Clozapine Combination and Augmentation Strategies in Patients With Schizophrenia —Recommendations From an International Expert Survey Among the Treatment Response and Resistance in Psychosis (TRRIP) Working Group

Abstract

Background Evidence for the management of inadequate clinical response to clozapine in treatment-resistant schizophrenia is sparse. Accordingly, an international initiative was undertaken with the aim of developing consensus recommendations for treatment strategies for clozapine-refractory patients with schizophrenia. Methods We conducted an online survey among members of the Treatment Response and Resistance in Psychosis (TRRIP) working group. An agreement threshold of ≥75% (responses “agree” + “strongly agree”) was set to define a first-round consensus. Questions achieving agreement or disagreement proportions of >50% in the first round, were re-presented to develop second-round final consensus recommendations. Results Forty-four (first round) and 49 (second round) of 63 TRRIP members participated. Expert recommendations at ≥75% agreement included raising clozapine plasma levels to ≥350 ng/ml for refractory positive, negative, and mixed symptoms. Where plasma level-guided dose escalation was ineffective for persistent positive symptoms, waiting for a delayed response was recommended. For clozapine-refractory positive symptoms, combination with a second antipsychotic (amisulpride and oral aripiprazole) and augmentation with ECT achieved consensus. For negative symptoms, waiting for a delayed response was recommended, and as an intervention for clozapine-refractory negative symptoms, clozapine augmentation with an antidepressant reached consensus. For clozapine-refractory suicidality, augmentation with antidepressants or mood-stabilizers, and ECT met consensus criteria. For clozapine-refractory aggression, augmentation with a mood-stabilizer or antipsychotic medication achieved consensus. Generally, cognitive-behavioral therapy and psychosocial interventions reached consensus. Conclusions Given the limited evidence from randomized trials of treatment strategies for clozapine-resistant schizophrenia (CRS), this consensus-based series of recommendations provides a framework for decision making to manage this challenging clinical situation.

Genome-wide association analyses of symptom severity among clozapine-treated patients with schizophrenia spectrum disorder

“…Previous studies have suggested that clozapine blood concentrations ≥350 ng/mL are associated with superior symptomatic outcome. 26 However, determining the required dose for an individual to achieve this target blood concentration and symptomatic relief can be challenging.…”

A Repeated Time-to-Positive Symptoms Improvement among Malaysian Patients with Schizophrenia Spectrum Disorders Treated with Clozapine

“…Recently, higher clozapine doses, concentrations, and treatment durations were reported in responders as compared to non-responders [ 32 ]. Furthermore, waiting for a delayed clozapine response for persistent positive symptoms was recommended over plasma level-guided dose escalation in the recent consensus recommendations by the TRRIP working group [ 33 ].…”

“…However, in a recent multicenter investigation with long follow-up, clozapine augmentation with the atypical antipsychotic, paliperidone, has shown significant relief of symptoms, lower number of hospitalization, and improved functionality [ 40 ]. Finally, a consensus of treatment strategies for refractory schizophrenia patients was introduced by the TRRIP working group, where combinations of clozapine and atypical antipsychotics such as aripiprazole or amisulpride were recommended for refractory positive and mixed symptoms [ 33 ], in line with the current study findings.…”

Clozapine and paliperidone palmitate antipsychotic combination in treatment-resistant schizophrenia and other psychotic disorders: A retrospective 6-month mirror-image study

“…Clozapine monotherapy is considered by most guidelines and expert consensus the most effective medication for TRS [27][28][29][30]. However, only 40% of people will meet response criteria, being necessary to establish well evidenced-bases clozapine augmentation strategies [31][32][33]. Recent systematic meta-review of available evidence and international expert consensus point that augmentation with second-generation antipsychotics and firstgeneration antipsychotics can be beneficial, but the supporting evidence is from low-quality studies [32,33].…”

“…However, only 40% of people will meet response criteria, being necessary to establish well evidenced-bases clozapine augmentation strategies [31][32][33]. Recent systematic meta-review of available evidence and international expert consensus point that augmentation with second-generation antipsychotics and firstgeneration antipsychotics can be beneficial, but the supporting evidence is from low-quality studies [32,33]. A previous retrospective 1-year mirror-image study reported that clozapine and various LAI antipsychotics (mainly first generation and risperidone) combination was beneficial and safe in a cohort of 17 multi-episode patients diagnosed with schizophrenia and schizoaffective disorder [3].…”