From the Guidelines
Clozapine is the most effective treatment for treatment-resistant schizophrenia, and it should be considered as the first-line treatment after two failed trials of other antipsychotic medications. According to the American Psychiatric Association practice guideline for the treatment of patients with schizophrenia 1, clozapine is recommended for patients with treatment-resistant schizophrenia. The guideline suggests that clozapine should be started at a low dose, typically 12.5-25mg daily, and gradually titrated up to an effective dose, usually between 300-450mg daily. Regular blood monitoring is mandatory due to the risk of agranulocytosis, with weekly blood tests for the first 6 months, then biweekly for 6 months, and monthly thereafter.
Some key points to consider when treating patients with treatment-resistant schizophrenia include:
- The importance of regular blood monitoring to minimize the risk of agranulocytosis
- The need to gradually titrate the dose of clozapine to minimize side effects
- The potential benefits of adding another antipsychotic or mood stabilizer to clozapine for patients who do not fully respond to clozapine alone
- The importance of integrating psychosocial interventions, such as cognitive behavioral therapy for psychosis, family therapy, and social skills training, with medication management for optimal outcomes
Recent studies have also explored the use of antipsychotic polypharmacy (APP) for the management of schizophrenia, with some studies suggesting that APP may be effective in reducing treatment side effects or residual symptoms in certain patient groups 1. However, the evidence for APP is still limited, and more research is needed to determine its safety and efficacy.
In terms of specific treatment strategies, the following may be considered:
- Adding another antipsychotic, such as risperidone (2-6mg daily) or aripiprazole (10-30mg daily), to clozapine for patients who do not fully respond to clozapine alone
- Using mood stabilizers, such as lamotrigine (100-200mg daily) or valproate (750-1500mg daily), in combination with clozapine
- Considering electroconvulsive therapy (ECT) for patients with persistent symptoms despite treatment with clozapine and other medications.
From the FDA Drug Label
1 INDICATIONS AND USAGE
- 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
- Treatment for treatment-resistant schizophrenia: Clozapine is indicated for the treatment of severely ill patients with schizophrenia who fail to respond adequately to standard antipsychotic treatment 2.
- Key points:
- Clozapine should be used only in patients who have failed to respond adequately to standard antipsychotic treatment.
- The effectiveness of clozapine in treatment-resistant schizophrenia was demonstrated in a 6-week, randomized, double-blind, active-controlled study comparing clozapine and chlorpromazine in patients who had failed other antipsychotics 2.
From the Research
Treatment Options for Treatment-Resistant Schizophrenia
- Clozapine is recognized as the most effective treatment option for treatment-resistant schizophrenia (TRS) 3, 4, 5
- Guidelines worldwide recommend clozapine as the first-line pharmacological agent for TRS 3, 5
- Response rates are higher when clozapine is initiated earlier in the treatment course 3
Administration and Monitoring of Clozapine
- Clozapine requires regular blood tests to screen for agranulocytosis 3, 4, 6
- Plasma leucocyte and granulocyte levels must be monitored weekly during the first 18-26 weeks of treatment, and regularly thereafter 3
- Therapeutic drug monitoring of clozapine trough plasma levels is helpful to guide dosing, with greatest efficacy at plasma clozapine levels ≥350 µg/L 3
Incidence of Agranulocytosis
- The incidence of agranulocytosis associated with clozapine is lower than previously estimated, with a reported incidence of 0.47% 6
- The risk of agranulocytosis may be related to the ability of clozapine to cause an immune response and affect neutrophil kinetics 7