The prospects of cariprazine in the treatment of schizophrenia

Introduction

In 2015, the United States Food and Drug Administration approved cariprazine for the treatment of schizophrenia. As cariprazine joins a growing field of effective antipsychotic agents, questions arise regarding its prospects for clinical utility. Greater potential for treating negative symptoms, anti-abuse potential, and a long half-life create cautious optimism that cariprazine has potential to be a unique and preferred treatment for select patients with schizophrenia.

Background

Schizophrenia is a chronic psychotic illness characterized by both positive and negative symptoms, resulting in significant impairment. Pathophysiology is associated with abnormalities in interconnected systems of neurotransmitters, primarily dopamine and serotonin, although histamine, glutamate, and gamma-aminobutyric acid (GABA) have been implicated as well. Typical antipsychotics such as haloperidol reduce positive symptoms by antagonism of the D₂ receptor in the mesocortical pathway, but its blockade of D₂ receptors elsewhere results in undesirable side effects such as cognitive impairment, Parkinsonism, and hyperprolactinemia. Furthermore, typical antipsychotics do not ameliorate, and may exacerbate, negative symptoms such as apathy, social withdrawal, and anhedonia. Atypical antipsychotics such as risperidone are preferred because they reduce positive and negative symptoms by antagonism of D₂ and serotonergic 5-HT_2A receptors. ¹ However, they are associated with metabolic adverse effects, such as hyperlipidemia, diabetes mellitus, and weight gain. Dopaminergic partial agonists such as aripiprazole may decrease dopaminergic overactivity (thus reducing positive symptoms) and increase dopaminergic underactivity (thus improving negative or cognitive symptoms), all while maintaining a favorable metabolic profile. ¹

Cariprazine is similar to newer antipsychotics in several ways. It demonstrated efficacy in acute exacerbations and maintenance treatment while displaying tolerability and safety. During these studies it maintained a favorable metabolic profile, a limited number of adverse effects, and a low discontinuation rate. ² It was also effective in reducing hostility, independent of the presence or absence of sedation. ³ Like aripiprazole and brexpiprazole, cariprazine is a partial agonist at dopamine D₂ and D₃ and serotonin 5-HT_1A receptors, an antagonist at serotonergic 5-HT_2B receptors, and displays little affinity at other receptor subtypes. ⁴ However, certain characteristics may confer some therapeutic advantage for cariprazine compared with other antipsychotics.

Advantages

In contrast with the other dopamine partial agonists, cariprazine exerts a preference for D₃ receptors, which may be beneficial for reducing negative symptoms. In a comparison trial with risperidone, rats that experienced phencyclidine (PCP)-induced cognitive impairments (recognition memory, reversal learning, social interaction, and rule learning) experienced improvements in these deficits after receiving cariprazine. ⁵ Furthermore, cariprazine demonstrated superiority to risperidone in attenuating social behavior deficits. ⁵ In another trial comparing cariprazine with aripiprazole, rodents which received PCP combined with social isolation demonstrated abnormal locomotor activity and impairments in novel object recognition, conditioned freezing response, and social interactions. Although both medications attenuated the neurodevelopmental deficits resembling positive symptoms and cognitive impairment, only cariprazine demonstrated efficacy in improving prosocial behavior, considered to be a negative symptom. ⁶ In another comparison study in rodents, cariprazine (but not aripiprazole) demonstrated upregulation of D₃ receptors, which was postulated to offer possible benefit for depression and negative symptoms. ⁷ In a randomized placebo-controlled, double-blind trial, patients receiving cariprazine demonstrated greater improvement in negative symptoms compared with patients receiving risperidone. ⁸ In addition, the cariprazine group demonstrated greater improvement in functioning, particularly with regard to self-care, interpersonal relationships, and socially useful activities. ⁸ The authors opined that improvement in self-care and interpersonal relationships may be particularly relevant in rehabilitation and involvement with community mental health treatments. ⁸ In the rodent and human studies, cariprazine’s superior improvement in cognitive and social impairment was attributed to its activity at D₃ receptors.

Cariprazine may also be particularly beneficial for patients with comorbid substance abuse. Substance abuse is frequently comorbid in patients with schizophrenia, contributing to worsening disease and increased morbidity and mortality. In a rodent study, cariprazine outperformed aripiprazole in reducing the rewarding effect of cocaine and preventing relapse after a period of withdrawal from cocaine and related cues; this was not considered to be due to sedation or motor impairment. ⁹ This reduction in substance use and relapse prevention was attributed to its D₂ partial agonism. Whether cariprazine’s anti-abuse potential can be extrapolated to humans and to other drugs of abuse remains to be tested.

Another advantage of cariprazine is its long half-life. Promoting and ensuring medication adherence in patients with schizophrenia is a challenge. Adherence can be hindered by complex dosing regimens, adverse effects, positive or negative symptoms (including cognitive impairments), or lack of therapeutic alliance. Cariprazine has a half-life of 1–3 weeks, longer than any antipsychotic agent. ¹⁰ This may be beneficial for patients who intermittently miss a few doses, as the medication will still be at therapeutic levels exerting a beneficial effect. ¹⁰ In turn, this may reduce the risk for decompensation and need for costly rehospitalization. However, a potential disadvantage of its long half-life is that the effective dose is rising for many weeks prior to achieving steady state. ¹⁰ Furthermore, adverse effects will persist for some time following dose reduction or medication discontinuation. This is a concern for conditions such as neuroleptic malignant syndrome (NMS). Although no cases of NMS have been reported with cariprazine, nonfatal cases have been reported with aripiprazole. Finally, if the dose is titrated too soon, this may lead to adverse effects after a few weeks, necessitating a dose reduction. ¹⁰

Summary

Cariprazine shares more similarities than differences with the newer atypical antipsychotics, particularly other dopamine partial agonists. This raises questions about its relative utility and necessity in an already-crowded treatment armamentarium for schizophrenia. What makes the future prospects for cariprazine ‘cautiously optimistic’ is not its effectiveness, tolerability, or favorable metabolic profile, but its extra benefit for improving negative symptoms, decreasing substance abuse, and maintaining efficacy in cases of missed doses. Cariprazine may be the treatment of choice for patients who have shown improvement in positive symptoms but continue to have disabling negative symptoms, or impairment in self-care and interpersonal relationships. ⁸ Given its action at serotonin receptors and the D₃ receptor, further trials utilizing varying doses of cariprazine are warranted to determine whether cariprazine would be preferred for patients with schizophrenia who also have significant comorbid depression.