Objective Treatment resistance complicates the management of schizophrenia. Research and clinical translation is limited by inconsistent definitions. To address this we evaluated current approaches and then developed consensus criteria and guidelines. Method A systematic review of randomized antipsychotic clinical trials in treatment resistant schizophrenia was performed. Definitions of treatment resistance were extracted. Subsequently, consensus operationalized criteria were developed by a working group of researchers and clinicians through i) a multi-phase, mixed methods approach; ii) identifying key criteria via an online survey; and iii) meetings to achieve consensus. Results 42 studies met inclusion criteria. Of these, 21 (50%) studies did not provide operationalized criteria, whilst in others, criteria varied considerably, particularly regarding symptom severity, prior treatment duration and antipsychotic dose thresholds. Important for the inability to compare results, only two (5%) studies utilized the same criteria. The consensus group identified minimum and optimal criteria, employing the following principles: 1) current symptoms of a minimum duration and severity determined by a standardized rating scale; 2) ≥moderate functional impairment; 3) prior treatment consisting of ≥2 different antipsychotic trials, each for a minimum duration and dose; 4) adherence systematically assessed and meeting minimum criteria; 5) ideally at least one prospective treatment trial; 6) criteria that clearly separated responsive from treatment resistant patients. Conclusions There is considerable variation in current approaches to defining treatment resistance in schizophrenia. We present consensus guidelines that operationalize criteria for determining and reporting treatment resistance, adequate treatment and treatment response in schizophrenia, providing a benchmark for research and clinical translation.

Meta-analyses of 21 interventions fully or partially recommended their use, with recommendations being positively correlated with the effect sizes of the pooled intervention. However, the effect sizes were inversely correlated with meta-analyzed study quality, reducing confidence in these recommendations. Higher-quality trials and patient-based meta-analyses are needed to determine whether subpopulations might benefit from combination treatment, as no single strategy can be recommended for patients with schizophrenia based on the current meta-analytic literature.