Study characteristics

Methods

Allocation: random.
Blinding: double.
Duration: 6 weeks (4 weeks presented usable data).*

Design: parallel.

Participants

Diagnosis: schizophrenia (DSM‐III‐R or RDC).
N = 53 (38 to relevant interventions).**
Age: mean 37 yrs.
Sex: M 38 (26 relevant), F 15 (12 relevant).
History: illness for ~13 yrs, clinically stable patients.
Excluded: patients with concurrent drug abuse, alcoholism, organic brain disorders and mental retardation.
Setting: community, Maryland Psychiatric Research Center Outpatient Program (US).

Consent: written informed consent required.

Interventions

1. Oral fluphenazine: dose 15 mg/day, N = 18.
2. Placebo, N = 20.
[3. Diazepam: dose 30 mg/day, N = 15].

Outcomes

Global state (CGI) ‐ not improved or worsened.

Unable to use ‐
Mental state: BPRS (no usable data).
Relapse (not given by each group).
Sleep change ratings (no data).

Notes

* Data were given only for the first 4 weeks of the study.
** Demographic data relate to the total of 38 people.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Random ‐ "a stratified randomization procedure...was used to assign drug treatment to balance study groups on gender, prior social function, and past duration of hospital care" (p300). No details as to randomisation methods.

Allocation concealment (selection bias)

Unclear risk

Not described.

Blinding (performance bias and detection bias)
All outcomes

Low risk

Double blind ‐ no further details. If participants experienced worsening or exacerbation of symptoms, they were removed from the study and treated on an open basis with fluphenazine.

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

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

No mention of participants lost to follow‐up or leaving the study early.

Selective reporting (reporting bias)

High risk

No scale data reported for BPRS or CGI.

Other bias

Unclear risk

Funding: supported in part by NIMH grants (MH‐35996 and MH‐40279).

Study characteristics

Methods

Allocation: random.
Blinding: double "identically appearing medication administrated from a bottle labelled only with the patient's name".
Duration: 6 weeks.

Design: parallel.

Participants

Diagnosis: chronic schizophrenia.
N = 76 (37 to relevant interventions).
Age: mean 33 yrs (range 18 to 45).
Sex: M 23, F 53.
History: 6 months preadmission period free of hospitalisation or shock treatment.
Excluded: childhood schizophrenia or autism, brain syndrome, IQ < 70, alcoholism, recent hepatitis, chronic physical illness, epilepsy, drug addiction.
Setting: inpatient, Central State Griffin Memorial Hospital (Oklahoma, US).

Consent: not stated.

Interventions

1. Oral fluphenazine: dose 2‐10 mg/day. N = 18.
2. Placebo. N = 19.
[3. Chlorpromazine: dose 100‐1000 mg/day. N = 20].
[4. Thioridazine: dose 100‐1000 mg/day. N = 19].

Outcomes

Global state (using CGI): not improved or worsened; average score (CGI severity of illness*).

Mental state: average score (BPRS*).
Leaving the study early: any reason; administrative/hospital transfer; AWOL; marked improvement allowing discharge.
Adverse effects: anticholinergic (dry mouth; blurred vision; nasal congestion; tachycardia; gastrointestinal distress); EPS (tremor; rigidity; associated movements; akinesia; akithisia; drooling; restlessness/ insomnia); CNS (anxiety/agitation/excitement/ confusion; sedation and lethargy; depression); cardiovascular (hypotension; syncope); others (rash).

Unable to use ‐
Global state: NOSIE (no SD).
Toxicity (no usable data).

Notes

Unscheduled dose adjustments were permitted for toxicity or intolerance.

*SDs imputed 'between groups' using RevMan calculator.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Random: "patients were assigned to treatment randomly in blocks of four" (p404) ‐ no further details.

Allocation concealment (selection bias)

Unclear risk

Participants were "assigned to treatment randomly in blocks of four" (p404) ‐ no further details.

Blinding (performance bias and detection bias)
All outcomes

Low risk

Double blind: "double blind design was maintained throughout the study" (p404) ‐ no further details. Identically‐appearing capsules were dispensed from a bottle labelled only with the participant name.

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

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Follow‐up: 85% ‐ n = 2 participants left the study early, but their final measures were obtained and used in the analysis (n = 1 receiving placebo due to behavioural deterioration and n = 1 receiving fluphenazine was discharged from the hospital as markedly improved after two weeks). A further n = 11 participants, however, were dropped without final measures being obtained (placebo: n = 1 went AWOL; n = 1 on convalescent leave; n = 1 transferred to another hospital. Thioridazine group: n = 2 AWOL; n = 1 medication intolerance. Chlorpromazine: n = 1 AWOL; n = 2 refused oral medication. Fluphenazine: n = 1 administrative transfer, n = 1 AWOL). Dichotomised data presented as ITT (only n = 1 missing from placebo). LOCF for CGI and BPRS.

Selective reporting (reporting bias)

Unclear risk

No SDs reported for all scale data.

Other bias

Unclear risk

Funding: supported in part by Public Health Service Grant MH 11666 and Research Scientist Development award No. K135278 from NIMH. Medication supplied by Smith Kline and French Laboratories (chlorpromazine and placebo); Sandoz Inc (thioridazine) and ER Squibb & Sons (fluphenazine).

Study characteristics

Methods

Allocation: random.
Blinding: double.
Duration: 6 weeks.

Design: multi‐centre, parallel.

Participants

Diagnosis: schizophrenia.
N = 463 (190 to relevant interventions).
Age: 16‐45 yrs.
Sex: male and female (equal distribution stated, however no number given).
History: newly admitted patients.
Excluded: childhood autism, brain syndrome, IQ < 70, epilepsy, drug addiction.
Setting: inpatient, Boston State Hospital (Massachusettes); District of Columbia General Hospital (Washington DC); Kentucky State Hospital (Kentucky); Malcolm Bliss Mental Health Center (Missouri); Mercy‐Dougleaa Hosptial (Pennsylvania); Payne‐Whitney CLinic (New York); Rochester State Hosptial (Rochester, New York); Springfield State Hospital (Maryland); Institute of Living (Conneticut, US).

Consent: not stated.

Interventions

1. Oral fluphenazine: dose 1‐16 mg/day. N = 92.
2. Oral placebo. N = 98.
[3. Paraenteral fluphenazine. N = 23].
[4. Chlorpromazine: dose 200 mg/day. N = 112].
[5. Thioridazine: dose 200 mg/day. N = 111].
[6. Paraenteral placebo. N = 27].

Additional medication:
Anti‐parkinsonian medications.*

Outcomes

Leaving the study early (any reason; treatment failure; serious complication of treatment; marked early remission; incorrect diagnosis; court cases, transfer, eloped).
Adverse effects: CNS (headache; drowsiness; convulsions or seizures) cardiovascular effects (dizziness, faintness, weakness) anticholinergic effects (increased salivation; dry mouth/throat; gastrointestinal distress and nausea; urinary disturbance; constipation; vomiting) endocrine (lactation; amenorrhoea; swelling of breasts) extrapyramidal effects (loss of associated movements; facial rigidity; rigidity; restlessness/insomnia; tremor; akithisia; dystonia) others (convulsion or seizures; diarrhoea; intercurrent infection; rash).

Unable to use ‐
Global state (no SD).**
Mental state: IMPS, WBRS (no SD).***

Notes

*44% of fluphenazine group and 5% of placebo received anti‐parkinsonian drugs.
**Global rating of severity of metal illness, Global rating of improvement.
***Results were not broken down by each drug group.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Random: participants were "randomly assigned to one of four treatments on a double‐blind basis" (p247).

Allocation concealment (selection bias)

Unclear risk

Stratified by sex with "randomized assignment to drug treatment within each sex group" (p247). In the three out of nine hospitals participating in the study that admitted approximately equal number of White and Black participants, this was taken into account and groups were further stratified by race.

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Double blind described, no further details. Participants received individually numbered containers of medication. A flexile dosage schedule permitted the treating physician to adjust dosage according to individuals' needs.

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

Incomplete outcome data (attrition bias)
All outcomes

High risk

Follow‐up: 74%. Reasons for removal of study included administrative removals (incorrect diagnoses; intercurrent medical illness; court cases, transfer, elopement, etc), treatment‐related removals (marked early remission; serious complication of treatment; treatment failure). Those lost were not included in the study report analysis.

Selective reporting (reporting bias)

High risk

No SDs reported for continuous data.

Other bias

Unclear risk

Funding: supported by NIMH grants (MH 04661, 04663, 04667, 04673, 04674, 04675, 04679, 04803). Medications provided free of charge from Sandoz Pharmaceuticals (Hanover); Squibb Institute for Medical Research (New Brunswick); Smith Kline and French Laboratories (Philiadelphia).

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

Study characteristics

Methods

Allocation: unclear.
Blinding: double.
Duration: 12 weeks.

Design: parallel.

Participants

Diagnosis: chronic schizophrenia.
N = 75 (50 to relevant interventions).
Age: mean 49 yrs.
Sex: all female.
History: hospitalisation > 2 yrs (mean ~20 yrs, ~SD 9), all have had previous unsuccessful phenothiazines treatment, and none leucotomised.
Excluded: physical illness, epilepsy.
Setting: inpatient, Mont Park Hospital, Victoria (Australia).

Consent: not stated.

Interventions

1. Oral fluphenazine: dose < 14 mg/day. N = 25.
2. Placebo. N = 25.
[3. Thioproperazine (max dose of 140 mg/day). N = 25].

Outcomes

Global state: MADRS* ‐ not improved or worsened.
Adverse effects ‐ extrapyramidal effects: dystonia; akinesia; parkinsonism; akathisia.
Leaving study early.**

Notes

* Rated as either 'no change', 'clear worsening' and 'marked worsening' using the Multidimensional Rating Scale of the Veterans' Administration (Lorr 1953).
** Two participants from fluphenazine group left the study early and they were considered to have the worst outcomes.
The ward sister's blind ratings of change of behaviour at the end of the trial: 9 placebo participants deteriorated in contrast to 6 participants on fluphenazine. One placebo participant required additional nursing care because of severe negativism.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

Randomisation unclear ‐ participants were "divided into three groups of 25 matched on age, chronicity and severity of illness" (p532).

Allocation concealment (selection bias)

Unclear risk

Not described.

Blinding (performance bias and detection bias)
All outcomes

Low risk

Double blind (implied) ‐ members of the ward staff were told that powerful phenothiazine drugs were to be administered, but were unaware of which participants were receiving the active medication. All medications were identical‐looking tablets, dispensed by a medical officer who "took no part in the rating procedure" (p533). Maximum blindness preserved in evaluations claimed, as neither physicians entered the closed wards between ratings and did not observe side effects during period of treatment. A blind assessment of overall change was made at the end of the trial by the ward sister.

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

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Follow‐up: 95% ‐ n = 4 participants were lost to follow‐up by 12 weeks of treatment, only n = 2 were accounted for as having discontinued from active drugs (n = 1 from fluphenazine; n = 1 from thioproperazine). ITT used for medium‐term data.

Selective reporting (reporting bias)

Unclear risk

None detected.

Other bias

Unclear risk

Funding: all drugs and placebos were provided free of charge by May and Baker (Australia) Limited ('Majeptil') and ER Squibb and Sons (Australia) Limited ('Anatensol').

Study characteristics

Methods

Allocation: randomly assigned.
Blindness: double.
Duration: 2 years (preceded by 2 months stabilisation phase with low dose of fluphenazine decanoate 5‐10 mg).

Design: parallel.

Participants

Diagnosis: schizophrenia (DSM‐III‐R).
N = 36.
Age: mean 40 yrs.
Sex: all male.
History: at least two documented episodes of acute schizophrenic illness or at least 2 years of continuing psychotic symptoms, randomly assigned when getting prodromal symptoms using Idiosyncratic Prodromal Scale.
Excluded: patients who could not be stabilised for 2 or more months with 10 mg or less of fluphenazine decanoate every 2 weeks.
Setting: community, outpatients at Brentwood Division of West Los Angeles Verterans Affairs Medical Center (US).

Consent: not stated.

Interventions

1. Oral fluphenazine hydrochloride: dose 10 mg/day. N = 17.
2. Placebo. N = 19.

Additional medication ‐
Fluphenazine decanoate: dose 5‐10 mg/2weeks for all patients. N = 36.

Factored to:
A. Behavioural skills training.
B. Supportive group therapy.**

Outcomes

Relapse: defined as number of psychotic exacerbations.*
Percentage of time in exacerbated state (skew).
Percentage of time in prodrome (skew).
Leaving the study early: non‐specific reasons.

Unable to use ‐
Adverse effects (no data).

Notes

* Defined as worsening of four points or more on the sum of the BPRS clusters for thought disturbance and paranoia or increase of three or more points on either cluster.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Random ‐ possible participants were stabilised on low dose fluphenazine decanoate (5 to 10 mg every 14 days) for two months and monitored every week using an idiosyncratic prodromal rating scale. Participants were randomised to either oral fluphenazine or placebo when they met criteria for a prodromal episode.

Allocation concealment (selection bias)

Unclear risk

Not described.

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Double blind (implied), as participants who never experienced prodromal episodes nor were assigned to either treatment were treated with 5 mg oral fluphenazine on an open label basis during exacerbations.

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

Incomplete outcome data (attrition bias)
All outcomes

High risk

Follow‐up: 81% ‐ n = 6 participants lost to follow‐up by two years of treatment. Only two participants accounted for as being omitted from analysis (n = 1 who dropped‐out during a prodromal episode, and n = 1 who reached the two‐year end point during a prodrome).

Selective reporting (reporting bias)

Unclear risk

None detected.

Other bias

Unclear risk

Funding: study supported by the Medical Research Service of the Department of Veterans Affairs, Washington DC (grant MH‐41573) from National Institute of Mental Health, Bethesda, Md; UCLA Mental Health Clinical Research Center for Schizophrenia (grant MH‐30911) from the National Institute of Mental Health.

Study characteristics

Methods

Allocation: random.
Blindness: double.
Duration: 6 weeks.

Design: cross‐over (after 3 weeks).

Participants

Diagnosis: chronic schizophrenia.
N = 38.
Age: 28‐58 yrs (mean 46 yrs).
Sex: all female.
Excluded: advanced age, doubtful diagnostic classification, epilepsy, severe sub‐normality.
History: in hospital 2‐35 yrs (mean 18 yrs).
Setting: inpatient, UK.

Consent: not stated.

Interventions

1. Oral fluphenazine: dose 2.5 mg/day. N = 19.
2. Placebo. N = 19.

Outcomes

Relapse.

Unable to use ‐

Improvement: no better or worse (data not reported by group).
Adverse effects (no data).

Lorr psychiatric rating scale (no SD, mean only).

Baker and Thorpe behaviour rating scale (no SD, mean only).

Notes

Participants had been receiving chlorpromazine three times a day and were "mostly stabilised" on a certain dose. They were then given doses of fluphenazine, with this drug substituted for the chlorpromazine at approx. one fortieth of the dose. A single daily dose was given of 2.5 mg (with the exception of two cases who received 20 mg) with dose increase of 2.5 mg/day (one tablet). After participants received fluphenazine for 2 months, they were rated and randomised into intervention groups, receiving dosages established in the stabilisation phase.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Random ‐ participants were divided into two random groups; no further details.

Allocation concealment (selection bias)

Unclear risk

Only hospital pharmacist knew the composition of the groups.

Blinding (performance bias and detection bias)
All outcomes

Low risk

Double blind ‐ only hospital pharmacist knew the composition of the groups; medication was administered with matching placebo.

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

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

No mention of participants lost to follow‐up or leaving the study early.

Selective reporting (reporting bias)

High risk

Data not clearly described as to the stage of trial and relevant groups (i.e. pre‐cross‐over or post‐cross‐over). Full data not reported for continuous outcomes (missing means and SDs).

Other bias

Unclear risk

Funding: fluphenazine tablets were provided by ER Squibb & Sons.

Study characteristics

Methods

Allocation: random.
Blindness: double.
Duration: 1 year (preceded by several months transitional period during which all patients were treated exclusively with fluphenazine decanoate and oral fluphenazine).

Design: parallel.

Participants

Diagnosis: schizophrenia (remitted).
N = 73 (50 to relevant interventions).
Sex: M 50, F 23.
Age: 17‐40 yrs.
History: reached a stable remission while receiving FD and FPZ and showed no adverse effects.
Excluded: history of severe drug abuse or chronic schizophrenics.*
Setting: psychiatric aftercare clinic, Long Island Jewish‐Hillside Medican Center (US).

Consent: informed consent obtained.

Interventions

1. Oral fluphenazine: dose 5‐20 mg/day. N = 28.
2. Placebo. N = 22.
[3. Fluphenazine decanoate: dose 0.5‐2.0 mL/2weeks. N = 23].

Additional medication:
Prophylactic procyclidine (5‐15 mg/day).**
Placebo procyclidine.
Psychotherapy biweekly during the first 6months and monthly thereafter.

Outcomes

Death.
Relapse (clinical judgement).
Leaving the study early.

Unable to use ‐
Social and vocational functioning (results not broken down by individual drugs).
Mental state: BPRS (no data).
Global state: CGI, PER‐C (no data).
KAS (no usable data).

Notes

* Chronic patients > 3 previous hospitalisations.
** Prophylactic procyclidine for patients receiving active treatment and in the first 2 months for patients receiving placebo to prevent the emergence of extrapyramidal side effects during the fluphenazine decanoate washout period.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Random: "randomly assigned" (p44). 15% of patients referred schizophrenics were re‐diagnosed using Kraepelinian Criteria as non schizophrenic and randomised separately but treated in the same manner.

Allocation concealment (selection bias)

Unclear risk

"Randomly assigned" (p44) ‐ no further details.

Blinding (performance bias and detection bias)
All outcomes

Low risk

Double blind: drugs were given in a "double blind fashion" (p44).

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

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Follow‐up: 89%. Drop‐outs mainly due to moving from the geographical area or refusing further care. None of these patient's conditions had deteriorated clinically.

Selective reporting (reporting bias)

High risk

Not all adverse effects reported by group. No data reported for individual groups using the BPRS, CGI, PER‐C, KAS scales.

Other bias

Unclear risk

Funding: supported by NIMH grant MH 21337‐03.