Psychopharmacology Oct 2016

Psychopharmacolo
gy
Presented by
Associate Professor Anthony Harris
Discipline of Psychiatry
The University of Sydney
Page 1
Psychopharmacology
Classes of medication
SSRI
Other SNRI/TCA etc
Anticonvulsant medications
Lithium
Antipsychotic medication
Use of medication in
Anxiety Disorders
Mood Disorders
Schizophrenia
Page 2
PHARMACOTHERAPY OF MDD
Page 3
MONOAMINE-DEFICIENCY HYPOTHESIS EXTENDED
Page 4
SECONDARY MESSENGER SYSTEMS
Page 5
THE MONOAMINE HYPOTHESIS OF

DEPRESSION
Page 6
SUMMARY
Page 7
ANTIDEPRESSANTS
Page 8
SELECTIVE SEROTONIN REUPTAKE INHIBITORS

AND OTHER NEWER ANTIDEPRESSANT AGENTS
Page 9
SSRI
Page 10
SSRI PROFILE
Page 11
SEROTONIN SYNDROME
Page 12
Age dependent complications
Young people increased levels of agitation

Elderly hyponatraemia
Page 13
SNRI
Page 14
NASSA
Page 15
NASSA PROFILE
Page 16
OTHER NEW AGENTS
Noradrenaline
Reuptake
Inhibitor (NARI)
Reboxetine
Questions
remain about
efficacy
Adverse
effects
include dry
mouth,
constipation,
insomnia,
tachycardia
Reversible
Inhibitor of
Moneamine
Oxidase
(RIMA)
Moclobemide
Well tolerated
Efficacy
debated
Initial dose
range too low
Melatonin
Receptor
Agonist
agomelatine
Well tolerated
Acts on
melatonin and
5HT2c
receptors
Efficacy
debated
Page 17
MOCLOBEMIDE (RIMA)
Page 18
MONOAMINE OXIDASE INHIBITORS AND

TRICYCLIC ANTIDEPRESSANTS
Page 19
MONOAMINE OXIDASE INHIBITORS
Page 20
IRREVERSIBLE MAO INHIBITORS
Page 21
MAOI adverse effects
Medication
Side Effects
Classical MAOIs
Hypotension, insomnia, agitation, weight gain,

sexual dysfunction
Page 22
Page 23
Page 24
Page 25
IS ANY ANTIDEPRESSANT BETTER?
Page 26
ANTIDEPRESSANT SIDE EFFECTS
Page 27
Antidepressants and weight gain
Serretti et al, 2010. J.Clin.Psychiatry
Page 28
Lithium
Page 29
Treatment of acute mania
Page 30
Page 31
Lithium for prophylaxis
Page 32
Time to recurrence Olanzapine

vs Lithium
Page 33
LITHIUM AUGMENTATION IN UNIPOLAR

DEPRESSION
Page 34
LITHIUM IN UNIPOLAR DEPRESSION
Page 35
LITHIUM IN UNIPOLAR DEPRESSION
Page 36
Adverse effects
Short term
Tremor
Fatigue
Diarrhoea
Thirst & Polyuria
Nausea & vomiting
Headache
Long term
Renal
Diabetes insipidus
CRF
Thyroid
Parathyroid
Weight gain
Teratogenic
Neural toxicity
Page 37
Lithium and renal function
Small but significant effect

for use of lithium on renal
function
Longer the patient is on
lithium the higher the
creatinine becomes
Page 38
Interaction of lithium with other

medications
Need to be aware of
interaction of lithium with a
wide range of commonly
prescribed medications
Avoidance of lithium or
careful monitoring is
required
Page 39
Monitoring required with lithium
Malhi et al, 2013. Australian Prescriber
Page 40
Other mood stabilisers

Sodium valproate
Effective anti-manic
medication either in
combination with
antipsychotic or as
monotherapy
Used as
antidepressant in
bipolar depression
Maintenance &
rapid cycling
Significant range of
adverse effects
including, cognitive,
teratogenicity, hepatic
Lamotrigine
Effective in
bipolar
depression
Difficulty with
range of adverse
effects
CNS: diplopia,
ataxia,
asthenia
Skin: rash,
StevensJohnson
syndrome
Carbemazpine
- Older
anticonvulsan
t
- Limited
evidemce for
use as an
antimanic
agent esp. in
combination
with other
agents
- Maintenance
- Adverse
Page 41
effects
TREATMENT GUIDELINE FOR DEPRESSION
Page 42
ANTIDEPRESSANT AND DEPRESSION SEVERITY
Fournier, J. C., DeRubeis, R. J., Hollon, S. D., & et al. (2010). Antidepressant drug effects and depression severity: A
patient-level meta-analysis. JAMA, 303(1), 47-53.
Page 43
TREATMENT OF MILD-MODERATE DEPRESSION
Antidepressant medications
are NOT particularly effective
for mild-to-moderate
depression or subthresholdto-mild depression.
Page 44
CPR FOR MOOD DISORDERS
Page 45
DEPRESSION: PHASES OF TREATMENT
Page 46
A SET PACE
Page 47
Page 48
OVERVIEW OF ANTIDEPRESSANTS
Page 49
OVERVIEW OF ANTIDEPRESSANTS
Page 50
Maintenance
Maintenance best when combined with

psychological treatment (BT,CBT, IPT)
Antidepressant therapy decreases the risk and
severity of relapse
Maintenance on the dose and treatment that got
someone better is recommended
Avoid rapid discontinuation
Page 51
Anxiety Disorders
Page 52
The Anxiety Disorders
Anxiety Disorders
Panic Disorder
Agoraphobia
Social Phobia
Generalised Anxiety Disorder
Specific Phobia
Treatment of choice is
psychological at least
initially
Behavioural Therapy
Cognitive Therapy
Cognitive Behavioural
Therapy
Obsessive Compulsive
Disorder
Trauma and Stressor
related Disorders
PTSD
Adjustment Disorders
Page 53
Pros and Cons
Side effects
Passive attitud
e
towards
treatment
Faster onset of
action, esp. wit
h
benzodiazepin Dependence (on
e some age
nts)
s
More obvious
Risk of
and prominent
recurrence afte
effects on
r
m
e
d
ic
ation
symptoms
cessation
Advantag
es
Disadvanta
ges
Page 54
When to Use Medications

for Anxiety Disorders? (2)
Presence of certain co-occurring psychiatric conditions or
complications
Depression and other mood disorders
Rationale:
Effectiveness of medications in treating depression and other

mood disorders
Lack of interest in psychological treatments
Chemical imba
Chemical imbalance
Too arduous
Discomfort before feeling better
Practical issues:
Unavailability of psychological treatments
Lower cost
Ease of administration
Ryan, J. (n.d.). USA Psychiatric Drug Warning! . Retrie

http://mindfreedom.org/campaign/usa/us
Page 55
Used under a
Which Medications Are Efficacious

in Anxiety Disorders?
Selective serotonin reuptake inhibitors (SSRIs):
sertraline, escitalopram, paroxetine, citalopram, fluvoxamine,
fluoxetine
Antidepressants
Serotonin and noradrenaline (norepinephrine) reuptake

inhibitors (SNRIs):
venlafaxine, duloxetine
Tricyclic antidepressants (TCAs):
imipramine, clomipramine
Classical monoamine oxidase inhibitors (MAOIs):
phenelzine, tranylcypromine
Benzodiazepines
diazepam, lorazepam, alprazolam

Page 56
Medications Are not Efficacious

for all Anxiety Disorders
PD
SSR
Is
OC
D
Cla
ss
ica
lM
AO
I
GA
D
Benzodiazepines &
Venlafaxine
SA
D
Page 57
Summary of the evidence for the

pharmacological treatment of Anxiety Disorders
Clomi Imipr
SSRIs pram amin
ine
e
Panic
Disorder
GAD
SAD
PTSD
OCD
MAOI
s
Venla
Dulox
faxin
BDZ
etine
e
Buspi
rone
Page 58
5
Evidence for benzodiazepines

Consistently effective
acute setting
Evidence base for Panic
Disorder, SAD, GAD.
Work quickly
Fairly well tolerated
Safe in overdose
Can be used on a prn basis
Some disappointment with
antidepressants
Page 59
5
Evidence for benzodiazepines

Consistently effective
acute setting
Evidence base for Panic
Disorder, SAD, GAD.
Work quickly
Fairly well tolerated
Safe in overdose
Can be used on a prn basis
Some disappointment with
antidepressants
Difficulty with dependence

Especially with short-acting BDZ
Withdrawal syndrome
long term taper required
Adverse effects
Learning and memory difficulties
Sedation
Motor coordination
Page 60
Other Medications for Anxiety Disorders

Medication
Usage
Second-generation
antipsychotics
For GAD/OCD*.
In conjunction with antidepressants for OCD and PTSD
Pregabalin
Hydroxyzine
Efficacious in the treatment of GAD
Buspirone
Beta-blockers
(propranolol,
atenolol)
In combination with antidepressants for performance

anxiety, GAD and SAD
Mirtazapine
Useful for patients with PTSD and GAD
Prazosin
Treating nightmares as part of PTSD
Anticonvulsants and
mood stabilisers
Combined with antidepressants in the treatment of PTSD

Page 61
Choice of Pharmacotherapy
When There Is no Difference in Efficacy
Factor that influences the decision
Speed of therapeutic response

Side effect profile/tolerability
SSRIs Venlaf
TCAs
BDZ
+++
++
+/++
+++
+++
+++
Presence of other mental disorders, especially

+++
depression & history of depression
Safety in overdose
+++
++
History of alcohol or other substance

abuse/dependence
+++
+++
+++
+++ Clear advantage

++ Some/relative advantage
+ Minimal advantage
0 No advantage
Page 62
ANTIPSYCHOTICS
Page 63
antipsychotics
generic
sedation
weight
gain
EPSE
Chol
prolactin
chlorpromazine
+++
+++
++
+++
+++
haloperidol
pericyazine
trifluoperazine
++
+++
+++
++
+++
+++
+
+
++
++++
++
+++
+
++
+
+
+
+
++
+++
+
+++
++
++
++
+/-
++
+
+
+
+
++
+
XXX
++
-
+++
0
+/0
+/+
+++
+
+++
0
amisulpride
aripiprazole
asenapine
clozapine
lurasidone
olanzapine
paliperidone
quetiapine
respiridone
ziprasidone
Page 64
Mode of action
Haloperidol binding IC50 vs treatment effect

from Seeman et al, Nature 1976.
Antipsychotic medications
are known to work via a
number of actions however
dopamine D2 antagonsim is
a common feature
More recent work point to
cholinergic, serotoninergic,
glutamatergic and
GABAergic modes of action
Interactions between
neurotransmitter systems
alter effects
Page 65
Pharmacological efficacy
Clozapine only
antipsychotic clearly more
efficacious
SGA = FGA
Reduced SGA
discontinuation, but not
significantly so
Efficacy of antipsychotics vs placebo

Leucht et al, Lancet 2013.
Page 66
Clozapine remains treatment of choice

in treatment resistant schizophrenia
CATIE extension (McEvoy et al, 2006) time to discontinuation for: therapeutic effect clozapine > Olz = Ris = Quet
For any reason clozapine > Ris = Quet
PANSS at 3 months clozapine >Ris = Quet
CUtLASS 2: (Lewis et al, 2006)

PANSS clozapine > SGA
other measures no difference
McEvoy
(2006) Am.J.Psych 163: 600-610; Lewis et al, (2006). Schizophrenia
The
Universityet
of al,
Sydney
Page 67
Bull. 32, 715-723
movement disorders
higher rate of movement
disorders at baseline
extrapyramidal up to 60%
dystonia - oculogyric,
torticollis, laryngeal
parkinsonism/akinesia
Akathisia
Tardive dyskinesia
Leucht et Page
al, 68
Lancet 2013.
Weight gain
All antipsychotics cause

weight gain
Olanzapine and clozapine
particularly a risk
Weight gain starts quickly
Low rates of physical
exercise, poor diets
96% people with psychotic
illness rated as sedentary or low
exercise vs 72% of general
population
Leucht et al, Lancet 2013
Page 69
cardiovascular system
BMI in people with a psychotic

illness and population comparison
Morgan et al, SHIP 2011
Increased rate of
metabolic syndrome (20%
with DM-type 2)
increased incidence of
sudden death with typical
antipsychotics and
clozapine (RR = 2.4)
prolongation of QTc
interval - caution with all
antipsychotics.
clozapine
myocarditis
cardiomyopathy
Page 70
QTc abnormalities
Prolongation of the QTc
interval increases the risk
of a ventricular arrythymia
called torsades de pointes
Increased risk in women,
K+, Mg++, CRF, cardiac
failure
Antipsychotics
Amisulpride, risperidone,
clozapine, fluphenazine,
ziprasidone, droperidol
Antidepressant meds
TCAs, citalopram
Other meds
Page 71
hyperprolactinaemia
Occurs with many
antipsychotics
Symptoms include
Breast enlargement,
galactorrhoea, menstrual
irregularity
Decreased libido
acne
Risks not clear at present
Disturbed fertility
?Breast Ca
?Bone demineralisation
Medication causing raised

prolactin
FGA
amisulpride
paliperidone
risperidone
clomipramine
Page 72
anticholinergic side effects

common with typical antipsychotics and clozapine
peripheral
dry mouth, blurred vision, constipation, bladder
tachycardia, hyperthermia
idiosyncratic hypersalivation for clozapine
central
learning difficulties, delirium
Page 73
neuroleptic malignant syndrome

exposure to dopaminergic agents
risk factors of dehydration, physical illness, high
doses of neuroleptics, ?lithium
Sx - confusion, autonomic instability, rigidity,
raised CPK
Tx - drug withdrawal, supportive
Page 74
Endocrine / obesity
Obesity
All bar ziprasidone
Significant problem with clozapine, olanzapine
Satiety?
Endocrine
Type II diabetes
Prolactin
Risperidone, amisulperide
Page 75
neurocognitive deficits
difficult to disentangle from effects of chronic
psychosis
Attention
Memory
Executive functions
reflect sedation and decreased motivation
Page 76
blood dyscrasias
phenothiazines (<1%) and clozapine (1-2%)
agranulocytosis
thrombocytopaenia
Eosinophilia
risks - ?age, genetic, myelosuppressive agents

monitor
Page 77
gender issues
reproduction and medication
low teratotoxicity
menstrual changes and galactorrhoea
sexuality
low libido
erectile problems/ impotence
appearance
Page 78
other reactions
polydipsia and water intoxication

seizures
hepatotoxicity
cardiac arhythmias
dermatological
temperature regulation abnormalities
Page 79
clozapine
Indications
treatment resistant Schizophrenia
failure to respond to at least two other
antipsychotics
reasonable trials
depot trial
severe side effects to other antipsychotics

severe tardive dyskinesia
aggression
Page 80
Clozapine adverse effects

Major limiting factor in use of medication
Agranulocytosis
Fatigue & sedation
Hypotension and tachycardia
Increased appetite and weight gain
Insulin resistance
Constipation
Hypersalivation/sialorroea
Urinary incontinence
Seizures
Page 81
clozapine screen
CPMS - compulsory monitoring requires
FBC (WBC>3.5), Blood Gp
usual additional
temp., HR, weight
Metabolic
BSL
lipids
Myocarditis
ECG
cardiac enzymes
Echocardiogram after 6 months
Page 82
Minimise side effects
Page 83
Guideline for pharmacological treatment

of schizophrenia
Page 84
Initial treatment regimen

Initial assessment
24 hours off antipsychotics use of benzodiazepines
Adequate Treatment with second generation
antipsychotic (SGA)
Amisulpride
Aripiprazole
Paliperidone
Quetiapine
Risperidone
Ziprasidone
Titrate for 6-8 weeks

and change if no
treatment response to
other SGA x 2-3
No response Trial clozapine
Start low, go slow

Treat for 2-5 years
Page 85
How long to treat before changing

antipsychotics?
Unclear how quickly
antipsychotics
should work
68% of change over
one year occurs in
first 4 weeks (Leucht et
al, 2005)
Evidence for late

response present
(Robinson et al, 2005)
Leucht et al, 2005. Biol Psychiatry 57, 1543-1549. Robinson et al, (2005).
Page 86
Schizophrenia Bull.705-722.
When do you stop medication?

National Guidelines vary:
range 0.5 2 yrs (Gaebel et al,
2005; BJP: 187, 248-255)
Relapse predicted by
medication discontinuation
(HR=4.9) [1]
Little belief in need for
treatment (HR=1.75; 95%
CI=1.16-2.65) [2]
Medication of low benefit
(HR 2.28; 95% CI 1.794.65) [2]
1.
Robinson et al, 1999. Arch. Gen. Psych. 56, 241-247;
2.
Perkins et al, 2006. Schizophrenia Res. 83, 53-63
Page 87
Monotherapy / Polypharmacy
Guidelines recommend against polypharmacy however
little research in area of success of augmentation
Antipsychotic + antipsychotic: Patients on polypharmacy
appear to have higher doses of medication, more side
effects and longer admissions for no more improvement
(Centorrino et al, 2004)
Increasing numbers of antipsychotics increased mortality

RR 2.50 CI 1.46 - 4.30 for every added antipsychotic
(Joukamaa et al, 2006)
Centorrino
et al (2004) Am J Psychiatry 161, 700-706. Joukamaa et al,Page
(2006)
Brit J
88
Psychiatry 188, 122-127. Glick et al (2006). J.Clin. Psychiatry67, 1261-1265
Encourage adherence
Medication Adherence: Asthma, Rheumatoid Arthritis and
Schizophrenia
PLACE IMAGE HERE
50
40
30
20
10
Full Adherence
Partial Adherence
Poor Adherence
Kyngas HA. Nurse Health Sci. 1999;1:195-202; Viller F et al. J Rheumatol. 1999;26:2114-2122.
Lam YWF et al. Poster. 2003 Biennial ICOSR Meeting; Colorado Springs, CO.; Byerly M et al.
Page 89
Poster. 2003 APA Meeting; San Francisco, CA.
Approaches to improving treatment

concordance
Improving compliance
Good communication
Engage, educate and negotiate
Target burden of side effects
Preference for atypical antipsychotics

Low dose
Simplify regimen
Involve family
Depot as a last resort
Page 90
General principles
Use one antipsychotic at a time.

Increase dose slowly, minimise side effects
Reasonable trial ie 4 weeks at maximal dose
If treatment fails consider other factors
compliance
Substance abuse
depression
Trial of clozapine
Page 91

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Psychopharmacolo

The University of Sydney

The University of Sydney

The University of Sydney

MONOAMINE-DEFICIENCY HYPOTHESIS EXTENDED

The University of Sydney

SECONDARY MESSENGER SYSTEMS

The University of Sydney

THE MONOAMINE HYPOTHESIS OF

The University of Sydney

The University of Sydney

The University of Sydney

SELECTIVE SEROTONIN REUPTAKE INHIBITORS

The University of Sydney

The University of Sydney

The University of Sydney

The University of Sydney

Age dependent complications

Young people increased levels of agitation

The University of Sydney

The University of Sydney

The University of Sydney

The University of Sydney

OTHER NEW AGENTS

The University of Sydney

MONOAMINE OXIDASE INHIBITORS AND

The University of Sydney

MONOAMINE OXIDASE INHIBITORS

The University of Sydney

IRREVERSIBLE MAO INHIBITORS

The University of Sydney

MAOI adverse effects

Hypotension, insomnia, agitation, weight gain,

The University of Sydney

The University of Sydney

The University of Sydney

The University of Sydney

IS ANY ANTIDEPRESSANT BETTER?

The University of Sydney

ANTIDEPRESSANT SIDE EFFECTS

The University of Sydney

Antidepressants and weight gain

The University of Sydney

Serretti et al, 2010. J.Clin.Psychiatry

The University of Sydney

Treatment of acute mania

The University of Sydney

The University of Sydney

Lithium for prophylaxis

The University of Sydney

Time to recurrence Olanzapine

LITHIUM AUGMENTATION IN UNIPOLAR

The University of Sydney

LITHIUM IN UNIPOLAR DEPRESSION

The University of Sydney

LITHIUM IN UNIPOLAR DEPRESSION

The University of Sydney

The University of Sydney

Lithium and renal function

Small but significant effect

The University of Sydney

Interaction of lithium with other

The University of Sydney