Abstract: The review currently includes four relevant randomised trials with 365 participants. The size of the included studies was between 42 and 158 participants with a study length between one and four months. Overall, the methods of sequence generation and allocation concealment were poorly reported. Most studies were rated as low risk of bias in terms of blinding. Overall, attrition bias in the studies was high. The effects of perphenazine and low-potency antipsychotic drugs seemed to be similar in terms of the primary outcome – response to treatment (perphenazine 58%, low-potency antipsychotics 59%, 2 RCTs, n = 138, RR 0.97 CI 0.74 to 1.26 – moderate quality of evidence). There was also no clear evidence of a difference in acceptability of treatment with the number of participants leaving the studies early due to any reason, however results were imprecise (perphenazine 30%, low-potency antipsychotics 28%, 3 RCTs, n = 323, RR 0.78 CI 0.35 to 1.76, very low quality of evidence). There were low numbers of studies available for the outcomes experiencing at least one adverse effect (perphenazine 33%, low-potency antipsychotics 47%, 2 RCTs, n = 165, RR 0.83 CI 0.36 to 1.95, low quality evidence) and experiencing at least one movement disorder (perphenazine 22%, low-potency first-generation antipsychotics 0%, 1 RCT, n = 69, RR 15.62 CI 0.94 to 260.49, low quality evidence), and the confidence intervals for the estimated effects did not exclude important differences. Akathisia was more frequent in the perphenazine group (perphenazine 25%, low-potency antipsychotics 22%, 2 RCTs, n = 227, RR 9.45 CI 1.69 to 52.88), whereas severe toxicity was less so (perphenazine 42%, low-potency antipsychotics 69%, 1 RCT, n = 96, RR 0.61 CI 0.41 to 0.89). There were three deaths in the low-potency group by four months but the difference between groups was not significant (perphenazine 0%, low-potency antipsychotics 2%, 1 RCT, n = 96, RR 0.14 CI 0.01 to 2.69, moderate quality evidence). No data were available for our prespecified outcomes of interest sedation or quality of life. Data were not available for other outcomes such as relapse, service use, costs and satisfaction with care. The event rates reported quote simple aggregates and are not based on the RRs. The results do not show a superiority in efficacy of high-potency perphenazine compared with low-potency first-generation antipsychotics. There is some evidence that perphenazine is more likely to cause akathisia and less likely to cause severe toxicity, but most adverse effect results were equivocal. The number of studies as well as the quality of studies is low, with quality of evidence for the main outcomes ranging from moderate to very low, so more randomised evidence would be needed for conclusions to be made.

Plain-language summary: The review aims to compare a high-potency first-generation antipsychotic, perphenazine with low-potency first-generation antipsychotics. A search for trials was run in 2010. Four trials that randomised a total of 365 people are included. The studies compared perphenazine with chlorpromazine, thioridazine and levomepromazine. Overall, the trials were of poor quality, poorly reported and small scale. Review authors also rated the quality of evidence for the main outcomes to range from moderate to very low quality. It was found that perphenazine was not obviously clinically superior to low-potency first-generation antipsychotic drugs but was more likely cause the movement disorder akathisia (inner restlessness and the inability to sit still). Low-potency first-generation antipsychotics are thought more likely to cause side effects such as sedation and hypotension but evidence from this review showed people taking perphenazine were just as likely to experience hypotension as those taking first-generation antipsychotics and no data were available for sedation. Other outcomes, such as re-hospitalisation, costs, healthy days and quality of life were not addressed in the studies. No firm conclusions can be made about perphenazine's superiority or inferiority over low-potency first-generation antipsychotics until newer and better conducted studies are completed. This plain language summary has been written by a consumer, Benjamin Gray, from Rethink Mental Illness.