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 to clozapine. When individuals do not fully respond to clozapine, this condition is called clozapine-resistant or ultra-resistant schizophrenia. Please click here to 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 > 350 ng/mL and that clozapine has been increased to the highest level that is tolerable with regard to side effects. Also, a small group benefits more slowly, and can require up to six months on a clozapine dosage. Consider using a measurement-based care approach to track the most meaningful outcomes to you and/or your patient (i.e., functioning over time or a specific symptom). Depending on their availability locally, 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. Multiple psychopharmacological interventions have been studied to augment clozapine, but few interventions have been consistently shown to be effective in high-quality studies. There is some data to support the role of electroconvulsive therapy for clozapine augmentation. 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 in 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.