Treating difficult-to-treat psychosis: Comments on Siskind et al. (2018)

To the Editor

Despite clozapine being the pharmacological agent of choice in treatment-resistant schizophrenia (Galletly et al., 2016), approximately 60% of patients trialled on this medication will have suboptimal clinical response (Siskind et al., 2018). The systematic review by Siskind et al. (2018) addresses the important question of clozapine augmentation strategies and was thorough in its consideration of both pharmacological and non-pharmacological interventions. The consideration of augmentation strategies was broad including electroconvulsive therapy and cognitive behaviour therapy, in addition to nutraceuticals and more novel pharmacological agents such as Ginkgo Biloba, memantine and minocycline. Their review comprehensively summarises the current evidence base and is of relevance to clinicians where augmentation is commonly trialled in the absence of clear guidance.

However, the study also has some important limitations that need to be considered. The array of well-planned a priori analyses (e.g. subgroup analyses for setting, mean dose of augmentation agent and clozapine levels) could not be conducted due to the lack of relevant data available from source materials. As such, the conclusions relating to ‘best evidence’ cannot be relied upon as definitive guidance. There is a clear need for high-quality clinical trials of promising augmentation strategies to be undertaken. Another issue to consider is the reviews’ high proportionate emphasis on low-quality studies from the Chinese database (16 out of 46 included studies). Clozapine use in China may follow a very different pattern to that in other parts of the world (Wang and Li, 2012). While the inclusion of the Chinese studies was considered to be a strength of the study by the authors, we wonder if this may have compromised the clinical relevance of this review to Australasia. Finally, the review failed to consider potential concurrent substance misuse, a ubiquitous challenge in day-to-day clinical practice. All of these factors impact the utility of the study’s findings.

Despite these limitations, we opine that review reflects a landmark study with high clinical relevance. It highlights the dearth of robust research that exists regarding this clinically common predicament. We thank the authors for providing a substantial foundation for future research. There is a clear need to systematically investigate the real-life effectiveness of clozapine augmentation strategies that we trial almost daily. We need to generate more robust research data in so that the decisions we make are based on evidence, not on anecdotal experience and site-specific cultural practice alone.