Add-On Pharmacotherapy in Schizophrenia: Does It Improve Long-Term Outcomes? A Systematic Review
Abstract
Background/Objectives: Residual symptoms-such as persistent negative or cognitive symptoms-and relapse remain common in schizophrenia (SCZ) despite the proven efficacy of antipsychotics. As a result, add-on medications are frequently prescribed in real-world clinical practice. Although these agents are often used chronically, most evidence supporting their benefits comes from short-term trials. This systematic review aimed to assess the effect of adjunctive medication on long-term clinical outcomes and relapse prevention. Methods: Following PRISMA guidelines, we searched PubMed and Scopus (2000-2025) for trials of add-on agents administered for ≥24 weeks in SCZ spectrum disorders. Eligible studies compared antipsychotic treatment as usual with and without an add-on pharmacological agent (or with an added placebo). The primary outcome was long-term symptom change evaluated via established clinical scales, while relapse was the secondary outcome. Risk of bias was assessed with the Cochrane RoB 2 tool (PROSPERO registration: CRD420251075647). Results: The 22 of 4101 selected studies were classified into a group of frequently used add-on agents in clinical practice (antidepressants, mood stabilizers) and a group of less common agents, encompassing cognitive enhancers, antibiotics and antioxidants/anti-inflammatory agents. Results regarding clinical efficacy were mixed for both groups and respective subcategories. Overall, no drug class produced robust benefits. Relapse was…
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Evidence Hub reads this as a systematic review. Its evidence level is 1 of 5 (Highest · pooled evidence). Pooled evidence from several studies sits at the top of the evidence pyramid.
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