Addressing negative symptoms of schizophrenia pharmacologically with cariprazine: evidence from clinical trials, a real-world study, and clinical cases

KEYWORDS:

• Schizophrenia
• negative symptoms
• psychopharmacotherapy
• antipsychotic

In a recent issue of Expert Opinion on Pharmacotherapy (2021), Joshua T. Kantrowitz posed the important question ‘How do we address treating the negative symptoms of schizophrenia pharmacologically?’ [1]. The editorial summarized the available evidence regarding approved medications by the Food and Drug Administration (FDA) as well as treatments targeting the glutamatergic, serotonergic and cholinergic receptors before providing an expert opinion on the matter: ‘At present, the choices for persistent negative symptoms treatment are limited. Currently available options include a time-limited trial of cariprazine or an antidepressant, with a switch to olanzapine or clozapine if improvement is not noted within a few months.’ [1]. While we do agree with many of the statements of the author, there are certain aspects regarding the novel antipsychotic medication, cariprazine, we feel are needed to be taken into consideration.

Cariprazine is a third-generation antipsychotic agent with a unique mechanism of action approved for the treatment of schizophrenia as well as bipolar I disorder (manic or mixed and depressive episodes) by the FDA. In contrast to other antipsychotic medications that are dopamine D₂ receptor antagonists, cariprazine is a dopamine D₃ receptor preferring D₃/D₂ receptors partial agonist in vitro as well in vivo, as shown by data acquired via positron emission tomography [2,3]. In fact, cariprazine’s potency for the D₃ receptor is higher than what is exhibited by dopamine itself, which in turn leads to a full D₃ receptor occupancy at clinically relevant doses [2]. Research has shown that alterations in dopamine D₃ receptor activity are a major contributor to the pathogenesis of negative symptoms in schizophrenia [4]. Indeed, the overexpression of D₃ receptors in the striatum in mice was found to disrupt incentive motivation [5], which is one of the five core domains of negative symptoms (avolition, anhedonia, asociality, alogia, blunted affect) [6].

As mentioned in the editorial, two recent meta-analyses have addressed and compared the efficacy of different antipsychotic medications on alleviating negative symptoms in schizophrenia [7,8]. In agreement with the author [1], we also believe that the results of the meta-analysis Huhn et al. should be interpreted with caution as the studies included were conducted with acutely ill patients and no criteria regarding negative symptoms were present [7]. Thus, effect sizes acquired might reflect more the improvements in secondary negative symptoms (negative symptoms that are secondary to positive or affective symptoms, antipsychotic side effects such as extrapyramidal symptoms or sedation [6]) rather than primary negative symptoms [1,7]. The other meta-analysis by Krause and colleagues however did focus on trials that included patients with predominant negative symptoms and according to the findings, a standardized mean difference (SMD) of −0.47 was detected for amisulpride based on four studies, and −0.29 for cariprazine based on one study [8]. However, what has been not pointed out in this editorial, is the fact that the four studies with amisulpride were conducted in comparison with placebo, whereas the −0.29 SMD for cariprazine was in comparison to risperidone [8]. In fact, according to Leucht and Davis, cariprazine doubles the effect size compared with placebo in improving negative symptoms when adding together the two effect sizes (cariprazine vs risperidone 0.31 and antipsychotic vs placebo 0.42) in an indirect comparison [9]. Importantly, to date, cariprazine is the only antipsychotic medication that has been proven in a clinical trial to be more effective in alleviating negative symptoms of schizophrenia in patients with predominant negative symptoms than another antipsychotic medication [4,10].

Support from post-hoc analyses of data from two clinical trials with patients exhibiting acute exacerbation of schizophrenia and moderate or severe negative symptoms further confirms the statements above [11]. Results indicated that changes form baseline to week 6 in the Positive and Negative Syndrome Scale factor score for negative symptoms (PANSS-FSNS) were significantly different for cariprazine and risperidone, but not for aripiprazole compared to placebo [11]. Nonetheless, after adjusting for changes in positive symptoms, differences versus placebo remained statistically significant for cariprazine, but not for risperidone, suggesting that improvement in negative symptoms for cariprazine was at least partially independent of improvements in positive symptoms [11].

In addition, a real-world study has also confirmed the results of the Nemeth et al. trial recently [10]. A 16-week, open-label observation study conducted in Latvia found support for the notion that cariprazine has the ability to improve negative symptoms in schizophrenia patients with predominant negative symptoms who have been treated with antipsychotics previously but without sufficient response [12]. In this trial significant improvement in the five domains of negative symptoms were detected from week 2 onwards [12]. Furthermore, the severity of the disorder according to the Clinical Global Impression – Severity (CGI-S) scale changed from moderately to mildly ill [12]. Due to these results, over 70% of the physicians reported to be either ‘satisfied’ or ‘very satisfied’ with the effectiveness of cariprazine [12].

Further real-life support for the fact that cariprazine is an effective treatment option for negative symptoms associated with schizophrenia comes from clinical cases. To give an example, cariprazine monotherapy was successfully utilized in a female patient with severe negative symptoms [13]. According to the report, the patient showed impressive clinical improvement after a 52-week cariprazine treatment as confirmed by a 70% change from baseline in the PANSS-FSNS [13]. In another case by Müller and Moeller, a patient with cariprazine showed significant improvement after ineffective quetiapine and amisulpride treatment and stayed on the cariprazine for over 2 years without any indication of relapse [14].

As with other antipsychotic medications however, adverse events can also emerge with cariprazine. In the Németh et all study, 53% of patients reported at least one adverse event, which was lower than what was reported for patients taking risperidone (57%) [10]. The most common treatment emergent adverse events (TEAEs) with cariprazine were insomnia (9%) and akathisia (8%) [10]. Similar results were acquired in the Latvian observational study as well, where about 40% of patients had at least one TEAE; most commonly akathisia (13%), anxiety (10%) or parkinsonism (6%) [12]. Nonetheless, the physicians overall impression about tolerability was highly positive: 45% were very satisfied and 39% were satisfied with cariprazine [12].

All in all, based on the reviewed evidence, we are reluctant to agree with the above mentioned statement of this editorial stating that current treatment options include a ‘time-limited trial of cariprazine’ [1]. Time-limited trials (TLT) are defined as medical therapies that are utilized over a defined period in order to see if the patient improves or not [15]. They are usually initiated in intensive care units in cases where treatments have clearly delineated limitations [15]. Based on the presented clinical trials data, our view is that they adequately confirm the efficacy and safety of cariprazine both after short- and long-term treatment.

Declaration of interest

All authors are employees of Gedeon Richter Plc. The authors have 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.

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Funding

This manuscript was not funded.