From the Guidelines
For patients with clozapine-resistant schizophrenia, the most evidence-supported approach is augmentation of clozapine with a second antipsychotic, particularly aripiprazole, as combining aripiprazole with clozapine may be effective in reducing treatment side effects or residual symptoms, as suggested by 1 and 1.
Treatment Options
When considering treatment options for patients with clozapine-resistant schizophrenia, several strategies can be employed:
- Augmentation of clozapine with a second antipsychotic, such as aripiprazole, which has been shown to be effective in reducing treatment side effects or residual symptoms 1
- Electroconvulsive therapy (ECT) combined with clozapine, which has demonstrated significant efficacy in some cases
- Other medication augmentation strategies, including adding mood stabilizers like lamotrigine or sodium valproate, or glutamatergic agents such as memantine
- Antidepressants, particularly SSRIs, may help with negative symptoms
- Cognitive behavioral therapy should be considered alongside pharmacological approaches
Key Considerations
- Treatment should be individualized based on symptom profile, side effect history, and patient preference, with careful monitoring for adverse effects, particularly when combining medications with clozapine
- Antipsychotic polypharmacy may be considered and discussed with patients from whom the aforementioned procedures do not produce a satisfactory treatment result, as suggested by 1 and 1
- The use of antipsychotic polypharmacy may be associated with a reduced risk of psychiatric hospitalization and all-cause mortality, as shown in some studies 1
Evidence-Based Recommendations
The most recent and highest quality studies, such as those published in 2021 1, provide evidence for the effectiveness of antipsychotic augmentation and other treatment strategies in patients with clozapine-resistant schizophrenia. These studies suggest that combining aripiprazole with clozapine may be a viable option for reducing treatment side effects or residual symptoms. However, it is essential to carefully weigh the potential benefits and risks of each treatment approach and to individualize treatment based on patient-specific factors.
From the FDA Drug Label
- 1 Treatment-Resistant Schizophrenia Clozapine tablets are indicated for the treatment of severely ill patients with schizophrenia who fail to respond adequately to standard antipsychotic treatment Because of the risks of severe neutropenia and of seizure associated with its use, clozapine tablets should be used only in patients who have failed to respond adequately to standard antipsychotic treatment
For patients with clozapine-resistant schizophrenia, the FDA drug label does not provide specific treatment options. The label indicates that clozapine is used for treatment-resistant schizophrenia, but it does not address what to do if a patient fails to respond to clozapine.
- Key points:
- Clozapine is indicated for severely ill patients with schizophrenia who have failed standard antipsychotic treatment.
- No specific treatment options are provided for patients who fail to respond to clozapine.
- The label emphasizes the risks associated with clozapine use, including severe neutropenia and seizures. 2 2
From the Research
Treatment Options for Clozapine-Resistant Schizophrenia
The treatment of clozapine-resistant schizophrenia (CRS) is a challenging clinical situation, with approximately 40%-70% of patients having a poor response to adequate treatment with clozapine 3. Several treatment options have been proposed, including:
- Augmentation strategies with other medications, such as antipsychotics, antidepressants, and mood stabilizers 4, 5
- Electroconvulsive therapy (ECT) as an augmentation to clozapine 6, 7
- Combination of clozapine with other antipsychotics, such as amisulpride and aripiprazole 4
- Psychosocial interventions, such as cognitive-behavioral therapy 4
Augmentation Strategies
Augmentation strategies with other medications have shown limited efficacy in treating CRS. A study found that antipsychotics, antidepressants, mood stabilizers, and ECT were mostly ineffective in augmenting clozapine response 3. However, another study found that augmentation with ECT was a safe and effective treatment option, with 50% of patients meeting the response criterion 6.
Electroconvulsive Therapy
ECT has been shown to be a effective augmentation strategy for CRS. A study found that ECT combined with clozapine was effective in reducing symptoms in patients with treatment-resistant schizophrenia 6. Another study found that ECT combined with two antipsychotics, clozapine and aripiprazole, was effective in achieving rapid alleviation of positive and negative symptoms 7.
Combination Therapy
Combination therapy with clozapine and other antipsychotics has also been proposed as a treatment option for CRS. A study found that combination of clozapine with amisulpride or oral aripiprazole achieved consensus as a treatment option for clozapine-refractory positive symptoms 4.
Psychosocial Interventions
Psychosocial interventions, such as cognitive-behavioral therapy, have also been proposed as a treatment option for CRS. A study found that cognitive-behavioral therapy reached consensus as a treatment option for CRS 4.
Optimization of Clozapine Treatment
Optimization of clozapine treatment has also been proposed as a way to prevent clozapine resistance from developing. This includes personalized dosing, adequate treatment durations, management of side effects and non-adherence, collaboration with patients and caregivers, and addressing clinician barriers to clozapine use 3.