All antipsychotics versus placebo

What are antipsychotics?

This topic includes both first and second generation antipsychotics.

Antipsychotics are effective for the symptoms of schizophrenia. Positive symptoms include the experiences of perceptual abnormalities (hallucinations) and fixed, false, irrational beliefs (delusions). Negative symptoms include a lack of ordinary mental activities such as emotional expression, social engagement, and motivation. Antipsychotics can also cause side effects. These include extrapyramidal symptoms such as dyskinesias (repetitive, involuntary, and purposeless body or facial movements), Parkinsonism (cogwheel muscle rigidity, pill-rolling tremor and reduced or slowed movements), akathisia (motor restlessness, especially in the legs, and resembling agitation), and dystonias (muscle contractions causing unusual twisting of parts of the body, most often in the neck). These effects are caused by the dopamine receptor antagonist action of antipsychotics. Other side effects may include weight, hormonal and metabolic changes, increased sedation, and ventricular anomalies (QTc prolongation).

What is the evidence for any antipsychotic efficacy compared to placebo?

Overall, moderate to high quality evidence finds a medium-sized effect of greater total symptom improvement with antipsychotics than with placebo. There was less variability in the response to antipsychotics than in the response to placebo, with older studies, those with younger patients, higher dose treatments, and greater mean difference in symptom change being associated with the least variability in response.

For particular antipsychotics, there were symptom improvements with (in descending order of efficacy compared to placebo): clozapine, amisulpride, thiotixene, zotepine, olanzapine, perphenazine, risperidone, thioridazine, zuclopenthixol, paliperidone, sulpiride, haloperidol, loxapine, chlorpromazine, flupentixol, clopenthixol, molindone, quetiapine, aripiprazole, ziprasidone, sertindole, asenapine, lurasidone, cariprazine, iloperidone, and brexpiprazole. There were no significant differences in symptoms between placebo and penfluridol, pimozide, perazine, fluphenazine, trifluoperazine, and levomepromazine.

For social functioning, there were improvements with (in descending order of efficacy compared to placebo) thioridazine, olanzapine, paliperidone, quetiapine, lurasidone, and brexpiprazole. There were no improvements in social functioning between placebo and aripiprazole, sertindole, amisulpride, ziprasidone, flupentixol, or risperidone.

For all-cause discontinuation (in descending order of effects, first being best), there was less discontinuation with clopenthixol, amisulpride, olanzapine, paliperidone, thiotixene, thioridazine, clozapine, loxapine, iloperidone, perphenazine, aripiprazole, risperidone, zuclopenthixol, zotepine, asenapine, quetiapine, lurasidone, brexpiprazole, haloperidol, and ziprasidone. There were no differences between placebo and perazine, levomepromazine, flupentixol, molindone, fluphenazine, chlorpromazine, cariprazine, sulpiride, sertindole, penfluridol, trifluoperazine, and pimozide.

For side effects (in ascending order of harm compared to placebo), there was less use of antiparkinson drugs with clozapine than with placebo, and more use of antiparkinson drugs with paliperidone, ziprasidone, risperidone, lurasidone, zotepine, cariprazine, chlorpromazine, sulpiride, perphenazine, molindone, zuclopenthixol, trifluoperazine, flupentixol, haloperidol, loxapine, penfluridol, fluphenazine, chlorpromazine, thiotixene, and pimozide.

There was more akathisia with aripiprazole, ziprasidone, thioridazine, asenapine, amisulpride, chlorpromazine, thiotixene, risperidone, cariprazine, loxapine, haloperidol, lurasidone, trifluoperazine, sulpiride, molindone, penfluridol, pimozide, fluphenazine, flupentixol, and zuclopenthixol.

There was more weight gain with haloperidol, amisulpride, asenapine, risperidone, paliperidone, clozapine, quetiapine, iloperidone, chlorpromazine, sertindole, olanzapine, and zotepine.

There was less prolactin elevation with aripiprazole, clozapine, and zotepine, and more prolactin elevation with olanzapine, asenapine, lurasidone, sertindole, haloperidol, amisulpride, risperidone, and paliperidone.

There was more sedation with aripiprazole, lurasidone, haloperidol, risperidone, asenapine, loxapine, olanzapine, chlorpromazine, thioridazine, thiotixene, ziprasidone, perazine, clozapine, clopenthixol, quetiapine, sulpiride, zotepine, and zuclopenthixol.

There was more QTc prolongation with quetiapine, olanzapine, risperidone, iloperidone, ziprasidone, amisulpride, and sertindole.

There was more anticholinergic side-effects haloperidol, olanzapine, clozapine, chlorpromazine, zotepine, iloperidone, thioridazine, and quetiapine.

October 2020