Can Australian psychiatrists prescribe clozapine off-label for treatment-refractory bipolar disorder?

To the Editor

The recent Royal Australian and New Zealand College of Psychiatrists (RANZCP) Guidelines (Malhi et al., 2015) for mood disorders supported clozapine’s use in treatment-refractory bipolar disorder (TRBD). The Guidelines noted that ‘Despite a lack of RCT evidence, clozapine is widely regarded as an option for treating severe refractory bipolar disorder’ (p. 1133). However, the Guidelines presented a major dilemma for psychiatrists as they also stated that the clozapine patient monitoring service (CPMS) would not allow prescription for any condition apart from schizophrenia.

The authors recognise the significance of the Guidelines recommending clozapine, having recently commented that the National Institute for Health and Care Excellence (NICE) Guidance was deficient in not including clozapine as an option for TRBD based on the evidence from 15 clinical trials that included 1044 patients (Bastiampillai et al., 2016). Clozapine might be the best antipsychotic medication for TRBD with unique mood-stabilising and anti-suicidal properties (Bastiampillai et al., 2016). Given the continuum that exists between schizo-affective disorder and schizophrenia, we would also suggest that clozapine be considered for treatment-refractory schizo-affective disorder.

In the context of these findings, we personally contacted the Australian CPMS and Novartis pharmaceuticals to determine whether clozapine could be monitored and prescribed off-label for TRBD. CPMS informed us that they would monitor any patient prescribed clozapine irrespective of the indication. Novartis who distribute clozapine stated that they did not ‘endorse’ the use of clozapine beyond treatment-resistant schizophrenia, but the decision to use clozapine off-label ultimately rested with both the clinician and the patient.

The role of worldwide clozapine regulatory and monitoring systems is to focus on reducing the risks of clozapine-induced agranulocytosis. When clozapine is prescribed off-label based on guideline recommendations for TRBD and schizo-affective disorder or randomised controlled trial (RCT) evidence for l-Dopa-induced psychosis (The Parkinson Study Group, 1999), these diagnoses should be recorded within the CPMS. This diagnostic recording would enable the systematic evaluation of clinical and safety outcomes for clozapine’s use beyond schizophrenia.

The RANZCP Guidelines also note that the Pharmaceutical Benefits Scheme does not give authority to prescribe clozapine for bipolar. Hence, the medication needs to be funded by either state mental health services or privately. Considering the demands and costs from TRBD, funding clozapine might prove cost-effective for state mental health services.

Due to clozapine’s current tightly restricted indications and a lack of clinician awareness of this option, many patients are being denied the opportunity to benefit from the medication’s potentially unique properties. In the light of the RANZCP Guidelines, these issues need to be addressed from the educational, policy and regulatory perspectives.