvement by 8 - 10
weeks.[5,7] To determine response to medication, it is important to ask
about change in those symptoms initially targeted for treatment. Side-
effects of the medication should also be determined, with particular

attention to those that patients may be reluctant to disclose (e.g.
sexual dysfunction). It may be useful to complete a symptom rating
scale (Table 2)[22] to help quantify response to medication.
Patients who are intolerant of a particular medication can of course
be switched to another agent. Within the SRIs, adverse effects may not
be seen when an alternative SSRI or clomipramine is used.
When there is a poor response to medication, it is important to
optimise dosage and duration of the medication. Although some
patients with OCD respond to standard doses of SRIs, others require
doses that are much higher than in depression. In adults, clomipramine
should be increased to approximately 250 mg, and the SSRIs should
be increased to maximal dosages (e.g. 60 - 80 mg of fluoxetine)
bearing in mind recent black box warnings (e.g. citalopram should
not be increased higher than 40 mg). Unfortunately, the likelihood of
side-effects also increases at these doses. Electrocardiogram (ECG)
monitoring may be necessary when children and adolescents, or
patients with pre-existing heart disease, are treated with clomipramine.
Response to SSRIs in OCD may take rather longer than in many
other disorders - up to 12 weeks. It is obviously important to give
each patient a trial of medication that is of adequate duration. Patients
therefore need to be educated that response may take a significant
length of time and that they need to remain optimistic even when no
change is seen at first.
At the end of a clinical trial of optimal dose and duration, patients
should be thoroughly reassessed. There is growing recognition of
the importance of residual anxiety symptoms in causing disability
and predicting relapse, and of the consequent necessity of aiming for
remission of symptoms as the endpoint of treatment.[23] Nevertheless,
many OCD patients who are judged ‘responders’ to medication
therapy may continue to experience obsessions and compulsions,
albeit with less intensity. In clinical trials, a decrease of 25 - 35% on the
Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) may correspond
to a categorical treatment response.[22]
4.6 Maintenance treatment
In patients where an SRI is effective, maintenance pharmacotherapy
should be instituted. Rapid discontinuation of these agents risks the
return of symptoms. Nevertheless, a maintenance dose of SSRIs in OCD
may be lower than the dose initially required during acute treatment.[21]
At least a year of maintenance pharmacotherapy is reasonable. When
a decision is made to attempt discontinuation of medication, it is
advisable to taper medication off slowly (e.g. by 25% every 2 months).
Concomitant behavioural treatment (exposure therapy and response
prevention) during pharmacotherapy may well increase chances of
being able to discontinue medication without relapse.
4.7 Managing partial and non-responders
Comparison of augmentation with switching strategies in OCD has not
been well researched. Augmentation offers the advantage of retaining
any possible gains from the first agent, but the potential disadvantages
of polypharmacy (more side-effects, drug interactions).[24] Of all the
augmentation strategies in the treatment of OCD, perhaps the most
important is augmentation of pharmacotherapy with additional
psychotherapy.[25]
Combined SRI and CBT treatment can be considered when the
patient has a co-occurring disorder that is SRI-responsive or has a
GUIDELINE
partial response to monotherapy. Combination of an SRI and CBT may
also reduce the chance of relapse when medication is discontinued. In
patients who have had a partial response to CBT monotherapy, it may
be useful to increase the intensity of treatments.[7]
However, when there is a partial response despite an optimum trial of
medication, or when there are comorbid tics, it may be useful to consider
augmentation. Certainly, in patients with comorbid tics, there is good
evidence that augmentation of an SRI with a dopamine blocker can be
effective.[26] About one-third to one-half of treatment-refractory OCD
patients will have a meaningful treatment response to antipsychotic
augmentation. The introduction of the new-generation antipsychotics
has led to increased use of these agents in the augmentation therapy
of OCD, and they appear useful in treatment-refractory patients even
in the absence of comorbid tics.[27-29] Another possible strategy is to
supplement an SSRI with a low dose of clomipramine,[30] although careful
monitoring of adverse effects and ECGs may be warranted with such a
combination. Other augmentation strategies have been suggested, but
there are few positive controlled trials. There is also relatively little work
on augmentation strategies in OCD-related disorders, although addition
of a dopamine blocker may also be useful in some of these patients.[31]
When OCD does not respond to a clinical trial of optimal dose and
duration, it is useful to reassess a number of factors. The presence
of certain features may impact on the choice of the subsequent
intervention.
4.7.1 Compliance
Clinicians often overestimate the compliance of their patients and
it is often useful to check with patients and their families whether
medication is being taken as prescribed. Many patients worry that
medication is addictive or is a ‘crutch’.
4.7.2 Comorbid substance use
In patients who fail to respond to pharmacotherapy, the possibility of
comorbid substance use should again be considered. There may be a
need for withdrawal before tackling the OCD per se.[32,33]
4.7.3 Comorbid personality disorders
Although SSRIs may be useful, additional interventions such as
psychotherapy may be crucial in patients with OCD and comorbid
personality disorder. While improvement in OCD symptoms may
reduce maladaptive behaviour in comorbid personality disorder, the
personality disorder itself may need to be a major target of treatment.
4.7.4 Underlying medical disorder
Patients with obsessive-compulsive and related disorders who
fail to respond to medication should be thoroughly reassessed for
an underlying medical disorder. In OCD in children, the role of
streptococcal throat infection may be particularly important.
4.7.5 Pharmacokinetic issues
Drug-drug interactions may result in a subtherapeutic dose of the
prescribed antidepressant.
4.7.6 Psychosocial issues
Psychosocial circumstances that continue to complicate the course
of OCD need to be assessed, as these may necessitate appropriate
August 2013 Vol. 19 No. 3 - SAJP 182
GUIDELINE
Table 2. Yale-Brown Obsessive-Compulsive Scale[22]
Question
‘I am now going to ask several questions about your obsessive thoughts.’
(Make specific reference to the patient’s target obsessions)
1. T
 ime occupied by obsessive thoughts
Q: How much of your time is occupied by obsessive thoughts?
How frequently do the obsessive thoughts occur?
2. Interference due to obsessive thoughts
Q: How much do your obsessive thoughts interfere with your social
or work (or role) functioning? Is there anything that you don’t do
because of them?
3. Distress associated with obsessive thoughts
Q: How much distress do your obsessive thoughts cause you?
4. Resistance against obsessions
Q: How much of an effort do you make to resist the obsessive thoughts?
How often do you try to disregard or turn your attention away from
these thoughts as they enter your mind?
5. Degree of control over obsessive thoughts
Q: How much control do you have over your obsessive thoughts? How
successful are you in stopping or diverting your obsessive thinking?
Can you dismiss them?
The next several questions are about your compulsive behaviours.’ (Make
specific reference to the patient’s target compulsions)
6. Time spent performing compulsive behaviours
Q: How much time do you spend performing compulsive behaviours?
How much longer than most people does it take to complete routine
activities because of your rituals? How frequently do you perform
compulsions?
183 SAJP - August 2013 Vol. 19 No. 3
Answer scale
0 = None.
1 = Mild, less than 1 hour/day or occasional intrusion.
2 = Moderate, 1 to 3 hours/day or frequent intrusion.
3 = Severe, greater than 3 and up to 8 hours/day or very frequent intrusion.
4 = Extreme, greater than 8 hours/day or near constant intrusion.
0 = None.
1 = Mild, slight interference with social or occupational activities, but
overall performance not impaired.
2 = Moderate, definite interference with social or occupational
performance, but still manageable.
3 = Severe, causes substantial impairment in social or occupational
performance.
4 = Extreme, incapacitating.
0 = None.
1 = Mild, not too disturbing.
2 = Moderate, disturbing, but still manageable.
3 = Severe, very disturbing.
4 = Extreme, near constant and disabling distress.
0 = Makes an effort to always resist, or symptoms so minimal doesn’t need
to actively resist.
1 = Tries to resist most of the time.
2 = Makes some effort to resist.
3 = Yields to all obsessions without attempting to control them, but does so
with some reluctance.
4 = Completely and willingly yields to all obsessions.
0 = Complete control.
1 = Much control, usually able to stop or divert obsessions with some effort
and concentration.
2 = Moderate control, sometimes able to stop or divert obsessions.
3 = Little control, rarely successful in stopping or dismissing obsessions,
can only divert attention with difficulty.
4 = No control, experienced as completely involuntary, rarely able to even
momentarily alter obsessive thinking.
0 = None.
1 = Mild (spends less than 1 hour/day performing compulsions), or
occasional performance of compulsive behaviours.
2 = Moderate (spends from 1 to 3 hours/day performing compulsions), or
frequent performance of compulsive behaviours.
3 = Severe (spends more than 3 and up to 8 hours/day performing
compulsions), or very frequent performance of compulsive behaviours.
4 = Extreme (spends more than 8 hours/day performing compulsions), or
near constant performance of compulsive behaviours (too numerous to
count).
continued...

Table 2 (continued). Yale-Brown Obsessive-Compulsive Scale[22]
Question
7. Interference due to compulsive behaviours
Q: How much do your compulsive behaviours interfere with your social
or work (or role) functioning? Is there anything that you don’t do
because of the compulsions?
8. Distress associated with compulsive behaviour
Q: How would you feel if prevented from performing your
compulsion(s)? How anxious would you become? How anxious do
you get while performing compulsions until you are satisfied they are
completed?
9. Resistance against compulsions
Q: How much of an effort do you make to resist the compulsions?
10. Degree of control over compulsive behaviour
Q: H
 ow strong is the drive to perform the compulsive behaviour? How
much control do you have over the compulsions?
intervention. In particular, the participation of friends and family in
rituals may serve to derail treatment.
After the failure of an adequate clinical trial of medication in a
patient where reassessment sheds no light on any further unresolved
factors, a different agent should be used. Although an SRI has
less chance of being effective in patients who have already failed a
number of trials of other SRIs, some of these patients (approximately
one-third of non-responders to initial SRI monotherapy) will in fact
ultimately respond to a new SRI.[34] Given the possible superiority
of clomipramine in certain cases of OCD and depression, it may be
argued that all OCD patients who have failed to respond to one or
more of the SSRIs deserve a trial of clomipramine.[35] While results
of studies correlating plasma drug levels and therapeutic response in
GUIDELINE
Answer scale
0 = None.
1 = Mild, slight interference with social or occupational activities, but
overall performance not impaired.
2 = Moderate, definite interference with social or occupational
performance, but still manageable.
3 = Severe, causes substantial impairment in social or occupational
performance.
4 = Extreme, incapacitating.
0 = None.
1 = Mild, only slightly anxious if compulsions prevented, or only slight
anxiety during performance of compulsions.
2 = Moderate, reports that anxiety would mount but remain manageable if
compulsions prevented, or that anxiety increases but remains manageable
during performance of compulsions.
3 = Severe, prominent and very disturbing increase in anxiety if
compulsions interrupted, or prominent and very disturbing increase in
anxiety during performance of compulsions.
4 = Extreme, incapacitating anxiety from any intervention aimed at
modifying activity, or incapacitating anxiety develops during performance
of compulsions.
0 = Makes an effort to always resist, or symptoms so minimal doesn’t need
to actively resist.
1 = Tries to resist most of the time.
2 = Makes some effort to resist.
3 = Yields to almost all compulsions without attempting to control them,
but does so with some reluctance.
4 = Completely and willingly yields to all compulsions.
0 = Complete control.
1 = Much control, experiences pressure to perform the behaviour but
usually able to exercise voluntary control over it.
2 = Moderate control, strong pressure to perform behaviour, can control it
only with difficulty.
3 = Little control, very strong drive to perform behaviour, must be carried
to completion, can only delay with difficulty.
4 = No control, drive to perform behaviour experienced as completely
involuntary and overpowering, rarely able to even momentarily delay
activity.
OCD have been mixed, in the case of clomipramine obtaining drug
levels at high doses may be useful. Anecdotal experience suggests
that certain non-SRI agents, such as the classic monoamine oxidase
inhibitors and venlafaxine, may on occasion be effective in treatment-
resistant OCD.[36] Recent trials of intravenous clomipramine also
show efficacy in treatment-resistant OCD.[37]
For patients who have failed multiple medication and behavioural
treatments (including intensive partial or full hospitalisation
programmes),[38] and where severity of the disorder is marked,
neurosurgery should also be considered.[39] Several studies have
suggested that specific lesions to or deep-brain stimulation of
components of corticostriatal and related pathways may lead to
significant reduction in OCD symptoms in treatment-refractory
August 2013 Vol. 19 No. 3 - SAJP 184
GUIDELINE
patients. Patients can be referred to specialised
centres for such treatments.
5. Algorithm
Fig. 1 outlines the treatment.
6. Summary points
• CBT and the serotonin reuptake inhibitors
(SRIs), clomipramine and the SSRIs, are
efficacious and safe first-line treatments
for OCD.
• Whether to commence CBT or an SRI
will depend on the nature and severity
of symptoms, presence of co-occurring
psychiatric and medical comorbidities
and their treatments, a patient’s access to
CBT, past treatment history, and patient
preference.
• CBT alone, consisting of exposure and
response prevention, is recommended
as first-line for a patient who is not
too depressed, anxious, or severely ill to
co-operate with this treatment modality, or
who prefers not to take medications and is
willing to engage with CBT.
• SRI first-line treatment is recommended for
a patient who has previously responded well
to an SSRI or other drug, prefers medication
treatment, or is not suited for CBT.
• Most patients will not experience substantial
improvement until 4 - 6 weeks after
initiating medication, and some patients
who ultimately respond will experience little
improvement by 8 - 10 weeks.
• Although some patients with OCD respond
to standard doses of SRIs, others require
doses that are much higher than those used
for depression. In adults, clomipramine
should be increased to approximately 250
mg, and the SSRIs should be increased to
maximal safe dosages (e.g. 60 - 80 mg of
fluoxetine).
• At least a year of maintenance
pharmacotherapy is reasonable in patients
who respond to medication.
• CBT (exposure and response prevention)
can be used alone or in combination
with medication. Psycho-education is also
crucial.
• When there is a partial response to an
optimal trial of medication, or when
there are comorbid tics, it may be useful
to consider augmentation. Many OCD
patients will have a meaningful treatment
response to antipsychotic augmentation.
185 SAJP - August 2013 Vol. 19 No. 3
Diagnosis of obsessive-compulsive disorder
Complicated?
Yes No
Serotonin reuptake inhibitor
Appropriate
intervention (see
text)
Response?
Remission?
No response
Intolerable
No response Optimise dose
and duration, then
reassess response
Reassess
Switch Response
medication, then
reassess
response
Switch Optimise dose
medications or
augument
Fig. 1. Algorithm for pharmacotherapy of obsessive-compulsive disorder.[40]
Additional reading 4. American Psychiatric Association. Diagnostic and Statistical
Manual of Mental Disorders, Fourth Edition, Text Revision
• J efferson JW, Altemus M, Griest JH, et al. An algorithm for the
(DSM-IV-TR). Washington, DC: American Psychiatric
pharmacologic treatment of obsessive compulsive disorder.
Psychopharmacology Bulletin 1996;31:487-490.
Association, 2000.
5. Bandelow B, Zohar J, Hollander E, et al. WFSBP Task Force
• M
 arch JS, Frances A, Carpenter D, Kahn D. Treatment of
on Treatment Guidelines for Anxiety, Obsessive-Compulsive
obsessive-compulsive Disorder. J Clin Psychiatry 1997;S4:1-
72.
and Post-Traumatic Stress Disorders. World Federation of
Societies of Biological Psychiatry (WFSBP) guidelines for the
• S tein DJ, Emsley RA. Treatment of the difficult obsessive-
pharmacological treatment of anxiety, obsessive-compulsive
compulsive disorder patient. In: Lader M, Naber D, eds.
and post-traumatic stress disorders - first revision. World
Difficult Clinical Problems in Psychiatry. London: Martin
Journal of Biological Psychiatry 2008;9:248-312. [http://
Dunitz, 1999.
dx.doi.org/10.1080/15622970802465807]
• Stein DJ, Hollander E. Serotonin reuptake inhibitors in
6. Pigott TA, L’Heureux F, Dubbert B, et al. Obsessive
obsessive-compulsive disorder and related disorders. In:
Feighner J, Boyer WF, eds. Selective Serotonin Reuptake
compulsive disorder: Comorbid conditions. J Clin Psychiatry
1994;55:15-32.
Inhibitors: Advances in Basic Research and Clinical Practice.
7. Koran LM, Hanna GL, Hollander E, et al. Practice guideline
2nd ed. New York: John Wiley, 1996.
for the treatment of patients with obsessive-compulsive
disorder. Am J Psychiatry 2007;164:5-53.
References 8. Swedo SE, Leonard HL, Garvey M, et al. Pediatric
1. Stein DJ, Hollander E. Serotonin reuptake inhibitors in autoimmune neuropsychiatric disorders associated with
obsessive-compulsive disorder and related disorders. In: streptococcal infections: Clinical description of the first 50
Feighner J, Boyer WF, eds. Selective Serotonin Reuptake cases. Am J Psychiatry 1998;155:264-271.
Inhibitors: Advances in Basic Research and Clinical Practice, 9. Geller DA, Biederman J, Stewart SE, et al. Which SSRI?
2nd ed. New York: John Wiley, 1996.
A meta-analysis of pharmacotherapy trials in pediatric
2. American Psychiatric Association. Diagnostic and Statistical obsessive-compulsive disorder. Am J Psychiatry
Manual of Mental Disorders, Fifth Edition. Washington, DC: 2003;160:1919-1928.
American Psychiatric Association, 2013. 10. King RA, Leonard H, March J, Work Group on Quality Issues.
3. Stein DJ, Hollander E, Rowland, et al. Quality of life and Practice parameters for the assessment and treatment of
pharmaco-economic aspects of obsessive-compulsive disorder: children and adolescents with obsessive-compulsive disorder.
A South African survey. S Afr Med J 1996;86:1579-1585. J Am Acad Child Adolesc Psychiatry 1998;37(S10):27-45.

11. Roose SP, Glassman AH, Attia E, et al. Comparative efficacy of selective serotonin reuptake
inhibitors and tricyclics in the treatment of melancholia. Am J Psychiatry 1994;151:1735-1739.
12. Anderson IM. Selective serotonin reuptake inhibitors versus tricyclic antidepressants: A meta-
analysis of efficacy and tolerability. J Affect Disord 2000;58:19-36.
13. Clerc GE, Ruimy P, Verdeau-Palles J. A double-blind comparison of venlafaxine and fluoxetine
in patients hospitalized for major depression and melancholia. The Venlafaxine French Inpatient
Study Group. Int Clin Psychopharmacol 1994;9:139-143.
14. Joyce PR, Mulder RT, Luty SE, et al. A differential response to nortriptyline and fluoxetine in
melancholic depression: The importance of age and gender. Acta Psychiatr Scand 2003;108:20-23.
[http://dx.doi.org/10.1034/j.1600-0447.2003.00120.x]
15. Hawkridge S, Stein DJ, Bouwer C. Combining neuroleptics with serotonin specific reuptake
inhibitors in Tourette’s syndrome. J Am Acad Child Adolesc Psychiatry 1996;35:703-704.
16. Nulman I, Rovet J, Stewart DE, et al. Neurodevelopment of children exposed in utero to
antidepressant drugs. New Engl J Med 1997;336:258-262.
17. Goodman WK, Price LH, Rasmussen SA, et al. The Yale-Brown Obsessive-Compulsive Scale. I.
Development, use, and reliability. Arch Gen Psychiatry 1989;46:1006-1011.
18. Stein DJ, Spadaccini E, Hollander E. Meta-analysis of pharmacotherapy trials for obsessive
compulsive disorder. Int Clin Psychopharmacology 1995;10:11-18.
19. Ackerman DL, Greenland S. Multivariate meta-analysis of controlled drug studies for
obsessive-compulsive disorder. J Clin Psychopharmacol 2002;22:309-317. [http://dx.doi.
org/10.1097/00004714-200206000-00012]
20. Stein DJ. Neurobiology of the obsessive-compulsive spectrum of disorders. Biological Psychiatry
2001;47:296-304.
21. Pato MT, Hill JL, Murphy DL. A clomipramine dosage reduction study in the course of long-
term treatment of obsessive compulsive disorder patients. Psychopharmacology Bulletin
1990;26:211-214.
22. Broocks A, Hohagen F. Psychotherapy in OCD. In: Fineberg N, Marazziti D, Stein DJ, eds.
Obsessive-Compulsive Disorder: A Practical Guide. London: Martin Dunitz, 2001.
23. Ballenger JC. Treatment of anxiety disorders to remission. J Clin Psychiatry 2001;62(S12):5-9.
24. Fava M. Augmentation and combination strategies in treatment-resistant depression. J Clin
Psychiatry 2001;62(S18):4-11.
25. Stein DJ, Fineberg N, Seedat S. An integrated approach to the treatment of OCD. In: Fineberg N,
Marazziti D, Stein DJ, eds. Obsessive-Compulsive Disorder: A Practical Guide. London: Martin
Dunitz, 2001.
GUIDELINE
26. McDougle CJ, Goodman WK, Leckman JF. Haloperidol addition in fluvoxamine-refractory
obsessive-compulsive disorder: A double-blind placebo-controlled study in patients with and
without tics. Arch Gen Psychiatry 1994;51:302-308.
27. McDougle CJ, Epperson CN, Pelton GH, et al. A double-blind, placebo-controlled study of
risperidone addition in serotonin reuptake inhibitor-refractory obsessive-compulsive disorder.
Arch Gen Psychiatry 2000;57:794-802. [http://dx.doi.org/10.1001/archpsyc.57.8.794]
28. Komossa K, Depping AM, Meyer M, et al. Second-generation antipsychotics for obsessive
compulsive disorder. Cochrane Database of Systematic Reviews. 2010;12:CD008141. [http://
dx.doi.org/10.1002/14651858.CD008141]
29. Bloch MH, Landeros-Weisenberger A, Kelmendi B, et al. A systematic review: Antipsychotic
augmentation with treatment refractory obsessive-compulsive disorder. Mol Psychiatry 2006;11:622-632.
30. Ravizza L, Barzega G, Bellino S, et al. Therapeutic effect and safety of adjunctive risperidone in
refractory obsessive-compulsive disorder (OCD). Psychopharmacology Bulletin 1996;32:677-682.
31. Stein DJ, Bouwer C, Hawkridge S, et al. Risperidone augmentation of serotonin reuptake
inhibitors in obsessive-compulsive and related disorders. J Clin Psychiatry 1997;58:119-122.
32. Castenada R, Sussman N, Westreich L, et al. A review of the effects of moderate alcohol intake on
the treatment of anxiety and mood disorders. J Clin Psychiatry 1996;57:207-212.
33. Schadé A, Marquenie LA, van Balkom AJLM, et al. Do comorbid anxiety disorders in alcohol-
dependent patients need specific treatment to prevent relapse? Alcohol Alcohol 2003;38:255-262.
[http://dx.doi.org/10.1093/alcalc/agg062]
34. Marazziti D, Dell’Osso L, Gemignani A, et al. Citalopram in refractory obsessive-compulsive
disorder: An open study. International Clinical Psychopharmacology 20001;16:215-219.
35. Hollander E, Mullen L, DeCaria CM, et al. Obsessive compulsive disorder, depression, and
fluoxetine. J Clin Psychiatry 1991;52:418-422.
36. Ananth J, Burgoyne K, Smith M, et al. Venlafaxine for treatment of obsessive-compulsive disorder.
Am J Psychiatry 1995;152:1832.
37. Koran LM, Sallee FR, Pallanti, S. Rapid benefit of intravenous pulse loading of clomipramine in
obsessive-compulsive disorder. Am J Psychiatry 1997;154:396-401.
38. Bystritsky A, Munford PR, Rosen RM, et al. A preliminary study of partial hospital management
of severe obsessive-compulsive disorder. Psychiatr Serv 1996;47:170-174.
39. Martuza RL, Chiocca EA, Jenike MA, et al. Stereotactic radiofrequency thermal cingulotomy for
obsessive-compulsive disorder. J Neuropsychiatry 1990;2:331-336.
40. Stein DJ, Seedat S, Niehaus DJH, et al. Psychiatric medications in primary care: Algorithms and
guidelines. Cape Town: University of Stellenbosch: Mental Health Information Centre, 2005:77.
August 2013 Vol. 19 No. 3 - SAJP 186
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Post-traumatic stress disorder
S Seedat
1. Introduction
Post-traumatic stress disorder (PTSD) is among the most prevalent
anxiety disorders, both in terms of lifetime and 12-month prevalence
rates documented in epidemiological studies worldwide. The National
Comorbidity Survey Replication (NCS-R) study conducted in the
USA, for example, found the lifetime prevalence of PTSD to be 6.8%
while the 12-month prevalence was 3.5%.[1,2] The South African
Stress and Health Study (SASH) documented lower lifetime (2.3%)
and 12-month (0.6%) rates, although PTSD was among the anxiety
disorders with the highest proportion of severe cases (36% of all
individuals diagnosed with PTSD were severely ill).[3] High rates of
PTSD (19.9%) have also been documented among South African
patients attending primary healthcare clinics.[4]
2. Diagnosis and clinical characteristics
The disorder represents a pathological response to a traumatic event,
characterised by symptoms of recurrent and intrusive distressing
recollections of the event (e.g. nightmares, a sense of reliving the
experience with illusions, hallucinations, or dissociative flashback
episodes, intense psychological or physiological distress at exposure
to cues that resemble the traumatic event); avoidance of stimuli
associated with the trauma (e.g. inability to recall important aspects of
the trauma, loss of interest, estrangement from others); and increased
arousal (sleep disturbances, irritability, difficulty concentrating,
hypervigilance, and exaggerated startle response).[5] These symptoms
cut across three recognised symptom clusters (re-experiencing,
avoidance or numbing and hyperarousal), produce distress and
impairment for individuals, and form the essential targets for
treatment. The Diagnositic and Statistical Manual of Mental Disorders,
Fifth Edition (DSM-V) includes an additional cluster of symptoms
characterised by negative alterations in cognition and mood. The
full symptom picture must be present for more than 1 month for
the diagnosis to be made.[6] PTSD is classified in the category of
trauma- and stressor-related disorders, and separate from the anxiety
disorders, in the DSM-V. Risk factors that increase the likelihood
of PTSD include severity of the traumatic exposure, history of past
trauma or previous psychiatric disorder, female gender, experience of
further stressful events and lack of social support.
3. Assessment
As a general rule, a comprehensive review of the differential diagnosis
of the anxiety symptoms should be done, ruling out or treating other
psychiatric diagnoses and medical causes. Thus, as part of the initial
diagnostic assessment, and after each subsequent treatment trial,
should response to treatment be unsatisfactory, it is important to
evaluate symptoms associated with PTSD (e.g. insomnia, aggression,
nightmares, suicidality, psychotic symptoms). Other considerations
include comorbid diagnoses (including depression, other anxiety
disorders, substance abuse, bipolar disorder), other issues such as
187 SAJP - August 2013 Vol. 19 No. 3
concurrent medical illness especially that which may be undiagnosed
(e.g. thyroid disease), ongoing trauma, and legal/compensation issues,
ongoing use of anxiety-producing substances (e.g. caffeine, other
stimulants), pregnancy, and poor adherence to treatment.[7] Those
with PTSD, with and without depression, are at increased risk for
suicidality, and it is important to assess suicide risk both at the initial
evaluation and subsequent follow-up visits.[7]
Longitudinal studies indicate that PTSD is a disorder of chronicity
in that symptoms appear shortly after the traumatic event, subside
in many individuals, but can persist in as many as 40% in the form
of chronic PTSD.5 Given that a significant number of cases of PTSD
are undiagnosed and undertreated, it is important to inquire about
exposure to trauma, and to maintain a high index of suspicion and
a high level of awareness of the disorder. Patients with PTSD are
frequent users of general medical and psychiatric services, have
high rates of coexisting psychiatric (e.g. major depressive disorder,
alcohol and drug use disorders, other anxiety disorders) and medical
conditions (e.g. asthma, gastrointestinal disorders), and, as already
mentioned, are at a high risk for suicide attempts.[8,9] These comorbid
diagnoses may complicate proper diagnosis and alter the course
of treatment. The disorder is also highly reactive to environmental
reminders of the traumatic event and to subsequent stressful life
events and can therefore have a fluctuating course.
4. Treatment
4.1 Treatment goals in PTSD
There are several specific goals of treatment that should all be borne in
mind: reducing symptom severity; preventing the occurrence of, and/
or treating, comorbid disorders; decreasing functional impairment;
modifying pathogenic fear schemas; building resilience; preventing
relapse; and improving quality of life of patients.[10] The most common
definitions of treatment response in PTSD patients are a decrease of
30% or more[11] in the Clinician Administered PTSD Scale (CAPS)
score[12] or a score of 1 (‘very much’) or 2 (‘much improved’)[13] in the
Clinical Global Impressions Scale-Improvement item (CGI-I).[14]
4.2 General aspects of treatment
The treatment of PTSD has been the subject of several recent meta-
analyses and systematic reviews. Several treatment guidelines are
available and these together have informed the treatment guideline
that is recommended here. They include guidelines from the World
Federation of Societies of Biological Psychiatry,[15] the US Institute
of Medicine (IOM),[16] the American Psychiatric Association,[17]
the UK National Institute of Clinical Excellence (NICE),[18] the
Australian National Centre for PTSD,[19] the British Association for
Psychopharmacology,[20] and the International Psychopharmacology
Algorithm Project (IPAP).[7] All of these guidelines acknowledge that
there are two distinct approaches that are of proven benefit in PTSD:
pharmacological and psychotherapeutic. Therefore, the first choice

to be made is whether to offer medication, psychotherapy, or both.
Psychotherapeutic treatments, if not used initially, can be added to, or
replace pharmacotherapy.
Chronic PTSD is defined as PTSD of more than 3 months’ duration.
Most treatment guidelines recommend the use of either selective
serotonin reuptake inhibitors (SSRIs) or exposure-based, trauma-
focused cognitive-behaviour therapy (TF-CBT) as first-line therapy.
However, it should be mentioned that both the US IOM guidelines[16]
and the UK NICE guidelines[18] on the sum of data suggest that
evidence for the efficacy of pharmacological therapies, namely
SSRIs, is at best tentative. The NICE guidelines,[18] for example, do
not recommend drug treatments as a routine first line for adults
with PTSD (for prescription either by a general practitioner or
psychiatrist), but rather advocate for the use of TF-CBT.
4.3 Acute treatment
An adequate trial requires 6 - 12 weeks, but the clinician should expect
some response after 4 - 6 weeks with adequate dosage. A minimum
course of exposure-based, TF-CBT is 8 - 12 weekly or biweekly
sessions for exposure to a single-incident trauma. More sessions
may be required in instances of multiple traumatic exposures or the
presence of comorbidity.
4.4 Maintenance treatment
PTSD is a disorder that is characterised by symptom persistence and
long-term treatment for at least 12 - 24 months is recommended. The
SSRIs and the serotonin-norepinephrine reuptake inhibitor (SNRI),
venlafaxine, have demonstrated long-term efficacy.
4.5 Pharmacological treatment
The SSRIs and SNRIs are the two groups of antidepressants that
have, to date, been the most rigorously studied in placebo-controlled
randomised controlled trials (RCTs) and are considered as first-line
agents for PTSD. Long-term efficacy (treatment for at least 12 - 24
months) has also been demonstrated with both classes of agents.[15]
Of the SSRIs, paroxetine, sertraline and fluoxetine currently have
the best evidence for efficacy.[7,15-17] Paroxetine and sertraline are
the only two that are US Food and Drug Administration (FDA)
indicated for PTSD. In a meta-analysis of 35 RCTs (of 14 weeks or
less in duration) involving a total of 4 597 participants, evidence
for efficacy was most convincing for the SSRIs, across all symptom
clusters and for co-occurring depression and disability.[13] However,
the SSRIs as a class seem to be less effective in combat-related PTSD
than in non-combat-related PTSD.[17] Even when treated with this
class of agents, response rates in PTSD rarely exceed 60% after a first
trial of medication and less than 20 - 30% of patients achieve full
remission. [7,15-17] This suggests that currently available, efficacious
agents still fall short of the ideal because of limited response and
remission rates, and tolerability issues.
4.6 Non-pharmacological treatment
There are now more than 50 published RCTs examining the efficacy
of CBT for PTSD.[20] TF-CBT has the best established research base of
well-designed RCTs. Prolonged exposure has been found to be highly
effective in the treatment of women with PTSD following sexual or
GUIDELINE
physical assault. A minimum course of 8 - 12 weekly or biweekly
sessions is recommended.
The components of CBT associated with the largest treatment effects
are cognitive therapy (CT) and prolonged exposure; they have been
shown to be superior to waitlist, supportive counselling, non-specific
therapies; and treatment as usual.[21] Eye movement desensitisation and
reprocessing (EMDR) which combines imaginal exposure with lateral
eye movements, like exposure and CT, also has established efficacy, but
critics of this procedure cite poor methodological quality and evidence
that the procedural component, which is purported to differentiate
it from exposure, is in fact ‘inactive’.[22] A recent Cochrane review[22]
concluded that EMDR was more effective than traditional therapies
or no therapy but not different from CBT and stress management.The
IOM found the quality of the body of evidence for EMDR to be too low
to inform conclusions regarding treatment efficacy.[16]
4.7 Special populations
4.7.1 Pregnancy and lactation
The risks of drug treatment during pregnancy need to be weighed
against the risks of withholding treatment for PTSD. During the first
trimester, SSRIs do not increase the risk of birth defects; the exception
to this is paroxetine, which is associated with a 1.5-fold increased risk
of congenital heart defects.[23] Clinical guidelines recommend that
paroxetine be discontinued during pregnancy. SSRIs taken after 20
weeks’ gestation may be associated with an increased risk of persistent
pulmonary hypertension in the neonate, and all antidepressants
administered in the third trimester may cause discontinuation
effects (e.g. increased muscle tone, irritability, disrupted sleep,
jitteriness) although these tend to be mild and self-limiting. Newer
antidepressants, such as venlafaxine, have been associated with poor
neonatal adaptation syndrome (tremors, irritability, shivering, feeding
disturbances, increased muscle tone, respiratory difficulties) although
it is unclear whether this is the result of medication withdrawal or
toxicity. Treatment is supportive and symptoms usually resolve within
2 weeks. Tricyclic antidepressants (TCAs) are regarded as relatively
safe in pregnancy although there is an increased risk of preterm
delivery compared with SSRIs or no antidepressants. Desipramine
is the preferred TCA during pregnancy owing to its relatively
weak anticholinergic effects.[24] Lithium (Ebstein’s anomaly) and
antiepileptic medications such as carbamazepine (neural tube defects,
craniofacial defects, cardiac malformations) and valproate (neural
tube defects, spina bifida, pulmonary atresia) carry an increased
risk of birth defects. To date, lamotrigine has not been associated
with intrauterine growth defects or neurobehavioural toxicity. No
significant risk of teratogenicity with the older atypical antipsychotics
(olanzapine, risperidone, quetiapine) has been documented. However,
the aforementioned antipsychotics are associated with maternal
hyperglycaemia, impaired glucose tolerance and weight gain which
could contribute to maternal complications during pregnancy.[24]
Newer atypical antipsychotics (e.g. aripiprazole, ziprasidone) have
been associated with delays in skeletal ossifications, increased fetal
weight and fetal mortality.
Long-term safety data on the use of antidepressants in pregnancy
are lacking. Important factors to consider include the time between
medication administration and feeding, and infant size and infant
August 2013 Vol. 19 No. 3 - SAJP 188
GUIDELINE
metabolism. Most SSRIs do not attain detectable levels in breast
milk and are not associated with disturbed infant development or
neuropathology. Sertraline and paroxetine may be good choices for
lactating women as these SSRIs have specifically been associated with
undetectable levels in infants. TCAs have been associated with few
adverse effects in breastfed infants, while newer antidepressants such
as venlafaxine and mirtazapine are considered to be moderately safe.
4.7.2 Children and adolescents
Young children with PTSD, rather than reliving the trauma through
repeated intrusive memories, may re-experience the trauma through
repetitive play. Avoidance phenomena may also be more difficult
to elicit in very young children who may struggle to verbalise their
experiences. In addition to PTSD and acute stress disorder (ASD),
traumatised children and adolescents may have a broad range of
other psychopathological outcomes, in particular mood and anxiety
disorders, behavioural disorders (e.g. attention-deficit hyperactivity
disorder, conduct disorder), and substance use disorders. As with
adults, interventions comprising psychotherapy (e.g. TF-CBT, family
therapy) and pharmacotherapy (e.g. SSRIs, alpha-adrenergic agonists)
are used. Practice parameters developed by the American Academy of
Child and Adolescent Psychiatry[25] recommend that the treatment of
mild PTSD begin with TF-CBT. Treatment studies suggest 12 sessions
of TF-CBT where PTSD is uncomplicated, but a number of children
and adolescents may require longer-term treatment. Currently little
is known about the effectiveness of pharmacotherapeutic agents in
paediatric PTSD as there have been few controlled studies of SSRIs.
Children and adolescents with more severe PTSD and with comorbid
mood and anxiety disorders are likely to benefit from an SSRI.[25]
4.7.3 The elderly
The assessment and treatment of PTSD may pose challenges for
psychiatrists involved in treating PTSD in older adults. Specific
symptom profiles may differ in the older adult, particularly in those
individuals with chronic PTSD. Distress when exposed to trauma-
related cues appears to be potentially salient and it is possible that
this symptom motivates other features of PTSD in older adults,
such as avoidance and emotional numbing.[26] This constellation of
symptoms may lead to misdiagnosis, for example, major depression
or dysthymic disorder. Several factors should be considered when
selecting a medication for an older patient with PTSD. These include
prior treatment response, target symptoms, concurrent physical
illness and medications, and drug tolerability. In order to reach the
optimal dose for an older patient without causing intolerable side-
effects, it is well worth remembering the adage ‘start low and go
slow’. Important considerations in pharmacological treatment also
include the heightened sensitivity for anticholinergic drug effects,
increased sensitivity for extrapyramidal symptoms, an increased
risk for orthostatic hypotension and electrocardiograph changes,
and the possibility of paradoxical reactions (e.g. aggression) to
benzodiazepines. SSRIs have been shown to be relatively safe in the
elderly and are generally better tolerated than TCAs. Recommended
doses of SSRIs for PTSD are the same as for younger adults. However,
the potential for SSRIs to cause gastrointestinal and other bleeds,
hyponatraemia, postural hypotension, and falls needs to be borne in
mind in this age group.
189 SAJP - August 2013 Vol. 19 No. 3
4.8 Managing partial and non-responders
See steps 3 and 4 of algorithm below.
4.9 Algorithm
Step 1. Initiating treatment
The starting dose can be low (fluoxetine 10 - 20 mg; sertraline 25 - 50
mg; paroxetine, 10 - 20 mg; venlafaxine 37.5 - 75 mg). Other SSRIs
include citalopram (10 - 20 mg), fluvoxamine (25 - 50 mg) and
escitalopram (5 - 10 mg), for which there is less evidence. Based on
currently available data for the SSRIs and SNRIs, statistically and
clinically significant improvement is often seen by weeks 2 to 4. An
adequate trial typically requires 6 - 12 weeks at an adequate dosage (e.g.
fluoxetine 20 - 40 mg; sertraline 50 - 100 mg; paroxetine 20 - 40 mg), but
some response should be expected after 4 - 6 weeks.[7]
Other antidepressant options for which there is less robust
evidence include mirtazapine, bupropion, and nefazodone. The
older antidepressants, such as TCAs, e.g. amitriptyline, imipramine
and the monoamine oxisase inhibitors (MAOIs, e.g. phenelzine)
have demonstrated efficacy in placebo-controlled studies that have
primarily included individuals with combat-related PTSD. In light
of the safety profiles and concerns of toxicity with these agents
(cardiotoxicity, seizure risk, and anticholinergic effects with the
TCAs, and dietary restrictions and risk of hypertensive crisis with
the MAOIs), they should preferably not be used as a first or second
choice.[7,15-17] Table 1 lists recommended drug doses.[15]
Step 2. Maintaining a response
It is important to note that while many patients will experience
symptom improvement within 12 weeks with at least a 50% reduction
in PTSD symptoms, further improvement in core symptoms, disability,
and overall functioning often occurs with continued treatment. If a
patient is adequately responsive (at least a 50% improvement) after
12 weeks of treatment and demonstrates no intolerance, medication
should be continued for at least 1 - 2 years .
Step 3. Managing partial response
If the patient is only partially responsive to the first trial of medication
(25 - 50% or more reduction in symptoms), it is prudent firstly to
optimise the dose of medication (i.e. titrate up to the maximum
allowed or tolerated dose). Before doing this, it is important to reassess
for persisting core PTSD symptoms (intrusion, avoidance, numbing,
and hyperarousal), sleep disturbances, other PTSD symptoms (e.g.
irritability, hostility, aggression, panic, psychotic symptoms), bipolar
spectrum disorder, and substance abuse.[7]
These ongoing symptoms can be saliently targeted through
augmentation strategies although it must be noted that the evidence-
base for augmentation strategies is limited. For example, olanzapine
and risperidone (for which there is double-blind, placebo-controlled
evidence for efficacy) can be used to target associated psychotic
symptoms (e.g. paranoid ideation), and aggression. It is important
to mention that since augmentation studies of antipsychotics
were essentially short-term trials, the possibility of occurrence
of severe adverse effects (viz. metabolic effects, cardiac effects,
tardive dyskinesia) remain a concern. Anticonvulsants (e.g. valproate,
lamotrigine, carbamazepine, topiramate), given their well-known
anti-kindling properties, may also be effective as augmentation

Table 1. Recommended daily drug doses for post-traumatic
stress disorder[15]*
Selective serotonin reuptake inhibitors (SSRIs)
Fluoxetine 20 - 40 mg
Sertraline 50 - 100 mg
Paroxetine 20 - 40 mg
Serotonin-norepinephrine reuptake inhibitors (SNRI)
Venlafaxine 75 - 300 mg
Noradrenergic and specific serotonergic antidepressants (NaSSA)
Mirtazapine 30 - 60 mg
Tricyclic antidepressants (TCAs)
Amitriptyline 75 - 200 mg
Imipramine 75 - 200 mg
Atypical antipsychotics
Risperidone 0.5 - 6 mg
Olanzapine (adjunctive) 2.5 - 20 mg
Other agents
Lamotrigine 25 - 500 mg
Prazosin (for nightmares) 1 - 10 mg
Phenelzine (MAOI) 45 - 90 mg
*Reprinted with permission from Bandelow B, Zohar J, Hollander E, et al. World Federation of
Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of anxi-
ety, obsessive compulsive and post-traumatic stress disorders – first revision. World Journal of
Biological Psychiatry 2008;9:248-312. Informa Healthcare. For educational purposes only.
for symptoms of irritability, impulsivity, labile mood, and anxiety,
while alpha-1 inhibiting agents (e.g. prazosin, guanfacine) have
shown promise in the treatment of nightmares, insomnia and other
sleep-related disturbances in PTSD.[27] Hypotension, syncope and
tachycardia are potential side-effects with prazosin; hence medical
history, risks of hypotension and blood pressure monitoring should
be considered. No data exist on the efficacy of benzodiazepines as
augmentation treatment, although there are some data indicating
their lack of efficacy as monotherapy (e.g. alprazolam) in chronic
PTSD.[28]
Exposure-based, TF-CBT (8 - 12 sessions) may also be considered
as an augmentation strategy at this point. However, there are currently
no published controlled studies of combined pharmacotherapy and
psychotherapy in PTSD.
Step 4. Managing non-response
If there is no response (i.e. less than 25% improvement) to an SSRI
and core PTSD symptoms persist after 4 - 6 weeks of an adequate
medication dose (e.g. fluoxetine 40 mg/day, sertraline 150 mg/day),
then it is advisable to switch to another SSRI, SNRI, or noradrenaline
and specific serotonergic antidepressant (NaSSA) such as mirtazapine,
bupropion; or alternatively to augment the same medication with
another agent. The choice of an augmentation agent will depend on
the presence of comorbid disorders; for example, the presence of a
comorbid anxiety or mood disorder would probably necessitate the
utilisation of an agent (e.g. antidepressant) that is effective for both
PTSD and that disorder.[20] It is not known whether a sequential trial of
a second SSRI is as effective as switching to an SNRI or NaSSA after the
GUIDELINE
first unsuccessful SSRI trial. [20] If there is still no response after 6 - 12
weeks, then it is recommended that one add an atypical antipsychotic,
anticonvulsant, a TCA, or CBT. If the patient fails on all of the above,
it is essential at this point to re-evaluate the diagnosis and to consider
switching (e.g. to a TCA or MAOI if these have not been tried already)
or to add a third medication.
4.10 Early interventions for PTSD
TF-CBT is the only early intervention (i.e. given 1 - 3 months after
trauma) that at the present time has convincing evidence of efficacy in
ASD and acute PTSD.[20] There is no good evidence that psychological
interventions (i.e. psychological debriefing), either single or multiple
sessions, given routinely to everyone following a traumatic exposure,
irrespective of symptoms, work. At present there is no conclusive
evidence for the use of drug treatments to prevent PTSD in the early
aftermath of trauma. Benzodiazepines are frequently prescribed in
the aftermath of a traumatic event to control associated nonspecific
behavioural disturbances (e.g. marked anxiety or agitation, insomnia)
and/or to reduce active post-traumatic symptoms (e.g. hypervigilance).
However, there is no compelling scientific evidence of the effectiveness
of benzodiazepines either in the prevention of PTSD or in the treatment
of core PTSD symptoms once they have developed.[22] In fact, there
is evidence to indicate that benzodiazepines may contribute to the
development and/or chronicity of PTSD symptoms.[28,29]
5. Summary points
• PTSD is a challenging disorder to treat.
• It should be recognised that the majority of individuals with PTSD
in South Africa may not have guaranteed access to diagnostic,
pharmacotherapeutic and evidence-based psychotherapeutic
services as suggested in this guideline.
• Antidepressants (in particular SSRIs) and CBT (exposure-based,
trauma-focused CBT) remain the mainstay of treatment for the
disorder.
• Use an SSRI or SNRI as first-line therapy and treat the patient at the
maximum tolerated dose for at least 4 - 6 weeks before assessing
responsiveness.
• Once a patient has responded to drug treatment, it should be
continued for at least 12 - 24 months before considering gradual
withdrawal.
• Cost should be factored into the choice of medication; the most
affordable medication should preferably be selected to allow for
funding of the minimum of 1 year of suggested pharmacotherapy.
• The minimum course of exposure-based, trauma-focused CBT is
8 - 12 weekly or biweekly sessions for exposure to a single-incident
trauma.
• In deciding on a treatment plan for the patient, it is important to
consider the following at baseline and follow-up assessments: the
presence of ongoing trauma, comorbid diagnoses (both psychiatric
and medical), suicidality, substance abuse, psychosis, pregnancy,
treatment compliance, pharmacokinetic (drug-drug interaction)
issues, and legal or compensation issues.
• There is no evidence for the efficacy of systematic, brief, single-
session interventions (i.e. debriefing) focusing on the traumatic
incident. However, providing general practical and social support and
guidance to anyone following a traumatic incident is recommended.
August 2013 Vol. 19 No. 3 - SAJP 190
GUIDELINE
• The quest to investigate novel pharmacological agents (e.g.
D-cycloserine, a partial agonist of N-methyl-D-aspartate (NMDA)
receptor through its mechanism on fear extinction) and therapeutic
strategies (e.g. virtual reality exposure therapy), for the management
of PTSD remains an ongoing pursuit.
• Several other novel agents (e.g. propranolol, hydrocortisone) have
been investigated in the prevention of PTSD (i.e. as prophylaxis)
with mixed results. Currently SSRIs are being investigated in
placebo-controlled trials as an early intervention in ASD to prevent
the later development of PTSD. However, there is insufficient
evidence to recommend the use of any of these agents.
References
1. Kessler RC, Berglund P, Demler O, et al. Lifetime prevalence and age-of-onset distributions
of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry
2005;62:593-602. [http://dx.doi.org/10.1001/archpsyc.62.6.593]
2. Kessler RC, Chiu WT, Demler O, et al. Prevalence, severity, and comorbidity of 12-month DSM-
IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 2005;62:617-
627. [http://dx.doi.org/10.1001/archpsyc.62.6.617]
3. Herman AA, Stein DJ, Seedat S, et al. The South African Stress and Health (SASH) study:
12-month and lifetime prevalence of common mental disorders. S Afr Med J 2009;99:339-344.
4. Carey PD, Stein DJ, Zungu-Dirwayi N, Seedat S. Trauma and posttraumatic stress disorder in an
urban Xhosa primary care population: Prevalence, comorbidity, and service use patterns. J Nerv
Ment Dis 2003;191:230-236.
5. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth
Edition, Text Revision (DSM-IV-TR). Washington, DC: American Psychiatric Association, 2000.
6. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (5th
ed.). Arlington, VA: American Psychiatric Association, 2013.
7. Davidson JRT, Bernick M, Connor KM, et al. A psychopharmacology algorithm for treating
posttraumatic stress disorder. Psychiatr Ann 2005;35:887-898.
8. Hidalgo RB, Davidson JR. Posttraumatic stress disorder: Epidemiology and health-related
considerations. J Clin Psychiatry 2000;61:5-13.
9. Nock MK, Hwang I, Sampson N, et al. Cross-national analysis of the associations among mental
disorders and suicidal behavior: findings from the WHO World Mental Health Surveys. PLoS
Med 2009;6:e1000123.
10. Ursano JR, Bell C, Eth S, et al. Practice guideline for the treatment of patients with acute stress
disorder and posttraumatic stress disorder. Am J Psychiatry 2004;161:S3-S31.
11. Hamner MB, Robert S, Frueh BC. Treatment-resistant posttraumatic stress disorder: Strategies for
intervention. CNS Spectrums 2004;9:740–752.
12. Blake DD, Weathers FW, Nagy lM. A clinical rating scale for assessing current and lifetime PTSD:
The CAPS 1. Behavioral Therapy 1990;18:187-188.
191 SAJP - August 2013 Vol. 19 No. 3
13. Stein DJ, Ipser JC, Seedat S. Pharmacotherapy for post traumatic stress disorder (PTSD).
Cochrane Database of Syst Revi 2006;1:CD 002795.
14. Guy W. ECDEU Assessment Manual for Psychopharmacology. Washington, DC: Government
Printing Office, 1976.
15. Bandelow B, Zohar J, Hollander E, et al. World Federation of Societies of Biological Psychiatry
(WFSBP) guidelines for the pharmacological treatment of anxiety, obsessive compulsive and
post-traumatic stress disorders–first revision. World J Biol Psychiatry 2008;9:248-312. [http://
dx.doi.org/10.1080/15622970802465807]
16. Committee on Treatment of Posttraumatic Stress Disorder. Treatment of Posttraumatic Stress
Disorder: An Assessment of the Evidence. Washington, DC: The National Academies Press,
2008.
17. Ursano RJ, Bell C, Eth S, et al. Practice guideline for the treatment of patients with acute stress
disorder and posttraumatic stress disorder. Am J Psychiatry 2004;161:3-31.
18. National Collaborating Centre for Mental Health. Post-traumatic Stress Disorder: The
Management of Post-traumatic Stress Disorder in Primary and Secondary Care. London:
National Institute for Health and Clinical Excellence, 2005.
19. Forbes D, Creamer M, Phelps A, et al. Australian guidelines for the treatment of adults with
acute stress disorder and post-traumatic stress disorder. Aust N Z J Psychiatry 2007;41:637-648.
20. Baldwin DS, Anderson IM, Nutt DJ, et al. Evidence-based guidelines for the pharmacological
treatment of anxiety disorders: Recommendations from the British Association for
Psychopharmacology. J Psychopharmacol 2005;19:567-596.
21. Watts BV, Schnurr PP, Mayo L, Young-Xu Y, Weeks WB, Friedman MJ. Meta-analysis of the
efficacy of treatments for posttraumatic stress disorder. J Clin Psychiatry 2013;74(6):e541-e550.
[http://dx.doi.org/10.4088/JCP.12r08225]
22. Cloitre M. Effective psychotherapies for posttraumatic stress disorder: A review and critique.
CNS Spectrums 2009;14:32-43.
23. Reid S, Barbui C. Long term treatment of depression with selective serotonin reuptake
inhibitors and newer antidepressants. BMJ 2010;340:752-756. [http://dx.doi.org/10.1136/
bmj.c1468]
24. Kloos AL, Dubin-Rhodin A, Sackett JC, et al. The impact of mood disorders and their
treatment on the pregnant woman, the fetus, and the infant. Curr Psychiatry Rep 2010;12:96-
103. [http://dx.doi.org/10.1007/s11920-010-0098-6]
25. American Academy of Child and Adolescent Psychiatry. Practice parameters for the
assessment and treatment of children and adolescents with posttraumatic stress disorder. J Am
Acad Child Adolesc Psychiatry 1998;37:4S-26S.
26. Averill PM, Beck JG. Posttraumatic stress disorder in older adults: A conceptual review. J
Anxiety Disord 2000;14:133-156.
27. Berger W, Mendlowicz MV, Marques-Portella C, et al. Pharmacologic alternatives
to antidepressants in posttraumatic stress disorder: a systematic review. Prog
Neuropsychopharmacol Biol Psychiatry 2009;33:169-180. [http://dx.doi.org/10.1016/j.
pnpbp.2008.12.004]
28. Gelpin E, Bonne O, Peri T, et al. Treatment of recent trauma survivors with benzodiazepines:
A prospective study. J Clin Psychiatry 1996;57:390-394.
29. Mellman TA, Bustamante V, David D, Fins AI. Hypnotic medication in the aftermath of
trauma. J Clin Psychiatry 2002;63:1183-1184.

Social anxiety disorder (social phobia)
S Seedat
1. Introduction
According to epidemiological studies, rates of social anxiety disorder
(SAD) or social phobia range from 3% to 16% in the general
population.[1,2] Social phobia and specific phobias have an earlier age
of onset than other anxiety disorders. The median age of onset for the
disorder is 13 years with an onset after age 25 relatively uncommon.
The disorder typically persists throughout adult life and is associated
with significant functional impairment.[3-5] Individuals with SAD are
more likely to be females; however in clinical samples SAD seems to be
more equally distributed among men and women.[4]
2. Diagnosis and clinical characteristics
SAD is characterised by an exaggerated and persistent fear of being
negatively evaluated in social and performance situations.[6] The
disorder is associated with physical, cognitive and behavioural
disturbances. The generalised subtype consists of fears of most
interactional and performance situations, while the non-generalised (or
circumscribed) subtype is restricted to a few specific situations, such as
public speaking or dating.[4,5] The generalised subtype or generalised
social anxiety disorder (GSAD) is associated with greater comorbidity,
chronicity, and functional impairment.[7] The avoidance of feared
situations impacts on daily routine, work, academic and social activities
and relationships. More than 80% of patients with SAD have a lifetime
history of at least one other psychiatric disorder, most commonly major
depression, panic disorder, generalised anxiety disorder, agoraphobia
and substance use disorders.[5-7] There is also considerable overlap
between SAD and avoidant personality disorder. [6,7]
SAD generally runs a chronic course and precedes mood, anxiety
and substance use disorders. Even in the absence of comorbidity, SAD
is associated with significant distress, including financial problems,
increased suicidal thoughts, reduced work and school performance,
poor social support and greater use of psychotropic medications.[5]
Despite significant suffering, only 50% of patients with SAD ever seek
treatment and when they do, it is usually when a comorbid condition
develops and necessitates treatment.[8]
3. Assessment
There are several aspects of the clinical presentation of patients with
SAD that may impact on treatment decisions.
First, it is important to assess the level of disability to help distinguish
social phobia from shyness.[9]
Second, SAD may be complicated by comorbid major depression,
which is usually responsive to first-line therapy options (e.g. selective
serotonin reuptake inhibitors (SSRIs) and dual-acting serotonin-
norepinephrine reuptake inhibitors (SNRIs)). Conversely, social anxiety
symptoms should be excluded in patients presenting with depression,
panic attacks restricted to social situations, or alcohol misuse.
Third, in patients with alcohol and substance use disorders
it is generally advisable to detoxify first, prior to commencing
pharmacotherapy for SAD.
GUIDELINE
Fourth, in women, pregnancy and lactation considerations may
necessitate the use of a non-pharmacological intervention (e.g.
cognitive-behavioural therapy) as first-line.
Fifth, the presence of comorbid medical disorders and the
prescription of concurrent medications must be borne in mind when
using an anti-anxiety agent, particularly in view of the potential for
drug-drug interactions and the potential impact of pharmacotherapy
for SAD on underlying medical conditions.
4. Treatment
4.1 Treatment goals
The need for treatment is determined by the severity and persistence
of symptoms, the presence of comorbid psychiatric disorder or
physical illness, the level of disability and impact on social functioning,
concomitant medication, and a history of good response to, or poor
tolerability of, previous treatment approaches. In line with this, the
main goals of treatment in SAD are to treat core symptoms and
comorbidities, reduce functional impairment and avoidance, and
improve the quality of life.
4.2 General aspects of treatment
Several treatment guidelines are available including those from
the World Federation of Societies of Biological Psychiatry,[10]
World Council on Anxiety, [11] the British Association for
Psychopharmacology[9] and the Canadian Psychiatric Association.[12]
Broadly speaking, these guidelines advocate for both pharmacological
and non-pharmacological approaches in the management of SAD.
4.3 Acute treatment
Current evidence clearly supports the use of SSRIs (escitalopram,
fluvoxamine, fluvoxamine controlled release (CR), paroxetine,
sertraline) and the SNRI venlafaxine extended release (ER) as first-
line pharmacological agents in the treatment of GSAD. Improvement
in symptoms should become manifest by week 4; however, up to
12 weeks of treatment are needed to more definitively assess efficacy.
In terms of psychotherapy, cognitive-behavioural therapy (CBT)
is the treatment of choice. There is no conclusive evidence that
pharmacotherapy is more effective than CBT or vice versa and the
evidence in favour of the combination of pharmacotherapy and CBT
is also limited.
4.4 Maintenance treatment
Drug treatment should be continued for a minimum period of 6
months in patients who have responded at 12 weeks. Several long-
term studies (double-blind and open-label) have been conducted
to examine the issue of relapse prevention.[13] These studies have
evaluated moclobemide, phenelzine and CBT, sertraline and exposure
therapy, fluvoxamine, paroxetine and escitalopram and venlafaxine
ER. Response rates in these studies range from 58% for venlafaxine ER
to 88% for escitalopram.
August 2013 Vol. 19 No. 3 - SAJP 192
GUIDELINE
4.5 Pharmacological treatment
Evidence from controlled trials indicates that SAD is responsive to a
wide range of medication treatments.[4] Drugs recommended as first-
line treatment include SSRIs (escitalopram, fluvoxamine, paroxetine
and sertraline) and the SNRI, venlafaxine. In a meta-analysis of
efficacy of the SSRIs, which examined outcomes from 15 separate
controlled studies (including trials of escitalopram, sertraline,
paroxetine, fluoxetine and fluvoxamine), all agents with the exception
of a single trial of fluoxetine (which did not separate from placebo),
showed efficacy in ameliorating symptoms of SAD.[14] Venlafaxine has
also been widely studied and venlafaxine ER has regulatory approval
for SAD in a number of countries.[4] In a head-to-head comparison
of venlafaxine and paroxetine, venlafaxine ER was as effective as
paroxetine, and both drugs were better than placebo.[15] The efficacy
of venlafaxine ER in SAD does not appear to be dose-related, i.e. lower
(75 mg/day) and higher (150 - 225 mg/day) doses have produced
similar therapeutic effects in trials.[16] The other SNRI, duloxetine, has
not been studied in controlled trials for SAD.
In addition to the SSRIs and venlafaxine, the monoamine
oxidase inhibitor (MAOI) phenelzine and the reversible inhibitor of
monoamine oxidase (RIMA) moclobemide have controlled evidence
for efficacy. Phenelzine is not widely used because of its requirement
of a low tyramine diet to prevent a hypertensive crisis. Moclobemide
has demonstrated comparable effectiveness among patients with and
without a comorbid anxiety disorder, as well as among patients with
different SAD subtypes (generalised and non-generalised SAD).[17]
There is preliminary evidence from randomised controlled trials
for the efficacy of pregabalin and gabapentin. Open trials of other
anticonvulsants (e.g. levetiracetam, tiagabine, topiramate) and the
antipsychotic olanzapine show some promise as acute treatments, but
adequate randomised controlled trials (RCTs) are lacking.[4,10]
Evidence for the efficacy of benzodiazepines (bromazepam and
clonazepam) in SAD is mixed.
Treatments with unproven efficacy in generalised social phobia
include the tricyclic antidepressant imipramine, buspirone, and the
beta-blocker, atenolol.[18]
4.6 Non-pharmacological treatment
The non-pharmacological treatment of choice for SAD is CBT or
exposure therapy alone. CBT for social phobia includes techniques of
psycho-education, in-session and in vivo exposure to feared situations,
and techniques intended to modify maladaptive or irrational thinking
patterns. Other techniques in the CBT umbrella are applied relaxation
and social skills training. The relative efficacy of CBT vs exposure
therapy is unclear, with some studies indicating comparable efficacy
while other studies show somewhat greater efficacy for CBT.[4,10] In
a recent meta-analysis of 32 RCTs that examined a variety of non-
pharmacological approaches, CBT was consistently shown to result
in significantly greater improvements in SAD symptoms than other
‘placebo’ conditions, such as supportive group therapy, self-exposure,
being wait-listed (i.e. waiting for an intervention) or pill placebo.[19]
4.7 Special populations
4.7.1 Pregnancy and lactation
The risks of drug treatment during pregnancy need to be weighed
against the risks of withholding treatment for SAD. During the
193 SAJP - August 2013 Vol. 19 No. 3
first trimester, SSRIs do not increase the risk of birth defects; the
exception to this is paroxetine which is associated with a 1.5-fold
increased risk of congenital heart defects.[20] Clinical guidelines
recommend that paroxetine be discontinued during pregnancy.
SSRIs taken after 20 weeks of gestation may be associated with an
increased risk of persistent pulmonary hypertension in the neonate,
and all antidepressants administered in the third trimester may
cause discontinuation effects (e.g. increased muscle tone, irritability,
disrupted sleep, jitteriness) although these tend to be mild and self-
limiting. There are no data, other than a single case report, on the safety
of moclobemide during pregnancy, while there are limited data on the
safety of the MAOIs. As animal studies are suggestive of teratogenicity
and use of MAOIs necessitates dietary modifications, MAOIs are
not considered first-line treatments for SAD in pregnancy. Newer
antidepressants, such as venlafaxine, have been associated with poor
neonatal adaptation syndrome (tremors, irritability, shivering, feeding
disturbances, increased muscle tone, respiratory difficulties) although
it is unclear whether this is the result of medication withdrawal
or toxicity. Treatment is supportive and symptoms usually resolve
within 2 weeks. In general, venlafaxine is considered to be moderately
safe in pregnancy. Benzodiazepine use during pregnancy has been
associated with neonatal morbidity, some congenital malformations
such as orofacial cleft, and may be associated with an increased risk for
preterm birth, low birth weight, floppy infant syndrome, and neonatal
withdrawal symptoms. Clonazepam monotherapy, specifically, has
not been associated with an increased risk of major malformations.
Gabapentin has been shown to be teratogenic in mice; its safety in
pregnant women has not been established and is best avoided during
pregnancy.[20]
Long-term safety data on the use of antidepressants in pregnancy
are lacking. Factors that are important to consider include the time
between medication administration and feeding, and infant size and
infant metabolism. Most SSRIs do not attain detectable levels in breast
milk and are not associated with disturbed infant development or
neuropathology. Sertraline and paroxetine may be good choices for
lactating women as these SSRIs have specifically been associated with
undetectable levels in infants. Benzodiazepines, such as clonazepam,
diazepam and lorazepam, are excreted in breast milk. However,
published data indicate that the levels detected in breast milk are low;
thus the nursing infant is unlikely to ingest significant amounts of the
drug in this way. Breastfeeding is possible, but the infant should be
carefully monitored for any adverse effects.
4.7.2 Children and adolescents
Shyness in young children may be a precursor to SAD in adulthood.
In children, common fears include fears about performance situations
such as speaking or performing in front of people, social interactional
fears such as joining in or starting a conversation, and interacting
with same-age peers.[21] Unlike adults, children with SAD are seen as
generally anxious and may experience more somatic symptoms, such
as headaches, stomach aches and nausea, as a result of their anxiety.
Impairments range from low self-esteem, social skills deficits, few
friendships to scholastic underachievement. Among adolescents, typical
fears include formal and informal social interactions, public observation
and performance, and situations requiring assertive behaviour. In
addition, adolescents seem to have more pervasive patterns of fear and

avoidance, as well as higher levels of social distress than either children
or adults. SAD in childhood and adolescence is highly comorbid with
depression. Comorbidity with anxiety and substance use disorders is
also common.[21]
Compared with adults, there is relatively less information available
on the safety, efficacy and long-term outcomes (relapse rates) of
SSRI or SNRI treatment. Open-label and double-blind placebo-
controlled studies have shown response rates ranging from 36% to
100%.[9-12] Fluoxetine, fluvoxamine, paroxetine and venlafaxine ER
have been evaluated in RCTs. These agents have been well tolerated
in children and adolescents in doses comparable to the adult dose.
Antidepressants, in particular SSRI use, have come under the spotlight
in recent years owing to concerns about their potential to increase
suicidal ideation and attempts.[21] While the safety profile of SSRIs
and other antidepressants specifically in children and adolescents
with SAD is not yet known, a review of 24 short-term (4 - 16 weeks)
trials involving nine antidepressant medications (including SSRIs)
in more than 4 400 youth with major depressive disorder, obsessive-
compulsive disorder, and other psychiatric disorders, documented a
4% rate of suicidal ideation and suicidal behaviours in patients treated
with antidepressants compared with a 2% rate in patients treated with
a placebo.[22] It is important to note that there were no completed
suicides in any of these studies.
CBT, as a 16-session treatment, has been shown to be an effective
strategy in both children and adolescents with SAD, with continued
improvement or maintenance of gains over a 1-year period.[21] The
benefits of combining CBT and medication for childhood SAD have
yet to be established.[21]
4.7.3 The elderly
The prevalence of SAD tends to decline in older adults (55 years of
age and older). SAD is more common in elderly patients who have
other psychiatric disorders, in particular major depression. Both
pharmacological treatments (e.g. SSRIs, venlafaxine) and CBT are
indicated for use in older adults with SAD; however, the standard of
practice has been to infer from data in younger patients and assume
their efficacy in older adults.[23]
Several factors should be considered when selecting a medication for
an older patient with SAD. Prior treatment response, target symptoms,
concurrent physical illness and medications, and drug tolerability should
all be taken into account. In order to reach the optimal dose for
an older patient without causing intolerable side-effects, it is well
worth remembering the adage ‘start low and go slow’.[23] Important
considerations in pharmacological treatment in the elderly include
heightened sensitivity for anticholinergic drug effects, increased
sensitivity for extrapyramidal symptoms, an increased risk for orthostatic
hypotension and electrocardiograph changes, and the possibility of
paradoxical reactions (e.g. aggression) to benzodiazepines. SSRIs have
been shown to be relatively safe and recommended doses of SSRIs for
SAD are the same as for younger adults. However, the potential for
SSRIs to cause gastrointestinal and other bleeds, hyponatraemia, postural
hypotension and falls needs to be borne in mind in this age group.
4.8 Managing partial and non-responders
See steps 3 and 4 of algorithm below.
GUIDELINE
4.9 Algorithm
Step 1. Initiating treatment with pharmacotherapy/psychotherapy
Choose an evidence-based pharmacological or psychological therapy
for the acute treatment of SAD.[9] Take account of patient clinical
features, needs and preference when choosing treatment. If the
decision is to start pharmacological treatment with an SSRI or SNRI,
the starting dose can be low (sertraline 25 - 50 mg; paroxetine 10 -
20 mg; venlafaxine 37.5 - 75 mg; fluvoxamine 25 - 50 mg; escitalopram
5 - 10 mg), with titration up to a maximally tolerated therapeutic dose
(Table 1). Although routine prescription of higher doses of SSRIs is
not recommended,[9] individual patients may benefit from higher
doses. For patients with comorbid mood (or anxiety) disorders, SSRIs
may be preferred because of their broad spectrum of action. There is
some evidence to suggest that major depressive disorder symptoms
tend to resolve before an improvement in SAD symptoms is seen.[24]
Evidence of symptom improvement should manifest by week 4.
However, patients should be advised that treatment periods of up
to 12 weeks are needed to assess efficacy, as there is some evidence
from double-blind controlled trials to suggest that non-responders
to treatment at 8 weeks become responders with 4 further weeks of
double-blind treatment.[25]
Step 2. Maintaining a response and preventing relapse
Double-blind studies indicate that continuing SSRI or SNRI
treatment from 12 weeks to 24 weeks (i.e. up to 6 months after
initiation) is associated with an increase in overall treatment
response rates. [9] Placebo-controlled relapse-prevention studies in
patients who have responded to previous acute treatment also reveal
Table 1. Recommended daily drug doses for social anxiety
disorder[10]*
Selective serotonin reuptake inhibitors (SSRIs)
Escitalopram 10 - 20 mg
Paroxetine 20 - 50 mg
Sertraline 50 - 150 mg
Fluvoxamine 100 - 300 mg
Citalopram 20 - 40 mg
Fluoxetine 20 - 40 mg
Serotonin-norepinephrine reuptake inhibitors (SNRI)
Venlafaxine 75 - 225 mg
Monoamine oxidase inhibitor (MAOI)
Phenelzine 45 - 90 mg
Benzodiazepines
Clonazepam 1.5 - 8 mg
Anticonvulsant
Gabapentin 600 - 3 600 mg
Reversible inhibitor of monoamine oxidase (RIMA)
Moclobemide 300 - 600 mg
*Reprinted with permission from Bandelow B, Zohar J, Hollander E, et al. World Federation
of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of
anxiety, obsessive compulsive and post-traumatic stress disorders – first revision. World Journal of
Biological Psychiatry 2008;9:248-312. Informa Healthcare. For educational purposes only.
August 2013 Vol. 19 No. 3 - SAJP 194
GUIDELINE
a significant advantage for staying on active medication (clonazepam,
escitalopram, paroxetine, sertraline) for up to 6 months, compared
with switching to placebo.[18] Therefore, continue drug treatment for
at least another 6 months in patients who are responding at 12 weeks
(i.e. show at least a 50% improvement in symptoms). Several of the
guidelines recommend continuing treatment for at least 12 months.
In patients at a high risk of relapse, it may be prudent to consider
cognitive therapy after an adequate response to drug treatment. It
is also vital that efficacy and tolerability are regularly monitored
during long-term treatment.[9]
Step 3. Managing partial response
If after 12 weeks, there is only a 25 - 50% reduction in symptoms
or a less than 25% reduction in symptoms, consider switching
to venlafaxine after non-response to acute treatment with an
SSRI. There is no clear evidence for the benefit of dose escalation
after an initial non-response. Switching between treatments with
proven efficacy is preferable. Alternative treatment strategies
include a switch to non-SSRI antidepressants, anticonvulsants and
benzodiazepines, as discussed above.
Open-label augmentation of SSRI treatment with buspirone[26] has
been reported as beneficial but placebo-controlled trials of pindolol
augmentation and clonazepam augmentation, respectively, were not
associated with greater treatment efficacy.[27,28]
Step 4. Managing non-response
If there is still no response, re-evaluate the diagnosis and reassess for
comorbid substance use disorders, undetected medical conditions,
comorbid personality disorders, psychosocial stressors and poor
compliance. Consider combining evidence-based pharmacological
treatments only where there are no contraindications to doing so. An
alternative strategy is to combine drug treatment with CBT. There
is some preliminary evidence for the usefulness of this approach. [29]
A recent randomised, double-blind placebo-controlled trial to
determine whether combined medication and cognitive behavioural
group treatment (CBGT) was superior to either monotherapy or
pill placebo found that combined phenelzine and CBGT treatment
was superior to either treatment alone and to placebo in terms
of rates of response and remission.[30] D-cycloserine, a partial
N-methyl-D-aspartate (NMDA) receptor agonist that facilitates fear
extinction, has been documented in several trials to be useful as an
augmentation to CBT in patients with SAD.
5. Summary points
• SAD is highly responsive to evidence-based acute treatments:
• Pharmacological: most SSRIs (escitalopram, fluoxetine, fluvox­
amine, paroxetine, sertraline), venlafaxine, phenelzine, moclo­
bemide, some benzodiazepines (clonazepam), anticonvulsants
(gabapentin, pregabalin) and olanzapine.
• Psychological: cognitive-behavioural therapy (CBT).
• There is no conclusive evidence that pharmacotherapy is more
effective than CBT for the treatment of social phobia.
• Treatment duration of up to 12 weeks is needed to assess efficacy.
• Drug treatment should be continued for at least a further 6 months
in patients who have responded at 12 weeks.
195 SAJP - August 2013 Vol. 19 No. 3
• Cost should be factored into the choice of medication; the most
affordable medication should preferably be selected to allow for
funding of the minimum period of suggested pharmacotherapy.
• In the longer term, consider CBT as this may reduce relapse rates
better than drug treatment.
• Monitor efficacy and tolerability regularly during long-term
treatment.
• Combining a drug and psychological approach is recommended
during the initial phase of treatment.
• Consider switching to venlafaxine after non-response to acute
treatment with an SSRI.
• Consider combining evidence-based pharmacological treatments if
there is non-response but only where there are no contraindications
to do so.
References
1. Kessler RC, Berglund P, Demler O, et al. Lifetime prevalence and age-of-onset distributions
of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry
2005;62:593-602. [http://dx.doi.org/10.1001/archpsyc.62.6.593]
2. Kessler RC, Chiu WT, Demler O, et al. Prevalence, severity, and comorbidity of 12-month DSM-
IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 2005;62:617-
627. [http://dx.doi.org/10.1001/archpsyc.62.6.617]
3. Schneier FR. Social anxiety disorder. BMJ 2003;327:515-516. [http://dx.doi.org/10.1136/
bmj.327.7414.515]
4. Westenberg HGM. Recent advances in understanding and treating social anxiety disorder. CNS
Spectrums 2009;14:24-33.
5. Schneier FR, Johnson J, Hornig CD, et al. Social phobia. Comorbidity and morbidity in an
epidemiologic sample. Arch Gen Psychiatry 1992;49:282-288. [http://dx.doi.org/10.1001/
archpsyc.1992.01820040034004]
6. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth
Edition, Text Revision (DSM-IV-TR). Washington, DC: American Psychiatric Association, 2000.
7. Ruscio AM, Brown TA, Chiu WT, et al. Social fears and social phobia in the USA: Results from the
National Comorbidity Survey Replication. Psychol Med 2008;38:15-28.
8. Wang PS, Lane M, Olfson M, et al. Twelve-month use of mental health services in the United
States: Results from the National Comorbidity Survey Replication. Arch Gen Psychiatry
2005;62:629-640. [http://dx.doi.org/10.1001/archpsyc.62.6.629]
9. Baldwin DS, Anderson IM, Nutt DJ, et al. Evidence-based guidelines for the
pharmacological treatment of anxiety disorders: Recommendations from the British
Association for Psychopharmacology. J Psychopharmacol 2005;19:567-596. [http://dx.doi.
org/10.1177/0269881105059253]
10. Bandelow B, Zohar J, Hollander E, et al. World Federation of Societies of Biological Psychiatry
(WFSBP) guidelines for the pharmacological treatment of anxiety, obsessive compulsive and post-
traumatic stress disorders – first revision. World Journal of Biological Psychiatry 2008;9:248-312.
[http://dx.doi.org/10.1080/15622970802465807]
11. Van Ameringen M, Allgulander C, Bandelow B, et al. WCA recommendations for the long-term
treatment of social phobia. CNS Spectrums 2003;8:40-52.
12. Canadian Psychiatric Association. Clinical practice guidelines. Management of anxiety disorders.
Can J Psychiatry 2006;51:9S-91S.
13. Ipser JC, Kariuki CM, Stein DJ. Pharmacotherapy for social anxiety disorder: a systematic review.
Expert Rev Neurother 2008;8(2):235-257. [http://dx.doi.org/10.1586/14737175.8.2.235]
14. Hedges DW, Brown BL, Shwalb DA, et al. The efficacy of selective serotonin reuptake inhibitors
in adult social anxiety disorder: A meta-analysis of double-blind, placebo-controlled trials. J
Psychopharmacol 2007;21:102-111.
15. Allgulander C, Mangano R, Zhang J, et al. SAD 388 Study Group. Efficacy of venlafaxine ER
in patients with social anxiety disorder: a double-blind, placebo-controlled, parallel-group
comparison with paroxetine. Human Psychopharmacology 2004;19:387-396.
16. Stein MB, Pollack MH, Bystritsky A, et al. Efficacy of low and higher dose extended-release
venlafaxine in generalized social anxiety disorder: A 6-month randomized controlled trial.
Psychopharmacology 2005;177:280-288.
17. Stein DJ, Cameron A, Amrein R, et al. Moclobemide Social Phobia Clinical Study Group.
Moclobemide is effective and well tolerated in the long-term pharmacotherapy of social
anxiety disorder with or without comorbid anxiety disorder. Int Clin Psychopharmacology
2002;17:161-170.
18. Blanco C, Raza MS, Schneier FR, Liebowitz MR. The evidence-based pharmacological treatment
of social anxiety disorder. International Journal of Neuropsychopharmacology 2003;6:427-442.
19. Ponniah K, Hollon SD. Empirically supported psychological interventions for social phobia in
adults: A qualitative review of randomized controlled trials. Psychol Med 2008;38:3-14.

20. Kloos AL, Dubin-Rhodin A, Sackett JC, et al. The impact of mood disorders and their treatment
on the pregnant woman, the fetus, and the infant. Curr Psychiatry Rep 2010;12:96-103. [http://
dx.doi.org/10.1007/s11920-010-0098-6]
21. Hitchcock CA, Chavira DA, Stein MB. Recent findings in social phobia among children and
adolescents. Isr J Psychiatry Relat Sci 2009;46:34-44.
22. Hammad TA, Laughren T, Racoosin J. Suicidality in pediatric patients treated with anti-
depressant drugs. Arch Gen Psychiatry 2006;63(3):332–339.
23. Sheikh JI, Cassidy EL. Treatment of anxiety disorders in the elderly: Issues and strategies. J
Anxiety Disord 2000;14:173-190.
24. Schneier FR, Blanco C, Campeas R, et al. Citalopram treatment of social anxiety disorder with
comorbid major depression. Depress Anxiety 2003;17:191-196.
25. Stein DJ, Stein MB, Pitts CD, et al. Predictors of response to pharmacotherapy in social anxiety
disorder: An analysis of 3 placebo-controlled paroxetine trials. J Clin Psychiatry 2002;63:152-155.
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GUIDELINE
26. Van Ameringen M, Mancini C, Wilson C. Buspirone augmentation of selective serotonin reuptake
inhibitors (SSRIs) in social phobia. J Affect Disord 1996;39:115-121.
27. Stein MB, Sareen J, Hami S, Chao J. Pindolol potentiation of paroxetine for generalized social
phobia: A double-blind, placebo-controlled, crossover study. Am J Psychiatry 2001;158:1725-
1727. [http://dx.doi.org/10.1176/appi.ajp.158.10.1725]
28. Seedat S, Stein MB. Double-blind, placebo-controlled assessment of combined clonazepam with
paroxetine compared with paroxetine monotherapy for generalized social anxiety disorder. J Clin
Psychiatry 2004;65:244-248.
29. Segool NK, Carlson JS. Efficacy of cognitive-behavioral and pharmacological treatments for
children with social anxiety. Depress Anxiety 2007;25:620-631.
30. Blanco C, Heimberg RG, Schneier FR, et al. A placebo-controlled trial of phenelzine, cognitive
behavioral group therapy, and their combination for social anxiety disorder. Arch Gen Psychiatry
2010;67:286-295. [http//:dx.doi.org/10.1001/archgenpsychiatry.2010.11]
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