Fluphenazine versus low-potency first-generation antipsychotic drugs for schizophrenia.

Cochrane Database of Systematic Reviews

Fluphenazine versus low-potency first-generation antipsychotic drugs for schizophrenia (Review) Tardy M, Huhn M, Engel RR, Leucht S

Tardy M, Huhn M, Engel RR, Leucht S. Fluphenazine versus low-potency first-generation antipsychotic drugs for schizophrenia. Cochrane Database of Systematic Reviews 2014, Issue 8. Art. No.: CD009230. DOI: 10.1002/14651858.CD009230.pub2.

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Fluphenazine versus low-potency first-generation antipsychotic drugs for schizophrenia (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

TABLE OF CONTENTS HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . . BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.1. Comparison 1 Comparison 1: FLUPHENAZINE versus LOW-POTENCY ANTIPSYCHOTIC DRUGS, Outcome 1 Clinical response: Response to treatment-short term. . . . . . . . . . . . . . . . . Analysis 1.2. Comparison 1 Comparison 1: FLUPHENAZINE versus LOW-POTENCY ANTIPSYCHOTIC DRUGS, Outcome 2 Leaving the study early: 1. Due to any reason. . . . . . . . . . . . . . . . . . . Analysis 1.3. Comparison 1 Comparison 1: FLUPHENAZINE versus LOW-POTENCY ANTIPSYCHOTIC DRUGS, Outcome 3 Leaving the study early: 2. Due to adverse effects. . . . . . . . . . . . . . . . . . Analysis 1.4. Comparison 1 Comparison 1: FLUPHENAZINE versus LOW-POTENCY ANTIPSYCHOTIC DRUGS, Outcome 4 Leaving the study early: 3. Due to inefficacy. . . . . . . . . . . . . . . . . . . . Analysis 1.5. Comparison 1 Comparison 1: FLUPHENAZINE versus LOW-POTENCY ANTIPSYCHOTIC DRUGS, Outcome 5 Adverse effects: 1. General-at least one adverse effect. . . . . . . . . . . . . . . . . Analysis 1.6. Comparison 1 Comparison 1: FLUPHENAZINE versus LOW-POTENCY ANTIPSYCHOTIC DRUGS, Outcome 6 Adverse effects: 2a. Specific-movement disorders. . . . . . . . . . . . . . . . . . Analysis 1.7. Comparison 1 Comparison 1: FLUPHENAZINE versus LOW-POTENCY ANTIPSYCHOTIC DRUGS, Outcome 7 Adverse effects: 2b. Specific-other. . . . . . . . . . . . . . . . . . . . . . . Analysis 2.1. Comparison 2 Subgroup analysis, Outcome 1 Response to treatment-each low-potency antipsychotic separately. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 3.1. Comparison 3 Sensitivity analysis, Outcome 1 Response to treatment-exclusion of non double-blind studies. Analysis 3.2. Comparison 3 Sensitivity analysis, Outcome 2 Response to treatment-fixed effects model. . . . . . ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .


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[Intervention Review]

Fluphenazine versus low-potency first-generation antipsychotic drugs for schizophrenia Magdolna Tardy1 , Maximilian Huhn2 , Rolf R Engel3 , Stefan Leucht4 1 Klinik und Poliklinik für Psychiatrie und Psychotherapie, Technische Universität München Klinikum rechts der Isar, München, Germany. 2 Klinik und Poliklinik für Psychiatrie und Psychotherapie, Universitätsklinikum der Technischen Universität München, München, Germany. 3 Psychiatric Hospital, Ludwig-Maximilians-University Munich, Muenchen, Germany. 4 Department of Psychiatry and Psychotherapy, Technische Universität München, München, Germany

Contact address: Magdolna Tardy, Klinik und Poliklinik für Psychiatrie und Psychotherapie, Technische Universität München Klinikum rechts der Isar, Möhlstr. 26, München, 81675, Germany. [email protected]. [email protected]. Editorial group: Cochrane Schizophrenia Group. Publication status and date: New, published in Issue 8, 2014. Review content assessed as up-to-date: 26 January 2011. Citation: Tardy M, Huhn M, Engel RR, Leucht S. Fluphenazine versus low-potency first-generation antipsychotic drugs for schizophrenia. Cochrane Database of Systematic Reviews 2014, Issue 8. Art. No.: CD009230. DOI: 10.1002/14651858.CD009230.pub2. Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT Background Antipsychotic drugs are the core treatment for schizophrenia. Treatment guidelines state that there is no difference in efficacy between any other antipsychotic compounds, however, low-potency antipsychotic drugs are often perceived as less efficacious than high-potency compounds by clinicians, and they also seem to differ in their side effects. This review examined the effects of the high-potency antipsychotic fluphenazine compared to those of low-potency antipsychotics. Objectives To review the effects of fluphenazine and low-potency antipsychotics for people with schizophrenia. Search methods We searched the Cochrane Schizophrenia Group Trials Register (November 2010). Selection criteria We included all randomised controlled trials (RCTs) comparing fluphenazine with first-generation low-potency antipsychotic drugs for people with schizophrenia or schizophrenia-like psychosis. Data collection and analysis We extracted data independently. For dichotomous data we calculated risk ratios (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis based on a random-effects model. Main results The review currently includes seven randomised trials and 1567 participants that compared fluphenazine with low-potency antipsychotic drugs. The size of the included studies was between 40 and 438 participants. Overall, sequence generation, allocation procedures and blinding were poorly reported. Fluphenazine was not significantly different from low-potency antipsychotic drugs in terms of response to treatment (fluphenazine 55%, low-potency drug 55%, 2 RCTs, n = 105, RR 1.06 CI 0.75 to 1.50, moderate quality evidence). There Fluphenazine versus low-potency first-generation antipsychotic drugs for schizophrenia (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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was also no significant difference in acceptability of treatment with equivocal numbers of participants leaving the studies early due to any reason (fluphenazine 36%, low-potency antipsychotics 36%, 6 RCTs, n = 1532, RR 1.00 CI 0.88 to 1.14, moderate quality evidence). There was no significant difference between fluphenazine and low-potency antipsychotics for numbers experiencing at least one adverse effect (fluphenazine 70%, low-potency antipsychotics 88%, 1 RCT, n = 65, RR 0.79 CI 0.58 to 1.07, moderate quality evidence). However, at least one movement disorder occurred significantly more frequently in the fluphenazine group (fluphenazine 15%, low-potency antipsychotics 10%, 3 RCTs, n = 971, RR 2.11 CI 1.41 to 3.15, low quality of evidence). In contrast, low-potency antipsychotics produced significantly more sedation (fluphenazine 20%, low-potency antipsychotics 64%, 1 RCT, n = 65, RR 0.31 CI 0.13 to 0.77, high quality evidence). No data were available for the outcomes of death and quality of life. The results of the primary outcome were robust in a number of subgroup and sensitivity analyses. Adverse effects such as akathisia (fluphenazine 15%, low-potency antipsychotics 6%, 5 RCTs, n = 1209, RR 2.28 CI 1.58 to 3.28); dystonia (fluphenazine 5%, low-potency antipsychotics 2%, 4 RCTs, n = 1309, RR 2.66 CI 1.25 to 5.64); loss of associated movement (fluphenazine 20%, low-potency antipsychotics 2%, 1 RCT, n = 338, RR 11.15 CI 3.95 to 31.47); rigor (fluphenazine 27%, lowpotency antipsychotics 12%, 2 RCTs, n = 403, RR 2.18 CI 1.20 to 3.97); and tremor (fluphenazine 15%, low-potency antipsychotics 6%, 2 RCTs, n = 403, RR 2.53 CI 1.37 to 4.68) occurred significantly more frequently in the fluphenazine group. For other adverse effects such as dizziness (fluphenazine 8%, low-potency antipsychotics 17%, 4 RCTs, n = 1051, RR 0.49 CI 0.32 to 0.73); drowsiness (fluphenazine 18%, low-potency antipsychotics 25%, 3 RCTs, n = 986, RR 0.67 CI 0.53 to 0.86); dry mouth (fluphenazine 11%, low-potency antipsychotics 18%, 4 RCTs, n = 1051, RR 0.63 CI 0.45 to 0.89); nausea (fluphenazine 4%, lowpotency antipsychotics 15%, 3 RCTs, n = 986, RR 0.25 CI 0.14 to 0.45); and vomiting (fluphenazine 3%, low-potency antipsychotics 8%, 3 RCTs, n = 986, RR 0.36 CI 0.18 to 0.72) results favoured fluphenazine with significantly more events occurring in the lowpotency antipsychotic group for these outcomes. Authors’ conclusions The results do not show a clear difference in efficacy between fluphenazine and low-potency antipsychotics. The number of included studies was low and their quality moderate. Therefore, further studies would be needed to draw firm conclusions about the relative effects of fluphenazine and low-potency antipsychotics.

PLAIN LANGUAGE SUMMARY Fluphenazine versus low-potency antipsychotic drugs for schizophrenia People with schizophrenia often hear voices or see things (hallucinations) and have strange beliefs (delusions). It is a serious, often long lasting, mental illness that can have a severe detrimental effect on all aspects of the sufferer’s life. Antipsychotic drugs are the main treatment for the symptoms of schizophrenia. Fluphenazine is an older antipsychotic that is effective in treating the symptoms of schizophrenia. However, most antipsychotics have side effects and when compared to newer antipsychotic drugs, fluphenazine is thought to be more likely to cause serious movement disorders such as involuntary shaking, tremors, muscle stiffness and the inability to sit still. Fluphenazine is also known to lower people’s mood. Prescribing low-strength or low-potency drugs can help reduce side effects but are often seen as less effective in treating symptoms. This review examined the effects of the high-potency antipsychotic fluphenazine compared with those of low-potency antipsychotics. A search for randomised trials comparing these types of drugs was carried out in 2010. The review includes seven studies with 1567 participants. Pooled data from two of these trials did not show a clear difference in effectiveness between fluphenazine and low-potency antipsychotics. However, evidence showed fluphenazine produced more movement disorders than low-potency antipsychotics, whereas the low-potency drugs were more likely to cause dizziness, drowsiness and sedation, a dry mouth, nausea and sometimes even vomiting. The number of included studies was low and the quality of evidence provided was moderate. Therefore, further good quality studies would be needed to draw firm conclusions about the relative effectiveness of fluphenazine compared to low-potency antipsychotics. Important information on service use, going into hospital again (rehospitalisation), costs and quality of life was missing and not reported. This plain language summary was written by a consumer Ben Gray from RETHINK mental illness. Fluphenazine versus low-potency first-generation antipsychotic drugs for schizophrenia (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]

FLUPHENAZINE versus LOW-POTENCY ANTIPSYCHOTIC DRUGS for schizophrenia Patient or population: patients with schizophrenia Settings: Inpatients and outpatients Intervention: FLUPHENAZINE versus LOW-POTENCY ANTIPSYCHOTIC DRUGS Outcomes

Illustrative comparative risks* (95% CI)

Assumed risk

Corresponding risk

Control

FLUPHENAZINE versus LOW-POTENCY ANTIPSYCHOTIC DRUGS

Response to treatment Study population Follow-up: mean 4 weeks 571 per 1000

Relative effect (95% CI)

No of Participants (studies)

Quality of the evidence (GRADE)

RR 1.03 (0.73 to 1.45)

103 (2 studies)

⊕⊕⊕ moderate1

RR 1 (0.88 to 1.14)

1532 (6 studies)

⊕⊕⊕ moderate1

589 per 1000 (417 to 829)

Moderate 539 per 1000

Acceptability of treat- Study population ment-leaving the study early due to any reason 360 per 1000 Follow-up: 1-6 months

555 per 1000 (393 to 782)

360 per 1000 (317 to 411)


203 per 1000 (179 to 231)

Comments

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Adverse effects-at least Study population one adverse effect Follow-up: mean 4 weeks 889 per 1000

RR 0.79 (0.58 to 1.07)

65 (1 study)

⊕⊕⊕ moderate1

RR 2.11 (1.41 to 3.15)

971 (3 studies)

⊕⊕

low1,2

RR 0.31 (0.13 to 0.77)

65 (1 study)

⊕⊕⊕⊕ high1,3

Not estimable

0 (0)

See comment

702 per 1000 (516 to 951)


Adverse effects-move- Study population ment disorders-at least one movement disorder 104 per 1000 Follow-up: 2-6 months

702 per 1000 (516 to 951)

220 per 1000 (147 to 329)


Adverse effects-other- Study population sedation 644 per 1000 Follow-up: 2-6 months

165 per 1000 (110 to 246)

200 per 1000 (84 to 496)


Adverse effects-death Quality of life

See comment

200 per 1000 (84 to 496) There were no data available on these important outcomes.

*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; 4


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. 1

Risk of bias: rated ’serious’ - many studies did not report the methods for sequence generation and/or allocation concealment, missing or unclear results for incomplete outcome data and selective reporting. 2 Imprecision: rated ’serious’ - only few studies contribute data to this event (number of events less than 300) an the CI was wide. 3 Large effect: statistically significant RR that was lower than 0.5 (the actual value was 0.31).

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BACKGROUND

Description of the condition Schizophrenia is often a chronic and disabling psychiatric disorder. It afflicts approximately one per cent of the population world-wide with little gender difference. Its typical manifestations are ’positive’ symptoms such as fixed, false beliefs (delusions) and perceptions without cause (hallucinations), ’negative’ symptoms such as apathy and lack of drive, disorganisation of behaviour and thought, and catatonic symptoms such as mannerisms and bizarre posturing (Carpenter 1994). The degree of suffering and disability is considerable, with 80% to 90% of people with schizophrenia not working (Marvaha 2004) and up to 10% dying by suicide (Tsuang 1978).

context, fluphenazine belongs to the high-potency antipsychotic drug group and is used for the treatment of psychoses such as schizophrenia. Typical examples of low-potency antipsychotic drugs are chlorpromazine, chlorprothixene, thioridazine or levomepromazine. It is an old psychiatric dogma that can be found in textbooks and guidelines that, with the exception of clozapine, there is no difference in efficacy between any antipsychotic compounds (Gaebel 2006; Lehman 2004). Nevertheless, low-potency antipsychotic drugs are often perceived as less efficacious than high-potency compounds by clinicians, and high- and low-potency antipsychotics also seem to differ in their adverse effects. Low-potency drugs are thought to be more likely to cause sedation or hypotonia, whereas highpotency drugs are more prone to produce extrapyramidal side effects.

How the intervention might work Description of the intervention Antipsychotic drugs are the mainstay of treatment for schizophrenia. They can be classified according to their biochemical structure (e.g. butyrophenones, phenothiazines, thioxanthenes, etc.), their risk of producing movement disorders (’atypical’ versus ’typical’ antipsychotics), and the doses necessary for an antipsychotic effect (high-potency versus low-potency antipsychotics). The classification into high-potency and low-potency medication means that for low-potency antipsychotic drugs, higher doses are necessary to obtain the same dopamine receptor occupancy and efficacy than for high-potency antipsychotic drugs (Seeman 1975). In this

Schizophrenia is considered to be a chronic disorder caused by hyper-dopaminergic states in the limbic system (Berger 2003). All antipsychotic drugs are believed to exert their antipsychotic effects by blocking dopamine receptors. Fluphenazine is a phenothiazine antipsychotic that is more potent than haloperidol (also a highpotency antipsychotic) and has around 50 to 70 times the potency of chlorpromazine (Figure 1). Fluphenazine has a bioavailability of 40% to 50% and a half-life of 15 to 30 hours. Its side-effect profile is similar to haloperidol, including akathisia, parkinsonism, tremor, tardive dyskinesia and the potentially fatal neuroleptic malignant syndrome.

Figure 1. Fluphenazine structure


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Low-potency medications have a lower affinity for dopamine receptors so that a higher dose is required to effectively treat symptoms of schizophrenia. They additionally also block receptors other than dopamine receptors, such as cholinergic or histaminergic receptors. This also explains the occurrence of side effects such as sedation or hypotonia, which are less frequent with highpotency drugs. The classification in high- and low-potency drugs is not entirely clear-cut, but attempts have been made to express this in terms of dose equivalence. The most frequently applied concept is based on chlorpromazine equivalents. Davis 1974 and Haase 1983, among others, provide data about comparable doses of various antipsychotic drugs to achieve an effect similar to 100 mg of chlorpromazine.

METHODS Criteria for considering studies for this review Types of studies We included all randomised controlled (parallel group or crossover) trials. We included trials that were described as randomised or where randomisation was implied. We excluded quasi-randomised trials, such as those that use alternation, an open list of random numbers, or any other method of recruitment where allocation to interventions is predictable.

Why it is important to do this review Cochrane systematic reviews on the effects of specific conventional antipsychotic drugs have compared the effects of one antipsychotic drug versus any other antipsychotic drug (e.g. pimozide versus any other antipsychotic drug, Mothi 2013). Systematic reviews have not evaluated the comparative effects of high-potency and low-potency antipsychotics. But many guidelines, for example the German national schizophrenia guideline (Gaebel 2006), or that of the World Federations of Societies of Biological Psychiatry (Falkai 2005), state that “all conventional antipsychotics if adequately dosed have comparable efficacy.” These guidelines contrast with a clinical impression that low-potency conventional antipsychotic drugs are less efficacious than high-potency conventional antipsychotic drugs. Conventional antipsychotic drugs are still the mainstay of treatment in countries that can not afford the newer, expensive “atypical” or “second-generation” antipsychotic drugs. But even in some richer nations such as Germany, conventional antipsychotic medications still account for 50% of the market-share (Lohse 2005). Recent studies have also called the superiority of the more expensive second-generation antipsychotics into question (Jones 2006; Leucht 2009b; Lieberman 2005). Therefore, research on conventional antipsychotic agents is essential (Leucht 2009). The results of this review could aid our understanding of the comparative efficacy and safety of conventional antipsychotic drugs. It is one of a series of reviews on this question (Table 1)

Types of participants People with schizophrenia and schizophrenia-like psychoses (schizophreniform and schizoaffective disorders). There is no clear evidence that the schizophrenia-like psychoses are caused by fundamentally different disease processes or require different treatment approaches (Carpenter 1994). We included studies irrespective of the diagnostic criteria used. Diagnostic criteria, such as ICD 10 (International Statistical Classification of Diseases ) or DSMIV, (Diagnostic and Statistical Manual of Mental Disorders) are not routinely used in clinical practice and restricting inclusion to trials that used operationally defined diagnostic criteria could reduce generalisation and representativeness. We were interested in making sure that information is as relevant to the current care of people with schizophrenia as possible so proposed to clearly highlight the current clinical state (acute, early post-acute, partial remission, remission) as well as the stage (prodromal, first episode, early illness, persistent) and as to whether the studies primarily focused on people with particular problems (for example, negative symptoms, treatment-resistant illnesses). Types of interventions

1. Intervention: fluphenazine

Any dose of oral mode of administration (no depots, or shortacting parenteral forms of administration).

OBJECTIVES To evaluate the effects of the high-potency antipsychotic drug fluphenazine compared with low-potency antipsychotic drugs. In particular, fluphenazine is perceived to be more efficacious than low-potency drugs by some clinicians. Therefore, efficacy is the primary outcome of this review.

2. Comparators: low-potency antipsychotic drugs

Low-potency conventional antipsychotic drugs in any oral form of administration and at any dose. We used the dose equivalence tables developed by Davis 1974 and/or Haase 1983 to define drugs as low-potency with a chlorpromazine equivalence roughly equal


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or higher than chlorpromazine. The chlorpromazine equivalences of sulpiride are often estimated to be approximately 100. However, its properties are similar to those of amisulpride, which is an atypical antipsychotic and not within the scope of this review. Moreover, sulpiride does not cause a lot of sedation, which is another important characteristic of low-potency antipsychotics. Therefore, we a priori decided to not consider sulpiride in this review.

7. Adverse effects 7.1 At least one adverse effect 7.2 Extrapyramidal/movement disorders 7.3 Cardiac effects 7.4 Hypotension 7.5 Sedation 7.6 Weight gain 7.7 Other

Types of outcome measures All outcomes were grouped into short term (up to 12 weeks), medium term (up to six months) and long term (longer than six months)

8. Quality of life

9. Participant’s/carer‘s satisfaction with care Primary outcomes

10. Economic outcomes 1. Clinical response Response to treatment as defined by the original studies

Secondary outcomes

1. Mental state: symptoms of schizophrenia 1.1 Overall symptoms-average score/change in mental state 1.2 Positive symptoms-average score/change in positive symptoms 1.3 Negative symptoms-average score/change in negative symptoms

5. ’Summary of findings’ table We used the GRADE approach to interpret findings (Schünemann 2008) and GRADE profiler (GRADE) to import data from RevMan 5 (Review Manager) to create ’Summary of findings for the main comparison’. These tables provide outcome-specific information concerning the overall quality of evidence from each included study in the comparison, the magnitude of effect of the interventions examined, and the sum of available data on all outcomes rated as important to patient-care and decision making. We have selected the following long-term main outcomes for inclusion in the ’Summary of findings’ table.

2. Global state: average score/change in global state 1. Response to treatment 3. Relapse-as defined by each of the studies

4. Leaving the study early 4.1 Acceptability of treatment-leaving the study early due to any reason 4.2 Leaving the study early due to inefficacy of treatment 4.3 Leaving the study early due to side effects

2. Leaving the study early - acceptability of treatment (leaving the study early due to any reason)

3. Adverse effects -at least one adverse effect

5. Service use 5.1 Rehospitalisation

4. Adverse effects - at least one movement disorder

6. Death 6.1 Death (all causes) 6.2 Suicide

5. Adverse effects - sedation


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6. Death

Data collection and analysis

Selection of studies 7. Quality of life

Search methods for identification of studies We did not apply any language restriction.

Two review authors (MT, MH) independently inspected all abstracts identified in the searches. We resolved any disagreement by discussion and, where doubt remained, we acquired the full article for further inspection. Once we obtained the full articles, at least two authors independently decided whether the studies met the review criteria. If we could not resolve disagreements by discussion, we consulted with a third author (SL) or sought further information from the study authors.

Electronic searches Data extraction and management Cochrane Schizophrenia Group Trials Register (November 2010) We searched the register using the phrase: [(*fluphenazine* in intervention of STUDY) OR (*fluphenazine* in title, abstract and index terms of REFERENCE entered > = 01/ 05/10)] This register is compiled by systematic searches of major databases, clinical trials registries, handsearches of relevant journals and conference proceedings (see Group Module).

1. Extraction

Originally two review authors (MT, MH) independently extracted data from all selected trials. We decided post-hoc to include all outcomes reported by a study, not only the predefined outcomes in the methods section. For the outcomes added post-hoc only a random sample of 25% were independently extracted by a second review author (MH). When disagreement arose, we resolved it by discussion with a third review author (SL). Where this was not possible, we contacted the study authors to resolve the dilemma.

Searching other resources 2. Management

We extracted data onto simple standard forms. 1. Reference searching

We inspected the references of all identified studies for more trials.

3. Scale-derived data

2. Previous reviews

We searched previous conventional reviews (Davis 1989; Klein 1969).

3. Personal contact

3.1 Valid measures We included continuous data from rating scales only if: (a) the psychometric properties of the measuring instrument have been described in a peer-reviewed journal (Marshall 2000); (b) the measuring instrument has not been written or modified by one of the trialists.

We contacted the first author of each included study for missing information and for the existence of further studies. 3.2 Endpoint versus change data 4. Drug companies

We contacted the original manufacturer of fluphenazine and asked them for further relevant studies and for missing information on identified studies.

Since there is no principal statistical reason why endpoint and change data should measure different effects (Higgins 2008b), we decided primarily to use scale endpoint data. If endpoint data were not available, we used change data. However, we only included dichotomous data in this meta-analysis.


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4. Common measure

To facilitate comparison between trials, we intended to convert variables that can be reported in different metrics, such as days in hospital (mean days per year, per week or per month) to a common metric (e.g. mean days per month).

Assessment of risk of bias in included studies Review authors MT, MH worked independently by using criteria described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) to assess trial quality. This new set of criteria is based on evidence of associations between overestimate of effect and high risk of bias of the article such as sequence generation, allocation concealment, blinding, incomplete outcome data and selective reporting. We resolved any disagreements by referring to the trial report, correspondence with the authors of the report and through discussions and involvement of another member of the review group (SL). We reported any quality assessments where there was lack of agreement between raters. Where inadequate details of randomisation and other characteristics of trials were provided, we contacted authors of the studies in order to obtain additional information.

Measures of treatment effect

1. Dichotomous data

For binary outcomes we calculated a standard estimation of the random-effects (Der-Simonian 1986) risk ratio (RR) and its 95% confidence interval (CI). It has been shown that RR is more intuitive (Boissel 1999) than odds ratios and that odds ratios tend to be interpreted as RR by clinicians (Deeks 2000). This misinterpretation then leads to an overestimate of the impression of the effect. Where possible, efforts were made to convert outcome measures to dichotomous data. This could be done by identifying cut-off points on rating scales and dividing participants accordingly into ’clinically improved’ or ’not clinically improved’. It was generally assumed that if there had been a 50% reduction in a scale-derived score such as the Brief Psychiatric Rating Scale (BPRS, Overall 1962) or the Positive and Negative Syndrome Scale (PANSS, Kay 1986), this could be considered as a clinically significant response (Leucht 2005a; Leucht 2005b). If data based on these thresholds were not available, we used the primary cut-off presented by the original authors.

2. Continuous data

2.1 Summary statistic

If available, for continuous outcomes, we planned to estimate the mean difference (MD) between groups. In the case of where scales were of such similarity to allow pooling we intended to calculate the standardised mean difference (SMD) and, whenever possible, transform the effect back to the units of one or more of the specific instruments. 2.2 Skewed data Continuous data on clinical and social outcomes are often not normally distributed. To avoid the pitfall of applying parametric tests to non-parametric data, we planned to apply the following standards to all data before inclusion: (a) enter data from studies of at least 200 participants in the analysis irrespective of the following rules, because skewed data pose less of a problem in large studies; (b) endpoint data: when a scale starts from the finite number zero, subtract the lowest possible value from the mean, and divide this by the standard deviation. If this value was lower than one, it strongly suggests a skew and we excluded the study. If this ratio is higher than one but below two, there is suggestion of skew. We would have entered the study and tested whether its inclusion or exclusion substantially changed the results. If the ratio was larger than two we would have included the study, because skew is less likely (Altman 1996; Higgins 2011); (c) change data: when continuous data are presented on a scale which includes a possibility of negative values (such as change data), it is difficult to tell whether data are skewed or not. We would have entered the study, because change data tend to be less skewed and because excluding studies would also lead to bias, since not all the available information was used. Unit of analysis issues

1. Cluster trials

Studies increasingly employ ’cluster randomisation’ (such as randomisation by clinician or practice) but analysis and pooling of clustered data poses problems. Firstly, authors often fail to account for intra class correlation in clustered studies, leading to a ’unit of analysis’ error (Divine 1992) whereby P values are spuriously low, confidence intervals unduly narrow and statistical significance overestimated. This causes type I errors (Bland 1997; Gulliford 1999). We decided that if cluster trials were included, and If results from trials had not adjusted for clustering, we would attempt to adjust the results for clustering, by multiplying the standard errors of the effect estimates (RR or MD, ignoring clustering) by the square root of the design effect. The design effect is calculated as DEff =1 + (M-1) ICC, where M is the average cluster size and ICC is the intra-cluster coefficient (Higgins 2008b). If an ICC was not available from the trial, we planned to use other sources to impute ICCs (Campbell 2000).


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Where clustering had been incorporated into the analysis of primary studies, we planned to present these data as if from a noncluster randomised study, but adjust for the clustering effect. If a cluster study has been appropriately analysed taking into account the ICC and relevant data documented in the report, synthesis with parallel group randomised trials would be possible using the generic inverse variance technique, where the natural logarithm of the effect estimate (and standard errors) for all included trials for that outcome would be calculated and entered into RevMan along with the log of the effect estimate (and standard errors) from the cluster randomised trial(s). We would have used the methods described in section 7.7.7.2 and 7.7.7.3 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) to obtain standard errors.

assumed that those participants lost to follow-up would have had the same percentage of events as those who remained in the study.

3. Continuous data

3.1 Missing standard deviations Where there are missing measures of variance for continuous data but an exact standard error and confidence intervals are available for group means, and either a P value or T value are available for differences in mean, we can calculate standard deviation value according to methods described in Section 7.7.3 of the Cochrane Handbook (Higgins 2011). If standard deviations had not been reported and could not be calculated from available data, we planned to ask authors to supply the data.

2. Cross-over trials

A major concern of cross-over trials is the carry-over effect. It occurs if an effect (e.g. pharmacological, physiological or psychological) of the treatment in the first phase is carried over to the second phase. As a consequence, on entry to the second phase the participants can differ systematically from their initial state despite a wash-out phase. For the same reason cross-over trials are not appropriate if the condition of interest is unstable (Elbourne 2002). As both effects are very likely in schizophrenia, we considered that randomised cross-over studies were eligible, but we intended to use data only up to the point of the first cross-over for analysis.

Assessment of heterogeneity

1. Clinical heterogeneity

We considered all included studies without any comparison to judge clinical heterogeneity. We inspected all studies for clearly outlying situations or people which we had not predicted would arise.and discussed them fully, if such situations or participants arose.

Dealing with missing data

2. Methodological heterogeneity

1. Overall loss of credibility

We considered all included studies initially, without seeing comparison data, to judge methodological heterogeneity. We inspected all studies for clearly outlying methods which we had not predicted would arise and discussed them if they were evident.

At some degree of loss of follow-up, data must lose credibility (Xia 2009). The loss to follow-up in randomised schizophrenia trials is often considerable calling the validity of the results into question. Nevertheless, it is unclear which degree of attrition leads to a high degree of bias. We did not exclude trials from outcomes on the basis of the percentage of participants completing them. However, we used the ’Risk of bias’ tool described above to indicate potential bias when more than 25% of the participants from the fluphenazine group and low-potency drug group left the studies prematurely, when the reasons for attrition differed between the intervention and the control group, and when no appropriate imputation strategies were applied.

2. Dichotomous data

Data were presented on a ’once-randomised-always-analyse’ basis, assuming an intention-to-treat analysis. If the authors applied such a strategy, we used their results. If the original authors presented only the results of the per-protocol or completer population, we

3. Statistical

3.1 Visual inspection We visually inspected graphs to investigate the possibility of statistical heterogeneity. 3.2 Employing the I2 statistic Heterogeneity between studies was investigated by considering the I2 method alongside the Chi2 ’P’ value. The I2 provides an estimate of the percentage of inconsistency thought to be due to chance (Higgins 2011). The importance of the observed value of I 2 depends on i. magnitude and direction of effects and ii. strength of evidence for heterogeneity (e.g. ’P’ value from Chi2 test, or a confidence interval for I2 ).


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An I2 estimate of 50% to 90% accompanied by a statistically significant Chi2 statistic, may represent substantial heterogeneity (Section 9.5.2 Cochrane Handbook for Systematic Reviews of Interventions - Higgins 2011) and reasons for heterogeneity were explored. If the inconsistency was high and the clear reasons were found, data were presented separately.

heterogeneity was evident among the trials in the subgroups, or in the pooled results, we stated hypotheses regarding these for future reviews or versions of this review. We did not undertake further analyses relating to these hypotheses. Sensitivity analysis

Assessment of reporting biases Reporting biases arise when the dissemination of research findings is influenced by the nature and direction of results (Egger 1997). These are described in Section 10 of the Cochrane Handbook (Higgins 2011). We are aware that funnel plots may be useful in investigating reporting biases but are of limited power to detect small-study effects. We decided in advance not to use funnel plots for outcomes where there were 10 or fewer studies, or where all studies were of similar sizes. In other cases, where funnel plots were possible, we planned to seek statistical advice in their interpretation. However, due to the limited number of included studies, we did not test for funnel plot asymmetry. Data synthesis We employed a random-effects model for analyses (Der-Simonian 1986). We understand that there is no closed argument for preference for use of fixed-effect or random-effects models. The random-effects method incorporates an assumption that the different studies are estimating different, yet related, intervention effects. This does seem true to us and the random-effects model takes into account differences between studies even if there is no statistically significant heterogeneity. Therefore, the random-effects model is usually more conservative in terms of statistical significance, although as a disadvantage it puts added weight onto smaller studies, which can either inflate or deflate the effect size. We examined in a sensitivity analysis whether using a fixed-effect model markedly changes the results of the primary outcome. Subgroup analysis and investigation of heterogeneity Subgroup analyses were applied only to the primary outcome.

1. Risk of bias

We analysed the effects of excluding trials that we judge to be at high risk of bias across one or more of the domains of randomisation (implied as randomised with no further details available): allocation concealment, blinding and outcome reporting for the meta-analysis of the primary outcome. If the exclusion of trials at high risk of bias did not substantially alter the direction of effect or the precision of the effect estimates, then we included data from these trials in the analysis.

2. Assessment of dosage

We included trials in a sensitivity analysis if doses between highpotency and low-potency antipsychotics were clearly discrepant by our judgement based on the chlorpromazine equivalence tables developed by Davis 1974, Haase 1983 and Andreasen 2010. If there was no substantive difference when studies with discrepant doses were added, then we employed all data from these studies.

3. Fixed-effect and random-effects

We synthesised data for the primary outcome using a fixed-effect model to evaluate whether the greater weights assigned to larger trials with greater event rates altered the significance of the results, compared with the more evenly distributed weights in the randomeffects model.

RESULTS

1. Subgroup analysis

Description of studies

In order to reduce clinical and methodological reasons for heterogeneity, we subgrouped trials that compared fluphenazine versus each single low-potency antipsychotic separately.

For substantive description of studies please see Characteristics of included studies and Characteristics of excluded studies tables. Results of the search

2. Investigation of heterogeneity

If we detected statistical heterogeneity and quantified it as significant, we noted whether significant heterogeneity was present within the subgroups. If unanticipated clinical or methodological

The search in the CSG register yielded 184 references from 115 studies. Thirteen studies were closely inspected. Seven publications on seven studies were included and nine publications on six studies were excluded (see Figure 2).


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Figure 2. Study flow diagram.


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Included studies

for measuring response (Guy 1976). One study (Childers 1964) based response to treatment on clinical judgment.

Seven studies (1567 participants) met the inclusion criteria. 6.2 Mental state 1. Length of trials

Of the included studies, three studies had a duration of one month and two studies a duration up to two months. Two studies fell in the medium-term category (three to six months).

None of the included studies reported scale-derived data on mental state.

6.3 Relapse 2. Participants

None of the included studies reported data on relapse.

In all the seven included studies, participants were diagnosed according to clinical diagnoses.

6.4 Leaving the study early

3. Setting

Four studies were conducted in hospitals and two studies included both inpatients and outpatients. Childers 1964 did not report on setting.

The number of participants leaving the study early were recorded for the categories any reason, adverse effects and lack of efficacy. Five out of seven included studies reported on this outcome.

6.5 Service use None of the included studies reported data on this outcome.

4. Study size

Cole 1964 was the largest study with 438 participants and Childers 1964 was the smallest one, randomising only 40 people with schizophrenia. One study had more than 50 participants and four studies randomised more than 120 people.

6.6 Adverse effects

In most studies flexible doses of antipsychotic drugs could be applied. The fluphenazine dose range was 2 to 20 mg/day. The dose ranges of the low-potency comparators were: 100 to 1600 mg/day chlorpromazine, 50 to 400 mg/day chlorprothixene, 200 to 1600 mg/day for thioridazine. In a few studies various low-potency antipsychotics could be administered.

Adverse effects such as at least one adverse event, at least one movement disorder, amenorrhoea, blurred vision, constipation, convulsion, depression, diarrhoea, dizziness, drooling, drowsiness, dry mouth, oedema, excitement, gastrointestinal disturbance, headache, intercurrent infection, lactation, nasal congestion, nausea, photosensitivity, rash, restlessness, swelling of breasts, syncope, tachycardia, urinary disturbances and vomiting, akathisia, akinesia, dyskinesia, dystonia, facial rigidity, hypotension, loss of associated movement, oculogyric crisis, rigor, sedation and tremor were reported in a dichotomous manner in terms of the number of participants with a given side effect.

6. Outcomes

6.7 Other missing outcomes

5. Interventions

None of the included studies reported data on death, quality of life, participants´ satisfaction with care and economic outcomes. 6.1 Response to treatment Our primary outcome was response to treatment as defined by the original studies. Of the seven included studies, only two studies reported sufficient data for the primary outcome response to treatment. One study (Clark 1971) used the Clinical Global Impression (CGI) of severity of illness (ranging from one ’not apparently ill’ to seven ’most severely ill’) and of improvement scores (ranging from one ’markedly improved’ to seven ’markedly worse’)

Excluded studies We excluded six studies. Two studies were excluded because they were not (appropriately) randomised (Cesarec 1974; Gunby 1968). Other reasons for exclusion were wrong intervention (Hordern 1964; Kane 1983) and no usable outcome (Chacon 1973; Galdi 1988).


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Risk of bias in included studies For graphical representations of our judgements of risk of bias please refer to Figure 3 and Figure 4. Full details of judgements are presented in the ’Risk of bias’ tables. Figure 3. ’Risk of bias’ graph: review authors’ judgements about each risk of bias item presented as percentages across all included studies.


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Figure 4. ’Risk of bias’ summary: review authors’ judgements about each risk of bias item for each included study.


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Allocation In all seven included studies random sequence generation was unclear. All were described as randomised, but four of them did not provide further details about random sequence generation. Three studies gave further information about randomisation, but these were rather superficial so that we still rated the studies as unclear in this regard. None of the seven studies provided any details on allocation concealment. Therefore, it was unclear in all of the studies whether adequate allocation concealment methods were used.

Blinding One study was an open study and thus rated to have a high risk of bias (Childers 1964). Five studies were described as doubleblind and provided at least a few details about the blinding methods (various forms of identical capsules (Clark 1971; Cole 1964; Galbrecht 1968; Hanlon 1965; Lasky 1962). The remaining study (NIMH 1967) was described as double-blind, but as not even a minimal description of the blinding procedure was provided, we judged it to be unclear in this regard.

Incomplete outcome data In two studies we rated attrition bias as unclear. Of these, one study did not report on incomplete outcome data (Childers 1964) and the other study (Galbrecht 1968) had an attrition rate of 18% but included almost all participants in the final analysis, except those who dropped out towards the end of the study. In five studies, attrition bias was high. Three of these studies had an attrition rate between 20% to 25%, analysed only completers or did not use a full intention-to-treat analysis. One study (Lasky 1962) had a very high attrition rate of 62%.

Effects of interventions Summary of findings for the See: main comparison FLUPHENAZINE versus LOW-POTENCY ANTIPSYCHOTIC DRUGS for schizophrenia For dichotomous data we calculated risk ratios (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis based on a random-effects model.

1. Fluphenazine versus low-potency antipsychotic drugs

1.1 Clinical response: Response to treatment as defined by the original studies

There was no significant difference in response to treatment in two short-term studies (fluphenazine 55%, low-potency drug 55%, 2 RCTs, n = 105, RR 1.06 CI 0.75 to 1.50, Analysis 1.1).

1.2 Leaving the study early

1.2.1 Due to any reason There was no significant difference between fluphenazine and lowpotency antipsychotics, neither in the short term (fluphenazine 4%, low-potency antipsychotics 3%, 4 RCTs, n = 871, RR 1.07 CI 0.81 to 1.42), nor in the medium term (fluphenazine 55%, lowpotency antipsychotics 60%, 2 RCTs, n = 661, RR 0.98 CI 0.85 to 1.13), and also not overall (fluphenazine 36%, low-potency antipsychotics 36%, 6 RCTs, n = 1532, RR 1.00 CI 0.88 to 1.14, Analysis 1.2).

1.2.2 Due to adverse effects Selective reporting We judged one study (Childers 1964) to have an unclear risk of bias for selective reporting, because there was insufficient information to assess selective reporting. The remaining six studies did not (sufficiently) report on predefined outcomes: Clark 1971; Cole 1964; Galbrecht 1968; Hanlon 1965; Lasky 1962; NIMH 1967.

There was no significant difference between fluphenazine and lowpotency antipsychotics, neither in the short term (fluphenazine 4%, low-potency antipsychotics 3%, 3 RCTs, n = 561, RR 1.28 CI 0.48 to 3.37), nor in the medium term (fluphenazine 2%, low-potency antipsychotics 5%, 2 RCTs, n = 661, RR 0.33 CI 0.02 to 4.41), and also not overall (fluphenazine 3%, low-potency antipsychotics 4%, 5 RCTs, n = 1222, RR 0.83 CI 0.33 to 2.11, Analysis 1.3).

Other potential sources of bias In six studies, we judged the risk of other potential sources of bias as low. We judged one study (Childers 1964) with an unclear risk of bias, as there was insufficient information to assess whether such biases existed.

1.2.3 Due to inefficacy of treatment There was no significant difference between fluphenazine and lowpotency antipsychotics in the short term (fluphenazine 2%, lowpotency antipsychotics 1%, 3 RCTs, n = 561, RR 1.45 CI 0.33 to


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6.39). There was a trend in favour of low-potency antipsychotics in the medium term but the difference was not statistically significant (fluphenazine 16%, low-potency antipsychotics 10%, 2 RCTs, n = 661, RR 1.55 CI 1.00 to 2.38). Overall, there was a significant difference in favour of low-potency antipsychotics (fluphenazine 10%, low-potency antipsychotics 6%, 5 RCTs, n = 1222, RR 1.54 CI 1.01 to 2.33, Analysis 1.4).

1.3 Adverse effects: 1. General - at least one adverse effect

There was no significant difference between fluphenazine and lowpotency antipsychotics (fluphenazine 70%, low-potency antipsychotics 88%, 1 RCT, n = 65, RR 0.79 CI 0.58 to 1.07, Analysis 1.5).

1.4. Adverse effects: 2a. Specific - movement disorders

1.4.7 Loss of associated movement There was a significant difference in favour of low-potency antipsychotics (fluphenazine 20%, low-potency antipsychotics 2%, 1 RCT, n = 338, RR 11.15 CI 3.95 to 31.47).

1.4.8 Oculogyric crisis There was no significant difference (fluphenazine 0%, low-potency antipsychotics 0.4%, 1 RCT, n = 338, RR 0.64 CI 0.03 to 15.68).

1.4.9 Rigor There was a significant difference in favour of low-potency antipsychotics (fluphenazine 27%, low-potency antipsychotics 12%, 2 RCTs, n = 403, RR 2.18 CI 1.20 to 3.97).

1.4.1 At least one movement disorder There was a significant difference in favour of low-potency antipsychotics (fluphenazine 15%, low-potency antipsychotics 10%, 3 RCTs, n = 971, RR 2.11 CI 1.41 to 3.15, Analysis 1.6).

1.4.10 Tremor There was a significant difference in favour of low-potency antipsychotics (fluphenazine 15%, low-potency antipsychotics 6%, 2 RCTs, n = 403, RR 2.53 CI 1.37 to 4.68).

1.4.2 Akathisia There was a significant difference in favour of low-potency antipsychotics (fluphenazine 15%, low-potency antipsychotics 6%, 5 RCTs, n = 1209, RR 2.28 CI 1.58 to 3.28).

1.5 Adverse effects: 2b. Specific - other

1.4.3 Akinesia

a. Allergy

There was no significant difference (fluphenazine 1%, low-potency antipsychotics 0.7%, 2 RCTs, n = 223, RR 2.09 CI 0.22 to 20.07).

For nasal congestion, there was no significant difference between the drugs (fluphenazine 10%, low-potency antipsychotics 10%, 3 RCTs, n = 741, RR 0.88 CI 0.55 to 1.43). This also applied to ’rash’ (fluphenazine 1%, low-potency antipsychotics 2%, 5 RCTs, n = 1374, RR 0.91 CI 0.33 to 2.49, Analysis 1.7).

1.4.4 Dyskinesia There was no significant difference (fluphenazine 16%, low-potency antipsychotics 5%, 1 RCT, n = 158, RR 1.98 CI 0.13 to 31.05). 1.4.5 Dystonia There was a significant difference in favour of low-potency antipsychotics (fluphenazine 5%, low-potency antipsychotics 2%, 4 RCTs, n = 1309, RR 2.66 CI 1.25 to 5.64). 1.4.6 Facial rigidity There was no significant difference between fluphenazine and lowpotency antipsychotics (fluphenazine 14%, low-potency antipsychotics 11%, 1 RCT, n = 338, RR 1.29 CI 0.72 to 2.33).

b. Anticholinergic There was no significant difference for blurring of vision (fluphenazine 5%, low-potency antipsychotics 4%, 2 RCTs, n = 375, RR 1.13 CI 0.43 to 2.98), constipation (fluphenazine 40%, low-potency antipsychotics 41%, 3 RCTs, n = 741, RR 1.03 CI 0.74 to 1.45), and drooling (fluphenazine 5%, low-potency antipsychotics 3%, 3 RCTs, n = 741, RR 1.59 CI 0.74 to 3.43). For dry mouth there was a significant difference in favour of fluphenazine (fluphenazine 11%, low-potency antipsychotics 18%, 4 RCTs, n = 1051, RR 0.63 CI 0.45 to 0.89). Urinary disturbances were equally common in both groups (fluphenazine 2%, low-potency antipsychotics 3%, 4 RCTs, n = 1051, RR 0.81 CI 0.36 to 1.81).


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c. Cardiovascular There was no significant difference for any cardiovascular outcome (hypotension-fluphenazine 5%, low-potency antipsychotics 13%, 2 RCT, 223 = 65, RR 0.68 CI 0.13 to 3.52; oedema-fluphenazine 0%, low-potency antipsychotics 2%, 2 RCTs, n = 403, RR 0.38 CI 0.04 to 3.21; syncope-fluphenazine 40%, low-potency antipsychotics 41%, 2 RCTs, n = 403, RR 1.02 CI 0.14 to 7.75; and tachycardia-fluphenazine 5%, low-potency antipsychotics 0%, 1 RCT, n = 65, RR 6.57 CI 0.28 to 154.69).

d. Central nervous system There was no significant difference for the outcome of convulsion (fluphenazine 40%, low-potency antipsychotics 41%, 1 RCT, n = 338, RR 0.64 CI 0.03 to 15.68) and depression (fluphenazine 0%, low-potency antipsychotics 0%, 1 RCT, n = 65, RR not estimable). There was a significant difference in favour of fluphenazine for dizziness (fluphenazine 8%, low-potency antipsychotics 17%, 4 RCTs, n = 1051, RR 0.49 CI 0.32 to 0.73), and drowsiness (fluphenazine 18%, low-potency antipsychotics 25%, 3 RCTs, n = 986, RR 0.67 CI 0.53 to 0.86). There was no significant difference for the outcome of excitement (fluphenazine 10%, low-potency antipsychotics 7%, 1 RCT, n = 65, RR 1.50 CI 0.27 to 8.29) and headache (fluphenazine 12%, low-potency antipsychotics 9%, 1 RCT, n = 338, RR 1.29 CI 0.68 to 2.45). For photosensitivity there was trend in favour of fluphenazine but the difference was not statistically significant (fluphenazine 0%, low-potency antipsychotics 2%, 4 RCTs, n = 1036, RR 0.26 CI 0.06 to 1.15), but for restlessness there was no significant difference (fluphenazine 33%, lowpotency antipsychotics 37%, 2 RCTs, n = 403, RR 0.89 CI 0.68 to 1.17). Risk of sedation was less for fluphenazine (fluphenazine 20%, low-potency antipsychotics 64%, 1 RCT, n = 65, RR 0.31 CI 0.13 to 0.77) but there was no clear difference for ’seizures’ (fluphenazine 0%, low-potency antipsychotics 0.7%, 2 RCTs, n = 648, RR 0.43 CI 0.02 to 8.21).

1 RCT, n = 338, RR 1.39 CI 0.45 to 4.27; lactation-fluphenazine 3%, low-potency antipsychotics 2%, 1 RCT, n = 338, RR 1.94 CI 0.49 to 7.61; and swelling of breasts-fluphenazine 40%, lowpotency antipsychotics 41%, 1 RCT, n = 338, RR 5.82 CI 0.61 to 55.30).

g. Immune system There was no significant difference for any immune system outcome (intercurrent infection-fluphenazine 3%, low-potency antipsychotics 3%, 1 RCT, n = 338, RR 1.29 CI 0.37 to 4.49, and oral infection-fluphenazine 0%, low-potency antipsychotics 0.6%, 1 RCT, n = 323, RR 0.34 CI 0.01 to 8.27).

1.6 Missing outcomes

There were no data on important other outcomes such as death, relapse, service use, quality of life or satisfaction with care.

2. Subgroup analyses All subgroup analyses were conducted only on the primary outcome response to treatment as defined by the original studies.

2.1 Different low-potency drugs

Two studies (Childers 1964; Clark 1971) compared fluphenazine with chlorpromazine and there was no significant difference in response to treatment (fluphenazine 55%, chlorpromazine 58%, 2 RCTs, n = 80, RR 0.95 CI 0.66 to 1.37). The comparison with thioridazine (fluphenazine 65%, thioridazine 68%, 1 RCT, n = 39, RR 0.95 CI 0.61 to 1.48) also did not show any significant difference.

e. Gastrointestinal

2.2 Investigation of heterogeneity

There was no significant difference for diarrhoea (fluphenazine 2%, low-potency antipsychotics 1%, 2 RCTs, n = 676, RR 1.94 CI 0.42 to 8.98) or ’gastrointestinal disturbance’ (fluphenazine 0%, low-potency antipsychotics 0.7%, 1 RCT, n = 323, RR 0.34 CI 0.01 to 8.27). There was, however, a significant difference in favour of fluphenazine for nausea (fluphenazine 4%, low-potency antipsychotics 15%, 3 RCTs, n = 986, RR 0.25 CI 0.14 to 0.45) and vomiting (fluphenazine 3%, low-potency antipsychotics 8%, 3 RCTs, n = 986, RR 0.36 CI 0.18 to 0.72).

There was no heterogeneity regards to the primary outcome response to treatment (P = 0.93, I2 = 0%).

3. Sensitivity analyses All sensitivity analyses were conducted only on the primary outcome response to treatment as defined by the original studies.

f. Hormonal

3.1 Exclusion of studies for which randomisation was implied because they were double-blind

There was no significant difference for any hormonal outcome (amenorrhoea-fluphenazine 4%, low-potency antipsychotics 3%,

Both studies that reported on response to treatment used random assignment (Childers 1964; Clark 1971).


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3.2 Exclusion of open studies

One study (Childers 1964) was not described as double-blind and was assumed to be open. Excluding this study did not change the overall results (fluphenazine 65%, low-potency drug 63%, 1 RCT, n = 63, RR 1.04 CI 0.70 to 1.54).

3.3 Fixed-effect model

When a fixed-effect model was applied, the efficacy of fluphenazine was not different from that of low-potency drugs (fluphenazine 55%, low-potency 57%, 2 RCTs, n = 103, RR 1.02 CI 0.72 to 1.45).

3.4 Assessment of dosage

There were no discrepant dosages reported in the two studies ( Childers 1964; Clark 1971) that reported on the primary outcome.

Conventional (first-generation, typical) antipsychotic drugs are still frequently used in the treatment of schizophrenia, both in poorer as well as in richer countries. This review compared fluphenazine with low-potency conventional antipsychotics. Seven randomised controlled trials (RCTs) with 1567 participants were included. Several general limitations must be considered. Only two studies reported data on the primary outcome, involving a total of 103 participants. Current registrational studies on new antipsychotics usually include several hundreds of participants (e.g. Kane 2011). Moreover, in the included studies the methods of sequence generation and blinding were often poorly reported. Outcomes which are clinically relevant, such as hospital admission, quality of life, employment, rehospitalisation or weight gain, were not reported at all. Overall, it is difficult to draw robust conclusions on the relative efficacy and tolerability of fluphenazine compared to low-potency antipsychotics. This is also supported by an average judgement of moderate quality for the outcomes in the ’Summary of findings’ table (see Summary of findings for the main comparison).

4. Other results 2. Treatment effects 4.1 Publication bias

Only two studies reported results on the primary outcome response to treatment, so that funnel plots were not meaningful and therefore, not applied.

4.2 ’Summary of findings’ table

The results of the outcomes response to treatment, leaving the study early, at least one adverse event, at least one movement disorder, sedation, death and quality of life were inspected more closely (see Summary of findings for the main comparison). Based on this tool, we considered the quality of the results on response to treatment, acceptability of treatment (leaving early due to any reason) and at least one adverse event to be moderate, for at least one movement disorder to be low and for sedation to be high. Moreover, no data on the predefined outcomes death and quality of life were available. The judgements derived from this instrument were used for the discussion section of the review (see Discussion - Summary of main results).

2.1 Clinical response The overall results of response to treatment do not suggest a difference in efficacy between fluphenazine and low-potency antipsychotic drugs. This result supports early work, which was not based on meta-analytic method (Davis 1989; Klein 1969) and does not confirm the clinical perception that low-potency antipsychotic drugs are less efficacious than fluphenazine. Due to the fact that only two studies reported on this outcome and that the number of participants was small, in total 103 participants, this result is inconclusive and underpowered. Also, the criteria and cut-offs used for the primary outcome response to treatment varied, although Furukawa 2011 showed that this is not so much of a problem as long as relative risks and odds ratios are used. Moreover, significantly more participants in the fluphenazine groups discontinued due to inefficacy of treatment, which is an effect opposite to the one expected. 2.2 Leaving the study early

DISCUSSION

Summary of main results

1. General

There was no significant difference between fluphenazine and lowpotency antipsychotics in the outcome leaving the study early due to any reason. It therefore seems that both fluphenazine and lowpotency antipsychotics are not different in their overall acceptability for participants with schizophrenia. We also found no significant difference in terms of leaving the studies early due to adverse effects. However, there was a significant superiority of lowpotency antipsychotics in terms of leaving the studies early due to inefficacy, as measured by five studies. As leaving the study early due to inefficacy can be a measure of response, low-potency


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antipsychotics seem to be more efficacious than fluphenazine for people with schizophrenia. However, the absolute risk difference was only approximately 2% and the confidence interval was very wide, therefore interpretations must be made with caution.

Overall completeness and applicability of evidence

1. Completeness 2.3 Adverse effects Fluphenazine produced more movement disorders in the form of ’at least one movement disorder’, akathisia, dystonia, loss of associated movement, rigor and tremor. Low-potency antipsychotics produced significantly more dizziness, drowsiness, dry mouth, nausea, sedation and vomiting. The findings on adverse effects are in line with today’s knowledge that high-potency and low-potency antipsychotics have a different affinities and binding properties to dopamine and other receptors and thus differ in the types of adverse effects. In particular, fluphenazine produces a variety of socalled movement disorders, while low-potency antipsychotics are associated with more anticholinergic side effects (e.g. dry mouth) and side effects from the sedation spectrum (sedation, drowsiness, dizziness).

2.4 Missing outcomes None of the included studies reported on service use, death, quality of life, participants’/carers’ satisfaction with care or economic outcomes. These outcomes may be more important for carers and policy makers than conventional measures of efficacy and tolerability. It is therefore disappointing that they are not available.

3. Publication bias Due to the limited number of studies which reported on the primary outcome, we did not test for funnel plot asymmetry.

4. Subgroup analyses and investigation of heterogeneity The effects of fluphenazine versus each single low-potency antipsychotic drug did not show any significant difference, but the results are clearly limited by the small number of trials assigned to each single low-potency drug. As there were only two studies we could also not provide reasonable statements on participants with special problems (e.g. those with a first-episode, treatmentresistant forms of schizophrenia etc).

5. Sensitivity analyses The exclusion of one study which was not explicitly described as double-blind did not change the overall results of the primary outcome. Also, the results of the primary outcome were not different when a fixed-effect model instead of a random-effects model was applied. Therefore, the results were robust with regard to these sensitivity analyses.

Of the seven included studies with a total of 1567 participants, only two small studies with 103 participants reported sufficient data for the primary outcome response to treatment. The small number of participants available alone shows that even the evidence on the primary outcome is incomplete. Moreover, there were only data for a limited number of low-potency antipsychotics (chlorpromazine, thioridazine, chlorprothixene). There were no studies on other low-potency antipsychotics such as levomepromazine, mesoridazine or promazine. There was no randomised evidence on simple but important adverse event such as death, QTc prolongation or weight gain, and there were no data on service use, quality of life and satisfaction of care. New studies with better outcome reporting would be needed to make stronger statements about the differences between fluphenazine and low-potency antipsychotics, which are important for routine care.

2. Applicability The discrepancy in the overall number of participants (1567) and those available for the primary outcome (103) shows that the results on response to treatment are only derived from a minority of the randomised participants, thus they can even not be generalised to all participants included in the review. Almost all the studies were from the 60s and did not apply operational diagnostic criteria such as DSM-III or its more recent versions, because these were simply not available. As in addition the criteria to diagnose schizophrenia have changed over time, it is possible that those older studies included participants who nowadays would have another diagnosis than schizophrenia, again limiting the applicability of the findings to current practice.

Quality of the evidence None of the included studies described the exact sequence generation and allocation concealment methods and were thus rated as unclear in this regard. Most of the included studies were said to be double-blind but for most of them details were not reported. Lack of blinding is not necessarily a problem for objective outcomes, but it can be highly problematic for subjective outcomes such as response to treatment or side effects that are simply recorded by open interviews. None of the studies was judged to be free of selective reporting, most of them failed to report on previously defined outcomes as well as on means and standard deviations for continuous outcomes. In summary, the overall quality of the studies according to these criteria was moderate (see Summary of findings for the main comparison).


21

Potential biases in the review process

3. For managers/policy makers

We combined all low-potency antipsychotics in a group and only addressed each drug separately in the primary outcome response to treatment by subgroup analysis. As there were only three different antipsychotics, all low-potency ones and two of them from the phenothiazine class, we feel that pooling them in one group might have been appropriate. Nevertheless, there are also differences between the various low-potency antipsychotics which have been missed by this procedure. The database for each single-low-potency drug would have been even smaller and more inconclusive. The study search was mainly based on the Cochrane Schizophrenia Group’s register of trials. The regular searches of the Trials Register are largely based on published literature. It is possible that there are unpublished studies we are not aware of. As most of the relevant literature is old, it is actually likely that trials have been missed.

There were no data on service use such as rehospitalisation, economic outcomes or quality of life, which are important outcomes for decision makers. Thus, it is not possible to make any recommendations apart from the fact that all of the examined drugs in this review have lost their patent protection and are therefore rather inexpensive.

Implications for research 1. General

Agreements and disagreements with other studies or reviews

The outcome reporting about the effects of fluphenazine versus low-potency antipsychotics on clinical response is insufficient. Few data were available, and long-term effects were not reported at all. Strict adherence to the CONSORT statement (Moher 2010) would make such studies much more informative. Also, it would be interesting to have comparisons between different low-potency first-generation antipsychotics, as they are likely to have different side effects.

We are not aware of other reviews on the efficacy of fluphenazine versus low-potency antipsychotic drugs.

2. Specific

2.1 Reviews

AUTHORS’ CONCLUSIONS Implications for practice

Studies we had to exclude because they were not directly relevant, however, do still show how this compound has been evaluated in many other ways. Some of these remain clinically relevant and may merit further systematic reviews (Table 2).

1. For clinicians

2.2 Trials Clinicians should know that in one efficacy outcome, leaving the studies early due to inefficacy, fluphenazine was slightly less efficacious than low-potency antipsychotics, but this was not consistent with the primary measure of this review ’response to treatment’. Fluphenazine produced more movement disorders than low-potency antipsychotics (significant differences were found for at least one movement disorder, akathisia, dystonia, loss of associated movement, rigor and tremor), while the latter were associated with dizziness, drowsiness and sedation, dry mouth, nausea and sometimes even vomiting.

The number of studies providing data on the primary outcome response to treatment was very low, the overall quality of the included studies was moderate at best. As first-generation antipsychotic drugs are still frequently prescribed, not only in poorer countries but also in wealthy nations such as Germany, we feel that further RCTs comparing fluphenazine and low-potency antipsychotic drugs are still warranted. We suggest a design of a future study in Table 3.

2. For people with schizophrenia

ACKNOWLEDGEMENTS

For people with schizophrenia, it might be important to know that the choice between trifluoperazine and low-potency antipsychotics should be largely based on differences in side effects. Movement disorders are more likely to appear under treatment with fluphenazine, whereas low-potency antipsychotics also have unpleasant side effects such as sedation, dizziness, drowsiness; dry mouth or nausea/vomiting.

The Cochrane Schizophrenia Group (CSG) Editorial Base in Nottingham produces and maintains standard text for use in the methods sections of their reviews. We have used this text as the basis of what appears here and adapted it as required. We are indebted to the CSG team for its assistance in the literature search and its continuous support, and we thank the peer-reviewers for their useful comments.


22

REFERENCES

References to studies included in this review Childers 1964 {published data only} Childers RT. Comparison of four regimens in newly admitted female schizophrenics. American Journal of Psychiatry 1964;120:1010–1. Clark 1971 {published data only} Clark ML, Huber WK, Charalampous KD, Serafetinides EA, Trousdale W, Colmore JP. Drug treatment in newly admitted schizophrenic patients. Archives of General Psychiatry 1971;25(5):404–9. Cole 1964 {published data only} National Institute of Mental Health Psychopharmacology Research Branch Collaborative Study Group. Phenothiazine treatment in acute schizophrenia. Archives of General Psychiatry 1964;10(3):246–61. Galbrecht 1968 {published data only} Galbrecht CR, Klett CJ. Predicting response to phenothiazines: the right drug for the right patient. Journal of Nervous and Mental Disease 1968;147:173–83. Hanlon 1965 {published data only} Hanlon TE, Michaux MH, Ota KY, Shaffer JW, Kurland AA. The comparative effectiveness of eight phenothiazines. Psychopharmacology 1965;7(2):89–106. Lasky 1962 {published data only} Lasky JJ, Klett CJ, Caffey EM, Bennett JL, Rosenblum MP, Hollister LE. Drug treatment of schizophrenic patients. A comparative evaluation of chlorpromazine, chloprothixene, fluphenazine, reserpine, thioridazine and triflupromazine. Diseases of the Nervous System 1962;23(12):698–706. NIMH 1967 {published data only} National Institute of Mental Health Psychopharmacology Research Branch Collaborative Study Group. Differences in clinical effects of three phenothiazines in “acute” schizophrenia. Diseases of the Nervous System 1967;28(6): 369–83.

References to studies excluded from this review Cesarec 1974 {published data only} Cesarec Z, Eberhard G, Nordgren L. A controlled study of the antipsychotic and sedative effects of neuroleptic drugs and amphetamine in chronic schizophrenics. A clinical and experimental-psychological study. Acta Psychiatrica Scandinavica Supplementum 1974;249:65–77. Chacon 1973 {published data only} Chacon C, Harper P. Clinical and work performance variables in phenothiazine therapy of schizophrenia. Acta Psychiatrica Scandinavica 1973;49(1):65–76.

Galdi 1988 {published data only} Galdi J, Bonato RR. Relationship of adverse drug reactions to length of hospital-stay in genetically subgrouped schizophrenics. Canadian Journal of Psychiatry [Revue Canadienne de Psychiatrie] 1988;33(9):816–8. Gunby 1968 {published data only} Gunby B, Brun H, Hartviksen I. Fluphenazine in the long term treatment of psychoses. A preliminary communication. Acta Psychiatrica Scandinavica Supplementum 1968;203: 225–30. Hordern 1964 {published data only} Hordern A, King A, Holt NF, Collins J, Toussaint J. Thioproperazine in chronic schizophrenia. British Journal of Psychiatry 1964;110:531–9. Kane 1983 {published data only} Kane JM. Low dose medication strategies in the maintenance treatment of schizophrenia. Schizophrenia Bulletin 1983;9(4):528–32. Kane JM, Rifkin A, Woerner M, Reardon G. Lowdose neuroleptics in outpatient schizophrenics. Psychopharmacology Bulletin 1982;18(1):20–1. Kane JM, Rifkin A, Woerner M, Reardon G, Kreisman D, Blumenthal R, et al. High-dose versus low-dose strategies in the treatment of schizophrenia. Psychopharmacology Bulletin 1985;21(3):533–7. ∗ Kane JM, Rifkin A, Woerner M, Reardon G, Sarantakos S, Schiebel D, et al. Low-dose neuroleptic treatment of outpatient schizophrenics. I. Preliminary results for relapse rates. Archives of General Psychiatry 1983;40(8):893–6.

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Campbell 2000 Campbell M, Grimshaw J, Steen N. Sample size calculations for cluster randomised trials. Changing Professional Practice in Europe Group (EU BIOMED II Concerted Action). Journal of Health Services Research and Policy 2000;5:12–6.

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Davis 1974 Davis JM. Overview: maintenance therapy in psychiatry: I. Schizophrenia. American Journal of Psychiatry 1975;132 (12):1237–45. Davis 1989 Davis JM, Barter JT, Kane JM. Antipsychotic drugs. Comprehensive Textbook of Psychiatry. Baltimore, MD: Williams and Wilkins, 1989. Deeks 2000 Deeks J. Issues in the selection for meta-analyses of binary data. Proceedings of the 8th International Cochrane Colloquium; 2000 Oct 25-28th; Cape Town, South Africa. Cape Town, 2000. Der-Simonian 1986 Der-Simonian R, Laird N. Meta-analysis in clinical trials. Controlled Clinical Trials 1986;7:177–88. Divine 1992 Divine GW, Brown JT, Frazer LM. The unit of analysis error in studies about physicians’ patient care behavior. Journal of General Internal Medicine 1992;7:623–9. Dold 2012 Dold M, Li C, Tardy M, Leucht S. Haloperidol versus first generation antipsychotics for schizophrenia. Cochrane Database of Systematic Reviews 2012, Issue 5. [DOI: 10.1002/14651858.CD009831] Egger 1997 Egger M, Davey-Smith G, Schneider M, Minder CSO. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;13:629–34. Elbourne 2002 Elbourne DR, Altman DG, Higgins JP, Curtin F, Worthington HV, Vail A. Meta-analyses involving crossover trials: methodological issues. International Journal of Epidemiology 2002;31:140–9. Falkai 2005 Falkai P, Wobrock T, Lieberman J. World Federation of Societies of Biological Psychiatry (WFSBP)-Guidelines for biological treatment of schizophrenia, part 1: Acute treatment of schizophrenia. World Journal of Biological Psychiatry 2005;6:132–91.

Guy 1976 Guy W. Clinical Global Impressions Scale. ECDEU Assessment Manual for Psychopharmacology (DOTES: Dosage Record and Treatment Emergent Symptom Scale). National Institute of Mental Health, 1976. Haase 1983 Haase HJ. Dosierung der Neuroleptika. Ein Leitfaden für Klinik und Praxis unter besonderer Berücksichtigung psychotisch Kranker. Erlangen: Perimed FachbuchVerlagsgesellschaft, 1983. Higgins 2008b Higgins JPT, Deeks JJ, Altman DG (editors). Chapter 16: Special topics in statistics. In: Higgins JPT, Green S (editors). Cochrane Handbook forSystematic Reviews of Interventions Version 5.0.1 [updated September 2008]. The CochraneCollaboration, 2008. Available from www.cochrane-handbook.org. Higgins 2011 Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.2 [updated September 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org. Jones 2006 Jones PB, Barnes TRE, Davies L, Dunn G, Lloyd H, Hayhurst KP, et al. Randomized controlled trial of the effect on quality of life of second- vs first-generation antipsychotic drugs in schizophrenia-cost utility of the latest antipsychotic drugs in schizophrenia study (CUtLASS 1). Archives of General Psychiatry 2006;63:1079–86. Kane 2011 Kane JM, Mackle M, Snow-Adami L, Zhao J, Szegedi A, Panagides J. A randomized placebo-controlled trial of asenapine for the prevention of relapse of schizophrenia after long-term treatment. Journal of Clinical Psychiatry 2011;72(3):349–55. Kay 1986 Kay SR, Opler LA, Fiszbein A. Positive and Negative Syndrome Scale (PANSS) Manual. North Tonawanda (NY): Multi-Health Systems, 1986.


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Klein 1969 Klein DF, Davis JM. Diagnosis and Drug Treatment of Psychiatric Disorders. Baltimore, MD: Williams and Wilkins, 1969. Lehman 2004 Lehman AF, Lieberman JA, Dixon LB. Practice guideline for the treatment of patients with schizophrenia, second edition. American Journal of Psychiatry 2004;161:1–56. Leucht 2005a Leucht S, Kane JM, Kissling W, Hamann J, Etschel E, Engel R. What does the PANSS mean?. Schizophrenia Research 2005;79:231–8. Leucht 2005b Leucht S, Kane JM, Kissling W, Hamann J, Etschel E, Engel R. Clinical implications of brief psychiatric rating scale scores. British Journal of Psychiatry 2005;187:366–71. Leucht 2009 Leucht S, Corves C, Arbter D, Engel R, Li C, Davis JM. A meta-analysis comparing second-generation and firstgeneration antipsychotics for schizophrenia. Lancet 2009; 373:31–41. Leucht 2009b Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet 2009;373 (9657):31–41. Lieberman 2005 Lieberman JA, Stroup TS, McEvoy JP. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. New England Journal of Medicine 2005;353:1209–23. Lohse 2005 Lohse MJ, Lorenzen A, Müller-Oerlinghausen B. Psychotropic drugs [Psychopharmaka]. Arzneimittel Verordnungs Report 2005:820–64. Marshall 2000 Marshall M, Lockwood A, Bradley C, Adams C, Joy C, Fenton M. Unpublished rating scales: a major source of bias in randomised controlled trials of treatments for schizophrenia. British Journal of Psychiatry 2000;176: 249–52.

Nolte 2004 Nolte S, Wong D, Latchford G, Boyle O, Anaenugwu A. Amphetamines for schizophrenia. Cochrane Database of Systematic Reviews. John Wiley & Sons, Ltd, 2004, issue 3. [DOI: 10.1002/14651858.CD004964; CD004964] Overall 1962 Overall JE, Gorham DR. The brief psychiatric rating scale. Psychological Reports 1962;10:799–12. Schünemann 2008 Schünemann HJ, Oxman AD, Vist GE, Higgins JPT, Deeks JJ, Glasziou P, et al. Chapter 12: Interpreting results and drawing conclusions. In: Higgins JPT, Green S (editors). Cochrane Handbook forSystematic Reviews of Interventions Version 5.0.1 [updated September 2008]. The CochraneCollaboration, 2008. Available from www.cochrane-handbook.org. Seeman 1975 Seeman P, Lee T. Antipsychotic drugs: direct correlation between clinical potency and presynaptic action on dopamine neurons. Science 1975;188:1217–9. Tardy 2011 Tardy M, Leucht S, Potapov A, Engel R, Dold M, Kissling W. Flupenthixol versus low-potency first generation antipsychotic drugs for schizophrenia. Cochrane Database of Systematic Reviews 2011, Issue 8. [DOI: 10.1002/ 14651858.CD009227; CD009227] Tardy 2011b Tardy M, Leucht S, Potapov A, Kissling W, Engel R, Huhn M, et al. Haloperidol versus low-potency first-generation antipsychotic drugs for schizophrenia. Cochrane Database of Systematic Reviews 2011, Issue 8. [DOI: 10.1002/ 14651858.CD009268; CD009268] Tardy 2011c Tardy M, Leucht S, Potapov A, Engel R, Huhn M, Kissling W. Perphenazine versus low-potency first generation antipsychotic drugs for schizophrenia. Cochrane Database of Systematic Reviews 2011, Issue 10. [DOI: 10.1002/ 14651858.CD009369; CD009369]

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Tardy 2011d Tardy M, Leucht S, Potapov A, Engel R, Dold M, Kissling W. Trifluoperazine versus low-potency first generation antipsychotic drugs for schizophrenia. Cochrane Database of Systematic Reviews 2011, Issue 10. [DOI: 10.1002/ 14651858.CD009396; CD009396]

Moher 2010 Moher D, Hopewell S, Schulz KF, Montori V, Gøtzsche PC, Devereaux PJ, et al. CONSORT 2010 Explanation and Elaboration: updated guidelines for reporting parallel group randomised trials. BMJ 2010;340:c869.

Tsuang 1978 Tsuang MT. Suicide in schizophrenics, manics, depressives, and surgical controls: a comparison with general population suicide mortality. Archives of General Psychiatry 1978;35: 153–5.

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Xia 2009 Xia J, Adams CE, Bhagat N, Bhagat V, Bhoopathi P, ElSayeh H, et al. Loss to outcomes stakeholder survey: the LOSS study. Psychiatric Bulletin 2009;33(7):254–7. ∗ Indicates the major publication for the study


25

CHARACTERISTICS OF STUDIES

Characteristics of included studies [ordered by study ID] Childers 1964 Methods

Randomisation: placed at random, no further details. Allocation: procedure not described. Blinding: n.i., probably open. Duration: 35 days. Design: cross-over (include first phase only). Location: n.i.. Setting: n.i..

Participants

Diagnosis: schizophrenia (clinical diagnosis). N = 40. Gender: n.i.. Age: mean 37 years. History: duration stable - n.i., duration ill-,n.i., number of previous hospitalisations - n. i., age at onset - n.i., severity of illness - n.i., baseline antipsychotic dose-n.i.

Interventions

1. Fluphenazine: flexible dose, allowed dose range n.i., mean dose 20 mg/day. N = 20 2. Chlorpromazine: flexible dose, allowed dose range n.i., mean dose 1000 mg/day. N = 20 Rescue medication: n.i..

Outcomes

Response to treatment: Clinical judgement.

Notes Risk of bias Bias

Authors’ judgement

Support for judgement

Random sequence generation (selection Unclear risk bias)

Placed at random, no further details.

Allocation concealment (selection bias)

Procedure not described.

Unclear risk

Blinding of participants and personnel High risk (performance bias) All outcomes

N.i., probably open.

Blinding of outcome assessment (detection High risk bias) All outcomes

N.i., probably open.

Incomplete outcome data (attrition bias) All outcomes

Study did not report on incomplete outcome data.

Unclear risk


26

Childers 1964

(Continued)

Selective reporting (reporting bias)

Unclear risk

Insufficient information to assess whether risk of selective reporting exists

Other bias

Unclear risk

Insufficient information to assess whether risk of other bias exists

Clark 1971 Methods

Randomisation: random, in blocks of four. Allocation: procedure not described. Blinding: double, identical capsule appearance. Duration: 4 weeks. Design: parallel. Location: single centre. Setting: inpatients.

Participants

Diagnosis: newly admitted, acutely exacerbated chronic schizophrenic participants N = 65. Gender: 17 males, 40 females. Age: mean 33.2 years. History: duration stable - n.i., duration ill - n.i., number of previous hospitalisations mean 2.5, age at onset - n.i., severity of illness - CGI baseline mean score 4.42, baseline antipsychotic dose - n.i.

Interventions

1. Fluphenazine: flexible dose, allowed dose range 2 to 10 mg/day, mean dose 7.28 mg/ day. N = 20 2. Chlorpromazine hydrochloride: flexible dose, allowed dose range 200 to 1000 mg/ day, mean dose 718 mg/day. N = 23 3. Thioridazine: flexible dose, allowed dose range 200-1000 mg/day, mean dose 760 mg/ day. N = 22 Rescue medication: usual night-time sedatives.

Outcomes

Response to treatment: CGI improvement score. Leaving the study early. Adverse effects: at least one adverse effect, movement disorders (akathisia, akinesia, rigor, tremor), adverse effects-other (blurred vision, constipation, depression, dizziness, drooling, dry mouth, oedema, excitement, gastrointestinal disturbance, hypotension, nasal congestion, oral infection, photosensitivity, rash, restlessness, sedation, syncope, tachycardia, urinary disturbances) Unable to use Mental: BPRS (incomplete data, no SD). Global: CGI (incomplete data). Behaviour: NOSIE (incomplete data). Cognitive: Purdue Pegboard Test, Digit Symbol Test (incomplete data)

Notes Risk of bias Fluphenazine versus low-potency first-generation antipsychotic drugs for schizophrenia (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

27

Clark 1971

(Continued)

Bias




Random, in blocks of four.



Unclear risk

Blinding of participants and personnel Low risk (performance bias) All outcomes

Double, identical capsule appearance.

Blinding of outcome assessment (detection Low risk bias) All outcomes

Double, identical capsule appearance.


High risk

8 out of 65 participants dropped out and were not included in the final analysis (2/20 in the fluphenazine and 6/45 in the low-potency group). Of the remaining 57 participants, one participant from the fluphenazine group dropped out but his data were retained for final analysis


High risk

Incomplete data (e.g. BPRS, no SD).

Other bias

Low risk

No evidence for other bias.

Cole 1964 Methods

Randomisation: randomly assigned to one of four drug groups, stratified by sex Allocation: procedure not described. Blinding: double, standard pink capsules no.2, code broken at the end of study Duration: 6 weeks. Design: parallel. Location: multicentre. Setting: in- and outpatients.

Participants

Diagnosis: newly admitted acute schizophrenic patients (clinical diagnosis) N = 338. Gender: n.i.. Age: mean 28.2 years. History: duration stable - n.i., duration ill - duration of symptoms prior to hospitalisation 2.6 months, number of previous hospitalisations - n.i., age at onset -, mean 25.5 years, severity of illness - doctors pretreatment global rating of mental illness 82% markedly ill, baseline antipsychotic dose - n.i.


28

Cole 1964

(Continued)

Interventions

1. Fluphenazine: flexible dose, allowed dose range min. 2 to 16 mg/day, mean dose 5.4 mg/day. N = 115 2. Chlorpromazine: flexible dose, allowed dose range 200 to 1600 mg/day, mean dose 654.8 mg/day. N = 112 3. Thioridazine: flexible dose, allowed dose range 200 to 1600 mg/day, mean dose 700 mg/day. N = 111 Rescue medication: antiparkinson medications, no other drug permitted

Outcomes

Leaving the study early. Adverse effects: movement disorders (akathisia, dystonia, rigor, tremor), adverse effectsother (amenorrhoea, blurred vision, constipation, convulsion, depression, diarrhoea, dizziness, drooling, drowsiness, dry mouth, oedema, facial rigidity, headache, hypotension, intercurrent infection, lactation, loss of associated movement, nasal congestion, nausea, oculogyric crisis, photosensitivity, rash, restlessness, swelling of breasts, syncope, urinary disturbances, vomiting) Unable to use Response to treatment: incomplete data, analysed by drugs vs placebo, not fluphenazine vs low-potency drugs Mental state: IMPS (incomplete data, analysed by drugs vs placebo) Behaviour: WBRS (incomplete data).





Randomly assigned to one of four drug groups, stratified by sex



Unclear risk


Double, standard pink capsules no.2, code broken at the end of study


Double, standard pink capsules no.2, code broken at the end of study


High risk

44 out of 223 participants from the low-potency drug group ans 24 out of 115 participants from the fluphenazine group left the study early (20%, 21%) and were excluded from final analysis (completers only)


High risk

Results for global rating and IMPS not available for drugs separately


29

Cole 1964

(Continued)

Other bias

Low risk

No clear other bias.

Galbrecht 1968 Methods

Randomisation: randomly assigned, no further details. Allocation: procedure not described. Blinding: double, capsules of identical appearance. Duration: 8 weeks. Design: parallel. Location: multicentre. Setting: inpatients.

Participants

Diagnosis: schizophrenia (clinical diagnosis), 47% paranoid, 31 chronic undifferentiated, 10 catatonic N = 310. Gender: 310 men. Age: n.i.. History: duration stable - n.i., duration ill-,n.i., number of previous hospitalisations - n. i., age at onset - n.i., severity of illness - n.i., baseline antipsychotic dose-n.i.

Interventions

1. Fluphenazine: flexible dose, allowed dose range 2.5 to 20 mg/day, mean dose 8.4 mg/ day. N = 104 2. Chlorpromazine: flexible dose, allowed dose range 200 to 1600 mg/day, mean dose 750 mg/day. N = 102 3. Thioridazine: flexible dose, allowed dose range 200 to 1600 mg/day, mean dose 700 mg/day. N = 104 Rescue medication: conventional sedatives, hypnotics, ancillary medications

Outcomes

Leaving the study early. Adverse effects: movement disorders (at least one movement disorder, akathisia, dystonia), adverse effects-other (blurred vision, dizziness, drowsiness, dry mouth, nausea, photosensitivity, rash, seizures, urinary disturbances, vomiting) Unable to use Mental state: IMPS (incomplete data, data only available for single items, no means, no SD)





Randomly assigned, no further details.



Unclear risk


30

Galbrecht 1968

(Continued)


Double, capsules of identical appearance.




Unclear risk

18% dropped out, but not all were lost from study, LOCF for those who droppedout towards the end of study (not indicated how many)


High risk

IMPS (no means, no SD).

Other bias

Low risk


Hanlon 1965 Methods

Randomisation: randomly assigned, no further details. Allocation: procedure not described. Blinding: double-blind, drug dispensed in standard unmarked pink capsules No. 1&0 size Duration: 30 days. Design: parallel. Location: n.i.. Setting: inpatients.

Participants

Diagnosis: psychotic (schizophrenic). N = 158. Gender: n.i.. Age: mean 36.3 years. History: duration stable - n.i., duration ill - n.i., number of previous hospitalisations - n.i. , age at onset - n.i., severity of illness - MSRPP mean 41.4 SD 15.3, baseline antipsychotic dose - n.i.

Interventions

1. Fluphenazine: flexible dose, allowed dose range n.i., mean dose 5.92 mg/day. N = 53 2. Chlorpromazine: flexible dose, allowed dose range n.i., mean dose 396 mg/day. N = 52 3. Thioridazine: flexible dose, allowed dose range n.i., mean dose 193 mg/day. N = 53 Rescue medication: antiparkinson medication (biperiden), mild sedation

Outcomes

Leaving the study early. Adverse effects: movement disorders (akathisia, akinesia, dyskinesia) Unable to use Mental state: IMPS (incomplete data, no mean, no SD). Behaviour: MACC (incomplete data). Personality: MMPI (incomplete data).


31

Hanlon 1965

(Continued)

Ward observer measures (incomplete data). Notes Risk of bias Bias







Unclear risk


Double-blind, drug dispensed in standard unmarked pink capsules No. 1&0 size


Double-blind, drug dispensed in standard unmarked pink capsules No. 1&0 size


High risk

22/105 (21%) from the low-potency and 13/53 (25%) from the fluphenazine group left the study early. No full ITT (at least 5 days of treatment)


High risk

No usable data on IMPS, MACC, MMPI.

Other bias

Low risk


Lasky 1962 Methods

Randomisation: randomly assigned, no further details. Allocation: procedure not described. Blinding: double, capsules of identical appearance. Duration: 24 weeks. Design: parallel. Location: multicentre. Setting: inpatients.

Participants

Diagnosis: schizophrenic men with acute psychotic symptoms (clinical diagnosis), 1/2 paranoid subtype, 1/3 undifferentiated N = 341. Gender: only men. Age: modal patient was 36 years old. History: duration stable - n.i., duration ill -n.i., number of previous hospitalisations - modal patients 3 to 4 times, age at onset - n.i., severity of illness - n.i., baseline antipsychotic dose-n.i.


32

Lasky 1962

(Continued)

Interventions

1. Fluphenazine: flexible dose, allowed dose range 2.5to 20 mg/day, mean dose 10 mg/ day. N = 84 2. Chlorpromazine: flexible dose, allowed dose range 200 to 1600 mg/day, mean dose 746 mg/day. N = 86 3. Thioridazine: flexible dose, allowed dose range 200 to 1600 mg/day, mean dose 845 mg/day. N = 84 4. Chlorprothixene: flexible dose, allowed dose range 50 to 400 mg/day, mean dose 224 mg/day. N = 87 Rescue medication: sedatives, hypnotics, side effects treated with appropriate medications

Outcomes

Leaving the study early. Adverse effects: movement disorders (at least one movement disorder, akathisia, dystonia), adverse effects-other (constipation, diarrhoea, dizziness, drooling, drowsiness, dry mouth, nasal congestion, nausea, photosensitivity, rash, seizures, urinary disturbances, vomiting) Unable to use Mental state: IMPS (incomplete data, analysed by single items only, no mean) Behaviour: PRP (incomplete data). Body weight (incomplete data).








Unclear risk






54 out of 84 participants in the fluphenazine group and 175 out of 257 participants in the low-potency group left the study early (64%, 68%), which is a high rate. Most were included in the final analysis (LOCF) , except those who dropped out during the first three weeks (there is no information on how many and from which group)

High risk


33

Lasky 1962

(Continued)


High risk

IMPS, PRP (all no means, no SD).

Other bias

Low risk


NIMH 1967 Methods

Randomisation: randomly assigned to one of three drug treatments, stratified by sex Allocation: procedure not described. Blinding: double, no further details. Duration: 26 weeks. Design: parallel. Location: multicentre. Setting: in- and outpatients.

Participants

Diagnosis: newly admitted acute schizophrenic patients. N = 323. Gender: n.i.. Age: mean 31 years. History: duration stable - n.i., duration ill - n.i., number of previous hospitalisations mean 1.7, age at onset - n.i., severity of illness - n.i., baseline antipsychotic dose - n.i.

Interventions

1. Fluphenazine: flexible dose, allowed dose range minimum 2 mg/day, mean dose 7.6 mg/day. N = 160 2. Chlorpromazine: flexible dose, allowed dose range minimum 200 mg/day, mean dose 690 mg/day. N = 163 Rescue medication: antiparkinson medication.

Outcomes

Leaving the study early. Unable to use Mental state: general assessment scales (rating by clinician of severity of illness, incomplete data, analysed by time and severity of illness, not by drugs), BPRS (incomplete data, only single items, no SD), IMPS (incomplete data, no SD) Behaviour: WBRS (incomplete data, no SD). Adverse effects: incomplete data.





Randomly assigned to one of three drug treatments, stratified by sex



Unclear risk


34

NIMH 1967

(Continued)

Blinding of participants and personnel Unclear risk (performance bias) All outcomes

Double, no further details.

Blinding of outcome assessment (detection Unclear risk bias) All outcomes

Double, no further details.


High risk

Participants leaving early due to administrative reasons were replaced (flu = 19, cpz = 13), 60 fluphenazine participants dropped out because of medical reasons and 62 on chlorpromazine. They were not included in final analysis (completers only). Altogether 529 participants were randomised, but analysis is on 487


High risk

All no usable data (BPRS, IMPS, WBRS no mean, no SD).

Other bias

Low risk


General Abbreviations n.i. - not indicated mg - milligram SD - standard deviation ITT - Intention-to-treat LOCF - Last-observation-carried-forward vs - versus Rating scales CGI - Clinical Global Impression PANSS - Positive and Negative Syndrome Scale BPRS - Brief Psychiatric Rating Scale IMPS - Inpatient Multidimensional Psychiatric Rating Scale MACC - Behavioral Adjustment Scale MMPI - Minnesota Multiphasic Personality Inventory MSRPP - Multidimensional Scale for Rating Psychiatric Patients NOSIE - Nurses Observation Scale for Inpatient Evaluation PRP - Psychotic Reaction Profile WBRS - Ward Behaviour Rating Scale


35

Characteristics of excluded studies [ordered by study ID]

Study

Reason for exclusion

Cesarec 1974

Method: not randomised, but double-blind. Participants: chronic schizophrenic participants. Intervention: fluphenazine, flupenthixol (high-potency), pimozide (high-potency), amphetamine

Chacon 1973

Method: randomised. Participants: chronic schizophrenic participants. Intervention: fluphenazine (intramuscular injection, no oral medication), chlorpromazine, placebo

Galdi 1988

Method: randomised. Participants: chronic schizophrenic participants. Intervention: fluphenazine, chlorpromazine, perphenazine. Outcome: no usable data, no mean, no SD, no data for leaving early or adverse effects

Gunby 1968

Method: not randomised, not double-blind.

Hordern 1964

Method: n.i., but double-blind. Participants: chronic schizophrenic participants. Intervention: fluphenazine and thioproperazine (medium/high-potency drug)

Kane 1983

Method: randomised. Participants: outpatient schizophrenics. Intervention: fluphenazine decanoate, no oral medication.

n.i.- not indicated SD - standard deviation


36

DATA AND ANALYSES

Comparison 1. Comparison 1: FLUPHENAZINE versus LOW-POTENCY ANTIPSYCHOTIC DRUGS

Outcome or subgroup title 1 Clinical response: Response to treatment-short term 2 Leaving the study early: 1. Due to any reason 2.1 short term 2.2 medium term 3 Leaving the study early: 2. Due to adverse effects 3.1 short term 3.2 medium term 4 Leaving the study early: 3. Due to inefficacy 4.1 short term 4.2 medium term 5 Adverse effects: 1. General-at least one adverse effect 6 Adverse effects: 2a. Specific-movement disorders 6.1 at least one movement disorder 6.2 akathisia 6.3 akinesia 6.4 dyskinesia 6.5 dystonia 6.6 facial rigidity 6.7 loss of associated movement 6.8 oculogyric crisis 6.9 rigor 6.10 tremor 7 Adverse effects: 2b. Specific-other 7.1 allergy-nasal congestion 7.2 allergy-rash 7.3 anticholinergic-blurred vision 7.4 anticholinergic-constipation 7.5 anticholinergic-drooling 7.6 anticholinergic-dry mouth 7.7 anticholinergic-urinary disturbances 7.8 cardiovascular-hypotension

No. of studies

No. of participants

2

105

Risk Ratio (M-H, Random, 95% CI)

1.06 [0.75, 1.50]

6

1532


1.00 [0.88, 1.14]

4 2 5

871 661 1222

Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI)

1.07 [0.81, 1.42] 0.98 [0.85, 1.13] 0.83 [0.33, 2.11]

3 2 5

561 661 1222


1.28 [0.48, 3.37] 0.33 [0.02, 4.41] 1.54 [1.01, 2.33]

3 2 1

561 661 65


1.45 [0.33, 6.39] 1.55 [1.00, 2.38] 0.79 [0.58, 1.07]

6

5690


2.28 [1.84, 2.82]

3

971


2.11 [1.41, 3.15]

5 2 1 4 1 1

1209 223 158 1309 338 338

Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI)

2.28 [1.58, 3.28] 2.09 [0.22, 20.07] 1.98 [0.13, 31.05] 2.66 [1.25, 5.64] 1.29 [0.72, 2.33] 11.15 [3.95, 31.47]

1 2 2 6 3 5 2

338 403 403 16809 741 1374 375

Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI)

0.64 [0.03, 15.68] 2.18 [1.20, 3.97] 2.53 [1.37, 4.68] 0.72 [0.62, 0.84] 0.88 [0.55, 1.43] 0.91 [0.33, 2.49] 1.13 [0.43, 2.98]

3

741


1.03 [0.74, 1.45]

3 4 4

741 1051 1051


1.59 [0.74, 3.43] 0.63 [0.45, 0.89] 0.81 [0.36, 1.81]

2

223


0.68 [0.13, 3.52]

Statistical method


Effect size

37

7.9 cardiovascular-oedema 7.10 cardiovascular-syncope 7.11 cardiovascular-tachycardia 7.12 central nervous system-convulsion 7.13 central nervous system-depression 7.14 central nervous system-dizziness 7.15 central nervous system-drowsiness 7.16 central nervous system-excitement 7.17 central nervous system-headache 7.18 central nervous system-photosensitivity 7.19 central nervous system-restlessness 7.20 central nervous system-sedation 7.21 central nervous system-seizures 7.22 gastrointestinal-diarrhoea 7.23 gastrointestinal-gastrointestinal disturbance 7.24 gastrointestinal-nausea 7.25 gastrointestinal-vomiting 7.26 hormonal-amenorrhoea 7.27 hormonal-lactation 7.28 hormonal-swelling of breasts 7.29 immune system-intercurrent infection 7.30 immune system-oral infection

2 2 1

403 403 65


0.38 [0.04, 3.21] 1.02 [0.14, 7.75] 6.57 [0.28, 154.69]

1

338


0.64 [0.03, 15.68]

1

65


0.0 [0.0, 0.0]

4

1051


0.49 [0.32, 0.73]

3

986


0.67 [0.53, 0.86]

1

65


1.5 [0.27, 8.29]

1

338


1.29 [0.68, 2.45]

4

1036


0.26 [0.06, 1.15]

2

403


0.89 [0.68, 1.17]

1

65


0.31 [0.13, 0.77]

2

648


0.43 [0.02, 8.21]

2 1

676 323

Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI)

1.94 [0.42, 8.98] 0.34 [0.01, 8.27]

3 3 1 1 1

986 986 338 338 338

Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI)

0.25 [0.14, 0.45] 0.36 [0.18, 0.72] 1.39 [0.45, 4.27] 1.94 [0.49, 7.61] 5.82 [0.61, 55.30]

1

338


1.29 [0.37, 4.49]

1

323


0.34 [0.01, 8.27]

Comparison 2. Subgroup analysis

Outcome or subgroup title 1 Response to treatment-each low-potency antipsychotic separately 1.1 versus chlorpromazine

No. of studies

No. of participants

2

119


0.95 [0.72, 1.26]

2

80


0.95 [0.66, 1.37]

Statistical method


Effect size

38

1.2 versus thioridazine

1

39


0.95 [0.61, 1.48]

Comparison 3. Sensitivity analysis

Outcome or subgroup title 1 Response to treatment-exclusion of non double-blind studies 2 Response to treatment-fixed effects model

No. of studies

No. of participants

1

63


1.04 [0.70, 1.54]

2

103

Risk Ratio (M-H, Fixed, 95% CI)

1.02 [0.72, 1.45]

Statistical method

Effect size

Analysis 1.1. Comparison 1 Comparison 1: FLUPHENAZINE versus LOW-POTENCY ANTIPSYCHOTIC DRUGS, Outcome 1 Clinical response: Response to treatment-short term. Review:

Fluphenazine versus low-potency first-generation antipsychotic drugs for schizophrenia

Comparison: 1 Comparison 1: FLUPHENAZINE versus LOW-POTENCY ANTIPSYCHOTIC DRUGS Outcome: 1 Clinical response: Response to treatment-short term

Study or subgroup

Childers 1964 Clark 1971

Total (95% CI)

Experimental

Control

Risk Ratio MH,Random,95% CI

Weight


n/N

n/N

9/20

9/20

25.5 %

1.00 [ 0.50, 1.98 ]

13/20

27/45

74.5 %

1.08 [ 0.73, 1.62 ]

40

65

100.0 %

1.06 [ 0.75, 1.50 ]

Total events: 22 (Experimental), 36 (Control) Heterogeneity: Tau2 = 0.0; Chi2 = 0.04, df = 1 (P = 0.84); I2 =0.0% Test for overall effect: Z = 0.34 (P = 0.74) Test for subgroup differences: Not applicable

0.2

0.5

Favours control

1

2

5

Favours fluphenazine


39

Analysis 1.2. Comparison 1 Comparison 1: FLUPHENAZINE versus LOW-POTENCY ANTIPSYCHOTIC DRUGS, Outcome 2 Leaving the study early: 1. Due to any reason. Review:


Comparison: 1 Comparison 1: FLUPHENAZINE versus LOW-POTENCY ANTIPSYCHOTIC DRUGS Outcome: 2 Leaving the study early: 1. Due to any reason

Study or subgroup

Experimental

Control


Weight


n/N

n/N

Clark 1971

3/20

6/45

1.0 %

1.13 [ 0.31, 4.05 ]

Cole 1964

24/115

44/223

8.1 %

1.06 [ 0.68, 1.65 ]

Galbrecht 1968

19/104

37/206

6.4 %

1.02 [ 0.62, 1.68 ]

13/53

22/105

4.4 %

1.17 [ 0.64, 2.13 ]

292

579

19.9 %

1.07 [ 0.81, 1.42 ]

1 short term

Hanlon 1965

Subtotal (95% CI)

Total events: 59 (Experimental), 109 (Control) Heterogeneity: Tau2 = 0.0; Chi2 = 0.13, df = 3 (P = 0.99); I2 =0.0% Test for overall effect: Z = 0.48 (P = 0.63) 2 medium term Lasky 1962

54/84

175/254

49.6 %

0.93 [ 0.78, 1.12 ]

NIMH 1967

79/160

75/163

30.6 %

1.07 [ 0.85, 1.35 ]

244

417

80.1 %

0.98 [ 0.85, 1.13 ]

100.0 %

1.00 [ 0.88, 1.14 ]

Subtotal (95% CI)

Total events: 133 (Experimental), 250 (Control) Heterogeneity: Tau2 = 0.0; Chi2 = 0.92, df = 1 (P = 0.34); I2 =0.0% Test for overall effect: Z = 0.22 (P = 0.82)

Total (95% CI)

536

996

Total events: 192 (Experimental), 359 (Control) Heterogeneity: Tau2 = 0.0; Chi2 = 1.39, df = 5 (P = 0.93); I2 =0.0% Test for overall effect: Z = 0.02 (P = 0.99) Test for subgroup differences: Chi2 = 0.28, df = 1 (P = 0.60), I2 =0.0%

0.5

0.7

Favours experimental

1

1.5

2

Favours control


40

Analysis 1.3. Comparison 1 Comparison 1: FLUPHENAZINE versus LOW-POTENCY ANTIPSYCHOTIC DRUGS, Outcome 3 Leaving the study early: 2. Due to adverse effects. Review:


Comparison: 1 Comparison 1: FLUPHENAZINE versus LOW-POTENCY ANTIPSYCHOTIC DRUGS Outcome: 3 Leaving the study early: 2. Due to adverse effects

Study or subgroup

Experimental

Control


Weight


n/N

n/N

Clark 1971

0/20

1/45

7.5 %

0.73 [ 0.03, 17.19 ]

Cole 1964

6/115

5/223

29.7 %

2.33 [ 0.73, 7.46 ]

2/53

7/105

22.1 %

0.57 [ 0.12, 2.63 ]

188

373

59.4 %

1.28 [ 0.48, 3.37 ]

1 short term

Hanlon 1965

Subtotal (95% CI)

Total events: 8 (Experimental), 13 (Control) Heterogeneity: Tau2 = 0.09; Chi2 = 2.23, df = 2 (P = 0.33); I2 =10% Test for overall effect: Z = 0.49 (P = 0.62) 2 medium term Lasky 1962

4/84

14/254

31.7 %

0.86 [ 0.29, 2.55 ]

NIMH 1967

0/160

7/163

9.0 %

0.07 [ 0.00, 1.18 ]

244

417

40.6 %

0.33 [ 0.02, 4.41 ]

100.0 %

0.83 [ 0.33, 2.11 ]

Subtotal (95% CI)

Total events: 4 (Experimental), 21 (Control) Heterogeneity: Tau2 = 2.50; Chi2 = 3.06, df = 1 (P = 0.08); I2 =67% Test for overall effect: Z = 0.84 (P = 0.40)

Total (95% CI)

432

790

Total events: 12 (Experimental), 34 (Control) Heterogeneity: Tau2 = 0.41; Chi2 = 6.49, df = 4 (P = 0.17); I2 =38% Test for overall effect: Z = 0.39 (P = 0.70) Test for subgroup differences: Chi2 = 0.92, df = 1 (P = 0.34), I2 =0.0%

0.5

0.7


1

1.5

2

Favours control


41

Analysis 1.4. Comparison 1 Comparison 1: FLUPHENAZINE versus LOW-POTENCY ANTIPSYCHOTIC DRUGS, Outcome 4 Leaving the study early: 3. Due to inefficacy. Review:


Comparison: 1 Comparison 1: FLUPHENAZINE versus LOW-POTENCY ANTIPSYCHOTIC DRUGS Outcome: 4 Leaving the study early: 3. Due to inefficacy

Study or subgroup

Experimental

Control


Weight


n/N

n/N

Clark 1971

0/20

0/45

Cole 1964

3/115

4/223

0/53

0/105

188

373

7.9 %

1.45 [ 0.33, 6.39 ]

Lasky 1962

11/84

26/254

39.7 %

1.28 [ 0.66, 2.48 ]

NIMH 1967

28/160

16/163

52.5 %

1.78 [ 1.00, 3.17 ]

244

417

92.1 %

1.55 [ 1.00, 2.38 ]

100.0 %

1.54 [ 1.01, 2.33 ]

1 short term

Hanlon 1965

Subtotal (95% CI)

Not estimable 7.9 %

1.45 [ 0.33, 6.39 ] Not estimable

Total events: 3 (Experimental), 4 (Control) Heterogeneity: not applicable Test for overall effect: Z = 0.50 (P = 0.62) 2 medium term

Subtotal (95% CI)


Total (95% CI)

432

790

Total events: 42 (Experimental), 46 (Control) Heterogeneity: Tau2 = 0.0; Chi2 = 0.56, df = 2 (P = 0.76); I2 =0.0% Test for overall effect: Z = 2.03 (P = 0.042) Test for subgroup differences: Chi2 = 0.01, df = 1 (P = 0.94), I2 =0.0%

0.5

0.7


1

1.5

2

Favours control


42

Analysis 1.5. Comparison 1 Comparison 1: FLUPHENAZINE versus LOW-POTENCY ANTIPSYCHOTIC DRUGS, Outcome 5 Adverse effects: 1. General-at least one adverse effect. Review:


Comparison: 1 Comparison 1: FLUPHENAZINE versus LOW-POTENCY ANTIPSYCHOTIC DRUGS Outcome: 5 Adverse effects: 1. General-at least one adverse effect

Study or subgroup

Clark 1971

Total (95% CI)

Experimental

Control


Weight


n/N

n/N

14/20

40/45

100.0 %

0.79 [ 0.58, 1.07 ]

20

45

100.0 %

0.79 [ 0.58, 1.07 ]

Total events: 14 (Experimental), 40 (Control) Heterogeneity: not applicable Test for overall effect: Z = 1.54 (P = 0.12) Test for subgroup differences: Not applicable

0.01

0.1


1

10

100

Favours control


43

Analysis 1.6. Comparison 1 Comparison 1: FLUPHENAZINE versus LOW-POTENCY ANTIPSYCHOTIC DRUGS, Outcome 6 Adverse effects: 2a. Specific-movement disorders. Review:


Comparison: 1 Comparison 1: FLUPHENAZINE versus LOW-POTENCY ANTIPSYCHOTIC DRUGS Outcome: 6 Adverse effects: 2a. Specific-movement disorders

Study or subgroup

Experimental

Control


Weight


n/N

n/N

19/104

16/206

8.4 %

2.35 [ 1.26, 4.38 ]

Lasky 1962

33/84

47/254

15.8 %

2.12 [ 1.47, 3.08 ]

NIMH 1967

0/160

2/163

0.5 %

0.20 [ 0.01, 4.21 ]

348

623

24.7 %

2.11 [ 1.41, 3.15 ]

1 at least one movement disorder Galbrecht 1968

Subtotal (95% CI)

Total events: 52 (Experimental), 65 (Control) Heterogeneity: Tau2 = 0.03; Chi2 = 2.44, df = 2 (P = 0.29); I2 =18% Test for overall effect: Z = 3.62 (P = 0.00029) 2 akathisia Clark 1971

3/20

3/45

1.8 %

2.25 [ 0.50, 10.20 ]

Cole 1964

14/115

12/223

6.5 %

2.26 [ 1.08, 4.73 ]

Galbrecht 1968

15/104

16/206

7.6 %

1.86 [ 0.96, 3.61 ]

8/53

1/105

1.0 %

15.85 [ 2.04, 123.42 ]

16/84

21/254

8.8 %

2.30 [ 1.26, 4.21 ]

376

833

25.8 %

2.28 [ 1.58, 3.28 ]

Hanlon 1965 Lasky 1962

Subtotal (95% CI)

Total events: 56 (Experimental), 53 (Control) Heterogeneity: Tau2 = 0.0; Chi2 = 3.91, df = 4 (P = 0.42); I2 =0.0% Test for overall effect: Z = 4.44 (P < 0.00001) 3 akinesia Clark 1971

1/20

0/45

0.4 %

6.57 [ 0.28, 154.69 ]

Hanlon 1965

0/53

1/105

0.4 %

0.65 [ 0.03, 15.79 ]

73

150

0.9 %

2.09 [ 0.22, 20.07 ]

Subtotal (95% CI) Total events: 1 (Experimental), 1 (Control)

Heterogeneity: Tau2 = 0.04; Chi2 = 1.02, df = 1 (P = 0.31); I2 =2% Test for overall effect: Z = 0.64 (P = 0.52) 4 dyskinesia Hanlon 1965

Subtotal (95% CI)

1/53

1/105

0.6 %

1.98 [ 0.13, 31.05 ]

53

105

0.6 %

1.98 [ 0.13, 31.05 ]

Total events: 1 (Experimental), 1 (Control) Heterogeneity: not applicable

0.05

0.2


1

5

20

Favours control

(Continued . . . )


44

(. . . Study or subgroup


Weight

Continued) Risk Ratio MH,Random,95% CI

Experimental

Control

n/N

n/N

Cole 1964

8/115

6/223

3.7 %

2.59 [ 0.92, 7.27 ]

Galbrecht 1968

3/104

1/206

0.9 %

5.94 [ 0.63, 56.43 ]

Lasky 1962

4/84

4/254

2.2 %

3.02 [ 0.77, 11.83 ]

NIMH 1967

0/160

1/163

0.4 %

0.34 [ 0.01, 8.27 ]

463

846

7.2 %

2.66 [ 1.25, 5.64 ]

Test for overall effect: Z = 0.49 (P = 0.63) 5 dystonia

Subtotal (95% CI)

Total events: 15 (Experimental), 12 (Control) Heterogeneity: Tau2 = 0.0; Chi2 = 2.13, df = 3 (P = 0.55); I2 =0.0% Test for overall effect: Z = 2.55 (P = 0.011) 6 facial rigidity Cole 1964

16/115

24/223

9.0 %

1.29 [ 0.72, 2.33 ]

115

223

9.0 %

1.29 [ 0.72, 2.33 ]

23/115

4/223

3.7 %

11.15 [ 3.95, 31.47 ]

115

223

3.7 %

11.15 [ 3.95, 31.47 ]

0/115

1/223

0.4 %

0.64 [ 0.03, 15.68 ]

115

223

0.4 %

0.64 [ 0.03, 15.68 ]

Clark 1971

9/20

13/45

7.6 %

1.56 [ 0.80, 3.03 ]

Cole 1964

28/115

19/223

10.3 %

2.86 [ 1.67, 4.89 ]

135

268

17.9 %

2.18 [ 1.20, 3.97 ]

Subtotal (95% CI)

Total events: 16 (Experimental), 24 (Control) Heterogeneity: not applicable Test for overall effect: Z = 0.85 (P = 0.39) 7 loss of associated movement Cole 1964

Subtotal (95% CI)

Total events: 23 (Experimental), 4 (Control) Heterogeneity: not applicable Test for overall effect: Z = 4.55 (P < 0.00001) 8 oculogyric crisis Cole 1964

Subtotal (95% CI) Total events: 0 (Experimental), 1 (Control) Heterogeneity: not applicable Test for overall effect: Z = 0.27 (P = 0.79) 9 rigor

Subtotal (95% CI)

Total events: 37 (Experimental), 32 (Control) Heterogeneity: Tau2 = 0.09; Chi2 = 1.98, df = 1 (P = 0.16); I2 =49% Test for overall effect: Z = 2.55 (P = 0.011) 10 tremor Clark 1971

6/20

6/45

3.9 %

2.25 [ 0.83, 6.13 ]

Cole 1964

14/115

10/223

5.9 %

2.71 [ 1.24, 5.92 ]

135

268

9.8 %

2.53 [ 1.37, 4.68 ]

Subtotal (95% CI)

0.05

0.2


1

5

20

Favours control

(Continued . . . ) Fluphenazine versus low-potency first-generation antipsychotic drugs for schizophrenia (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

45


Experimental

Control

n/N

n/N


Weight



Total (95% CI)

1928

100.0 %

3762

2.28 [ 1.84, 2.82 ]

Total events: 221 (Experimental), 209 (Control) Heterogeneity: Tau2 = 0.04; Chi2 = 25.20, df = 21 (P = 0.24); I2 =17% Test for overall effect: Z = 7.62 (P < 0.00001) Test for subgroup differences: Chi2 = 13.56, df = 9 (P = 0.14), I2 =34%

0.05

0.2

1


5

20

Favours control

Analysis 1.7. Comparison 1 Comparison 1: FLUPHENAZINE versus LOW-POTENCY ANTIPSYCHOTIC DRUGS, Outcome 7 Adverse effects: 2b. Specific-other. Review:


Comparison: 1 Comparison 1: FLUPHENAZINE versus LOW-POTENCY ANTIPSYCHOTIC DRUGS Outcome: 7 Adverse effects: 2b. Specific-other

Study or subgroup

Experimental

Control


Weight


n/N

n/N

Clark 1971

1/20

0/45

0.2 %

6.57 [ 0.28, 154.69 ]

Cole 1964

14/115

32/223

4.3 %

0.85 [ 0.47, 1.52 ]

Lasky 1962

6/84

22/254

2.5 %

0.82 [ 0.35, 1.97 ]

219

522

7.1 %

0.88 [ 0.55, 1.43 ]

1 allergy-nasal congestion

Subtotal (95% CI)

Total events: 21 (Experimental), 54 (Control) Heterogeneity: Tau2 = 0.0; Chi2 = 1.60, df = 2 (P = 0.45); I2 =0.0% Test for overall effect: Z = 0.51 (P = 0.61) 2 allergy-rash Clark 1971

1/20

1/45

0.3 %

2.25 [ 0.15, 34.20 ]

Cole 1964

1/115

5/223

0.5 %

0.39 [ 0.05, 3.28 ]

0.05

0.2


1

5

20

Favours control

(Continued . . . )


46


Experimental

Control


Weight


n/N

n/N

0/104

4/206

0.3 %

0.22 [ 0.01, 4.03 ]

Lasky 1962

5/84

8/254

1.7 %

1.89 [ 0.64, 5.62 ]

NIMH 1967

0/160

2/163

0.3 %

0.20 [ 0.01, 4.21 ]

483

891

3.1 %

0.91 [ 0.33, 2.49 ]

Galbrecht 1968

Subtotal (95% CI)

Total events: 7 (Experimental), 20 (Control) Heterogeneity: Tau2 = 0.24; Chi2 = 4.78, df = 4 (P = 0.31); I2 =16% Test for overall effect: Z = 0.18 (P = 0.86) 3 anticholinergic-blurred vision Clark 1971 Galbrecht 1968

Subtotal (95% CI)

2/20

3/45

0.8 %

1.50 [ 0.27, 8.29 ]

4/104

8/206

1.5 %

0.99 [ 0.31, 3.21 ]

124

251

2.3 %

1.13 [ 0.43, 2.98 ]

Total events: 6 (Experimental), 11 (Control) Heterogeneity: Tau2 = 0.0; Chi2 = 0.15, df = 1 (P = 0.69); I2 =0.0% Test for overall effect: Z = 0.25 (P = 0.80) 4 anticholinergic-constipation Clark 1971

1/20

5/45

0.5 %

0.45 [ 0.06, 3.61 ]

Cole 1964

32/115

60/223

6.9 %

1.03 [ 0.72, 1.49 ]

Lasky 1962

5/84

12/254

2.0 %

1.26 [ 0.46, 3.47 ]

219

522

9.4 %

1.03 [ 0.74, 1.45 ]

Subtotal (95% CI)

Total events: 38 (Experimental), 77 (Control) Heterogeneity: Tau2 = 0.0; Chi2 = 0.76, df = 2 (P = 0.68); I2 =0.0% Test for overall effect: Z = 0.19 (P = 0.85) 5 anticholinergic-drooling Clark 1971

1/20

2/45

0.4 %

1.13 [ 0.11, 11.70 ]

Cole 1964

10/115

10/223

2.6 %

1.94 [ 0.83, 4.52 ]

Lasky 1962

0/84

5/254

0.3 %

0.27 [ 0.02, 4.88 ]

219

522

3.3 %

1.59 [ 0.74, 3.43 ]

Subtotal (95% CI)

Total events: 11 (Experimental), 17 (Control) Heterogeneity: Tau2 = 0.0; Chi2 = 1.81, df = 2 (P = 0.40); I2 =0.0% Test for overall effect: Z = 1.19 (P = 0.24) 6 anticholinergic-dry mouth Clark 1971

0/20

10/45

0.3 %

0.10 [ 0.01, 1.70 ]

Cole 1964

21/115

62/223

5.9 %

0.66 [ 0.42, 1.02 ]

8/104

30/206

3.2 %

0.53 [ 0.25, 1.11 ]

8/84

31/254

3.2 %

0.78 [ 0.37, 1.63 ]

323

728

12.5 %

0.63 [ 0.45, 0.89 ]

Galbrecht 1968 Lasky 1962

Subtotal (95% CI)

Total events: 37 (Experimental), 133 (Control) Heterogeneity: Tau2 = 0.0; Chi2 = 2.24, df = 3 (P = 0.52); I2 =0.0%

0.05

0.2


1

5

20

Favours control


47


Experimental

Control

n/N

n/N


Weight


Test for overall effect: Z = 2.67 (P = 0.0076) 7 anticholinergic-urinary disturbances Clark 1971

0/20

1/45

0.2 %

0.73 [ 0.03, 17.19 ]

Cole 1964

4/115

15/223

1.8 %

0.52 [ 0.18, 1.52 ]

Galbrecht 1968

3/104

3/206

0.9 %

1.98 [ 0.41, 9.64 ]

1/84

3/254

0.5 %

1.01 [ 0.11, 9.56 ]

323

728

3.4 %

0.81 [ 0.36, 1.81 ]

Lasky 1962

Subtotal (95% CI)

Total events: 8 (Experimental), 22 (Control) Heterogeneity: Tau2 = 0.0; Chi2 = 1.94, df = 3 (P = 0.59); I2 =0.0% Test for overall effect: Z = 0.51 (P = 0.61) 8 cardiovascular-hypotension Clark 1971

1/20

6/45

0.6 %

0.38 [ 0.05, 2.91 ]

Hanlon 1965

1/53

1/105

0.3 %

1.98 [ 0.13, 31.05 ]

73

150

0.9 %

0.68 [ 0.13, 3.52 ]


Heterogeneity: Tau2 = 0.0; Chi2 = 0.91, df = 1 (P = 0.34); I2 =0.0% Test for overall effect: Z = 0.46 (P = 0.64) 9 cardiovascular-oedema Clark 1971

0/20

1/45

0.2 %

0.73 [ 0.03, 17.19 ]

Cole 1964

0/115

4/223

0.3 %

0.21 [ 0.01, 3.95 ]

135

268

0.5 %

0.38 [ 0.04, 3.21 ]


Heterogeneity: Tau2 = 0.0; Chi2 = 0.32, df = 1 (P = 0.57); I2 =0.0% Test for overall effect: Z = 0.89 (P = 0.37) 10 cardiovascular-syncope Clark 1971

1/20

1/45

0.3 %

2.25 [ 0.15, 34.20 ]

Cole 1964

0/115

2/223

0.3 %

0.39 [ 0.02, 7.98 ]

135

268

0.6 %

1.02 [ 0.14, 7.75 ]


Heterogeneity: Tau2 = 0.0; Chi2 = 0.74, df = 1 (P = 0.39); I2 =0.0% Test for overall effect: Z = 0.02 (P = 0.98) 11 cardiovascular-tachycardia Clark 1971

Subtotal (95% CI)

1/20

0/45

0.2 %

6.57 [ 0.28, 154.69 ]

20

45

0.2 %

6.57 [ 0.28, 154.69 ]

Total events: 1 (Experimental), 0 (Control) Heterogeneity: not applicable Test for overall effect: Z = 1.17 (P = 0.24) 12 central nervous system-convulsion

0.05

0.2


1

5

20

Favours control


48


Experimental

Control


Weight


n/N

n/N

0/115

1/223

0.2 %

0.64 [ 0.03, 15.68 ]

115

223

0.2 %

0.64 [ 0.03, 15.68 ]

0/20

0/45

Not estimable

20

45

Not estimable

Clark 1971

0/20

15/45

0.3 %

0.07 [ 0.00, 1.13 ]

Cole 1964

14/115

54/223

4.7 %

0.50 [ 0.29, 0.87 ]

5/104

18/206

2.1 %

0.55 [ 0.21, 1.44 ]

6/84

37/254

2.7 %

0.49 [ 0.21, 1.12 ]

323

728

9.9 %

0.49 [ 0.32, 0.73 ]

Cole 1964

Subtotal (95% CI) Total events: 0 (Experimental), 1 (Control) Heterogeneity: not applicable Test for overall effect: Z = 0.27 (P = 0.79) 13 central nervous system-depression Clark 1971

Subtotal (95% CI) Total events: 0 (Experimental), 0 (Control) Heterogeneity: not applicable Test for overall effect: not applicable 14 central nervous system-dizziness

Galbrecht 1968 Lasky 1962

Subtotal (95% CI)

Total events: 25 (Experimental), 124 (Control) Heterogeneity: Tau2 = 0.0; Chi2 = 2.07, df = 3 (P = 0.56); I2 =0.0% Test for overall effect: Z = 3.47 (P = 0.00051) 15 central nervous system-drowsiness Cole 1964

42/115

117/223

8.3 %

0.70 [ 0.53, 0.91 ]

Galbrecht 1968

13/104

41/206

4.4 %

0.63 [ 0.35, 1.12 ]

1/84

14/254

0.6 %

0.22 [ 0.03, 1.62 ]

303

683

13.3 %

0.67 [ 0.53, 0.86 ]

Lasky 1962

Subtotal (95% CI)

Total events: 56 (Experimental), 172 (Control) Heterogeneity: Tau2 = 0.0; Chi2 = 1.41, df = 2 (P = 0.50); I2 =0.0% Test for overall effect: Z = 3.20 (P = 0.0014) 16 central nervous system-excitement Clark 1971

2/20

3/45

0.8 %

1.50 [ 0.27, 8.29 ]

20

45

0.8 %

1.50 [ 0.27, 8.29 ]

14/115

21/223

3.9 %

1.29 [ 0.68, 2.45 ]

115

223

3.9 %

1.29 [ 0.68, 2.45 ]

Subtotal (95% CI) Total events: 2 (Experimental), 3 (Control) Heterogeneity: not applicable Test for overall effect: Z = 0.46 (P = 0.64) 17 central nervous system-headache Cole 1964

Subtotal (95% CI)

0.05

0.2


1

5

20

Favours control


49


Experimental

Control

n/N

n/N


Weight


Total events: 14 (Experimental), 21 (Control) Heterogeneity: not applicable Test for overall effect: Z = 0.79 (P = 0.43) 18 central nervous system-photosensitivity 0/20

5/45

0.3 %

0.20 [ 0.01, 3.44 ]

0/104

4/206

0.3 %

0.22 [ 0.01, 4.03 ]

Lasky 1962

0/84

4/254

0.3 %

0.33 [ 0.02, 6.13 ]

NIMH 1967

0/160

1/163

0.2 %

0.34 [ 0.01, 8.27 ]

368

668

1.1 %

0.26 [ 0.06, 1.15 ]

Clark 1971 Galbrecht 1968

Subtotal (95% CI)

Total events: 0 (Experimental), 14 (Control) Heterogeneity: Tau2 = 0.0; Chi2 = 0.10, df = 3 (P = 0.99); I2 =0.0% Test for overall effect: Z = 1.78 (P = 0.075) 19 central nervous system-restlessness Clark 1971

1/20

2/45

0.4 %

1.13 [ 0.11, 11.70 ]

Cole 1964

44/115

96/223

8.2 %

0.89 [ 0.67, 1.17 ]

135

268

8.7 %

0.89 [ 0.68, 1.17 ]

Subtotal (95% CI)

Total events: 45 (Experimental), 98 (Control) Heterogeneity: Tau2 = 0.0; Chi2 = 0.04, df = 1 (P = 0.84); I2 =0.0% Test for overall effect: Z = 0.82 (P = 0.41) 20 central nervous system-sedation 4/20

29/45

2.4 %

0.31 [ 0.13, 0.77 ]

20

45

2.4 %

0.31 [ 0.13, 0.77 ]

0/104

0/206

0/84

3/254

0.3 %

0.43 [ 0.02, 8.21 ]

188

460

0.3 %

0.43 [ 0.02, 8.21 ]

Cole 1964

3/115

2/223

0.7 %

2.91 [ 0.49, 17.16 ]

Lasky 1962

0/84

2/254

0.3 %

0.60 [ 0.03, 12.37 ]

199

477

1.0 %

1.94 [ 0.42, 8.98 ]

Clark 1971

Subtotal (95% CI) Total events: 4 (Experimental), 29 (Control) Heterogeneity: not applicable Test for overall effect: Z = 2.54 (P = 0.011) 21 central nervous system-seizures Galbrecht 1968 Lasky 1962

Subtotal (95% CI)

Not estimable

Total events: 0 (Experimental), 3 (Control) Heterogeneity: not applicable Test for overall effect: Z = 0.56 (P = 0.57) 22 gastrointestinal-diarrhoea


0.05

0.2


1

5

20

Favours control


50


Experimental

Control

n/N

n/N


Weight


Heterogeneity: Tau2 = 0.0; Chi2 = 0.79, df = 1 (P = 0.38); I2 =0.0% Test for overall effect: Z = 0.85 (P = 0.40) 23 gastrointestinal-gastrointestinal disturbance 0/160

1/163

0.2 %

0.34 [ 0.01, 8.27 ]

160

163

0.2 %

0.34 [ 0.01, 8.27 ]

Cole 1964

6/115

65/223

2.8 %

0.18 [ 0.08, 0.40 ]

Galbrecht 1968

3/104

17/206

1.5 %

0.35 [ 0.10, 1.17 ]

3/84

23/254

1.5 %

0.39 [ 0.12, 1.28 ]

303

683

5.8 %

0.25 [ 0.14, 0.45 ]

NIMH 1967

Subtotal (95% CI) Total events: 0 (Experimental), 1 (Control) Heterogeneity: not applicable Test for overall effect: Z = 0.66 (P = 0.51) 24 gastrointestinal-nausea

Lasky 1962

Subtotal (95% CI)

Total events: 12 (Experimental), 105 (Control) Heterogeneity: Tau2 = 0.0; Chi2 = 1.55, df = 2 (P = 0.46); I2 =0.0% Test for overall effect: Z = 4.62 (P < 0.00001) 25 gastrointestinal-vomiting Cole 1964

3/115

17/223

1.5 %

0.34 [ 0.10, 1.14 ]

Galbrecht 1968

3/104

17/206

1.5 %

0.35 [ 0.10, 1.17 ]

3/84

23/254

1.5 %

0.39 [ 0.12, 1.28 ]

303

683

4.4 %

0.36 [ 0.18, 0.72 ]

Lasky 1962

Subtotal (95% CI)

Total events: 9 (Experimental), 57 (Control) Heterogeneity: Tau2 = 0.0; Chi2 = 0.03, df = 2 (P = 0.98); I2 =0.0% Test for overall effect: Z = 2.89 (P = 0.0039) 26 hormonal-amenorrhoea Cole 1964

5/115

7/223

1.6 %

1.39 [ 0.45, 4.27 ]

115

223

1.6 %

1.39 [ 0.45, 4.27 ]

4/115

4/223

1.2 %

1.94 [ 0.49, 7.61 ]

115

223

1.2 %

1.94 [ 0.49, 7.61 ]

3/115

1/223

0.5 %

5.82 [ 0.61, 55.30 ]

Subtotal (95% CI) Total events: 5 (Experimental), 7 (Control) Heterogeneity: not applicable Test for overall effect: Z = 0.57 (P = 0.57) 27 hormonal-lactation Cole 1964

Subtotal (95% CI) Total events: 4 (Experimental), 4 (Control) Heterogeneity: not applicable Test for overall effect: Z = 0.95 (P = 0.34) 28 hormonal-swelling of breasts Cole 1964

0.05

0.2


1

5

20

Favours control


51


Experimental

Control


Weight


n/N

n/N

115

223

0.5 %

5.82 [ 0.61, 55.30 ]

4/115

6/223

1.4 %

1.29 [ 0.37, 4.49 ]

115

223

1.4 %

1.29 [ 0.37, 4.49 ]

0/160

1/163

0.2 %

0.34 [ 0.01, 8.27 ]

160

163

0.2 %

0.34 [ 0.01, 8.27 ]

5465

11344

100.0 %

0.72 [ 0.62, 0.84 ]

Subtotal (95% CI) Total events: 3 (Experimental), 1 (Control) Heterogeneity: not applicable Test for overall effect: Z = 1.53 (P = 0.13) 29 immune system-intercurrent infection Cole 1964

Subtotal (95% CI) Total events: 4 (Experimental), 6 (Control) Heterogeneity: not applicable Test for overall effect: Z = 0.40 (P = 0.69) 30 immune system-oral infection NIMH 1967

Subtotal (95% CI) Total events: 0 (Experimental), 1 (Control) Heterogeneity: not applicable Test for overall effect: Z = 0.66 (P = 0.51)

Total (95% CI)

Total events: 318 (Experimental), 1000 (Control) Heterogeneity: Tau2 = 0.06; Chi2 = 77.48, df = 62 (P = 0.09); I2 =20% Test for overall effect: Z = 4.11 (P = 0.000039) Test for subgroup differences: Chi2 = 54.00, df = 28 (P = 0.00), I2 =48%

0.05

0.2


1

5

20

Favours control


52

Analysis 2.1. Comparison 2 Subgroup analysis, Outcome 1 Response to treatment-each low-potency antipsychotic separately. Review:


Comparison: 2 Subgroup analysis Outcome: 1 Response to treatment-each low-potency antipsychotic separately

Study or subgroup

Experimental

Control


Weight


n/N

n/N

9/20

9/20

16.9 %

1.00 [ 0.50, 1.98 ]

13/20

14/20

42.7 %

0.93 [ 0.60, 1.43 ]

40

40

59.6 %

0.95 [ 0.66, 1.37 ]

1 versus chlorpromazine Childers 1964 Clark 1971


Heterogeneity: Tau2 = 0.0; Chi2 = 0.03, df = 1 (P = 0.85); I2 =0.0% Test for overall effect: Z = 0.29 (P = 0.78) 2 versus thioridazine Clark 1971

13/20

13/19

40.4 %

0.95 [ 0.61, 1.48 ]

20

19

40.4 %

0.95 [ 0.61, 1.48 ]

60

59

100.0 %

0.95 [ 0.72, 1.26 ]

Subtotal (95% CI) Total events: 13 (Experimental), 13 (Control) Heterogeneity: not applicable Test for overall effect: Z = 0.23 (P = 0.82)

Total (95% CI) Total events: 35 (Experimental), 36 (Control)

Heterogeneity: Tau2 = 0.0; Chi2 = 0.03, df = 2 (P = 0.98); I2 =0.0% Test for overall effect: Z = 0.36 (P = 0.72) Test for subgroup differences: Chi2 = 0.00, df = 1 (P = 1.00), I2 =0.0%

0.01

0.1

Favours control

1

10

100



53

Analysis 3.1. Comparison 3 Sensitivity analysis, Outcome 1 Response to treatment-exclusion of non doubleblind studies. Review:


Comparison: 3 Sensitivity analysis Outcome: 1 Response to treatment-exclusion of non double-blind studies

Study or subgroup

Experimental

Clark 1971

Total (95% CI)

Control


Weight


n/N

n/N

13/20

27/43

100.0 %

1.04 [ 0.70, 1.54 ]

20

43

100.0 %

1.04 [ 0.70, 1.54 ]

Total events: 13 (Experimental), 27 (Control) Heterogeneity: not applicable Test for overall effect: Z = 0.17 (P = 0.86) Test for subgroup differences: Not applicable

0.01

0.1

1

Favours control

10

100


Analysis 3.2. Comparison 3 Sensitivity analysis, Outcome 2 Response to treatment-fixed effects model. Review:


Comparison: 3 Sensitivity analysis Outcome: 2 Response to treatment-fixed effects model

Study or subgroup

Childers 1964 Clark 1971

Total (95% CI)

Experimental

Control

n/N

n/N

Risk Ratio

Weight

9/20

9/20

34.4 %

1.00 [ 0.50, 1.98 ]

13/20

27/43

65.6 %

1.04 [ 0.70, 1.54 ]

40

63

100.0 %

1.02 [ 0.72, 1.45 ]

M-H,Fixed,95% CI

Risk Ratio M-H,Fixed,95% CI

Total events: 22 (Experimental), 36 (Control) Heterogeneity: Chi2 = 0.01, df = 1 (P = 0.93); I2 =0.0% Test for overall effect: Z = 0.13 (P = 0.90) Test for subgroup differences: Not applicable

0.01

0.1

Favours control

1

10

100



54

ADDITIONAL TABLES Table 1. Series of similar reviews Title

Reference

Haloperidol versus first generation antipsychotic drugs

Dold 2012

Haloperidol versus low-potency antipsychotic drugs

Tardy 2011b

Flupenthixol versus low-potency antipsychotic drugs

Tardy 2011

Perphenazine versus low-potency first generation antipsychotic Tardy 2011c drugs for schizophrenia Trifluoperazine versus low-potency antipsychotic drugs

Tardy 2011d

Table 2. Comparisons suggested by excluded studies

Comparison

Excluded study tag

Current relevant Cochrane review

Amphetamine for schizophrenia

Cesarec 1974

Nolte 2004

Flupenthixol (high-potency) fluphenazine for schizophrenia

versus Cesarec 1974

-

Fluphenazine (intramuscular injection) Chacon 1973 versus chlorpromazine for schizophrenia

-

Fluphenazine (intramuscular injection) Chacon 1973 versus placebo for schizophrenia

-

Fluphenazine decanoate for schizophrenia

David 2004

Pimozide (high-potency) fluphenazine for schizophrenia

Kane 1983

versus Cesarec 1974

Thioproperazine (medium/high-potency Hordern 1964 drug) versus fluphenazine for schizophrenia

Mothi 2013

-

Table 3. Design of a future study

Methods

Allocation: randomised-clearly described generation of sequence and concealment of allocation. Blinding: double-described and tested. Duration: long term.


55

Table 3. Design of a future study

(Continued)

Participants

People with schizophrenia or schizophrenia-like disorder. N = 500. Age: any. Sex: both. History: any.

Interventions

1. Fluphenazine (oral). 2. Any low-potency antipsychotic (oral).

Outcomes

Response (primary outcome). Rehospitalisation. Mental state (BPRS). Global state (CGI). Leaving the study early (including specific causes). Death (natural and unnatural causes). Adverse effects. Quality of life. Satisfaction with care. Employment.

N = number of participants, BPRS = Brief Psychiatric Rating Scale, CGI = Clinical Global Impressions Scale

CONTRIBUTIONS OF AUTHORS Magdolna Tardy: protocol development, trial selection, data extraction, report writing. Maximilian Huhn: protocol development, trial selection, data extraction, report writing. Rolf Engel: protocol development. Stefan Leucht: protocol development, advice, report writing.

DECLARATIONS OF INTEREST Magdolna Tardy: none known. Maximilian Huhn: none known. Rolf Engel: none known. Stefan Leucht-has received honoraria for lectures from Abbvie, Astra Zeneca, BristolMyersSquibb, ICON, EliLilly, Janssen, Johnson & Johnson, Roche, SanofiAventis, Lundbeck and Pfizer; honoraria for consulting/advisory boards from Roche, EliLilly, Medavante, BristolMyersSquibb, Alkermes, Janssen, Johnson & Johnson and Lundbeck. EliLilly has provided medication for a study with SL as primary investigator.


56

SOURCES OF SUPPORT Internal sources • Freistaat Bayern, Germany.

External sources • Bundesministerium für Bildung und Forschung Grant number 01KG09228816532, Germany. • National Insitute for Health Research, UK. NIHR Cochrane Programme Grant: Ref number 10/4001/15-Cost effective treatments and diagnostic approaches for people with schizophrenia within the NHS

DIFFERENCES BETWEEN PROTOCOL AND REVIEW We have updated some of the text of the methods section to reflect current formatting in the Cochrane Schizophrenia Group template. These changes are structural changes only and do not reflect a change in statistical methods. We decided post-hoc to include all outcomes reported by a study, not only the predefined outcomes in the methods section. A randomised sample of 25% of the newly extracted outcomes was independently extracted by a second review author (Maximilian Huhn).

INDEX TERMS Medical Subject Headings (MeSH) Akathisia, Drug-Induced; Antipsychotic Agents [adverse effects; ∗ therapeutic use]; Dyskinesia, Drug-Induced; Fluphenazine [adverse effects; ∗ therapeutic use]; Randomized Controlled Trials as Topic; Schizophrenia [∗ drug therapy]

MeSH check words Humans


57

Trifluoperazine versus low-potency first-generation antipsychotic drugs for schizophrenia.

Perphenazine versus low-potency first-generation antipsychotic drugs for schizophrenia.

Efficacy of antipsychotic drugs for schizophrenia.

Efficacy of antipsychotic drugs for schizophrenia.

Haloperidol vs. Low-Potency Antipsychotic Drugs for Schizophrenia.

Efficacy of antipsychotic drugs for schizophrenia - Authors' reply.

Fluphenazine decanoate (depot) and enanthate for schizophrenia.

Antipsychotic medications for schizophrenia.

Antipsychotic combinations for schizophrenia.

Antipsychotic medications for schizophrenia.

Neurotensin, antipsychotic drugs, and schizophrenia. Basic and clinical studies.

Effects of antipsychotic drugs on insight in schizophrenia.

Antipsychotic medications for schizophrenia--reply.

Chlorpromazine versus every other antipsychotic for schizophrenia: a systematic review and meta-analysis challenging the dogma of equal efficacy of antipsychotic drugs.

Mechanisms of action of atypical antipsychotic drugs. Implications for novel therapeutic strategies for schizophrenia.

Strategies for Early Non-response to Antipsychotic Drugs in the Treatment of Acute-phase Schizophrenia.

Neural basis for the ability of atypical antipsychotic drugs to improve cognition in schizophrenia.

Long-acting injectable versus daily oral antipsychotic treatment trials in schizophrenia: pragmatic versus explanatory study designs.

Letter: Dosage for antipsychotic drugs (concl.).

Guidelines for the dosage of antipsychotic drugs.

Early antipsychotic intervention and schizophrenia.

Low dose fluphenazine decanoate in maintenance treatment of schizophrenia.

Pharmacokinetics of haloperidol and fluphenazine decanoates in chronic schizophrenia.

Possible dose-side effect relationship of antipsychotic drugs: relevance to cognitive function in schizophrenia.