Trifluoperazine for schizophrenia

Luciana de Oliveira Marques; Bernardo Soares; Mauricio Silva de Lima

doi:10.1002/14651858.CD003545.pub2

. 2004 Jan 26;2004(1):CD003545. doi: 10.1002/14651858.CD003545.pub2

Trifluoperazine for schizophrenia

Luciana de Oliveira Marques ^1,^✉, Bernardo Soares ², Mauricio Silva de Lima ³

Editor: Cochrane Schizophrenia Group

PMCID: PMC7003674 PMID: 14974020

Abstract

Background

Trifluoperazine is an inexpensive accessible 'high potency' antipsychotic drug, widely used to treat schizophrenia or related psychoses.

Objectives

To estimate the effects of trifluoperazine compared with placebo and other drugs.

Search methods

Searches of the Cochrane Schizophrenia Group's register of trials (March 2002), supplemented with hand searching, reference searching, personal communication and contact with industry.

Selection criteria

All clinical randomised trials involving people with schizophrenia and comparing trifluoperazine with any other treatment.

Data collection and analysis

Studies were reliably selected and quality rated and data was extracted. For dichotomous data, relative risks (RR) were estimated, with 95% confidence intervals (CI). Where possible, we undertook intention‐to‐treat analyses. For statistically significant results, the number needed to treat (NNT) was calculated. We estimated heterogeneity (I‐square technique) and publication bias.

Main results

1162 people from 13 studies were randomised to trifluoperazine or placebo. For global improvement, small short‐term studies favoured trifluoperazine (n=95, 3 RCTs, RR 0.62 CI 0.49 to 0.78 NNT 3 CI 2 to 4). Loss to follow up was about 12% in both groups (n=280, 7 RCTs, RR 0.99 CI 0.62 to 1.57) and more people allocated trifluoperazine used antiparkinson drugs to alleviate movements disorders compared with placebo (n=195, 4 RCTs, RR 5.06 CI 2.49 to 10.27, NNH 4 CI 2 to 9). 2230 people from 49 studies were randomised to trifluoperazine or another older generation antipsychotic. Trifluoperazine was not clearly different in terms of 'no substantial improvement' (n=1016, 27 RCTs, RR 1.06 CI 0.98 to 1.14) or leaving the study early (n=930, 22 RCTs, RR 1.15 CI 0.83 to 1.58). Almost identical numbers of people reported at least one adverse event (˜60%) in each group (n=585, 14 RCTs, RR 0.99 CI 0.87 to 1.13), although trifluoperazine was more likely to cause extrapyramidal adverse effects overall when compared to low potency antipsychotics such as chlorpromazine (n=130, 3 RCTs, RR 1.66 CI 1.03 to 2.67, NNH 6 CI 3 to 121). One small study (n=38) found no clear differences between trifluoperazine and the atypical drug, sulpiride.

Authors' conclusions

Although there are shortcomings and gaps in the data, there appears to be enough consistency over different outcomes and periods to confirm that trifluoperazine is an antipsychotic of similar efficacy to other commonly used neuroleptics for people with schizophrenia. Its adverse events profile is similar to that of other drugs. It has been claimed that trifluoperazine is effective at low doses for patients with schizophrenia but this does not appear to be based on good quality trial based evidence.

Plain language summary

Trifluoperazine for schizophrenia

Trifluoperazine is inexpensive and widely accessible. Thousands of people with schizophrenia have participated in studies and therefore we are reasonably sure that it is a potent antipsychotic drug and as good as similar older drugs. Most people taking it do experience adverse effects, but this also applies to other older drugs. Not enough comparisons with newer generations of drugs have been undertaken to be sure of how trifluoperazine compares to them.

Background

The most commonly prescribed antipsychotic drugs (chlorpromazine, haloperidol and trifluoperazine), are the benchmarks against which all others are compared. They have too rarely been the subjects of quantitative, systematic reviews. Now that synthesis of trials comparing placebo with chlorpromazine, and placebo with haloperidol, for people with schizophrenia are maintained in the Cochrane Library (Thornley 2001, Joy 2001), only trifluoperazine remains to be reviewed.

Trifluoperazine is a long‐established, widely used 'conventional' antipsychotic drug. It has been claimed that it is effective at low doses (Ban 1966, Bazire 2000, Reardon 1989). Trifluoperazine has been considered effective and safe since the 1960s (Reardon 1989, APA 1997), and is considered a first‐line drug for people in the acute phase of schizophrenia (APA 1997). Conventional antipsychotic medications vary, both in potency and propensity to induce adverse effects such as, the so‐called 'extrapyramidal adverse effects', or EPS. With EPS, the normally fluid movements of everyday living become stiff and tremulous, facial expression becomes limited and some repetitive movements of the mouth and face may become gross and disfiguring. These EPS are said to occur more frequently with 'high‐potency' compounds such as haloperidol and trifluoperazine. Sedation and low blood pressure, so often associated with antipsychotic drugs, is said to be less frequent with the 'high potency' trifluoperazine (APA 1997).

The search to identify antipsychotic drugs with minimal adverse effects, and a broader spectrum of efficacy, has produced a class of drug known as atypical antipsychotics. As a group, it is claimed that these cause reduced EPS and have some efficacy in the treatment of the negative symptoms of schizophrenia (apathy, inability to express emotions, poverty of speech and lack of motivation). From the whole class of 'atypicals' , only clozapine has proved to be more potent for treating refractory symptoms (Wahlbeck 2001, Duggan 2002, Hunter 2003), although even this is in question (Geddes 2000). Atypical antipsychotics are more expensive than the conventional drugs, and cost has become part of the controversy concerning their prescribing (Wood Mackenzie 1998, Meltzer 1996). Cost is a major influence on accessibility of treatments, especially for middle or low‐income countries.

Technical background   Trifluoperazine is a phenothiazine derivative, 10‐[3‐(4‐methyl‐1‐piperazinyl)propyl]‐2‐trifluoromethylpheno thiazine(hydrochloride), sold as Stelazine by GlaxoSmithkline (tablets of 1mg, 2 mg, 5mg and 10 mg). The daily dose ranges from 12 to 50 mg (APA 1997). It may be administered orally once or twice a day.

Trifluoperazine is related chemically to chlorpromazine, but it has high milligram potency, and an adverse effect profile (mainly the incidence of extrapyramidal symptoms) similar to haloperidol (Luckey 1967). It has a specific action on the brain: D2 receptors blockade. The blockade of postsynaptic D2 receptors in mesolimbic and mesocortical projection is responsible for initiating the therapeutic actions of typical antipsychotic drugs. The blockade in striatum is responsible for the extrapyramidal effects and in the tuberoinfundubular system of the hypothalamus can produce hyperprolactinemia (Arana 2000). Although D2 blockade takes hours, clinical effects usually take weeks, probably because the decrease of homovallinic acid levels (principal metabolite of dopamine) is expected to take several weeks (Bazire 2000). The risk of extrapyramidal reactions (pseudo parkinsonism, acute dystonic reaction, akathisia and tardive dyskinesia) is suggested to be higher than in other phenothiazines. Trifluoperazine has a low potency of cholinergic blockade (confusion, agitation, dry mouth, blurred vision, urinary retention) and causes less sedation and orthostatic hypotension (histaminic and alpha‐adrenergic antagonism). It is usually well tolerated (Kaplan 1998).

Objectives

To examine the effects of trifluoperazine compared to placebo, and other antipsychotic drugs, for people with schizophrenia.

Methods

Criteria for considering studies for this review

Types of studies

All relevant randomised controlled trials were included. Where a trial was described as 'double‐blind' but it was implied that the study was randomised and the demographic details of each group were similar, it was included. Quasi‐randomised studies, such as those allocated by using alternate days of the week, were excluded.

Types of participants

People with schizophrenia and non‐affective serious/chronic mental illness irrespective of mode of diagnosis, age, sex and chronicity of illness.

Types of interventions

1. Trifluoperazine: any dose and mode or pattern of administration. If a high/low dichotomy was not provided within the trial, high dose was defined as over 30 mg/day, and low dose as any lesser dose. If different doses of trifluoperazine were randomised these studies were also of interest.

2. Placebo.

3. Other typical antipsychotics: any dose and mode or pattern of administration. Examples of such drugs are chlorpromazine and haloperidol.

4. Atypical antipsychotics: any dose and mode or pattern of administration. Examples of such drugs are clozapine, olanzapine, quetiapine, and risperidone.

Types of outcome measures

As schizophrenia is often a life‐long illness, and trifluoperazine is used as an ongoing treatment, outcomes were grouped according to time periods: immediate (seven days or less), short term (eight days to three months), medium term (> three months to one year) and long term (more than one year).

Primary outcomes

1. Service utilisation outcomes   1.1 Hospital admission.

2. Global outcomes   2.1 No clinically significant response in global state ‐ as defined by each of the studies.

3. Mental state   3.1 No clinically significant response in mental state ‐ as defined by each of the studies.

4. Extrapyramidal adverse effects   4.1 Incidence of use of antiparkinsonian drugs.

Secondary outcomes

1. Death   1.1 Suicide.   1.2 Other causes.

2. Service utilisation outcomes   2.1 Days in hospital.     3. Global outcomes   3.1 Average score/change in global state.

4. Mental state   4.1 Average score/change in mental state.   4.2 No clinically significant response on negative symptoms ‐ as defined by each of the studies.   4.3 Average score/change in negative symptoms.   4.4 Relapse as defined in the study.

5. Behaviour   5.1 Leaving the study early.   5.2 No clinically significant response in behaviour ‐ as defined by each of the studies.   5.3 Average score/change in behaviour.

6. Extrapyramidal adverse effects   6.1 No clinically significant extrapyramidal adverse effects ‐ as defined by each of the studies.   6.2 Average score/change in extrapyramidal adverse effects.

7. Other adverse effects, general and specific   7.1 Number of people dropping out due to adverse effects.   7.2 Cardiac effects.   7.3 Anticholinergic effects.   7.4 Antihistaminic effects.   7.5 Prolactin related symptoms.

8. Social functioning   8.1 No clinically significant response in social functioning ‐ as defined by each of the studies.   8.2 Average score/change in social functioning.

9. Economic outcomes

10. Quality of life/ satisfaction with care for either recipients of care or careers.   10.1 Significant change in quality of life / satisfaction ‐ as defined by each of the studies.   10.2 Average score/change in quality of life / satisfaction.   10.3 Employment status.

11. Cognitive functioning

Search methods for identification of studies

Electronic searches

Trifluoperazine is known by many names. We constructed the following search phrase to assist identification:

Trifluoperazine‐phrase = *10‐[3‐(4‐methyl‐1‐piperazinyl)propyl]‐2‐trifluoromethylpheno thiazine (hydrochloride)* or *terfluzine* or *terfluzinor discimer* or *eskazine foille* or *iremo* or *piero* or *jatroneural* or *modalina* or *oxyperazine* or *sedofren* or *sporalon* or *stelazine* or *stelazina* or *stelium* or *terflurazine* or *terfluoperazine* or *SKF 5019* or *7623 RP* or *trifluoperazine* or *Solazine*.

1. The Cochrane Schizophrenia Group's Register (March 2002) was searched using the phrase:

{[(trifluoperazine‐phrase) in title, abstract or index terms of REFERENCE] or [*trifluoperazine* in interventions of STUDY]}

This register is compiled by methodical searches of BIOSIS, CINAHL, Dissertation abstracts, EMBASE, LILACS, MEDLINE, PSYNDEX, PsycINFO, RUSSMED, Sociofile, supplemented with hand searching of relevant journals and numerous conference proceedings (see Group Module).

Searching other resources

1. Reference searching   References of all identified studies were also inspected for more trials.     SCISEARCH ‐ Science Citation Index (1974 to 2001) was used to trace papers that had cited included trials. These reports were inspected in order to identify further studies.

2. Personal contact   The first author of each included study was contacted for information regarding unpublished trials.

3. Industry   Pharmaceutical companies were contacted for additional data or reports of trials.

Data collection and analysis

1. Selection of trials   All reports of identified studies were inspected by the principal reviewer (LOM). A random sample of ten percent of reports was re inspected by MSL in order to ensure reliability of selection. Where disagreement occurred this was resolved by discussion, or, when there was still doubt, reviewers acquired the full article for further inspection. Once the full articles were obtained LOM decided whether they met review criteria and this was checked by MSL on a 10% sample. Again, if disagreement occurred this was resolved by discussion and when this was not possible further information was sought. These trials were added to the list of those awaiting assessment pending acquisition of this further information.     2. Quality assessment   Trials were classified into three quality categories, as described in the Cochrane Collaboration Handbook (Clarke 2001) by the lead reviewer (LOM). A random sample (10%) of trial reports was re inspected by MSL. When disputes arose regarding which category a trial should be allocated to, again, resolution was attempted by discussion. When this was not possible, and further information was necessary, data were not entered into the analyses and the study was allocated to the list of those awaiting assessment. Only trials in Category A or B were included in the review.     3. Data extraction   Data from selected trials were extracted twice by LOM blind to the first extraction. A random selection were independently re inspected by MSL (10%). When disputes arose reviewers attempted resolution by discussion. If doubt remained and further information was necessary to resolve the dilemma, reviewers did not enter the data and added them to the list of those awaiting assessment, pending further information.

4. Data synthesis   4.1 Data types   Outcomes are assessed using continuous (for example, average changes on a behaviour scale), categorical (for example, one of three categories on a behaviour scale, such as 'little change', 'moderate change' or 'much change') or dichotomous measures (for example, either 'no important changes' or 'important changes' in a person's behaviour). RevMan software does not currently support categorical data so they were only presented in the text of the review.     4.2 Incomplete data   With the exception of the outcome of leaving the study early, trial outcomes were not included if more than 40% of people were not reported in the final analysis. Reviewers felt that such a degree of attrition would threaten the validity of any findings.     4.3 Dichotomous data   Where the original authors of the studies gave outcomes such as 'clinically improved' or 'not clinically improved' based on their clinical judgment, predetermined criteria or any scale, this was recorded in RevMan. If data was from a rater not clearly stated to be independent then it was only included if it did not change the results, otherwise it was presented separately with a label 'prone to bias'.

Where possible, efforts were made to convert relevant categorical or continuous outcome measures to dichotomous data by identifying cut off points on rating scales and dividing people accordingly into groups. We used the cut off points 'moderate or severe impairment' for end of study data or 'no better or worse' for change data. For example, the Brief Psychiatric Rating Scale (BPRS ‐ Overall 1962) is frequently used as a measure of change of symptoms in studies. The reviewers defined a 50% change on this particular scale as clinically important, although it was recognised that for many people, especially those with chronic or severe illnesses, a less rigorous definition of important improvement, for example, 25% on the BPRS, would be equally valid. If individual patient data were available, the 50% cut off was used for non‐chronically ill people and 25% for those with chronic illness.

This review presents an intention to treat analysis. As long as over 60% of people completed the study, everyone allocated to the intervention was counted whether or not they completed follow up. It was assumed that those who left the study early had a negative outcome, with the exception of the outcome of death. Also with regard to 'reasons for leaving the study early' because of adverse events or relapse, only patients not accounted for were assumed to have a negative outcome. This was felt to be a more reasonable interpretation of limited data. These data were included as long as this did not change the results. This was tested by a sensitivity analysis.

Where trialists presented data as 'last result carried forward' for those who left the study early, these data were only included if they did not change the overall results, otherwise, they were presented separately with the label 'prone to bias'. Where there was genuine uncertainty as to how the trialists had handled data, this uncertainty was tested using a range of possible missing values. If this affected the results then it was presented separately with a label 'prone to bias'.

We used relative risk (RR) and 95% confidence interval (CI) based on the random effects model as the preferred statistic for summation, as this takes into account differences between studies even if heterogeneity is not statistically significant. Data were inspected to see if analysis using a Mantel‐Haenszel odds ratio and fixed effects models made a substantive difference. Where possible, reviewers estimated the number needed to treat / harm (NNT/H).     4.4 Continuous data   In the case of continuous data, completer analysis is presented.     4.4.1 Rating scales   A wide range of instruments is available to measure mental health outcomes. These instruments vary in quality and many are not valid, or even ad hoc. For outcome instruments some minimum standards have to be set. They are that: i. the psychometric properties of the instrument should have been described in a peer‐reviewed journal; ii. the instrument should either be a self‐report, or completed by an independent rater or relative (not the therapist); and iii. the instrument should be a global assessment of an area of functioning.     4.4.2 Normal distribution   Mental health continuous data are often not normally distributed. To avoid the pitfall of applying parametric tests to non‐parametric data the following standards were applied to all data before inclusion: i. standard deviations and means were reported in the paper or were obtainable from the authors; ii. if the data were finite measures from, for example 0‐100, when the standard deviation was multiplied by two, the result should be less than the mean, otherwise the mean was unlikely to be an appropriate measure of the centre of the distribution (Altman 1996). Continuous data, if normally distributed, were summated using a calculation of the weighted mean difference (WMD). Non‐normally distributed data were reported in the 'Other data types' tables. Endpoint scale‐derived data is finite, ranging from one score to another. Change data is more problematic and for it the rule described above does not hold. Although most change scores are likely to be skewed, it cannot be proven, so they were presented in MetaView. Where both endpoint and change were available for the same outcome the reviewers presented the former in preference.     4.5 Sensitivity analyses   4.5.1 Primary outcomes for an intention‐to‐treat analysis were compared with those from a completer‐only analysis.

4.6 Subgroup analysis   4.6.1 Trials that used low doses of trifluoperazine were compared with those where high doses (over 30 mg/day) were employed.

4.6.2 Studies with less than 40% of people leaving early were compared with those with higher rates.

5. Heterogeneity   As well as inspecting the graphical presentations, the reviewers checked whether the differences between results of trials were greater than would be expected by chance alone using tests of heterogeneity (Chi squared). A significance level of less than 0.10 was interpreted as evidence of heterogeneity. When heterogeneity was present, a sensitivity analysis was undertaken. Outlying studies were removed from the pooled measure if they caused a substantive change in the overall findings and these data were presented and discussed separately.

6. Assessing the presence of publication bias   Data from all included trials were entered into a funnel graph (trial effect versus trial size or 'precision') in an attempt to investigate the likelihood of overt publication bias. A formal test of funnel plot asymmetry (which suggests potential publication bias) was undertaken where appropriate, according to the methods of Egger 1997. Significance levels of p < 0.1 were set a priori to detect the presence of asymmetry. Where only 3‐4 studies reported an outcome, or there was little variety in sample size (or precision estimate) between studies, tests of asymmetry were not appropriate.

7. Tables and figures   Where possible, data were entered into RevMan so the area to the left of the line of no effect indicated a favourable outcome for trifluoperazine.

Results

Description of studies

Please also see Included and Excluded studies tables.

1. Awaiting assessment   Four studies have been ordered but not yet obtained (Toru 1969, Gallant 2000, Kogeorgos 1995, Ortega‐Soto 1996). A further eighteen did not fulfil inclusion criteria but we have contacted the authors and await their response before these are excluded. One Polish paper has not yet been translated (Terminska 1989).

2. Excluded studies   The majority of excluded studies either did not have a control group (n=7) or were not stated to be randomised (n=32). Some randomised studies used interventions that were not the focus of this review or involved people who did not suffer from schizophrenia (n=7). Ten randomised trials had to be excluded as no data were usable, for example, one was a crossover study with no information for the first stage. Two trials did not report the number of people randomised to each group.

3. Included studies   Fifty studies were included.

3.1 Methods   All included studies were described as randomised. Follow‐up periods ranged from three days to 13 months. Twenty‐eight were in the short duration category (less than three months) and six were of intermediate duration (three months to one year). Only one was over one year (long duration, Donlon 1978).

3.2 Participants   The number of people in the included studies ranged from 18 to 360 (mean 52 SD 50). 47% of studies had 40 or fewer participants but a total of 2583 people have participated in the 50 trials.

From the studies reporting information on the sex of participants, there were 1271 men and 971 women. Ages ranged from 14 to 74 years (mean from 18 studies was about 43 years). Only two studies specifically focused on adolescents (Bagadia 1980, Malik 1980).

Most participants had a diagnosis of schizophrenia although some studies were included if most people had schizophrenia or a schizophrenia‐like illness. For example, Coons 1962 reported that 79% of participants had schizophrenia, and Marjerrison 1964 and Denber 1972 that over 80% of included people suffered from schizophrenia. Rubin 1971 included one person with manic‐depressive disorder and Brauzer 1968 included a single person with chronic brain syndrome with psychoses. Andersen 1974 randomised 40 people with schizophrenia or "paranoid syndrome" and the participants in O'Brien 1974 were 30 people with hostility, suspiciousness, paranoia and aggressiveness.

Only nine studies described the diagnostic criteria used; the remainder appeared to have made a clinical diagnosis without the use of operational criteria. Many trials (n=30) involved only people with chronic illness, two during an acute exacerbation of this illness. Two studies involved people whose illness was designated as highly treatment resistant. The remainder included acutely ill people and first episode patients.

3.3 Setting   Most studies were conducted in inpatient settings. Only six trials included only people who were not in hospital. Most trial centres were in USA (30) or Canada (10). Five were in India, two in Australia, two in Europe (Sweden, UK) and one in Peru.

3.4 Interventions   The mean dose of trifluoperazine, based on the 25 studies which reported it, was about 28 mg/day (SD ˜20 mg/day, median 26 mg/day) and the range, taken from 35 studies, was 4 to 100 mg/day. Three studies used intramuscular trifluoperazine (Brauzer 1968, Gallant 1968 II, Perales 1974).

Eleven studies employed a separate placebo arm. Forty‐nine studies compared trifluoperazine with oral typical antipsychotics (for comparison compounds and their frequency of use please see Table 4). For the purposes of this review, loxapine and molindone are considered as typical drugs. Only Edwards 1980 compared trifluoperazine to an atypical antipsychotic (sulpiride). Twenty‐four studies stated they used other medications to alleviate adverse effects or problematic behaviour as required. These drugs included benztropine mesylate, biperiden, trihexphenidyl, chloral hydrate, metyprylon, phenobarbital, chlorpromazine, thioridazine, and short action sedatives. Rubin 1971 reported that some patients received psychotherapy in addition to medication.

1. Comparison compounds used in trifluoperazine studies.

Drug	Number of studies
loxapine	7
pimozide	6
thiothixene	4
molindone	4
SKF 14336 ‐ acridan derivative	4
chlorpromazine	4
haloperidol	4
trifluperidol	3
fluphenazine	1
fluspirilene	1
penfluridol	1
cetbutindole	1
triperidol	1
clorprothixene	1
clothiapine	1
butaperazine	1
SKF 7261	1
GP‐45795	1

Date	Event	Description
15 February 2010	Amended	Contact details updated.
31 October 2008	Amended	Converted to new review format.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Global state: 1a. No substantial improvement (defined as slight improvement or worse) ‐ by time period	6	415	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.66, 0.94]
1.1 short term (0‐3 months)	3	95	Risk Ratio (M‐H, Random, 95% CI)	0.63 [0.50, 0.79]
1.2 medium term (+3 months‐1 year)	3	320	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.85, 1.00]
2 Global state: 1b. No substantial improvement (short term) ‐ by rater's role	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
2.1 doctor rated	1	27	Risk Ratio (M‐H, Random, 95% CI)	0.62 [0.38, 1.00]
2.2 nurse rated	1	27	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.67, 1.11]
3 Global state: 1c. No substantial improvement ‐ by dose of trifluoperazine	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
3.1 low dose (15mg/day)	1	240	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.88, 0.99]
3.2 high dose (80mg/day)	1	240	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.89, 0.99]
4 Global state: 2. Not discharged from hospital ‐ by dose of trifluoperazine	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
4.1 low dose (15mg/day)	1	240	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.96, 1.01]
4.2 high dose (80mg/day)	1	240	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.96, 1.01]
5 Global state: 3. Use of additional antipsychotics or sedatives	2	77	Risk Ratio (M‐H, Random, 95% CI)	1.07 [0.18, 6.31]
6 Mental state: Delusions and hallucinations by the end of the study	1	23	Risk Ratio (M‐H, Random, 95% CI)	0.44 [0.19, 0.99]
7 Behaviour: 1. No improvement (Wings Behaviour Rating Scale) ‐ by >8 weeks ‐ 6 months	1	40	Risk Ratio (M‐H, Random, 95% CI)	0.41 [0.25, 0.70]
8 Behaviour: 2. Agitation	1	52	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.28, 3.58]
9 Leaving the study early	7		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
9.1 any reason	7	280	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.59, 1.48]
9.2 due to adverse events	3	142	Risk Ratio (M‐H, Random, 95% CI)	1.12 [0.24, 5.11]
9.3 due to relapse or worsening	5	205	Risk Ratio (M‐H, Random, 95% CI)	0.90 [0.50, 1.62]
10 Adverse events: 1. At least one adverse effect	2	67	Risk Ratio (M‐H, Random, 95% CI)	1.40 [0.90, 2.18]
11 Adverse events: 2. Cardiovascular	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
11.1 ECG abnormalities ‐ minor	1	27	Risk Ratio (M‐H, Random, 95% CI)	1.86 [0.58, 5.94]
11.2 hypertension	1	40	Risk Ratio (M‐H, Random, 95% CI)	2.0 [0.20, 20.33]
12 Adverse events: 3. Extrapyramidal	5		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
12.1 non‐specific ‐ any movement disorder	2	79	Risk Ratio (M‐H, Random, 95% CI)	2.27 [1.19, 4.33]
12.2 non‐specific ‐ antiparkinson drugs needed	4	195	Risk Ratio (M‐H, Random, 95% CI)	5.06 [2.49, 10.27]
12.3 specific ‐ akathisia (motor restlessness)	1	40	Risk Ratio (M‐H, Random, 95% CI)	3.00 [0.13, 69.52]
12.4 specific ‐ dyskinesia	1	27	Risk Ratio (M‐H, Random, 95% CI)	3.71 [0.47, 29.06]
12.5 specific ‐ oculogyric crisis	1	27	Risk Ratio (M‐H, Random, 95% CI)	3.71 [0.47, 29.06]
12.6 specific ‐ rigidity	1	40	Risk Ratio (M‐H, Random, 95% CI)	9.00 [1.25, 64.59]
12.7 specific ‐ tremors	1	40	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.01, 7.72]
13 Adverse events: 4. Haematological	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
13.1 eosinophilia >5%	1	27	Risk Ratio (M‐H, Random, 95% CI)	1.86 [0.41, 8.49]
13.2 leukocytosis	1	27	Risk Ratio (M‐H, Random, 95% CI)	1.55 [0.46, 5.22]
13.3 urea nitrogen increase	1	27	Risk Ratio (M‐H, Random, 95% CI)	1.39 [0.28, 7.05]
14 Adverse events: 5. Neurological	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
14.1 convulsions	1	52	Risk Ratio (M‐H, Random, 95% CI)	0.5 [0.10, 2.50]
14.2 faintness	1	52	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.12, 3.67]
14.3 urinary incontinence	1	52	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.22, 4.50]
15 Adverse events: 6. Somnolesence	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
15.1 drowsiness	3	119	Risk Ratio (M‐H, Random, 95% CI)	2.94 [1.42, 6.10]
15.2 insomnia	2	67	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.07, 12.05]
16 Adverse events: 7. Weight	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
16.1 gain >10 lb	1	27	Risk Ratio (M‐H, Random, 95% CI)	1.24 [0.34, 4.51]
16.2 loss >10 lb	1	27	Risk Ratio (M‐H, Random, 95% CI)	2.17 [0.71, 6.66]
17 Adverse events: 8. Miscellaneous	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
17.1 anorexia	1	52	Risk Ratio (M‐H, Random, 95% CI)	0.8 [0.24, 2.65]
17.2 blurred vision	3	119	Risk Ratio (M‐H, Random, 95% CI)	1.72 [0.47, 6.26]
17.3 nausea	1	27	Risk Ratio (M‐H, Random, 95% CI)	1.39 [0.28, 7.05]
17.4 oedema ‐ face	1	52	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.22, 4.50]
17.5 rashes	3	119	Risk Ratio (M‐H, Random, 95% CI)	1.09 [0.30, 4.01]
17.6 swallowing ‐ difficulties	1	52	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.22, 4.50]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Global state: 1a. No substantial improvement (defined as slight improvement or worse) ‐ by time period	28	1016	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.98, 1.14]
1.1 by 3 months	22	816	Risk Ratio (M‐H, Random, 95% CI)	1.04 [0.94, 1.15]
1.2 3 months to 1 year	5	175	Risk Ratio (M‐H, Random, 95% CI)	1.07 [0.93, 1.24]
1.3 1 year to 2 years	1	25	Risk Ratio (M‐H, Random, 95% CI)	1.09 [0.87, 1.36]
2 Global state: 1b. No substantial improvement (short term) ‐ by rater's role	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
2.1 doctor rated	1	29	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.48, 1.53]
2.2 nurse rated	1	29	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.74, 1.32]
2.3 patent rated	3	131	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.54, 1.32]
3 Global state: 1d. No substantial improvement ‐ subgroup analysis ‐ acute vs chronic	24	833	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.97, 1.14]
3.1 acutely ill people	10	351	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.84, 1.27]
3.2 chronically ill people	14	482	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.96, 1.15]
4 Global state: 1e. No substantial improvement ‐ subgroup analysis ‐ mixed diagnoses vs schizophrenia only	21	792	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.91, 1.13]
4.1 mixed diagnoses ‐ short term studies only	4	115	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.80, 1.53]
4.2 schizophrenia only ‐ short term studies	17	677	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.90, 1.12]
5 Global state: 2. Not discharged from hospital ‐ by time period	3	121	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.82, 1.47]
5.1 by 3 months	1	43	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.79, 1.58]
5.2 3 months to 1 year	2	78	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.62, 1.80]
6 Global state: 3. Use of additional antipsychotics or sedatives	3	78	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.33, 1.91]
7 Mental state: 1. Delusions and hallucinations by the end of the study	1	22	Risk Ratio (M‐H, Random, 95% CI)	1.33 [0.39, 4.62]
8 Mental state: 2. Other specific effects	9		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
8.1 anxious	1	31	Risk Ratio (M‐H, Random, 95% CI)	0.35 [0.02, 8.08]
8.2 depressed	5	244	Risk Ratio (M‐H, Random, 95% CI)	0.68 [0.33, 1.40]
8.3 excitement	5	273	Risk Ratio (M‐H, Random, 95% CI)	0.52 [0.17, 1.58]
9 Behaviour: 1. No improvement (Wings Behaviour Rating Scale)	1	40	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.47, 2.14]
10 Behaviour: 2. Specific effects	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
10.1 lethargy	2	85	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.23, 2.21]
10.2 restlessness	1	54	Risk Ratio (M‐H, Random, 95% CI)	0.8 [0.24, 2.66]
10.3 violent and aggressive	1	54	Risk Ratio (M‐H, Random, 95% CI)	0.5 [0.05, 5.19]
10.4 unspecified behavioural problems	2	129	Risk Ratio (M‐H, Random, 95% CI)	1.08 [0.21, 5.49]
11 Leaving the study early: 1. Any reason ‐ by time period	32	1300	Risk Ratio (M‐H, Random, 95% CI)	1.22 [0.92, 1.62]
11.1 by 3 months	22	930	Risk Ratio (M‐H, Random, 95% CI)	1.15 [0.83, 1.58]
11.2 by 3 months to 1 year	9	345	Risk Ratio (M‐H, Random, 95% CI)	1.80 [0.99, 3.27]
11.3 by 1 year to 2 years	1	25	Risk Ratio (M‐H, Random, 95% CI)	0.18 [0.03, 1.36]
12 Leaving the study early: 2. Due to adverse events ‐ by time period	8	320	Risk Ratio (M‐H, Random, 95% CI)	1.24 [0.49, 3.11]
12.1 by 3 months	3	129	Risk Ratio (M‐H, Random, 95% CI)	0.66 [0.11, 4.05]
12.2 by 3 months to 1 year	5	191	Risk Ratio (M‐H, Random, 95% CI)	1.54 [0.53, 4.49]
13 Leaving the study early: 3. Due to relapse or worsening ‐ by time period	13	431	Risk Ratio (M‐H, Random, 95% CI)	1.31 [0.72, 2.38]
13.1 by 3 months	6	203	Risk Ratio (M‐H, Random, 95% CI)	1.07 [0.41, 2.78]
13.2 by 3 months to 1 year	6	203	Risk Ratio (M‐H, Random, 95% CI)	1.74 [0.78, 3.85]
13.3 by 1 year to 2 years	1	25	Risk Ratio (M‐H, Random, 95% CI)	0.19 [0.01, 3.52]
14 Leaving the study early: 4. Due to refusal of treatment ‐ by time period	3	110	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.27, 2.50]
14.1 by 3 months	2	85	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.28, 3.52]
14.2 by 1 year to 2 years	1	25	Risk Ratio (M‐H, Random, 95% CI)	0.46 [0.05, 4.46]
15 Adverse events: 1. Reporting at least one adverse event	14	585	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.88, 1.13]
16 Adverse events: 2. Anticholinergic	16		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
16.1 blurred vision	14	606	Risk Ratio (M‐H, Random, 95% CI)	1.18 [0.91, 1.55]
16.2 constipation	7	276	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.75, 1.10]
16.3 dry mouth	11	466	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.77, 1.44]
16.4 nasal congestion	3	149	Risk Ratio (M‐H, Random, 95% CI)	1.61 [0.47, 5.48]
16.5 urinary difficulties	1	40	Risk Ratio (M‐H, Random, 95% CI)	2.0 [0.20, 20.33]
16.6 unspecified	2	129	Risk Ratio (M‐H, Random, 95% CI)	1.04 [0.43, 2.49]
17 Adverse events: 3. Cardiovascular	11		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
17.1 any unspecified cardiovascular problem	2	129	Risk Ratio (M‐H, Random, 95% CI)	1.21 [0.54, 2.73]
17.2 ECG abnormalities ‐ minor	1	29	Risk Ratio (M‐H, Random, 95% CI)	1.07 [0.45, 2.55]
17.3 hypertension	2	111	Risk Ratio (M‐H, Random, 95% CI)	1.26 [0.21, 7.66]
17.4 hypotension	6	252	Risk Ratio (M‐H, Random, 95% CI)	0.55 [0.28, 1.10]
17.5 palpitations	1	40	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.39, 2.58]
17.6 syncope	2	97	Risk Ratio (M‐H, Random, 95% CI)	0.36 [0.06, 2.17]
17.7 tachycardia	1	57	Risk Ratio (M‐H, Random, 95% CI)	0.44 [0.09, 2.10]
18 Adverse events: 4. Endocrine	7		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
18.1 amenorrhoea	2	62	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.24, 2.86]
18.2 galactorrhoea	2	71	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.16, 3.86]
18.3 weight gain >10 lb	5	207	Risk Ratio (M‐H, Random, 95% CI)	1.25 [0.92, 1.71]
18.4 weight loss >10 lb	2	116	Risk Ratio (M‐H, Random, 95% CI)	2.00 [0.54, 7.45]
19 Adverse events: 5a. Extrapyramidal ‐ non specific	28		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
19.1 any unspecifed extrapramidal effect	12	485	Risk Ratio (M‐H, Random, 95% CI)	1.12 [0.88, 1.42]
19.2 use of antiparkinson agents	19	707	Risk Ratio (M‐H, Random, 95% CI)	1.04 [0.86, 1.25]
20 Adverse events: 5b. Extrapyramidal ‐ specific problems	20		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
20.1 akathisia	18	719	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.70, 1.17]
20.2 dyskinesia, tardive	2	62	Risk Ratio (M‐H, Random, 95% CI)	2.54 [0.71, 9.02]
20.3 dystonic symptoms ‐ unspecified	14	520	Risk Ratio (M‐H, Random, 95% CI)	1.09 [0.72, 1.65]
20.4 facial expression abnormal	4	147	Risk Ratio (M‐H, Random, 95% CI)	0.62 [0.33, 1.16]
20.5 gait, Parkinsonian	5	152	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.67, 1.57]
20.6 oculogyric crisis	3	101	Risk Ratio (M‐H, Random, 95% CI)	1.21 [0.52, 2.82]
20.7 Parkinsonism syndrome	1	40	Risk Ratio (M‐H, Random, 95% CI)	7.24 [1.00, 52.64]
20.8 rigidity	15	636	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.79, 1.42]
20.9 salivation, increased	7	283	Risk Ratio (M‐H, Random, 95% CI)	1.08 [0.64, 1.84]
20.10 tremor	14	612	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.75, 1.12]
21 Adverse effects: 5c. Extrapyramidal ‐ average daily dose of antiparkinson agent (trihexyphenidyl)	1	40	Mean Difference (IV, Random, 95% CI)	‐2.2 [‐2.78, ‐1.62]
22 Adverse events: 5d‐i. Extrapyramidal ‐ subgroup analysis ‐ high vs low potency control groups ‐ any effect	12	485	Risk Ratio (M‐H, Random, 95% CI)	1.12 [0.88, 1.42]
22.1 vs high potency control group	9	355	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.79, 1.34]
22.2 vs low potency control group	3	130	Risk Ratio (M‐H, Random, 95% CI)	1.66 [1.03, 2.67]
23 Adverse events: 5d‐ii. Extrapyramidal ‐ subgroup analysis ‐ high vs low potency control groups ‐ rigidity	15	636	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.79, 1.42]
23.1 vs high potency control group	12	513	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.79, 1.36]
23.2 vs low potency control group	3	123	Risk Ratio (M‐H, Random, 95% CI)	1.29 [0.36, 4.60]
24 Adverse events: 5d‐iii. Extrapyramidal ‐ subgroup analysis ‐ high vs low potency control groups ‐ anti'p drugs	19	707	Risk Ratio (M‐H, Random, 95% CI)	1.04 [0.86, 1.25]
24.1 vs high potency control group	13	430	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.76, 1.15]
24.2 vs low potency control group	6	277	Risk Ratio (M‐H, Random, 95% CI)	1.68 [0.80, 3.50]
25 Adverse events: 5d‐iv. Extrapyramidal ‐ subgroup analysis ‐ specific drugs ‐ any effect	9	355	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.79, 1.34]
25.1 vs loxapine	5	225	Risk Ratio (M‐H, Random, 95% CI)	1.15 [0.91, 1.46]
25.2 vs other high potency antipsichotics	4	130	Risk Ratio (M‐H, Random, 95% CI)	0.84 [0.49, 1.43]
26 Adverse events: 6. Gastrointestinal	12		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
26.1 any ‐ unspecified	2	129	Risk Ratio (M‐H, Random, 95% CI)	1.67 [0.58, 4.82]
26.2 abdominal discomfort	1	40	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.22, 2.01]
26.3 diarrhoea	2	111	Risk Ratio (M‐H, Random, 95% CI)	2.94 [0.47, 18.60]
26.4 nausea or vomiting	11	457	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.51, 1.32]
27 Adverse events: 7. Haematological	7		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
27.1 any haematological abnormality ‐ unpsecified	1	87	Risk Ratio (M‐H, Random, 95% CI)	1.95 [0.52, 7.32]
27.2 blood cell count ‐ eosinophilia >5%	1	29	Risk Ratio (M‐H, Random, 95% CI)	1.43 [0.39, 5.28]
27.3 blood cell count ‐ leukocytosis	2	72	Risk Ratio (M‐H, Random, 95% CI)	1.17 [0.43, 3.15]
27.4 liver enzyme elevation ‐ alkaline phosphatase	2	54	Risk Ratio (M‐H, Random, 95% CI)	0.59 [0.25, 1.39]
27.5 liver enzyme elevation ‐ bilirubin	2	68	Risk Ratio (M‐H, Random, 95% CI)	0.18 [0.03, 0.92]
27.6 liver enzyme elevation ‐ SGOT	4	169	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.17, 4.07]
27.7 liver enzyme elevation ‐ SGPT	2	81	Risk Ratio (M‐H, Random, 95% CI)	0.28 [0.05, 1.62]
27.8 renal function ‐ urea nitrogen elevated	1	29	Risk Ratio (M‐H, Random, 95% CI)	1.61 [0.31, 8.24]
28 Adverse events: 8. Neurological	14		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
28.1 confusional state	3	150	Risk Ratio (M‐H, Random, 95% CI)	1.16 [0.46, 2.95]
28.2 convulsions	1	52	Risk Ratio (M‐H, Random, 95% CI)	5.0 [0.25, 99.34]
28.3 dizziness or giddiness	3	125	Risk Ratio (M‐H, Random, 95% CI)	1.81 [0.71, 4.61]
28.4 faintness or weakness	12	537	Risk Ratio (M‐H, Random, 95% CI)	1.27 [0.91, 1.77]
28.5 parasthesia	1	40	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.34, 2.93]
28.6 urinary incontinence	1	52	Risk Ratio (M‐H, Random, 95% CI)	7.00 [0.38, 129.11]
29 Adverse events: 9. Somnolescence	20		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
29.1 drowsiness	20	816	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.72, 1.10]
29.2 insomnia	12	469	Risk Ratio (M‐H, Random, 95% CI)	1.23 [0.87, 1.73]
30 Adverse events: 10. Miscellaneous	19		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
30.1 anorexia	6	228	Risk Ratio (M‐H, Random, 95% CI)	1.34 [0.81, 2.20]
30.2 breathlessness	1	57	Risk Ratio (M‐H, Random, 95% CI)	0.37 [0.02, 8.69]
30.3 bulimia	1	57	Risk Ratio (M‐H, Random, 95% CI)	0.37 [0.02, 8.69]
30.4 difficulty swallowing	1	52	Risk Ratio (M‐H, Random, 95% CI)	7.00 [0.38, 129.11]
30.5 eye changes ‐slight pigmentation	1	25	Risk Ratio (M‐H, Random, 95% CI)	0.37 [0.09, 1.56]
30.6 eye changes ‐ worsening of cataracts	2	114	Risk Ratio (M‐H, Random, 95% CI)	2.0 [0.38, 10.49]
30.7 headache	5	169	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.59, 1.32]
30.8 hiccough	1	52	Risk Ratio (M‐H, Random, 95% CI)	5.38 [0.27, 106.98]
30.9 joint pain	1	40	Risk Ratio (M‐H, Random, 95% CI)	1.25 [0.39, 3.99]
30.10 lacrimation	1	57	Risk Ratio (M‐H, Random, 95% CI)	0.37 [0.02, 8.69]
30.11 local tissue reactions (IM preparations)	1	52	Risk Ratio (M‐H, Random, 95% CI)	0.5 [0.05, 5.18]
30.12 oedema of face	1	52	Risk Ratio (M‐H, Random, 95% CI)	7.00 [0.38, 129.11]
30.13 rashes	10	489	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.53, 2.33]
30.14 sweating, facial	2	84	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.47, 2.01]
30.15 sweating, general	3	128	Risk Ratio (M‐H, Random, 95% CI)	0.46 [0.12, 1.80]
30.16 unspecified	2	129	Risk Ratio (M‐H, Random, 95% CI)	1.52 [0.52, 4.48]
31 Patient's drug preference: Would prefer a different medication	1	54	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.52, 1.31]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Global state: 1a. No substantial improvement (defined as slight improvement or worse)	1	38	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.44, 1.81]
2 Global state: 2. Severely ill or worse	1	38	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.43, 2.30]
3 Global state: 3. Use of additional sedatives	1	38	Risk Ratio (M‐H, Random, 95% CI)	2.0 [0.58, 6.85]
4 Mental state	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
4.1 emotional lability	1	38	Risk Ratio (M‐H, Random, 95% CI)	0.14 [0.01, 2.59]
4.2 euphoria	1	38	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.04, 2.93]
5 Leaving the study early	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
5.1 any reason	1	38	Risk Ratio (M‐H, Random, 95% CI)	0.5 [0.05, 5.06]
5.2 due to deterioration	1	38	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.07, 14.85]
6 Behaviour: Agitation	1	38	Risk Ratio (M‐H, Random, 95% CI)	0.11 [0.01, 1.93]
7 Adverse events: 1. Extrapyramidal	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
7.1 non‐specific ‐ use of antiparkinson drugs	1	38	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.16, 6.38]
7.2 specific ‐ akathisia	1	38	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.13, 3.55]
7.3 specific ‐ dyskinesia, oral	1	38	Risk Ratio (M‐H, Random, 95% CI)	3.00 [0.34, 26.33]
7.4 specific ‐ dystonic reaction	1	38	Risk Ratio (M‐H, Random, 95% CI)	5.0 [0.26, 97.70]
7.5 specific ‐ rigidity	1	38	Risk Ratio (M‐H, Random, 95% CI)	1.33 [0.34, 5.17]
7.6 specific ‐ salivation, excessive	1	38	Risk Ratio (M‐H, Random, 95% CI)	2.0 [0.41, 9.65]
7.7 specific ‐ tremor	1	38	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.29, 3.43]
8 Adverse events: 2. Miscellaneous	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
8.1 dry mouth	1	38	Risk Ratio (M‐H, Random, 95% CI)	3.00 [0.13, 69.31]
8.2 headache	1	38	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.16, 6.38]
8.3 nausea	1	38	Risk Ratio (M‐H, Random, 95% CI)	3.00 [0.13, 69.31]
8.4 perspiration, excessive	1	38	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.07, 14.85]
8.5 rash	1	38	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.01, 7.70]
8.6 urinary frequency	1	38	Risk Ratio (M‐H, Random, 95% CI)	3.00 [0.13, 69.31]
8.7 weakness/lethargy	1	38	Risk Ratio (M‐H, Random, 95% CI)	3.00 [0.13, 69.31]

Methods	Allocation: randomly assigned, no further details.   Blindness: double (identical oral preparations, but not in IM preparation ‐ saline by a senior nurse).   Design: 2 parallel groups, single centre.   Duration: 16 weeks.   Analysis: not clearly described in the report, (ITT)?*   Country: Canada.
Participants	Diagnosis: schizophrenia, no further details.   N=24.   Age: mean 33.1 years.   Sex: M 15, F 9.   Setting: hospital.   History: acutely disturbed (mean length of illness 98.5 months.
Interventions	1. Trifluoperazine: dose (mean 40 mg/day). N=13.   2. Fluspirilene: dose (mean 3.25 ml, 1 amp IM/week). N=11.
Outcomes	Leaving the study early.   Side effects. Unable to use ‐   Mental state: (BPRS ‐ only graph; NOSIE ‐ no data).   Laboratory tests ‐ no data.   EKG ‐ no data.
Notes	*ITT unclear.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Methods	Allocation: randomly assigned (random number table, blocks of 5, matched for treatment symptom severity (BPRS), sex, ward, evaluator).   Blindness: double.   Design: 5 parallel groups.   Duration: 70 days‐preceeded by 21 days where all had chlorpromazine 100 mg/day.   Analysis: not clearly described in the report, (ITT?)*.   Country: Canada.
Participants	Diagnosis: "schizophrenics", no further details.   N=80.   Age: range 20‐60 years.   Sex: "equally represented".   Setting: hospital.   History: chronic, hospitalised for the last 2 years, no exacerbation in last year, in hospital for only social or personal reasons.
Interventions	1. Trifluoperazine: dose 5 mg/tds. N=16.   2. Trifluoperazine: dose 15 mg/day. N=16.   3. Pimozide: dose 3 mg/day. N=16.   4. Pimozide: dose 6 mg/day. N=16.   5. Placebo: N=16.   Chlorpromazine, methyprylon, benztropine as required.
Outcomes	Leaving the study early. Unable to use ‐   Mental state: (BPRS ‐ 'p' values only).   Behavior: (NOSIE ‐ graph only).   Side effects: (Extrapyramidal symptom rating BEP ‐ graph only).   Insight scale: (Echelle D"Autocritique ‐ no usable data).
Notes	* ITT unclear.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Methods	Allocation: randomly assigned acording to a code prepared in advanced and held by the pharmacist" ‐ no information how the code was prepared.   Blindness: double.   Duration: 4 weeks (preceeded by 3 days washout).   Design: 2 parallel groups, single centre.   Analysis: intention to treat performed only for global change in condition, others outcomes were not clearly described*.   Country: USA.
Participants	Diagnosis: described elsewhere ‐ Angus 1969.   N=52.   Age: range 20‐48 years, mean 37.3 years.   Sex: M 16, F 36.   Setting: hospital.   History: acute schizophrenia or acute exacerbation of chronic schizophrenia.
Interventions	1. Trifluoperazine: range 20‐45 mg/day (mean 35mg). N=25.   2. Molindone: range 40‐120 mg/day (mean 75mg). N=27.
Outcomes	Global state: (global rating of change in condition).   Side effects.   Use of antiparkinson agents.   Leaving the study early. Unable to use ‐   Mental state: (BPRS ‐ no SD).   Behaviour: (NOSIE ‐ no SD).
Notes	* ITT unclear in some outcomes.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Low risk	A ‐ Adequate

Methods	Allocation: randomised after ranking for withdrawal on Psychotic Reaction Profile, no further details.   Blindness: double (raters reported as blind, identical capsules).   Design: double cross‐over, single centre.   Duration: 2 week placebo washout, 7 weeks on one drug, 2 weeks placebo washout, 7 weeks on second drug.   Analysis: intention‐to‐treat not clearly described in the report.   Country: USA.
Participants	Diagnosis: schizophrenia, no further details.   N=60.   Age: range 23‐65 years, mean 43 years.   Sex: all male.   Setting: hospital.   History: chronic illness (mean hospitalisation 15 years).
Interventions	1. Trifluoperazine: range 5‐40 mg/day. N=30.   2. Thioridazine: range 200‐800 mg/day. N=30.
Outcomes	Leaving the study early. Unable to use ‐   Mental state: (BPRS; Psychotic Reaction Profile ‐ only significance tests).   Adverse events: (only significance tests).
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Methods	Allocation: randomly assigned (described on Andersen 1972 preliminary results), no further details.   Blindness: double (commercial preparations but administered by people not involved in the trial).   Design: 2 parallel groups.   Duration: 3 months.   Analysis: intention‐to‐treat not performed in the trial.   Country: Sweden.
Participants	Diagnosis: schizophrenia or paranoid syndrome.**   N=40.   Age: range 21‐65 years.   Sex: M 19, F19.   Setting: hospital.   History: chronic patients.   Inclusion: hospitalisation < 10 years, no organic disorders, no substance abuse, no depression episodes, no violent patients.
Interventions	1. Trifluoperazine: range 3‐12 mg/bid (mean 4.34 mg). N=20.   2. Pimozide: range 3‐14 mg/day (mean 3.92 mg). N=20.
Outcomes	Side effects.   Use of antiparkinson agents.   Leaving the study early. Unable to use ‐   Mental state: (scale ‐ 'p' values only).   Behaviour: (Wing behaviour scale ‐ 'p' values only).   Side effects: (point rating scale ‐ validity unknown).
Notes	** Mixed diagnosis.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Methods	Allocation: randomly assigned (according to a code prepared in advance and held by the pharmacist).   Blindness: double.   Design: 2 parallel group, single centre.   Duration: 6 months (results in 6 weeks).   Analysis: intention‐to‐treat.   Country: USA.
Participants	Diagnosis: Scheneider criteria.   N=42.   Age: range 17‐57 years, mean 38.5 years.   Sex: M 14, F 28.   Setting: hospital.
Interventions	1.Trifluoperazine: range 7.5‐45 mg/day. N=22.   2.SK&F 14,336: range 100‐600 mg/day. N=20.
Outcomes	Global state: (global ratings of improvement).   Side‐effects.   Use of antiparkinson agents. Unable to use ‐   Mental state: (BPRS ‐ no data).   Behaviour: (NOSIE ‐ no data).   Leaving the study early ‐ no usable data.   Global state: (degree of severity of the illness scale ‐ no data).
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Low risk	A ‐ Adequate

Methods	Allocation: randomly divided, no further details.   Blindness: double (identical capsules, coded bottles).   Design: 2 parallel groups, single centre.   Duration: 8 weeks (preceded by one placebo week and off of study medication for at least 60 days).   Analysis: intention‐to‐treat not performed.   Country: USA.
Participants	Diagnosis: schizophrenia, no further information.   N=40.   Age: range 22‐49 years.   Sex: M 20, F 18.   Setting: hospital.   History: chronic (length of hospitalisation 3‐17 years).
Interventions	1. Trifluoperazine: dose (weeks 2 to 5, 15 mg/day, weeks 6 to 9, 24 mg/day). N=20.   2. SK&F 7261: dose (weeks 2 to 5, 3 mg/day), (weeks 6 to 9, 6 mg/day). N=20.
Outcomes	Leaving the study early.   Side effects: (total number, weight gain).   Global state: (change in condition). Unable to use ‐   Psychological findings.   Mental state: (Lorr psychiatric rating scale).   Laboratory tests.   Vital signs.
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Methods	Allocation: "randomly divided", no further details.   Blindness: double (identical capsules dispensed from individual bottles).   Design: 3 parallel groups, single centre.   Duration: 10 weeks (preceeded by 60 days washout).   Analysis: intention to treat.   Country: USA.
Participants	Diagnosis: schizophrenia, no further details.   N=42.   Age: range 21‐53 years, mean 41 years.   Sex: M 21, F21.   Setting: hospital.   History: chronic schizophrenia (time in hospital 3‐27 years).   Excluded: physical or neurologic disorders.
Interventions	1. Trifluoperazine: dose 5 mg/day (week 1) increasing to 40 mg/day by (week 5). N=14.   2. Butaperazine: dose 25 mg/day (week 1) increasing to 200 mg/day by (week 5). N=14.   3. Placebo. N=14.   * Half of the patients in each group received Artane 2 mg t.i.d., and the others "placebo Artane".   Use of prophylactic antiparkinson medication.
Outcomes	Global state.   Side effects: (Extrapyramidal, lethargy). Unable to use ‐   Mental state: (Psychotic Reaction Profile; Beckomberga rating scale).   Behaviour: (Tulane test battery; Minimal Social Behavior).   Laboratory tests: (no data).   Physiological measures.
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Methods	Allocation: "prearranged randomised procedure", no further details.   Blindeness: double, (identical capsules supplied in individual bottles only with the subjects study number).   Design: 2 parallel groups, two centres.   Duration: 30 days.   Analysis: intention‐to‐treat.   Country: USA.
Participants	Diagnosis: schizophrenia, no further information.   N=40.   Age: range 18‐54 years, mean 34.3 years.   Sex: M 21, F 19.   Setting: hospital.   History: newly admitted patients, trifluoperazine group > paranoid diagnosis.
Interventions	1. Trifluoperazine: range 5‐30 mg/day. N=21.   2. Thiothixene: range 5‐30 mg/day. N=19.
Outcomes	Global state: (global ratings of improvement).   Side effects: (EPS). Unable to use ‐   Mental state: (BPRS, only graphs).
Notes	#The groups differ on sex, age and diagnostic type.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Methods	Allocation: divided on a random basis, no further details.   Blindness: double, no further information.   Design: 2 parallel groups, single centre.   Duration: 8 weeks (preceded by 4 weeks washout + 2 weeks assessment period).   Analysis: intention‐to‐treat.   Country: USA.
Participants	Diagnosis: schizophrenia, no further details.   N=24.   Age: range 30‐55 years, mean 43.9 years.   Setting: hospital.   Sex: 12 M, 12 F.   History: chronic, mean length of hospitalisation ˜ 17 years, range 5‐29 years.
Interventions	1. Trifluoperazine: range 10‐60 mg/day. N=12.   2. Loxapine: range 20‐120 mg/day. N=12.
Outcomes	Global state: (CGI).   Side effects: (EPS, hypotension). Unable to use ‐   Mental state: (BPRS ‐ no usable data).   Behaviour: (NOSIE ‐ no usable data).   Laboratory tests: (ECG ‐ no data).
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Methods	Allocation: pre‐randomised list, blocks of 3, provided by drug company.   Blindness: double (identical capsules).   Design: 3 parallel groups, single centre.   Duration: 4 weeks.   Analysis: intention‐to‐treat performed only for some outcomes.   Country: USA.
Participants	Diagnosis: schizophrenia, confirmed by research psychiatry.   N=42.   Age: range: 21‐57 years.   Sex: M 21, F 16.   Setting: hospital.   History: newly admitted chronic patients.   Excluded: < 2 years of illness; < 18 years of age; mental deficiency, epilepsy, organic brain disease, metabolic disorders, liver, renal or cardiac disease.
Interventions	1. Trifluoperazine: dose 10 mg/day initially, then increasing to maximum 50 mg/day (mean 36 mg). N=14.   2. Loxapine: dose 20 mg/day initially, then increased to maximum 100 mg/day, (mean 71mg). N=15.   3. Placebo: 2‐10 capsules. N=13.
Outcomes	Leaving the study early.   Side effects: (total; EPS; insomnia; weight; EKG).   Global state: (CGI; use of additional sedation).   Laboratory tests. Unable to use ‐   Mental state: (BPRS ‐ no SD).   Efficacy: (analysis of covariance ‐ no usable data).   Behaviour: (NOSIE ‐ no usable data).   Physiological measures: (BP, pulse ‐ no data).
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Methods	Allocation: randomly assigned (by Dr. Coons independently, code in a sealed envelope).   Blindness: double (identical capsules, coded bottles).   Design: 3 parallel groups, single centre.   Duration: 6 weeks (preceded by 8 days washout).   Analysis: intention‐to‐treat.   Country: Canada.
Participants	Diagnosis: ** mixed (˜79,4% schizophrenia; ˜12% affective psychoses; ˜5% psychoneuroses; ˜3.6% outros, ˜12% leucotomy).   N=117.   Age: ˜47 years.   Sex: female.   Setting: hospital.   History: long term hospital patients (mean˜141 months).
Interventions	1. Trifluoperazine: dose 15 mg/day. N=39.   2. Chlorpromazine: dose 150 mg/day. N=39.   3. Placebo. N=39.
Outcomes	Use of antiparkinson agents. Unable to use ‐   Behaviour: (Hospital Adjustment Scale ‐ no data).
Notes	** Mixed diagnosis.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Low risk	A ‐ Adequate

Methods	Allocation: randomly assigned, (random code was unknown until the end of study).   Blindness: double (identical capsules dispensed by the research nurse).   Design: 2 parallel groups, single centre.   Duration: average of 36 days.   Analysis: intention‐to‐treat.   Country: USA.
Participants	Diagnosis: ** 26 schizophrenics; 1 psychose + mental deficiency and 3 involutional psychoses.   N=31 (30 patients, one patient participated twice).   Age: no data.   Sex: only female.   Setting: hospital.   History: acute illness.
Interventions	1. Trifluoperazine: dose (mean 58.7 mg/day). N=15.   1. Thiothixene: dose (mean 49 mg/day). N=16.
Outcomes	Side effects: (total number; specific).   Global state: (global clinical evaluation).   Weight changes.   Use of antiparkinson agents.   Leaving the study early. Unable to use ‐   Mental state: (IMPS).
Notes	** Mixed diagnosis, one patient participated twice.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Low risk	A ‐ Adequate

Methods	Allocation: randomly assigned in advance and held by the hospital pharmacist (open list of random numbers). Blindness: double.   Design: 2 parallel groups, single centre.   Duration: 6 weeks (preceded by 1 month washout if possible).   Analysis: intention‐to‐treat not performed in the trial.   Country: UK.
Participants	Diagnosis: schizophrenia, Schneider 1959.   N=38.   Age: range 25‐74 years, majority 55‐64 years.   Sex: M 33, F 5.   Setting: hospital.   History: long‐stay inpatients, 36 ill >10 years.
Interventions	1. Trifluoperazine: range 15‐45 mg/day (mean 27.7 mg). N=19.   2. Sulpiride: range 600‐1800 mg/day (mean 1212 mg). N=19.
Outcomes	Global state: (change in condition; severity of illness).   Leaving the study early.   Use of hypnotic.   Use of antiparkinson agents.   Side effects: (specific list). Unable to use ‐   Mental state: (BPRS ‐ no SD).   Side effects: (Simpson and Angus Scale ‐ no SD).   Physiological measures: (handwriting, weight, pulse, blood pressure ‐ no SD).   Live events ‐ denominator unclear.
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Low risk	A ‐ Adequate

Methods	Allocation: randomly assigned, random code not broken to the end of study.   Blindness: double (identical capsules).   Design: 2 parallel groups, single centre.   Duration: 12 weeks (preceded by 4 weeks washout).   Analysis: intention‐to‐treatnot performed in the trial.   Country: USA.
Participants	Diagnosis: schizophrenia, no further details.   N=41.   Age: mean 30 years.   Sex: M 14, F 27.   Setting: hospital.   History: majority of cases undifferentiated and paranoid.   Inclusion: duration of present illness of not more than 2 years and hospital admissions not longer than 5 years.
Interventions	1. Trifluoperazine: dose 15 mg/day (first week), 30 mg/day (second week), maximum 45 mg/day (mean 26 mg). N=20.   2. SKF 14336: dose 200 mg/day (first week), 400 mg/day (second week), maximum 600 mg/day (mean 385 mg). N=21.
Outcomes	Global state: (global judgement of the psychiatrists).   Use of antiparkinson agents.   Side effects.   Leaving the study early.   Side effects: (abnormal laboratory tests). Unable to use ‐   Mental state: (BPRS; IMPS ‐ only graphs).
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Low risk	A ‐ Adequate

Methods	Allocation: randomly allocated.   Blindness: double (identical capsules).   Design: 2 parallel groups, single centre.   Duration: 28 days.   Analysis: intention‐to‐treat not performed in the trial.   Country: India.
Participants	Diagnosis: schizophrenia, no further details.   N=54.   Age: range 14‐19 years mean ˜17 years.   Sex: M 25, F 27 (2 not reported).   Setting: hospital.   History: adolescent schizophrenics.   Exclusion: sensivity to study drugs, ECT in the last 8 weeks, brain syndrome, convulsive disorders, mental retardation or autism.
Interventions	1. Trifluoperazine: dose mean 23.57 mg/day, maximum 35 mg. N=27.   2. Loxapine succinate: dose mean 91.5 mg/day, maximum 120 mg. N=27.   Antiparkinson medication as required.
Outcomes	Global state: (CGI, patient's self evaluation).   Patient's drug preference.   Leaving the study early. Unable to use ‐   Mental state: (BPRS ‐ no SD).   Use of antiparkinson drugs ‐ no data.   Physiological measures: (BP, pulse ‐ no data).   Laboratory tests ‐ no data.
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

PERMALINK

Trifluoperazine for schizophrenia

Luciana de Oliveira Marques

Bernardo Soares

Mauricio Silva de Lima

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Background

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Results

Description of studies

1. Comparison compounds used in trifluoperazine studies.

Risk of bias in included studies

Effects of interventions

Discussion

Authors' conclusions

Implications for practice.

Implications for research.

What's new

History

Acknowledgements

Data and analyses

Comparison 1. TRIFLUOPERAZINE versus PLACEBO.

1.1. Analysis.

1.2. Analysis.

1.3. Analysis.

1.4. Analysis.

1.5. Analysis.

1.6. Analysis.

1.7. Analysis.

1.8. Analysis.

1.9. Analysis.

1.10. Analysis.

1.11. Analysis.

1.12. Analysis.

1.13. Analysis.

1.14. Analysis.

1.15. Analysis.

1.16. Analysis.

1.17. Analysis.

Comparison 2. TRIFLUOPERAZINE versus TYPICAL ANTIPSYCHOTICS.

2.1. Analysis.

2.2. Analysis.

2.3. Analysis.

2.4. Analysis.

2.5. Analysis.

2.6. Analysis.

2.7. Analysis.

2.8. Analysis.

2.9. Analysis.

2.10. Analysis.

2.11. Analysis.

2.12. Analysis.

2.13. Analysis.

2.14. Analysis.

2.15. Analysis.

2.16. Analysis.

2.17. Analysis.

2.18. Analysis.

2.19. Analysis.

2.20. Analysis.

Methods	Allocation: randomly assigned by the pharmacist, no further details.   Blindness: double (identical capsules).   Design: 2 parallel groups, single centre.   Duration: 24 weeks (preceded by 4 weeks washout).   Analysis: intention‐to‐treat not performed in global state.   Country: Australia.
Participants	Diagnosis: schizophrenia, no further details.   N=54.   Age: mean 45 years.   Sex: only male.   History: average duration of illness 22 years; majority chronic undifferentiated schizophrenics.
Interventions	1. Trifluoperazine: range 11.25‐37.5 mg/day. N=27.   2. SKF 14336: range 150‐500 mg/day. N=27.
Outcomes	Leaving the study early.   Global state: (Global evaluation of improvement).   Side effects: (EPS, skin and eyes changes). Unable to use ‐   Mental state: (BPRS ‐ no SD).   Behaviour: (NOSIE ‐ no SD).
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Methods	Allocation: randomly assigned (code held by a technician who was not responsible for allocation).   Blindness: double (identical capsules, coded bottles).   Design: 2 parallel groups, 2 centres.   Duration: 3 weeks.   Analysis: intention‐to‐treat not performed in the trial.   Country: USA.
Participants	Diagnosis: patients with symptoms of hostility, suspiciousness, paranoia and aggressiveness; 20 schizophrenics*.   N=30.   Age: mean ˜30 years.   Sex: M 22, F 2.   Setting: hospital.
Interventions	1. Trifluoperazine: dose 9‐48 mg/day. N=15.   2. Haloperidol: dose 3‐20 mg/day. N=15.
Outcomes	Global state.   Leaving the study early.   Use of antiparkinson agents. Unable to use ‐   Mental state: (BPRS; Global Hostility; Global Paranoia ‐ no SD).   Psychological Tests: (Buss‐Durkee hostility inventory; Rozenzweig picture frustration test; MMPI and Rorshach test ‐ no data).
Notes	**Mixed diagnosis.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Low risk	A ‐ Adequate

Methods	Allocation: randomly assigned by random table (independently and secretly by the head of the project).   Blindness: double (treatment and evaluation made by 2 independent psychiatrists blind to drug taken).   Design: 2 parallel groups, single centre.   Duration: 45 days.   Analysis: intention‐to‐treat.   Country: Peru.
Participants	Diagnosis: schizophrenia no further details.   N=30.   Age: range 19‐43 years, mean 31.3 years.   Sex: M 26, F 4.   Setting: hospital.   History: acute state of paranoid schizophrenia.
Interventions	1. Trifluoperazine: dose first 5 days 2‐8 amp (2‐8 mg IM), then 10‐40 mg. N=15.   2. Clotiapine: dose first 5 days 1‐4 amp (40‐160 mg IM), then 40‐60 mg. N=15.
Outcomes	Global state: (clinical evaluation).   Side effects. Unable to use ‐   Mental state: (BPRS).   Side effects: (Extrapiramidal signs ‐ Bordeau scale).   Use of antiparkinson agents.
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Low risk	A ‐ Adequate

Methods	Allocation: randomly assigned (held by the pharmacist).   Blindness: double (identical capsules, coded bottles).   Design: 4 parallel groups, single centre.   Duration: 16 weeks (in strict double‐blind conditions) + 22 weeks, no washout period.   Analysis: intention to treat.   Country: USA.
Participants	Diagnosis: schizophrenia, no further details.   N=80.   Age: mean 40.6 years.   Sex: males.   Setting: hospital.   History: chronic (average hospitalisation 10 years).   Excluded: people > 55 years and organic factors.   Included: inadvertently 3 with lobotomies (2 in the thioridazine group and other in the chlorpromazine).
Interventions	1. Trifluoperazine: 10‐50 mg/day, maximum 35 mg, 12 received less than the maximum. N=20.   2. Thioridazine: 200‐1000 mg/day, maximum 958 mg, 3 received less than the maximum. N=20.   3. Chlorpromazine: 200‐1000 mg/day, maximum 894 mg/day, 3 received less than the maximum. N=20.   4. Placebo: 2‐10 capsules.   Occasional additional medication, phenobarbital and benzotropine methansulfonate.
Outcomes	Global state: (Clinical Evaluation).   Side effects.   Leaving the study early.   Use of antiparkinson agents. Unable to use ‐   Behaviour: (Behaviour rating scale ‐ no SD).   Mental state: (MMPI ‐ only 43 patients took the tests).
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Low risk	A ‐ Adequate

Methods	Allocation: randomly assigned (by administrative personnel not involved with patient treatment or evaluation).   Blindness: double (identical capsules).   Design: 2 parallel groups.   Duration: 4 weeks, but it was permitted to remove patients at the end of 2 weeks or to continue beyond the 4 weeks.   Analysis: only 2 weeks ratings were analysed because of the small sample size.   Country: USA.
Participants	Diagnosis: schizophrenia, no further information.   N=21.   Age: range 16‐48 years, mean 24 years.   Sex: no information.   Setting: hospital.   History: acute illness; patients must not have been hospitalised during the preceding 12 months, or have childhood schizophrenia, or brain syndrome, or mental deficiency, alcoholism, epilepsy or drug addiction.
Interventions	1. Trifluoperazine: range 15‐30 mg/day. N=10.   2. Trifluperidol: range 3‐6 mg/day. N=11.   Without washout period; using antiparkinson drug only if dose reduction of the antipsychotic did not provide relief.
Outcomes	Leaving the study early (at the end of 2 weeks). Unable to use ‐   Global state: (Global rating of Pathology; Global rating of improvement ‐ no SD).   Mental state: (BPRS; MMPI; IMPS ‐ no SD).   Side effects: (no data available).
Notes	# Analysis performed in 2 weeks.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Low risk	A ‐ Adequate

Methods	Allocation: randomly assigned (by a person who was not responsible for recruiting patients).   Blindness: double (identical capsules, coded bottles).   Design: 2 parallel groups, single center.   Duration: 4 weeks preceded by 3 days washout (evaluation carried out by the same physician, study lasted over 3 years).   Analysis: intention‐to‐treat.   Country: USA.
Participants	Diagnosis: acute schizophrenia, no further details.   N=43.   Age: range 16‐61 years, mean 31.7 years.   Sex : M 27, F 16.   Setting: hospital.   History: newly hospitalised, mean admitted ˜2 times, 6 first admissions.   Exclusion: ill health.
Interventions	1. Trifluoperazine: range 20‐50 mg/day, mean 35 mg. N=19.   2. Loxapine succinate: range 40‐80 mg/day, mean 74 mg. N=24.   Antiparkinson drugs and chlorayl hydrate as required.
Outcomes	Global state: (discharge).   Leaving the study early.   Side effects: (unwanted effects checklist, use of neurological rating scale).   Use of antiparkinson agents.   Laboratory tests. Unable to use ‐   Global state: (CGI ‐ no usable data).   Mental state: (BPRS ‐ no usable data).   Physiological measures: (BP, EEG, opthalmic tests, pulse ‐ no data).
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Low risk	A ‐ Adequate

Study	Reason for exclusion
Abraham 1987	Allocation: randomised.   Participants: people with schizophrenia.   Interventions: trifluoperazine and ECT versus trifluoperazine with simulated ECT.
Barsa 1959	Allocation: not randomised.
Brannen 1969	Allocation: randomised.   Participants: people with chronic schizophrenia.   Interventions: promethazine versus trifluoperazine versus placebo.   Outcomes: no usable data, 57% lost to follow up.
Buffaloe 1961	Allocation: unclear, double‐blind crossover study.   Participants: people with schizophrenia.   Interventions: first phase only trifluoperazine, second phase trifluoperazine plus parnate versus trifluoperazine.   Outcomes: no data available.
Cabrera 1990	Allocation: unclear, double‐blind study.   Participants: people with schizophrenia.   Interventions: interferon "intratecal" + oral placebo versus trifluoperazine + chlorpromazine + trihexifenidil + lumbar injection of distilled water.
Calwell 1964	Allocation: "randomly divided" ‐ no further description, multiple crossover (medication was changed every 4 weeks).   Participants: women with chronic schizophrenia.   Interventions: oxypertine versus trifluoperazine.   Outcomes: no data reported for first arm of crossover.
Carscallen 1968	Allocation: "double‐blind technique" ‐ no further details.   Participants: people with schizophrenia.   Interventions: trifluoperazine 10 mg/day versus trifluoperazine 100 mg/day.   Outcomes: no data available.
Casey 1961	Allocation: randomised.   Participants: people with schizophrenia.   Interventions: d‐amphetamine versus isocarboxazid versus imipramine versus trifluoperazine versus placebo but chlorpromazine given to everyone.
Childers 1961	Allocation: not randomised.
Childers 1962	Allocation: randomised.   Participants: people with extrapyramidal symptoms.   Interventions: benzotropine methanesulfonate plus chlorpromazine or trifluoperazine or fluphenazine versus procyclidine plus chlorpromazine or trifluoperazine or fluphenazine, no data for trifluroperazine group alone.
Childres 1962 b	Allocation: not randomised, "placed in temporal sequence".
Crane 1970	Allocation: randomised.   Participants: people with schizophrenia.   Interventions: trifluoperazine 80 mg/day versus trifluoperazine 16 mg/day versus placebo.   Outcomes: no usable data.
D'Elia 1974	Allocation: randomised.   Participants: people with schizophrenia.   Interventions: trifluoperazine versus pimozide.   Outcomes: EEG study, no data available.
Den Boer 2000	Allocation: double‐blind procedure.   Participants: people with schizophrenia.   Interventions: neuroleptic treatment (trifluoperazine, chlorpromazine, haloperidol, thioridazine) plus ritanserin versus neuroleptic treatment plus placebo.
Dewolfe 1971	Allocation: randomised, crossover trial.   Interventions: prolixin enanthate versus thorazine‐stelazine, not stelazine.
DiMascio 1965	Allocation: randomised   Participants: healthy volunteers.
Eitan 1992	Allocation: "were assigned", no further details, double‐blind crossover study .   Participants: people with schizophrenia.   Interventions: chlorpromazine versus thioridazine versus trifluoperazine versus haloperidol versus placebo.   Outcomes: no data reported for individual arms of cross‐over.
Fish 1966	Allocation: not randomised.
Forrester 1958	Allocation: not randomised.
Gardos 1968	Allocation: "were assigned" ‐ no further details.   Participants: psychotic patients ‐ no further details.   Interventions: two different samples, withdrawn group (trifluoperazine 10 mg versus trifluoperazine 5 mg + chlorpromazine 50 mg) and agitated group (chlorpromazine 200 mg versus trifluoperazine 5 mg+ chlorpromazine 200 mg).   Outcomes: no data available.
Gottfries 1971	Allocation: not randomised.
Guido 1960	Allocation: not randomised.
Held 1970	Allocation: randomised.   Participants: people with schizophrenia.   Interventions: thorazine versus melleril versus stelazine versus prolixin versus proketazine versus trifalon versus haloperidol versus placebo.   Outcomes: no usable data.
Janecek 1963	Allocation: not randomised.
Jones 1970	Allocation: not randomised.
Jones 1971	Allocation: not randomised.
Joshi 1980	Allocation: unclear ‐ double‐blind study.   Participants: people with schizophrenia.   Interventions: combined modality therapy (trifluoperazine + vitamins versus trifluoperazine + placebo).
Joshi 1982	Allocation: unclear ‐ double‐blind.   Participants: people with schizophrenia.   Interventions: combined modality therapy (trifluoperazine, vitamins B1, B6, B12, chlorpromazine and placebo).
Kalinin 1986	Allocation: randomised.   Participants: people with schizophrenia.   Interventions: insulin coma therapy versus individual pharmacotherapy (haloperidol, trifluoperazine plus sedatives ‐ amitriptyline and lithium).
Kline 1977	Allocation: not randomised.
Knight 1979	Allocation: double‐blind crossover trial.   Participants: people with chronic schizophrenia.   Interventions: thiothixene versus combination of trifluoperazine and chlorpromazine.
Lal 1974	Allocation: randomised ‐ crossover study.   Participants: people with oral dyskinesia.
Lapolla 1965	Allocation: randomised.   Participants: "preponderance of schizophrenia".   Interventions: only trifluoperazine, no control group.
Lovett 1987	Allocation: not randomised.
Luckey 1967	Allocation: randomised.   Participants: people with schizophrenia.   Interventions: haloperidol versus trifluoperazine.   Outcomes: 66% of people were not reported in the final analysis.
Macdonald 1959	Allocation: not randomised.
Mandel 1962	Allocation: randomised, crossover trial.   Participants: people with schizophrenia.   Interventions: trifluoperazine versus butyrylperazine.   Outcomes: no usable data.
Mena 1964	Allocation: double‐blind controlled study.   Participants: "chronic outpatients".
Monroe 1965	Allocation: randomisation not mentioned, described as controlled.   Participants: mixed diagnosis.
Montero 1971	Allocation: "double‐blind".   Participants: people with paranoid schizophrenia.   Interventions: thioridazine versus trifluoperazine plus chlorpromazine.
Morton 1968	Allocation: randomised ‐ withdrawal study.
Moyano 1975	Allocation: unclear, double‐blind.   Participants: people with schizophrenia.   Interventions: trifluoperazine versus loxapine succinate.
Oybir 1962	Allocation: not randomised.
Pecknold 1977	Allocation: randomised   Participants: people with schizophrenia.   Interventions: clomacran versus trifluoperazine.   Outcomes: 50% left the study.
Polvan 1971	Allocation: not randomised.
Rudy 1958	Allocation: not randomised.
Schiele 1963	Allocation: randomised.   Participants: people with schizophrenia.   Interventions: trifluoperazine plus tranilcipromine versus trifluoperazine plus placebo.   Outcomes: no data reported for the individual drugs.
Sharpley 1964	Allocation: "double‐blind study".   Interventions: pargyline plus tranylcypromine versus pargyline plus tranylcypromine plus trifluoperazine.
Stanley 1961	Allocation: not randomised, case control study.
Talbot 1964	Allocation: unclear.   Participants: people with schizophrenia.   Interventions: trifluoperazine plus chlorpromazine versus placebo.
Teja 1975	Allocation: randomised.   Participants: people with schizophrenia.   Interventions: trifluoperazine versus chlorpromazine versus thiothixene versus haloperidol versus placebo.   Outcomes: no usable data.
Tetreault 1968	Allocation: randomised.   Participants: people with chronic mental disease.   Interventions: trial 1 ‐ trifluperidol versus trifluoperazine, trial 2 ‐ TPS‐23 versus chlorpromazine versus placebo.   Outcomes: no data available.
Tolan 1959	Allocation: not randomised.
Uddyback 1962	Allocation: not randomised, case series.
Vogt 1961	Allocation: not randomised
Weckowicz 1960	Allocation: not randomised.
Weston 1961	Allocation: randomised.   Participants: people with schizophrenia.   Interventions: trifluoperazine versus placebo.   Outcomes: no data available.
Wilson 1961	Allocation: unclear, "Latin square", crossover design.   Participants: people with schizophrenia.   Interventions: chlorpromazine versus prochlorperazine versus trifluoperazine versus placebo.   Outcomes: no data available.
Winnik 1962	Allocation: not randomised.