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Pimozide for schizophrenia or related psychoses

  1. Meghana Mothi1,*,
  2. Stephanie Sampson2

Editorial Group: Cochrane Schizophrenia Group

Published Online: 5 NOV 2013

Assessed as up-to-date: 17 MAY 2007

DOI: 10.1002/14651858.CD001949.pub3


How to Cite

Mothi M, Sampson S. Pimozide for schizophrenia or related psychoses. Cochrane Database of Systematic Reviews 2013, Issue 11. Art. No.: CD001949. DOI: 10.1002/14651858.CD001949.pub3.

Author Information

  1. 1

    Newsam Centre, Seacroft Hospital, General Adult Psychiatry, Leeds, UK

  2. 2

    The University of Nottingham, Cochrane Schizophrenia Group, Nottingham, UK

*Meghana Mothi, General Adult Psychiatry, Newsam Centre, Seacroft Hospital, Leeds and York NHS Foundation Trust, York Road, Leeds, LS14 6WB, UK. m.mothi@nhs.net.

Publication History

  1. Publication Status: New search for studies and content updated (conclusions changed)
  2. Published Online: 5 NOV 2013

SEARCH

 
Characteristics of included studies [ordered by study ID]
Abuzzahab 1980*

MethodsAllocation: not described.
Blinding: double.
Duration: 3 years.
Setting: outpatient.

Design: parallel.


ParticipantsDiagnosis: chronic schizophrenia.

N = 62.

Age: range 19-64 years; mean ˜ 31.5 years.

Sex: 20M, 40F.

Ethnicity: not stated.

History: at least two previous hospitalisations.

Included: not stated.

Excluded: significant medical disease; severely regressed; organic brain involvement; those who required heavy sedation or chemical restraint; pregnancy; people taking oral contraceptives.

Consent: not stated.


Interventions1. Pimozide: dose range 2-20 mg/d, mean dose 5.5 mg/d, n = 31. 2. Fluphenazine: dose range 3-30 mg/d, mean dose 12.7 mg/d, n = 31.


OutcomesLeaving the study early: up to 15 months.

Unable to use -
Leaving the study early: data not given by treatment group.

Mental state: BPRS: no standard deviation.

Global state: CGI: no data reported.

Social functioning: Katz Adjustment Scale (Katz 1963): no data reported.

Symptoms: TESS: no data reported.
Adverse effects: side effects including insomnia; drowsiness; Parkinson-like effects; autonomic nervous system effects; miscellaneous effects (headache, dizziness, other): unclear denominator.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskDouble blind: no description of randomisation.

Allocation concealment (selection bias)Unclear riskNo description of allocation concealment.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind: no further details.

Incomplete outcome data (attrition bias)
All outcomes
High riskFollow-up: 24%, quote: 'fifteen patients continued treatment for the full three years. During the first year of treatment, 22 patients left and 29 left during the third year of treatment. Six patients terminated during the second year' (p548). Ultimate numbers of people leaving the study early and reasons are not explained.

Selective reporting (reporting bias)High riskNo data reported for CGI; Katz Adjustment Scale. Overall reporting was poor, with no SD provided for continuous-scale data and use of unclear denominators.

Other biasUnclear riskFunding: supported in part by Grant MYP 5106, USPHS (B.C. Schiele, M.D.), and by the Psychopharmacology Fund, Minneapolis, Minnesota (USA).

Rating scales: raters were not stated to be independent of treatment, quote: ‘…the same psychiatrist evaluated patients in pretreatment, weekly during the first month, monthly during the first year, and at 3-month intervals during the second and third years’ (p72).

Amin 1977

MethodsAllocation: random.
Blinding: double.
Duration: 16 weeks.

Setting: outpatient.

Design: parallel.


ParticipantsDiagnosis: schizophrenia.

N = 20.

Age: range 20-63 years; mean ˜ 38.6 years.

Sex: 6M, 14F.

Ethnicity: not stated.

History: Before the study, each participant had been receiving neuroleptic medication and was stabilised on a constant daily dosage during the last two weeks, for at least four weeks*.

Included: illness duration ≥ 2 years.

Excluded: not stated.

Consent: not stated.


Interventions1. Pimozide: dose range 2-12 mg (frequency not reported), n = 10.

2. Trifluoperazine: dose range 5-30 mg (frequency not reported), n = 10.

Flexible dosage schedule over a 16-week period*.


OutcomesGlobal state: no improvement (measured using the CGI)**.

Global state: relapse (undefined).
Adverse effects: anticholinergic effects (blurred vision; dry mouth); central nervous system effects (drowsiness; faintness; headache; insomnia); extrapyramidal side effects (akathisia; dystonia; increased salivation; stiffness; tardive dyskinesia; tremor).
Leaving the study early: because of relapse; because of adverse effects; any reason.

Unable to use -
Mental state: BPRS (no totals or SD).


Notes*The pre-study neuroleptic medication was gradually reduced and discontinued in all 20 participants within the first 28 days of the clinical trial.

**Global state data given as LOCF.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomised: no further details.

Allocation concealment (selection bias)Unclear riskRandomly assigned: no further details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind: no further details.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskFollow-up: 100% (LOCF), 75% completed the study, pimozide: n = 2 did not complete the trial. Quote: 'one was discontinued after 28 days due to severe amenorrhoea, insomnia and tremor, and the second participant was discontinued after 56 days for administrative reasons'; trifluoperazine: n = 3 did not complete the trial: quote: 'one patient was discontinued after 28 days because of clinical deterioration, and the other two participants were discontinued after 84 days for administrative reasons' (p16). It is not clear whether these were included in the analysis.

Selective reporting (reporting bias)Unclear riskNo continuous data provided for the BPRS. Quote: 'one patient was not rated on the CGI', no further description (p16).

Other biasUnclear riskFunding: not stated.

Rating scales: raters were not stated to be independent of treatment.

Andersen 1972

MethodsAllocation: not described.
Blinding: double.
Duration: 3 months.

Setting: inpatient.

Design: parallel.


ParticipantsDiagnosis: schizophrenia or paranoid syndrome.

N = 40.

Age: range 21-65 years.

Sex: 20M, 20F.

Ethnicity: not stated.

History: not stated.

Included: hospitalised patients of both sexes between ages of 21 and 65 and suffering from schizophrenia or paranoid syndromes.

Excluded: hospitalisation for 10 consecutive years or longer; gross neurological or somatic disorders unrelated to the main condition; history of alcoholism/drug addiction; history of clear-cut depressive episodes (eliminating schizoaffective disorder); episodes of violence during hospitalisation.

Consent: not stated.


Interventions1. Pimozide: dose range 3-14 mg/d, mean dose 3.92 mg/d, n = 20. 2. Trifluoperazine: dose range 3-12 mg bid, mean dose 4.34 mg bid, n = 20.


OutcomesGlobal state: relapse (undefined).

Adverse effects: extrapyramidal adverse effects (use of antiparkinsonian drugs).
Leaving the study early: any reason.

Unable to use -
Behaviour: Wing Behaviour Scale (Wing 1974) ('P' value only).

Activity of Daily Life scale ('P' value only).
Mental state: S-scale (modified scale with 'P' value only).
Adverse effects: validity unknown.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskNo description of randomisation.

Allocation concealment (selection bias)Unclear riskNo description of allocation concealment.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind: trifluoperazine was administered twice a day and pimozide was administered once a day; therefore dummy tablets were used to preserve double-blind conditions.

Incomplete outcome data (attrition bias)
All outcomes
Low riskFollow-up: 90%, n = 2 (one from each group) withdrew from the study after 3 weeks because of 'deterioration with psychomotor excitation' (p3). They were excluded from final results, which present data for n = 38 (n = 19 in each treatment group).

Selective reporting (reporting bias)High riskNo standard deviations reported with continuous data.

Other biasUnclear riskFunding: supported in part by a grant from LEO Research Foundation, Helsingborg: grant no. 70.039.

Rating scales: raters were independent of treatment: quote: They 'were not members of the hospital staff and had no contact with patients except in connection with the ratings [and were] unaware which drug the patient was receiving and knew nothing about the patients' behaviour in the wards' (p3).

Anumonye 1976

MethodsAllocation: random.
Blinding: single.
Duration: 4 weeks (pimozide group followed for 12 months for long-term side effects).

Setting: initially hospitalised, but could move to community, admitted to Lagos State Psychiatric Hospital, Yaba, Lagos or Psychiatric Unit Lagos University Teaching Hospital, Nigeria.

Design: parallel.


ParticipantsDiagnosis: chronic schizophrenia.

N = 24.

Age: range 16-45 years.

Sex: 16M, 8F.

Ethnicity: Nigerian.

History: not stated.

Included: chronic illness, unsociable, aggressive or impulsive behaviour, frequent hospitalisation (hospitalisation between 2 and 3 years).

Excluded: not stated.

Consent: not stated.


Interventions1. Pimozide: dose range 1-4 mg/d, n = 12.
2. Chlorpromazine: dose range 300-600 mg/d, n = 12.


OutcomesMental state: no improvement (measured using the BPRS, including participants rated as having achieved 'absent' improvement).
Leaving the study early: because of adverse effects; for any reason.

Unable to use -

Mental state: BPRS ('P' values only).
Adverse effects: only 6 and 12 month data for pimozide reported.


NotesBefore commencement of the study, participants with chronic schizophrenia were under conventional neuroleptic maintenance therapy, receiving either haloperidol or chlorpromazine. These were withdrawn for one week before pimozide was introduced as a single daily dose. Study drugs were administered according to a flexible dosing regimen. No other medication was permitted apart from 'bed time sedatives' (p19).


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomised: participants were 'matched for age and duration of illness' and were randomly assigned (p19), no further details provided.

Allocation concealment (selection bias)Unclear riskNo description of allocation concealment.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskSingle blind: participants were blinded to the intervention. Quote: 'the attending physician knew only that the patient was given either chlorpromazine or pimozide, which had been pre-packaged for each patient', and 'drugs were administered separately by a single-blind procedure' (p19). Whether blinding has been successful has not been tested.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskFollow-up: (after the 4-week comparison of chlorpromazine vs placebo), all 24 participants completed the initial 4-week course on admission. On discharge, 4 participants on pimozide and 2 on chlorpromazine did not return to the clinic. Details of attrition are not clear. However it is clear that none of the participants discontinued the trial because of adverse effects. Late clinical global assessment and side effects (at 6 and 12 months) are reported for only 8 participants on pimozide who continued with follow-up.

Selective reporting (reporting bias)High riskStatistical reporting was incomplete. No adverse effects were presented for participants taking chlorpromazine.

Other biasUnclear riskFunding: not stated.

Rating scales: completed by an independent psychologist.

Barnes 1983

MethodsAllocation: random.
Blinding: double (double dummy design).
Duration: 1 year.

Setting: outpatient, community: Community Nurses' Clinic, South London (London Borough of Southwark), UK.

Design: parallel.


ParticipantsDiagnosis: chronic schizophrenia (PSE).

N = 36.

Age: mean ˜ 49 years.

Sex: 18M, 18F.

Ethnicity: not stated.

History: not stated.

Included: outpatients regularly receiving depot fluphenazine decanoate in the catchment area (London Borough of Southwark).

Excluded: doubt as to diagnosis of schizophrenia; unwilling to enter trial; receiving regular depot fluphenazine for less than six months; severe physical illness; if equivalent pimozide dose was calculated to be more than 20 mg/d.

Consent: informed consent required from participants (unpublished data).


Interventions1. Pimozide: + placebo injection, mean dose 5.3 mg/d, n = 17.
2. Fluphenazine: decanoate injection, mean dose 8.2 mg/wk + placebo tablet, n = 19.


OutcomesGlobal state: relapse (undefined).

Leaving the study early: any reason.

Social functioning: Social Behaviour Assessment Schedule (SBAS, skewed).


NotesThose allocated to the fluphenazine group continued to receive their dose unchanged but were given additional placebo tablets, and those who were allocated pimozide received additional placebo injections.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomised: participants were matched on the basis of age, sex and weekly fluphenazine dose; assigned by independent statistician.

Allocation concealment (selection bias)Low riskAllocation by an independent statistician. (unpublished data) **contact with trial author stated that an independent statistician randomly allocated participants using a series of selected envelopes, when all participants gave their consent for inclusion in the study, the envelopes were opened and participants were randomly allocated accordingly.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind: double dummy design, assessor blind (unpublished data). Those allocated to the fluphenazine group continued to receive their dose unchanged but were given additional placebo tablets, and those who were allocated pimozide received additional placebo injections (p194).

Incomplete outcome data (attrition bias)
All outcomes
Low riskFollow-up: 100% (LOCF), data on number of people leaving the trial early have been indicated and accounted for. SBAS assessments were completed for all participants except one at the endpoint assessment, as the participant was abroad from the time of relapse until the end of the trial. 1-Year follow-up of all participants who had begun the trial, including all withdrawals, early leavers and relapsed participants who were involved in the analysis (p195).

Selective reporting (reporting bias)Unclear riskNone detected.

Other biasUnclear riskFunding: not stated.

Rating scales: raters were not stated to be independent of treatment.

Chouinard 1970

MethodsAllocation: random.
Blinding: double.
Duration: 12 weeks.

Setting: inpatient, Douglas Hospital, Quebec, CA.

Design: parallel.


ParticipantsDiagnosis: chronic schizophrenia.

N = 20.

Age: range 26-56 years; mean ˜ 45 years.

Sex: 8M 12F.

Ethnicty: not stated.

History: all hospitalised for at least two years (except one participant who was hospitalised for one year); mean length of hospitalisation 14.07 years.

Included: chronic illness, < 16 on Verdun Target Symptom Rating Scale (VTSRS).

Excluded: physical illness; previous treatment with fluphenazine.

Consent: not stated.


InterventionsAfter a two-week drug-free interval:

1. Pimozide: + placebo, max dose 10 mg/d, n = 10. 2. Fluphenazine: max dose 15 mg/d, n = 10.

Drugs were administered on a fixed dosage schedule.*


OutcomesGlobal state: relapse (undefined).
Adverse effects: drowsiness; excitement; rigidity; tremor; dystonia; akathisia; diarrhoea; nausea and vomiting; incontinence of faeces; hypotension; orthostatic hypotension; granulocytopenia; granular casts; albumin; dizziness and weakness; weight loss; acne vulgaris. Leaving the study early.

Unable to use -

Mental state: BPRS ('P' values only, no SD), Verdun Target Symptom Rating Scale ('P' values only, no SD).


Notes*According to the schedule, two capsules were administered daily, one in the morning and one in the evening. This was gradually increased to a maximum of 10 capsules a day (five in the morning and five in the evening) by the 5th week and participants were maintained on this dose until the end of the 12th week.

**Participants in the fluphenazine group received their total amount of medication in two divided doses, whereas pimozide participants were given the total daily dosage of medication in the morning and were given an inactive identical-looking placebo in the evening (p599).


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomised: no further details.

Allocation concealment (selection bias)Unclear risk'Randomly assigned' (p599): no further details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind: Quote, 'drugs were supplied in identical capsules' (p599). Not clear as to who was blinded. Not tested if blinding was successful.

Incomplete outcome data (attrition bias)
All outcomes
Low riskFollow-up: 100% (LOCF). Quote: 'one male patient treated with pimozide was discontinued the study after 54 days of drug treatment due to severely disorganised psychotic behaviour which could not be controlled by intramuscular chlorpromazine administration' (p600).

Selective reporting (reporting bias)Unclear riskNurses Observation Scale for Inpatient Evaluation (NOSIE) stated as used, but no data were reported.

Other biasHigh risk*Rapid deterioration in six participants after the initial wash-out period required an increase in dosage above the level planned for in the protocol.

Funding: study supported by the Public Health Service Research Grant MH-05202-09 from the US Department of Health, Education and Welfare, Washington, DC (USA). Drugs used were provided by McNeil Laboratories Inc, Fort Washington, Pennsylvania (USA) and were supplied through McNeil Laboratories, Don Mills, Ontario (CA).

Rating scales: raters not stated to be independent of treatment.

Chouinard 1982

MethodsAllocation: random.
Blinding: double.
Duration: 4 weeks.

Setting: inpatient, admitted through the emergency room of Hôpital Louis-H. Lafontaine, Montréal (CA).

Design: parallel.


ParticipantsDiagnosis: schizophrenia (RDC).

N = 40.

Age: range 20-64 years (pimozide age range = 23-64, median = 36; chlorpromazine age range = 20-54, median = 33).

Sex: 26M, 14F; pimozide M/F=13/7; chlorpromazine M/F=13/7.

Ethnicity: not stated.

History: n = 24 exhibited paranoid schizophrenia, and n = 26 were non-paranoid (Tsuang and Winokur (1974) criteria). None of the participants had received long-acting neuroleptic drugs for at least two weeks before the study.

Included: aged between 18 and 65 years; primary hospital diagnosis of schizophrenia confirmed by the research psychiatrist on the basis of the Research Diagnostic Criteria (RDC); two or more of the target symptoms listed in NIMH Psychopharmacology Service Centre collaborative study of acute schizophrenia must be present.

Excluded: physical illness; childhood onset; chronic or acute brain syndrome; alcoholism or drug addiction; epilepsy; IQ < 70.

Consent: all participants/relatives/guardians required to give written informed consent.


Interventions1. Pimozide: dose range 10-70 mg/d, mean dose 30 mg/d, n = 20.
2. Chlorpromazine: dose range 300-1500 mg/d, mean dose 832 mg/d, n = 20.

Dose adjusted according to response. Procyclidine HCI was the only antiparkinsonian medication administered during the trial, and was done so once significant Parkinson-like symptoms appeared.


OutcomesMental state: use of additional medication*.

Adverse effects: constipation; sedation; dizziness; headache. Leaving the study early: any reason.

Unable to use -
Adverse effects: extrapyramidal adverse effects (numbers requiring antiparkinsonian drugs - data not reported for individual participants but as a weekly total).

Mental state: BPRS ('P' values only, no SD).

Global state: CGI ('P' value only, no SD).


Notes*PRN medication was permitted for acute agitation, participants received supplementary doses of the drug they were receiving in the trial. Pimozide PRN 5-490 mg/wk; chlorpromazine PRN 150-450 mg/wk.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomised: no further details.

Allocation concealment (selection bias)Unclear risk'Randomly assigned' (p13), no further details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind: pimozide and chlorpromazine were administered in 'identical capsules under double-blind conditions' (p14). Pimozide was given once in the morning, and chlorpromazine was administered on an equally divided regimen to aid blinding, participants receiving pimozide were given a placebo tablet at night. Participants who required additional medication received doses under double-blind conditions. No further details related to success of blinding methods.

Incomplete outcome data (attrition bias)
All outcomes
Low riskFollow-up, 100%. All participants completed the 4-week trial.

Selective reporting (reporting bias)High riskStatistical reporting was incomplete (no SDs). Treatment Emergent Symptom Form and Extrapyramidal Symptom Rating Scale stated as used, but no data were reported; results from laboratory tests not reported.

Other biasUnclear riskFunding: not stated.

Rating scales: raters not stated to be independent of treatment.

Claghorn 1974

MethodsAllocation: random.
Blinding: double.
Duration: 6 months (preceded by 2 week stabilisation period on standard antipsychotic).

Setting: outpatient clinic, Texas Research Institute of Mental Sciences in Houston, Texas (USA).

Design: parallel.


ParticipantsDiagnosis: chronic schizophrenia.

N = 87.

Age: range 21-65 years; mean age: pimozide = 40.1 (range 24–65); trifluoperazine = 44.9 (range 22–65).

Sex: 23M, 64F (pimozide 16M:27F; trifluoperazine 7M:37F).

Ethnicity: not stated.

History: diagnosis of schizophrenia of at least two years, or hospitalised at least once for the disorder.

Included: > 2 years' illness, hospitalised at least once.

Excluded: not stated.

Consent: not stated.


Interventions1. Pimozide: mean dose 5.16 mg/d, n = 43.
2. Trifluoperazine: mean dose 12.53 mg/d, n = 44.*


OutcomesAdverse effects: insomnia; drowsiness; sedation; Parkinsonism; restlessness; tremor; akathisia; rigidity; stiffness; involuntary movements; blurred vision; jittery; dizziness; nervousness; nausea; vomiting; stomach cramps; lack of appetite; headache; dysuria; nocturia; dry mouth; rash; itching; increased weight; decreased weight; hypotension.

Unable to use -
Global state: CGI ('P' value only, no SDs). Mental state: BPRS (to measure therapeutic efficacy) ('P' value only, no SDs).
Social functioning: Evaluation of Social Functioning Form ('P' value only, no SDs).


Notes*Dose increased by fixed regimen. Antiparkinsonian medication was permitted (chloral hydrate).


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomised: no further details.

Allocation concealment (selection bias)Unclear risk'Random assignment' (p1006), no further details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind: Medication was supplied in identical appearing capsules (p1006): no further details.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskFollow-up, unclear: no details provided.

Selective reporting (reporting bias)High riskStatistical reporting was incomplete for all scale data (no SDs).

Other biasUnclear riskFunding: not stated.

Rating scales: not stated to be independent of treatment.

Clark 1975*

MethodsAllocation: random.
Blinding: double.
Duration: 6 months.

Setting: outpatient, Mental Health Centre, Norman, Oklahoma (USA).

Design: parallel.


ParticipantsDiagnosis: schizophrenia (n = 32 undifferentiated; n = 7 paranoid; n = 1 schizoaffective).

N = 40.

Age: range 24-60 years.

Sex: all female.

Ethnicity: n = 32 White; n = 8 Black.

History: in good physical health; maintained on medication in an outpatient status for at least 3 months; schizophrenia present for at least two years.

Included: schizophrenia for at least 2 years; outpatient status of at least 3 months; good physical health.

Excluded: quote: 'regressed or mentally retarded patients' (p137); drug addiction/alcoholism; severe depression; pregnancy/imminent chance for pregnancy; unreliability in taking prescribed medication on an outpatient basis; participants requiring additional sedation or extremely high doses of prestudy medication for control of their symptoms; participants who were expected to be 'unresocializable'.

Consent: written permission required from participant and from a responsible family member where 'legally incompetent'.


InterventionsUpon entering study, all previous neuroleptic medication was stopped abruptly and the once-a-day study medication immediately initiated:

1. Pimozide: dose range 2-16 mg, average daily dose 5.5 mg, dose max. 20 mg/d, n = 15.
2. Thioridazine: dose max. 750 mg/d, average daily dose 188.8 mg (range 75-375), n = 15.
3. Placebo: mean 3.3 capsules (range 1-10), n = 10.

Stabalisation period of two weeks: maximum dose allowed 5 capsules per day (10 mg pimozide; 375 mg thioridazine); following stabilisation, dosages adjustments up to 10 capsules a day were permitted (20 mg pimozide; 750 mg thioridazine). Dosage adjustments were also made according to the appearance of toxic symptoms or side effects, concomitant medication was prescribed for Parkinsonism/night-time sedation as necessary.


OutcomesGlobal state: no improvement (defined as 'treatment failures' (p138)).

Mental state: adverse effects: tremor; rigidity; akathisia; sedation/lethargy; faint/dizzy/weak; nausea; diarrhoea; dermatitis; dry mouth; blurred vision; nasal congestion; constipation; restlessness/excitement; insomnia; tension/anxiety; depression; thinking/memory defects; abnormal laboratory data (haematology; liver); weight loss; weight gain; anorgasmia; headache; dystonic symptoms; chest pain; lactation; substernal pain. Leaving the study early.

Unable to use -
Mental state: BPRS (no SD).
Global state: CGI (no SD).
Social functioning: Family Rating Form, Patient Rating Form of Social Adjustment Scale, modification of Katz-Lyerly scale ('Pp' values only, no SD).


Notes*Quote: 'initiation of treatment was staggered, beginning one group of 8 at a time, in order to facilitate measurements. An attempt to balance each group for age, duration of illness, and time since last hospitalisation was made' (p137). A sufficient number of capsules were prescribed to each participant at each visit to maintain them until the time of the next visit. Participants were instructed to take the total daily dose as a single morning administration before breakfast.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomised: Quote, 'patients were allocated to treatment in random fashion in blocks of 8 with 3 allocated to pimozide, 3 to thioridazine and 2 to placebo' (p137).

Allocation concealment (selection bias)Low riskRandomly allocated: Quote, 'patients were allocated to treatment in random fashion in blocks of 8' (p137).

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind: Quote: 'each patient received medication from her own individual stock bottle labelled with her name only, and the double blind technique was followed throughout. All medication was prepared in identically-appearing capsules' (p137).

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskFollow-up: 60%. All participants terminating before two weeks were dropped from the study, 3 participants in pimozide group and 1 each in thioridazine and placebo groups left the study in less than 2 weeks. Of the remaining 35 participants, only 24 completed the full 24 weeks. Of the 11 who completed more than 2 weeks but less than 24 weeks of the study, n = 2 each in pimozide and thioridazine group and n = 5 in placebo group were withdrawn as treatment failures; n = 1 in placebo was found to have glaucoma; n = 1 in thioridazine developed an intercurrent medical complication not related to drug therapy.

Selective reporting (reporting bias)High riskStatistical reporting was incomplete for all scale data (no SDs).

Other biasHigh riskFunding: funded in part by U.S.P.H.S Grants MH 11666 and MH 21408, and a grant-in-aid from McNeil Laboratories, Inc. (George H. Stevens M.D.).

Rating scales: research nurse and project psychiatrist not stated to be independent to the study.

De Ronchi 1996

MethodsAllocation: random.
Blinding: single.
Duration: 60 days.

Setting: inpatient, institute of Psychiatry, University of Bologna, Italy.

Design: parallel.


ParticipantsDiagnosis: schizophrenia (n = 8 residual type; n = 3 disorganised type; n = 2 undifferentiated; n = 7 paranoiac, DSM-III).

N = 20.

Age: range 19-59 years; mean 34.7 ± 10.27 = 3 years (levosulpiride: range 19-43 years, mean 30.8 ± 6.92 years; pimozide: range 19-59 years, mean 39.3 ± 11.16 years).

Sex: 8M, 12F (Levosulpiride 4M, 6F; pimozide 4M, 6F).

Ethnicity: not stated.

History: age of onset levosulpiride group: mean 25.5 ± 4.3 years (range 18-34 years); pimozide group: mean 22.6 ± 4.25 years (range 16-30 years). Previous treatment, n = 7 in the levosulpiride group and n = 9 in the pimozide group had previously received haloperidol; n = 1 in the levosulpiride group had previously received levomepromazine; n = 1 in the pimozide group had previously received pimozide; n = 7 in the levosulpiride group and n = 9 in the pimozide group had previously received orphenadrine; and n = 3 in the levosulpiride group had previously received benzodiazepines.

Included: diagnosis of schizophrenia; predominant negative symptoms (based on assessments using SAPS and SANS); stabilisation on haloperidol at 2 mg/d (however, n = 3 receiving levosulpiride and n = 1 receiving pimozide with recent-onset schizophrenia were admitted to the study without previous treatment with haloperidol).

Excluded: relevant medical problems; drug and alcohol addiction; severe neurological disease; psychomotor agitation; hypersensitivity to study drugs; heart disease involving arrhythmias and an increase in Q-T interval.

Consent: verbal informed consent obtained from all participants, trial accepted by the ethics committee of the University of Bologna.


Interventions1. Pimozide: oral, 4 mg/d (one tablet in the morning) + haloperidol 2 mg/d, n = 10.

2. Levosulpiride: oral, 200 mg/d (100 mg tablets divided into two doses, in the morning and in the evening) + haloperidol 2 mg/d, n = 10.*


OutcomesGlobal state: average endpoint score (CGI-I and CGI-S, skew); no improvement (assessed using the CGI).

Mental state: average endpoint score (SAPS, skewed) average endpoint score (SANS).

Adverse effects: constipation; mammary tension; average endpoint score (EPS; autonomic effects; endocrine system effects; amenorrhoea; akathisia; weight gain; headache; galactorrhoea; insomnia; hypotension; nausea; weight loss; akinesia; rigidity; drowsiness; constipation; tachycardia; tremor; dizziness; blurred vision; dry mouth; gynecomastia) (mean ± SD, skewed).

Leaving study early: any reason; due to adverse effects.

Unable to use -

Clinical and laboratory variables (no usable data).


Notes*Primary outcome of this study was to compare the therapeutic activity of levosulpiride at low doses with pimozide in schizophrenic participants whose negative symptoms were not relieved by haloperidol. The only other medications that were permitted included anticholinergenic drugs or benzodiazepines. This included, in the levosulpiride group: n = 7 concomitantly receiving orphenadrine and n = 3 concomitantly receiving flurazepam; and in the pimozide group: n = 9 concomitantly receiving orphenadrine.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomised: no further details.

Allocation concealment (selection bias)Unclear riskNot described.

Blinding (performance bias and detection bias)
All outcomes
High riskSingle blind (participant).

Incomplete outcome data (attrition bias)
All outcomes
Low riskFollow-up: 100% (LOCF). n = 1 participant treated with 300 mg/d levosulpiride alone dropped out after 15 days because of menstrual delay, mammary tension, galactorrhoea, tachycardia and tremors.

Selective reporting (reporting bias)Unclear riskNone detected.

Other biasUnclear riskFunding: test drugs supplied by Ravizza Farmaceutici, Milan, Italy.

Rating scales: raters not stated to be independent of treatment.

Denijs 1973

MethodsAllocation: random.
Blinding: double.
Duration: 6 months, preceded by 3-week withdrawal, 2-month pimozide dose optimisation phase.

Setting: inpatient, Sancta Maria Hospital, The Netherlands.

Design: parallel.


ParticipantsDiagnosis: schizophrenia (DSM-II).

N = 40.

Age: range 26-80 years; mean ˜ 59 years.

Sex: all female.

Ethnicity: not stated.

History: phase 1: lasting three weeks, all original participants (n = 74); neuroleptics were gradually replaced with pimozide tablets. These were given once daily as 1 mg tablets (Orap): quote: 'the optimal individual daily dose was determined by according to the clinical benefit and possible side-effects' (p50). Phase 2: lasting two months, the efficacy of pimozide as a maintenance therapy was assessed and the daily dose further individually adapted. No other neuroleptics were permitted, participants who could not be effectively treated with pimozide alone were removed from the trial and were classified as therapy failures. Median inpatient stay of 24 years (range 1-43 years).

Included: participants successfully maintained on pimozide.

Excluded: participants who could not be treated efficiently with pimozide alone (therapy failures); participants who had shown aggressiveness in the previous month (during ‘phase 2’).

Consent: not stated.


Interventions1. Pimozide: mean dose 7.72 ± 2.64 mg/d, n = 20.
2. Placebo: n = 20.

If deterioration were noted, a higher dose of the double-blind treatment was initially instituted; on further deterioration, the double-blind medication was continued unchanged, but haloperidol (Serenase) was additionally given on an individually adapted dosage (median dose 4.5 mg; range 0-25 mg).


OutcomesGlobal state: relapse (increase in psychotic symptoms).

Mental state: use of additional medication (haloperidol).
Adverse effects: death.
Leaving the study early: any reason.

Unable to use -
Mental state score: OFCRS (no usable data).
Adverse effects: Scale Two Rating (a modified scale; 'P' values only).
Ward bearing and behaviour: OFCRS (no usable data).


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomised: participants were, Quote: 'randomly divided between two groups' (p50).

Allocation concealment (selection bias)Unclear risk'Randomly divided' (p50), no further details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind: phase 3 was conducted under 'strict double-blind conditions' (p50). Pimozide and placebo tablets were identical in appearance; were packed in quantities sufficient for at least six months. Quote: 'for the double blind phase[phase 3]... patients were selected on basis of their favourable response to pimozide during the open phase [phase 1]' (p50).

Incomplete outcome data (attrition bias)
All outcomes
Low riskFollow-up: 100% (LOCF). 38 of 40 participants completed the six-month double-blind trial. Two participants withdrawn from the study, who had completed four months of the trial before dropping, were accounted for and included in the final evaluation of results. One participant receiving pimozide was withdrawn because of illness and died a few days later, toxic-infectious shock was determined as the cause of death: quote 'no phenomena suggestive of drug-related death were found' (p55). The other participant, receiving placebo, experienced a considerable increase in psychotic symptoms, refused to take medication and had to be withdrawn from the study.

Selective reporting (reporting bias)High riskStatistical reporting was incomplete for all scale data (no SDs).

Other biasUnclear riskFunding: pimozide provided by Janssen Pharmaceutica (Beerse, Belgium).

Rating scales: raters not stated to be independent of treatment.

Donlon 1977

MethodsAllocation: random.
Blinding: double.
Duration: 1 year.

Setting: outpatient.

Design: parallel.


ParticipantsDiagnosis: schizophrenia.

N = 46.

Age: range 19-54 years; mean ˜ 39.5 years.

Sex: 19M,27F.

Ethnicity: not stated.

History: maintained on various neuroleptics for an average of about 4 years; control of symptoms had been maintained in all participants with a variety of other neuroleptic drugs for at least two weeks before entry into the study.

Included: good physical health; two or more of the following symptoms: conceptual disorganisation, emotional withdrawal, blunted affect, bizarre mannerisms, unusual thought content, hallucinations.

Excluded: evidence of epilepsy; severe depression; severely regressed patients with generally deficient mental and intellectual backgrounds; senile or ‘mentally retarded’ patients (p119); organic brain disease; pregnancy; patients who required heavy sedation or chemical restraint to control symptoms.

Consent: not stated.


Interventions1. Pimozide: mean dose 9.6 mg/d*, max. dose 20 mg, n = 23.
2. Fluphenazine: mean dose 12.5 mg/d*, max. dose 30 mg/d, n = 23.

'Supplemental short-acting neuroleptic medication was permitted for symptoms of decompensation during the transition to study drugs' (p120).

Antiparkinsonian drugs administered only on appearance of marked symptoms; chloral hydrate permitted on a short-term basis for insomnia.


OutcomesLeaving the study early: because of adverse effects; for any reason.

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Global state: CGI ('P' values only).
Mental state: BPRS ('P' values only).
Adverse effects: ('P' values only).
Social functioning: Katz Scale, Social Adjustment Inventory ('P' values only).


Notes*'Each participant assigned 26 bottles, each containing 150 capsules of either pimozide 2.0 mg or fluphenazine 3.0 mg. The initial dose was 1-4 capsules once daily (2.0 to 8.0 mg pimozide; 3.0 mg to 12.0 mg for fluphenazine) depending on the previous neuroleptic medication requirements' (p120). Dose according to response up to maximum.

Participants whose symptoms could not be controlled with the maximum dose of study drugs were considered 'treatment failures' (p120).


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomised: no further details.

Allocation concealment (selection bias)Unclear riskParticipants were, Quote: 'assigned randomly... by a disinterested third party' (p120). No further details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind: no further details.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskFollow-up: 67% with pimozide. n = 3 were uncooperative, n = 2 experienced limiting side effects, n = 2 thought the drug was ineffective and n = 2 were withdrawn for 'personal reasons'; in fluphenazine: n = 1 were uncooperative, n = 1 failed to return, n = 2 experienced limiting side effects, n = 1 thought the drug was ineffective, n = 1 withdrew because they thought that the drug was ineffective, and n = 1 were withdrawn and required amitriptyline.

Selective reporting (reporting bias)High riskStatistical reporting was incomplete for all scale data (no SDs).

Other biasUnclear riskFunding: research supported in part by a grant from McNeil Laboratories Inc., Washington, PA (USA).

Rating scales: not stated to be independent of treatment.

Falloon 1978

MethodsAllocation: random.
Blinding: double.
Duration: 1 year (with a further six-month follow-up period).

Setting: outpatient, community taken from admissions of St. John's Hospital, Stone (UK).

Design: parallel.


ParticipantsDiagnosis: schizophrenia (n = 43 classified as PSE definite and n = 1 probable schizophrenia).

N = 44.

Age: range 17-60 years; mean ˜ 39 years.

Sex: 19M, 25F.

Ethnicity: n = 4 West Indian; n = 1 Indian; n = 1 Chinese; n = 1 German; n = 37 British.

History: n = 31 age of onset < 35 years, n = 13 age of onset > 35 years; n = 13 had been ill for < 1 year, n = 31 had been ill for > 1 year; n = 31 had been hospitalised for less than one year, n = 12 had been hospitalised for longer than one year.

Included: diagnosis of schizophrenia; selected after admission to psychiatric hospital with acute symptoms of schizophrenia.

Excluded: indefinite hospital admission.

Consent: informed consent required.


Interventions1. Pimozide: median dose 8 mg/d, max. 16 mg/d (active pimozide tablets + inert fluphenazine injections), n = 24.
2. Fluphenazine decanoate: median dose 25 mg/2 wk, max. 50 mg/wk (active fluphenazine injections + inert pimozide tablets), n = 20.

3. Placebo, n = 8*.

Flexible drug dosage. Additional neuroleptic medications were prohibited, but minor tranquillisers, sedatives, anti-depressants and antiparkinsonian medication were administered as required. All trial medication was dispensed by a community nurse at a follow-up clinic.


OutcomesGlobal state: relapse (defined as, quote: 'reappearance or exacerbation of schizophrenic symptoms that led to withdrawal from the trial, whether or not it resulted in re-admission to hospital. This decision was made by the supervising clinician', p61).

Service utilisation: hospital admission.
Mental state: any clinically significant response in mental state (presence of first-rank symptoms; depression as assessed on the abbreviated PSE schedule).
Adverse effects: rigidity; akathisia; tremor; gait disturbance; oral dyskinesia; salivation; drowsiness; dry mouth; blurred vision; constipation; hypotension; sedation; urine retention; weight gain; skin disorders; vomiting; headaches.
Leaving the study early: any reason.

Unable to use -

Regularity of medication (not within remit of protocol).
Social impairment: MRC Social Performance Schedule (no global score, no SDs).


Notes*The comparison of pimozide vs placebo was made during a six-month follow-up period, in which all injections (both active and placebo) were withdrawn from a selection of participants who had remained well throughout the previous 12-month period of the trial. All injections from the 12-month trial were withdrawn, and the 20 participants in this group continued to receive tablets from the follow-up clinic under double-blind conditions, n = 12 were on active pimozide, and n = 8 received placebo, all were followed-up for a further 6 months (p61). Participants who received placebo alone had previously been taking fluphenazine decanoate.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomised: 'randomly allocated' (p61) no further details.

Allocation concealment (selection bias)Unclear risk'Randomly allocated': no further details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind: double dummy; Quote, 'in order to preserve double blind conditions, patients were required to take both an injection and a tablet' (p60).

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskFollow-up: 86%; for the 12-month trial period, only data for n = 38 participants for adverse effects. From n = 53 people who consented to enter the trial, quote: 'a few patients were withdrawn at a later stage of the trial because of an unsatisfactory response to treatment... a further group of patients (7%) commenced the trial regime in hospital, but did not continue the medication after the first monthly follow-up; small number refused to continue treatment or relapsed soon after discharge' (p62). Unclear reporting, exact numbers are not made clear.

Selective reporting (reporting bias)High riskStatistical reporting was incomplete for all scale data (no SDs).

Other biasUnclear riskFunding: Janssen Pharmaceutica provided pimozide and placebo tablets; E.R. Squibb and Sons provided the material for the placebo injections (p70). Supported in part by a grant from the Oxford Regional Health Authority (p274).

Rating scales: Clinical and social assessments were made independently by the research clinician and a social worker employing a standardised interview (p61).

Friedman 2011

MethodsAllocation: random.
Blinding: double.
Duration: 12 weeks.

Setting: inpatient and outpatient at Mount Sinai Hospital, Pilgrim Psychiatric Centre, Manhattan Psychiatric Centre, New York (USA).

Design: parallel.


ParticipantsDiagnosis: schizophrenia and schizoaffective disorder (DSM-IV).

N = 53.

Age: pimozide 45.5 years; placebo 44.4 years.

Sex: pimozide 21M; 4F; placebo 20M; 8F.

Ethnicity: pimozide: Asian n = 0; Black n = 13; Hispanic n = 5; White n = 7; placebo: Asian n = 1; Black n = 4; Hispanic n = 6; White n = 17.

History: receiving clozapine, unresponsive to therapy, with a minimum plasma 378 ng/mL for period of 8 weeks before trial.

Included: schizophrenia/schizoaffective disorder, unresponsive to optimum trial of clozapine monotherapy.

Excluded: any other antipsychotic medication (with the exception of benzodiazepine; benztropine; valproic acid); drug/alcohol abuse within 6 months preceding study entry.

Consent: not stated.


Interventions1. Pimozide: mean dose 6.48 mg/d + clozapine mean dose 518.8 mg/d, max. dose 8 mg/d (or to 'desired clinical effect'), n = 25.

2. Placebo: + clozapine mean dose 478.1 mg/d, max. dose 8 mg/d (or to 'desired clinical effect'), n = 28.**


OutcomesLeaving the study early: because of adverse effects.

Adverse effects: abnormal laboratory data (absolute neutrophil count count; plasma glucose level; total cholesterol level; triglyceride level); cardiovascular effects (bigeminy; hypotension); cardiovascular adverse effects average endpoint score (systolic blood pressure; diastolic blood pressure; heart rate; QTc); intensified symptom; extrapyramidal adverse effects: Extrapyramidal Symptom Rating Scale (ESRS, skewed), average change score (Parkinsonism; dyskinesia; dystonia); hypersalivation.

Unable to use -
Mental state: PANSS, average change score (skewed).

Global state: Clinical Global Impression (CGI), average change score (skewed).

Quality of life: Specific Level of Functioning Scale (work skills; social acceptability; interpersonal relationships; physical function; personal care) (SLOF, skewed).


Notes*Last observation carried forward for results.

**No changes to clozapine dose were permitted, nor was the addition of another psychotropic medication permitted (with the exception of benztropine), for the study duration.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomised: in a 1:1 fashion (p1290).

Allocation concealment (selection bias)Unclear riskNot described.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind: physician blinded (p1290) not tested whether successful.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskFollow-up: 100% (LOCF). 85% of participants completed the study, n = 1 randomly assigned to pimozide withdrew early because of severe EPS, and n = 2 withdrew because of severe adverse events deemed unrelated to the study medication. In total n = 5 randomly assigned to placebo withdrew early (n = 2 because of intensified positive symptoms; n = 1 because of an episode of bigeminy; n = 1 because of hypotension, and n = 1 after withdrawal of consent).

Selective reporting (reporting bias)Unclear riskMention of specific adverse effects was made (hypersalivation), and it was stated that other side effects showed no significant difference; however, none were reported (p1292).

Other biasHigh riskFunding: supported by NIMH, Grant MH0678060182. Jean-Pierre Lindenmayer, Frances Alcantra, Parak Mohan, Adel Iskander, David Adler, Philip Harvey and Kenneth Davis’ wife have all received grant support from various pharmaceutical companies, including Johnson & Johnson; Eli Lilly and Company; Pfizer; AstraZeneca; Otsuka; Dainippon-Sumitomo; Merck and Shire Pharmaceuticals. Jean-Pierre Lindenmayer has served as a consultant to Eli Lilly; Johnson and Johnson; Merck and Shire Pharmaceuticals. Philip Harvey has served as a consultant to Eli Lilly; Johnson & Johnson; Merck; Shire Pharmaceuticals and Dainippon-Sumitomo America. David Adler has received speaker honoraria from Eli Lilly and Company (p1294).

Rating scales: ESRS ratings were carried out by different personnel from those performing the PANSS and functional competence ratings.

Gowardman 1973

MethodsAllocation: random.
Blinding: double.
Duration: 3 months.

Setting: inpatient.

Design: parallel.


ParticipantsDiagnosis: paranoid schizophrenia (n = 15); catatonic (n = 1); hebephrenic (n = 3); schizoaffective psychosis (n = 1).

N = 20.

Age: range 28-72; mean ˜ 49 years.

Sex: all male.

Ethnicity: 'all European except one' (p487).

History: n = 1 had a prefrontal leucotomy; n = 1 had well-compensated rheumatic heart disease; n = 1 was catatonic and had not spoken for 20 years.

Included: physically healthy; severe positive symptoms; disturbed affect and social behaviour.

Excluded: not stated.

Consent: not stated.


Interventions1. Pimozide: oral, mean dose 5.1 mg, max. dose 6 mg/d, received in the morning with matched placebo in the evening, n = 10.
2. Haloperidol: oral, mean dose 10.15 mg, max. dose 14 mg/d, received in the morning and evening, n = 10.

No other medication was prescribed; however, drugs taken to control extrapyramidal symptoms were permitted.


OutcomesGlobal state: no improvement (global evaluation, which included all aspects of behaviour in the two groups, rated as 'poor' or 'worse').

Mental state: no improvement in psychomotor activity (any clinically significant response).

Adverse effects: laboratory studies: white blood cells (leukocytosis); red blood cells (macrocytosis).

Leaving the study early: any reason.

Unable to use -
Mental state: withdrawal; thinking disorientation; paranoid belligerence and agitated depression (unpublished scale).
Adverse effects: side effects; EPS (no usable data).


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomised: 'randomly allotted by the hospital pharmacist' (p487); no further details.

Allocation concealment (selection bias)Low risk'Randomly allotted': allocation by the hospital pharmacist, suggesting adequate separation of allocation and treatment.

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind: Quote, 'investigators did not know who was receiving which drug. The drugs were supplied in identical capsules' (p487). To ensure participant blinding, those receiving pimozide were given the active medication in the morning and a matched placebo in the evening, and participants receiving haloperidol were given the active medication in both the morning and the evening, the capsules were indistinguishable in outward appearance (p488).

Incomplete outcome data (attrition bias)
All outcomes
Low riskFollow-up: 100%, 'all patients completed the trial period of three months' (p488).

Selective reporting (reporting bias)High riskAdverse effects were mentioned (including dystonic reactions and Parkinsonism); however, neither specific side effects nor group numbers were reported.

Other biasUnclear riskFunding: not stated.

Rating scales: not stated.

Gross 1974*

MethodsAllocation: random.
Blinding: double.
Duration: 16 weeks.

Setting: inpatient, residents of Harbor View House, USA, a rehabilitative 'half-way house', offering 24-hour supervision.

Design: parallel.


ParticipantsDiagnosis: schizophrenia.

N = 61.

Age: pimozide: mean = 44.8, range 21-66 years; trifluoperazine: mean = 47.5, range 20-67 years; placebo: mean = 44.8, range 24-64 years.

Sex: 37M, 24F (pimozide: 11M, 10F; trifluoperazine: 14M, 6F; placebo: 12M, 8F).

Ethnicity: not stated.

History: diagnosis of chronic schizophrenia for at least two years/previous psychiatric hospitalisation for schizophrenia, with symptoms severe enough to have required continuous treatment with antipsychotic medication within the past three months.

Included: demonstrated ‘key schizophrenic symptoms’ including conceptual disorganisation; emotional withdrawal; blunted affect; bizarre mannerisms; unusual thought content; hallucinations. Demonstrable capacity to respond to psychotropic drug treatment as evidenced by improvement in the ‘manifestations of his psychosis’.

Excluded: epilepsy; drug addiction; severe depression; mental retardation; organic brain disease; significant physical disease or those who require heavy sedation or chemical restraint to control symptoms.

Consent: not stated.


Interventions1. Pimozide: dose range 2-12 mg/d, mean 6.3 mg/d, n = 21.
2. Trifluoperazine: dose range 5-30 mg/d, mean 17.5 mg/d, n = 20.
3. Placebo: n = 20.*


OutcomesGlobal state: no improvement (measured using the CGI).
Leaving the study early: because of adverse effects; for any reason.

Adverse effects: intensified symptoms.

Unable to use -
Global state: CGI therapeutic effect (improvement data more meaningful).
Mental state: BPRS (no usable data).
Adverse effects: (no usable data).
Social functioning: Family Rating Form (no usable data), Harbor View House Resident Rating Report (unpublished scale).


Notes*Before transfer to study medication, participants had received a neuroleptic for at least four weeks, the last two weeks of which were stabilised at a fixed daily dose, not exceeding  chlorpromazine 500 mg; thioridazine 500 mg; trifluoperazine 30 mg and fluphenazine 30 mg.

Drugs administered once daily before breakfast in identical capsules containing pimozide 2 mg; trifluoperazine 5 mg or placebo.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomised: 'randomly assigned' (p698). No further details.

Allocation concealment (selection bias)Unclear risk'Randomly assigned': no further details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind: 'identical appearing capsules' provided (p698): no further details.

Incomplete outcome data (attrition bias)
All outcomes
High riskFollow-up: 59%24% of pimozide-treated participants, 45% of trifluoperazine-treated participants and 55% of placebo-treated participants failed to complete the study for various reasons.

Selective reporting (reporting bias)High riskStatistical reporting was incomplete for all scale data (no SDs).

Other biasUnclear riskFunding: pimozide medication provided by McNeil Laboratories, Fort Washington, Pennsylvania (USA).

Raters: not stated to be independent of treatment.

Gunduz-Bruce 2013

MethodsAllocation: randomised.

Blinding: double blind.

Duration: 12 weeks.

Setting: outpatient, West Haven VA, West Haven, Connecticut (USA); Connecticut Mental Health Center of Yale Department of Psychiatry, New Haven, Connecticut (USA) and the Zucker-Hillside Hospital of Long Island Jewish Health Care System, New York, New York (USA).

Design: parallel.


ParticipantsDiagnosis: schizophrenia (DSM-IV).
N = 32* (N = 28 included in analysis).

Age: range 18-60 years; pimozide: mean = 44.3; placebo: mean = 41.5.
Sex: 20M, 8F (pimozide: 10M, 4F; placebo: 10M, 4F).

Ethnicity: pimozide: Asian n = 0; Black n = 3; Hispanic n = 1; White n = 10; placebo: Asian n = 2; Black n = 2; Hispanic n = 1; White n = 9.

History: before randomisation, a stable dose of clozapine for the past 2 weeks with a blood level of at least 350 ng/mL was targeted.

Inclusion criteria: diagnosis of schizophrenia or schizoaffective disorder (DSM-IV); minimum Brief Psychiatric Rating Scale (BPRS) score of 35 and BPRS psychotic symptom cluster score of at least 8; currently taking clozapine with a blood level between 350 and 1000 ng/mL and receiving a stable dose of clozapine for the past 2 weeks; able to give informed consent.

Exclusion criteria: history of significant medical/neurological disease such as thyroid, renal, or hepatic abnormality; seizure disorder; history of neuroleptic malignant syndrome; current substance abuse determined by urine toxicology cardiac arrhythmia; sinus bradycardia (heart rate < 60/min); sinus tachycardia (heart rate > 110/min); supraventricular tachycardia; ventricular tachycardia; Wolff-Parkinson-White syndrome; first-, second- and third-degree atrioventricular (AV) block; atrial fibrillation; atrial flutter and junctional complexes in baseline electrocardiogram (ECG). Study doctors will examine the EKGs and will consult with an internist/cardiologist as needed; QTc > 450 ms; current use of macrolide antibiotics (e.g. erythromycin, clarithromycin), azole antifungal agents (e.g. ketoconazole, itraconazole), protease inhibitors (e.g. ritonavir, indinavir), nefazodone and other medications that are associated with prolonged QTc; current use of antipsychotics other than clozapine; current use of sertraline; IQ level below 70; high risk for suicidal/homicidal behavior; pregnancy; lack of birth control for females of childbearing age (female participants must report use of effective method of birth control such as birth control pills, condoms, barrier methods or abstinence or must have written statement from their doctors that they are medically sterile); non-English speaking.

Consent: written informed consent obtained from each participant.


Interventions1. Pimozide: oral, started at 1 mg/d and maximum 4 mg/d by end of week 7 + clozapine (stable dose determined prerandomisation of at least 350 ng/mL targeted), n = 14.

2. Placebo: oral, sugar pill + clozapine (stable dose determined prerandomisation of at least 350 ng/mL targeted), n = 14.


OutcomesGlobal state: average endpoint score (CGI severity; CGI improvement).

Mental state: average endpoint score (BPRS total; BPRS psychosis subscale); average endpoint score (SANS).

Adverse effects: cardiovascular (QTc).

Leaving the study early: any reason.

Unable to use -

Socioeconomic status; weight; Strauss Carpenter level of function; Schedule for the Deficit Syndrome; neurocognitive battery; AIMS; and EPS using the Simpson-Angus Scale, as per the protocol; however, no data reported.

Digit Span and Letter-Number Sequencing; verbal learning and memory (RAVLT); verbal fluency (COWAT); attention/executive functioning (Trail Making Test, Parts A and B) not specified in protocol to review.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomised: participants were 'randomized to identical-looking pimozide or placebo capsules by the research pharmacist who was not involved with the subjects' (p345). No further details.

Allocation concealment (selection bias)Unclear riskNo details: participants were 'stratified as to whether they were receiving psychoactive medications such as mood stabilizers' to ensure that equal numbers were randomly assigned to either group based on treatment profile (p345).

Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind: 'identical-looking pimozide or placebo capsules' provided (p345) no further details.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskFollow-up: 88%. Four participants left the study early before medication was given; 'twenty-eight subjects completed most of the study procedures' (p345). Of the 28 participants remaining in the study, two participants from the pimozide augmentation group left early, n = 1 because of early termination caused by QTc prolongation, and n = 1 as the result of withdrawn consent (LOCF).

Selective reporting (reporting bias)High riskProtocol to the study stated that socioeconomic status; weight; Strauss Carpenter level of function; Schedule for the Deficit Syndrome; neurocognitive battery; AIMS; and EPS using the Simpson-Angus Scale would each be assessed; however, no data were reported.

Other biasUnclear riskFunding: supported by the Stanley Medical Research Institute (#02T-251 to H.GB).

Raters: not stated to be independent of treatment.

Haas 1982

MethodsAllocation: not described.
Blinding: double.
Duration: 30 days.

Setting: inpatient.

Design: parallel.


ParticipantsDiagnosis: schizophrenia (ICD); n = 19 paranoid-hallucinatory type; n = 10 chronic undifferentiated type; n = 1 schizoaffective type.

N = 30.

Age: range 19-61 years, mean ˜ 39 years.

Sex: 13M, 17F.

Ethnicity: not stated.

History: All participants needed admission and none of them had received depot neuroleptics during at least the three weeks before hospitalisation.

Included: no physical disease, needed admission, no depot ≥ 3 weeks.

Excluded: other somatic and psychic diseases (epilepsy, alcoholism, organic brain disease) and pregnancy.

Consent: informed consent required.


Interventions1. Pimozide: dose range 40-60 mg/d, n = 15.
2. Haloperidol: dose range 40-60 mg/d, n = 15.*


OutcomesGlobal state: no improvement (as assessed by using the CGI, including those still rated as 'severely' or 'moderately ill' by 30 days).

Mental state: use of additional medication (promethazine and chloral hydrate).

Adverse effects: extrapyramidal symptoms (akathisia; rigidity; tremor; dyskinesia; seizure); drowsiness; fatigue; sleep disturbances; inner restlessness; sweating; dizziness; blurred vision; sensations of heat; hypotension; tachycardia; enhanced appetite; increased thirst; obstipation; dry mouth; loss of appetite.**

Leaving the study early.

Unable to use -

Global state: CGI (no SD).
Mental state: BPRS (no SD).


Notes*Initial dose for both drugs was 10-40 mg/d (2.5 mg in 1 mL) and increased up to the fifth day day to 60 mg, then continued according to clinical needs. Chloral hydrate (1.5 g/d) or, if necessary, promethazine (100 mg/d) was given as sleep medication. Biperidan (2-mg tablets) was given if extrapyramidal signs were observed.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskDouble blind: randomisation not described.

Allocation concealment (selection bias)High riskNo description of allocation concealment.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble-blind: 'presentation of the drugs was identical in liquid form' (p71). No further details. Not tested if blinding was successful.

Incomplete outcome data (attrition bias)
All outcomes
High riskFollow-up: 93%. 28 participants completed the trial. One expressed the wish to quit at the end of day 10, and another developed severe side effects.

Selective reporting (reporting bias)High riskStatistical reporting was incomplete for all scale data (no SDs).

Other biasUnclear riskFunding: Janssen Pharmaceutica (Beeres, Belgium) provided drugs and measurements of plasma drug levels for the study.

Rating scales: not stated to be independent of treatment.

Huber 1971

MethodsAllocation: random.
Blinding: double.
Duration: 12 weeks.

Setting: inpatient, housed together on a 'special research ward area'.

Design: parallel.


ParticipantsDiagnosis: schizophrenia; n = 1 residual; n = 16 chronic undifferentiated; n = 1 simple; n = 1 schizoaffective.

N = 20.

Age: range 26-56 years, mean ˜ 43 years.

Sex: all male.

Ethnicity: not stated.

History: Two weeks before treatment, each participant's antipsychotic medication was converted into an equivalent dose of thioridazine so that all participants were receiving the same neuroleptic medication for two weeks before beginning pimozide or placebo treatment. All antiparkinsonian medication was discontinued one week before the new treatment was begun.

Included: not stated.

Excluded: not stated.

Consent: not stated.


Interventions1. Pimozide: average dose 45.7 mg (frequency unclear) oral, dose increased up to 40 mg/d (or 8 capsules a day), n = 10.
2. Placebo: average dose 39.5 mg (frequency unclear) oral, n = 10.*


OutcomesGlobal state: no improvement (as assessed by using the psychiatrist's CGI ratings, including those still rated as 'no change' or 'worse' in improvement).

Mental state: specific (auditory hallucinations).
Adverse effects: various.**
Leaving the study early.

Unable to use -

Mental state: BPRS (no SD).
Behavior: NOSIE (no SD).


Notes*No 'dry-out period' employed.

Dose adjustments were permitted in the event of toxicity or intolerance. Antiparkinsonian medication (benztropine mesylate) was permitted if, quote, 'deemed necessary by the investigator' (p304).

**ITT analysis performed.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomised: 'randomly assigned' (p304). No further details.

Allocation concealment (selection bias)Unclear riskNo description of allocation concealment.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind: 'Double blind procedure was followed throughout'. No further details. Not tested if blinding was successful.

Incomplete outcome data (attrition bias)
All outcomes
High riskFollow-up: 95%. 19 participants completed the trial. One participant dropped out before beginning the medication phase after developing severe hyperpyrexia. Analysis was completed on 19 participants.

Selective reporting (reporting bias)High riskStatistical reporting was incomplete for all scale data (no SDs).

Other biasUnclear riskFunding: supported in part by USPHS Grant MH 11666 and Research Scientist Development Award K135278 from NIMH. McNeil Laboratories provided medication and a grant-in-aid as additional partial support.

Rating scales: BPRS was completed at beginning and end of study by the psychiatrist; NOISE was completed at four-week intervals throughout the study; CGI was obtained from both the psychiatrist and nursing services.

Kline 1977

MethodsAllocation: not described.
Blinding: double.
Duration: 16 weeks.

Setting: outpatient.

Design: parallel.


ParticipantsDiagnosis: schizophrenia.

N = 44.

Age: range 20-53 years.

Sex: 19M, 25F.

Ethnicity: not stated.

History: chronic schizophrenia of at least 2 years' duration or previous history of hospitalisation for schizophrenia with exacerbation of symptoms severe enough to require treatment with antipsychotic medication within the preceding three months. Only those stabilised on drugs were selected for the study. Before the study, participants received neuroleptic medication for at least four weeks, and the dosage was stable for two weeks.*

Included: required treatment for increasing symptoms in last 3 months, ill ≥ 2 years/history of hospitalisation, stabilised on drugs.

Excluded: severe depression; mental retardation; organic brain disease or those requiring heavy sedation or chemical restraint to control symptoms.

Consent: not described.


Interventions1. Pimozide: dose range 4-12 mg/d, mean dose 15.7 mg/d, max 8 mg/d, n = 22.
2. Trifluoperazine: dose range 5-25 mg/d, mean dose 6.5 mg/d, n = 22.**


OutcomesGlobal state: no improvement*** (measured using the CGI, including participants rated with 'no change'; 'minimally worse'; 'much worse' or 'very much worse' in improvement).

Mental state: no improvement (measured using the BPRS, including participants rated with 'no change' or 'worsened' improvement).
Leaving the study early.

Adverse effects: insomnia; drowsiness; akathisia; anxiety; rigidity; Parkinson-like tremor; blurred vision; increased salivation; headache; dizziness; nausea; abdominal cramps; constipation; decreased weight.

Need for antiparkinsonian drugs.

Unable to use -
Global state: CGI (therapeutic effect, improvement more clinically meaningful).


Notes*Maximum daily dosages for stabilising drugs were as follows: chlorpromazine 500 mg; thioridazine 500 mg; fluphenazine 30 mg and trifluoperazine 30 mg.

**Additional medication given throughout the study included antidepressants (imipramine and amitriptyline); antiparkinsonian medication (trihexyphenidyl and benztropine mesylate (2 mg)); anxiolytic (diazepam) and chloral hydrate (for sleeping difficulties) (500-1000 mg).

***Global state CGI data given as last observation carried forward.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskDouble blind: no description of randomisation.

Allocation concealment (selection bias)High riskNo description of allocation concealment.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind: no further details.

Incomplete outcome data (attrition bias)
All outcomes
High riskFollow-up: unclear, data reported for all participants by 16 weeks for global state using the CGI, but data incomplete for mental state using the BPRS, with around 52% of participants lost in the total. LOCF for global state data. Numbers of participants leaving the study are inconsistently reported.

Selective reporting (reporting bias)High riskStatistical data incomplete: only 'final' CGI data provided for all participants in results as LOCF, but data for BPRS were presented for each time of rating. Complete numbers of participants lost to follow-up are unclear.

Other biasUnclear riskFunding: pimozide tablets provided by McNeil Laboratories Inc., Fort Washington, Pennsylvania (USA).

Rating scales: not stated to be independent of treatment.

Kolivakis 1974

MethodsAllocation: random.
Blinding: double.
Duration: 6 months.

Setting: outpatient.

Design: parallel.


ParticipantsDiagnosis: schizophrenia.

N = 51.

Age: range 17-60 years, mean ˜ 38 years.

Sex: 22M, 29F.

Ethnicity: not stated.

History: participants had been stabilised on neuroleptic medication for at least two weeks and were abruptly transferred to the study medication.

Included: chronic illness, > 1 positive/negative symptom, stabilised on antipsychotics for > 2 weeks.

Excluded: not stated.

Consent: not stated.


Interventions1. Pimozide: dose range 2.5-21 mg, mean dose 7 mg/d, n = 26.
2. Chlorpromazine: dose range 75-450 mg, mean dose 216 mg/d, n = 25.

Dose titrated upward according to response.


OutcomesGlobal outcome: no improvement (measured using the CGI, including participants rated with 'minimal' or 'unchanged' improvement).
Adverse effects: drowsiness; restlessness; increased leukocyte counts; intensified symptoms; death.
Leaving the study early: for any reason; because of adverse effects.

Unable to use -
Mental state: BPRS ('P' values only).
Social functioning: Katz Social Adjustment Scale ('P' values only).


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomised: 'randomly assigned' (p999). No further details.

Allocation concealment (selection bias)Unclear risk'Randomly assigned': no further details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind: 'identical appearing capsules' (p999). No further details.

Incomplete outcome data (attrition bias)
All outcomes
High riskFollow-up: 67%: attrition included; n = 4 participants in both groups with 'intensified symptoms'; n = 3 receiving pimozide and n = 4 receiving chlorpromazine refused or forgot to take the medication; and n = 1 suicide was reported in the chlorpromazine group (this participant was receiving 75 mg chlorpromazine daily upon admission to the study; two weeks into the study, a 'fit of rage' resulted in a fracture to his arm and loss of his job). Chlorpromazine was increased to 225 mg daily. Six days later, while taking the same dosage, he committed suicide (p1002). Only data for the remaining n = 35 are presented in the analysis.

Selective reporting (reporting bias)High riskFor mental state outcomes using the BPRS, quote, 'under the protocol, only patients whose symptoms had been brought under control with other neuroleptics were evaluated. Since a large number of the symptoms at the start of the study were rated 2 (very mild) or less, they were not expected to improve noticeably with further treatment. To provide a better measure of the drugs' abilities to reduce symptom severity, only the results with the BPRS symptoms rated 3 (mild) to 7 (extremely severe) were included in this analysis' (p1000). No statistical data were presented for this outcome. Not all adverse effects were reported, only those 'most frequently observed' (p1002).

Other biasUnclear riskFunding: pimozide tablets provided by McNeil Laboratories Inc., Fort Washington, Pennsylvania (USA).

Rating scales: not stated to be independent of treatment.

Kudo 1972

MethodsAllocation: random.
Blinding: double.
Duration: 2 months.

Setting: inpatient.

Design: parallel.


ParticipantsDiagnosis: schizophrenia; n = 4 hebephrenia; n = 32 paranoid; n = 7 catatonic; n = 9 unclassified; n = 4 unknown.

N = 56.

Age: range 17-57 years.

Sex: 28M, 28F.

Ethnicity: not stated.

History: not stated.

Included: no active symptoms; reduced activity; willing to participate in work therapy.

Exclusion: not stated.

Consent: not stated.


Interventions1. Pimozide: + placebo, dose range 3-8 mg/d, n = 28.
2. Carpipramine: + placebo, dose range 75-200 mg/d, n = 28.*


OutcomesGlobal state: no improvement (made as a ‘comparative global judgement’ using the Schizophrenic Rating Scale for doctors, Keio method**).
Adverse effects: intensified symptoms; akathisia; parkinsonism; salivation; headache; dizziness; restlessness; drowsiness; insomnia; fatigue; perspiration; rash; dry mouth; constipation; diarrhoea; nausea and vomiting; decreased appetite; increased appetite; gastrointestinal disturbances; dysuria; pollakisuria; palpitation; amenorrhoea.
Leaving the study early: for any reason; because of adverse effects.

Unable to use -

Effectiveness on each symptom (not specified in the protocol).


Notes*Starting daily dose was 3 tablets for both pimozide and carpipramine, which was maintained for one week and was increased according to participants' symptoms in subsequent weeks.

**Appears to be a published scale, but a reference is not yet available.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomised: the order in which participants received pimozide was randomly assigned. Participants were matched in pairs for sex, clinical picture and age, the exact method was not described (p686).

Allocation concealment (selection bias)Unclear riskNo description of allocation concealment.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind: tablets were identical in appearance (p686). No further details.

Incomplete outcome data (attrition bias)
All outcomes
High riskFollow-up: 92%. One participant from each group left early before completion. No further details provided.

Selective reporting (reporting bias)Unclear riskNone obvious.

Other biasUnclear riskFunding: not stated.

Rating scales: not stated to be independent of treatment.

McCreadie 1980

MethodsAllocation: random.
Blinding: double.
Duration: 9 months.

Setting: inpatient, hostel ward of the rehabilitation unit of Gartnavel Royal Hospital, Glasgow, UK, and day patients attending the hospital's industrial and occupational therapy departments.

Design: parallel.


ParticipantsDiagnosis: 'definite schizophrenia' (Feighner 1972 criteria).

N = 34.

Age: range 19-70 years, mean ˜ 51 years.

Sex: all male.

Ethnicity: not stated.

History: n = 9 inpatients (average length of illness as estimated from first hospital admission 26 years (mean)) and n = 26 day patients (average length of illness 18 years (mean)).

Included: physically fit; fulfilled Feighner criteria for 'definite schizophrenia'; in the opinion of both medical and nursing staff well controlled on and benefiting from long-acting intramuscular antipsychotic medication; consent from participant/next of kin.

Excluded: not stated.

Consent: required from participant or next of kin.


InterventionsAll participants were switched to fluphenazine decanoate (if not already receiving) at least three months before the trial began.

1. Pimozide: 'intermittent', mean dose 8 mg/oral, maximum 32 mg every 4 days/wk, n = 16.

2. Fluphenazine decanoate: mean dose 12.5 mg/IM, maximum 50 mg weekly, n = 18.

To ensure double-blind conditions, participants received active fluphenazine injections and placebo pimozide tablets, or placebo fluphenazine injections and active pimozide tablets.


OutcomesGlobal state: relapse (defined as exacerbation of positive symptoms).

Adverse effects: dyskinesia, need for additional antiparkinsonian medication.

Leaving the study early.

Unable to use -

Mental state: Hamilton-Lorr Scale, Kraweicka Scale (depression and anxiety) (outcome reported but no usable data presented).

Behaviour: Wing Ward Behaviour Scale (independent behaviour) (outcome reported but no usable data presented).


NotesNumbers of participants differ between the abstract and the full paper.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomised: no further description.

Allocation concealment (selection bias)Unclear risk'Blindly allocated': no further description.

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind: 'to ensure double-blind conditions, participants received active fluphenazine injections and placebo pimozide tablets, or placebo fluphenazine injections and active pimozide tablets'.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskFollow-up: 97%. One participant receiving pimozide refused all medication from the sixth month and therefore was withdrawn from the trial; 'he was counted neither as a relapse nor as a non-relapse' (p512).

Selective reporting (reporting bias)High riskNot all data reported for listed outcomes.

Other biasUnclear riskFunding: not stated, Janssen Pharmaceuticals and ER Squibb acknowledged for supplying the medication and for providing 'advice'.

Rating scales: participants' mental state was assessed independently by two psychiatrists.

McCreadie 1982*

MethodsAllocation: random.
Blinding: double.
Duration: 10 months.

Setting: inpatient, hostel wards of Crichton Royal Hospital, Dumfries (UK).

Design: parallel.


ParticipantsDiagnosis: 'definite schizophrenia' (Feighner 1972 criteria).

N = 29.

Age: mean ˜ 55 years.

Sex: all male.

Ethnicity: not stated.

History: average length of illness as estimated from first hospital admission 27 years (mean).

Included: physically fit; fulfilled Feighner criteria for 'definite schizophrenia'; in the opinion of both medical and nursing staff well controlled on and benefiting from antipsychotic medication; consent from participant/next of kin

Excluded: not stated.

Consent: not stated.


Interventions1. Pimozide: 'intermittent', dose range 10-60 mg/oral, mean 40 mg/IM weekly, n = 13.

2. Fluphenazine decanoate: dose range 2-25 mg/IM, mean 14 mg/IM biweekly, n = 15.

Pimozide was administered daily for the first week, four consecutive days weekly for the second, twice weekly for the third and once weekly thereafter on Monday mornings. The once weekly dose was four times the initial daily dose, subject to a maximum of 60 mg. The maximum weekly dose of fluphenazine (which in most cases was given twice-weekly, also on Monday mornings) was 50 mg.


OutcomesGlobal state: relapse (defined as exacerbation of positive symptoms).

Adverse effects: dyskinesia.

Leaving the study early.

Unable to use -

Mental state: Hamilton-Lorr Scale, Kraweicka Scale (outcome reported but no usable data presented).

Behaviour: Wing Ward Behaviour Scale (outcome reported but no usable data presented).


NotesOne participant was receiving fluphenazine decanoate, and five participants were receiving daily pimozide before the study began; a further five participants were receiving intramuscular flupenthixol decanoate.

If participants were taking antiparkinsonian medication at the start of the trial, the dose of this was steadily reduced and the drug eventually discontinued if signs of parkinsonism were no more than 'mild'. Antiparkinsonian medication was prescribed if signs were 'moderate' or 'severe'.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomised: no further description.

Allocation concealment (selection bias)Unclear risk'Blindly allocated': no further description.

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind: 'to ensure double-blind conditions, participants received active fluphenazine injections and placebo pimozide tablets, or placebo fluphenazine injections and active pimozide tablets'.

Incomplete outcome data (attrition bias)
All outcomes
High riskFollow-up: 58%. n = 5/13 taking pimozide and n = 6/15 taking fluphenazine were withdrawn (reasons included exacerbation of positive symptoms; depression; suicidal ideas and attempts; family request to withdraw; tardive dyskinesia and complaints of tiredness).

Selective reporting (reporting bias)High riskNot all data reported for listed outcomes.

Other biasUnclear riskFunding: supported by a research grant from Dumfries and Galloway Health Board. Janssen Pharmaceuticals and Squibb Limited provided 'advice', medication and 'other materials'.

Rating scales: participants' mental state was assessed independently by two psychiatrists.

McCreadie 1987

MethodsAllocation: random.
Blinding: double.
Duration: 5 weeks.

Setting: inpatient (first admission), Crichton Royal Hospital, Dumfries (UK).

Design: parallel.


ParticipantsDiagnosis: schizophrenia.

N = 46.

Age: range 16-68 years, mean ˜ 31 years.

Sex: 21M, 25F.

Ethnicity: not stated.

History: In the three months before hospital admission, 26% had received small doses of thioridazine or chlorpromazine; up to seven days after admission, participants could receive droperidol for severe behavioural disturbances.

Included: first episode (26% previously had antipsychotics).

Excluded: not stated.

Consent: not stated.


Interventions1. Pimozide: (+ dummy injections) mean dose 18.8 mg/d, n = 23.
2. Flupenthixol: (+ dummy tablets) mean dose 20 mg/d, n = 23.

ECT, droperidol, other antipsychotics, procyclidine, temazepam as required.


OutcomesLeaving the study early.*

Mental state: additional medication.

Unable to use -
Mental state: Krawiecka Scale ('P' values only).
Adverse effects: antiparkinsonian drug use (denominators unclear).
Behaviour: Wing Behaviour Scale ('P' values only).
Cognitive functioning: WAIS, Mill Hill Vocabulary Matrices ('P' values only).


Notes*Only 5-week data extracted. Data from 1-year, 2-year follow-up, not by experimental group.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomised: participants were randomly allocated to receive either medication.

Allocation concealment (selection bias)Unclear riskNo description of allocation concealment.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind: 'double dummy design', no further description.

Incomplete outcome data (attrition bias)
All outcomes
High riskFollow-up: 91%. n = 15/23 receiving pimozide completed the five weeks of treatment (n = 3 refused to continue; n = 1 discharged himself against medical advice; n = 1 developed skin rash), and a further n = 3 switched to maintenance therapy; n = 17/23 receiving flupenthixol completed the five weeks (n = 1 was discharged with no significant elevation in plasma prolactin levels; n = 1 was discharged and left Scotland; n = 1 discharged himself against medical advice, and a further n = 3 switched to maintenance therapy).

Selective reporting (reporting bias)Unclear riskNumbers of participants differ between the original reports and the follow-up reports.

Other biasHigh riskFunding: Janssen Pharmaceutica and Lundbeck Limited provided 'financial support'.

Raters: not stated to be independent of treatment.

McInnes 1978

MethodsAllocation: random.
Blinding: double.
Duration: 13 weeks.

Setting: inpatient, locked ward, Cherry Farm Hospital, Dunedin, New Zealand.

Design: parallel.


ParticipantsDiagnosis: residual schizophrenia (n = 14); paranoid schizophrenia (n = 1); Korsakoff's (n = 2); bipolar disorder (n = 1).

N = 18.

Age: range 39-80 years, mean ˜ 70 years.

Sex: all male.

Ethnicity: not stated.

History: before the trial, n = 10 participants were not taking medication; n = 2 participants were receiving chlorpromazine; n = 6 participants were receiving thioridazine; all had a long history of institutionalised behaviour.

Included: long-term inpatients (9 months-47 years).

Excluded: not stated.

Consent: not stated.


Interventions1. Pimozide: dose data not given, n = 9.
2. Placebo: n = 9.


OutcomesLeaving the study early: because of adverse effects.

Unable to use -
Social functioning: activity withdrawal, Venables Scale ('P' values only).


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomised: participants were 'randomly assigned' by 'flicking a coin', using a 'double blind code' (p171).

Allocation concealment (selection bias)Unclear riskNo description of allocation concealment.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind: no further description.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskFollow-up: unclear.

Selective reporting (reporting bias)Unclear riskNone detected.

Other biasUnclear riskFunding: none stated.

Rating scales: not stated to be independent of treatment.

Nishikawa 1985

MethodsAllocation: random.
Blinding: double.
Duration: 1 year.

Setting: outpatient, Seiwakai Nishikawa Hospital, Hamada, Japan.

Design: parallel.


ParticipantsDiagnosis: schizophrenia (DSM-III).

N = 106*.

Age: mean ˜ 40 years.

Sex: 78M, 28F.

Ethnicity: not stated.

History: participants in recovery stage or remission and had reported regularly to the Seiwakai Nishikawa Hospital, Hamada, Japan.

Included: in remission or residual phase.

Excluded: not stated.

Consent: not stated.


Interventions1. Pimozide alone:

  • pimozide: dose 2 mg/d, n = 13.
  • pimozide: dose 6 mg/d, n = 11.


2. Thioridazine alone:

  • thioridazine: dose 25 mg/d, n = 12.
  • thioridazine: dose 75 mg/d, n = 10.


3. Pimozide + thioridazine:

  • pimozide and thioridazine: dose pimozide (2 mg/d), thioridazine (25 mg/d), n = 11.
  • pimozide and thioridazine: dose pimozide (2 mg/d), thioridazine (75 mg/d), n = 11.
  • pimozide and thioridazine: dose pimozide (6 mg/d), thioridazine (25 mg/d), n = 12.
  • pimozide and thioridazine: dose pimozide (6 mg/d), thioridazine (75 mg/d), n = 13.


Each drug was combined with 10 mg nitrazepam (for insomnia) and 2 mg trihexyphenidyl (for drug-induced parkinsonism). All drugs were administered orally once per day at night-time.


OutcomesGlobal state: relapse (undefined).

Leaving the study early: any reason.

Unable to use -
Mental state: symptom-free days (data not separated into participant groups, attrition of 77%).

Data for the placebo group.*


Notes*Data for n = 13 not included in the results, as these data were derived from a previous study conducted by the author and utilised for a retrospective placebo control.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomised: no further details.

Allocation concealment (selection bias)Unclear riskParticipants were 'randomly assigned' (p1162): no further details.

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind: drug appearance, taste, volume made identical 'by adding a common gastric acid' (p1162).

Incomplete outcome data (attrition bias)
All outcomes
High riskFollow-up: Of n = 106, six participants left early because they took drugs irregularly and therefore were excluded from the final data and analysis. A further number of n = 76 discontinued designated use of assigned drugs through overdosage (n = 21) or relapse (n = 55). It is not clear whether the additional n = 76 remained in the analysis for mental state (these data were subsequently considered unusable).

Selective reporting (reporting bias)High riskSome data are not reported for each participant group. Scale data are presented without standard deviations. Data from a previous trial were 'utilised for retrospective placebo control' (p1162).

Other biasUnclear riskFunding: not stated.

Rating scales: not stated to be independent of treatment.

Pecknold 1980

MethodsAllocation: random.
Blinding: double.
Duration: 4 weeks.

Setting: inpatient, psychiatric service of St. Mary's Hospital, Côte-des-Neiges, Montréal, Canada.

Design: parallel.


ParticipantsDiagnosis: acute schizophrenia.

N = 20.

Age: range 21-53 years, mean ˜ 33 years.

Sex: 13M, 7F.

Ethnicity: not stated.

History: not stated.

Included: good physical health.

Excluded: latent or residual schizophrenia, organic brain syndrome, epilepsy, alcoholism, depression.

Consent: informed consent obtained.


Interventions1. Pimozide: dose range 10-70 mg/d + placebo, n = 10.
2. Chlorpromazine: dose range 300-2100 mg/d, n = 10.
No washout period. Doses were individually titrated. Additional medication: pimozide, chlorpromazine oral/IM (only for extreme agitation, in both treatment groups), procyclidine for EPS.


OutcomesGlobal state: no improvement (using the CGI); average endpoint score (CGI).

Mental state: average endpoint score (BPRS).
Adverse effects: blurred vision; dry mouth; nausea; vomiting; dizziness; insomnia; sedation; fatigue. Extrapyramidal adverse effects: Extrapyramidal Symptom Scale (EPS) average endpoint score (skewed); tremor; hypersalivation; rigidity; gait disturbance; restlessness.

Leaving study early: for any reason; because of adverse effects.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomised: no further details.

Allocation concealment (selection bias)Unclear risk'Randomly assigned' (p209): no further details.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind: no further details.

Incomplete outcome data (attrition bias)
All outcomes
High riskFollow-up: 80% completed the study, two participants left early from each treatment group: with pimozide, both participants discontinued treatment because of rapid deterioration without control of psychotic symptoms and the presence of limiting side effects. With chlorpromazine, one participant left early owing to lack of symptom control and one owing to limiting side effects. Results were missing from two participants in the chlorpromazine group for improvement using the BPRS. Data for these participants were not included in the analysis.

Selective reporting (reporting bias)High riskNo statistical data reported for the CGI (Item II).

Other biasUnclear riskFunding: partially supported by St. Mary's Foundation (Project in Psychoactive Agents); medication supplied by McNeil Laboratories, Inc., Fort Washington, Pennsylvania (USA).

Rating scales: treating psychiatrist, not independent of treatment.

Pinard 1972

MethodsAllocation: random.
Blinding: double.
Duration: 70 days (preceded by 21 days where all had chlorpromazine 100 mg/d).

Setting: inpatient, St.-Jean-de-Dieu Hospital, Research Unit, Montréal, Canada.

Design: parallel.


ParticipantsDiagnosis: chronic schizophrenia, BPRS mean ˜ 45.
N = 80*.

Age: range 20-60 years.

Sex: 40M, 40F.

Ethnicity: not stated.

History: not stated.

Included: hospitalised > 2 years; no exacerbation in the last year; in hospital only for social or personal reasons.

Excluded: not stated.

Consent: not stated.


Interventions1. Pimozide: dose 3 mg/d, n = 16.
2. Pimozide: dose 6 mg/d, n = 15.
3. Trifluoperazine: dose 5 mg/three times daily, n = 14.
4. Trifluoperazine: dose 15 mg/d, n = 15.
5. Placebo: n = 14.

Chlorpromazine, methyprylon, benztropine as required.


OutcomesAdverse effects: acute cholecystitis; intensified symptoms.

Leaving the study early:for any reason; because of adverse effects.

Unable to use -
Mental state: BPRS ('P' values only).
Adverse effects: extrapyramidal symptoms, BEP (graph only).
Behaviour: NOSIE (graph only).
Insight scale: l'Echelle d'Auto-Critique (only correlations).


Notes*6 participants not accounted for.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomised: number table, blocks of 5, matched for treatment, symptom severity (BPRS), sex, ward, evaluator (p22).

Allocation concealment (selection bias)Unclear riskNo description of allocation concealment.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind: no further details.

Incomplete outcome data (attrition bias)
All outcomes
High riskFollow-up: n = 6 participants left during the study. 'Of these, n = 3 were on trifluoperazine and n = 2 on placebo. They had suffered psychotic setbacks and two had suicidal thoughts. The sixth was on pimozide and had to undergo surgery for an acute cholecystitis' (p23). A further n = 6 were not accounted for.

Selective reporting (reporting bias)High riskStatistical reporting was incomplete for all scale data (no SDs).

Other biasUnclear riskFunding: not stated.

Rating scales: independent of treatment.

Silverstone 1984

MethodsAllocation: random.
Blinding: double.
Duration: 28 days.

Setting: inpatient.

Design: parallel.


ParticipantsDiagnosis: acute schizophrenia.
N = 22.

Age: range 19-68 years, mean ˜ 39 years.

Sex: 11M, 11F.

Ethnicity: not stated.

History: None had received more than one dose of antipsychotics in the previous week or had been given an injection of a long-acting depot drug within the previous 4 weeks.

Included: not stated.

Excluded: not stated.

Consent: All participants had signed consent forms.


Interventions1. Pimozide: dose range 5-50 mg/d, n = 10.
2. Haloperidol: dose range 5-50 mg/d, n = 12.

Chlorpromazine IM, procyclidine (for EPS), temazepam/nitrazepam (for sedation at night-time) as required.


OutcomesMental state: severity of symptoms (Montgomery Asberg Depression Rating Scale) (skewed).

Adverse effects: extrapyramidal symptoms (Parkinsonian tremor and rigidity; acute dystonia); drowsiness; dry mouth; nausea; constipation; palpitations; postural hypotension; blurred vision; headache; urinary retention.
Leaving the study early: for any reason; because of adverse effects.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomised: no further details.

Allocation concealment (selection bias)Unclear riskNo description of allocation concealment.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind: matching capsules.

Incomplete outcome data (attrition bias)
All outcomes
High riskFollow-up: 82%. n = 18 completed the 28 days of treatment; n = 3 were withdrawn from the haloperidol group, of these, two were unwilling to continue after developing EPS and left the hospital against advice. n = 1 participant taking pimozide was withdrawn because of intercurrent illness. It is unclear whether these participants were included in the analysis.

Selective reporting (reporting bias)Unclear riskNone detected.

Other biasHigh riskFunding: not stated: Pimozide was assayed by radioimmunoassay at Janssen Pharmaceutica; haloperidol was assayed using a commercial radioimmunoassay kit' (p257). One author was an employee of Janssen Pharmaceutica at the time of the study.

Rating scales: not stated to be independent of treatment.

Vergara 1977

MethodsAllocation: random.
Blinding: double.
Duration: 16 weeks (preceded by 2-week antipsychotic stabilisation period).

Setting: outpatient.

Design: parallel.


ParticipantsDiagnosis: schizophrenia.
N = 20.

Age: range 20-55, mean ˜ 38 years.

Sex: 13M, 7F.

Ethnicity: not stated.

History: Before the study, each participant had received various neuroleptic medications (stabilised at a constant daily dose during the last two weeks) for at least four weeks. Prestudy medication was discontinued in n = 13 of the participants within 28 days; the remaining participants took up to 84 days to discontinue prestudy medication.

Included: chronic illness, antipsychotics > 1 month.

Excluded: not stated.

Consent: not stated.


Interventions1. Pimozide: dose range 2-12 mg/d, n = 10.
2. Trifluoperazine: dose range 5-30 mg/d, n = 10.*

(Dosages adjusted on the basis of clinical criteria to achieve optimal therapeutic effect.)


OutcomesGlobal state: relapse (defined as 'clinical deterioration'); no improvement (assessed using the CGI).

Leaving the study early: because of relapse; because of adverse effects; for any reason.

Unable to use -

Global state: CGI (no SDs, 'P' value only).
Mental state: BPRS (no SDs, 'P' value only).
Adverse effects: Treatment Emergent Symptoms Scale (TESS) (no data reported).


Notes*The neuroleptic medications that participants were receiving before inclusion in the study were gradually reduced and discontinued during the course of the clinical trial.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomised: participants were 'randomly assigned', no further details.

Allocation concealment (selection bias)Unclear riskNo description of allocation concealment.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind: no further details.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskFollow-up: unclear, 80% completed the study: In the pimozide group, n = 8/10 completed the study (n = 1 was withdrawn because of clinical deterioration; n = 1 was withdrawn because of drowsiness and dizziness), and in the trifluoperazine group, n = 8/10 completed the study (n = 1 was withdrawn because of clinical deterioration; n = 1 was withdrawn because of tremor and rigidity). All participants are accounted for under CGI results. It is unclear how many were included in the overall analysis (for BPRS and adverse effects).

Selective reporting (reporting bias)High riskStatistical reporting was incomplete for all scale data (no SDs). No data were reported using TESS; individual adverse effects were not reported.

Other biasUnclear riskFunding: not stated.

Rating scales: not stated to be independent of treatment.

Wilson 1982*

MethodsAllocation: random.
Blinding: double.
Duration: 52 weeks (preceded by 2 weeks of stabilisation on constant dose of non-trial antipsychotic).

Setting: outpatient, Veterans Administration Hospital outpatient psychiatric clinic (USA).

Design: parallel.


ParticipantsDiagnosis: schizophrenia (DSM-III).
N = 43.

Age: range 24-60 years.

Sex: 42M, 1F.

Ethnicity: not stated.

History: Those included were stabilised on a constant dose of some neuroleptic other than chlorpromazine for at least two weeks, then were shifted abruptly to study medication.

Included: presence of psychotic symptoms for at least 1.5 years; demonstrated capability of responding to drug treatment; possessing conceptual disorganisation, emotional withdrawal, blunted affect, bizarre mannerisms, unusual thought content or hallucinations.

Excluded: epilepsy; severe depression; motor retardation; organic brain disease; those who required heavy doses of medication or chemical restraints to control aggressive or other acutely troubling symptoms; significant cardiac disease; ophthalmologic disease demonstrated by slit-lamp examination or those with abnormal laboratory values on prestudy examination that were deemed to be of clinical significance.

Consent: informed consent obtained.


Interventions1. Pimozide: dose range 2-8 mg, mean dose 7.3 mg/d, max. 20 mg/d, n = 21.
2. Chlorpromazine: dose range 95-380 mg, mean dose 381 mg/d, max. 950 mg/d, n = 22.

Dose adjusted according to response. Initial dose varied according to each participant's previous medication requirements.


OutcomesLeaving the study early: for any reason; because of adverse effects.

Unable to use -
Global state: CGI (44% loss of data).
Mental state: BPRS (44% loss of data, no data reported).
Physical tests: ECG (44% loss of data, no data reported).
Social functioning: Evaluation of Social Functioning Scale (56% loss of data).

Adverse effects (no data reported).


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomised: 'randomly assigned', no further details.

Allocation concealment (selection bias)Unclear riskNo description of allocation concealment.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind: 'double blind fashion', both single daily doses, identical capsules (p62).

Incomplete outcome data (attrition bias)
All outcomes
High riskFollow-up: 55%. n = 19 failed to complete the study after being enrolled for at least one week. For pimozide, reasons included uncooperativeness (n = 3), limiting of adverse reaction (n = 1), drug ineffectiveness (n = 2) and other reasons (n = 2); for chlorpromazine, reasons included uncooperativeness (n = 2), failure to return (n = 1), limiting adverse reaction (n = 4), drug ineffectiveness (n = 2) and other reasons (n = 2) (p64).

Selective reporting (reporting bias)High riskStatistical reporting was incomplete for all scale data (no SDs). Data not reported for 'adverse drug experiences'.

Other biasUnclear riskFunding: funded in part by McNeil Laboratories, Fort Washington, Pennsylvania (USA).

Rating scales: not stated to be independent of treatment.

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Baggio 1970Allocation: not randomised, case series.

Baro 1972Allocation: not randomised, case series.

Bobon 1968Allocation: not randomised, case series.

Brugmans 1968Allocation: "double blind", no further details.
Participants: people with schizophrenia.
Interventions: pimozide versus placebo.
Outcomes: no usable data.

Cetin 2000Allocation: randomised.
Participants: people with psychosis.
Interventions: pimozide versus risperidone.
Outcomes: no usable data.

Cheadle 1979Allocation: not randomised, case series.

Chouinard 1979Allocation: randomised.
Participants: people with schizophrenia.
Interventions: pimozide versus chlorpromazine.
Outcomes: no usable data.

Clark 1971Allocation: randomised.
Participants: people with schizophrenia.
Interventions: pimozide versus placebo.
Outcomes: no usable data.

Crow 1986Allocation: randomised.
Participants: people with non-affective psychosis.
Interventions: continuing drug (chlorpromazine or fluphenazine or haloperidol or pimozide or trifluoperazine) versus placebo (drug withdrawal).
Outcome: no usable data, results not broken down by individual drug, and withdrawal study.

d'Elia 1974Allocation: randomised.
Participants: people with schizophrenia.
Interventions: pimozide versus trifluoperazine.
Outcomes: no usable data.

Feinberg 1988Allocation: not randomised, case series.

Friedman 1997Allocation: not randomised, case series.

Frussa Filho 1988Allocation: not randomised, review.

Garton 1979Allocation: not randomised, case series.

Gomez Perez 1994Allocation: not randomised, review.

Hass 1982Allocation: not randomised.

Holl 1992Allocation: not randomised, review.

Huber 1983Allocation: not randomised, review.

Ibarra 1996Allocation: unclear.
Participants: people with delusional disorders.
Interventions: pimozide alternated with placebo, no parallel group.

Johnstone 1997Allocation: randomised.
Participants: patients with functional psychotic illness.
Interventions: pimozide versus lithium versus pimozide+lithium versus placebo.
Outcome: no usable data, graph data and significance tests.

Kenway 1971Allocation: randomised, cross-over.
Participants: people with schizophrenia.
Interventions: pimozide versus fluphenazine.
Outcome: no usable data, no pre-cross-over data.

Kenway 1973Allocation: not randomised, case series.

Konig 1971Allocation: not randomised, case series.

Koo 1996Allocation: not randomised, review.

Krumholz 1970Allocation: unclear, cross-over study.
Participants: people with schizophrenia.
Interventions: pimozide versus placebo.
Outcomes: no usable data.

Lapierre 1976Allocation: randomised.
Participants: people with schizophrenia.
Interventions: pimozide + group psychotherapy versus fluphenazine + group psychotherapy.
Outcomes: no usable data.

Lehmann 1970Allocation: 'sequential assignment'.
Participants: people with schizophrenia.
Intervention: pimozide versus fluphenazine.
Outcomes: no usable data.

Mahal 1975Allocation: randomised.
Participants: people with schizophrenia.
Interventions: pimozide versus placebo.
Outcomes: no usable data.

Marshall 1971Allocation: not randomised, case series.

Masiak 1976Allocation: not randomised, case control design.

McCoy 1992Allocation: not randomised, case report.

McCreadie 1978Allocation: not randomised.

McCreadie 1983Allocation: not randomised.

Meltzer 1986Allocation: not randomised, review.

Moller 1994Allocation: not randomised, review.

Morris 1970Allocation: randomised (cross-over design).
Participants: people with schizophrenia.
Interventions: pimozide versus fluphenazine.
Outcomes: no usable data (data not recorded pre-cross-over).

Neziroglu 1997Allocation: not randomised, review.

Opler 1994Allocation: not randomised, review.

Opler 1995Allocation: not randomised, review.

Phillips 1996Allocation: not randomised, review.

Pinals 1996Allocation: not randomised, review.

Poldinger 1976Allocation: randomised.
Participants: people with psycho-vegetative syndrome and anxiety neurosis, not schizophrenia or related disorders.

Reyntjens 1972Allocation: randomised.
Participants: people with stress-induced psychic and functional disorders, not schizophrenia or related disorders.

Ruiz 1975Allocation: randomised.
Participants: people with schizophrenia.
Interventions: pimozide versus placebo.
Outcomes: no usable data.

Sims 1975Allocation: randomised (cross-over design).
Participants: people with schizophrenia.
Interventions: pimozide versus fluphenazine.
Outcomes: no usable data.

Singh 1971Allocation: not randomised, case series.

Smythies 1974Allocation: 'double blind crossover', allocation not described.
Participants: people with schizophrenia.
Intervention: pimozide versus thioridazine.
Outcome: no data available.

Srinivasan 1994Allocation: not randomised, case series.

Sterkmans 1968Allocation: not randomised, case series.

Sugerman 1971Allocation: not randomised, case series.

Svestka 1972Allocation: randomised, cross-over design.
Participants: people with schizophrenia.
Intervention: pimozide versus perphenazine.
Outcome: no pre-cross-over data.

Tegeler 1983Allocation: not randomised, review.

Tueth 1983Allocation: not randomised, review.

Ungvari 1986Allocation: not randomised, ABA study.

van Kammen 1982Allocation: randomised.
Participants: people with schizophrenia.
Intervention: amphetamine infusion versus placebo infusion, pimozide subsequently given to all participants.

van Kammen 1987Allocation: not randomised, case series.

Van Wyck 1972Allocation: randomised, cross-over design.
Participants: patients with schizophrenia.
Interventions: pimozide versus placebo.
Outcome: no pre-cross-over data.

Vanelle 1996Allocation: not randomised, review.

Watt 1983Allocation: not randomised, case series.

Welbel 1979Allocation: not randomised, case series.

 
Characteristics of studies awaiting assessment [ordered by study ID]
Umene 1972

MethodsAllocation: unclear.
Blinding: double.
Duration: 8 weeks.

Setting: inpatient.

Design: parallel.

ParticipantsDiagnosis: chronic schizophrenia.
n = 92.

Age: unclear.

Sex: unclear.

Ethnicity: unclear.

History: unclear.

Included: unclear.

Excluded: unclear.

Consent: informed consent obtained.

Interventions1. Pimozide: max. dose 12 tablets (1 mg) a day.

2. Chlorpromazine: max. dose 24 tablets (25 mg) a day.

OutcomesUnclear.

NotesStudy awaits translation from Japanese.

 
Comparison 1. PIMOZIDE versus PLACEBO

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Global state: 1. Relapse - clinical diagnoses1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 medium term (3-12 months)
120Risk Ratio (M-H, Fixed, 95% CI)0.22 [0.03, 1.78]

 2 Global state: 2. No improvement3102Risk Ratio (M-H, Random, 95% CI)0.84 [0.69, 1.02]

    2.1 short term (<3 months)
240Risk Ratio (M-H, Random, 95% CI)0.61 [0.15, 2.45]

    2.2 medium term (3-12 months)
262Risk Ratio (M-H, Random, 95% CI)0.84 [0.67, 1.06]

 3 Mental state: 1. Specific symptoms2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 anxiety/tension - medium term (3-12 months)
125Risk Ratio (M-H, Fixed, 95% CI)2.06 [0.09, 46.11]

    3.2 auditory hallucinations - short term (<3 months)
119Risk Ratio (M-H, Fixed, 95% CI)3.3 [0.15, 72.08]

    3.3 depression - medium term (3-12 months)
125Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.05, 9.47]

 4 Adverse effects: 1. Extrapyramidal adverse effects2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 dystonia - medium term (3-12 months)
125Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.05, 9.47]

    4.2 akathisia - short term (<3 months)
119Risk Ratio (M-H, Fixed, 95% CI)5.5 [0.30, 101.28]

    4.3 akathisia - medium term (<3 months)
125Risk Ratio (M-H, Fixed, 95% CI)0.22 [0.03, 1.85]

    4.4 restlessness - medium term (3-12 months)
125Risk Ratio (M-H, Fixed, 95% CI)2.0 [0.24, 16.61]

    4.5 rigidity - short term (<3 months)
119Risk Ratio (M-H, Fixed, 95% CI)5.5 [0.30, 101.28]

    4.6 rigidity - medium term (3-12 months)
125Risk Ratio (M-H, Fixed, 95% CI)1.33 [0.14, 12.82]

    4.7 tremor - short term (<3 months)
119Risk Ratio (M-H, Fixed, 95% CI)3.3 [0.15, 72.08]

    4.8 tremor - medium term (3-12 months)
125Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.20, 4.95]

 5 Adverse effects: 2. Anticholinergic effects1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    5.1 blurred vision - medium term (3-12 months)
125Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.20, 4.95]

    5.2 dry mouth - medium term (3-12 months)
125Risk Ratio (M-H, Fixed, 95% CI)0.23 [0.01, 5.12]

 6 Adverse effects: 3. Cardiovascular effects2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    6.1 blood pressure increase - short term (<3 months)
119Risk Ratio (M-H, Fixed, 95% CI)3.3 [0.15, 72.08]

    6.2 chest pain - medium term (<3 months)
125Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    6.3 dizziness - medium term (3-12 months)
125Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.11, 3.99]

    6.4 ECG: primary changes in T waves - short term (<3 months)
119Risk Ratio (M-H, Fixed, 95% CI)3.3 [0.15, 72.08]

 7 Adverse effects: 4. Abnormal laboratory tests2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    7.1 haematological - any abnormal data - medium term (3-12 months)
125Risk Ratio (M-H, Fixed, 95% CI)0.53 [0.19, 1.51]

    7.2 haematological - increase white cell count >12,000 - short term (<3 months)
119Risk Ratio (M-H, Fixed, 95% CI)0.56 [0.06, 5.14]

    7.3 liver function - any abnormal data - less than 12 months
125Risk Ratio (M-H, Fixed, 95% CI)2.06 [0.09, 46.11]

    7.4 liver function - increase alkaline phosphate > 35 I.U. - short term (<3 months)
119Risk Ratio (M-H, Fixed, 95% CI)1.67 [0.36, 7.82]

    7.5 renal - abnormal blood urea nitrogen balance - medium term (3-12 months)
125Risk Ratio (M-H, Fixed, 95% CI)0.23 [0.01, 5.12]

 8 Adverse effects: 5. Central nervous system effects2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    8.1 drowsiness - short term (<3 months)
119Risk Ratio (M-H, Fixed, 95% CI)0.22 [0.01, 4.05]

    8.2 sedation - medium term (3-12 months)
125Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.03, 3.20]

    8.3 headache - medium term (3-12 months)
125Risk Ratio (M-H, Fixed, 95% CI)2.33 [0.60, 9.02]

    8.4 insomnia - medium term (3-12 months)
125Risk Ratio (M-H, Fixed, 95% CI)0.58 [0.31, 1.09]

    8.5 memory defects - medium term (3-12 months)
125Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 9 Adverse effects: 6. Dermatological effects1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    9.1 dermatitis - medium term (3-12 months)
125Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.03, 3.20]

 10 Adverse effects: 7. Endocrine effects1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    10.1 galactorrhoea - medium term (3-12 months)
130Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 11 Adverse effects: 8. Gastrointestinal effects2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    11.1 acute cholecystitis - short term (<3 months)
145Risk Ratio (M-H, Fixed, 95% CI)1.41 [0.06, 32.53]

    11.2 constipation - medium term (3-12 months)
125Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    11.3 diarrhoea - medium term (3-12 months)
125Risk Ratio (M-H, Fixed, 95% CI)0.22 [0.03, 1.85]

    11.4 nausea - medium term (3-12 months)
125Risk Ratio (M-H, Fixed, 95% CI)0.22 [0.03, 1.85]

 12 Adverse effects: 9. Other4262Risk Ratio (M-H, Fixed, 95% CI)0.57 [0.34, 0.96]

    12.1 anorgasmia - medium term (3-12 months)
125Risk Ratio (M-H, Fixed, 95% CI)2.06 [0.09, 46.11]

    12.2 intensified symptoms - short term (<3 months)
145Risk Ratio (M-H, Fixed, 95% CI)0.09 [0.00, 1.83]

    12.3 intensified symptoms - medium term (3-12 months)
141Risk Ratio (M-H, Fixed, 95% CI)0.42 [0.15, 1.16]

    12.4 weight loss - short term (<3 months)
119Risk Ratio (M-H, Fixed, 95% CI)0.63 [0.28, 1.46]

    12.5 weight loss - medium term (3-12 months)
125Risk Ratio (M-H, Fixed, 95% CI)0.44 [0.09, 2.20]

    12.6 weight gain - medium term (3-12 months)
125Risk Ratio (M-H, Fixed, 95% CI)3.44 [0.18, 64.88]

    12.7 ocular pigment deposit increase - short term (<3 months)
119Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    12.8 ocular pigment deposit decrease - short term (<3 months)
119Risk Ratio (M-H, Fixed, 95% CI)0.37 [0.02, 8.01]

    12.9 nasal congestion - medium term (3-12 months)
125Risk Ratio (M-H, Fixed, 95% CI)0.23 [0.01, 5.12]

    12.10 dreams (unpleasant) - short term (<3 months)
119Risk Ratio (M-H, Fixed, 95% CI)3.3 [0.15, 72.08]

 13 Leaving the study early: 1. Due to adverse effects3104Risk Ratio (M-H, Fixed, 95% CI)0.21 [0.03, 1.33]

    13.1 short term (<3 months)
145Risk Ratio (M-H, Fixed, 95% CI)0.23 [0.02, 2.29]

    13.2 medium term (3-12 months)
259Risk Ratio (M-H, Fixed, 95% CI)0.19 [0.01, 3.75]

 14 Leaving the study early: 2. Any reason4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    14.1 short term (<3 months)
390Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.30, 3.39]

    14.2 medium term (3-12 months)
266Risk Ratio (M-H, Fixed, 95% CI)0.35 [0.17, 0.72]

 
Comparison 2. PIMOZIDE versus PLACEBO: withdrawal study

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Global state: 1. Relapse - clinical diagnoses1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 medium term (3-12 months)
140Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.01, 7.72]

 2 Mental state: 1. Use of additional medication1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 medium term (3-12 months)
140Risk Ratio (M-H, Fixed, 95% CI)0.18 [0.06, 0.51]

 3 Adverse effects: 1. Death1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 medium term (3-12 months)
140Risk Ratio (M-H, Fixed, 95% CI)3.0 [0.13, 69.52]

 4 Leaving the study early: 1. Any reason1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 medium term (3-12 months)
140Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.07, 14.90]

 
Comparison 3. PIMOZIDE versus ANY ANTIPSYCHOTIC

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Service utilisation: 1. Hospital admission1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 medium term (3-12 months)
144Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.35, 1.98]

 2 Global state: 1. Relapse - clinical diagnoses9Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 short term (<3 months)
260Risk Ratio (M-H, Fixed, 95% CI)1.67 [0.23, 11.87]

    2.2 medium term (3-12 months)
7227Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.57, 1.17]

 3 Global state: 2. No improvement10Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 short term (<3 months)
5146Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.48, 1.17]

    3.2 medium term (3-12 months)
6186Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.75, 1.31]

 4 Global state: 3. Average score - CGI (high = poor)1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    4.1 short term (<3 months)
116Mean Difference (IV, Fixed, 95% CI)-0.15 [-1.25, 0.95]

 5 Mental state: 1. Average score - BPRS (high = poor)1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    5.1 short term (<3 months)
116Mean Difference (IV, Fixed, 95% CI)-13.88 [-28.21, 0.45]

 6 Mental state: 2. Average score - MADRS (high = poor, skewed)Other dataNo numeric data

    6.1 short term (<3 months)
Other dataNo numeric data

 7 Mental state: 3. No improvement2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    7.1 short term (<3 months)
254Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.43, 1.96]

    7.2 medium term (3-12 months)
123Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.08, 15.41]

 8 Mental state: 4. Specific symptoms5Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    8.1 anxiety/tension - medium term (3-12 months)
3161Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.20, 2.29]

    8.2 depression - short term (<3 months)
144Risk Ratio (M-H, Fixed, 95% CI)0.61 [0.30, 1.21]

    8.3 depression - medium term (3-12 months)
274Risk Ratio (M-H, Fixed, 95% CI)0.48 [0.26, 0.89]

    8.4 no improvement in psychomotor activity - short term (<3 months)
120Risk Ratio (M-H, Fixed, 95% CI)0.4 [0.10, 1.60]

    8.5 presence of first-rank symptoms - short term (<3 months)
144Risk Ratio (M-H, Fixed, 95% CI)0.56 [0.24, 1.29]

    8.6 presence of first-rank symptoms - medium term (3-12 months)
144Risk Ratio (M-H, Fixed, 95% CI)0.53 [0.25, 1.11]

 9 Mental state: 5. Use of additional medication3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    9.1 short term (<3 months)
3114Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.77, 1.49]

 10 Adverse effects: 1. Extrapyramidal adverse effects - specific13Risk Ratio (M-H, Random, 95% CI)Subtotals only

    10.1 akathisia - short term (<3 months)
4148Risk Ratio (M-H, Random, 95% CI)1.18 [0.79, 1.76]

    10.2 akathisia - medium term (3-12 months)
5219Risk Ratio (M-H, Random, 95% CI)1.17 [0.26, 5.22]

    10.3 acute dyskinesia - short term (<3 months)
129Risk Ratio (M-H, Random, 95% CI)2.68 [0.62, 11.64]

    10.4 dystonia - short term (<3 months)
242Risk Ratio (M-H, Random, 95% CI)0.78 [0.25, 2.48]

    10.5 dystonia - medium term (3-12 months)
250Risk Ratio (M-H, Random, 95% CI)1.30 [0.28, 6.00]

    10.6 gait disturbance - short term (<3 months)
259Risk Ratio (M-H, Random, 95% CI)1.18 [0.16, 8.62]

    10.7 gait disturbance - medium term (3-12 months)
138Risk Ratio (M-H, Random, 95% CI)0.25 [0.03, 2.04]

    10.8 hypersalivation - short term (<3 months)
3115Risk Ratio (M-H, Random, 95% CI)0.98 [0.31, 3.12]

    10.9 hypersalivation - medium term (3-12 months)
3102Risk Ratio (M-H, Random, 95% CI)0.88 [0.13, 6.15]

    10.10 involuntary movements - medium term (3-12 months)
187Risk Ratio (M-H, Random, 95% CI)0.34 [0.01, 8.14]

    10.11 Parkinsonism - short term (<3 months)
156Risk Ratio (M-H, Random, 95% CI)1.25 [0.37, 4.17]

    10.12 Parkinsonism - medium term (3-12 months)
2131Risk Ratio (M-H, Random, 95% CI)2.12 [0.28, 15.90]

    10.13 restlessness - short term (<3 months)
3101Risk Ratio (M-H, Random, 95% CI)1.20 [0.62, 2.34]

    10.14 restlessness - medium term (3-12 months)
3134Risk Ratio (M-H, Random, 95% CI)2.59 [0.41, 16.49]

    10.15 rigidity - short term (<3 months)
6186Risk Ratio (M-H, Random, 95% CI)1.21 [0.71, 2.05]

    10.16 rigidtiy - medium term (3-12 months)
5219Risk Ratio (M-H, Random, 95% CI)1.12 [0.24, 5.25]

    10.17 seizure - short term (<3 months)
129Risk Ratio (M-H, Random, 95% CI)0.36 [0.02, 8.07]

    10.18 tardive dyskinesia - short term (<3 months)
143Risk Ratio (M-H, Random, 95% CI)0.79 [0.05, 11.85]

    10.19 tardive dyskinesia - medium term (3-12 months)
4108Risk Ratio (M-H, Random, 95% CI)1.27 [0.73, 2.23]

    10.20 tremor - short term (<3 months)
6186Risk Ratio (M-H, Random, 95% CI)1.52 [0.97, 2.38]

    10.21 tremor - medium term (3-12 months)
4175Risk Ratio (M-H, Random, 95% CI)1.46 [0.68, 3.11]

    10.22 use of antiparkinsonian drugs - short term (<3 months)
267Risk Ratio (M-H, Random, 95% CI)1.46 [0.54, 3.94]

    10.23 use of antiparkinsonian drugs - by medium term (3-12 months)
3116Risk Ratio (M-H, Random, 95% CI)0.84 [0.41, 1.72]

 11 Adverse effects: 2. Extrapyramidal adverse effects: average score - EPS (high = poor, skewed)Other dataNo numeric data

    11.1 short term (<3 months)
Other dataNo numeric data

 12 Adverse effects: 3. Death1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    12.1 suicide - medium term (3-12 months)
151Risk Ratio (M-H, Fixed, 95% CI)0.32 [0.01, 7.53]

 13 Adverse effects: 4. Anticholinergic effects9Risk Ratio (M-H, Random, 95% CI)Subtotals only

    13.1 blurred vision - short term (<3 months)
4110Risk Ratio (M-H, Random, 95% CI)0.98 [0.46, 2.09]

    13.2 blurred vision - medium term (3-12 months)
5219Risk Ratio (M-H, Random, 95% CI)0.98 [0.45, 2.12]

    13.3 dry mouth - short term (<3 months)
5166Risk Ratio (M-H, Random, 95% CI)0.84 [0.54, 1.31]

    13.4 dry mouth - medium term (3-12 months)
4175Risk Ratio (M-H, Random, 95% CI)0.44 [0.23, 0.85]

    13.5 sweating - short term (<3 months)
285Risk Ratio (M-H, Random, 95% CI)2.16 [0.29, 15.96]

    13.6 urinary retention - short term (<3 months)
3121Risk Ratio (M-H, Random, 95% CI)1.26 [0.28, 5.67]

    13.7 urinary retention - medium term (3-12 months)
2125Risk Ratio (M-H, Random, 95% CI)0.26 [0.03, 2.25]

 14 Adverse effects: 5. Cardio-vascular effects10Risk Ratio (M-H, Random, 95% CI)Subtotals only

    14.1 chest pain - medium term (3-12 months)
130Risk Ratio (M-H, Random, 95% CI)0.33 [0.01, 7.58]

    14.2 dizziness - short term (<3 months)
5161Risk Ratio (M-H, Random, 95% CI)0.73 [0.26, 2.02]

    14.3 dizziness - medium term (3-12 months)
3161Risk Ratio (M-H, Random, 95% CI)1.08 [0.34, 3.43]

    14.4 ECG changes - short term (<3 months)
156Risk Ratio (M-H, Random, 95% CI)0.33 [0.04, 3.01]

    14.5 hypotension - short term (<3 months)
4143Risk Ratio (M-H, Random, 95% CI)1.13 [0.50, 2.59]

    14.6 hypotension - medium term (3-12 months)
143Risk Ratio (M-H, Random, 95% CI)0.32 [0.07, 1.46]

    14.7 hypotension (postural) - short term (<3 months)
242Risk Ratio (M-H, Random, 95% CI)0.33 [0.06, 1.92]

    14.8 hypertension - short term (<3 months)
156Risk Ratio (M-H, Random, 95% CI)1.0 [0.07, 15.21]

    14.9 hypertension - medium term (3-12 months)
187Risk Ratio (M-H, Random, 95% CI)0.51 [0.05, 5.44]

    14.10 palpitations - short term (<3 months)
278Risk Ratio (M-H, Random, 95% CI)1.28 [0.31, 5.28]

    14.11 substernal pain - medium term (3-12 months)
130Risk Ratio (M-H, Random, 95% CI)0.33 [0.01, 7.58]

    14.12 tachycardia - short term (<3 months)
129Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 15 Adverse effects: 6. Abnormal laboratory tests4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    15.1 haematological - granulocytopenia - short term (<3 months)
120Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.02, 7.32]

    15.2 haematological - leukocytosis - short term (<3 months)
120Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.34, 2.93]

    15.3 haematological - leukocytosis - medium term (<3 months)
151Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.06, 14.55]

    15.4 haematological - macrocytosis - short term (<3 months)
120Risk Ratio (M-H, Fixed, 95% CI)5.0 [0.27, 92.62]

    15.5 haematological - any abnormal lab haematology - medium term (3-12 months)
130Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.31, 3.28]

    15.6 liver function - abnormal laboratory data - medium term (3-12 months)
130Risk Ratio (M-H, Fixed, 95% CI)0.2 [0.03, 1.51]

    15.7 renal function - albumin in urinalysis - short term (<3 months)
120Risk Ratio (M-H, Fixed, 95% CI)3.0 [0.14, 65.90]

    15.8 renal function - granular casts in urinalysis - short term (<3 months)
120Risk Ratio (M-H, Fixed, 95% CI)3.0 [0.14, 65.90]

    15.9 renal function - urea / nitrogen abnormal - medium term (3-12 months)
130Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 16 Adverse effects: 7. Central nervous system effects12Risk Ratio (M-H, Random, 95% CI)Subtotals only

    16.1 drowsiness - short term (<3 months)
7226Risk Ratio (M-H, Random, 95% CI)0.77 [0.60, 1.00]

    16.2 drowsiness - medium term (3-12 months)
5229Risk Ratio (M-H, Random, 95% CI)0.61 [0.33, 1.11]

    16.3 excitement - short term (<3 months)
120Risk Ratio (M-H, Random, 95% CI)3.0 [0.14, 65.90]

    16.4 excitement - medium term (3-12 months)
187Risk Ratio (M-H, Random, 95% CI)0.68 [0.12, 3.88]

    16.5 faintness - medium term (3-12 months)
120Risk Ratio (M-H, Random, 95% CI)0.2 [0.01, 3.70]

    16.6 fatigue - short term (<3 months)
3101Risk Ratio (M-H, Random, 95% CI)1.07 [0.57, 2.00]

    16.7 headache - short term (<3 months)
4161Risk Ratio (M-H, Random, 95% CI)0.67 [0.21, 2.07]

    16.8 headache - medium term (3-12 months)
5219Risk Ratio (M-H, Random, 95% CI)2.14 [0.84, 5.45]

    16.9 insomnia - short term (<3 months)
3101Risk Ratio (M-H, Random, 95% CI)1.02 [0.67, 1.55]

    16.10 insomnia - medium term (3-12 months)
4181Risk Ratio (M-H, Random, 95% CI)0.92 [0.35, 2.39]

    16.11 memory defects - medium term (3-12 months)
130Risk Ratio (M-H, Random, 95% CI)0.33 [0.01, 7.58]

    16.12 restlessness - short term (<3 months)
156Risk Ratio (M-H, Random, 95% CI)0.88 [0.37, 2.09]

    16.13 restlessness - medium term (3-12 months)
295Risk Ratio (M-H, Random, 95% CI)2.46 [0.26, 22.89]

    16.14 sedation - short term (<3 months)
143Risk Ratio (M-H, Random, 95% CI)0.79 [0.47, 1.34]

    16.15 sedation - medium term (3-12 months)
3155Risk Ratio (M-H, Random, 95% CI)0.30 [0.12, 0.72]

 17 Adverse effects: 8. Dermatological effects7Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    17.1 acne vulgaris - short term (<3 months)
120Risk Ratio (M-H, Fixed, 95% CI)3.0 [0.14, 65.90]

    17.2 dermatitis - medium term (3-12 months)
130Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.07, 14.55]

    17.3 itching - medium term (3-12 months)
2131Risk Ratio (M-H, Fixed, 95% CI)0.61 [0.08, 4.46]

    17.4 rashes - short term (<3 months)
3145Risk Ratio (M-H, Fixed, 95% CI)1.75 [0.47, 6.53]

    17.5 rashes - medium term (3-12 months)
2125Risk Ratio (M-H, Fixed, 95% CI)0.38 [0.11, 1.31]

 18 Adverse effects: 9. Endocrine effects3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    18.1 amenorrhoea - short term (<3 months)
156Risk Ratio (M-H, Fixed, 95% CI)5.0 [0.25, 99.67]

    18.2 amenorrhoea - medium term (3-12 months)
120Risk Ratio (M-H, Fixed, 95% CI)3.0 [0.14, 65.90]

    18.3 galactorrhoea - medium term (3-12 months)
130Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.01, 7.58]

 19 Adverse effects: 10. Gastrointestinal effects12Risk Ratio (M-H, Random, 95% CI)Subtotals only

    19.1 abdominal cramps - medium term (3-12 months)
3151Risk Ratio (M-H, Random, 95% CI)1.97 [0.35, 10.95]

    19.2 anal incontinence - short term (<3 months)
120Risk Ratio (M-H, Random, 95% CI)3.0 [0.14, 65.90]

    19.3 appetite decrease - short term (<3 months)
285Risk Ratio (M-H, Random, 95% CI)1.34 [0.22, 8.07]

    19.4 appetite decrease - medium term (3-12 months)
2107Risk Ratio (M-H, Random, 95% CI)1.05 [0.16, 6.84]

    19.5 appetite increase - short term (<3 months)
285Risk Ratio (M-H, Random, 95% CI)0.65 [0.15, 2.83]

    19.6 constipation - short term (<3 months)
5190Risk Ratio (M-H, Random, 95% CI)0.64 [0.31, 1.30]

    19.7 constipation - medium term (3-12 months)
4132Risk Ratio (M-H, Random, 95% CI)0.75 [0.30, 1.88]

    19.8 diarrhoea - short term (<3 months)
276Risk Ratio (M-H, Random, 95% CI)1.02 [0.11, 9.33]

    19.9 diarrhoea - medium term (3-12 months)
130Risk Ratio (M-H, Random, 95% CI)3.0 [0.13, 68.26]

    19.10 nausea and vomiting - short term (<3 months)
276Risk Ratio (M-H, Random, 95% CI)0.28 [0.05, 1.61]

    19.11 nausea - short term (<3 months)
116Risk Ratio (M-H, Random, 95% CI)5.0 [0.28, 90.18]

    19.12 nausea - medium term (3-12 months)
5203Risk Ratio (M-H, Random, 95% CI)0.64 [0.24, 1.69]

    19.13 vomiting - short term (<3 months)
259Risk Ratio (M-H, Random, 95% CI)3.0 [0.14, 64.26]

    19.14 vomiting - medium term (3-12 months)
2125Risk Ratio (M-H, Random, 95% CI)0.77 [0.08, 7.40]

    19.15 acute cholecystitis - short term (<3 months)
160Risk Ratio (M-H, Random, 95% CI)2.81 [0.12, 66.40]

 20 Adverse effects: 11. Genitourinary effects3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    20.1 anorgasmia - medium term (3-12 months)
130Risk Ratio (M-H, Fixed, 95% CI)3.0 [0.13, 68.26]

    20.2 nocturia - medium term (3-12 months)
187Risk Ratio (M-H, Fixed, 95% CI)0.34 [0.01, 8.14]

    20.3 dysuria - short term (<3 months)
156Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.01, 7.85]

 21 Adverse effects: 12. Other11Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    21.1 increased thirst - short term (<3 months)
129Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    21.2 nasal congestion - medium term (3-12 months)
130Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    21.3 intensified symptoms - short term (<3 months)
2116Risk Ratio (M-H, Fixed, 95% CI)0.48 [0.09, 2.50]

    21.4 intensified symptoms - medium term (3-12 months)
292Risk Ratio (M-H, Fixed, 95% CI)0.59 [0.27, 1.28]

    21.5 weight loss - short term (<3 months)
120Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.04, 2.69]

    21.6 weight loss - medium term (3-12 months)
3161Risk Ratio (M-H, Fixed, 95% CI)1.38 [0.48, 3.98]

    21.7 weight gain - short term (<3 months)
143Risk Ratio (M-H, Fixed, 95% CI)1.58 [0.16, 16.17]

    21.8 weight gain - medium term (3-12 months)
4175Risk Ratio (M-H, Fixed, 95% CI)1.55 [0.56, 4.33]

 22 Social functioning: 1. Average score - SBAS (high = poor, skewed)Other dataNo numeric data

    22.1 medium term (3-12 months)
Other dataNo numeric data

 23 Leaving the study early: 1. Due to relapse4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    23.1 short term (<3 months)
120Risk Ratio (M-H, Fixed, 95% CI)3.0 [0.14, 65.90]

    23.2 medium term (3-12 months)
376Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.28, 2.78]

 24 Leaving the study early: 2. Due to adverse effects14Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    24.1 short term (<3 months)
7258Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.32, 2.01]

    24.2 medium term (3-12 months)
7252Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.57, 1.72]

 25 Leaving the study early: 3. Any reason25Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    25.1 short term (<3 months)
11368Risk Ratio (M-H, Fixed, 95% CI)1.23 [0.63, 2.40]

    25.2 medium term (3-12 months)
14523Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.69, 1.09]

    25.3 long term (>12 months)
162Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.60, 1.67]

 
Analysis 3.6 Comparison 3 PIMOZIDE versus ANY ANTIPSYCHOTIC, Outcome 6 Mental state: 2. Average score - MADRS (high = poor, skewed).
Mental state: 2. Average score - MADRS (high = poor, skewed)

StudyInterventionMeanSDN

short term (<3 months)

Silverstone 1984pimozide4.73.6110

Silverstone 1984haloperidol4.74.1512

 
Analysis 3.11 Comparison 3 PIMOZIDE versus ANY ANTIPSYCHOTIC, Outcome 11 Adverse effects: 2. Extrapyramidal adverse effects: average score - EPS (high = poor, skewed).
Adverse effects: 2. Extrapyramidal adverse effects: average score - EPS (high = poor, skewed)

StudyInterventionMeanSDN

short term (<3 months)

Pecknold 1980pimozide10.123.848

Pecknold 1980chlorpromazine0.751.488

 
Analysis 3.22 Comparison 3 PIMOZIDE versus ANY ANTIPSYCHOTIC, Outcome 22 Social functioning: 1. Average score - SBAS (high = poor, skewed).
Social functioning: 1. Average score - SBAS (high = poor, skewed)

StudyInterventionMeanSDN

medium term (3-12 months)

Barnes 1983pimozide7.16.917

Barnes 1983fluphenazine7.36.119

 
Comparison 4. PIMOZIDE + ANY ANTIPSYCHOTIC versus ANY ANTIPSYCHOTIC

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Global state: 1. Relapse - clinical diagnoses1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 medium term (3-12 months)
169Risk Ratio (M-H, Fixed, 95% CI)0.28 [0.15, 0.50]

 2 Leaving the study early: 1. Any reason1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 medium term (3-12 months)
169Risk Ratio (M-H, Fixed, 95% CI)0.56 [0.42, 0.74]

 
Comparison 5. PIMOZIDE + ANY ANTIPSYCHOTIC versus ANY ANTIPSYCHOTIC + PLACEBO

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Global state: 1. Average score - CGI (high = poor, skewed)Other dataNo numeric data

    1.2 medium term (3-12 months)
Other dataNo numeric data

 2 Global state: 2. Average score - CGI-S (high = poor)1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    2.1 short term (<3 months)
128Mean Difference (IV, Fixed, 95% CI)0.0 [-0.49, 0.49]

 3 Global state: 3. Average score - CGI-I (high = poor)1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    3.1 short term (<3 months)
128Mean Difference (IV, Fixed, 95% CI)0.60 [0.01, 1.19]

 4 Mental state: 1. Average score - BPRS (high = poor)1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    4.1 short term (<3 months)
128Mean Difference (IV, Fixed, 95% CI)1.70 [0.14, 3.26]

 5 Mental state: 2. Average score - BPRS psychosis subscale (high = poor)1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    5.1 short term (<3 months)
128Mean Difference (IV, Fixed, 95% CI)1.70 [0.96, 2.44]

 6 Mental state: 3. Average score - PANSS (high = poor, skewed)Other dataNo numeric data

    6.1 medium term (3-12 months)
Other dataNo numeric data

 7 Mental state: 4. Average score - SANS (high = poor)1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    7.1 short term (<3 months)
128Mean Difference (IV, Fixed, 95% CI)1.0 [-3.37, 5.37]

 8 Adverse effects: 1. Extrapyramidal adverse effects - specific1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    8.1 hypersalivation - medium term (3-12 months)
153Risk Ratio (M-H, Fixed, 95% CI)2.99 [0.89, 10.04]

 9 Adverse effects: 2. Extrapyramidal adverse effects: average score - ESRS (high = poor, skewed)Other dataNo numeric data

    9.1 parkinsonism - medium term (3-12 months)
Other dataNo numeric data

    9.2 dystonia - medium term (3-12 months)
Other dataNo numeric data

    9.3 dyskinesia - medium term (3-12 months)
Other dataNo numeric data

 10 Adverse effects: 3. Cardiovascular effects1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    10.1 bigeminy - medium term (3-12 months)
153Risk Ratio (M-H, Fixed, 95% CI)0.37 [0.02, 8.73]

    10.2 hypotension - medium term (3-12 months)
153Risk Ratio (M-H, Fixed, 95% CI)0.37 [0.02, 8.73]

 11 Adverse effects: 4. Cardiovascular effects - average score (high = poor)1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    11.1 QTc (ms) - short term (<3 months)
128Mean Difference (IV, Fixed, 95% CI)7.40 [3.62, 11.18]

 12 Adverse effects: 5. Cardiovascular effects - average score (high = poor, skewed)Other dataNo numeric data

    12.1 diastolic blood pressure (mm Hg) - medium term (3-12 months)
Other dataNo numeric data

    12.2 heart rate (bpm) - medium term (3-12 months)
Other dataNo numeric data

    12.3 QTc (ms) - medium term (3-12 months)
Other dataNo numeric data

    12.4 systolic blood pressure (mm Hg) - medium term (3-12 months)
Other dataNo numeric data

 13 Adverse effects: 6. Abnormal laboratory tests - average score (skewed)Other dataNo numeric data

    13.1 absolute neutrophil count (count/mm 3) - medium term (3-12 months)
Other dataNo numeric data

    13.2 plasma glucose level (mg/dL) - medium term (3-12 months)
Other dataNo numeric data

    13.3 total cholesterol level (mg/dL) - medium term (3-12 months)
Other dataNo numeric data

    13.4 triglyceride level (mg/dL) - medium term (3-12 months)
Other dataNo numeric data

 14 Adverse effects: 7. Other1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    14.1 intensified symptoms - medium term (3-12 months)
153Risk Ratio (M-H, Fixed, 95% CI)0.22 [0.01, 4.44]

 15 Quality of life: 1. Average score - SLOF (high = better, skewed)Other dataNo numeric data

    15.1 physical function (SLOF) - medium term (3-12 months)
Other dataNo numeric data

    15.2 personal care (SLOF) - medium term (3-12 months)
Other dataNo numeric data

    15.3 interpersonal relationships (SLOF) - medium term (3-12 months)
Other dataNo numeric data

    15.4 social acceptability (SLOF) - medium term (3-12 months)
Other dataNo numeric data

    15.5 work skills (SLOF) - medium term (3-12 months)
Other dataNo numeric data

 16 Leaving the study early: 1. Due to adverse effects281Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.22, 3.25]

    16.1 short term (<3 months)
128Risk Ratio (M-H, Fixed, 95% CI)3.0 [0.13, 67.91]

    16.2 medium term (3-12 months)
153Risk Ratio (M-H, Fixed, 95% CI)0.56 [0.11, 2.80]

 17 Leaving the study early: 2. Any reason281Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.35, 3.33]

    17.1 short term (<3 months)
128Risk Ratio (M-H, Fixed, 95% CI)5.0 [0.26, 95.61]

    17.2 medium term (3-12 months)
153Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.18, 2.53]

 
Analysis 5.1 Comparison 5 PIMOZIDE + ANY ANTIPSYCHOTIC versus ANY ANTIPSYCHOTIC + PLACEBO, Outcome 1 Global state: 1. Average score - CGI (high = poor, skewed).
Global state: 1. Average score - CGI (high = poor, skewed)

StudyInterventionMeanSDN

medium term (3-12 months)

Friedman 2011pimozide + clozapine-0.140.5625

Friedman 2011placebo + clozapine-0.350.5728

 
Analysis 5.6 Comparison 5 PIMOZIDE + ANY ANTIPSYCHOTIC versus ANY ANTIPSYCHOTIC + PLACEBO, Outcome 6 Mental state: 3. Average score - PANSS (high = poor, skewed).
Mental state: 3. Average score - PANSS (high = poor, skewed)

StudyInterventionMeanSDN

medium term (3-12 months)

Friedman 2011pimozide + clozapine-0.7510.6025

Friedman 2011placebo + clozapine-3.5910.1528

 
Analysis 5.9 Comparison 5 PIMOZIDE + ANY ANTIPSYCHOTIC versus ANY ANTIPSYCHOTIC + PLACEBO, Outcome 9 Adverse effects: 2. Extrapyramidal adverse effects: average score - ESRS (high = poor, skewed).
Adverse effects: 2. Extrapyramidal adverse effects: average score - ESRS (high = poor, skewed)

StudyInterventionMeanSDN

parkinsonism - medium term (3-12 months)

Friedman 2011pimozide + clozapine1.594.3725

Friedman 2011placebo + clozapine1.374.2728

dystonia - medium term (3-12 months)

Friedman 2011pimozide + clozapine-0.091.6325

Friedman 2011placebo + clozapine0.501.9828

dyskinesia - medium term (3-12 months)

Friedman 2011pimozide + clozapine-0.051.8925

Friedman 2011placebo + clozapine-0.214.0128

 
Analysis 5.12 Comparison 5 PIMOZIDE + ANY ANTIPSYCHOTIC versus ANY ANTIPSYCHOTIC + PLACEBO, Outcome 12 Adverse effects: 5. Cardiovascular effects - average score (high = poor, skewed).
Adverse effects: 5. Cardiovascular effects - average score (high = poor, skewed)

StudyInterventionMeanSDN

diastolic blood pressure (mm Hg) - medium term (3-12 months)

Friedman 2011pimozide + clozapine-0.329.3925

Friedman 2011placebo + clozapine1.048.7428

heart rate (bpm) - medium term (3-12 months)

Friedman 2011pimozide + clozapine1.5912.3925

Friedman 2011placebo + clozapine2.167.3328

QTc (ms) - medium term (3-12 months)

Friedman 2011pimozide + clozapine9.0424.7025

Friedman 2011placebo + clozapine-1.5029.5928

systolic blood pressure (mm Hg) - medium term (3-12 months)

Friedman 2011pimozide + clozapine0.9110.5925

Friedman 2011placebo + clozapine-1.3713.3928

 
Analysis 5.13 Comparison 5 PIMOZIDE + ANY ANTIPSYCHOTIC versus ANY ANTIPSYCHOTIC + PLACEBO, Outcome 13 Adverse effects: 6. Abnormal laboratory tests - average score (skewed).
Adverse effects: 6. Abnormal laboratory tests - average score (skewed)

StudyInterventionMeanSDN

absolute neutrophil count (count/mm 3) - medium term (3-12 months)

Friedman 2011pimozide + clozapine0.271.0725

Friedman 2011placebo + clozapine-0.401.5228

plasma glucose level (mg/dL) - medium term (3-12 months)

Friedman 2011pimozide + clozapine4.3118.8725

Friedman 2011placebo + clozapine-0.1014.2028

total cholesterol level (mg/dL) - medium term (3-12 months)

Friedman 2011pimozide + clozapine-1.5625.3425

Friedman 2011placebo + clozapine-12.2940.0128

triglyceride level (mg/dL) - medium term (3-12 months)

Friedman 2011pimozide + clozapine-5.1946.6025

Friedman 2011placebo + clozapine-28.3560.3528

 
Analysis 5.15 Comparison 5 PIMOZIDE + ANY ANTIPSYCHOTIC versus ANY ANTIPSYCHOTIC + PLACEBO, Outcome 15 Quality of life: 1. Average score - SLOF (high = better, skewed).
Quality of life: 1. Average score - SLOF (high = better, skewed)

StudyInterventionMeanSDN

physical function (SLOF) - medium term (3-12 months)

Friedman 2011pimozide + clozapine01.2825

Friedman 2011placebo + clozapine0.180.6628

personal care (SLOF) - medium term (3-12 months)

Friedman 2011pimozide + clozapine0.282.6525

Friedman 2011placebo + clozapine0.503.1928

interpersonal relationships (SLOF) - medium term (3-12 months)

Friedman 2011pimozide + clozapine0.525.3825

Friedman 2011placebo + clozapine0.413.1928

social acceptability (SLOF) - medium term (3-12 months)

Friedman 2011pimozide + clozapine0.523.1625

Friedman 2011placebo + clozapine0.182.8128

work skills (SLOF) - medium term (3-12 months)

Friedman 2011pimozide + clozapine0.524.0225

Friedman 2011placebo + clozapine0.183.0328

 
Comparison 6. PIMOZIDE + ANY ANTIPSYCHOTIC versus ANY ANTIPSYCHOTIC + ANY ANTIPSYCHOTIC

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Global state: 1. No improvement1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 short term (<3 months)
120Risk Ratio (M-H, Fixed, 95% CI)5.0 [0.70, 35.50]

 2 Global state: 2. Average score - CGI-S (high = poor)1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    2.1 short term (<3 months)
120Mean Difference (IV, Fixed, 95% CI)2.5 [1.30, 3.70]

 3 Global state: 3. Average score - CGI-I (high = poor)1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    3.1 short term (<3 months)
120Mean Difference (IV, Fixed, 95% CI)1.50 [0.93, 2.07]

 4 Mental state: 1. Average score - SANS (high = poor)1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    4.1 short term (<3 months)
120Mean Difference (IV, Fixed, 95% CI)24.0 [5.98, 42.02]

 5 Mental state: 2. Average score - SAPS (high = poor, skew)Other dataNo numeric data

    5.1 short term (<3 months)
Other dataNo numeric data

 6 Adverse effects: 1. Extrapyramidal adverse effects - average score (high = poor, skew)Other dataNo numeric data

    6.1 akathisia - short term (<3 months)
Other dataNo numeric data

    6.2 akinesia - short term (<3 months)
Other dataNo numeric data

    6.3 EPS symptoms - short term (<3 months)
Other dataNo numeric data

    6.4 rigidity - short term (<3 months)
Other dataNo numeric data

    6.5 tremor - short term (<3 months)
Other dataNo numeric data

 7 Adverse effects: 2. Anticholinergenic effects - average score (high = poor, skew)Other dataNo numeric data

    7.1 blurred vision - short term (<3 months)
Other dataNo numeric data

    7.2 dry mouth - short term (<3 months)
Other dataNo numeric data

 8 Adverse effects: 3. Cardio-vascular effects - average score (high = poor, skew)Other dataNo numeric data

    8.1 dizziness - short term (<3 months)
Other dataNo numeric data

    8.2 hypotension - short term (<3 months)
Other dataNo numeric data

    8.3 tachycardia - short term (<3 months)
Other dataNo numeric data

 9 Adverse effects: 4. Autonomic effects - average score (high = poor, skew)Other dataNo numeric data

    9.1 autonomic effects - short term (<3 months)
Other dataNo numeric data

 10 Adverse effects: 5. Central nervous system effects - average score (high = poor, skew)Other dataNo numeric data

    10.1 drowsiness - short term (<3 months)
Other dataNo numeric data

    10.2 headache - short term (<3 months)
Other dataNo numeric data

    10.3 insomnia - short term (<3 months)
Other dataNo numeric data

 11 Adverse effects: 6. Endocrine effects - average score (high = poor, skew)Other dataNo numeric data

    11.1 amenorrhoea - short term (<3 months)
Other dataNo numeric data

    11.2 endocrine system effects - short term (<3 months)
Other dataNo numeric data

    11.3 galactorrhoea - short term (<3 months)
Other dataNo numeric data

 12 Adverse effects: 7. Gastrointestinal effects - average score (high = poor, skew)Other dataNo numeric data

    12.1 constipation - short term (<3 months)
Other dataNo numeric data

    12.2 nausea - short term (<3 months)
Other dataNo numeric data

    12.3 weight gain - short term (<3 months)
Other dataNo numeric data

    12.4 weight loss - short term (<3 months)
Other dataNo numeric data

 13 Adverse effects: 8. Gastrointestinal effects1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    13.1 constipation - short term (<3 months)
120Risk Ratio (M-H, Fixed, 95% CI)3.0 [0.14, 65.90]

 14 Adverse effects: 9. Other1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    14.1 mammary tension - short term (<3 months)
120Risk Ratio (M-H, Fixed, 95% CI)5.0 [0.70, 35.50]

 15 Adverse effects: 10. Other - average score (high = poor, skew)Other dataNo numeric data

    15.1 gynaecomastia - short term (<3 months)
Other dataNo numeric data

 16 Leaving the study early: 1. Due to adverse effects1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    16.1 short term (<3 months)
120Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.02, 7.32]

 17 Leaving the study early: 2. Any reason1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    17.1 short term (<3 months)
120Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.02, 7.32]

 
Analysis 6.5 Comparison 6 PIMOZIDE + ANY ANTIPSYCHOTIC versus ANY ANTIPSYCHOTIC + ANY ANTIPSYCHOTIC, Outcome 5 Mental state: 2. Average score - SAPS (high = poor, skew).
Mental state: 2. Average score - SAPS (high = poor, skew)

StudyInterventionMeanSDN

short term (<3 months)

De Ronchi 1996pimozide + haloperidol31.020.810

De Ronchi 1996levosulpiride + haloperidol6.94.710

 
Analysis 6.6 Comparison 6 PIMOZIDE + ANY ANTIPSYCHOTIC versus ANY ANTIPSYCHOTIC + ANY ANTIPSYCHOTIC, Outcome 6 Adverse effects: 1. Extrapyramidal adverse effects - average score (high = poor, skew).
Adverse effects: 1. Extrapyramidal adverse effects - average score (high = poor, skew)

StudyInterventionMeanSDN

akathisia - short term (<3 months)

De Ronchi 1996pimozide + haloperidol0.00.010

De Ronchi 1996levosulpiride + haloperidol0.20.410

akinesia - short term (<3 months)

De Ronchi 1996pimozide + haloperidol0.70.510

De Ronchi 1996levosulpiride + haloperidol0.00.010

EPS symptoms - short term (<3 months)

De Ronchi 1996pimozide + haloperidol1.71.110

De Ronchi 1996levosulpiride + haloperidol0.51.010

rigidity - short term (<3 months)

De Ronchi 1996pimozide + haloperidol0.60.510

De Ronchi 1996levosulpiride + haloperidol0.10.310

tremor - short term (<3 months)

De Ronchi 1996pimozide + haloperidol0.40.510

De Ronchi 1996levosulpiride + haloperidol0.20.410

 
Analysis 6.7 Comparison 6 PIMOZIDE + ANY ANTIPSYCHOTIC versus ANY ANTIPSYCHOTIC + ANY ANTIPSYCHOTIC, Outcome 7 Adverse effects: 2. Anticholinergenic effects - average score (high = poor, skew).
Adverse effects: 2. Anticholinergenic effects - average score (high = poor, skew)

StudyInterventionMeanSDN

blurred vision - short term (<3 months)

De Ronchi 1996pimozide + haloperidol0.10.310

De Ronchi 1996levosulpiride + haloperidol0.00.010

dry mouth - short term (<3 months)

De Ronchi 1996pimozide + haloperidol0.30.510

De Ronchi 1996levosulpiride + haloperidol0.10.310

 
Analysis 6.8 Comparison 6 PIMOZIDE + ANY ANTIPSYCHOTIC versus ANY ANTIPSYCHOTIC + ANY ANTIPSYCHOTIC, Outcome 8 Adverse effects: 3. Cardio-vascular effects - average score (high = poor, skew).
Adverse effects: 3. Cardio-vascular effects - average score (high = poor, skew)

StudyInterventionMeanSDN

dizziness - short term (<3 months)

De Ronchi 1996pimozide + haloperidol0.00.010

De Ronchi 1996levosulpiride + haloperidol0.00.010

hypotension - short term (<3 months)

De Ronchi 1996pimozide + haloperidol0.60.510

De Ronchi 1996levosulpiride + haloperidol0.40.510

tachycardia - short term (<3 months)

De Ronchi 1996pimozide + haloperidol0.10.310

De Ronchi 1996levosulpiride + haloperidol0.00.010

 
Analysis 6.9 Comparison 6 PIMOZIDE + ANY ANTIPSYCHOTIC versus ANY ANTIPSYCHOTIC + ANY ANTIPSYCHOTIC, Outcome 9 Adverse effects: 4. Autonomic effects - average score (high = poor, skew).
Adverse effects: 4. Autonomic effects - average score (high = poor, skew)

StudyInterventionMeanSDN

autonomic effects - short term (<3 months)

De Ronchi 1996pimozide + haloperidol1.21.210

De Ronchi 1996levosulpiride + haloperidol0.50.710

 
Analysis 6.10 Comparison 6 PIMOZIDE + ANY ANTIPSYCHOTIC versus ANY ANTIPSYCHOTIC + ANY ANTIPSYCHOTIC, Outcome 10 Adverse effects: 5. Central nervous system effects - average score (high = poor, skew).
Adverse effects: 5. Central nervous system effects - average score (high = poor, skew)

StudyInterventionMeanSDN

drowsiness - short term (<3 months)

De Ronchi 1996pimozide + haloperidol0.10.310

De Ronchi 1996levosulpiride + haloperidol0.00.010

headache - short term (<3 months)

De Ronchi 1996pimozide + haloperidol0.00.010

De Ronchi 1996levosulpiride + haloperidol0.00.010

insomnia - short term (<3 months)

De Ronchi 1996pimozide + haloperidol0.00.010

De Ronchi 1996levosulpiride + haloperidol0.00.010

 
Analysis 6.11 Comparison 6 PIMOZIDE + ANY ANTIPSYCHOTIC versus ANY ANTIPSYCHOTIC + ANY ANTIPSYCHOTIC, Outcome 11 Adverse effects: 6. Endocrine effects - average score (high = poor, skew).
Adverse effects: 6. Endocrine effects - average score (high = poor, skew)

StudyInterventionMeanSDN

amenorrhoea - short term (<3 months)

De Ronchi 1996pimozide + haloperidol0.00.010

De Ronchi 1996levosulpiride + haloperidol0.00.010

endocrine system effects - short term (<3 months)

De Ronchi 1996pimozide + haloperidol1.00.810

De Ronchi 1996levosulpiride + haloperidol0.80.810

galactorrhoea - short term (<3 months)

De Ronchi 1996pimozide + haloperidol0.10.310

De Ronchi 1996levosulpiride + haloperidol0.00.010

 
Analysis 6.12 Comparison 6 PIMOZIDE + ANY ANTIPSYCHOTIC versus ANY ANTIPSYCHOTIC + ANY ANTIPSYCHOTIC, Outcome 12 Adverse effects: 7. Gastrointestinal effects - average score (high = poor, skew).
Adverse effects: 7. Gastrointestinal effects - average score (high = poor, skew)

StudyInterventionMeanSDN

constipation - short term (<3 months)

De Ronchi 1996pimozide + haloperidol0.10.310

De Ronchi 1996levosulpiride + haloperidol0.00.010

nausea - short term (<3 months)

De Ronchi 1996pimozide + haloperidol0.00.010

De Ronchi 1996levosulpiride + haloperidol0.00.010

weight gain - short term (<3 months)

De Ronchi 1996pimozide + haloperidol0.40.510

De Ronchi 1996levosulpiride + haloperidol0.60.510

weight loss - short term (<3 months)

De Ronchi 1996pimozide + haloperidol0.00.010

De Ronchi 1996levosulpiride + haloperidol0.00.010

 
Analysis 6.15 Comparison 6 PIMOZIDE + ANY ANTIPSYCHOTIC versus ANY ANTIPSYCHOTIC + ANY ANTIPSYCHOTIC, Outcome 15 Adverse effects: 10. Other - average score (high = poor, skew).
Adverse effects: 10. Other - average score (high = poor, skew)

StudyInterventionMeanSDN

gynaecomastia - short term (<3 months)

De Ronchi 1996pimozide + haloperidol0.50.510

De Ronchi 1996levosulpiride + haloperidol0.20.410

 
Comparison 7. Sensitivity Analysis: PIMOZIDE vs ANY ANTIPSYCHOTIC - 1. risk of bias

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Mental state: 1. No improvement2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 unclear
124Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.21, 2.66]

    1.2 high risk
130Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.41, 2.70]

 2 Extrapyramidal adverse effects: 1. Specific - Parkinsonism3187Risk Ratio (M-H, Fixed, 95% CI)1.55 [0.56, 4.26]

    2.1 unclear
2143Risk Ratio (M-H, Fixed, 95% CI)1.21 [0.40, 3.64]

    2.2 high risk
144Risk Ratio (M-H, Fixed, 95% CI)5.0 [0.25, 98.52]

 
Summary of findings for the main comparison. PIMOZIDE versus PLACEBO for schizophrenia or related psychoses

PIMOZIDE versus PLACEBO for schizophrenia or related psychoses

Patient or population: patients with schizophrenia or related psychoses
Settings: Inpatient and outpatient (UK, USA)
Intervention: PIMOZIDE versus PLACEBO

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

PlaceboPIMOZIDE

Global state: relapse medium term (3-12 months)
Clinical diagnoses
Follow-up: 1 year
375 per 1000 182 per 1000
(11 to 667)
RR 0.22
(0.03 to 1.78)
20
(1 study)
⊕⊝⊝⊝
very low2,3

Mental state: no improvement medium term (3-12 months) not reportedSee comment.See comment.Not estimable-See comment.No study reported this outcome.

Mental state: specific symptoms first-rank symptoms medium term (3-12 months) not reportedSee comment.See comment.Not estimable-See comment.No study reported this outcome.

Adverse effects: extrapyramidal adverse effects: Parkinsonism (rigidity) short term (<3 months)
Clinical diagnoses
Follow-up: 12 weeks
0 per 100040 per 1000
(0 to 0)
RR 5.5
(0.3 to 101.28)
19
(1 study)
⊕⊝⊝⊝
very low3,5,6

Adverse effects: extrapyramidal adverse effects:Parkinsonism (rigidity) medium term (3-12 months)
Clinical diagnoses
Follow-up: 6 months
100 per 10001133 per 1000
(14 to 1000)
RR 1.33
(0.14 to 12.82)
25
(1 study)
⊕⊝⊝⊝
very low3,6,7

Adverse effects: extrapyramidal adverse effects:Parkinsonism (tremor) medium term (3-12 months)
Clinical diagnoses
Follow-up: 6 months
200 per 10001200 per 1000
(40 to 990)
RR 1
(0.2 to 4.95)
25
(1 study)
⊕⊝⊝⊝
very low3,6,7

Quality of life: no significant change in quality of life/satisfaction medium term (3-12 months) not reportedSee comment.See comment.Not estimable-See comment.No study reported this outcome.

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio.

GRADE Working Group grades of evidence:
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1Mean baseline risk presented for single study.
2Indirectness: 'serious'; comparison of pimozide vs placebo was made during a six-month follow-up period, in which all injections (both active and placebo) were withdrawn from a selection of participants who had remained well throughout the previous 12-month period of the trial.
3Imprecision: 'very serious'; small sample size.
4Mean baseline risk: only one trial reported with 0 events in the control group and 2 events in the intervention group.
5Risk of bias: 'serious'; not all participants from the study accounted for.
6Imprecision: 'very serious'; confidence intervals for best estimate of effect include both 'no effect' and appreciable benefit/harm.
7Risk of bias: 'serious'; raters not independent of treatment in this small, single study.
 
Summary of findings 2. PIMOZIDE versus ANY ANTIPSYCHOTIC for schizophrenia or related psychoses

PIMOZIDE versus ANY ANTIPSYCHOTIC for schizophrenia or related psychoses

Patient or population: patients with schizophrenia or related psychoses
Settings: Inpatient and outpatient (Canada, Japan, UK, USA)
Intervention: PIMOZIDE versus ANY ANTIPSYCHOTIC

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ANY ANTIPSYCHOTICPIMOZIDE

Global state: relapse medium term (3-12 months)
Clinical diagnoses
Follow-up: mean 38 weeks
Low1 RR 0.82
(0.57 to 1.17)
227
(7 studies)
⊕⊕⊕⊝
moderate2

100 per 100082 per 1000
(57 to 117)

Moderate1

400 per 1000328 per 1000
(228 to 468)

High1

800 per 1000656 per 1000
(456 to 936)

Mental state: no improvement medium term (3-12 months)
As defined in each study
Follow-up: 16 weeks
83 per 1000391 per 1000
(7 to 1000)
RR 1.09
(0.08 to 15.41)
23
(1 study)
⊕⊝⊝⊝
very low2,4,5

Mental state: presence of first-rank symptoms medium term (3-12 months)
Clinical diagnoses
Follow-up: 1 years
550 per 10003291 per 1000
(138 to 611)
RR 0.53
(0.25 to 1.11)
44
(1 study)
⊕⊕⊝⊝
low6,7

Adverse effects: extrapyramidal adverse effectsParkinsonism (rigidity) short term (< 3 months)
Clinical diagnoses
Follow-up: mean 14 weeks
Low8 RR 1.25
(0.37 to 4.17)
186
(6 studies)
⊕⊕⊝⊝
low2,9

100 per 1000125 per 1000
(37 to 417)

Moderate8

300 per 1000375 per 1000
(111 to 1000)

High8

600 per 1000750 per 1000
(222 to 1000)

Adverse effects: extrapyramidal adverse effects Parkinsonism (rigidity) medium term (3-12 months)
Clinical diagnoses
Follow-up: mean 26 weeks
See comment.See comment.Not estimable219
(5 studies)
⊕⊕⊝⊝
low6
Not pooled10

Adverse effects: extrapyramidal adverse effects Parkinsonism (tremor) medium term (< 3 months)
Clinical diagnoses
Follow-up: mean 29 weeks
Low11 RR 1.45
(0.68 to 3.09)
175
(4 studies)
⊕⊕⊝⊝
low2,9

0 per 10000 per 1000
(0 to 0)

Moderate11

150 per 1000218 per 1000
(102 to 463)

High11

300 per 1000435 per 1000
(204 to 927)

Quality of life: no significant change in quality of life/satisfaction medium term (3-12 months) not reportedSee comment.See comment.Not estimable-See comment.No study reported this outcome.

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio.

GRADE Working Group grades of evidence:
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1Calculated from the included studies: presents 3 risks based on the control group risks, 'moderate' equates with that of the control group (25.7%).
2Imprecision: 'serious': confidence intervals for best estimate of effect include both 'no effect' and appreciable benefit/harm.
3Mean baseline risk presented for single study.
4Risk of bias: 'very serious': no description of randomisation.
5Risk of bias: 'very serious': numbers of participants lost to follow-up are unclear, as are the numbers of participants included in the analysis.
6Imprecision: 'very serious': confidence intervals for best estimate of effect include both 'no effect' and appreciable benefit/harm.
7Imprecision: 'very serious': small sample size.
8Calculated from the included studies: presents 3 risks based on control group risks, 'moderate' equates with that of control group (30.4%).
9Risk of bias: 'serious': each included study was judged to be at high risk of bias across one or more of the domains of randomisation.
10Not pooled: high levels of heterogeneity (Chi² = 8.31, I² = 52%) due to differing doses of study medication and differing antipsychotics used as control.
11Calculated from the included studies: presents 3 risks based on the control group risks, 'moderate' equates with that of the control group (10.2%).
 
Summary of findings 3. PIMOZIDE + ANY ANTIPSYCHOTIC versus ANY ANTIPSYCHOTIC for schizophrenia or related psychoses

PIMOZIDE + ANY ANTIPSYCHOTIC versus ANY ANTIPSYCHOTIC for schizophrenia or related psychoses

Patient or population: patients with schizophrenia or related psychoses
Settings: Inpatient and outpatient (Japan, USA)
Intervention: PIMOZIDE + ANY ANTIPSYCHOTIC versus ANY ANTIPSYCHOTIC

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ANY ANTIPSYCHOTICPIMOZIDE + ANY ANTIPSYCHOTIC

Global state: relapsemedium term (3-12 months)
Clinical diagnoses
Follow-up: 1 years
773 per 10001216 per 1000
(116 to 386)
RR 0.28
(0.15 to 0.50)
69
(1 study)
⊕⊕⊝⊝
low2

Mental state: no improvementmedium term (3-12 months)not reportedSee comment.See comment.Not estimable-See comment.No study reported this outcome.

Mental state: presence of first-rank symptoms medium term (3-12 months)not reportedSee comment.See comment.Not estimable-See comment.No study reported this outcome.

Adverse effects: extrapyramidal adverse effects Parkinsonismshort term (< 3 months) not reportedSee comment.See comment.Not estimable-See comment.No study reported this outcome.

Adverse effects: extrapyramidal adverse effects Parkinsonismmedium term (3-12 months) not reportedSee comment.See comment.Not estimable-See comment.No study reported this outcome.

Quality of life: average change score medium term (3-12 months)
Specific Level of Functioning, SLOF (high = better, skewed)
The mean quality of life: average change score medium term (3-12 months) in the intervention groups was
0 higher
(0 to 0 higher)
53
(1)
See comment.Results are skewed and are presented in a separate table (see Data and analyses).

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio.

GRADE Working Group grades of evidence:
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1Mean baseline risk presented for single study.
2Risk of bias: 'serious'; incomplete participant data.
 
Summary of findings 4. PIMOZIDE + ANY ANTIPSYCHOTIC versus ANTIPSYCHOTIC + PLACEBO for schizophrenia or related psychoses

PIMOZIDE + ANY ANTIPSYCHOTIC versus ANTIPSYCHOTIC + PLACEBO for schizophrenia or related psychoses

Patient or population: patients with schizophrenia or related psychoses
Settings: inpatient and outpatient (US)
Intervention: PIMOZIDE + ANY ANTIPSYCHOTIC versus ANTIPSYCHOTIC + PLACEBO

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ANTIPSYCHOTIC + PLACEBOPIMOZIDE + ANY ANTIPSYCHOTIC

Global state: relapse medium term (3-12 months)Study populationRR 0.64
(0.37 to 1.1)
507
(4 studies)
No study reported this outcome.

160 per 1000102 per 1000
(59 to 176)

Moderate

208 per 1000133 per 1000
(77 to 229)

Mental state: no improvement medium term (3-12 months) not reportedSee comment.See comment.Not estimable-See comment.No study reported this outcome.

Mental state: presence of first-rank symptoms medium term (3-12 months) not reportedSee comment.See comment.Not estimable-See comment.No study reported this outcome.

Adverse effects: extrapyramidal adverse effects Parkinsonism short term (< 3 months) not reportedSee comment.See comment.Not estimable-See comment.No study reported this outcome.

Adverse effects: extrapyramidal adverse effects Parkinsonism medium term (3-12 months)
Extrapyramidal Symptom Rating Scale (ESRS)
Follow-up: 12 weeks
See comment.See comment.Not estimable53
(1 study)
⊕⊕⊝⊝
low1
Data for this outcome are skewed and are presented in a separate table.

Quality of life: average change score medium term (3-12 months)
Specific Level of Functioning scale (SLOF)
Follow-up: 12 weeks
See comment.See comment.Not estimable53
(1 study)
⊕⊕⊝⊝
low1
Data for this outcome are skewed and are presented in a separate table.

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio.

GRADE Working Group grades of evidence:
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1Imprecision: rated 'very serious'; data for this outcome were highly skewed and were not included in the meta-anlysis.
 
Summary of findings 5. PIMOZIDE + ANY ANTIPSYCHOTIC versus ANTIPSYCHOTIC + ANTIPSYCHOTIC for schizophrenia or related psychoses

PIMOZIDE + ANY ANTIPSYCHOTIC versus ANTIPSYCHOTIC + ANTIPSYCHOTIC for schizophrenia or related psychoses

Patient or population: patients with schizophrenia or related psychoses
Settings: inpatient (Italy)
Intervention: PIMOZIDE + ANY ANTIPSYCHOTIC versus ANTIPSYCHOTIC + ANTIPSYCHOTIC

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ANTIPSYCHOTIC + ANTIPSYCHOTICPIMOZIDE + ANY ANTIPSYCHOTIC

Global state: relapse medium term (3-12 months) not reportedSee comment.See comment.Not estimable-See comment.No study reported this outcome.

Mental state: no improvement medium term (3-12 months) not reportedSee comment.See comment.Not estimable-See comment.No study reported this outcome.

Mental state: presence of first-rank symptoms medium term (3-12 months) not reportedSee comment.See comment.Not estimable-See comment.No study reported this outcome.

Adverse effects: extrapyramidal adverse effects Parkinsonism (rigidity) short term (< 3 months)
Extrapyramidal Symptom Rating Scale (ESRS)
Follow-up: 2 months
See comment.See comment.Not estimable20
(1 study)
⊕⊝⊝⊝
very low1,2
Data for this outcome are skewed and are presented in a separate table.

Adverse effects: extrapyramidal adverse effects Parkinsonism (tremor) short term (< 3 months)
Extrapyramidal Symptom Rating Scale (ESRS)
Follow-up: 2 months
See comment.See comment.Not estimable20
(1 study)
⊕⊝⊝⊝
very low1,3
Data for this outcome are skewed and are presented in a separate table.

Quality of life: average change score medium term (3-12 months) not reportedSee comment.See comment.Not estimable-See comment.No study reported this outcome.

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval.

GRADE Working Group grades of evidence:
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1Risk of bias: rated 'serious'; no double-blinding in the single study.
2Imprecision: rated 'very serious'; data for this outcome were highly skewed and were not included in the meta-analysis.
3No explanation was provided.
 
Table 1. Suggested design for future trials

MethodsAllocation: randomised, with sequence generation and concealment of allocation clearly described.
Blindness: double.
Duration: 12 months at least.

ParticipantsDiagnosis: people with schizophrenia.
n = 300*.
Sex: both.
Age: any.

Intervention1. Pimozide (any dose and pattern of administration) vs:

Other antipsychotic of choice.

2. Pimozide + any (atypical/typical) antipsychotic vs:

Any (atypical/typical) antipsychotics.

3. Pimozide low dose vs:

Standard dose.

OutcomesMental state: relapse**, negative symptoms, delusional disorder, behaviour, total amounts of medication used, clinically relevant global endpoints.
Adverse events.
Quality of life.
Subjective reports of participants and relatives.
Service outcomes: length of hospitalisation, change in legal status.
Economic evaluations: cost-effectiveness, cost-benefit.

Notes*Size of study with sufficient power to highlight about a 10% difference between groups for primary outcome.
**Primary outcomes.

Rating scales: to be administered by an independent party.

 
Table 2. Differences between original review and 2012 update

MajorMinor

1. Additions have been made to Types of interventions: The protocol to the current review did not specify a comparison with specific named drugs (atypical or typical) nor dosages, which is certainly a comparison of interest for people receiving treatment as well as for clinicians administering medication and was subsequently addressed in the final text.

2. Fixed-effect model used in this 2012 update, whereas a random-effects model was used in the originally published review. The review authors believe that a random-effects model puts added weight onto small studies, which often are the most biased (see Data synthesis). However, a random-effects model was used (1) in a sensitivity analysis to inspect whether this changes the estimate of the effect, and (2) when considerable heterogeneity was present.
1. The Data collection and analysis section has been updated to reflect changes in methodology that have occurred whilst this review was being written, namely, inclusion of Risk of Bias tables and Summary of Findings tables.

2. Types of outcome measures have been modified/clarified from the original protocol, this decision was not influenced by the results. Economic outcomes of direct and indirect costs have been qualified as 'defined by each study', to take into account that what may constitute a direct or an indirect cost can differ between trial authors. A further subcategory of 'cost-effectiveness' has been added, again, a factor that would be 'defined by each study'.

3. Further, the protocol specified a global state outcome of 'no clinically important change in global state (as defined by individual studies)'; this has been changed to 'any clinically important change in global state (as defined by individual studies)'. The direction of the graphs has been modified to represent an unfavourable outcome for intermittent treatment when results are presented to the left of the line of no effect.