Treatment of schizotypal disorder: A systematic review and GRADE evaluation of the certainty of evidence

Background Evidence to guide treatment for schizotypal disorder is scarce, and clinical guidelines remain undeveloped. This systematic review synthesized current evidence on pharmacological and psychotherapeutic interventions targeting clinical symptoms, cognition, and functioning in schizotypal disorder. Methods We searched PsychINFO, Embase, Medline, and Cochrane Register of Controlled Trials (25/03/2025) without date restrictions, supplemented by handsearching. Eligible studies were screened, quality appraised, and data extracted by two independent authors. Due to substantial heterogeneity, findings were synthesized narratively, and evidence certainty was rated using GRADE. Results Twenty-one studies met inclusion criteria. Most had some concerns regarding risk of bias. Pharmacological trials most frequently investigated antipsychotics, with preliminary evidence suggesting benefits of thiothixene and, to a lesser extent, risperidone, olanzapine, and haloperidol in reducing general psychiatric symptoms, although effects on depressive symptoms were mixed. Dopamine agonists and central alpha-2A agonists showed domain-specific cognitive improvements, particularly when combined with cognitive remediation therapy and social skills training. Among psychotherapeutic approaches, metacognitively oriented and evolutionary systems therapies demonstrated consistent symptom reductions, while integrated interventions temporarily reduced negative symptoms and psychosis risk. Functional improvements were most evident in multimodal interventions combining pharmacological and psychosocial components. Across interventions, the overall certainty of evidence was graded very low to low. Conclusions Current treatment evidence for schizotypal disorder is limited and heterogeneous. Larger, high-quality randomized controlled trials are needed to establish efficacy across clinical, cognitive, and functional domains and to inform development of evidence-based treatment guidelines.