Clozapine resistant schizophrenia: Newer avenues of management

Abstract

About 40%-70% of the patients with treatment-resistant schizophrenia have a poor response to adequate treatment with clozapine. The impact of clozapine-resistant schizophrenia (CRS) is even greater than that of treatment resistance in terms of severe and persistent symptoms, relapses and hospitalizations, poorer quality of life, and healthcare costs. Such serious consequences often compel clinicians to try different augmentation strategies to enhance the inadequate clozapine response in CRS. Unfortunately, a large body of evidence has shown that antipsychotics, antidepressants, mood stabilizers, electroconvulsive therapy, and cognitive-behavioural therapy are mostly ineffective in augmenting clozapine response. When beneficial effects of augmentation have been found, they are usually small and of doubtful clinical significance or based on low-quality evidence. Therefore, newer treatment approaches that go beyond the evidence are needed. The options proposed include developing a clinical consensus about the augmentation strategies that are most likely to be effective and using them sequentially in patients with CRS. Secondly, newer approaches such as augmentation with long-acting antipsychotic injections or multi-component psychosocial interventions could be considered. Lastly, perhaps the most effective way to deal with CRS would be to optimize clozapine treatment, which might prevent clozapine resistance from developing. Personalized dosing, adequate treatment durations, management of side effects and non-adherence, collaboration with patients and caregivers, and addressing clinician barriers to clozapine use are the principal ways of ensuring optimal clozapine treatment. At present, these three options could the best way to manage CRS until research provides more firm directions about the effective options for augmenting clozapine response.

Place of the partial dopamine receptor agonist aripiprazole in the management of schizophrenia in adults: a Delphi consensus study

“…Perhaps up to half of patients with treatment-resistant schizophrenia (TRS) do not respond satisfactorily to clozapine [ 129 ] and these patients often have particularly severe disease [ 130 ]. Although a number of strategies have been proposed for treating patients with TRS who do not respond to clozapine, including augmentation with other antipsychotics, there is no consensus on which strategy represents the most beneficial approach [ 131 – 133 ]. Augmentation with aripiprazole may be of interest in this context.…”

Difference between treatment-resistant schizophrenia and clozapine-resistant schizophrenia

“…We read the impressive review article by Chakrabarti[ 1 ] with great enthusiasm and appreciation. The author suggests that clinicians need newer treatment approaches that go beyond the evidence for patients with clozapine-resistant schizophrenia (CRS).…”

“…The TRRIP Work Group also recommend a minimum dose of 500 mg/d for patients who cannot undergo the blood test for clozapine concentration[ 2 ]. In the review article[ 1 ], the recommended adequate dose of clozapine is 200 to 500 mg/d, which may be low for patients with CRS.…”

“…Besides, when pooling available evidence for the management of CRS, we need to include studies that specifically addressing patients with a valid diagnosis of CRS. For example, Chakrabarti[ 1 ] cited a study by Masoudzadeh and Khalillian[ 3 ] who compared three interventions for patients with TRS, namely, clozapine, electroconvulsive therapy (ECT), and combined clozapine and ECT. In this study, a 40% reduction in the Positive and Negative Syndrome Scale scores was observed in patients who were treated with only clozapine[ 3 ].…”

Third-generation antipsychotics in patients with schizophrenia and non-responsivity or intolerance to clozapine regimen: What is the evidence?

“…The Treatment Response and Resistance in Psychosis (TRRIP) Working Group defined URS as the persistence of moderate to severe positive, negative, or cognitive manifestations in patients diagnosed with schizophrenia, after an adequate period of clozapine administration ( 7 ). Other definitions include dose range of clozapine between 200 and 500 mg/day, blood levels of clozapine ≥ 350 ng/mL, ≥ 2 months of treatment administration, with ≥ 80% of prescribed doses administered during the monitored period, moderate baseline levels of functional impairment assessed by standardized scales, moderately severe symptoms of psychosis assessed by validated instruments, less than 20% reduction of symptoms during the trial, and persistence of moderately-severe clinical manifestations and dysfunctions after the clozapine administration ( 5 ). Still, other authors include in the definition of URS more accurate limits, i.e., persistent moderately-severe BPRS total scores (≥ 45) and at least two to four positive symptoms on BPRS of ≥ 4 (moderate severity), at least a moderate score (≥ 4) on CGI scale, and persistence of GAF ≤ 40 during the last 5 years ( 8 ).…”