Schizophrenia is a crippling condition characterised by psychotic experiences such as delusions and hallucinations. It can be hugely debilitating for the patient and their family and it can also be an enormous challenge for psychiatrists and other health and social care professionals who are responsible for providing care and support to the service user.

Currently, there are very few alternatives to drug treatment for effectively managing schizophrenia. However, even experienced clinicians often struggle to select the most appropriate medication for their patients. Therefore, four recent Cochrane reviews assessing the efficacy of four common antipsychotic drugs (Chlorpromazine, Quetiapine, Trifluoperazine and Pimozide) in randomised controlled trials (RCTs) may be of help to clinicians.

Methods

All of these reviews were carried out by the Cochrane Schizophrenia Group, so similar methods were used across the four reviews. All review teams searched the Cochrane Schizophrenia Group Trials Register, inspected reference lists and also contacted relevant drug companies, drug approval agencies and authors of trials for additional information.

One of the reviews (the Trifluoperazine review by Koch et al, 2014) also undertook a search for economic studies using the Cochrane Schizophrenia Group’s Health Economic Database.

Results

Chlorpromazine vs. placebo (Adams et al, 2014)

• 55 studies with a total of 4561 patients were included
• GRADE quality evidence of all studies was very low to low
• Compared to placebo, Chlorpromazine:
  • Reduced the number of participants experiencing relapse after six to 24 months
  • Led to global improvement in symptoms and functioning
  • Is sedating, leads to motor side effects, weight gain and lowers blood pressure

The authors concluded that:

Chlorpromazine’s global position as a ‘benchmark’ treatment for psychoses is not threatened by the findings of this review. Chlorpromazine, in common use for half a century, is a well-established but imperfect treatment.

Trifluoperazine vs. placebo (Koch et al, 2014)

• Ten studies with 686 patients were included
• Overall quality evidence (GRADE) was low and based on a handful of small trials
• Superior to placebo regarding medium term clinical global state and medium term attrition due to relapse or symptoms worsening
• Equivocal data regarding side effects profile and related study dropout or discontinuation
• Trifluoperazine may have a favourable economic basis

The authors concluded that:

Trifluoperazine is an effective antipsychotic for people with schizophrenia. Furthermore, our review provides supportive evidence that trifluoperazine increases the risk of extrapyramidal adverse effects.

Quetiapine vs. other atypical antipsychotics (Asmal et al, 2013)

• The authors included 35 RCTs that compared quetiapine to a host of other antipsychotic drugs
• Overall quality evidence (GRADE) was low to moderate
• There were no comparisons to amisulpride, sertindole or zotepine
• Key findings are that Quetiapine:
  • Is likely less efficient than control drugs
  • Is associated with slightly fewer motor side effects, fewer metabolic side effects of but increased QTc prolongation compared to olanzapine
  • Is associated with slightly fewer motor side effects, less prolactin release and related side effects but stronger cholesterol release compared to risperidone
  • May be associated with fewer motor side effects and less prolactin release and weight gain compared to paliperidone, but data are limited
  • Is associated with fewer motor side effects and less prolactin release, but more sedation and weight gain than zipraisonde

The authors concluded that quetiapine may have selective benefits over some compounds while at the same time caution that most studies:

That have been reported within existing comparisons are of very limited value because of assumptions and biases within them.

Pimozide vs. placebo, no treatment or other antipsychotics (Mothi and Sampson, 2013)

• The authors included 32 studies, five with placebo control, 26 against any antipsychotics and one compared pimozide plus any antipsychotic vs. two antipsychotics
• Overall quality evidence is very low to low
• Key findings are that Pimozide:
  • Is likely more efficient than placebo
  • Is likely comparable to other antipsychotics (e.g. chlorpromazine) in terms of efficacy and adverse effects
  • Pimozide augmentation may be associated with fewer relapses at medium term

The authors conclude that:

(…) enough overall consistency over different outcomes and timescales is present to confirm that pimozide is a drug with efficacy similar to that of other, more commonly used antipsychotic drugs such as chlorpromazine for people with schizophrenia.

Conclusions

While highly informative regarding specific side effect domains (e.g. motor symptoms or metabolic effects), the reviews discussed here add to an already complicated and multifaceted picture of antipsychotics. In addition, most studies suffer from poor methodological quality and their conclusions are of unclear clinical significance.

Having said that, knowledge of specific side effects (e.g. worse metabolic measures with Olanzapine) may aid clinicians in optimising their drug choice to provide a more tailored approach to individual patient profiles.

As is often the case with Cochrane reviews, these new studies highlight the need for more rigorous future clinical research and optimised protocols.

Links

Adams, C. E., Awad, G. A., Rathbone, J., Thornley, B., & Soares-Weiser, K. (2014). Chlorpromazine versus placebo for schizophrenia. The Cochrane Database of Systematic Reviews, 1, CD000284. doi:10.1002/14651858.CD000284.pub3

Asmal, L., Flegar, S. J., Wang, J., Rummel-Kluge, C., Komossa, K., & Leucht, S. (2013). Quetiapine versus other atypical antipsychotics for schizophrenia. The Cochrane Database of Systematic Reviews, 11, CD006625. doi:10.1002/14651858.CD006625.pub3

Koch, K., Mansi, K., Haynes, E., Adams, C. E., Sampson, S., & Furtado, V. A. (2014). Trifluoperazine versus placebo for schizophrenia. The Cochrane Database of Systematic Reviews, 1, CD010226. doi:10.1002/14651858.CD010226.pub2

Mothi, M., & Sampson, S. (2013). Pimozide for schizophrenia or related psychoses. The Cochrane Database of Systematic Reviews, 11, CD001949. doi:10.1002/14651858.CD001949.pub3