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Off-label use of antipsychotics: Are we mad?

Article  in  Expert Opinion on Drug Safety · October 2007

DOI: 10.1517/14740338.6.5.533 · Source: PubMed

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 Review

Central & Peripheral Nervous Systems

Off-label use of antipsychotics:

are we mad?
Camilla Hawt & Jean Stubbs
St. Andrew\ Heabhcare, Billing Road, Northampton, UK

The off-label prescribing of antipsychotic drugs to psychiatric patients of all

ages is very common. Such off-label use is a necessary part of the art of
psychiatry but brings with it increased responsibilities for the prescriber as, if
the patient suffered an adverse reaction, liability would rest with the
prescriber and/or their employers. This article reviews the frequency and
nature of the off-label prescribing of antipsychotic drugs for psychiatric
indications to children, adults and the elderly. lt also reviews the evidence
base for doing so in a variety of common, and also s.ome less common, clinical
situations. The review is mainly concerned with off-label indications but a
short section on high dose antipsychotics is also included. The review
concludes that the off-label prescription of antipsychotics frequently lacks
the support of robust clinical trials. When prescribing off-label, the prescriber
must carry out a careful risk assessment of the risks and benefits for the
individual patient. They should also inform the patient that the prescription
is off-label.

Keywords: antipsychotic, off-label, prescribing

Expert Opin. DrugSaf (2007) 6(5):533-545

t. lntroduction
The term 'ofllabel prescribing' refers to the use of a drug outside the terms of
its licence, known in the UK as the 'Marketing Authorisation and previously called
the 'Product Licence'. There are several ways in which a drug may be prescribed
off-label: by prescribing a dose in excess of that specified by the Marketing
Authorisation; prescribing for an unlicensed indication; prescribing for a patient
group outside of that specified by the Marketing Authorisation, such as children
or the elderly; or by altering the dosage form, for example, by crushing tablets. In
many countries, doctors are free to prescribe off-label and do so frequently,
although in some countries restrictions are placed on off-label prescribing; for
example, by hedth insurance companies and individual institutions 1r1. A report in
the British Medical Journal in 2004 highlighted the difficulties doctors face in India
where medical practitioners cannot legally prescribe drugs for treatments other than
those for which they were initially approved by the licensing authority tzt.
Much useful information and guidance about offJabel prescribing in psychiatry is
contained in a document published recently by the Royal College of Psychiatrists tal.
Off-label prescribing increases the doctort professional responsibiliry 141. The use of
a drug ofllabel represents an area of potentially increased risk, as the national body
that licenses drugs for medicinal use (in the UK the Medicines and Healthcare
products Regulatory Agenry) has not examined the risks or benefits of using the
drug in these circumstances. Should the patient suffer an adverse event from the
drug, liability would rest with the prescriber andlor their employers (who is liable
varies from country to country) unless they can demonstrate that they have acted
responsibly and in the best interests of the patient. The doctor would have to explain
the deviation from the manufacturert prescribing guidelines and justify doing so;

10.1511/14740338.6.5.533 @ 2007 lnforma UK Ltd ISSN 1474-0338

Off-label use of antipsychotics: are we mad?
for example, based on widespread use ofthe drug for a parricular
ofllabel indication and evidence of benefit ro patienrs t5l.
Some off-label uses are so commonplace thar they are listed in
textbooks and national prescribing guidelines. This type of
well-established usage has been referred to as 'near label' tal.
It is certainly true that the use of many ofllabel drugs in
psychiatry brings benefits to parients and for some drugs and
indications ofllabel use may represent the best therapy for
their condition. A consensus meeting of senior clinicians and
regulators from a number of European counrries and the US
concluded that ofllabel prescribing was a necessary pa:r. of
the art of medicine t6l. However, sometimes drugs are used
offJabel in unconventional ways such that the benefits to
the patient are less established and the risls may be greater.
Such use is more controversial as the risk-benefit analysis is
less favourable and places the prescriber at risk of controversy.
In the US, a recent report by the Agency of Healthcare
Research and Qualiry (AHRQ) t1011 found poor evidence for
the efficary of arypical antipsychodcs (also known as
second generation or novel antipsychodcs) for many ofllabel
indications, as well as problems wirh troublesome and serious
side effects.
z. Why does off-label prescribing arise?
The process in the UK by which a pharmaceutical company
obtains a Marketing Authorisation for a drug has been
described by Healy and Nutt, 1998 tet. A company applies for
a Marketing Authorisation for a particular clinical indication,
often in a narrowly defined patient population. In order that
a new drug satisfies the regulatory authorities' requirements
for safety and efficary, clinical trials are carried our on a
relatively healthy group of padents suffering from a single
disorder. It is easier for a company to recruit adult subjects to
clinicai trials than it is to use; for example, children, the elderly
or patients with learning disabilities. For these latter groups,
issuesof consent and ethics arise and these subjects may be less
physicallyrobust and may be taking medication for co-morbid
conditions. For relatively uncommon disorders, it may not be
possible to recruit sufficient numbers to a clinical trial. Other
scenarios, for example the ffeatment of acutely disturbed
behaviour by rapid tranquillisation, may be difficult to
study for a vaiety of reasons. Patients requiring rapid
tranquillisation are generally acutely ill. They are often unable
to give informed consent to take part in a clinical trial and
they may require other medications, hence recruitment of
adequate numbers of suitable patients is difficult. Another
consideration is that clinical trials are not 'real world' by
definition. They are usually of relatively short duration and
do not study the effect of combinations of drugs. Data on
drug safery from randomised clinical trials (RCTs) are poorly
and unsatisfactorily reported, and, generally, serious adverse
reactions are detected only several years after the drug
was marketed. Once a drug has a Marketing Authorisation
for a given disorder, the company may apply for further
534 Expert Opin. Drug Saf. (2007) 6(5)
authorisations for other disorders. Several arypical
antipsychotics first gained Marketing Authorisations for
use in the treatment of schizophrenia. Subsequently, the
pharmaceutical companies concerned have gained Marketing
Authorisations for the drugs to be used in the treatment of
mania. lVhether a company applies for use of their drug in the
treatment of other disorders or patient groups depends on
several factors, including the likely financial return of
doing so. Once a drug is no longer under patent there is
litde prospect of clinical trials being conducted to establish
its efficary in the treatment of unlicensed disorders or
patient groups.
The primary indication for most antipsychotics is
schizophrenia. Typical (also known as first-generation or
classical) antipsychotics are also licensed for a variety ofother
psychiatric and behavioural disorders, such as violent and
impulsive behaviour (see Thble 1 for the psychiatric indications
of commonly used rypical antipsychotics in the UI!. Of the
atypicals, olanzapine, risperidone and quetiapine have approval
for the treatment of acute mania as well as for schizophrenia.
Olanzapine also has approval for maintenance therapy in
bipolar affbctive disorder in the UK (Thble 2). More licensed
indications are generally reported in the summary of product
characteristics of the (older) rypicals compared to the (newer)
atypicals, as is clearly highlighted by Tables t and2. Criteria to
approve the new indications of use of medications are more
restrictive thin they were some decades ago. This fact influ-
ences the differences in the rates of ofllabel prescribing for
rypical and atypical antipsychotics.
3. How common is the off',label use
of antipsychotics?
In psychiatry ofllabel prescribing is common. In a postal
questionnaire of psychiatrists in southern England, of the
116 respondents, 650/o stated that they had prescribed
medication ofllabel within the past month tzl. A total of 49o/o
said they had prescribed a drug for an unlicensed indication
within the last month, l9o/ohadprescribed a drug at above the
British National Formulary (BNF) recommended dosage
range and l2o/ohadprescribed a drug to a patient outside the
recommended age range.
3.i Frequency of off-label antipsychotic prescribing
for adults
There is evidence that the oFlabel prescribing of antiprychotics
for adults is common, especially for unlicensed indications. In
a study of atypical antipsychotics prescribed for 502 psychiat-
ric in-patients conducted in one health district in England in
1994 - 2001, olarnapine was the atypical that was most fre-
quency prescribed offlabel (44.5o/o of instances) t8t. Affective
disorders (18.4o/o) and organic disorders (l2.4Vo) were the main
disorders treated oFlabel. A survey of psychotropic prescribing
for psychiaric in-patients in England found olanzapine to be
the psychotropic most commonly prescribed o$label tsl.
 Haw & Stubbs

Table 1. Licensed indications for some of the more commonly used typical antipsychotics in the UK.

Antipsychotic Licensedindications Comments on use in children and the elderly

Chlorpromazine Schizophrenia and other psychoses Licensed for use in children (for schizophrenia
Mania and autism) and in the elderly
Short-term management of severe anxiety For the elderly use a third to a half of the
Psychomotor agitation, excitement and violent or adult dose
dangerously impulsive behaviour
Haloperidol Schizophrenia and other psychoses Licensed for use in children and the elderly
Mania For the elderly use half the adult dose
Short-term management of psychomotoragitation, Use in children for the management of anxiety
behaviour
excitement and violent or dangerously impulsive is not recommended
elderly
Agitation and restlessness in the Parenteral use is not recommended for children,
Short-term management of severeanxiety in the elderly use half the adult dose
Trifluoperazine Schizophrenia and other psychoses Licensed for use in children and the elderly
Short-term management of psychomotor agitation,
excitement and violent or dangerously impulsive behaviour
Short-term management of severe anxiety

Table 2. Licensed indications for atypical antipsychotics available in the UK.

Antipsychotic Licensed indications Comments on use in children and the elderly

Amisulpride Schizophrenia Not licensed for children aged < 15 years

Aripiprazole Schizophrenia Not licensed for children aged < 18 years
Clozapine _. Treatment-resistant or treatment-intolerant Not licensed for children aged < 16 years
schizophrenia . Lower starting dose and increments in elderly
Psychosis in Parkinson's disease

Olanzapine Schizophrenia Not licensed for children aged < 'l 8 years
Mania Elderly: consider lower starting dose and increments
Prevention of recurrence in bipolar disorder
Quetiapine Schizophrenia Not licensed for children aged < 18 years
Mania Elderly: lower starting dose and smaller increments

Risperidone Acute and chronic psychoses Not licensed for children aged < 15 years
Mania Elderly: lower starting dose and smaller increments
Risperidone depot injection Schizophrenia and other psychoses Not licensed for children aged < 18 years
Elderly: lower maximum dosage

Sertindole Schizophrenia where patient is enrolled in a Not licensed for children aged < 18 years
clinical study and is intolerant of one or more Elderly: slower dosage titration than adults
antipsychotics
Zotepine Schizophrenia Not licensed for children aged < 18 years
Elderly: lower starting dose and maximum dose

In a study of arypical antipsychotic medication prescribed older typical drugs have a wider range of licensed indications
to 73,981 IJS veterans, 43o/o of patients were prescribed an than the newer atypicals and are less often prescribed, having
atypical antipsychotic for an ofllabel indication gro1. A study been largely replaced by arypicals.
of antipsychotic prescribing by Italian general practitioners
conducted in 1999 - 2OO2 reported that prescribing for unli- 3.2 Frequency of off-label antipsychotic prescribing
censed indications was more common for atypical (54o/o) than for the elderly
for typical antipsychotics (19%) 1rr1. Similar findings were The use of antipsychotics in eldedy.patients is frequently
reported by an Italian study of prescribing for psychiatric for unlicensed indications, although use of ofllabel dosages is
in-patients 1121. Nearly 50o/o of atypical antipsychotics were for less common than in adults. Among Austrian community
ofllabel indications. The corresponding figure for typical psychiatric patients eged 49 - 70 yeats, antipsychotics were
antipsychotics was < l5o/o.The difference in the frequency of prescribed almost exclusively for ofllabel indications tr:1.
off-label use of typicals and arypicals is likely to be because the There are a number of reports that have examined the

Expeft Opin. Drug Saf. (2007) 5(5) 535

Off-label use of antipsychotics: are we mad?
frequenry of antipsychotic use in elderly patients for the
treatment of behavioural and psychiatric symptoms of
dementia (BPSD), which is an ofllabel indication. Studies
from two countries (UK and Canada) have reported increasing
rates of antipsychotic prescribing to older patients in nursing
and care homes for the elderly t14,151. In a study from a
third country Australia, antipsychotics were prescribed
for 25o/o of nursing home residents, and rwo-thirds of
those given antipsychotics had dementia or cerebral disease
and not schizophrenia tl6l. In the study of antipsychotic
prescribing by Italian general pracitioners previously referred
to, the most common ofllabel use for atypicals was
for BPSD rrrt.
3.r Frequency of off-label prescribing for children
and adolescents
Most antipsychotic prescribing for children and adolescents
is ofllabel because of the age of the patients. Indeed, children
have been described as 'therapeutic orphans' as so many
medicines are nor licensed for use in their age group 1171.
Although some of the older typical antipsychotics are
licensed for use in children, until recently no atypical
antipsychotic was licensed for use in children < 15 years
of age. In June 2007 the FDA approved the use of
risperidone for the ffeatment of schizophrenia in adolescents
aged 13 - Tlyears and the treatment of bipolar mania in
children and adolescents aged l0 - 17 years.
A small survey of UK child and adolescent psychiatrists
found that 63Vo were prescribing antipsychotics and, 50o/o
said they would consider using antipsychotics for aggressive
behaviour t181. Most prescribing would be ofllabel because
of the age of the patients. In the US, the ofllabel use of
antipsychotics to treat behavioural and psychiatric disorders
has gready increased in recent years t19,201. In one US study
of children admitted to a residential treatment faciliry
antipsychotics were the most common psychotropic drugs
prescribed, and in 55o/o of instances were prescribed for
offJabel indications t211. In anorher US study, this time
of prescribing for out-patients at two treatment centres, of
those children prescribed antipsychotics, in rwo-thirds ofthe
cases this was for aggression, an unlicensed indication tzzl.
A study of residential treatment facilities in four US states
found that 117 out of 732 (160lo) children were receiving
antipsychotics for oFlabel indications, often for aggression
or other behavioural symptoms iz3l. In a drug udlisation
study based on pharmacy dispensing records and carried out
in the Netherlands, among children aged 0 - 19 years the
prevalence ofantipsychotic use increased from 1.6 per 1000 in
1995 to 3.4 per 1000 in 1999 t24)-
+. Off-label indications for antipsychotics
in adult psychiatric patients
The following sections describe some of the ofllabel
indications for antipsychotics and summarise effrcaq da:a
s35 Expert Opin. Drug Saf. (2007) 6(5)
as well as UK guideline recommendations. The ofllabel use
ofclozapine and high dose antipsychotics is also discussed.
4.1 Generalised anxiety disorder
Generalised anxiety disorder (GAD) is one of the most
common psychiatric disorders in the general population and
antipsychotics are frequently prescribed for the relief of
symptoms. Some older antipsychotics (e.g., chlorpromazine
and haloperidol), but not the atypicals, are licensed for this.
El-Khayat and Baldwin (1998) collated the evidence from
studies of the use of antipsychotic drugs in the treatment
of GAD Lz\. They observed that although many authors
commented on the value of antipsychotics in relieving anxiery
symptoms as an alternative to benzodiazepines, few recent
papers recommended their use in this way. Most of the studies
of the use of antipsychotics in GAD could be criticised on
methodological grounds, and no study had considered the
risk-benefit ratio carefully.
The British Association for Psychopharmacology has
produced evidence-based guidelines for the pharmacological
treatment of anxiery disorders which concluded that anti-
psychotic drugs have only a limited role in treatment due to
their side effect burden and limited evidence base izel. The
guidelines do, however, cite Mendels et al. Lztl as evidence of
the efficary of trifluoperazine in GAD tzzl. In this large, multi-
centre RCT] trifluoperazine was compared with placebo for
the short-term treatment of GAD. Low dose trifluoperazine
was superior to placebo on all outcome measures and
discontinuation due to adverse side effects was uncommon.
In a more recent review, Gao and colleagues examined the
efficacy of typical and atypical antipsychotics in the treatment
of primary and comorbid anxiety symptoms and disorders tzal.
Six RCTs of antipsychotics for primary GAD were identified.
Except for the aforementioned trial of trifluoperazine, they
found no large, well-designed studies of antipsychotics in the
treatment of anxiety disorders. However, two recent RCTs
reported that two atypicals, olanzapine and risperidone, are
efficacious in non- or partial-responders to treatment with
anxiolytics alone tzq,aol.
4.2 Obsessive-compulsive disorder
Serotonin re-uptake inhibitors (SRIs) are the drugs ofchoice
for the ueatment of obsessive-compulsive disorder (OCD).
A problem arises because - 40o/o ofpatients are not adequately
responsive to these drugs tarl. One of the most studied
approaches for .treatment-resistant patients is antipsychotic
augmentation, which consists of adding an antipsychotic to
the on going SRI. Good results have been obtained with low
doses of some typical antipsychotics including haloperidol and
pimozide BA. ln a meta-analysis of ten trials of antipsychotic
augmentation of SRI, response occurred more often in patients
randomized to an antipsychotic than to placebo t::t. The
antipsychotics involved were haloperidol (1 trial), risperidone
(3 trids), olanzapine (2 trial$ and quetiapine (4 trials). OCD
does not respond to antipsychotic monotherapy tarl.

Given the side effect profiles of rypical antipsychotics,
researchers have, in the last few years, tried atypical
antipsychotics as augmentation drugs. Low doses of risperidone,
olanzapine and, more recently, quetiapine have proved
effective in a series of openJabel trials and in double-blind
studies taal. The AHRQ found the evidence of efficacy to be
stronger for risperidone and quetiapine than for olanzapine,
with no studies of ziprasidone or aripiprazole troll. It remains
uncertain how long patients would need to remain on
augmented treatment, because, in a small retrospective study of
antipsychotic augmentation for resistant OCD, most patients
who had responded to the addition ofan antipsychotic relapsed
when tle antipsychotic was stopped t:tl.
4.3 Treatment-resistant anxiety disorders
In a Cochrane review of pharmacotherapy augmentation
strategies in
treatment-resistant anxiety disorders, 28 RCTs
were identified but, of these, 20 were concerned with anti-
psychotic augmentation trials in OCD patients resistant to
SRIs taol. Avariety of antipsychotics were superior to placebo
but most trials were short-term (an average of 7 wee[s). The
authors concluded that more data are needed from longer
term trials and comparisons to antipsychotic augmentation,
such as cognitive therapy and switching drugs. However, as
mentioned in Section 4.1, two recent RCTs have demonstrated
efficary for risperidone and olanzapine augmentation in
treatment-resistant GAD tzs,:ol.
4.4 Post-traumatic stress disorder
Clinical practice guidelines for the management of
post-traumatic stress disorder (PTSD) commissioned by the
National Institute for Health and Clinical Excellence (NICE)
recommend that medication should be considered a second
line treatment for PTSD 1:21. Antipsychotic medication is not
included in their recommendations.
Atypical antipsychotics are not FDA approved or licensed
in the UK for the treatment of PTSD, but they have been used
in cases that are more severe, involve nightmares or flashbacks
that have not responded to other treatment, and/or when
psychotic symptoms may be present along with PTSD.
TheAHRQreview of efficary of atypicals in PTSD found a
paucity of RCTs meeting their inclusion criteria; only six
placebo-controlled trials t1011. The qualiry of evidence for
atypicals as augmentation therapy for combat-related PTSD
in men was low and that for their use as monotherapy in
women with non-combat related PTSD was very low. The
trials studied either risperidone or olanzapine. No data were
available for other atypicals.
4.s Psychotic depression
Antipsychotics are not licensed for the treatmeot of psychotic
depression. A review of antidepressant plus antipsychotic in
the treatment of psychodc depression (unipolar major
depressive disorder with a current episode featuring psychotic
symptoms) found no evidence that the combination of an
Expert Opin. Drus Saf. (2007) 6(5)
Haw & Stubbs
antidepressant plus an antipsychotic was more effective than
an anddepressant alone t381. An earlier Cochrane review came
to the same conclusion but highlighted that although a very
large number of research articles have been published in this
area there is a dearthof RCTs t:ql. Their treatment recom-
mendation was tlat the patient should initially be treated
with an anddepressant alone and an antipsychotic added if
there is an inadequate response. Another literature review of
treatment for psychotic depression concluded that there was
considerable retrospective effrcacy data for the use of triryclic
anddepressants in combination with rypical antipsychotics
but accompanied by a significant side effect burden. There was
more limited and variable data supporting the use of second-
generation antidepressants either alone or in combination with
atypical antipsychotics, but with a more acceptable side
effect profile t+ol. The authors concluded that treatment for
psychotic depression cannot be ppperly evidence-based until
the necessary RCTs have been conducted. The American
Psychiatric Association t<rt and UK NICE guideline t<zt both
recommend a combination strategy of antidepressant and
antipsychotic as firstline treatment for people with psychotic
depression. The British Association for Psychopharmacology
guidelines on the treatment of depressive disorders contains
useful guidance t4l. The document does not discuss the use
of antipsychotics.
a.e Bipolbr depression
Fewer studies have been designed for bipolar depression than
bipolar mania. Because antipsychotic agents have been shown
to diminish depressive symptoms during the treatment of
mania, atypical agents are now b'eing studied for use in bipolar
depression 144,4\.The AHRQ ll0ll found the evidence sparse
and conflicting regarding atypical antipsychotics as primary
therapy for bipolar depression compared with conventional
therapy. However, two large RCTs by the BOLDER
study group, each involving > 500 patients with bipolar I
or II, reported that quetiapine monotherapy in a dose of
300 or 600 mglday was more effective than placebo [<e,<zl.
In the US, but not the UK, the combination of olanzapine
and fluoxetine and monotherapywith quetiapine are approved
for bipolar depression. Aripriprazole, olanzapine, risperidone
and ziprasidone are approved for mixed episodes associated
with bipolar disorder.
4.7 Treatment-resistant unipolar depression
Nemeroff identified seven studies (one case series, five
open and one double-blind) which examined the efficacy
of using an atypical antipsychotic in combination with an
antidepressant in treatment-resistant unipolar depression tasl.
The author concluded that the available studies provided
preliminary evidence that atypicals appear to be a useful
addition for ffeatment-resistant unipolar depression. However,
it is clear that better quality evidence of efficacy and of
the risk-benefit ratio is needed. The AHRQ also reviewed
studies of arypical antipsychotic augmentation in patients
s37
Off-label use of antipsychotics: are we mad?
with treatment-resistant depression 1rorl. There was a modest
amount of evidence that the addition of an arypical
antipsychotic to an SRI antidepressant is no more efFective
than an SRI alone. In conclusion, the overall quality ofstudies
was low, heterogeneous and based on sparse data.
4.8 Insomnia
Small doses of sedative atypical antipsychotics, such
quetiapine and olanzapine, are commonly used by psychiatrists
to aid sleep in patients with a variety of psychiatric diagnoses.
This practice is not evidence-based and commentary in the
literature about the use of antipsychotics in this way is almost
non-existent tasl. The commonly quoted radonal for this
practice is that it is less harmful than prescribing hypnotics or
benzodiazepines which have addictive porendal. The doses of
atypicals used (in the region of 7 5 - 1 00 mg of quetiapine) are
thought to be unlikely to lead to major side effects. However,
atypicals are relatively expensive and potentially side eflbcts
may be serious, for example, quetiapine can cause hypotension
and hyperglycaemia.
s. Special patient groups
s.t Off-label use of antipsychotics in children
Antipsychotics are used for both psychotic and non-psychotic
disorders in -child and adolescent psychiatry. There are
few rypical antipsychotics licensed for use in children and
adolescents and even fewer arypical antipsychotics.
In the UK the typical antipsychotics with approved
psychotropic indications are: haloperidol (for schizophrenia
and other psychoses, psychomotor agitation and dangerously
impulsive behaviour andTourettet syndrome); chlorpromezine
(for childhood schizophrenia and autism); and trifluoperazine
(for schizophrenia and other psychoses, psychomotor agitation
and dangerously impulsive behaviour and for short-term
adjunctive management of severe anxiery).
The typical antipsychotics with approved US paediatric
indications are: haloperidol (for Tourettet syndrome,
treatment-resistant severe behavioural disorders and treatment
resistant hyperactivity with conduct disorders); pimozide
(Tourettet syndrome); and thioridazine (for severe behavioural
problems and hyperactivity with conduct disorder). The
atypical antipsychotic, risperidone, is licensed for the
treatment of irritability associated with autistic disorder in
children and adolescents, schizophrenia in adolescents and
bipolar mania associated with bipolar I disorder in children
and adolescents in the US.
\7ith the above exception in the US, atypical antipsychotics
are not MHRA or FDA approved for use in children or
adolescents but, increasingly, doctors are prescribing them for
a range of conditions in young people, from mood disorders
to behavioural problems and attention deficit hyperactivity
disorder (ADHD).
Several major studies detailing the increases in prescribing
rates for atypical antipsychotics have shed light on which
538 Expeft Opin. Drug Saf. (2007) 6(5)
drugs are being prescribed for which patients and what
disorders [20,50]. Much ofthe increase represents the prescribing
of antipsychotics for behavioural indications. Modest evidence
from controlled clinical trials suggests antipsychotics may be
helpful in reducing severe disruptive behaviours in children
with autism and mental retardation. However, there is no firm
evidence supporting the use ofantipsychotics for behavioural
as conditions such as ADHD 1201. Drug trials in children are
limited and short term due to ethical and legal difficulties
of conducting research on children and so the increase in
prescribing has not been paralleled by a comparable increase
in clinical research evaluating safety and efficary. Prescribers
rely on limited research data, extrapolations from adult
psychopharmacology and clinical experience. The use of
atypical antipsychotics in children is associated with weight
gain and prolactin elevation t5.rl. Few studies have addressed
other metabolic side effects such as hyperlipidaemia and
impaired glucose tolerance, but, as in adults, before prescribing
these drugs, serious consideration should be given to potential
side effects and patients should be monitored for metabolic
syndrome and daytime somnolence.
s.z Off-label use of antipsychotics in the elderly
Antipsychotics remain the mainstay for the treatment of
schizophrenia in elderly people 1521. teatment recommen-
dations are derived largely from studies of their use in
younger poprllations. Most manufacturers of such medicines
recommend the prescription of reduced doses in the
elderly. This would appear prudent, given the reduced renal
function, cardiovascular instabiliry and cognitive decline of
older people.
Antipsychotics have also been widely used in the elderly to
manage BPSD. None of the atypical antipsychotics and only
one of the rypical antipsychotics (haloperidol) has UK approval
for this indication.
Accumuladng safety data, in particular for the atypical
antipsychotic drugs olanzapine and risperidone, Ied to the
UK Committee on the Safety of Medicines issuing a warning
in March 2004, advising that risperidone and olanzapine
should no longer be used to manage BPSD and that patients
already receiving these drugs for BPSD should be switched to
other treatments [r02]. Specifically, a threefold increase in
cerebrovascular events, including stroke, among older adults
with BPSD was reported in dementia patients treated with
these arypical antipsychotics. In April 2005, the FDA issued a
public health advisory notice advising that the use of arypical
antipsychotics in the ueatment of BPSD was associated with
an increased mortaliry of - 7 .6- to I .7 -fold based on an analysis
of 17 placebo-controlled trials of olanzapine, aripiprazole,
risperidone or quetiapine t1031. Very similar results were
reported from a systematic review with meta-analysis of
15 RCTs comparing arypicals with placebo for BPSD t:at.
Some clinicians expressed concern. that antipsychotic
treatment would, as a consequence of the warnings, be
withheld and that clinicians would switch to prescribing

rypical antipsychotics [la]. Indeed, there is evidence that the
risk of cerebrovascular events and increased mortaliry is similar
for rypicals and arypicals t5r,561. However, two studies in older
adults, one in patients with dementia, have reported a higher
risk of death in patients receiving rypicals than atypicals tsz,tsl.
Although still recognising the risks of prescribing anti-
psychotics for BPSD, the realiry is that their use may be
necessary in severe cases [104]. Evidence ofefficary for physical
aggression, agitation and psychosis is best for olanzapine and
risperidone t5e-$).The evidence for the efficary of rypicals is
less and their side effect profile different. In the CATIE-AD
RCT study, the adverse efFects of arypicals offset advantages
in their efficacy in the treatment of behavioural and psycho-
logical symptoms of Alzheimert disease toal. Patients with
psychosis, aggression or agitation were randomized to receive
olanzapine (mean dose 5.5 nglday), quetiapine (mean dose
56.5 mglday), risperidone (mean dose 1.0 mg/day) or placebo.
The time to discontinuation of treatment due to adverse
effects or intolerabiliry favoured placebo and no significant
difiFerences were found with regard to improvement on the
Clinical Global improvement scale.
s. Specialist off-label indications
In the following section, the evidence base for prescribing
antipsychotics for certain more specialist clinical problems is
discussed. This includes quotations from major guidelines
where these exist,
6.1 Personality disorders
No antipsychotic is licensed for the ffeatment of personality
disorders. Typical antipsychotics have been studied in low
doses in the treatment of schizorypal and borderline
personality disorders, but seldom in a satisfactory way 165).
Antipsychotics have also been used to prevent recurrent
self-harm and in one RCT flupentixol was efficacious in
preventing further episodes 10e1.
Subsequent studies have turned to the use of arypical
antipsychotics. Three RCTs have provided evidence that
olanzapine is more effective than placebo and may be more
effective than fluoxetine in treating borderline personality
disorder 1ror1. Aripiprazole was more effective than placebo
for the treatment of borderline personaliry disorder in one
small S-week trial involving a total of 52 patients rcA.
Risperidone was more effective than placebo for the treat-
ment of schizorypal personaliry disorder in one small 9-week
trial (25 patients in total) tesl.
A Cochrane systematic review of pharmacological inter-
ventions for people with borderline personality disorder
identified only six small, short RCIs (total number of patients:
448) involving antipsychotics i6el. The authors concluded that
although antipsychotics may affect some mental state symP-
toms more effectively than placebo, the results were difficult to
interpret clinically and there was little evidence of advantage of
one antipsychotic over another. The APA Practice Guideline
Expeft Opin. Drug Saf. (2007) 6(5)
Haw & Stubbs
for the ffeatment of patients with borderline personality
disorder recommends low-dose atypical antipsychotics for the
treatment of cognitive-perceptual symPtoms t701.
6.2 Acquired brain injury
Antipsychotics are not licensed for use in patients with
acquired brain injury. Use of rypical antipsychotics, such as
haloperidol, for the control of agitation during the acute
recovery phase on medical and surgical wards, is not recom-
mended as these patients are particularly vulnerable to motor
side effects and confusion t7ll. A Cochrane review of drug
treatment for agitation or aggression after acquired brain
injury including injury to tfie brain from a head injury, found
good evidence was lacking about which drugs work tzzl.
Evidence of this is reflected in the fact that no RCTs involving
antipsychotics were identified.
A typical antipsychotic, levomepJomazine, has been reported
as an effective treatment for agitation in acquired brain injury
patients in one specialist rehabilitation unit tz:1. Atypical
antipsychotics with sedative ProPerties, for example olanzapine
or quetiapine, have been used where there is associated psychosis,
fear or suspiciousness, or ifurgent sedation is needed tz+1.
o.t Challenging behaviour in people with
learning disability
The term 'challenging behaviour', in the absence of mental
illness, encompasses a wide range of behaviours that may be
harmful to people or proPerry may be difficult to manage
and may limit access to community facilities. Antipsychotic
medications have been used to modify such behaviours in
people with learning disabiliry but there is little solid evidence
to suggest the benefits outweigh the risk t751. In this Cochrane
review, only nine RCTs of antiprychotics for the management
of challenging behaviour were identified and these did not
provide evidence ofrisks or benefits to this patient population.
Conducting RCTs in learning disabled populations with
challenging behaviours presents Practical as well as ethical
diffi culties. However, programmed withdrawal of antipsychotic
drugs from adults with intellectual disabilities resulted in
poor clinical outcome, with 48.7o/o experiencing a deteriora-
tion in problem behaviours or mental health. Only 7 .60/o were
successfully completely withdrawn from antipsychotics and
the mean antipsychotic dosage was higher at the end of the
study than at the beginninglT6).
Following the last revision of the Cochrane review (2004)
there has been more recent evidence to suPport the use of
risperidone in children with intellectual disabilities and
behavioural disorders, although these studies are of variable
quality ranging from RCTs to openJabel studies tzzl.
z. Other off-label usages of antipsychotics
This section describes off-label prescribing ofclozapine, use of
antipsychotics at above the dosage range recommended by the
manufacturer and dose form modification.
539
 Off-label use of antipsychotics: are we mad?

z.t Off-label use of clozapine tablets are enteric coated or modified release (paliperidone
Clozapine is licensed for the treatment of schizophrenia in prolonged release is newly available in the UB. Dlse form
Patients unresponsive to, or intolerant of;, conventional modification is a common pracrice on wards for older adults
antipsychotic drugs. In the UK it is also indicated for and in nursing homes, as many older people have trouble
psychosis in Parkinsont disease and in the US for the swallowing their medication. A recenr review of the literature
reduction of risk in suicidal behaviour in schizophrenia and and of data from the UK National Reporting and Learning
schizoaffective disorder. System found no reports of adverse events relating to dose
Despite the - 1o/o risk of granulocytopenia or agranulo- form modification of antipsychotics [s6]. However, dose form
cytosis, clozapine has been used in a variety of ofllabel indica- modification of any drug can lead ro underdosing because of
tions,includingrefractorymania,psychoticdepression,rggression spillage or when medication is added to food which is only
in psychotic patients, the reduction of tardive dyskinesia pardy earen. Chlorpromazine tablets should not be crushed as
symproms and bordedine personaliry disorder tzs,zql. the powder can cause skin sensitisation in the administrator.
Clozapine has also been used ofllabel in the treatment of
childhood-onset schizophrenia tsol and in adolescents with a. The tolerability and safety
bipolar disorder, intermittent explosive disorder and PTSD tarl. of antipsychotics
Clearly, the ofllabel use of clozapine requires a very rhorough
risk-benefi t analysis for individual patienrs. All antipsychodcs carry the risk of adverse side effects. These
can affect every system of the body and for the typical
z.z High-dose antipsychotics antipsychotics include anticholinergic side effects (..g., dry
The term'high dose'is used here to describe the prescription mouth, urine hesitanry, constipation and visual disturbance)
of a drug at above the dosage range recommended by the whereas their effects on noradrenergic mechanisms can lead to
manufacturer. Use of high doses of typical antipsychotics to postural hypotension and disturbances of sexual function. As a
treat patients with refractory schizophrenic illnesses became a consequence of their antihistaminergic action, many rypical
well-established psychiatric pracrice in the 1960s and eady antipsychotics are sedative. Interference with dopaminergic
1970s. However, RCTs failed to demonstrate clinical effrcacy transmission can lead to both endocrinological side effects, such
of so-called rnega-dose over convenrional dose therapy and as hyperprolactinaemia, and extrapyramidal side effects tszl.
there were increasing concerns about the safety of such regimes, Although the side effects involving the extrapyramidal system
especially with respect to sudden cardiac deaths. In the UK, are the most important for rypical antipsychotics, the combi-
this situation led to the Royal College of Psychiatrists issuing a nation of all those mentioned is likely to influence patients
consensus statement warning psychiatrists of the dangers of, quality of life and affect compliance. Other serious adverse
and lack of evidence for, high-dose therapy tszl. Use of a single effects include seizures, potentially fatal agranulocytosis and
antipsychotic at above the recommended maximum dose then neuroleptic malignant syndrome.
declined, although recent studies ofits frequenry are lacking. Patients with some psychiatric disorders are more likely to
In a UK multi-centre audit of antipsychotic prescribing to develop side effects than others. For example, patients with
3132 in-patients carried out in 1998, prescriptions above bipolar afFective disorder are more likely than those with
BNF recommended dosages occurred for only 1olo patients schizophrenia to develop extrapyrimidial side ef[ects and
prescribed an antipsychotic ts3l. High-dose therapy arising tardive dyskinesia iss,eql with rypical antipsychotics. Similarly,
out of the use of multiple antipsychotics was much more patients with bipolar depression more often report somno-
frequent (l9o/o). In another UK study of antipsychotic lence and discontinue treatment with quetiapine than those
prescribing to 502 patients, only 0.4o/o parienrs were prescribed with mania or schizophrenia tsol. The risk-benefit ratio is,
an atypical antipsychotic ar above the BNF recommended therefore, different for patients with different psychiatric
dosage 1a1. A US study of atypical antipsychotic prescribing disorders. Different doses of antipsychotics are used to treat
for a Medicaid-enrolled population conducted in 2003 different disorders. In a study of antipsychotic drug use in
reported on the use of dosages above those recommended in older people, risperidone doses were significantly lower for
the product labelling t841. A rotal of 60/o of patients were patients with dementia and mood disorders than for those
prescribed high doses of atypicals. A study conducted in six with schizophrenia, and this latter-most group experienced
East Asian countries in 2001 examining high dose anti- more side effects tqrl.
psychotic use in patients with schizophrenia reported that In recent years the use of rypical antipsychotics has
9.3o/o of patients were receiving > 1000 chlorpromazine declined. Instead, clinicians have switched their prescribing to
equivalents due to a single antipsychotic ta!. atypicals, which have a different, and generally regarded as
better, side effect profile. However, patients receiving atypicals
73 Dose form modification long-term are at increased risk of developing a number of
Crushing tablets or opening capsules which are not specifically serious disorders including weight gain and metabolic
designed for this purpose can alter the pharmacokinetic and syndrome (diabetes mellitus, dyslipidaemia and hypertension,
pharmacodynamic profile of the medication, for example if with associated obesity) lez-g4.The much promoted advantage

Expert Opin. Drug Saf. (2007) 6(5)


of reduced risk of extrapyramidal symptoms with the atypical
antipsychotic drugs needs to be balanced against these other
adverse effects.
The growth of off-label prescribing is raising questions on
safery in addition to the recognised side effects when products
are used for different purposes than they were tested and
approved. The issue of risks has become more pressing as
the atypica.l antipsychotic drugs are being prescribed widely
off-label for children. Atypicals cause weight gain and
prolactin elevation in children. It is thought that the risk of
developing these side efFects is higher in younger children 1irl.
Daytime somnolence is another unwanted side effect of
atypicals and this may be particularly burdensome in children
and adolescents ts;1.
Elderly patients prescribed antipsychotics are at risk of
sedation and of falls tqel. There is no evidence that newer
atypical antipsychotics are associated with fewer falls than the
older typical antipsychotics pzl. A further risk to be considered
in patients with dementia is.that antipsychotics increase the
risk of cerebrovascular events by approximately threefold
(see Section 5.2). Another potential problem is that most
antipsychotics cause QTc prolongation, with the associated
risk of developing torsades de pointes and sudden death tssl.
Ar age > 65 years is one predictor of QTc lengthening trrl.
Other predictors include use of thioridazine and droperidol
(both are no longer marketed in the UK, although both are
still available in the US), high-dose antipsychotics and other
medications such as methadone.
g. Expert opinion
'When considering prescribing an antipsychotic oFlabel for a
patient, the clinician first needs to weigh up the risks and
benefits of using an antipsychotic for that patient. This may
be difficult because often there is a dearth of information to
inform the risk-benefit relationship. Sometimes, but not
always, the benefits of treatment can be judged to outweigh
the risla of not prescribing. Consideration should also be
given to non-pharmacological measures. In general, it is pref-
erable to prescribe a drug that is licensed for the condition
needing treatment rather than an unlicensed one. However,
sometimes the risk-benefit profile of an ofllabel antipsychotic
in a given patient will be better than say a benzodiazepine,
Expert Opin. Drug Saf. (2007) 5(5)
Haw & Stubbs
where problems of dependence and abuse may outweigh the
benefits. Some oFlabel antipsychotic use is common place,
for example, the widespread practice of prescribing a low
dose of an atypicd, antipsychotic with sedative properties to
patients with agitated depression. Greater difficulry arises
when treating uncommon conditions and special groups of
patients. Further considerations are the dosage and likely
duration of treatment, low dose, short-term use of arypical
antipsychotics being less hazardous than higher dosage
long-term use with respect to weight gain and the metabolic
syndrome. Patient factors, such as body mass index and
pre-existing risk factors for cardiovascular disease also need to
be considered in the risk analysis.
\7hen prescribing for an ofllabel indication reference
should be made to the available evidence base for the
effectiveness of the drug for that indication.
'!7here there is
limited evidence but using an offTlabel antipsychotic aPPears
to be the best treatment option it is helpful to use the '3T'
approach: target the symptoms requiring treatment; titrate
the drug dose from a low starting dose; and timeJimit the
prescription so that ineffective treatment is not allowed to
continue long-term.
'SThere
possible, the patient should be fully informed that it
is proposed to use an antipsychotic off-label. A discussion of
the alternative treatment options should also take place with
reference to the risk-benefit ratio for each drug. Ifthe patient
lacks the' mental capacity to give informed consent to
treatment, a discussion about the treatment should take place
with the relatives or carers. It is important from a medicoJegal
point ofview to document the discussion with the patient and
once the drug has been prescribed to make regular follow-up
notes about the response to treatment. It is not always possible
to make evidence-based prescribing decisions and indeed
psychiatry would not advance without therapeutic innovation.
\7here treatment with an antipsychotic is not mainstream
practice it may be prudent to obtain a second opinion.
Ultimately, the clinician has to do what they consider is best
for the individual patient in order to relieve their distress.
Acknowledgement
The authors would like to thank the anonymous referees for
their helpful comments and contributions to the paper.
541
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Affiliation
Camilla Hawt MB BChir MRCP MRCPsych &
Jean Stubbs MSc MRPharmS
tAuthor for correspondence
St. Ardrewt Hospital, Billing Road,
Nonhmpton. NNI 5DG, UK
Tel: +44 604 616192;
E-mail: chaw@standrew.co.uk

Expert Opin. Drug Saf. (2007) 6(5) 545

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