Add-On Pharmacotherapy in Schizophrenia: Does It Improve Long-Term Outcomes? A Systematic Review

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 systematically reported in only one study, with low overall relapse rates (2.5%). Risk-of-bias assessment did not reveal significant methodological concerns, apart from high attrition (average 29.5%). Conclusions: Evidence for the long-term efficacy of add-on pharmacological treatments in SCZ is inconsistent, with no agent demonstrating reliable benefits. These findings raise concerns regarding long-term polypharmacy and also highlight the need for further investigations. Future studies should prioritize longer follow-up, relapse outcomes and realistic treatment patterns.