Tips for Overcoming Clozapine Resistance
There are several steps you can take when you find your psychosis patients are not responding adequately to clozapine therapy.
Clozapine is often referred to as a “gold-standard” medication for treatment-resistant psychosis; however, estimates suggest that at least 40 percent of patients treated with clozapine do not show an adequate response (at least a 20 percent reduction in their Positive and Negative Syndrome Score [PANSS] or similar assessment) (1). Given that 1 in 3 people with psychosis fails to respond to initial antipsychotic therapies before being prescribed clozapine, this means that 1 in 8 psychosis patients will have a refractory illness that will fail to respond to first-line treatments and clozapine.
Here at the British Columbia Psychosis Program at the University of British Columbia Hospital in Vancouver, we see many patients with this refractory disorder; half of the patients who arrive at our inpatient treatment center are already on clozapine. We therefore developed a structured approach to treat this population, combining our own clinical experience with a thorough review of the literature.
The first step is to ensure that a patient has received an adequate dose of clozapine, as reflected by a plasma concentration of at least 1,070 nM/L, for 8 to 12 weeks (2). If the patient is a rapid clozapine metabolizer (due to genetic makeup or because he or she is a heavy smoker), we augment the clozapine with 25 mg to 50 mg of fluvoxamine since it can inhibit cytochrome 1A2 and slow down drug metabolism. Although this strategy can complicate treatment, the hospital setting allows us to closely monitor the patient.
If psychosis persists despite an adequate clozapine trial, the most efficient next step is electroconvulsive therapy (ECT). Although a 2016 study by Petrides et al. found that roughly half of clozapine-resistant patients respond to ECT (3), it can be challenging to convince patients with paranoia that ECT is the best treatment option. Furthermore, maintenance ECT is sometimes required to avoid relapse.
If ECT is ineffective or the patient refuses, the next step is often pharmacological augmentation of clozapine with the anticonvulsant topiramate. In a recent meta-analysis, 150 mg of topiramate was associated with improvements in positive psychotic symptoms while also helping reduce the weight gain and metabolic problems associated with clozapine (4). Low-dose aripiprazole (10 mg to 15 mg) might offer the same benefits, though the evidence for this agent is less robust (5).
Sulpiride is one other possibility, though this medication is not generally available in North America. In Canada, sulpiride can be imported for a patient if the need is justified to Health Canada (the equivalent of the Food and Drug Administration), but this approval process may take several months. Moreover, evidence from randomized trials in favor of sulpiride augmentation is modest, but this is true for all interventions in this population (6).
The last step of our approach is augmentation with cognitive-behavioral therapy (CBT). The BC Psychosis Program is fortunate to have a trained, onsite psychologist readily available, which allows patients the opportunity to receive CBT as part of their treatment plan. However, not every hospital or community-based treatment center has access to CBT, and the evidence for efficacy in the refractory population is limited, which is why we place it as the last step in the plan. (7)
We recently did a retrospective evaluation of 19 patients with schizophrenia or schizoaffective disorder for whom we applied this approach. Many of these patients had total PANSS scores over 100 and Clinical Global Impression scores of 6.3 (on a 1-7 scale) upon arrival, so this was a severely ill group. At discharge, their scores for both these scales had dropped about 20 percent, which is in the clinically adequate range.
These findings are encouraging; once we have data on more patients, we will have more statistically relevant conclusions. ■
1. Lee J, Takeuchi H, Fervaha G, et al. Subtyping Schizophrenia by Treatment Response: Antipsychotic Development and the Central Role of Positive Symptoms. Can J Psychiatry. 2015;60:515-522.
2. Treatment Resistant Schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) Working Group Consensus Guidelines on Diagnosis and Terminology. Am J Psychiatry. 2017;174(3):216-229.
3. Petrides G, Malur C, Braga RJ, et al. Electroconvulsive Therapy Augmentation in Clozapine-Resistant Schizophrenia: A Prospective, Randomized Study. Am J Psychiatry. 2015; 172:52-58.
4. Zheng W, Xiang YT, Xiang YQ, et al. Efficacy and Safety of Adjunctive Topiramate for Schizophrenia: A Meta-Analysis of Randomized Controlled Trials. Acta Psychiatr Scand. 2016;134(5):385-398.
5. Srisurapanont M, Suttajit S, Maneeton N, and Maneeton B. Efficacy and Safety of Aripiprazole Augmentation of Clozapine in Schizophrenia: A Systematic Review and Meta-Analysis of Randomized-Controlled Trials. J Psychiatr Res. 2015;62:38-47.
6. Wang J, Sampson S. Sulpiride Versus Placebo for Schizophrenia. Cochrane Database Syst Rev. 2014(4).
7. Barretto EM, Kayo M, Avrichir BS, et al. A Preliminary Controlled Trial of Cognitive Behavioral Therapy in Clozapine-Resistant Schizophrenia. J Nerv Ment Dis. 2009;197(11):865-868.
Randall F. White, M.D., is a clinical professor of psychiatry at the University of British Columbia in Vancouver, and medical director of the BC Psychosis Program