The effect of second-generation antipsychotics on anxiety/depression in patients with schizophrenia: A systematic review and meta-analysis

Objective: Despite the high prevalence of anxiety in schizophrenia, no established guideline exists for the management of these symptoms. We aimed to synthesize evidence on the effect of second-generation antipsychotics (SGAs) on anxiety in patients with schizophrenia. Methods: We systematically searched Medline, Embase, PsycInfo, Web of Science, PubMed, and Cochrane library to identify randomized controlled trials of SGAs that reporting anxiety measures in schizophrenia. The search was limited to English-language articles published before February 2024. Data were pooled using a random-effects model. Results: Among 48 eligible studies, 29 (n = 7712) were included in the meta-analyses comparing SGAs to placebo, haloperidol, or another SGAs for their effect on anxiety/depression. SGAs had a small effect on anxiety/depression versus placebo (SMD = −0.28 (95 % CI [−0.34, −0.21], p < .00001, I² = 47 %, n = 5576)) associated with efficacy for positive (z = 5.679, p < .001) and negative symptoms (z = 4.490, p < .001). Furthermore, SGAs were superior to haloperidol (SMD = −0.44, 95 % CI [−0.75, −0.13], p = .005, n = 1068) with substantial study-level heterogeneity (I² = 85 %). Excluding one study of quetiapine in first-episode patients (SMD = −3.05, n = 73), SGAs showed a small effect on anxiety/depression versus haloperidol without heterogeneity (SMD = −0.23, 95 % CI [−0.35, −0.12], p = 01; I² = %0). Risperidone's effect on anxiety/depression was comparable to olanzapine (SMD = −0.02, 95 % CI [−0.24,0.20], p = .87, I² = 45 %, n = 753) and amisulpride (SMD = 0.27, 95 % CI [−1.08,0.61], p = .13, I² = 50 %, n = 315). Conclusion: While SGAs showed a small effect on anxiety/depression, the findings are inconclusive due to scarcity of research on comorbid anxiety in schizophrenia, heterogeneity of anxiety symptoms, and the scales used to measure anxiety. Further studies employing specific anxiety scales are required to explore antipsychotics, considering their receptor affinity and augmentation with serotonin/norepinephrine reuptake inhibitors or benzodiazepines for managing anxiety in schizophrenia.