What can clinicians do when individuals have either a partial or no response to clozapine?

Although clozapine has a unique efficacy for individuals with treatment resistant schizophrenia, some individuals may have enduring positive, negative, or cognitive symptoms of the illness. Up to 60% of individuals may have an incomplete response of symptoms to clozapine.  When individuals do not fully respond to clozapine, this condition is called clozapine-resistant or ultra-resistant schizophrenia. View the Treatment Response and Resistance in Psychosis (TRRIP) guidelines for definitions of treatment resistant schizophrenia and ultra-treatment resistant schizophrenia.

Prior to considering augmentation strategies, prescribers should first ensure that clozapine has been optimized. First, clinicians should ensure the clozapine level is greater than 350 ng/mL and that clozapine has been increased to the highest level that is tolerable with regard to side effects. Consider using a measurement-based care approach to track the most meaningful outcomes to you and your patient (e.g., symptoms and functioning over time). Clinicians should add evidence-based psychosocial interventions for schizophrenia such as cognitive-behavioral therapy for psychosis, supported employment, assertive community treatment, or social skills training. About half of patients improve with the use of electroconvulsive therapy for clozapine augmentation. Multiple psychopharmacological interventions have been studied to augment clozapine, but few interventions have been consistently shown to be effective in high-quality studies. A meta-analysis (Siskind et al, 2018) suggests the interventions with the greatest efficacy for symptoms were aripiprazole and sodium valproate. There was some evidence to support memantine for negative symptoms. There was limited data to support the use of adding another first-generation antipsychotic medication, lamotrigine, or topiramate. These findings should be interpreted with caution, and augmentation strategies should be considered on a case-by-case basis, carefully weighing the risks and benefits of each option.

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