When Symptoms Persist: Clozapine Augmentation Strategies

Abstract

Recent data and clinical experience confirm that, in spite of superior efficacy for treatment-refractory schizophrenia, a substantial proportion of patients receiving clozapine will continue to experience disabling symptoms. Optimizing clozapine monotherapy is the first step in the management of "clozapine nonresponders." Described here is a synthesis of the available literature on the range and efficacy of clozapine augmentation strategies that may be used when monotherapy fails. Treatment options include adjunctive antipsychotic medications, mood stabilizers, selective serotonin reuptake inhibitors, glycinergic agents, and electroconvulsive therapy. The evidence favoring one augmentation strategy over another is lacking; overall, adjunctive therapy is associated with only modest clinical improvement. Moreover, case series and open-labeled clinical trials dominate the extant literature, and there is a dearth of double-blind trials comparing these augmentation agents. Current systematic efforts to enhance the treatment of these patients with adjunctive therapies are worthy of being studied in carefully conducted clinical trials.

Association of Disrupted in Schizophrenia 1 (DISC1) missense variants with ultra-resistant schizophrenia

“…These latter patients, who do not respond to clozapine either, are considered to have 'super-refractory' or ultra-resistant schizophrenia (URS). [9][10][11] In contrast with patients who at least partially respond to antipsychotic medications (including those who respond to clozapine), patients with URS continue to experience moderate-to-severe persistent positive psychotic symptoms and no social and/or occupational remission in spite of treatment with clozapine and at least two periods of treatment with conventional or atypical antipsychotic drugs. Such patients represent a challenge for understanding the mechanisms behind schizophrenia and the response to antipsychotic drugs as well as a major social and economic burden.…”

“…Such patients represent a challenge for understanding the mechanisms behind schizophrenia and the response to antipsychotic drugs as well as a major social and economic burden. 9 After reviewing the literature, we have proposed operational clinical and biological criteria derived from Kane's definition of treatment-resistant schizophrenia and standards defining eligibility to clozapine augmentation strategies. 5,10 In an attempt to improve therapeutic response by personalizing antipsychotic treatment, pharmacogenetics aims to identify the underlying mechanisms of treatment resistance.…”

Augmentation Strategies in Patients with Schizophrenia Who Show Partial Response to Clozapine Treatment

“…1999, Anıl ve ark. 2002.Bu hastalar klozapin tedavisine dirençli veya yüksek dirençli şizofreni hastaları olarak adlandırılır (Buckley ve ark. 2001, Williams ve ark.…”

Clinical aspects of super-refractory schizophrenia: a 6-month cohort observational study

“…Such patients are known as Clozapine resistant, incomplete responders 4 or having Super Refractory Schizophrenia (SRS). 5 Patients with SRS have been the subject of a number of studies, mainly through small clinical trials where several Clozapine augmentation strategies were tested, such as association with antipsychotics, antidepressants or mood stabilizers. [4][5][6] However, the main mechanism that underlies SRS remains largely unknown, and only a few studies have addressed this issue using different methodological perspectives.…”