First-Episode Psychosis Drug Choice: No Clear Winner

Megan Brooks

July 28, 2017

For patients with a first episode of schizophrenia, haloperidol (Haldol, Ortho-McNeil) should not be used, and the choice among second-generation antipsychotics should be guided by their side effect profile, researchers advise on the basis of a systematic review and meta-analysis of relevant research.

"Haloperidol seems to be a suboptimum treatment option for acute treatment of first-episode schizophrenia, but we found little difference between second-generation antipsychotics. Thus, the choice of treatment should be guided primarily by side-effects," conclude Stefan Leucht, MD, from the Department of Psychiatry and Psychotherapy, Technische Universitat Munchen, Munich, Germany, and colleagues.

The study was published online July 20 in Lancet Psychiatry.

FEP Drug Choice "Controversial"

The first episode of schizophrenia is a "pivotal phase of this debilitating illness," and which drug to use "remains controversial," the authors note.

They used pairwise and network meta-analyses to summarize the evidence from 19 randomized trials for efficacy and tolerability of 12 antipsychotic drugs in the short-term treatment of first-episode schizophrenia in a total of 2669 patients.

For overall reduction of symptoms, the network meta-analysis suggested significant superiority of amisulpride (multiple brands), olanzapine (Zyprexa, Lilly), ziprasidone (Geodon, Pfizer), and risperidone (Risperdal, Janssen) over haloperidol, but the evidence was of very low to moderate quality, the authors say.

Antipsychotic SMD (95% CI)
Amisulpride -0.37 (-0.61 to -0.14)
Olanzapine -0.25 (-0.39 to -0.12)
Ziprasidone -0.25 (-0.48 to -0.01)
Risperidone -0.14 (-0.27 to -0.01)
SMD, standardized mean difference
CI, confidence interval


The superiority of several second-generation antipsychotics over haloperidol mirrors that seen in a conventional meta-analysis published in 2013, the authors note.

By contrast, little difference was seen between second-generation antipsychotics. The only significant differences were that amisulpride was superior to quetiapine (Seroquel, AstraZeneca) for overall symptom reduction, and olanzapine was superior to risperidone in reduction of negative symptoms.

However, the researchers say the superiority of amisulpride over quetiapine was based on only one open-label trial, and this result did not remain significant when open-label studies were excluded from the sensitivity analysis of the primary outcome. The only significant finding after this analysis was that olanzapine was superior to haloperidol and quetiapine.

In their pairwise meta-analyses, overall functioning and quality-of-life outcomes did not differ between drugs, but very few data were available.

In terms of discontinuation for any reason, aripiprazole, quetiapine, risperidone, and olanzapine were superior to haloperidol. For dropout due to inefficacy, olanzapine and risperidone were superior to haloperidol.

Olanzapine was used at least once to treat parkinsonian symptoms. Quetiapine was associated with less akathisia than haloperidol, aripiprazole, risperidone, and olanzapine, but, again, evidence was of very low to low quality. Molindone (Moban, CorePharma) was superior to risperidone, haloperidol, and olanzapine with respect to weight gain, and it was superior to risperidone with respect to increase in prolactin release.

"Until findings are available from better-quality studies to elucidate differences in efficacy, treatment decisions for first-episode schizophrenia should be guided mainly by side-effects, for which the general patterns were similar to those found in chronic patients," the investigators write.

Patient Input Critical

"Nobody can fail to appreciate the importance of providing the very best treatment for a person having his or her first episode of schizophrenia," Prof David Taylor, from the Institute of Pharmaceutical Sciences, King's College London, United Kingdom, writes in an accompanying editorial.

"Few would argue" with the conclusions of this analysis, he writes. "Haloperidol has a well-deserved reputation for causing acute and chronic movement disorders which, at least in the former case, is borne out by the findings of this network meta-analysis."

The analysis found "no clear victor in terms of efficacy," Dr Taylor notes. "Where adverse effects were concerned, there were losses and gains, typified by olanzapine, which less frequently caused extrapyramidal symptoms and akathisia than some other drugs, but led to more weight gain.

"Their findings indicate that choice of antipsychotic in first-episode schizophrenia should be made on the basis of likely adverse effects, guided as far as possible by the results of this meta-analysis and the patient’s informed preference, and later decisions should take into account the patient’s experience of these effects," Dr Taylor concludes.

"Choosing an antipsychotic based on adverse effects is not simple. Nor should this choice really be made by the prescriber. Patients have the most relevant views of how well they are likely to tolerate given side-effects," he adds.

The study had no commercial funding. Dr Leucht has received honoraria for consulting from LB Pharma, Lundbeck, Otsuka, Roche, and TEVA, for lectures from AOP Orphan, ICON, Janssen, Lilly, Lundbeck, Otsuka, Pfizer, Roche, and Servier, and for a publication from Roche. Dr Taylor has received grants and personal fees from Janssen, Lundbeck, and Sunovion and personal fees from Otsuka.

Lancet Psychiatry. Published online July 20, 2017. Abstract, Comment


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