Antidepressive Effect of Antipsychotics in the Treatment of Schizophrenia: Meta-Regression Analysis of Randomized Placebo-Controlled Trials

Abstract

Background: Antipsychotics improve the positive symptoms of schizophrenia. However, little is known about the extent of antidepressive effects of antipsychotics and their correlation with effects on other symptom domains in schizophrenia. The aim was to investigate whether antidepressive effects of antipsychotics have a significant correlation with the effects on specific symptom domains of schizophrenia.

Methods: Electronic databases were searched to identify eligible studies that reported antidepressive effects of antipsychotics for the treatment of adult patients with schizophrenia in double-blind, randomized placebo-controlled trials (RCTs). Mean change from baseline in depressive symptoms was meta-analyzed, and the correlation with the effects on other symptom domains was examined through meta-regression analysis.

Results: Thirty-five RCTs (13 890 patients) were included in this meta-analysis. Overall, antipsychotics showed greater efficacy than placebo in reducing depressive symptoms, with small to medium effect sizes (standardized mean difference = -0.27, 95% confidence interval -0.32 to -0.22, P < .001). All the antipsychotics, except for chlorpromazine, haloperidol, and ziprasidone, were associated with significantly greater decreases in depressive symptoms compared with placebo (standardized mean difference = -0.19 to -0.40). A higher antidepressive effect was significantly correlated with a higher improvement in Positive and Negative Syndrome Scale/Brief Psychiatric Rating Scale total, positive, and negative, and Positive and Negative Syndrome Scale-general psychopathology symptoms (β = .618, P < .001; β = .476, P < .001; β = .689, P < .001; β = .603, P < .001, respectively).

Conclusions: Second-generation antipsychotics (except for ziprasidone) were associated with small to medium effects sizes on improvement in depressive symptoms among adult patients with schizophrenia. The antidepressive effect of antipsychotics was significantly correlated with improvement in other symptom domains, with the highest correlation observed for improvement in negative symptoms.

Prospero registration number: CRD42019133015.

Keywords: Antipsychotics; antidepressants; meta-regression; psychopathology; schizophrenia.

Figure 1.

Effect sizes of all studies included in the analysis, forest plot. AP, antipsychotic drug; ARI, aripiprazole; ASE, asenapine; BRE, brexpiprazole; CP, chlorpromazine; HAL, haloperidol; CI, confidence interval; LUR, lurasidone; OLA, olanzapine; PAL, paliperidone; PBO, placebo; QUE, quetiapine; RIS, risperidone; SMD, standardized mean difference; ZIP, ziprasidone. SMDs < 0 favor the antipsychotic treatment.

Figure 2.

Meta-regression analysis of improvement in depressive symptoms on improvement in clinical symptoms. BPRS, Brief Psychiatric Rating Scale; CGI-S, Clinical Global Impressions–Severity illness scale; PANSS, Positive and Negative Syndrome Scale; SMD, standardized mean difference. (a) Correlation between improvement in depressive symptoms and improvement in PANSS/BPRS total score. (b) Correlation between improvement in depressive symptoms and improvement in positive symptoms. (c) Correlation between improvement in depressive symptoms and improvement in negative symptoms.

Figure 3.

Summary of subgroup analyses for depressive symptoms. AP, antipsychotic drug; BPRS, Brief Psychiatric Rating Scale; CDSS, Calgary Depression Scale for Schizophrenia; FGA, first-generation antipsychotic drug; HAM-D, Hamilton Rating Scale for Depression; MADRS, Montgomery Åsberg Depression Rating Scale; NbN, neuroscience-based nomenclature; PANSS, Positive and Negative Syndrome Scale; PBO, placebo; SCZ, schizophrenia; SGA, second-generation antipsychotic drug; SMD, standardized mean difference; SzAD, schizoaffective disorder. SMDs lower than 0 favor the antipsychotic treatment. Bold case indicates that results of the subgroup were statistically significant. P values <.05 indicate statistical significance. (a) M1–M5 are drug mechanisms of action according to the neuroscience-based nomenclature (NbN). M1: receptor antagonists (D₂) clopenthixol, fluphenazine, haloperidol, perphenazine, pimozide, pipotiazine, sulpiride, and trifluoperazine. M2: receptor antagonists (D₂, 5-HT₂) chlorpromazine, iloperidone, loxapine, lurasidone, olanzapine, sertindole, thioridazine, ziprasidone, and zotepine. M3: receptor partial agonists (D₂, 5-HT_1A) aripiprazole, brexpiprazole, and cariprazine. M4: receptor antagonists (D₂, 5-HT₂, NE, α ₂) asenapine, paliperidone, and risperidone. M5: receptor antagonist (D₂, 5-HT₂) and reuptake inhibitor (NET) quetiapine.