Additional perspective on cariprazine and negative symptoms

KEYWORDS:

• Cariprazine
• negative symptoms
• schizophrenia
• pharmaceuticals
• effect sizes

Dear Editor, I appreciate the enthusiasm that Dr Nemeth et al. express for the compound cariprazine in Nemeth et al. [1]. In particular, the authors should be enthusiastic about their trial demonstrating that cariprazine shows significant improvement for predominant negative symptoms relative to an active comparator (risperidone). Due to a focus on a wider review of the investigational and marketed treatment landscape for negative symptoms and my journal-specified limitation in citations, this trial was discussed, but not directly cited in my review [2]. Indeed, as Nemeth et al. note, most negative symptoms targeting trials of D₂R antipsychotics, including the discussed trials of amisulpride, compare with placebo and not an active compound. Thus, as Nemeth et al. note, in [3], cariprazine showed benefits over and above any potential benefits of risperidone.

Nevertheless, several of the points raised by Nemeth et al. bear further discussion and rebuttal. In my editorial [2], I specifically reviewed, singled out and recommended a trial of cariprazine as a treatment for negative symptoms in schizophrenia. This recommendation is consistent with other expert guidance [4]. Nemeth et al. appear to feel that a stronger recommendation is warranted but unfortunately offers limited additional support beyond several case reports, an open-label study, and a post hoc analysis of two acute phase clinical trials [5]. Many other antipsychotics can offer a similar level of additional evidence (see references [6–9] for examples), and it is unclear why these additional reports should move the needle over and above the double-blind report [3]. In particular, while the post hoc analysis does further narrow the sample to create a more homogenous group with negative symptoms [5], it is limited by the enrollment criteria of acutely exacerbated symptoms, raising a concern of pseudospecificity of improvement in extrapyramidal side effects, paranoia-induced withdrawal, or depression.

The strongest evidence for cariprazine having unique efficacy comes from the previously discussed comparison with risperidone [3]. Nevertheless, this study has several limitations, which must be considered if the evidence is fully weighted. As noted by Krause et al., this is a single trial ‘sponsored by cariprazine’s manufacturer’ [10] and has not been independently replicated. While I agree with Krause et al. on the significance of this study, study sponsorship is a known source of potential bias [11], and pharma sponsored studies are ‘strongly associated with results that favour the sponsors’ interests’ [12].

Moreover, while showing superiority over and above risperidone is a strength, Krause et al. also note that ‘placebo-controlled evidence is lacking.’ Thus, while the comparison of risperidone vs cariprazine is a strength, the lack of placebo-controlled evidence for cariprazine in a predominant negative symptoms group is also a limitation. This limitation is highlighted by the suggestion by Nemeth et al. that Leucht and Davis [13] explicitly recommend that the small effect size of cariprazine vs risperidone (0.31) can be added to the overall standardized mean difference (SMD) effect sizes of antipsychotics vs placebo (0.42), essentially ‘doubling’ the effect size. This assertion by Nemeth et al. is at best misleading, as in the next sentence [13], Leucht and Davis note that ‘However, this comparison is indirect, and therefore very prone to bias.’ Even if one would fully agree in principle with this concept, a more accurate comparison would be adding the effect size for negative symptoms vs placebo of cariprazine itself (0.31) or risperidone (0.37) [14]. Moreover, all of these potentially additive effect sizes vs placebo are taken from trials of acutely exacerbated patients [14] and have the aforementioned limitations. Moreover, while this may be a smaller concern for use in patients with predominant negative symptoms, for overall symptoms, cariprazine has a modest effect size of 0.34 vs placebo, on the lower end of overall efficacy.

Cariprazine’s modest effect size is somewhat balanced by improved tolerability [15], particularly for weight gain. Cariprazine ranks near to lower end of weight gain offenders, showing a mean 0.73 kg in an acute study meta-analysis, compared with 1.89 kg for clozapine and 2.78 kg for olanzapine [14]. Of note, these weight gain comparisons may be more clinically relevant than the small difference in adverse events compared with risperidone cited by Nemeth et al.

Finally, Nemeth et al. were ‘reluctant to agree with’ the recommendation of a ‘time limited trial of cariprazine … with a switch to olanzapine or clozapine if improvement is not noted within a few months.’ Nemeth et al. are correct that the term ‘time-limited’ is common in intensive care unit (ICU) literature [16], but even in this literature, the full definition of time-limited refers to ‘an agreement between clinicians and a patient/family to use certain medical therapies over a defined period to assess if the patient improves or deteriorates according to agreed-on clinical outcomes. If the patient improves, disease directed therapy continues.’ This principle is not specific to the ICU, nor is it specific to cariprazine, and avoids keeping people on ineffective therapies indefinitely. It is unclear why the recommendation to switch treatments if no improvement is noted within a few months is something Nemeth et al. are reluctant to agree with.

Expert opinion

In summary, as initially stated in [2], I agree with Nemeth et al. that cariprazine is one of the few marketed options that has demonstrated specific benefits for predominant negative symptoms in schizophrenia in double-blind trials. Additional direct placebo-controlled comparisons of D₂R and novel mechanism antipsychotics would be beneficial, as would independent replication of the cariprazine effects on predominant negative symptoms. Based on the current available evidence, assuming tolerability and continued control of positive and overall symptoms, a time-limited, up to six-month trial of cariprazine seems prudent. After that, the subject should be assessed for the risk-benefit ratio of continued treatment with cariprazine, as they should with any treatment.

Declaration of interest

JT. Kantrowitz reports having received consulting payments within the last five years from Alphasights, Charles River Laboratories, Medscape, Putnam, techspert.io, Third Bridge, MEDACorp, Parexel, groupH, Simon Kucher, the ECRI Institute, ExpertConnect, Schlesinger Group, CelloHealth, Acsel Health, Strafluence, Guidepoint, L.E.K., System Analytic, Kinetix Group, Slingshot, Smart Analyst, Transperfect, Anthem, Semantics MR LTD, BVF Partners, LifeSci Capital, Piper Jaffray, IQVIA, and Krog & Partners Incorporated. Furthermore, he has served on the advisory board of Alkermes Aristada Schizophrenia, MedinCell Psychiatry, the Karuna Mechanism of Action (MOA). He has conducted clinical research supported by the National Institute of Mental Health (NIMH), Sunovion, Eli Lilly and Company, Alkermes, Roche, Cerevance, Corcept, Takeda, Taisho, Lundbeck, Boehringer Ingelheim, NeuroRX, and Teva within the last five years. Dr Kantrowitz was a co-investigator on a study that receives lumateperone and reimbursement for safety testing for an investigator-initiated research from Intra-Cellular Therapies Inc. He also owns a small number of shares of common stock from GlaxoSmithKline. He has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This manuscript was not funded.