Perphenazine versus low-potency first-generation drugs for schizophrenia

Schizophrenia is a severe mental illness where people experience ‘positive symptoms’ (such as hearing voices, seeing things and having strange beliefs) and ‘negative symptoms’ (such as tiredness, apathy and loss of emotion).

Antipsychotic drugs are the main treatment for schizophrenia and can be grouped into older drugs (‘typical’ or first-generation) and newer drugs (‘atypical’ or second-generation), and within these groups you can have low strength (low-potency) or high strength (high-potency) antipsychotics. Perphenazine is a high-potency first-generation antipsychotic. Low-potency antipsychotics are often seen by psychiatrists and health professionals as less effective in treating schizophrenia than high-potency antipsychotic drugs; they also differ in side effects. Low-potency antipsychotic drugs often cause sleepiness and low blood pressure whereas high-potency antipsychotic drugs often produce movement disorders such as restlessness, shaking and tremors. Typical examples of low-potency first-generation antipsychotic drugs are chlorpromazine, chlorprothixene, thioridazine or levomepromazine.

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.

Authors' conclusions: 

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.

Read the full abstract...

Antipsychotic drugs are the core treatment for schizophrenia. Treatment guidelines state that there is no difference in efficacy between the various first-generation antipsychotics, however, low-potency first-generation antipsychotic drugs are sometimes perceived as less efficacious than high-potency first-generation compounds by clinicians, and they also seem to differ in their side effects.


To review the effects of high-potency, first-generation perphenazine compared with low-potency, first-generation antipsychotic drugs for people with schizophrenia.

Search strategy: 

We searched the Cochrane Schizophrenia Group Trials Register (October 2010).

Selection criteria: 

We included all randomised controlled trials (RCTs) comparing perphenazine with first-generation, low-potency antipsychotic drugs for people with schizophrenia or schizophrenia-like psychoses.

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 and using a random-effects model.

Main results: 

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.