23 March 2026 : Review article
Antidepressant Augmentation of Antipsychotic Treatment in Schizophrenia: A Narrative Review
Weihao Li ABDEF 1, Biyao Gao
ABDEF 1, Yilin Liu ABDE 1, Weiguo He BDEF 2, Wenhui Zha ABDE 1, Shanshan Du BDEF 1, Yong Zeng AEFG 1, Yunqiao Zhang ABDEF 1*
DOI: 10.12659/MSM.951119
Med Sci Monit 2026; 32:e951119
Introduction
Clinical Features of and Overlap Between Schizophrenia and Depressive Disorders
Biological and Pathophysiological Foundations Relevant to Antidepressant Use
Antidepressant Classes: A Brief Overview
Antidepressants in Schizophrenia: Clinical Strategies and an Overview of the Evidence
Safety Considerations and Drug Interaction Risks in Combined Treatment
Future Directions
Conclusions
References
Table 1 Antidepressants preferred for adjunctive use in schizophrenia: clinical targets and safety notes.
| Antidepressants | Recommend or not | Disease | Recommended medication combination | Conclusion |
|---|---|---|---|---|
| Sertraline | Yes | Schizophrenia | Sertraline + Risperidone [,]Sertraline + Ziprasidone []Sertraline + computerized cognitive behavioral therapy []59 | It improves negative symptoms and cognitive function. However, when administered in combination with aripiprazole, the risk of adverse reactions such as ‘hiccups’ should be monitored |
| Fluoxetine | Yes | Schizophrenia | Fluoxetine + Risperidone []Fluoxetine + Olanzapine []119 | Fluoxetine used in combination with low-dose SGA reduces drug adverse reactions and shows good efficacy. When combined with olanzapine, it promotes neurogenesis in the hippocampus |
| Fluvoxamine | Yes | Schizophrenia | Fluvoxamine + Clozapine [,]Fluvoxamine + Risperidone []69 | The combination of fluvoxamine with clozapine or risperidone appears to be effective and generally well tolerated, with potential benefits for negative symptoms and cognitive functioning |
| Duloxetine | Yes | Schizophrenia | Duloxetine + Risperidone [,]72 | Duloxetine plus risperidone improved negative symptoms in stable schizophrenia versus placebo in an RCT, potentially through 5-HT/NE modulation linked to motivational and affective deficits |
| Mirtazapine [,]77 | Yes | Schizophrenia | Mirtazapine + Aripiprazole [,]Mirtazapine + Venlafaxine + MECT []84 | Used alongside antipsychotics, it has been reported to improve sleep and reduce negative symptoms in some cases, although treatment effects are not uniform across individuals. |
| Vortioxetine | Yes | Schizophrenia | Vortioxetine + SGA [,,]90 | This combination regimen can alleviate “negative symptoms” and cognitive function [,]90 |
| SGA – second-generation antipsychotic; RCT – randomized controlled trial; 5-HT – 5-hydroxytryptamine; NE – norepinephrine; MECT – modified electroconvulsive therapy. | ||||