Treatment-Resistant Schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) Working Group Consensus Guidelines on Diagnosis and Terminology

Abstract

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.

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“…This study strengthened several previous findings, including the largest association with the major histocompatibility complex locus on chromosome 6, involvement of an N-methyl-D-aspartate (NMDA) receptor (GRIN2A) with other glutamatergic genes, and the DRD2 gene—the D 2 receptor is an essential target of antipsychotics 43. Discovered in 1950, antipsychotics are proven effective at treating psychosis and their mechanism of action provides insight into aspects of the molecular underpinnings of psychosis 6. The finding that mean doses of different antipsychotics were correlated with their binding affinity for D 2 demonstrated how essential D 2  binding is to antipsychotic action 44…”

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“…In effect, the results of any trial of any drug in 'refractory (or resistant) schizophrenia' are substantially dependent on what that term means. An analysis of 42 studies [26] found that half did not provide details of how treatment resistance was defined and only two (5%) of the remainder used the same criteria.…”