Application to add clozapine to the Essential List of ... · 4 Begin with one-half of a 25-mg tablet (12.5 mg) once or twice daily and continue with daily increments of 25-50 mg/day

Application to add clozapine to the Essential List of Medicines

as a complementary medicine for treatment resistant schizophrenia

1

1. Summary statement of the proposal for inclusion

Currently the 17th edition of WHO Model List of Essential Medicines includes Haloperidol and Chlorpromazine

under 24.1 Medicines for psychotic disorders. The evidence review and the consequent recommendations of the

guideline development group for WHO’s mental health Gap Action Programme Intervention Guide (mhGAP-IG)

identified some medicines in addition to psychosocial interventions for the treatment of psychotic disorders in 2009

(1,2). The recommendations identified First Generation Antipsychotics (FGAs) haloperidol or chlorpromazine as a

first choice and Second Generation Antipsychotics (SGAs) as their alternatives if availability and cost is not a

constraint. The same recommendations reserved clozapine for individuals with psychosis who do not respond to

other antipsychotics provided that laboratory facilities are available for regular monitoring of the white bold cells.

About one quarter of patients with schizophrenia do not respond to treatment. We reviewed systematic reviews since

2009 and concluded that the recommendation on clozapine for treatment resistant schizophrenia is still valid .

We do not propose clozapine for the core list of essential medicine but as a complementary medicine to be

prescribed only by mental health specialists so that care can be taken in the selection of treatment resistant patients

and regular medical and laboratory examinations are ensured for the prevention of adverse effects especially

agranulocytosis.

2. Name of the focal point in WHO submitting or supporting the application (where relevant)

Dr M.Taghi Yasamy,

Department of Mental Health and Substance Abuse (MSD)

World Health Organization

Geneva

[email protected]

3. Name of the organization(s) consulted and/or supporting the application

Dr Corrado Barbui,

WHO Collaborating Centre for Research and Training in Mental Health,

Department of Public Health and Community Medicine, Section of Psychiatry and Clinical Psychology,

University of Verona, Verona, Italy

[email protected]

4. International Nonproprietary Name (INN, generic name) of the medicine

Clozapine

5. Formulation proposed for inclusion; including adult and paediatric (if appropriate)

Clozapine: Oral tablets of 25mg , 100mg and 200mg

6. International availability - sources, if possible manufacturers and trade names

The patent for Clozaril (Novartis) expired in 1998 (3). Ever since a considerable number of pharmaceuticals have

started manufacturing the generic medicine, some of them based in emerging economy countries. In addition to

justifiable worries about adverse effects, the need for blood tests, the need for specialists to monitor treatment

protocols; one of the reasons for underutilization has been considered as minimized efforts to market it after it

became largely a generic medicine (4). Yet, even a number of low and middle income countries have added it to

their national list of essential medicines (5). Though at least in US clozapine seems to have the least frequency of

off-label use as compared with other antipsychotics (6); some low and middle income countries are reporting off

mailto:[email protected]

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label use for example for the treatment of substance abuse despite its sensitive safety profile (7). Overall, it seems

that availability is increasing with a slow pace but appropriate use for treatment refractory schizophrenia seems to be

much lower than expected.

Trade names:

Asaleptin

Clopine

Clozaril

Denazapine

Fazaclo ODT

Iprox

Leponex

Lepotex

Sizopine

Zaponex

Manufacturers:

Azur pharma international iii ltd

Caraco pharmaceutical laboratories ltd

Ivax pharmaceuticals inc sub Teva pharmaceuticals

Mylan pharmaceuticals inc

Novartis pharmaceuticals corp

Panpharma

Par pharmaceutical

Sandoz inc

See also Appendix 1 for the brands and manufacturers in Netherland and Switzerland.

7. Whether listing is requested as an individual medicine or as an example of a therapeutic group

As an individual medicine

8. Information supporting the public health relevance

Schizophrenia is a severe form of mental illness. Though the incidence is low, as it starts mostly in a young age (15-

35 years) and lasts long, the prevalence is considerable affecting at least 26 million people world-wide. It has a high

potential for becoming a serious disability in the absence of the right treatment and appropriate social approach

toward the patient. Though schizophrenia is a prototype, psychosis is not limited to schizophrenia. Mood disorders

especially bipolar disorder may develop into psychotic states especially at the peak of the disorder. Delusional

disorders, acute and transient psychotic disorders, schizoaffective disorders are some of the other types of psychoses.

Schizophrenia alone causes 8.3 million of lost years due to disability among men and 8 million years among women

(8).

A review of the world literature found treatment gaps to be 32% for schizophrenia. The gap in the same study was

only 18% for Europe but about 57% for Latin American and Caribbean countries (9). There are effective

interventions for schizophrenia. Appropriate treatment includes a balanced mix of psychosocial and pharmacological

approaches. Human rights violation of people with schizophrenia is high. Many people with this disorder end up in

mental hospitals or residential care and are sometimes forced to spend long period of times in these centers. Care of

persons with schizophrenia can be provided at community level, with sound treatment, and active family and

community involvement. The earlier the treatment is initiated, the more effective it will be. Many programmes have

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demonstrated the feasibility of providing care to people with severe mental illness even in low and middle income

countries through the primary health care systems. Psychosis is one of the priority conditions in the WHO mental

health Gap Action Programme (mhGAP).

Treatment resistance

Though social adversities, interpersonal problems, long term residential services, stigma and isolation and treatment

non-adherence have their role in chronicity and deterioration of this illness; the issue of resistance to

pharmacological treatments in about 25% of patients has always been a matter of public health concern (10,11).

There have been different definitions of treatment resistant schizophrenia (TRS) but what has been common in the

past has been at least two failed adequate trials with different antipsychotics (at chlorpromazine-equivalent doses of

≥ 600 mg/day for ≥ 6 consecutive weeks (see 12 for a review). Clozapine has been considered as one of the most

underutilized treatments for schizophrenia. In 2008, it was used to treat only 4.4% of patients with schizophrenia in

the U.S. (4) despite good evidence in favour of its effectiveness for treatment resistant schizophrenia (10,11). In the

pivotal trial comparing clozapine to chlorpromazine, 30% of treatment resistant patients responded to clozapine as

compared with 4% to chlorpromazine (11). Another reviewer considered the range to be between 30-50% (12).

Public concerns over safety considerations of clozapine is high in view of possibility of adverse effects such as

agranulocytosis; seizures, metabolic side effects; myocarditis and other cardiovascular adverse effects. Though these

adverse effects can be detected and prevented under close monitoring (4), we propose that use of clozapine needs to

be limited to those individuals with the disorder who do not respond to medicines with better safety profiles.

9. Treatment details and guideline

The recommendations developed by the guideline development group for mhGAP-IG indicated, with standard

strength, that Clozapine is not suitable for routine use for psychotic disorders:

“Second-generation antipsychotics (with the exception of clozapine) may be considered in individuals with

psychotic disorders (including schizophrenia) as an alternative to haloperidol or chlorpromazine if availability can

be assured and cost is not a constraint.”

But the same recommendations made an exception for treatment resistant psychotic disorders:

“For individuals with psychotic disorders (including schizophrenia) who do not respond to adequate dose and

duration of other antipsychotic medicines, clozapine may be considered by non-specialist health care providers,

preferably under the supervision of mental health professionals, only if routine laboratory monitoring is available.”

However, since the guideline was developed for non-specialized care providers, it did provide details of

management with clozapine.

“Clozapine may be considered by non-specialist health-care providers, preferably under the supervision of mental

health professionals. It should only be considered if routine laboratory monitoring is available, because of the risk

of life-threatening agranulocytosis.”

NICE Guideline, 2010 suggests to “Offer clozapine to people with schizophrenia whose illness has not responded

adequately to treatment despite the sequential use of adequate doses of at least two different antipsychotic drugs. At

least one of the drugs should be a non-clozapine second-generation antipsychotic.”(13).

FDA also considers clozapine for treatment resistant schizophrenia and also patients with schizophrenia who have a

high risk of suicide (14):

Starting dose:

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Begin with one-half of a 25-mg tablet (12.5 mg) once or twice daily and continue with daily increments of 25-50

mg/day. If well tolerated, increase to a reach a target dose of 300-450 mg/day by the end of 2 weeks. Subsequent

increments should not exceed once or twice weekly, in increments not more than 100 mg. A divided dosage

schedule is preferable to prevent some adverse effects.

Dose Adjustment:

Daily dosing should continue on a divided basis until an effective and tolerable dose level is sought. Many patients

may respond well at doses between 300-600 mg/day. For some it may be necessary to raise the dose to the 600-900

mg/day. Rapid increasing of dosage may lead to adverse reactions especially seizures which is dose dependent.

Dosing should not exceed 900 mg/day.

Maintenance Treatment:

Responding patients should be continued on clozapine at the lowest level needed to maintain remission. Patients

should be periodically reassessed to determine the need for maintenance treatment.

Ending of Treatment:

In the event of planned termination of clozapine therapy, gradual reduction in dose is recommended over a 1-2-week

period.

Re-starting Treatment after discontinuation:

For patients who have been off clozapine even for a couple of days, treatment needs to be reinitiated with one-half

of a 25-mg tablet (12.5 mg) once or twice daily again. If that dose is well tolerated, in most cases it may be feasible

to reach a therapeutic dose more quickly than was recommended for the initial treatment

10. Summary of comparative effectiveness in a variety of clinical settings:

Identification of clinical evidence, available data, and estimates of comparative effectiveness:

The department of mental health and substance abuse sponsored/conducted a series of systematic reviews in 2009

for the development of mental health GAP Action Programme Intervention Guide (mhGAP-IG). This included also

systematic reviews to see whether typical and second generation antipsychotic medications are safe and effective for

the treatment of psychosis ( see Appendix 2 for details).

We reviewed additional systematic reviews since 2009 to see whether the recommendation on treatment resistant

schizophrenia is still valid. We have summarized the more recent systematic reviews in Appendix 3. Here are our

conclusions:

- Esslai et al 2009 (10), conducted a systematic review of 42 trials with 3950 participants and compared

Clozapine versus FGAs . Clozapine showed better clinical improvement for treatment resistant

schizophrenia as compared with FGAs.

- Leucht S et al 2009 (15), included 150 double-blind, mostly short-term, studies, with 21 533 participants.

Compared nine second generation antipsychotic drugs including clozapine compared with first generation

drugs. No analysis was performed on treatment resistance. In general clozapine and 3 other SGAs

amisulpiride, olanzapine and risperidone were more efficacious than others for schizophrenia.

- Leucht S et al 2009 (16), included 78 studies with 13,558 participants. They conducted a head to head

comparisons of amisulpride, aripiprazole, olanzapine, Clozapine, quetiapine, risperidone, sertindole ,

ziprasidone and zotepine. Clozapine was equal to some SGAs but more efficacious than zotepine. Also

more efficacious than risperidone in doses >400 mg/day. No conclusion could be made for treatment

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resistant schizophrenia. Though they showed them to be almost similar, the authors mention in addition to

low dose of clozapine, other methodological issues such as the variation of criteria (patients may not have

been treatment refractory).

- Asenjo Lobos C et al 2010 (17), The systematic review was on 27 blinded randomized controlled trials,

with 3099 participants . They compared Clozapine versus other atypical antipsychotics for schizophrenia.

Again there was no focus on treatment resistance. Though many participants were diagnosed as treatment

resistant to prior antipsychotics but “the criteria and definitions used for treatment resistance varied across

trials”. In general clozapine was more efficacious than zotepine. More efficacious than risperidone based

on leaving the trial because of inefficiency but in terms of improving general mental state similar to

risperidine and others.

- Komossa K et al 2010 (18), The review included 45 blinded RCTs with 7760 participants. They compared

risperidone versus other atypical antipsychotics for people with schizophrenia and schizophrenia-like

psychosis. Again there was no focus on treatment resistance. With risperidone, less patients left the

studies because of adverse effects as compared with clozapine. Clozapine seemed to be more efficacious

than resperidone in terms of the number patients who left the study for being ineffective. There was no

other superiority of clozapine. The authors argue two possible explanations: various definitions of response

to treatment and lower dose of clozapine as compared with pivotal studies.

In addition to traditional randomized trials there have been two other major long term studies by National

Institute of Mental Health(NIMH) with a “real-life” approach which went through different phases in the

last decade. Some but not all systematic reviews have included their trials. The CATIE study had three

main characteristics: An innovative outcome was "all-cause treatment discontinuation." to capture the

overall effectiveness of the medications. A second was that the dose ranges of the study drugs were not

equivalent. And the third was that the study was not powered for non-inferiority.

CATIE showed that the difference between SGAs and perphenazine a FGA as minimal, clozapine was

most effective for patients whose symptoms did not improve with first-line treatment (19)

A complementary Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS) tried

switching between SGAs. The authors of both studies concluded that, with the possible exception of

clozapine, SGAs do not markedly differ from FGAs with regard to compliance, quality of life and

effectiveness (20).

We excluded all other systematic reviews which compared other head to head comparisons and had

mentioned clozapine but did not find any trials comparing with clozapine. One of these reviews

included only one trial on clozapine.

Overall, there is no new finding questioning the preference of clozapine for treatment resistant

schizophrenia. However, at least in usual dose ranges clozapine does not seem to be preferable to other

SGAs for treatment of schizophrenia in general and the first recommendation of mhGAP seems to be valid

too. Also the recent definition of NICE for treatment resistance seems to be technically defendable( 21)

provided that availability and cost is not an issue.

Offer clozapine to people with schizophrenia whose illness has not responded adequately to treatment

despite the sequential use of adequate doses of at least two different antipsychotic drugs. At least one of the

drugs should be a non-clozapine second-generation antipsychotic.

11. Summary of comparative evidence on safety*:

1. Estimate of total patient exposure to date

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Clozapine is the oldest atypical antipsychotic medicine used for the treatment of schizophrenia. Discovery and

research on clozapine started in late 1950th. Trials were conducted and the medicine was released in Switzerland,

West Germany, Austria and Finland in 1970th. Reports of lethal agranulocytosis led to its withdrawal by the

manufacturer in 1975. The medicine was forgotten for about one decade but the resumption of a new series of

studies particularly in US showed that clozapine was more effective against treatment-refractory schizophrenia than

other antipsychotics, and FDA followed by health authorities in many other countries approved its use for treatment-

resistant schizophrenia, with close hematologic monitoring for granulocytopenia (10, 11).

It is not possible to estimate the global number of patients exposed to clozapine as the situation in most parts of the

world is not clear. But clozapine was prescribed 1.56 million times in US in 2008 (12). This has been for 4.4% of

patients with schizophrenia in the same year (5). Given the long duration of presence of the medicine in the market

and the cumulative number of users, we should by now have a comprehensive list of possible adverse effects

reported so far.

2. Adverse effects/reactions

1. Agranulocytosis, though uncommon, is a potentially life-threatening adverse event. Agranulocytosis, is

defined as an ANC of less than 500/mm3. In the initial studies the cumulative incidence per year was about

1.3% with a fatality of about 3% among those who developed agranulocytosis. During this period among

patients who continued the drug beyond the third month, the weekly incidence of agranulocytosis fell to a

substantial degree.

2. Myocarditis , clozapine is associated with an increased risk of fatal myocarditis, especially during, but not

limited to, the first month of therapy.

3. Other cardiovascular and respiratory effects: Orthostatic hypotension, with or without syncope and rarely

accompanied by respiratory and/or cardiac arrest. Orthostatic hypotension is more likely to occur during

initial titration in association with rapid dose escalation.

Since collapse, respiratory arrest and cardiac arrest during initial treatment has occurred in patients who

were being administered benzodiazepines or other psychotropic drugs, caution is advised when clozapine is

initiated in patients taking a benzodiazepine or any other psychotropic drug.

4. Increased mortality in elderly patients with dementia-related psychosis.

5. Seizures. Dose dependant. Caution in patients with a history of seizures or other predisposing factors.

Most common side effects/reactions :

Drowsiness/sedation, fatigue, dizziness, headache,

Benign hyperthermia, disturbances in sweating/temperature regulation

Rigidity, akathisia, extrapyramidal symptoms, tremor, dysarthria,

Seizures / convulsions / myoclonic jerks

Tachycardia, hypertension, postural hypotension, syncope, ECG changes

blurred vision

Constipation, urinary incontinence, urinary retention

Nausea, vomiting,

Elevated liver enzymes

Dry mouth or hypersalivation

Weight gain

3. Identification of variation in safety due to health systems and patient factors

3.1. Health system factors:

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Agranulocytosis is a potentially fatal adverse adverse event, the peak of incidence is about 3 months after initiation

and then starts to decrease. Weekly checking of white blood cells for 18 weeks and then monthly monitoring needs

to be done until one months after the discontinuation. No patient should be started on the medication when facilities

for laboratory tests of white blood cells is not available and when there is no guarantee that the patient will be

available for such a follow up. Clozapine should be delivered through a distribution system that can ensure such

precautionary measures

Clozapine should be prescribed under specialist supervision and for treatment resistant schizophrenia. There is no

experience on prescription by non-specialists. Even when offered at the community level, it is the specialists who

initiate it and monitor the use through teamwork (22). Community support systems should become more aware

about drug induced metabolic syndromes that might be left unattended outside the health services (23).

3.2. Patient factors:

Like other antipsychotics, off label use especially for people with dementia may increase death rates and is

contraindicated .

According to FDA(14) clozapine is contraindicated in patients with:

Hypersensitivity to clozapine or any other component of the drug, those with myeloproliferative disorders,

uncontrolled epilepsy, paralytic ileus, or a history of clozpine-induced agranulocytosis or severe granulocytopenia.

in severe central nervous system depression or comatose states. It should not also be used simultaneously with other

agents which potentially cause agranulocytosis or otherwise suppress bone marrow function.

• Summary of comparative safety against comparators

Clozapine and olanzapine are the most likely SGAs to lead to weight gain and glucose and lipid abnormalities .

Amisulpride and risperidone carry a risk of some dose-related extrapyramidal symptoms and substantial increase in

prolactin levels, The use of clozapine is restricted to refractory patients because of the risk of agranulocytosis, but it

also carries a risk of seizures, anticholinergic effects, constipation, sedation, postural hypotension, hypersalivation,

myocarditis, and pancreatitis. Sertindole and ziprasidone carry the strongest risk of QTc prolongation among

second-generation antipsychotics.

Contrary to the very unpleasant safety profile of clozapine, in some studies in high income countries such as Finland,

even a decreased mortality was reported in those under clozapine and this was initially attributed to lower suicide

rates and later also to lowered substance abuse and more regular health monitoring. The initial report (24) ignited an

unresolved debate (see 25 as an example).

12. Summary of available data on comparative cost** and cost-effectiveness within the pharmacological class

or therapeutic group:

• range of costs of the proposed medicine

According to the International Drug Price Indicator Guide(26), the unit price of clozapine ranges from US$ 0.0365

in Ghana to US$ 0.7046 in Botswana with a median of US$ 0.2026 and high/low ratio of 19.30. The wide range of

prices shows the possibility of providing lower cost clozapine in those countries where it is not affordable. For

example according to the Organization of Eastern Caribbean States / Pharmaceutical Procurement Service

(OECS/PPS) the price should be US$ 0.1960(27).

• comparative cost-effectiveness presented as range of cost per routine outcome (e.g. cost per case, cost per

cure, cost per month of treatment, cost per case prevented, cost per clinical event prevented, or, if possible

and relevant, cost per quality adjusted life year gained)

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The cost of treatment of a person suffering from chronic schizophrenia using older antipsychotic drugs was

estimated to be about $2 per month (28).

In 2008 a WHO study concluded that the most cost-effective interventions were those using older antipsychotic

drugs combined with psychosocial treatment, delivered via a community-based service model (I$ 2350–7158 per

averted disability-adjusted life year averted, I$ 1670–3400 following country-level contextualization within each of

the sub regions. The relative cost-effectiveness of interventions making use of newer, “atypical” antipsychotic drugs

was estimated to be much less favourable (29). Even a cost utility analysis in UK in 2008 found clozapine only

marginally cost effective (30). However the situation might have changed ever since as generic medicines have

become available at a wider level. It is clear that with the high prices of brand medicines such as clozapine, reducing

the treatment gap for treatment resistant schizophrenia will not be achievable in low resource contexts. How-ever

based on the controversy about clinical equivalence of different generic productions (3,31,32), it would be a

national decision to make sure about the quality of generic clozapine in different contexts.

13. Summary of regulatory status of the medicine (in country of origin, and preferably in other countries as

well)

Clozapine is FDA approved for treatment resistant schizophrenia and also for “reducing the risk of recurrent

suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at chronic risk for

re-experiencing suicidal behavior, based on history and recent clinical state”.

Clozapine has also been recommended by UK’s NICE guidelines and Australian Register of Therapeutic Goods

(ARTG)for treatment resistant schizophrenia (13,33). Clozapine is not a “controlled medicine” but in most countries

it is under dispensary controls on distribution and requires blood tests for agranulocytosis and registered results of

tests at regular interval before it can be dispensed.

14. Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia, United

States Pharmacopoeia)

International Pharmacopoeia, No

British Pharmacopoeia, Yes

European Pharmacopoeia, Yes

United States Pharmacopoeia, Yes

15. Proposed (new/adapted) text for the WHO Model Formulary

CLOZAPINE

WARNING:

Clozapine may cause agranulocytosis which might prove fatal. Distribution, prescription and delivery of the

medicine should strictly follow the detailed precautions and requirements mentioned in the formulary

9

Tablets: 25mg, 100mg, 200mg

Indications: Treatment resistant schizophrenia

Contraindications:

Patients with a history of drug-induced granulocytopenia/agranulocytosis, or with bone marrow disorders

Previous hypersensitivity to clozapine or to any other components of the formulation

Circulatory collapse and/or CNS depression due to any cause, comatose conditions

Alcoholic and other toxic psychoses, drug intoxication

Psychosis associated with dementia

Severe renal or cardiac disease (e.g. myocarditis)

Severe hepatic disease; hepatic failure

Uncontrolled epilepsy

Paralytic ileus

Precautions:

Agranulocytosis

Clozapine may cause agranulocytosis. Its use should be limited to patients with schizophrenic who are non-

responsive to, or intolerant of other antipsychotic drugs with the following conditions:

A normal leucocyte findings (white blood cell count > 3.500 cmm with normal differential blood count) and in

whom there is a regular white blood cell (WBC) counts and absolute neutrophil counts (ANC) (weekly during the

first 18 weeks, at least monthly thereafter throughout treatment, and for 1 month after discontinuation of clozapine).

Before starting clozapine, a white blood cell count (WBC) and differential count (DC) to calculate ANC must be

performed within 10 days prior to starting treatment to ensure that only patients with normal white blood cell (WBC)

counts and normal ANC are included.

Although granulocytopenia or agranulocytosis are generally reversible upon withdrawal of the drug,

agranulocytosis can prove fatal. The majority of cases occur within the first 18 weeks of treatment. Because

immediate withdrawal of the drug is required to prevent agranulocytosis, monitoring the white blood cell (WBC)

count is mandatory.

Drugs known to have a potential to depress bone marrow function should not be used concurrently with clozapine.

In addition, the concomitant use of long-acting depot antipsychotics should be avoided.

Dosage:

Starting dose:

Begin with one-half of a 25-mg tablet (12.5 mg) once or twice daily and continue with daily increments of 25-50 mg/day. If well tolerated, increase to a reach a target dose of 300-450 mg/day by the end of 2 weeks. Subsequent

increments should not exceed once or twice weekly, in increments not more than 100 mg. A divided dosage

schedule is preferable to prevent some adverse effects.

Dose Adjustment:

10



mg/day. Rapid increasing of dosage may lead to adverse reactions especially seizures which is dose dependent.

Dosing should not exceed 900 mg/day.



mg/day. Rapid increasing of dosage may lead to adverse reactions especially seizures which is dose dependent. Dosing should not exceed 900 mg/day.

Maintenance Treatment:

Responding patients should be continued on clozapine at the lowest level needed to maintain remission. Patients

should be periodically reassessed to determine the need for maintenance treatment.

Ending of Treatment:

In the event of planned termination of clozapine therapy, gradual reduction in dose is recommended over a 1-2-week

period.

Re-starting Treatment after discontinuation:

For patients who have been off clozapine even for a couple of days, treatment needs to be reinitiated with one-half

of a 25-mg tablet (12.5 mg) once or twice daily again. If that dose is well tolerated, in most cases it may be feasible

to reach a therapeutic dose more quickly than was recommended for the initial treatment

Adverse effects:

2. Adverse effects/reactions

1. Agranulocytosis, Though uncommon, is a potentially life-threatening adverse event. Agranulocytosis, is

defined as an ANC of less than 500/mm3. In the initial studies the cumulative incidence per year was about 1.3%. In

the U.S., under a weekly WBC count monitoring system, there was a 3% fatality. During this period among patients

who continued the drug beyond the third month, the weekly incidence of agranulocytosis fell to a substantial degree.

2. Myocarditis , clozapine is associated with an increased risk of fatal myocarditis, especially during, but not

limited to, the first month of therapy.

3. Other cardiovascular and respiratory effects: Orthostatic hypotension, with or without syncope and

rarely accompanied by respiratory and/or cardiac arrest. Orthostatic hypotension is more likely to occur during

initial rapid dose escalation.

Since collapse, respiratory arrest and cardiac arrest during initial treatment has occurred in patients under

benzodiazepines or other psychotropic drugs, caution is advised when clozapine is initiated in patients taking a

benzodiazepine or any other psychotropic drug.

4. Increased mortality in elderly patients with dementia-related psychosis.

5. Seizures: Dose-dependent. Caution in patients with a history of seizures or other predisposing factors.

Common side effects/reactions:

Leukopenia / decreased WBC / neutropenia, eosinophilia, leukocytosis

Drowsiness/sedation, fatigue, dizziness, headache,

Benign hyperthermia, disturbances in sweating/temperature regulation

Rigidity, akathisia, extrapyramidal symptoms, tremor, dysarthria,

Seizures / convulsions / myoclonic jerks

11

Tachycardia, hypertension, postural hypotension, syncope, ECG changes

blurred vision

Constipation, urinary incontinence, urinary retention

Nausea, vomiting,

Elevated liver enzymes

Dry mouth or hypersalivation

Weight gain

Uncommon:

Agranulocytosis, anaemia, thrombocytopenia, thrombocythemia, circulatory collapse,arrhythmias,myocarditis,

pericarditis cardiomyopathy, cardiac arrest,dysphagia, ileus impaction, parotid gland enlargement, intestinal

obstruction/faecal impaction, neuroleptic malignant syndrome

Rare and very rare:

Sudden unexplained death, restlessness, agitation, confusion, delirium, intensification of dream activity, tardive

dyskinesia, obsessive compulsive symptoms, anaemia, thrombocytopenia, thrombocythemia, circulatory collapse,

arrhythmias, myocarditis, pericarditis, cardiomyopathy, cardiac arrest, dysphagia, ileus impaction, parotid gland

enlargement, intestinal obstruction/faecal impaction, hepatitis, cholestasis, cholestatic jaundice, fulminant hepatic

necrosis , acute pancreatitis, increased CPK, impaired glucose tolerance, diabetes aggravated, diabetes mellitus,

including in patients with no history of hyperglycaemia or diabetes mellitus, ketoacidosis, hyperosmolar coma,

severe hyperglycaemia, hypertriglyceridaemia, hypercholesterolaemia, , acute interstitial nephritis, priapism,

impotence, changes in ejaculation, dysmenorrhea, allergic asthma, thromboembolism including pulmonary

embolism, skin reactions

Interaction with other medicines:

- May augment action of medicines that may increase QTc interval

- Concomitant use of benzodiazepines may lead to circulatory collapse and even cardiac arrest

- Concomitant use of lithium may increase risk of neuroleptic malignant syndrome

- May lead to onset of seizures when given with valproic acid

- May increase hypotensive action of related medicines

References:

1. WHO | mhGAP Evidence Resource Centre

www.who.int/mental_health/mhgap/evidence/en/ accessed 25 November 2012

2. mhGAP Intervention Guide for mental, neurological and substance use disorders in non-

specialized health settings

http://www.who.int/mental_health/publications/mhGAP_intervention_guide/en/index.htm

l accessed 25 November 2012

3. Tse G, Thompson D, Procyshyn RM. Generic Clozapine: A Cost-Saving Alternative to

Brand Name Clozapine? PharmacoEconomics. 2003;21(1):1–11

4. Meltzer HY. Clozapine: balancing safety with superior antipsychotic efficacy. Clin

Schizophr Relat Psychoses. 2012 Oct;6(3):134–44.

http://www.who.int/mental_health/mhgap/evidence/en/

http://www.who.int/mental_health/publications/mhGAP_intervention_guide/en/index.html

http://www.who.int/mental_health/publications/mhGAP_intervention_guide/en/index.html

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5. National Medicines List/Formulary/Standard Treatment Guidelines

http://www.who.int/selection_medicines/country_lists/en/index.html accessed 1 October

2012

6. Leslie DL, Rosenheck R. Off-label use of antipsychotic medications in Medicaid. Am J

Manag Care. 2012;18(3):e109-17.

7. WHO ATLAS on Substance Use (2010) - Resources for the prevention and treatment of

substance use disorders www.who.int/substance_abuse/publications/atlas_report/profiles

accessed 1 October 2012

8. WHO, Global burden of disease, 2004 update 2008

www.who.int/topics/global_burden_of_disease/en/ accessed 1 October 2012

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generation antipsychotic drugs for schizophrenia: a meta-analysis. The Lancet.

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Analysis of Head-to-Head Comparisons of Second-Generation Antipsychotics in the

Treatment of Schizophrenia. Am J Psychiatry. 2009,1;166(2):152–63.

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Clozapine versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst

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Risperidone versus other atypical antipsychotics for schizophrenia. Cochrane Database of

Systematic Reviews [Internet]. John Wiley & Sons, Ltd; 1996 [cited 2012 Dec 06].

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http://www.who.int/topics/global_burden_of_disease/en/

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_in_Schizophrenia_.2.aspx

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use of antipsychotics medications in the United States, 1995-2008. Pharmacoepidemiol

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Metabolic Syndrome in Adults Prescribed Clozapine in Community and Long-stay In-

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effectiveness analysis. Bull World Health Organ. 2008 Jul;86(7):542–51.

30. Davies LM, Barnes TR, Jones PB, Lewis S, Gaughran F, Hayhurst K, et al. A randomized

controlled trial of the cost-utility of second-generation antipsychotics in people with

psychosis and eligible for clozapine. Value Health. 2008;11(4):549–562.

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generic clozapine. Community Ment Health J. 2005 Aug;41(4):393–8.

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psychoative drugs. Clinical Therapeutics. 2003 Jun;25(6):1578–92.

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PI-00528-3 accessed 5 December 2012

http://adisonline.com/cnsdrugs/Fulltext/2009/23080/The_CATIE_and_CUtLASS_Studies_in_Schizophrenia_.2.aspx

http://adisonline.com/cnsdrugs/Fulltext/2009/23080/The_CATIE_and_CUtLASS_Studies_in_Schizophrenia_.2.aspx

http://erc.msh.org/mainpage.cfm?file=1.0.htm&module=dmp&language=english

http://apps.who.int/medicinedocs/en/m/abstract/Js19552en/

http://www.who.int/mental_health/management/schizophrenia/en/

https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2009-PI-00528-3

https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2009-PI-00528-3

14

Appendix 1.

Netherland Medicines Information Bank on Clozapine

http://www.cbg-meb.nl/CBG/en/_search/searchresult/default.htm?qry=clozapine&language=en

Marketing authorisation number Order descending Product name Order ascending

RVG 21823 Clozapine 25 mg, tabletten



RVG 23635=21823 Clozapine Mylan 25 mg, tabletten

RVG 23636=21825 Clozapine Mylan 100 mg, tabletten

RVG 23677=21823 Clozapine 25 mg Teva, tabletten

RVG 23678=21825 Clozapine 100 mg Teva, tabletten

RVG 25049 Clozapine Sandoz 25, tabletten 25 mg



RVG 26334 Clozapine Actavis 25 mg, tabletten






RVG 35271 Clozapine Sandoz 200 mg, tabletten

RVG 103899 Clozapine G.L. 25 mg, tabletten



RVG 103903 Clozapine Leyden Delta 25 mg, tabletten



http://www.cbg-meb.nl/CBG/en/_search/searchresult/default.htm?qry=clozapine&language=en

15

RVG 103906 Clozapine-Mezadin 25 mg, tabletten



RVG 103912 Clozapine Synthon 25 mg, tabletten



Official Swiss Price List at

https://bag.e-mediat.net/SL2007.Web.External/ShowPreparations.aspx

1. Leponex Tabl 25 mg Novartis Pharma

2. Leponex Tabl 100 mg Novartis Pharma

https://bag.e-mediat.net/SL2007.Web.External/ShowPreparations.aspx

16

Appendix 3Table 1. Additional relevant systematic reviews on Clozapine following the evidence review for mhGAP

in 2009

Reviewers Comparisons Methods and

search strategy

Included

analysis on

treatment

resistant schizo

phrenia

Results Applicant’s brief

conclusions

Esslai et al, 2009 (10)

Cochrane review comparing Clozapine versus typical neuroleptics

42 trials and

3950 participants

For the update

of this review

(November

2008) they

searched all

relevant

randomised

controlled trials

(RCTs) from the

Cochrane Schizophrenia

Group Trials

Register. Significant risk of bias;

The clinical effect is, at

least in the short-term, not reflected in measures of

global functioning such as

ability to leave the hospital

and maintain an occupation

YES

They mention

“resistant to

typical

neuroleptics”

Better clinical improvement RR 0.72(0.7-0.8), fewer relapses RR 0.62 (05-0.8), reduction of symptoms WMD -4.22 (-7.8—4.1), reduction negative symptoms WMD -7.21 CI (-8.9 to -5.6), more acceptable in long term treatment RR 0.60 (0.5 to 0.7)

The clinical effects of clozapine were more pronounced in participants resistant to

typical neuroleptics in terms of clinical improvement (n=370, 4 RCTs, RR 0.71 CI 0.6 to 0.8, NNT 4 CI 3 to 6) and symptom reduction. 34% of them had a clinical improvement after Clozapine

Adverse effects: More blood problems, drowsiness. Hypersalivation, temperature increase but fewer motor adverse effects

Better clinical improvement under clozapine for treatment resistant schizophrenia as compared with typical neuroleptics. Clozapine caused more

blood problems, sedation and some other side effects but less motor adverse effects.

Leucht S et

al , 2009 (15)

Nine second

generation antipsychotic drugs including clozapine compared with first generation

drugs

Included 150

double-blind, mostly short-term, studies, with 21 533 participants. Excluded open studies. Compared overall efficacy (main outcome),

positive, negative and depressive symptoms, relapse, quality of life, extrapyramidal side-effects, weight gain, and

sedation.

No Only 4 second generation drugs were better

than first-generation drugs for overall efficacy: amisulpride −0·31 [−0·44 to −0·19, ], clozapine −0·52 [−0·75 to −0·29, p], olanzapine −0·28 [−0·38 to −0·18, ], and risperidone −0·13 [−0·22 to −0·05]). Second-generation antipsychotic drugs induced fewer extrapyramidal side-effects

than did haloperidol (even at low doses). With the exception of aripiprazole and ziprasidone, second-generation antipsychotic drugs induced more weight gain, in various degrees, than did haloperidol but not than low-potency first-generation drugs.

No analysis on treatment

resistance. Clozapine and 3 other SGAs amisulpiride, olanzapine and risperidone more efficacious for schizophrenia in general.

Range of adverse effects different for each SGA.

Leucht S et al, 2009 b (16)

Head to head comparisons of amisulpride, aripiprazole, olanzapine, Clozapine,

quetiapine, risperidone, sertindole , ziprasidone

78 studies with 167

relevant arms and

13,558 participants.

Searched the

Cochrane

Schizophrenia

Group’s Register for

randomized, at least

single blind trials in

the treatment of

schizophrenia or

related disorders.

Only Cochrane

Yes,

but they are skeptical about the results of

sensitivity analysis (See results).

Olanzapine proved superior to aripiprazole, quetiapine, risperidone, and ziprasidone. Risperidone was more efficacious than quetiapine and ziprasidone.

Clozapine proved superior to zotepine weighted mean difference = – 6.0,

p=0.002). and, in doses >400 mg/day, to risperidone. The comparison with risperidone was significantly heterogeneous due to one

In the treatment for schizophrenia and related disorders, clozapine was equal to some but more efficacious than zotepine. Also more efficacious than risperidone in doses >400

mg/day. No conclusion about treatment resistant patients.

17

and zotepine.

quality A and B

were included. No

language

restrictions.

study sponsored by clozapine’s manufacturer; excluding the study did not change the overall results.

Authors state in the discussion that in their opinion, clozapine is a more efficacious drug and that ”…the most likely explanation for not finding clozapine superior here is that most studies used low or very low clozapine dosages. They also mention that sensitivity analysis of treatment-resistant patients failed to

show a superiority of clozapine, but they mention that criteria varied and the patients may not have been as refractory as those in the pivotal studies as hardly any studies had a run-in phase to confirm refractoriness. No publication bias was detected.

In addition to using the low dosage of clozapine in the studies involved; in the sensitivity analysis they

looked similar but the authors mentioned methodological issues such as the variation of criteria (patients may not have been treatment refractory).

Asenjo Lobos C et

al, 2010 (17)

Clozapine versus other

atypical antipsychotics for schizophrenia

27 blinded randomised

controlled trials, with 3099 participants from the Cochrane Schizophrenia Groups Register (June 2007) and reference lists of

all included randomised controlled trials. Manually searched appropriate journals and conference

proceedings relating to clozapine combination strategies and contacted relevant pharmaceutical

companies.

No,

They mention the

diversity of definition of treatment resistance

Fewer participants in the clozapine groups left the trials early due to inefficacy than

risperidone RR 0.40 (0.23 to 0.70), suggesting a certain higher efficacy of clozapine. Clozapine was more efficacious than zotepine in improving the participants general mental state MD -6.00 (-9.83 to -2.17), but not consistently more than olanzapine, quetiapine, risperidone and

ziprasidone. There was no significant difference between clozapine and olanzapine or risperidone in terms of positive or negative symptoms of schizophrenia. According to two studies from China quetiapine was more efficacious for negative symptoms than clozapine MD 2.23 (0.99 to 3.48).

Adverse effects: Clozapine had a higher attrition rate due to adverse effects than olanzapine RR 1.60 (1.07 to 2.40)and risperidone RR 1.88 (1.11 to 3.21). Fewer extrapyramidal side-effects than risperidone RR 0.39 ( 0.22 to 0.68), zotepine RR 0.05 ( 0.00 to 0.86). More blood problems than olanzapine more

hypertension, sedation than olanzapine, risperideone and quetiapine and more seisures than olanzapine and resperidone. More weight gain than resperidone. clozapine did not alter prolactin levels whereas olanzapine, risperidone and zotepine did. More ECG changes than quetiapine and resperidone,

No focus on treatment resistance.

In general clozapine more efficacious than zotepine. More efficacious than risperidone based on leaving the trial because of inefficiency but in terms of improving general mental state similar to risperidine

and others. Many participants were diagnosed as treatment resistant to prior antipsychotics but the criteria and definitions used for treatment resistance

varied across trials.

Komossa K et al, 2010 (18)

Risperidone

versus other

atypical

antipsychotics

for people with

schizophrenia

and

schizophrenia-

like

psychosis.

The review included 45 blinded RCTs with 7760 participants. Searched the Cochrane Schizophrenia

Group Trials Register (April

NO The number of RCTs available for each comparison varied; of them 11 were with clozapine with an attrition of 33.4%. Although this attrition was not as high as in some other comparisons of this review, it nevertheless limits the interpretation of all results beyond the outcome of leaving the studies

early. A similar number of participants in the

No focus on treatment resistance. Clozapine seems to be more efficacious than resperidone in terms of patients who leave the study for the same reason. Less patients leave the studies because of

adverse effects of resperidone. There was no

18

2007) which is based on regular searches of BIOSIS,

CENTRAL, CINAHL, EMBASE, MEDLINE and PsycINFO. Inspected the references of all identified studies

for more trials. Contacted the first author of each included study for missing information. Contacted the manufacturers of

all atypical antipsychotics included for additional data. Included all randomised, blinded trials comparing oral risperidone with

amisulpride, aripiprazole,

clozapine, olanzapine, quetiapine, sertindole, ziprasidone or zotepine.

Attrition was high and

risperidone and the clozapine groups left the studies early due to any reason, suggesting a comparable overall acceptability of both compounds.

There were few significant differences in overall acceptability of treatment as measured by leaving the studies early. Risperidone was slightly less acceptable than olanzapine, and slightly more acceptable than ziprasidone in this regard. Risperidone improved the general mental state slightly less than olanzapine, but

slightly more than and. The comparisons with the other SGA drugs were equivocal. Risperidone was also less efficacious than olanzapine and clozapine in terms of leaving the studies early due to inefficacy, but more efficacious than ziprasidone in the same outcome.

Fewer participants in the risperidone group than in the clozapine group left the studies early due to adverse events. Risperidone produced somewhat more extrapyramidal side effects than a number of other SGAs. Risperidone also increased prolactin levels clearly more than all comparators, except for amisulpride and sertindole for which no data were available.

Other adverse events were less consistently reported, but risperidone may well produce more weight gain and/or associated metabolic problems than amisulpride (, aripiprazole and ziprasidone but less than clozapine, olanzapine, quetiapine and sertindole. It may be less sedating than clozapine and quetiapine, produce fewer

seizures than clozapine and less sexual dysfunction in men than sertindole . One reason for the failure to find a consistent superiority of clozapine may be that efficacy was addressed in different ways (e.g. different scales or different definitions of response to

treatment), Frequently the results were even based on only one RCT. Another possible explanation may be relatively low clozapine doses.

other superiority of clozapine. The authors argue two possible explanations: various definitions of

response to treatment and lower dose of clozapine as compared with pivotal studies.

Antipsychotic medications for psychotic disorders

Q1: In individuals with psychotic disorders (including schizophrenia), are antipsychotic drugs safe and effective?

Background Antipsychotic drugs are the mainstay of pharmacological treatment for patients with psychotic disorders, including schizophrenia. The earliest antipsychotics, chlorpromazine and haloperidol have been used for about 5 decades. Many newer antipsychotics have been developed in the last 2 decades. Traditionally, antipsychotics are divided into two classes: the older (including haloperidol and chlorpromazine) first generation, and the newer, more expensive, second generation. The criteria for this separation are not clearly defined. A belief that the second‐generation medicines is superior to the first‐generation ones is not confirmed by the evidence and the high costs of the former has led to a continuing debate about their real benefits. Despite the introduction of newer antipsychotics, haloperidol and chlorpromazine are still the most frequently prescribed antipsychotic drugs worldwide and they are included in the World Health Organization List of Essential Medicines. A clear recommendation on antipsychotic medication use for psychotic disorders is necessary for clinical practice.

Population/Intervention(s)/Comparator/Outcome(s) (PICO)

Population: adults with psychotic disorders (including schizophrenia)

Interventions: antipsychotics drugs

Comparisons: placebo

Outcomes: symptoms severity

prevention of relapses

disability and functioning

quality of life

adverse effects of treatment

1


mortality

treatment adherence

users' and families' satisfaction with care

List of the systematic reviews identified by the search process INCLUDED IN GRADE TABLES OR FOOTNOTES Irving CB, Adams CE, Lawrie S (2006). Haloperidol versus placebo for schizophrenia. Cochrane Database of Systematic Reviews, (4):CD003082. Adams CE et al (2007). Chlorpromazine versus placebo for schizophrenia. Cochrane Database of Systematic Reviews, (2):CD000284. Leucht S et al (2009). How effective are second‐generation antipsychotic drugs? A meta‐analysis of placebo‐controlled trials. Molecular Psychiatry, 14:429‐47.

PICO Table

Serial no.

Intervention/Comparison Outcomes Systematic reviews used for GRADE

Explanation

I Haloperidol/ Placebo

Symptoms severity Prevention of relapses Disability and functioning Adverse effects of treatment Quality of life Mortality

Irving et al, 2006 Irving et al, 2006 No evidence available Irving et al, 2006 No evidence available No evidence available

2


Treatment adherence Users' and families' satisfaction with care

Irving et al, 2006 No evidence available.

II Chlorpromazine vs placebo

Symptoms severity Prevention of relapses Disability and functioning Adverse effects of treatment Quality of life Mortality Treatment adherence Users' and families' satisfaction with care

Adams et al, 2007 Adams et al, 2007 Adams et al, 2007 Adams et al, 2007 No evidence available. Adams et al, 2007 Adams et al, 2007 No evidence available.

III Second‐generation antipsychotic drugs vs placebo (amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, sertindole, ziprasidone, zotepine)

Symptoms severity Disability and functioning Adverse effects of treatment Treatment acceptability (adherence) Quality of life Users' and families' satisfaction with care

Leucht et al, 2009 No evidence available. Leucht et al, 2009 Leucht et al, 2009 No evidence available. No evidence available.

3


Narrative description of the studies that went into the analysis

Irving et al, 2006 included 21 controlled trials randomising 1519 patients with schizophrenia or non affective psychotic disorders to haloperidol or placebo. A wide range of doses of haloperidol was used in the trials. The greatest dose was used in Howard 1974 (doses up to 200 mg/day). Most studies used doses in the range of 4mg/day to 20 mg/day. Sixteen studies used doses or had ranges including doses greater than 7.5 mg/day. All studies included people with schizophrenia. The majority of participants were hospitalised and chronically ill. Four studies specifically stated that participants were currently in acute phase.

Adams et al, 2007 included 50 placebo controlled studies of chlorpromazine in patients with schizophrenia or non affective psychoses, with a mean number of participants of 99 ranging from 21 to 838. Over 4992 people have been included in trials relating to the review, 1625 were given chlorpromazine. The doses of chlorpromazine in these studies ranged from 25mg/day to 2400mg/day. The mean dose was 574 mg/day (SD 446). None of the included studies attempted to quantify quality of life or levels of satisfaction.

Leucht et al, 2009 included 38 studies with 7323 participants: amisulpride (N= 5), aripiprazole (N= 7), clozapine (N= 1), olanzapine (N= 6), quetiapine (N= 5), risperidone (N= 7), sertindole (N= 3), ziprasidone (N= 4), zotepine (N=3; three studies provided results on two SGA drugs). Most of the studies were short‐term and examined patients with positive symptoms, while only six studies examined patients with predominantly negative symptoms (four amisulpride studies, one olanzapine and amisulpride study and one zotepine study). Almost all studies were conducted by pharmaceutical companies and usually for registrational purposes. The minimum duration of washout was usually not more than a few days. The median of mean age was 38 years.

GRADE Tables Table 1

Author(s): Clive E Adams and Lorenzo Tarsitani Date: 2009-06-08 Question: HALOPERIDOL versus PLACEBO for schizophrenia Settings: largely in hospital Bibliography: Irving CB, Adams CE, Lawrie S (2006). Haloperidol versus placebo for schizophrenia. Cochrane Database of Systematic Reviews, (4):CD003082.

Summary of findings Quality assessment

No of patients Effect

No of studies

Design Limitations Inconsistency Indirectness Imprecision Other

considerations HALOPERIDOL versus

PLACEBO control

Relative (95% CI)

Absolute

Quality

Importance

4


Symptom severity ‐ Global effect: No marked global improvement (0‐24 weeks)

173/217 (79.7%)

303 fewer per 1000 (from 199 fewer to 383 fewer)

10 randomised trials

serious1 no serious inconsistency

serious2 no serious imprecision

none

118/250 (47.2%)

84.6%

RR 0.62 (0.52 to 0.75)


⊕⊕ΟΟ LOW

CRITICAL

Relapse or not remaining in remission (<52 weeks)

23/23 (100%)


2 randomised trials

no serious limitations

no serious inconsistency

serious2 very serious3 none

32/47 (68.1%)

100%

RR 0.7 (0.57 to 0.87)


⊕ΟΟΟ VERY LOW

CRITICAL

Disability and functioning

0/0 (0%) 0 fewer per 1000 (from 0

fewer to 0 fewer) 0 no evidence

available none

0/0 (0%)

0%

RR 0 (0 to 0)


CRITICAL

Adverse events: Movement disorders ‐ non‐acute ‐ needing antiparkinson medication or parkinsonism

13/192 (6.8%)

230 more per 1000 (from 73 more to 562 more)

7 randomised trials




none

71/217 (32.7%)

0%

RR 4.4 (2.08 to 9.3)


⊕⊕⊕Ο MODERATE

CRITICAL

Adverse events: Weight gain

1/104 (1%)88 more per 1000 (from 3

more to 735 more) 1 randomised

trials no serious limitations



none

10/103 (9.7%)

1%

RR 10.1 (1.32 to 77.46)



CRITICAL

All cause mortality

0 no evidence available

none 0/0 (0%) 0/0 (0%) RR 0 (0 to 0)

0 fewer per 1000 (from 0 fewer to 0 fewer) IMPORTANT

5


0% 0 fewer per 1000 (from 0

fewer to 0 fewer)

Quality of life

0/0 (0%) 0 fewer per 1000 (from 0


available none

0/0 (0%)

0%

RR 0 (0 to 0)


IMPORTANT

Treatment adherence ‐ Leaving the study early (0‐24 weeks)

236/587 (40.2%)






none

185/615 (30.1%)

16.3%

RR 0.82 (0.72 to 0.93)



IMPORTANT

User' and family satisfaction

0/0 (0%) 0 fewer per 1000 (from 0


available none

0/0 (0%)

0%

RR 0 (0 to 0)


IMPORTANT

1 Methodological limitations, many studies were published from the sixties. 2 The majority of participants were hospitalised and chronically ill. 3 Low overall sample size. 4 Only one study contributed to the analysis.

Table 2

Author(s): Clive E Adams and Lorenzo Tarsitani Date: 2009-06-10 Question: CHLORPROMAZINE versus PLACEBO for schizophrenia Settings: Largely in Hospital Bibliography: Adams CE et al (2007). Chlorpromazine versus placebo for schizophrenia. Cochrane Database of Systematic Reviews, (2):CD000284.


No of patients Effect Quality

Importance

6


No of studies


considerations CHLORPROMAZINE versus PLACEBO

control Relative (95% CI)

Absolute

Symptom severity ‐ Global impression: No global improvement (0‐6 months)

595/790 (75.3%)



no serious limitations1

serious2 no serious indirectness

no serious imprecision

none

564/921 (61.2%)

78.5%

RR 0.74 (0.69 to 0.79)



CRITICAL

Relapse ‐ medium term (0 ‐ 6 months)

160/352 (45.5%)


5 randomised trials

very serious3 very serious4 no serious indirectness


none

91/531 (17.1%)

45.1%

RR 0.48 (0.39 to 0.58)


⊕ΟΟΟ VERY LOW

CRITICAL

Relapse ‐ long term (6 months ‐ 2 years)

176/248 (71%)


3 randomised trials

very serious5 serious6 no serious indirectness


none

106/264 (40.2%)

72%

RR 0.57 (0.48 to 0.67)


⊕ΟΟΟ VERY LOW

CRITICAL

Disability and functioning

0/0 (0%) 0 fewer per 1000 (from 0


available none

0/0 (0%)

0%

RR 0 (0 to 0)


CRITICAL

Adverse effects: 1. Central nervous system ‐ acute movement disorders (dystonia)

5/382 (1.3%)


5 randomised trials

serious7 no serious inconsistency

no serious indirectness


none

32/560 (5.7%)

0%

RR 3.47 (1.5 to 8.03)



CRITICAL

Adverse effects: 1. Central nervous system ‐ parkinsonism (includes EPS)

7


40/542 (7.4%)






none

123/723 (17%)

0%

RR 2.01 (1.5 to 2.7)



CRITICAL

Adverse effects: 2. Metabolic ‐ weight increase

7/90 (7.8%)305 more per 1000 (from 103 more to 733 more)

5 randomised trials




serious9 none

31/75 (41.3%)

7.7%

RR 4.92 (2.32 to 10.43)



CRITICAL

Quality of life (Better indicated by lower values)


‐ none

0 0MD 0 higher (0 to 0

higher) IMPORTANT

All cause mortality

0/7 (0%) not pooled 0 no evidence available

none 0/7 (0%)

0%

not pooled

not pooled IMPORTANT

Treatment acceptability (total drop‐out 9 weeks to 6 months)






none 144/1004 (14.3%)

157/775 (20.3%)

RR 0.65 (0.53 to 0.79)


⊕⊕⊕⊕HIGH

CRITICAL

Treatment acceptability (total drop‐out 0‐8 weeks)





none 78/438 (17.8%)

149/507 (29.4%)

RR 0.72 (0.59 to 0.88)



CRITICAL

User' and family satisfaction

0/0 (0%) 0 fewer per 1000 (from 0


available none

0/0 (0%)

0%

RR 0 (0 to 0)


IMPORTANT

8


1 Only 2 studies (Kurland et al, 1961; Cooper et al, 2000) with dropout rate >30% were included in this analysis. 2 I-squared test is between 51% and 69% in the analyses pooled by Adams et al, 2007. 3 This analysis include 2 (Peet et al, 1981, Rappaport et al, 1978) studies out of 5, with more than 30% drop-outs. 4 No explanation was provided. 5 One (Engelhardt et al, 1960) out of 3 studies has a 37% drop-out rate. 6 I-squared test = 72%. 7 One study (Kurland et al, 1961) out of five has a drop-out rate >30. 8 I-squared test = 59%. 9 Small overall sample size. 10 From analysis 1.14 of Adam 2007. 11 I-squared test is 54%.

Table 3

Author(s): Corrado Barbui Date: 2009-09-07 Question: Should amisulpride vs placebo be used for schizophrenia? Settings: Largely in Hospital Bibliography: Leucht S et al (2009). How effective are second-generation antipsychotic drugs? A meta-analysis of placebo-controlled trials. Molecular Psychiatry, 14:429-47.



No of studies


considerations amisulpride placebo

Relative (95% CI)

Absolute

Quality

Importance

symptom severity (positive and negative) (Better indicated by lower values)

11 randomised trials serious2 no serious inconsistency


reporting bias405 05,6 ‐

0.54 lower (0.81 to 0.27 lower)

⊕ΟΟΟ VERY LOW

CRITICAL

non‐responder rates

37 randomised trials serious2 no serious inconsistency5



reporting bias40/0 (0%)5,8 0%

RR 0.66 (0.58 to 0.76)9


⊕⊕ΟΟ LOW

CRITICAL

disability and funcrtioning (Better indicated by lower values)

0 no evidence ‐ none 0 0 MD 0 higher (0 to 0 higher) CRITICAL

9


available

adverse effects (antiparkinson medication)



serious11 reporting bias40/0 (0%)5,12 0%

RR 0.87 (0.24 to 3.2)9

0 fewer per 1000 (from 0 fewer to 0 more)

⊕ΟΟΟ VERY LOW

IMPORTANT

adverse effects (sedation)


none 0/0 (0%) 0% RR 0 (0 to 0)


IMPORTANT

treatment acceptability (total dropouts)

513 randomised trials no serious limitations

no serious inconsistency5




RR 0.69 (0.48 to 1)9



IMPORTANT

quality of life (Better indicated by lower values)


‐

none 0 0 MD 0 higher (0 to 0 higher) IMPORTANT

user's and family's satisfaction (Better indicated by lower values)


‐


1 From Figure 1 of Leucht et al, 2009. 2 Loss to follow up exceeds 30%. 3 Only one study contributed to the analysis. 4 Authors reported that the funnel plot was asymmetrical. 5 Not reported. 6 The total number of patients included in this analysis was 241. 7 From Figure 2 of Leucht et al, 2009. 8 The total number of patients included in this analysis was 487. 9 Estimates below 1 are in favor of second-generation antipsychotics. 10 From Figure 3 of Leucht et al, 2009. 11 Confidence interval ranges from appreciable benefit to appreciable harm. 12 The total number of patients was 514. 13 From Table 3 of Leucht et al, 2009. 14 The total number of included patients was 618.

10


Table 4

Author(s): Corrado Barbui Date: 2009-09-07 Question: Should aripiprazole vs placebo be used for schizophrenia? Settings: Largely in Hospital Bibliography: Leucht S et al (2009). How effective are second-generation antipsychotic drugs? A meta-analysis of placebo-controlled trials. Molecular Psychiatry, 14:429-47.



No of studies


considerations aripiprazole placebo

Relative (95% CI)

Absolute

Quality

Importance






0.41 lower (0.51 to 0.31 lower)

⊕⊕ΟΟ LOW

CRITICAL






RR 0.81 (0.75 to 0.87)8


⊕⊕ΟΟ LOW

CRITICAL

disability and functioning (Better indicated by lower values)


‐

none 0 0 MD 0 higher (0 to 0 higher) CRITICAL






RR 1.07 (0.81 to 1.41)8

0 more per 1000 (from 0 fewer to 0 more)

⊕⊕ΟΟ LOW

IMPORTANT


411 randomised trials serious2 no serious no serious serious12 reporting bias4 0/0 (0%)3,13 0% RR 1.38 (0.82 to 0 more per 1000 (from 0 ⊕ΟΟΟ

IMPORTANT

11


inconsistency3 indirectness 2.34)8 fewer to 0 more) VERY LOW







RR 0.80 (0.72 to 0.89)8



IMPORTANT



‐




‐


1 From Figure 1 of Leucht et al, 2009. 2 Loss to follow-up exceeds 30%. 3 Not reported. 4 Authors reported that the funnel plut was asymmetrical. 5 The total number of included patients was 1556. 6 From Figure 2 of Leucht et al, 2009. 7 The total number of included patients was 1123. 8 Estimates below 1 favor second-generation antipsychotic drugs. 9 From Figure 9 of Leucht et al, 2009. 10 The total number of included patients was 1310. 11 From Figure 11 of Leucht et al, 2009. 12 Confidence interval ranges from appreciable benefit to appreciable harm. 13 The total number of included patients was 1107. 14 From Table 3 of Leucht et al, 2009. 15 The total number of included patients was 1615.

Table 5

Author(s): Corrado Barbui Date: 2009-09-07 Question: Should clozapine vs placebo be used for schizophrenia? Settings: Largely in Hospital Bibliography: Leucht S et al (2009). How effective are second-generation antipsychotic drugs? A meta-analysis of placebo-controlled trials. Molecular Psychiatry, 14:429-47.

12




No of studies

Design Limitations Inconsistency Indirectness ImprecisionOther

considerations clozapine placebo

Relative (95% CI)

Absolute

Quality

Importance



serious4 very serious5

reporting bias6

03 03,7 ‐ 1.64 lower (2.61 to 0.68 lower) ⊕ΟΟΟVERY LOW

CRITICAL



none 0/0 (0%)

0/0 (0%)

Not estimable 0 fewer per 1000 (from 0 fewer to

0 fewer) CRITICAL



‐




none 0/0 (0%) 0% RR 0 (0 to 0)


IMPORTANT



none 0/0 (0%) 0% RR 0 (0 to 0)


IMPORTANT

treatment acceptability (total dropout)



serious4 very serious9

reporting bias60/0

(0%)3,100%

RR 0.40 (0.22 to 0.76)11


⊕ΟΟΟVERY LOW

IMPORTANT

13




‐




‐


1 From Figure 1 of Leucht et al, 2009. 2 Loss to follow-up exceeds 30%. 3 Not reported. 4 Only one study contributed to the analysis. 5 Only 22 patients were included. 6 Authors reported that the funnel plot was asymmetrical. 7 The total number of included patients was 22. 8 From Table 3 of Leucht et al, 2009. 9 The total number of included patients was 24. 10 The total number of included patients was 24. 11 Estimates below 1 favor second-generation antipsychotic drugs.

Table 6

Author(s): Corrado Barbui Date: 2009-09-07 Question: Should olanzapine vs placebo be used for schizophrenia? Settings: Largely in Hospital Bibliography: Leucht S et al (2009). How effective are second-generation antipsychotic drugs? A meta-analysis of placebo-controlled trials. Molecular Psychiatry, 14:429-47.



No of studies


considerations olanzapine placebo

Relative (95% CI)

Absolute

Quality

Importance


14






0.59 lower (0.83 to 0.35 lower)

⊕⊕ΟΟ LOW

CRITICAL






RR 0.82 (0.73 to 0.92)8


⊕⊕ΟΟ LOW

CRITICAL



‐





serious10 reporting bias4 0/0 (0%)3,11

0% RR 1.23 (0.52 to

2.93)80 more per 1000 (from 0

fewer to 0 more) ⊕ΟΟΟ

VERY LOWIMPORTANT





0% RR 1.93 (0.76 to

4.9)80 more per 1000 (from 0


VERY LOWIMPORTANT






reporting bias4 0/0 (0%)3,15

0% RR 0.70 (0.46 to

1.05)80 fewer per 1000 (from 0

fewer to 0 more) ⊕⊕⊕Ο

MODERATEIMPORTANT



‐




‐

none 0 0 MD 0 higher (0 to 0 higher)

15

1 From Figure 1 of Leucht et al, 2009. 2 Loss to follow-up exceeds 30%. 3 Not reported.


4 Authors reported that the funnel plot was asymmetrical. 5 The total number of included patients was 992. 6 From Figure 2 of Leucht et al, 2009. 7 The total number of included patients was 582. 8 Estimates below 1 favor second-generation antipsychotic drugs. 9 From Figure 9 of Leucht et al, 2009. 10 Confidence interval ranges from appreciable benefit to appreciable harm. 11 The total number of included patients was 481. 12 From Figure 11 of Leucht et al, 2009. 13 The total number of included patients was 408. 14 From Table 3 of Leucht et al, 2009. 15 The total number of included patients was 1088.

Table 7

Author(s): Corrado Barbui Date: 2009-09-07 Question: Should quetiapine vs placebo be used for schizophrenia? Settings: Largely in Hospital Bibliography: Leucht S et al (2009). How effective are second-generation antipsychotic drugs? A meta-analysis of placebo-controlled trials. Molecular Psychiatry, 14:429-47.



No of studies


considerations quetiapine placebo

Relative (95% CI)

Absolute

Quality

Importance






0.42 lower (0.72 to 0.13 lower)

⊕⊕ΟΟ LOW

CRITICAL






RR 0.88 (0.75 to 1.04)8


⊕⊕ΟΟ LOW

CRITICAL


16



‐






0% RR 0.79 (0.46 to



VERY LOWIMPORTANT






0% RR 2.02 (1.18 to

3.47)80 more per 1000 (from 0

more to 0 more) ⊕⊕ΟΟ LOW

IMPORTANT







0% RR 0.79 (0.68 to


fewer to 0 fewer) ⊕⊕⊕Ο

MODERATEIMPORTANT



‐




‐


1 From Figure 1 of Leucht et al, 2009. 2 Loss to follow-up exceeds 30%. 3 Not reported. 4 Authors reported that the funnel plot was asymmetrical. 5 The total number of included patients was 735. 6 From Figure 2 of Leucht et al, 2009. 7 The total number of included patients was 750. 8 Estimates below 1 favor second-generation antipsychotic drugs. 9 From Figure 9 of Leucht et al, 2009. 10 Confidence interval ranges from appreciable benefit to appreciable harm. 11 The total number of included patietns was 521. 12 From Figure 11 of Leucht et al, 2009. 13 The total number of included patients was 750.

17


14 From Table 3 of Leucht et al, 2009. 15 The total number of included patients was 750.

Table 8

Author(s): Corrado Barbui Date: 2009-09-07 Question: Should risperidone vs placebo be used for schizophrenia? Settings: Largely in Hospital Bibliography: Leucht S et al (2009). How effective are second-generation antipsychotic drugs? A meta-analysis of placebo-controlled trials. Molecular Psychiatry, 14:429-47.



No of studies


considerations risperidone placebo

Relative (95% CI)

Absolute

Quality

Importance






0.59 lower (0.78 to 0.39 lower)

⊕⊕ΟΟ LOW

CRITICAL






RR 0.62 (0.51 to 0.75)8


⊕⊕ΟΟ LOW

CRITICAL



‐







RR 1.24 (0.89 to 1.71)8


⊕⊕ΟΟ LOW

IMPORTANT

18







RR 1.29 (0.73 to 2.29)8


⊕⊕ΟΟ LOW

IMPORTANT







RR 0.70 (0.57 to 0.86)8



IMPORTANT



‐




‐


1 From Figure 1 of Leucht et al, 2009. 2 Loss to follow-up exceeds 30%. 3 Not reported. 4 Authors reported that the funnel plot was asymmetrical. 5 The total number of patients was 977. 6 From Figure 2 of Leucht et al, 2009. 7 The total number of included patients was 997. 8 Estimates below 1 favor second-generation antipsychotics. 9 From Figure 9 of Leucht et al, 2009. 10 The total number of included patients was 323. 11 From Figure 11 of Leucht et al, 2009. 12 The total number of included patients was 665. 13 From Table 3 of Leucht et al, 2009. 14 The total number of included patients was 955.

Table 9

Author(s): Corrado Barbui Date: 2009-09-07 Question: Should sertindole vs placebo be used for schizophrenia? Settings: Largely in Hospital Bibliography: Leucht S et al (2009). How effective are second-generation antipsychotic drugs? A meta-analysis of placebo-controlled trials. Molecular Psychiatry, 14:429-47.

19




No of studies


considerations sertindole placebo

Relative (95% CI)

Absolute

Quality

Importance






0.42 lower (0.58 to 0.25 lower)

⊕⊕ΟΟ LOW

CRITICAL

non‐response rates





RR 0.91 (0.81 to 1.02)8


⊕⊕ΟΟ LOW

CRITICAL



‐






0% RR 0.79 (0.51 to



VERY LOWIMPORTANT





0% RR 1.23 (0.53 to

2.87)80 more per 1000 (from 0


VERY LOWIMPORTANT







0% RR 0.96 (0.83 to


fewer to 0 more) ⊕⊕⊕Ο

MODERATEIMPORTANT

20




‐




‐


1 From Figure 1 of Leucht et al, 2009. 2 Loss to follow-up exceeds 30%. 3 Not reported. 4 Authors reported that the funnel plot was asymmetrical. 5 The total number of included patients was 629. 6 From Figure 2 of Leucht et al, 2009. 7 The total number of included patients was 661. 8 Estimates below 1 favor second-generation antipsychotic drugs. 9 From Figure 9 of Leucht et al, 2009. 10 Confidence interval ranges from appreciable benefit to no difference. 11 The total number of included patients was 661. 12 From Figure 11 of Leucht et al, 2009. 13 Confidence interval ranges from appreciable benefit to appreciable harm. 14 The total number of included patients was 315. 15 From Table 3 of Leucht et al, 2009. 16 The total number of included patients was 661.

Table 10

Author(s): Corrado Barbui Date: 2009-09-07 Question: Should ziprasidone vs placebo be used for schizophrenia? Settings: Largely in Hospital Bibliography: Leucht S et al (2009). How effective are second-generation antipsychotic drugs? A meta-analysis of placebo-controlled trials. Molecular Psychiatry, 14:429-47.


No of patients Effect Quality

Importance

21


No of studies


considerations ziprasidone placebo

Relative (95% CI)

Absolute






0.48 lower (0.65 to 0.32 lower)

⊕⊕ΟΟ LOW

CRITICAL






RR 0.82 (0.71 to 0.94)8


⊕⊕ΟΟ LOW

CRITICAL



‐






RR 1.33 (0.7 to 2.51)8


⊕ΟΟΟ VERY LOW

IMPORTANT





RR 2.08 (0.62 to 6.95)8


⊕ΟΟΟ VERY LOW

IMPORTANT







RR 0.73 (0.63 to 0.84)8



IMPORTANT



‐



22



‐


1 From Figure 1 of Leucht et al, 2009. 2 Loss to follow-up exceeds 30%. 3 Not reported. 4 Authors reported that the funnel plot was asymmetrical. 5 The total number of patients was 584. 6 From Figure 2 of Leucht et al, 2009. 7 The total number of included patients was 291. 8 Estimates below 1 favor second-generation antipsychotic drugs. 9 From Figure 9 of Leucht et al, 2009. 10 Confidence interval ranges from appreciable benefit to appreciable harm. 11 The total number of included patients was 598. 12 From Figure 11 of Leucht et al, 2009. 13 The total number of included patients was 291. 14 From Table 3 of Leucht et al, 2009. 15 The total number of included patients was 598.

Table 11

Author(s): Corrado Barbui Date: 2009-09-07 Question: Should zotepine vs placebo be used for schizophrenia? Settings: Largely in hospital Bibliography: Leucht S et al (2009). How effective are second-generation antipsychotic drugs? A meta-analysis of placebo-controlled trials. Molecular Psychiatry, 14:429-47.



No of studies


considerations zotepine placebo

Relative (95% CI)

Absolute

Quality

Importance





reporting bias403,5 03 ‐

0.55 lower (0.89 to 0.21 lower)

⊕⊕ΟΟLOW

CRITICAL

23





serious7 reporting bias40/0

(0%)3,80%

RR 0.65 (0.32 to 1.33)9


⊕ΟΟΟVERY LOW

CRITICAL



‐





serious7 reporting bias40/0

(0%)3,110%

RR 1.49 (0.6 to 3.72)9


⊕ΟΟΟVERY LOW

IMPORTANT






0% RR 4.60 (1.21 to

17.5)90 more per 1000 (from 0 more

to 0 more) ⊕⊕ΟΟLOW

IMPORTANT






0% RR 0.94 (0.64 to


fewer to 0 more) ⊕⊕ΟΟLOW

IMPORTANT



‐




‐


1 From Figure 1 of Leucht et al, 2009. 2 Loss to follow-up exceeds 30%. 3 Not reported. 4 Authors reported that the funnel plot was asymmetrical.

24


5 The total number of included patietns was 304. 6 From Figure 2 of Leucht et al, 2009. 7 Confidence interval ranges from appreciable benefit to appreciable harm. 8 The total number of included patients was 227. 9 Estimates below 1 favor second-generation antipsychotic drugs. 10 From Figure 9 of Leucht et al, 2009. 11 The total number of included patients was 227. 12 From Figure 11 of Leucht et al, 2009. 13 The total number of included patients was 312. 14 From Table 3 of Leucht et al, 2009. 15 The total number of included patients was 312.

Additional information that was not GRADEd

COST

Rosenheck et al 2008a; 2008b: The cost of second‐generation antipsychotics in the treatment of schizophrenia is about $10 per day, more than ten times the cost of generic first‐generation antipsychotics

DOSE

Waraich et al, 2002: This review selected studies with people being treated for acute schizophrenia, randomised to two or more dose ranges of haloperidol. Using low doses (>3‐7.5mg/day) did not clearly result in loss of efficacy (no clinically important improvement in global state, versus >7.5‐15mg/day n=48, 1 RCT, RR 1.09 CI 0.7 to 1.8; versus >15‐35mg/day n=81, 2 RCTs, 0.95 CI 0.8 to 1.2). Doses of haloperidol in the range of >3‐7.5 mg/day had a lower rate of development of clinically significant extrapyramidal adverse effects than higher doses (clinically significant extrapyramidal adverse effects, versus >7.5‐15mg/day n=64, 2 RCTs, RR 0.12 CI 0.01 to 2.1; versus >15‐35mg/day n=144, 3 RCTs RR 0.59 CI 0.5 to 0.8, NNH 3 CI 2 to 6; versus >35mg/day n=86, 2 RCTs, RR 0.70 CI 0.5 to 1.1).

Liu & De Haan, 2009: This review shows, in the short term, that when low dose chlorpromazine (≤400mg/day) was compared with medium dose (401‐800 mg/day), all measured extrapyramidal adverse effects tended to be lower in the low dose group (n=70, 2 RCTs, RR dystonia 0.20 CI 0.04 to 0.97). When low dose was compared with high (>800mg/day) data were taken from only one study and a significantly greater number of people in the high dose group left early due to disabling adverse effects (n=416, RR 0.10 CI 0.04 to 0.27). Significantly less dystonia and unspecified extrapyramidal adverse effects were reported in the low dose group (n=416, dystonia RR 0.11 CI 0.02 to 0.45, extrapyramidal adverse effects RR 0.43 CI 0.32 to 0.59). People in both groups experienced akathisia (n=416, RR1.00 CI 0.55 to 1.83).

25


CLOZAPINE SAFETY

Miller 2000: Clozapine has demonstrated superior efficacy in relieving positive and negative symptoms in treatment‐resistant schizophrenic patients. The use of clozapine has been limited because of infrequent but serious side effects, the most notable being agranulocytosis. In recent years, however, mandatory blood monitoring has significantly reduced both the incidence of agranulocytosis and its associated mortality. USE DURING PREGNANCY AND LACTATION

NCCMH 2007: Women with schizophrenia who are planning a pregnancy or pregnant or breastfeeding should be treated with low‐dose oral typical antipsychotics, such as haloperidol, chlorpromazine.

Reference List

Adams CE et al (2007).Chlorpromazine versus placebo for schizophrenia. Cochrane Database of Systematic Reviews, (2):CD000284.

Cooper SJ et al (2000). A placebo controlled comparison of zotepine versus chlorpromazine in patients with acute exacerbation of schizophrenia. Acta Psychiatrica Scandinavica, 101:218‐5.

Engelhardt DM et al (1969). Prevention of psychiatric hospitalization with use of psychopharmacological agents. Journal of the American Medical Association, 173:147–9.

Irving CB, Adams CE, Lawrie S (2006). Haloperidol versus placebo for schizophrenia. Cochrane Database of Systematic Reviews, (4):CD003082. Kurland AA et al (1961). The comparative effectiveness of six phenothiazine compounds, phenobarbital and inert placebo in the treatment of acutely ill patients: global measures of severity of illness. Journal of Nervous and Mental Disease, 133:1–18. Leucht S et al (2009).How effective are second‐generation antipsychotic drugs? A meta‐analysis of placebo‐controlled trials. Molecular Psychiatry, 14:429‐47. Liu X, De Haan S (2009). Chlorpromazine dose for people with schizophrenia. Cochrane Database of Systematic Reviews, (2):CD007778.

Miller DD. (2000). Review and management of clozapine side effects. Journal of Clinical Psychiatry, 61(Suppl 8):14‐7.

26


National Collaborating Centre for Mental Health (NCCMH) (2007). Antenatal and Postnatal Mental Health: The NICE guideline on Clinical Management and Service Guidance. London: British Psychological Society & Royal College of Psychiatrists.

Peet M et al (1981). Propranolol in schizophrenia. I. Comparison of propranolol, chlorpromazine and placebo. British Journal of Psychiatry, 139:105‐11. Rappaport M et al (1978). Are there schizophrenics for whom drugs may be unnecessary or contraindicated? International Pharmacopsychiatry, 13:100‐11. Rosenheck RA, Leslie DL, Doshi JA. (2008a). Second‐generation antipsychotics: cost‐effectiveness, policy options, and political decision making. Psychiatric Services, 59:515‐20.

Rosenheck RA et al (2008b). Rethinking antipsychotic formulary policy. Schizophr Bulletin, 34:375‐80.

Waraich PS et al (2002). Haloperidol dose for the acute phase of schizophrenia. Cochrane Database of Systematic Reviews, (3):CD001951.

From evidence to recommendations

Factor Explanation

Narrative summary of the evidence base

In terms of proportion of patients showing a response, there is evidence that both haloperidol (Responders: 52.8 versus 20.3; RR 0.62, 0.52 to 0.75, absolute risk difference 30.3 %) and chlorpromazine (Responders: 38.8 versus 25.9; RR 0.74, 0.69 to 0.79 absolute risk difference 19.6%) were significantly more effective than placebo in psychotic disorders including schizophrenia.

In terms of relapse, there is evidence that haloperidol (RR 0.70, 0.57 to 0.87, absolute risk difference 30%) and chlorpromazine (RR 0.48, 0.39 to 0.58 up to six‐months; RR 0.56, 0.48 to 0.67 up to two years) are significantly more effective than placebo.

In terms of disability and functioning no evidence was available.

There is consistent evidence that both haloperidol (RR 4.40, 2.08 to 9.30) and

27


28

chlorpromazine (RR 2.01, 1.50 to 2.70) significantly increased the risk of movement disorders.

There is limited evidence that both haloperidol (RR 10.1, 1.32 to 77.46) and chlorpromazine (RR 4.92, 2.32 to 10.43) significantly increased the risk of weight gain.

In terms of proportion of patients showing a response, all second‐generation antipsychotic drugs (amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, sertindole, ziprasidone, zotepine) were more effective than placebo (see GRADE tables), but the pooled effect size for overall symptoms (primary outcome) was moderate. Overall, the absolute difference in responder rates was at 17% (41% responded to drug compared with 24% to placebo, number needed to treat = 6). There was no difference in terms of EPS between any second‐generation antipsychotic drugs and placebo.

Summary of the quality of evidence For haloperidol, the quality of evidence was LOW and VERY LOW for symptom reduction and relapse prevention respectively. The quality of evidence was MODERATE for adverse events.

For chlorpromazine, the quality of evidence was MODERATE and VERY LOW for symptom reduction and relapse prevention respectively. The quality of evidence was MODERATE for adverse events.

For second‐generation antipsychotic drugs (amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, sertindole, ziprasidone, zotepine), the quality of evidence was LOW/VERY LOW for symptom reduction and treatment response. The quality of evidence was MODERATE for treatment discontinuation.

Balance of benefits versus harms In studies carried out in individuals with psychotic disorders, including


schizophrenia, antipsychotics are associated with a beneficial effect.

In terms of tolerability, both haloperidol and chlorpromazine are associated with a large increase in the risk of movement disorders. This risk is dose related. Low doses of haloperidol (3 to 7.5 mg/day) and chlorpromazine (≤400mg/day) have a lower rate of development of clinically significant extrapyramidal adverse effects than higher doses.

Both haloperidol and chlorpromazine are associated with an increase in the risk of weight gain.

Clozapine treatment is associated with an increased risk of development of agranulocytosis.

Values and preferences including any variability and human rights issues

Important issues are the short and long term consequences of disability, lack of functioning, discrimination and stigma associated with psychotic symptoms and psychotic relapses. However, there are significant concerns about safety and tolerability associated with antipsychotic medications. A further important issue is the burden of taking medication daily with negative consequences in terms of treatment adherence. Additionally, extrapyramidal symptoms may lead to easy identification of people treated for a mental disorder.

Costs and resource use and any other relevant feasibility issues

Haloperidol, chlorpromazine and other first generation antipsychotics are associated with low acquisition costs.

The cost of second generation antipsychotics in the treatment of schizophrenia may be more than ten times the cost of generic first‐generation antipsychotics.

In many LAMICs continuous availability of antipsychotic in non specialized health care is a challenge.

29


Haloperidol and chlorpromazine are available in WHO Essential Medicine List as antipsychotic medicines.

Recommendation(s)

Haloperidol or chlorpromazine should be routinely offered to individuals with psychotic disorders (including schizophrenia). Strength of recommendation: STRONG Second‐generation antipsychotics (with the exception of clozapine) may be considered in individuals with psychotic disorders (including schizophrenia) as an alternative to haloperidol or chlorpromazine if availability can be assured and cost is not a constraint. Strength of recommendation: STANDARD For individuals with psychotic disorders (including schizophrenia) who do not respond to adequate dose and duration of other antipsychotic medicines, clozapine may be considered by non‐specialist health care providers, preferably under the supervision of mental health professionals, only if routine laboratory monitoring is available. Strength of recommendation: STANDARD In individuals with psychotic disorders (including schizophrenia), minimal effective dose of antipsychotics should be used, paying attention to minimizing adverse effects. Strength of recommendation: STRONG In women with psychotic disorders (including schizophrenia) who are planning a pregnancy or pregnant or breastfeeding, low‐dose oral haloperidol or chlorpromazine may be considered. Strength of recommendation: STANDARD Any additional remarks

Generating more evidence on outcomes like disability and functioning, quality of life, users' and families' satisfaction with care with use of these medicines is necessary.

Relative advantages and disadvantages of use of first generation versus second generation antipsychotics in non specialized health care settings.

30

Documents

Application to add clozapine to the Essential List of ... · 4 Begin with one-half of a 25-mg tablet (12.5 mg) once or twice daily and continue with daily increments of 25-50 mg/day