Response to Joshi and Langley-Degroot

To the Editor: We would like to thank Drs. Joshi and Langley-Degroot (1) for their letter on our commentary and initiation of this discussion. In our commentary, published in the July 2016 issue of the Residents' Journal (2), we called for an increase in the effective use of clozapine for treatment-resistant schizophrenia via increased resident education. Specifically, we recommended the incorporation of clozapine clinics in psychiatric residency training programs. The goal of these programs would be to increase prescriber comfort and familiarity with the appropriate prescription of clozapine.

Drs. Joshi and Langley-Degroot raised a valid concern regarding superior efficacy and improved outcomes of clozapine in the wake of a network meta-analysis conducted by Samara et al. (3). Samara et al. reported that there is "little evidence of the superiority of clozapine compared with other second-generation antipsychotics in treatment-resistant schizophrenia among the randomized effectiveness studies" (3). However, there are some limitations of this network meta-analysis, which need to be carefully interpreted. We have highlighted several limitations that should be kept in mind when interpreting a meta-analysis or network meta-analysis.

A meta-analysis is as good as the included studies (4). A meta-analysis may not only inherit individual biases in the study but also include new biases because of the selection of the studies and heterogeneity among the included study populations and settings (4). A network meta-analysis allows assessment of the relative effectiveness of several treatment options across a network of randomized controlled trials even if no studies directly compared them (5). An important aspect of a network meta-analysis is that if there are inconsistencies between direct and indirect evidence, one should investigate the sources of inconsistency to explain the differences. Meta-regression has been used to explore imbalance distribution of effect modifiers (5). Samara et al. used meta-regression analysis with antipsychotic dose and trial reduction as moderator variables, which did not show any significant effect on treatment efficacy, but the statistical power of meta-regressions was markedly weak (6). This highlights an important aspect and limitation of their meta-analysis, wherein the dosage of clozapine in included randomized controlled trials and duration and the likelihood of underdosing in the industry-funded trials could have constituted a serious problem and affected the results (3). The limitations of the Samara et al. meta-analysis were explained well in their discussion (3). Thus, the results of their meta-analysis could indicate "a problem of the individual included randomized-controlled trials rather than of clozapine" (7). We agree with their conclusion regarding trials comparing clozapine with other second-generation antipsychotics among patients with treatment-resistant schizophrenia and using high-dosage clozapine (3).

Another important aspect of clozapine is the improvement in outcomes other than psychopathology change, such as decreased hospitalization, lower hospital readmissions, reduced suicide attempts, and reduction in the number and severity of aggressive incidents (8). The Samara et al. meta-analysis underscores the importance of not only appraising each trial separately but at the same time understanding the limitations of a meta-analysis or network meta-analysis.

The second point Drs. Joshi and Langley-Degroot raised is regarding the incorporation of exposure to clozapine initiation early in training. We agree with any approach that would be helpful in increasing residents' comfort level and familiarity with clozapine. And this is why we believe that a clozapine clinic could be one such option whereby residents could not only learn about this medication but also receive adequate experience in its use and management of its side effects. While we agree that establishing clozapine clinics in residency training programs would create significant challenges, we believe that the added educational value and exposure would benefit both resident prescribers and patients receiving clozapine. The problems arise when lack of experience with clozapine results in residents being either hesitant to appropriately prescribe clozapine or are undertrained in its safe use.

Unfortunately, current methods of familiarizing residents with clozapine may not be effective. We recently conducted a survey of 164 U.S. psychiatry residents regarding their comfort levels with the appropriate usage of clozapine (9). The results of this survey showed that 41% of resident respondents did not feel comfortable prescribing clozapine. This number is worrying, as it indicates that a significant portion of the future generation of psychiatrists is uncomfortable with the use of one of the most effective treatments in our field. We feel that clozapine clinics may provide a solution to this problem, and most U.S. psychiatry residents appear to share this sentiment. When the residents in our survey were asked whether they would feel more comfortable prescribing clozapine if trained in a clozapine clinic, 83% agreed.

In summary, we agree with Drs. Joshi and Langley-Degroot that there are certain limitations to clozapine treatment and that the incorporation of clozapine clinics in residency training programs would be a difficult task. However, we also believe that there is a concerning lack of familiarity with clozapine among psychiatric residents and that this is a problem that needs to be addressed.