Beyond the specifics of clozapine: a call for broader sample replication

We read with interest the article by Wolpe et al (2023),^{Reference Wolpe, Chen, Kirkpatrick, Jones, Jenkins and Cardinal1} in which the researchers study the association between negative symptoms and sedation secondary to antipsychotics. This is an important topic to advance clinical knowledge in the field.

This article raises two important topics. On the one hand, the researchers used patient-reported sleep hours as an indirect proxy for sedation produced by an antipsychotic. Although the authors provided ample and convincing reasoning for this choice in the article's supplementary materials, we believe it would also be interesting to analyse the relationship between negative symptoms and sleep hours produced exclusively during the day, since it is reasonable to think that they may have a greater impact on motivation and pleasure (MAP) than total sleep hours. One factor that could support this possibility is pharmacological treatment with modafinil, which has considerable evidence in the treatment of negative and cognitive symptoms of schizophrenia through an increase in daytime arousal.^{Reference Saavedra-Velez, Yusim, Anbarasan and Lindenmayer2}

On the other hand, and more importantly, we believe that studying patients treated with clozapine restricts the sample to a very specific subgroup: individuals with treatment-resistant schizophrenia. Such individuals have, at a group level, more prominent symptoms in the positive, negative and cognitive spheres, longer duration of illness, greater cumulative exposure to other antipsychotics and greater functional impairment.^{Reference Nucifora, Woznica, Lee, Cascella and Sawa3} All of this may have a direct as well as an indirect impact on the severity of negative symptoms, which is not convincingly studied in this article. Moreover, clozapine is one of the few drugs (and arguably the only one) that has consistently demonstrated improvement in negative symptoms^{Reference Siskind, McCartney, Goldschlager and Kisely4} (as corroborated by this article). This opens the door to postulate that, if this sedation could be effectively combatted, the beneficial effects of clozapine in this regard could be much broader, but it remains unclear whether the findings of this article might be exclusive of people with treatment-resistant schizophrenia or, rather, generalisable.

Another interesting aspect is that, according to the results of the linear mixed-effects model estimating the predictors of MAP, there is a statistically significant inverse correlation between the daily dose of clozapine and negative symptoms. As sedation associated with clozapine is a dose-dependent adverse effect,^{Reference Nielsen, Damkier, Lublin and Taylor5} this could suggest that there are other mediating factors in the relationship between these variables in this subgroup of patients.

For the above reasons, we believe it is highly relevant to replicate this study in a more representative sample, in order to study this relationship in a broad and generalisable way. This would also allow clarification as to whether the effectiveness of other more recent drugs that have shown evidence in the treatment of these symptoms (such as cariprazine^{Reference Bitter, Mohr, Raspopova, Szulc, Samochowiec and Micluia6}) could also be mediated by the (relative lack of) sedation they produce. If this were the case, the implications of this finding could be significant and open the door to the development of new pharmacological treatment strategies for these symptoms.