Cariprazine to Treat Schizophrenia and Bipolar Disorder in Adults

Abstract

Purpose of Review

Antipsychotics are the standard of care when it comes to the treatment of Schizophrenia, and they are often used in Bipolar as well. Their use can come with adverse effects such as extrapyramidal movements, metabolic complications as well as cardiovascular complications such as a prolonged QT interval. Treatment for these side effects ranges from the treatment of the complications up to the cessation of the medication, which could come at the expense of the user’s stability. Both schizophrenia and bipolar disorder have an increased risk of suicide and increased morbidity. The purpose of this review presents the background, evidence, and indications for the use of the new second-generation antipsychotic Cariprazine, which has a primary function as a D3 and D2 partial agonist, with higher selectivity for the D3 receptor type.

Recent Findings

Schizophrenia is currently teated by dopamine antagonists and/or 5HT modulators, each with their own set of side effects. Bipolar disorder is mostly treated with mood stabilizers. Studies looking at the efficacy and safety of cariprazine have shown in two phase II trials and phase III trials the decrease in PANSS scores in schizophrenia. The most common adverse effects were akathisia, insomnia, constipation, and other extrapyramidal side effects. A unique side effect of Cariprazine caused bilateral cataract and cystic degeneration of the retina in the dog following daily oral administration for 13 weeks and/or 1 year and retinal degeneration in rats following daily oral administration for 2 years. Another study showed that cariprazine had significant efficacy in preventing relapse in patients with schizophrenia. The time to the loss of sustained remission was significantly longer (P = .0020) for cariprazine compared to placebo (hazard ratio = 0.51) during the double-blind treatment. 60.5% of patients treated with cariprazine and 34.9% of patients treated with placebo sustained remission through the final visit (odds ratio [OR] = 2.85; P = .0012; number needed to treat [NNT] = 4. Another Phase IIIb study looked at negative symptoms and used the Positive and Negative Syndrome Scale Factor Score for Negative Symptoms (PANSS-FSNS), and it found that the use of cariprazine, from baseline to week 26, led to a greater least-squares mean change in PANSS-FSNS than did risperidone. Another study looked at the quality of life years with the treatment of cariprazine and showed those treated with cariprazine had superior quality of life compared to those treated with risperidone. In terms of bipolar disorder, it showed a decrease in depressive symptoms as measured by decreased MADRs scores with a dose of 3.0mg/day. A phase II study looked at the use of cariprazine in mania or mix states and showed cariprazine significantly decreased YMRS scores compared to placebo, least-square mean difference of –6.1 (p < 0.001). The metabolic parameters demonstrated comparable changes except for fasting glucose in which cariprazine was associated with elevations in glucose levels compared to placebo (p < 0.05). Another phase III study showed significant differences in YMRS total score mean change between cariprazine versus placebo-treated group. Changes in metabolic profiles in all mentioned studies were minimal.

Summary

Cariprazine, in recent studies, has shown some promise in being able to treat both bipolar disorder in manic, depressed, and mixed states as well as schizophrenia. Side effects noted as adverse events in these studies are similar in profile to the medications that were developed in the past. With better relapse prevention, cariprazine could be a reasonable alternative clozapine.

Introduction

Schizophrenia and bipolar disorder remain widely studied chronic psychiatric conditions in scientific literature. However, further research is always needed to confirm the etiology, pathophysiology, and treatment options that may be provided in order to improve the quality of life for these patient populations.

The DSM-5 criteria state that a diagnosis of schizophrenia requires two or more of the following: delusions, hallucinations, disorganized speech, catatonic behavior, and presence of negative symptoms^1,2 The DSM-5 criteria has updated negative symptoms in schizophrenia from prior versions.^3,4 These include avolition and diminished emotional expression. Schizophrenia presents with a broad spectrum of symptoms, with some diagnostic symptoms appearing in as few as 2% of patients diagnosed with this disorder.¹ Some reports estimate that individuals with schizophrenia have between a two to threefold increase in mortality, higher risk of premature death due to comorbidities, and heightened rates of suicide.^5–7 Advancement to the DSM-5 allowed for the elimination of categories of questionable validity, reliability, and clinical use, allowing for more succinct diagnoses of the disorder; however, further development of treatment options would allow for a reduction in the reported negative patient outcomes.^1,8–10

Bipolar disorder is currently divided into bipolar I disorder and bipolar II disorder. For a diagnosis of bipolar I disorder, the DSM-5 states that criteria must be met for a manic episode, which is described as at least seven days of abnormally excitable or irritable mood, increased goal-oriented behaviors, or any duration of time if behaviors impede function and require hospitalization. Three or more of the following must be present and recognized as abnormal from typical behavior for the individual: grandiosity, reduced sleep, excessive talkativeness, “racing” thoughts, distractibility, increased goal-oriented behavior, psychomotor agitation, or impulsive behaviors. Manic episodes may be preceded or followed by a hypomanic or major depressive episode. As is the case with individuals with schizophrenia, bipolar disorder has exhibited an increased risk of mortality and suicide.^11–13 Although evidence has been shown that monoamine neurotransmitters are involved, any singular dysfunction has yet to be identified.¹¹ Current pharmacological treatment has been reported to lack sufficient data to improve patient outcomes in terms of morbidity.¹⁴

In addition to psychosis, schizophrenia and bipolar mania share another common feature, altered dopaminergic activity. Both disorders have been determined to exhibit increased dopamine synthesis capacity, and the dopamine alterations have been linked to psychotic features.^15,16 This is consistent with prior hypotheses that dopamine dysfunction played a role in the development of psychosis in patients. Atypical antipsychotics have been designed primarily to modulate dopaminergic function in order to treat mood disorders. This review seeks to examine the efficacy of the drug Cariprazine to treat schizophrenia and bipolar disorder in adults.

Schizophrenia and Bipolar Disorder Background

Linkage and Genome-Wide Association studies have shown problems in genes associated with neurodevelopmental processes, glutamate and dopamine regulation, and immune system activation for schizophrenic patients. Recent Epigenetic studies have also shown a link between abnormal DNA methylation and histone modification sites, aberrant gene expression regulation, and environmental influences on the development of schizophrenia in patients.¹⁷ On the other hand, problems in genes associated with voltage-gated calcium channels have been reported as a possible etiology of bipolar disorder.¹⁸

Epidemiology

The percentage of new patients diagnosed with schizophrenia each year has been stable across countries over the past 50 years.¹⁹ Studies have documented that the heritability of schizophrenia can be as high as 80%. It has also been reported that if one parent suffers from schizophrenia, the probability that the offspring will also have schizophrenia is 13%. If it is both parents, the probability increases to 20%.¹⁹ Since the diagnosis of schizophrenia at an earlier age has been shown to cause social stagnation, there is a reported uneven distribution of prevalence rates.

Most individuals are diagnosed with schizophrenia around the ages of 20 to 35 years old and experience a prodromal phase of 5 years with the onset of the first positive symptom of 1 year before a definitive diagnosis is made.²⁰ It has been observed that women contract schizophrenia three to four years later than men, and show a more frequent and severe second peak of onset around menopause.

Due to its early onset, bipolar disorder can be a disabling illness. A 49.1% increase in prevalence cases for BD has been reported from 1990 to 2013.²¹ Recent epidemiological findings have determined the age cutoffs for Bipolar Disorder to range from 50 to 65 years. Symptoms of mania in bipolar disorder present similar across ages, although recent evidence suggests that the overall severity of mania decreases with time. It is important to note that much of the existing epidemiological data comprises patients in their 60s with data missing on individuals in their 70s and 80s. However, it is important to note that the course of illness can be highly variable.²²

Risk Factors

The environmental factors associated with the development of schizophrenia include date and place of birth, seasonal effects, infectious diseases, illnesses present in mother during pregnancy and delivery, history of substance abuse, and stress.⁸ Individuals with schizophrenia have often been found to be born at the end of winter and beginning of spring.¹⁹ It should be noted that these times of the year are also a high season for influenza and other acute respiratory tract infections. Studies have suggested that viral infections in pregnancy may cause changes in the brain associated with an early onset of schizophrenia.⁸ For instance, it has been shown that exposure to influenza A virus during development results in an increase in kynurenic acid that disrupts normal brain development.²³ It has also been proposed that a lack of sun exposure in the winter months leads to a deficit in vitamin D needed for fetal brain growth. Hence, brain development in the developing fetus can be negatively impacted.²⁴ Similarly, factors associated with urban lifestyles such as stress, excess noise, pollution, crime, illegal drug availability, family breakdown, and other negative factors have been shown to affect the early development of schizophrenia.²⁵ Recent studies have also shown that birth complications and cannabis abuse were predictors for an earlier onset in patients, even with no family history. Abusing lysergic acid diethylamide (LSD), phencyclidine, methamphetamine, cocaine, opiates, alcohol, tobacco, and cannabis have been shown to cause psychosis in individuals with a history of psychosis or those susceptible to it.²⁶ Even though the reported literature that list environmental factors for schizophrenia show some aspects of bias, epidemiological studies consistently show a pattern of association between environmental risk factors and onset of psychosis.⁸

Candidate genes for schizophrenia (notable examples include DISC1, DISC2, COMT, DTNBP1, and NRG1 genes) were proposed, however, the identification of the single nucleotide polymorphism (SNP) in the gene CTNNA3 could point to the gene-environment etiology of schizophrenia.²⁷ It was found that carriers of the minor allele for the SNP had a 5-fold risk of later developing schizophrenia if their mothers had a CMV infection. On the other hand, children not carrying the allele had no increased risk from maternal CMV.⁸ Moreover, a functional single nucleotide polymorphism that substitutes Methionine instead of Valine at codon 66 has also been identified as a possible cause of schizophrenia.⁸ This change results in abnormal sorting and release of mature brain-derived neurotrophic factors. This can affect neuronal development, differentiation, and plasticity. It has been reported in the literature that the Val66Met polymorphism leads to a range of clinical features of schizophrenia, including the age of onset, symptoms, response to therapeutic agents, neurocognitive function, and brain morphology.⁸ Additionally, case-control association studies between schizophrenia and SNP’s have shown a strong association between schizophrenia and single nucleotide polymorphism in the CTXN3 gene (cortexin 3). The purposed mechanism is that cortexin 3 is involved in brain development, particularly in the development of GABAergic neurotransmission and metabolism of amyloid precursor protein, which could impact neuronal maturation, migration, and synapse creation.⁸

There are additional environmental risk factors associated with bipolar disorder. These include exposure to stress and anxiety, exposure to prenatal factors, head injury, drugs, physical or sexual abuse, and other forms of stress. However, it is important to note that the link has been reported to be moderate at most.⁹

Presentation

The biological characterization of the symptoms of schizophrenia is unclear, which makes diagnosis difficult with common laboratory investigations. However, common symptoms include positive symptoms such as delusions and hallucinations and negative ones such as flattened affect and lack of motivation.²²

Bipolar disorder clinically manifests as recurrent manic or hypomanic episodes followed by depression, presence of cognitive deficits, and impaired functioning.¹⁰ Patients with bipolar disorder also have several comorbid conditions. Of note, the most important association is with frontotemporal dementia.²² The presentation of bipolar in the pediatric population is slightly different, as dysregulation disorder presents very similarly to bipolar in children.²⁸

Current Treatment of Schizophrenia and Bipolar Disorder

The treatment of schizophrenia includes antipsychotic drugs and psychological interventions.²⁹ Antipsychotics are classified by first, second, and third generations. First-generation antipsychotics are dopamine receptor antagonists, mainly targeting D₂ receptors. Second-generation antipsychotics (SGAs) antagonize serotonin 5-HT_2A receptors and antagonize D₂ receptors.³⁰ The third-generation antipsychotics (TGAs) are D₂ partial agonists, and depending on the dopamine concentration can have antagonistic effects on dopamine receptors.^31,32

While antipsychotics treat positive symptoms such as hallucinations and disordered thoughts, few provide relief of negative symptoms and cognitive dysfunction.³³ A review by Moller & Czobor sought to examine pharmacotherapy for the treatment of negative symptoms of schizophrenia and determined that SGAs fell short of treating negative symptoms. However, some SGAs were more effective compared to FGAs regarding treating general and negative symptoms.^34,35 A systematic review and meta-analysis on adjunctive antidepressants for treating negative symptoms of schizophrenia found that antidepressants combined with antipsychotics were more effective than antipsychotic monotherapy.³⁶

Discontinuation and non-adherence to treatment is a significant obstacle regarding the treatment of schizophrenia.³⁷ A meta-analysis of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and the European First-Episode Schizophrenia Trial (EUFEST) found that increased hostility, substance use, and deficient insight were associated with poor medication adherence.³⁸

A review of fourteen randomized controlled trials (RCTs) investigated psychological interventions for schizophrenia and substance use disorder patients. While the number of studies reviewed were limited, the review concluded that integrated treatment programs such as Behavioral Treatment for Substance Abuse in Severe and Persistent Mental Illness (BTSAS) and Family Intervention for Dual Disorder (FIDD) were efficacious in treating patients having both schizophrenia and substance use disorder.^38,39 The review also supported family interventions, contingency management, relapse prevention, and motivational interviewing as part of integrated treatment programs.⁴⁰

Long-acting injectable antipsychotics, such as Invega, Abilify, and Haldol, a treatment option with the potential to improve adherence and decrease the rate of relapse in patients with schizophrenia.²⁹ The study showed that clozapine and long-acting injectable first and second-generation antipsychotics were the treatments associated with the lowest rates of rehospitalization and treatment failure. The study concluded that these treatments had the highest rates of preventing relapse in patients with schizophrenia.⁴¹

First-generation Antipsychotics

The first-generation antipsychotics can be classified into the following groups: phenothiazines (e.g., chlorpromazine), butyrophenones (e.g., haloperidol), thioxanthenes (e.g., clopenthixol), dihydroindolones (e.g., molindone), and dibenezpines (e.g., loxapine).³² A disadvantage of FGAs is the narrow ability to provide symptomatic relief of negative and cognitive dysfunction symptoms.³¹

The first-generation antipsychotics lack of selectivity regarding dopamine pathways results in many side effects. Blocking dopamine receptors in the nigrostriatal pathway causes extrapyramidal side effects such as dyskinesia, akathisias, and tremors. Blocking dopamine receptors in the mesocortical pathway may bring about negative symptoms. Decreasing dopamine activity in the tuberoinfundibular system results in increased prolactin production, leading to sexual dysfunction and hyperprolactinemia.^42,43

Second and Third generation Antipsychotics

Second-generation antipsychotics include risperidone, paliperidone, ziprasidone, lurasidone, clozapine, olanzapine, and quetiapine. Although they have fewer associated side effects, particularly decreased extrapyramidal side effects, second-generation antipsychotics have been associated with metabolic dysfunction, including diabetes and significant weight gain.³²

One of the SGAs, clozapine, is the current drug of choice for treatment-resistant schizophrenia. The second trial of the Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia study (CUtLASS) evaluated clozapine versus other SGAs on symptoms and quality of life in schizophrenia patients who had a poor response to two or more antipsychotics.

While there was no change in the quality of life between the groups, the study found that clozapine-treated patients had improved symptoms compared to the other SGA-treated groups.^29,44 In 2008, the US Food and Drug Administration (FDA) mandated that antipsychotic drug manufacturers add black box warnings to labels and prescribing information because of the link found between antipsychotics and an increased mortality risk in elderly dementia patients. A review by Muscatello et al. evaluated augmentation strategies for clozapine and found that add-ons such as antidepressants, antipsychotics, and mood stabilizers lack substantiation regarding efficacy in the treatment of refractory schizophrenia.⁴⁵

Third generation antipsychotics are represented by aripirazole, brexpiprazole, and cariprazine. In contrast to other antipsychotics, third-generation antipsychotics have a more favorable side effect profile of decreased levels of prolactin, thereby avoiding hyperprolactinemia and caused fewer extrapyramidal side effects.³¹

Bipolar Disorder I Treatment-Mania

The current treatment of acute mania in bipolar disorder includes mood stabilizers and antipsychotics. Atypical antipsychotics are preferred over typical antipsychotics due to the decreased risk of tardive dyskinesia, and other extrapyramidal side effects.^46,47 A systematic review and network meta-analysis of sixty-two double-blind drug trials found combination therapy of an antipsychotic and a mood stabilizer more effective than monotherapy of either medication class.⁴⁸ Antidepressants can be prescribed as adjunctive treatment with a mood stabilizer or an atypical antipsychotic.^49,50

Bipolar Disorder I & II – Depression

First-line treatment for depression in bipolar disorder includes monotherapy with either quetiapine or lurasidone, or combined lithium or lamotrigine. Another option is quetiapine or lurasidone with a mood stabilizer such as lithium or valproate.^51–54 Treatment for bipolar II depression is similar with quetiapine monotherapy being recommended.^55,5,⁶ Antidepressants in the treatment of bipolar depression can negatively impact mood cycling, and monotherapy is not recommended.^46,49

Cariprazine Drug Information

Cariprazine is an atypical antipsychotic medication indicated for the treatment of schizophrenia and bipolar mania.⁵⁷ It is available in 1.5, 3, 4.5, and 6 mg capsules to be taken once daily, with a recommendation of 1.5–6 mg per day for schizophrenia and 3–6 mg per day for bipolar mania.^58,59 Doses above 6 mg are not recommended as they have been shown to increase the risk of adverse reaction without adding therapeutic benefit.⁵⁹ Patients with hypersensitivity to cariprazine have been known to experience dermatological effects (rash, urticaria), and angioedema events (edema of the tongue, face, and pharynx). Known interactions involve strong CYP3A4 inhibitors, in which case the dosage should be reduced by half. Withdrawal of the CYP3A4 inhibitor may require an increase in cariprazine dosage. Dementia-related psychosis patients were noted to have an increased risk of death compared to controls; up to 1.7 times that of patients given a placebo, with most of these deaths appearing to be either cardiovascular or infectious.⁵⁹ Cariprazine, like other antipsychotics, does carry a black box warning regarding increased mortality in elderly patients as well.⁵⁹ Cariprazine adverse reactions of note include cerebrovascular incidents, including stroke and transient ischemic attack predominantly in elderly patients with dementia-related psychosis, neuroleptic malignant syndrome, tardive dyskinesia, metabolic changes, and orthostatic hypotension.⁵⁹ However, the most common adverse reactions involved extrapyramidal symptoms and akathisia present in both schizophrenia and bipolar mania patients, with the addition of dyspepsia, vomiting, somnolence, and restlessness in patients with bipolar mania.⁵⁹ One interesting side effect in preclinical trials was found in both rats and dogs. Cariprazine caused bilateral cataract and cystic degeneration of the retina in the dog following daily oral administration for 13 weeks and/or 1 year and retinal degeneration in the rat following daily oral administration for 2 years.⁵⁹

While all atypical antipsychotic medications have a risk of metabolic changes and should be monitored for such, patients on cariprazine showed similar changes to control in shifts from fasting glucose, dyslipidemia, and orthostatic hypotension, although changes in body weight were higher on cariprazine in 6-week schizophrenia and 3-week bipolar mania trials.⁵⁹ Neonates may experience extrapyramidal symptoms as well as withdrawal symptoms if cariprazine is given to pregnant patients in the third trimester.

Mechanism of Action

Most recent studies have described cariprazine to primarily function as a D3 and D2 partial agonist, with higher selectivity for the D3 receptor type.^60–63 Unlike other atypical antipsychotics, cariprazine has been shown to have high D3 antagonist properties, which may be attributed to cariprazine having a higher affinity for the D3 receptor than dopamine itself.^60,64 This had led researchers to theorize that cariprazine can displace dopamine at the D3 receptor more so than other atypical antipsychotics that are currently available. The D3 partial agonism of cariprazine has been shown to have antipsychotic, antidepressant, and procognitive effects in rodents.^65,66 Many atypical antipsychotics function as D2 modulators; however, comparable drugs, such as aripiprazole, have resulted in agitation and akathisia in patients. Cariprazine, though also a D2 partial agonist, has been shown to display less agonism than drugs like aripiprazole or bifeprunox.^60,64 This was theoretically designed to make cariprazine a potential candidate for reduced agitation and akathisia compared to other atypical antipsychotics.⁶⁰ In addition to dopamine receptors, cariprazine has been shown to have an affinity for the 5HT1A receptor, yet, it has a lesser degree of affinity for the 5HT2A receptor than most atypical antipsychotics.^{60–62,64,67} Prior human imaging studies have estimated that clinical antipsychotic efficacy is attained at about 60 to 75% occupancy of dopamine D2 receptors.⁶⁸ Positron emission tomography (PET) study of male subjects with schizophrenia displayed that 14 days of treatment with cariprazine at its minimal recommended dose of 1.5 mg per day was sufficient to elicit 69% occupancy of the D2 and D3 receptors in both the caudate nucleus and nucleus accumbens, as well as 75% in the putamen.⁶³ After 14 days of 3 mg per day, over 90% occupancy had been noted.⁶³

Pharmacokinetics/Pharmacodynamics

The currently available antipsychotics have been shown to have limited efficacy in the treatment of negative symptoms and cognitive impairment present in patients with schizophrenia and bipolar disorder. Cariprazine, a novel antipsychotic drug, has been shown to be superior in the treatment of negative and extrapyramidal symptoms present in schizophrenic patients and as well as patients with bipolar disorder. It is important to note that the negative symptoms resolved excluded depression.^69,70

Pharmacodynamics

Cariprazine has been shown to display partial agonist activity at dopamine D2 and serotonin 5-HT1A receptors. It also shows antagonist activity at serotonin 5-HT2A receptors and exhibits a high affinity for dopamine (D2 and D3) and serotonin (5-HT1A) receptors. Moreover, Cariprazine has been shown in studies to display a low affinity for serotonin 5-HT2C and alpha1A-adrenergic receptors. Cariprazine is a high-affinity antagonist for 5-HT2B receptors, shows a moderate affinity for 5-HT2A receptors, binds to histamine H1 receptors, and shows no affinity for muscarinic cholinergic receptors. This differentiates it pharmacologically from other antipsychotics.⁷⁰

Pharmacokinetics

Cariprazine is metabolized primarily by CYP3A4 enzyme and, to a lesser extent, by CYP2D6 enzyme. The active metabolites are desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR). DCAR is metabolized further into DDCAR by CYP3A4 and CYP2D6. The compound DDCAR is then further metabolized by CYP3A4 to a hydroxylated metabolite. It takes Cariprazine 3 to 6 hours to reach peak concentrations in plasma. Cariprazine’s half-life is two to four days with DCAR’s half-life being 1–2 days and DDCAR half-life being 1–3 weeks.⁷¹ Clinical trials have found that treatment with Cariprazine results in minimal side effects.⁷² Due to its high utility and low side effect profile, Cariprazine has been approved by the FDA as of 2015.⁷⁰

Clinical Studies: Safety and Efficacy

Schizophrenia – Phase II Studies

A six week, double-blind, placebo-controlled study investigated the safety, efficacy, and tolerability of low dose, 1.5–4.5 mg/day, and high dose, 6–12 mg/day cariprazine. The cariprazine treatment effect overall did not prove to be statistically significant. The total score difference of PANSS from baseline to the sixth week was the primary efficacy parameter. The low dose cariprazine group demonstrated significant improvement in symptoms of schizophrenia compared to the placebo group based on the primary efficacy parameter.⁴¹

A Phase II, double-blind, randomized, placebo-controlled clinical trial investigated the safety and efficacy of cariprazine for treating acute exacerbation of schizophrenia. Patients were randomized to cariprazine (1.5, 3.0, 4.5 mg/day), placebo, or 4.0 mg/day risperidone, and received treatment for six weeks. At the 6^th week, the PANSS total score improvement was statistically significant versus placebo for cariprazine 1.5 mg/day, 3.0 mg/day, and 4.5 mg/day (least-squares mean difference [LSMD]: –7.6, –8.8, –10.4, respectively; p < 0.001; LOCF) and risperidone (–15.1, p < 0.001; LOCF). The most frequent adverse events for cariprazine included but not limited to (⩾5% and at least twice the rate of the placebo group) insomnia, extrapyramidal disorder, akathisia, and constipation. Based on the results, the study concluded that cariprazine might be a significant option in the treatment of schizophrenia.⁴²

Another study examined the long-term safety and efficacy of cariprazine for patients with schizophrenia. This was an extension study for patients who previously completed a six week, phase IIb lead-in study examining cariprazine (1.5, 3.0, or 4.5 mg/day), placebo, or risperidone 4.0 mg/day for the treatment of acute exacerbation of schizophrenia.⁴² Patients in this extension study were started at 1.5 mg/day with a possible 1.5 mg dose increases with the maximum dose being 4.5 mg. The common adverse effects were akathisia (14%), insomnia (14%), and weight gain (12%), which were similar compared to the common adverse events of the lead-in study akathisia, insomnia, constipation, and other extrapyramidal symptoms. The extension study did not observe prolactin elevation, changes in cardiovascular parameters, or high levels of sedation with long-term cariprazine. The study showed no new safety concerns regarding the long-term treatment of cariprazine in the treatment of schizophrenia.⁴³

Schizophrenia – Phase III Studies

A Phase III randomized, double-blind trial examined the efficacy, tolerability, and safety of cariprazine in patients with acute exacerbation of schizophrenia. Patients were randomized to placebo, cariprazine 3 mg/day, cariprazine 6 mg/day, or aripiprazole 10 mg/day for six weeks. The efficacy parameters were the mean change from baseline to week 6 in PANSS total score and CGI-S. At week 6, the least-squares mean differences (LSMDs) in PANSS total score change significantly favored cariprazine 3 and 6 mg/d versus placebo (LSMD [95% CI]: 3 mg/d, –6.0 [–10.1 to –1.9], adjusted P = .0044; 6 mg/d, –8.8 [–12.9 to –4.7], adjusted P < .0001). Cariprazine 3 and 6 mg/d had improved CGI-S compared to placebo (LSMD [95% CI]: 3 mg/d, –0.4 [–0.6 to –0.2], adjusted P = .0044; 6 mg/d, –0.5 [–0.7 to –0.3], adjusted P < .0001). There were also significant differences in PANSS and CGI-S with placebo vs. aripiprazole: PANSS (LSMD [95% CI]: –7.0 [−11.0 to –2.9], P = .0008) and CGI-S (LSMD [95% CI]: –0.4 [–0.6 to –0.2], P = .0001). All groups had insomnia as a common adverse effect. Cariprazine 6 mg/d had the common adverse events of akathisia. Both placebo and cariprazine 6 mg/d had a headache as a common adverse effect. The study indicates that cariprazine 3 and 6 mg/d is safe, efficacious, and well-tolerated in treating acute exacerbation of schizophrenia.⁴⁴

Another phase III trial examined the safety and efficacy of cariprazine 3 to 6 mg/day and cariprazine 6 to 9 mg/day in the treatment of acute exacerbation of schizophrenia. Statistically significant least squares mean differences were observed at the sixth week for PNSS (3–6 mg/d: –6.8, P = 0.003; 6–9 mg/d: –9.9, P < 0.001) and CGI-S scores (3–6 mg/d: –0.3, P = 0.012; 6–9 mg/d: –0.5, P < 0.001) in favor of cariprazine to placebo. The common adverse effects of both cariprazine groups included akathisia, tremor, and extrapyramidal disorder. In general, the metabolic parameters demonstrated small and similar mean changes. All groups demonstrated decreased prolactin levels. The results of the study indicated cariprazine 3–6 mg/day and cariprazine 6–9 mg/day as effective in the treatment of schizophrenia.⁴⁵

A one-year open-label long-term study investigated the efficacy and safety of cariprazine (3–9 mg/day) for patients with schizophrenia. The was study comprised of new patients and patients who had completed one of two phase-III lead-in studies. Approximately 39% of the 586 patients completed the study. The most common (⩾10%) adverse events included akathisia (16%), headache (13%), insomnia (13%), and weight gain (10%). Serious adverse events occurred in 59 (10.1%) patients. During open-label treatment, 73 (12.5%) patients discontinued the study due to adverse events. Mean changes in metabolic, hepatic, and cardiovascular parameters were not considered clinically relevant. The study demonstrated that prolactin levels did slightly decrease, and the mean weight gain was 1.5 kg. The study noted that there was no evidence of decreased efficacy of cariprazine after one year of pharmacotherapy. The results of the study concluded that cariprazine might be a safe long-term treatment option for schizophrenia.⁴⁶

Another study investigated the safety, efficacy, and tolerability of cariprazine for the prevention of relapse in schizophrenia; total study duration was up to 97 weeks. Patients were first treated with 3–9 mg/day of cariprazine during a 20-week open-label treatment. The open-label treatment involved eight weeks of a flexible dosing phase and twelve weeks of a fixed-dose phase. Upon completion of the open-label study, eligible patients were randomized to cariprazine (3, 6, or 9 mg/day) or placebo for a duration of up to 72 weeks of double-blind treatment. The study demonstrated that the time to relapse was significantly longer in cariprazine treated patients compared to placebo-treated patients (P = .0010, log-rank test). In 24.8% of cariprazine-treated patients and in 47.5% of placebo-treated patients relapse occurred (hazard ratio [95% CI] = 0.45 [0.28, 0.73]). The TEAEs that ⩾ 10% of patients reported during open-label treatment included akathisia (19.2%), insomnia (14.4%), and headache (12.0%). In the double-blind treatment, there were no cariprazine adverse events ⩾ 10%. The study results demonstrated that cariprazine had significant efficacy in preventing relapse in patients with schizophrenia.⁴⁷

Post hoc analyses examined the data from a cariprazine relapse prevention study and examined the efficacy of cariprazine in maintaining remission in clinically stable patients with schizophrenia. The study defined symptomatic remission as scores of ⩽ 3 on 8 items from the general, positive, and negative symptoms subscales of the PANSS. Additionally, sustained remission included patients meeting the remission criteria at current and all previous double-blind visits or for ⩾ 6 consecutive months. 169/200 patients (84.5%) met the criteria for symptomatic remission. The time to the loss of sustained remission was significantly longer (P = .0020) for cariprazine compared to placebo (hazard ratio = 0.51) during the double-blind treatment. 60.5% of patients treated with cariprazine and 34.9% of patients treated with placebo sustained remission through the final visit (odds ratio [OR] = 2.85; P = .0012; number needed to treat [NNT] = 4). Approximately double as many cariprazine-treated patients (39.6%) as placebo-treated (21.2%) patients met the symptomatic remission criteria at all visits ⩾ 6 consecutive months immediately before/including the final double-blind visit (OR = 2.44; P = .0057; NNT = 6). The study also demonstrated more cariprazine-treated patients (41.6%) than placebo-treated (27.3%) patients sustained remission for any ⩾ 6 consecutive month period (OR = 1.90, P = .0379; NNT = 7). The study showed that cariprazine was efficacious in providing higher rates of remission and significantly greater sustained remission in patients with schizophrenia.⁴⁸

Schizophrenia – Additional Studies

A study involving 12 weeks of treatment examined the pharmacokinetic properties of cariprazine and its metabolites, desmethyl-cariprazine, and didesmethyl-cariprazine. In the study, participants were randomized doses of 3, 6, or 9 mg/day. For cariprazine and desmethyl-cariprazine, a steady-state was reached within 1–2 weeks. Didesmethyl-cariprazine reached steady-state in 4 weeks. The terminal half-life of cariprazine ranged from 31.6 to 68.4, desmethyl-cariprazine (29.7 to 37.5), and didesmethyl-cariprazine (314 to 446) hours. The study did not observe any abnormal laboratory values or considerable differences from baseline in extrapyramidal symptoms. The study concluded that cariprazine might be a favorable treatment option for schizophrenia.⁴⁹

Schizophrenia ~ Studies regarding Negative Symptoms

In a Phase IIIb, randomized, double-blind trial investigated the mono-therapeutic treatment of cariprazine vs. risperidone for 26 weeks in adult patients with long-term (>2 years) stable schizophrenia who had predominantly negative symptoms (>6 months). Patients were randomized to cariprazine (3 mg, 4.5 mg [target dose], or 6 mg/day) or to risperidone (3 mg, 4 mg [target dose], or 6 mg/day). The study evaluated the Positive and Negative Syndrome Scale Factor Score for Negative Symptoms (PANSS-FSNS) score change from baseline to the 26th week/end of treatment. The study screened 533 patients and randomized to treatment 461 (86%) patients (230 for cariprazine and 231 for risperidone). Four hundred sixty patients were included in the safety population. The study included 227/230 (99%) patients in the cariprazine group and 229/230 (99%) patients in the risperidone group in the modified intention-to-treat population (178 [77%] in each group completed 26 weeks of treatment). 4.2 mg (SD 0.6) of cariprazine and 3.8 mg (0.4) of risperidone were the mean daily doses. 123 (54%) cariprazine patients, and 131 (57%) risperidone patients reported events such as akathisia, worsening of schizophrenia, insomnia, anxiety, headache). The study found that the use of cariprazine, from baseline to week 26, led to a greater least-squares mean change in PANSS-FSNS than did risperidone (–8.90 points for cariprazine vs. –7.44 points for risperidone; least-squares mean difference –1.46, 95% CI –2.39 to –0.53; p=0.0022; effect size 0.31). The results of the study showed cariprazine to be superior to risperidone for the treatment of predominant negative symptoms of schizophrenia.⁵⁰

A study, based on the PANSS data from the clinical trial, analyzed the potential gain in quality-adjusted life-years (QALYs) due to cariprazine treatment in patients with predominantly negative symptoms of schizophrenia compared to risperidone.⁵⁰ The study constructed a Markov model based on the Mohr–Lenert approach and data derived from clinical trials, to estimate the potential QALY gains. The study found that patients in the cariprazine group had a higher probability of reaching better states of health than the risperidone group. The data showed, after one year of treatment, an estimated QALY gain of 0.029 per patient. The deterministic and probabilistic sensitivity analyses were conducted and confirmed the results. The study showed that patients with predominantly negative symptoms of schizophrenia who are treated with cariprazine have a superior quality of life compared to those treated with risperidone.⁵¹

Bipolar Depression

An eight week, randomized, double-blind, placebo-controlled study examined the effects of cariprazine (0.75, 1.5, 3.0 mg/day) on bipolar I patients currently experiencing a major depressive episode. The study found 0.75 mg/day dosage similar compared to the placebo. Patients in the 1.5 mg/day cariprazine group demonstrated significant improvement versus placebo regarding MADRS scores; the least-squares mean difference was –4.0 (95% CI= –6.3, –1.6; significant after adjustment for multiple comparisons). Cariprazine 3.0 mg/day versus placebo demonstrated a larger reduction in MADRS score (–2.5, 95% CI=–4.9, –0.1), but this was not significant after adjusting for multiple comparisons. The study reported a similar significance pattern regarding CGI-S (1.5 mg/day: least-squares mean difference= –0.4, 95% CI=–0.6, –0.1; 3.0 mg/day: –0.3, 95% CI=–0.5, –0.0). The common adverse events (⩾ 10%) associated with cariprazine were akathisia and insomnia. Patients in the 1.5 mg/day cariprazine group demonstrated significant improvement based on CGI-S and total MADRS scores, which implied the 1.5 mg/day could be an effective dose for treating bipolar I depression.²⁶

A phase III trial provided a further assessment of cariprazine in treating bipolar I depression. Patients were randomized to placebo, 1.5 mg/day, or 3.0 mg/day cariprazine. Both cariprazine 1.5 mg/day and 3.0 mg/day demonstrated greater efficacy by decreasing the MADRS total score versus placebo; the least-squares mean differences: cariprazine 1.5 mg/day was –2.5 (95% CI= –4.6, –0.4) and cariprazine 3.0 mg/day was –3.0 (95% CI= –5.1, –0.9). The data regarding the cariprazine groups and CGI-S scores were not statistically significant. The common adverse events (in at least 5% in either cariprazine group and twice the rate of placebo) were akathisia, sedation, nausea, and dizziness. Between the groups, the metabolic and weight parameters demonstrated small and similar mean changes. The study concluded both 1.5 mg/day and 3.0 mg/day of cariprazine was effective in improving depressive symptoms associated with bipolar I depression.⁵⁵

Bipolar Mania

A sixteen week, open-label study demonstrated the safety and tolerability of cariprazine (3-12 mg/day) with bipolar mania patients. The study began with 402 in the safety population; however, only 132 completed the study. The most common serious adverse events were mania [2.2%] and depression [1.2%]. 83.3% had adverse events which included akathisia (32.6%), headache (16.7%), constipation (10.7%), and nausea (10.4%). The mean body weight increased by < 1kg. The study also showed that 9.3% had ⩾ 7% weight gain, 5.7% had sedation, and 3% had somnolence. At the sixteenth week, the mean YMRS total score decreased by –15.2. Overall, cariprazine of 3-12 mg/day (6.2 mg/day mean dose) was well tolerated in bipolar I patients with associated acute manic or mixed episodes.⁵⁶

A phase II trial looked into the safety, efficacy, and tolerability of cariprazine (3–12 mg/day) in the treatment of acute manic or mixed episodes associated with bipolar I disorder. Patients were randomized to flexible-dose cariprazine or placebo for three weeks. Cariprazine significantly decreased YMRS scores compared to placebo, least-square mean difference of –6.1 (p < 0.001). Additionally, cariprazine significantly decreased CGI-S scores versus placebo, the least square mean difference of –0.6 (p < 0.001). From baseline to the third week, each YMRS item’s change was significant for cariprazine compared to placebo (all, p < 0.05). At the 3rd week, a larger percentage of cariprazine versus placebo-treated patients reached YMRS response (48% versus 25%; p < 0.001) and remission criteria (42% versus 23%; p = 0.002). Due to AEs, 12 placebo (10%) and 17 cariprazine (14%) patients discontinued the trial. Akathisia, extrapyramidal disorder, headache, nausea, dyspepsia, and constipation were the most common AEs (> 10% for cariprazine). The metabolic parameters demonstrated comparable changes except for fasting glucose in which cariprazine was associated with elevations in glucose levels compared to placebo (p < 0.05). The study concluded that cariprazine was effective compared to placebo in treating acute manic or mixed episodes associated with bipolar I disorder.⁵⁷

A phase III trial investigated the efficacy, safety, and tolerability of both high and low doses of cariprazine in the treatment of acute manic or mixed episodes of bipolar I disorder. Patients were randomized to cariprazine 3–6 mg/day, cariprazine 6–12 mg/day, or placebo for three weeks. The LSMD for change from baseline to the third week in the Young Mania Rating Scale (YMRS) total score was statistically significant in favor of both cariprazine groups compared to placebo (LSMD [95% CI]: 3–6 mg/day, –6.1 [–8.4 to –3.8]; 6–12 mg/day, –5.9 [–8.2, –3.6]; P < .001 [both]). On all 11 YMRS single items, both low and high dose cariprazine groups demonstrated statistical significance versus placebo (all comparisons, P < .05). The change from baseline for both cariprazine groups was statistically significant versus placebo regarding CGI-S scores (LSMD [95% CI]: 3–6 mg/day, −0.6 [–0.9 to –0.4]; 6–12 mg/day, –0.6 [–0.9 to –0.3]; P < .001 [both]). The most common adverse event (⩾ 5% and twice the rate of placebo) for both cariprazine groups was akathisia, and the most common adverse events for the 6–12 mg/day cariprazine group were tremor, nausea, and constipation. The study concluded that high and low dose cariprazine demonstrated efficacy in treating acute manic or mixed episodes of bipolar I disorder compared to placebo.⁵⁸

A phase III randomized, double-blind, placebo-controlled flexible-dose study evaluated the efficacy of cariprazine (3–12 mg/day) in treating patients with acute manic or mixed episodes associated with bipolar I disorder. Patients receiving cariprazine 3–12 mg/day compared to placebo demonstrated a significant mean change in YMRS total score from baseline to the third week (P = 0.0004). By the first post-baseline assessment (day 4), the study observed significant differences in YMRS total score mean change between cariprazine versus placebo-treated group; and such differences persisted through the duration of the double-blind treatment (all assessments, P < 0.01). The cariprazine group exhibited statistically significant improvement compared to placebo regarding YMRS response (⩾ 50% improvement: cariprazine, 58.9%; placebo, 44.1%; P= 0.0097), remission (YMRS total score ⩽ 12: cariprazine, 51.9%; placebo, 34.9%; P=0.0025), mean change in CGI-S score (P = 0.0027) and PANSS total score (P = 0.0035). The most common adverse events the cariprazine group (⩾ 10% and twice placebo) were akathisia, tremor, extrapyramidal disorder, dyspepsia, and vomiting. Between the groups, the metabolic parameters demonstrated small and similar mean changes from baseline. The study concluded 3–12 mg/day cariprazine effective in treating acute manic and mixed episodes associated with bipolar I disorder.⁵⁹

A posthoc analysis examined the data from three similarly designed studies on the efficacy of cariprazine (3–12 mg/day) in the treatment of mania associated with bipolar I disorder. The three trials were RGH-MD-31 [NCT00488618], RGH-MD-32 [NCT01058096], and RGH-MD-33 [NCT01058668]. The combined intent-to-treat (ITT) population included placebo=429 and cariprazine=608. On all 11 YMRS single items, cariprazine demonstrated statistically significant superiority versus placebo (p < 0.0001). At the conclusion of treatment, significantly more cariprazine patients had mild to no symptoms on 11 YMRS items compared to placebo (p < 0.0001); significantly more cariprazine patients had mild to no symptoms regarding the 4 YMRS core symptoms of speech, content, irritability, and disruptive–aggressive behavior (p < 0.0001). Significantly more cariprazine-treated patients compared to placebo-treated patients shifted from moderate/worse symptoms to mild/no symptoms on all 11 (p < 0.0001), and from marked/worse symptoms to mild/no symptoms on 9 of 11 YMRS items (p < 0.05). The analysis concluded that cariprazine demonstrated efficacy in treating mania.⁶⁰

Conclusion

Schizophrenia and bipolar disorder are psychiatric conditions related to the dysregulation of dopamine, resulting in impairment of function and reduced quality of life. Dopaminergic changes in these disorders may result in a broad spectrum of clinical manifestations, including delusions, disorganized thought, disorganized, speech, and irritability. Atypical antipsychotics have been designed to modify the activity of the dopamine system in an attempt to regulate factors of these disorders that impair daily function, and have been shown to reduce agitation, delusions, mania, and more. Most available drugs for the treatment of schizophrenia and bipolar disorder work by either partially agonizing or antagonizing different dopamine receptors.

Prolonged use of atypical psychotics can result in tardive dyskinesia, metabolic changes, orthostatic hypotension, neuroleptic malignant syndrome, and extrapyramidal symptoms such as acute dystonia and akathisia. Cariprazine, in recent studies, has shown some promise in being able to treat both bipolar disorder in manic, depressed, and mixed states as well as schizophrenia. Side effects noted as adverse events in these studies are similar in profile to the medications that were developed in the past though metabolic profiles were noted to not be elevated or have only a slight elevation as compared to baseline, which makes this drug seemingly superior to second-generation antipsychotics. This only compares to clozapine in terms of lessening increases in metabolic profile. However, there isn’t a noted need for continual lab monitoring, as seen in clozapine. Howevver, clozapine has been shown to decrease suicidiality in patients with schizophrenia or schizoaffective disorder while cariprazine does not show this effect. Since this is the case and it has been shown in studies to be effective in relapse prevention, perhaps cariprazine could be a viable alternative to clozapine in patients who were intolerant to other medications.

Table 1. Clinical Efficacy and Safety – Schizophrenia.

Author Year	Groups Studied And Intervention	Results And Findings	Conclusions
Kane, J. et al. (2015)73	Phase III trial on the efficacy and safety of cariprazine 3 to 6 mg/d or cariprazine 6 to 9 mg/d in the treatment of acute exacerbation of schizophrenia. Efficacy measures included the change from baseline to the 6th week in total PNSS and CGI-S scores. NCT01104779	Statistically significant least-squares mean differences were observed for PNSS and CGI-S scores in favor of cariprazine versus placebo. Common TEAEs in both cariprazine groups included akathisia, extrapyramidal disorder, and tremor. All groups had decreased prolactin levels. Regarding metabolic parameters, the mean changes were generally small and similar.	Cariprazine 3–6 and 6–9 mg/d was efficacious and generally well tolerated.
Durgam, S. et al. (2016)74	6 week, double-blind, placebo controlled study on low and high dose cariprazine in patients with a schizophrenia diagnosis of at least 1 year. Efficacy measures were Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression-Severity (CGI-S). NCT00404573	The low dose cariprazine group’s symptoms significantly improved compared to the placebo group based on the primary efficacy parameter. The overall effect of cariprazine was not significant.	While the overall treatment effect of cariprazine was not significant, the 1.5–4.5 mg/day (low dose) group had significantly improved symptoms and was well tolerated.
Nakamura, T. et al. (2016)75	28 week (12 week treatment) randomized, open-label study on the pharmacokinetics of cariprazine anddesmethyl-cariprazine and didesmethyl-cariprazine. Safety and efficacy of cariprazine was also analyzed.	For cariprazine and desmethyl-cariprazine, steady state was reached within 1–2 weeks; didesmethyl-cariprazine reached steady state in 4 weeks. TEAEs incidence was 97.4%; 15.8% of patients discontinued due to adverse events. The study did not observe any abnormal laboratory values or major differences from baseline in extrapyramidal symptoms.	Cariprazine and associated metabolites achieved steady state at 4 weeks. The study concluded that cariprazine taken once daily was well tolerated.
Durgam, S. et al. (2014)76	Phase II, double-blind, randomized, placebo- and active-controlled fixed dose study on cariprazine (1.5, 3.0, 4.5 mg/day), placebo, or 4.0 mg/day risperidone for the treatment of acute exacerbation of schizophrenia. Efficacy parameters included PANSS and CGI-S. adverse events (AEs), vital signs, laboratory. measures, and extrapyramidal symptom (EPS) scales made up the safety parameters. NCT00694707 RGH-MD-16	PANSS total score improvement at week 6 was statistically significant versus placebo for cariprazine 1.5 mg/d, 3.0 mg/d, and 4.5 mg/d and risperidone. For all active treatments, there was a significant improvement on CGI-S. Frequent AEs for cariprazine included akathisia, insomnia, extrapyramidal disorder, constipation. Mean changes were small and similar in regard to metabolic parameters.	Based on the results of the study, cariprazine in patients with acute exacerbation of schizophrenia is both safe and efficacious.
Durgam, S. et al. (2015)77	Phase III randomized, double-blind study lasting ~20 months examined the efficacy, tolerability, and safety of cariprazine in patients with acute exacerbation of schizophrenia. The efficacy parameters were the mean change from baseline to week 6 in PANSS total score and CGI-S. NCT01104766 RGH-MD-04	At week 6, the least-squares mean differences (LSMDs) in PANSS total score change significantly favored cariprazine 3 and 6 mg/d versus placebo. Cariprazine 3 and 6 mg/d had improved CGI-S compared to placebo. There were also significant differences in PANSS and CGI-S with placebo vs. aripiprazole. All groups had insomnia as a common TEAE. Cariprazine 6 mg/d was associated with TEAE of akathisia. Both placebo and cariprazine 6 mg/d had headache as a TEAE.	Cariprazine 3 and 6 mg/d is safe, efficacious, and well tolerated regarding the treatment of acute exacerbation of schizophrenia.
Durgam, S. et al. (2017)78	48 week single-arm, open-label extension study on long-term safety and efficacy of cariprazine for patients with schizophrenia. NCT00839852 RGH-MD-17	Approximately 50 % of patients were able to complete the 48 week study. Prolactin elevation or changes in cardiovascular parameters were not observed with long-term cariprazine.	There were no new safety concerns associated with long-term treatment. Overall, cariprazine (1.5–4.5 mg/day) treatment was safe and well tolerated.
Durgam, S. et al. (2016)79	Study duration of up to 97 weeks on safety, efficacy, and tolerability of cariprazine for the prevention of relapse in schizophrenia. Efficacy parameter was time to relapse. NCT01412060	The time to relapse was significantly longer in cariprazine treated patients compared to placebo treated patients. In 24.8% of cariprazine-treated patients and in 47.5% of placebo-treated patients relapse occurred. The TEAEs that ⩾ 10% of patient reported during open-label treatment included akathisia (19.2%), insomnia (14.4%), and headache (12.0%). In the double-blind treatment, there were no cariprazine adverse events ⩾ 10%.	Cariprazine had significant efficacy in the prevention of relapse in patients with schizophrenia.
Cutler, A. et al. (2018)80	53 week open-label long-term study on cariprazine 3–9 mg/day for patients with schizophrenia. The study comprised of new patients and patients who had completed one of two phase III lead-in studies. NCT01104792	Approximately 39% of patients completed the 53 weeks study. Prolactin levels demonstrated a slight decrease. There were no safety issues. The mean weight gain was 1.5kg. Most common AEs included akathisia, headache, insomnia, and weight gain. Serious AEs occurred in 10.1%. Due to AEs, 12.5% discontinued the study.	Long term 9 mg/day cariprazine appeared to be safe and well tolerated.
Németh, G. et al. (2017)81	Phase 3b randomized double-blind trial regarding monotherapy of cariprazine vs. risperidone for 26 weeks in adult patients with long-term stable schizophrenia who had predominantly negative symptoms. EudraCT Number 2012-005485-36	4.2 mg for cariprazine and 3.8 mg for risperidone were the mean daily doses. 54% of cariprazine patients and 57% of risperidone patients reported TEAEs such as akathisia, insomnia, worsening of schizophrenia. From baseline to week 26, the use of cariprazine led to a greater least-squares mean change in PANSS-FSNS than did risperidone.	Cariprazine is an efficacious treatment for negative symptoms of schizophrenia.
Németh, B. et al. (2017)82	A study on the potential gain in quality-adjusted life years (QALYs) over a period of 54 weeks due to cariprazine treatment in patients with predominantly negative symptoms of schizophrenia compared to risperidone. This study is based on the PANSS data from the (Eudra CT, number 2012-005485-36) clinical trial.	Patients in the cariprazine group had a higher probability of reaching better states of health than the risperidone group.	Cariprazine can provide gain in QALYs in patients with predominantly negative symptoms of schizophrenia compared with risperidone.
Earley, W. et al. (2019)83	Post hoc analyses examined the efficacy of cariprazine in treating moderate/severe negative symptoms of schizophrenia. The studies gathered data from two similarly constructed, six week, phase II/III studies cariprazine studies (NCT00694707, NCT01104766).	Significant differences in contrast to placebo for cariprazine and risperidone, but not aripiprazole, and versus aripiprazole for cariprazine. Differences in contrast to placebo remained statistically significant for cariprazine but not for risperidone after adjusting for positive symptom changes. The PANSS-FSNS response rates were significantly higher for patients on cariprazine than the placebo.	Cariprazine is an effective treatment for the negative symptoms of schizophrenia.
Correll, C. et al. (2019)84	Post hoc analyses examined the data from a cariprazine relapse prevention study (NCT01412060) and examined the efficacy of cariprazine in maintaining remission in patients with schizophrenia. The study defined symptomatic remission as scores of ⩽ 3 on 8 items from the General, Positive, and Negative Symptoms subscales of the PANSS. Additionally, sustained remission included patients meeting the remission criteria at current and all previous double-blind visits or for ⩾ 6 consecutive months.	The time to loss of sustained remission was significantly longer for cariprazine compared to placebo during the double-blind treatment. 60.5% of patients treated with cariprazine and 34.9% of patients treated with placebo sustained remission through the final visit. Approximately double as many cariprazine-treated patients (39.6%) as placebo-treated (21.2%) patients met the symptomatic remission criteria at all visits ⩾ 6 consecutive months immediately before/including the final double- blind visit. The study also demonstrated more cariprazine-treated patients (41.6%) than placebo-treated (27.3%) patients sustained remission for any ⩾ 6 consecutive month period.	Cariprazine was effective in providing higher rates of remission and significantly greater sustained remission in patients with schizophrenia.
Fleischhacker, W. et al. (2019)85	Post hoc analysis examined the score change from baseline to the 26th week on individual components of PANSS and PANSS-derived factor models. The analysis was based on phase IIIb clinical trial (EudraCT Number 2012-005485-36) that investigated cariprazine vs. risperidone in the treatment of patients with schizophrenia who had predominantly negative symptoms.	Significant difference was observed from baseline in favor of cariprazine in contrast to risperidone on the following PANSS items (N1-N5), but this difference was not observed for N6 or N7. The study demonstrated statistically significant improvement for cariprazine versus risperidone in all PANSS-derived negative symptom factor models. On PANSS-based factors examining additional symptoms, there was a significant change from baseline for cariprazine compared to risperidone.	Cariprazine may have efficacy across a broad-spectrum in the treatment of negative symptoms of schizophrenia.

Table 2. Clinical Efficacy and Safety – Bipolar Disorder.

Author Year	Groups Studied And Intervention	Results And Findings	Conclusions
Calabrese, J. et al. (2015)86	Phase III, double-blind trial of efficacy, safety, and tolerability of high (6–12 mg/day) and low (3–6 mg/day) doses of cariprazine in the treatment of acute manic or mixed episodes of bipolar I disorder. Efficacy parameters were change from baseline to the 3rd week in Young Mania Rating Scale (YMRS) total score and CGI-S score. NCT01058668 RGH-MD-33	The LSMD for change from baseline to the third week in the YMRS total score was statistically significant in favor of both cariprazine groups compared to placebo. On all 11 YMRS single items, both cariprazine groups demonstrated statistical significance vs. placebo. The change from baseline for both cariprazine groups was statistically significant vs. placebo regarding CGI-S scores. Common TEAEs for both cariprazine groups was akathisia; and for the 6–12 mg/day cariprazine group were tremor, nausea, and constipation.	Cariprazine was well-tolerated; however, there was a greater incidence of akathisia with cariprazine than placebo. Both high and low dose cariprazine demonstrated efficacy in treating acute manic or mixed episodes of bipolar I disorder compared to placebo.
Vieta, E. et al. (2015)87	A post-hoc analysis examined the data from three similarly designed studies on the efficacy of cariprazine (3–12 mg/day) in the treatment of mania associated with bipolar I disorder. The trials included: RGH-MD-31 [NCT00488618] RGH-MD-32 [NCT01058096] RGH-MD-33 [NCT01058668]	On all 11 YMRS single items, cariprazine demonstrated statistically significant superiority vs. placebo. Significantly more cariprazine patients had mild to no symptoms on 11 YMRS items vs. placebo; significantly more cariprazine patients had mild to no symptoms regarding the 4 YMRS core symptoms of speech, content, irritability, and disruptive–aggressive behavior. Significantly more cariprazine patients vs. placebo shifted from moderate/worse symptoms to mild/no symptoms on all 11, and from marked/worse symptoms to mild/no symptoms on 9 of 11 YMRS items.	Cariprazine demonstrated efficacy in treating mania associated with bipolar I disorder.
Sachs, G. et al. (2015)88	Phase III trial of the efficacy of cariprazine (3–12 mg/day) in treating patients with acute manic or mixed episodes associated with bipolar I disorder. Efficacy parameters included change from baseline to the 3rd week in YMRS total score and (CGI-S) score. NCT01058096 RGH-MD-32	Cariprazine vs. placebo demonstrated a significant mean change in YMRS total score from baseline to the third week. Cariprazine vs. placebo exhibited statistically significant improvement in YMRS response, remission, mean change in CGI-S score and PANSS total score. The most common TEAEs in the cariprazine group were akathisia, tremor, extrapyramidal disorder, dyspepsia, and vomiting. Between the groups, the metabolic parameters demonstrated small and similar mean changes from baseline.	Cariprazine (3–12 mg/day) was effective in treating acute manic and mixed episodes associated with bipolar I disorder.
Durgam, S. et al. (2015)89	Phase II trial on the safety, efficacy, and tolerability of cariprazine (3–12 mg/day) in the treatment of acute manic or mixed episodes associated with bipolar I disorder. NCT00488618	Cariprazine significantly decreased YMRS scores and CGI-S scores. The change for YMRS items was significant for cariprazine vs. placebo. A larger percentage of cariprazine vs. placebo-treated patients reached YMRS response and remission criteria. Akathisia, extrapyramidal disorder, headache, nausea, dyspepsia, and constipation were the most common AEs. Metabolic parameters demonstrated comparable changes except with fasting glucose in which cariprazine was associated with elevations in glucose levels vs. placebo.	Cariprazine was effective compared to placebo in treating acute manic or mixed episodes associated with bipolar I disorder.
Earley, W. et al. (2018)90	Post-hoc analyses examined the data from three studies on the efficacy of cariprazine in manic and mixed episodes associated with bipolar I disorder to evaluate response and remission. The trials included: NCT00488618 NCT01058096 NCT01058668	Response rates and remission for cariprazine were greater compared to placebo.	Cariprazine improved manic symptoms. The improvement in manic symptoms did not lead to depressive symptoms.
McIntyre, R. et al. (2019)91	Post-hoc analysis examined three studies regarding the efficacy of cariprazine in treating mania with mixed features associated with bipolar I disorder. The analysis looked at the cariprazine effects regarding manic and depressive symptoms. Criteria for patients with mania and mixed features: ⩾ 3 depressive symptoms (DSM-5), ⩾ 2 depressive symptoms (DS), and MADRS total score of ⩾ 10. The trials included: NCT00488618 NCT01058096 NCT01058668	The mean YMRS score for cariprazine was significant compared to placebo. YMRS response and remission criteria were met by more cariprazine-treated patients vs. placebo with the response and remission data for ⩾ 2 DS and ⩾ 10 MADRS being statistically significant. There was also. improvement in depressive symptoms vs. placebo with the data being significant for the ⩾ 10 MADRS subgroup	Manic and depressive symptoms were reduced by cariprazine in the examined subpopulations with various levels of efficacy.
Earley, W. et al. (2019)92	Phase III trial assessed cariprazine in treating bipolar I depression. Efficacy parameters were changes from baseline to week 6 in MADRS score and CGI-S score. NCT02670551	Cariprazine 1.5 mg/day and 3.0 mg/day demonstrated greater efficacy by decreasing the MADRS total score vs. placebo. The data for the cariprazine groups and CGI-S scores were not statistically significant. The common TEAEs were akathisia, sedation, nausea, and dizziness. Between the groups, the metabolic and weight parameters demonstrated small and similar mean changes.	1.5 mg/day and 3.0 mg/day of cariprazine were effective in improving depressive symptoms associated with bipolar I depression.
Fava, M. et al. (2018)93	Phase 2, 19 week double-blind, randomized study of adjunctive cariprazine (0.1-0.3 and 1.0-2.0 mg/day) for treatment-resistant major depressive disorder. The primary endpoint was the total score change of MADRS and the secondary endpoint was CGI-S. NCT00854100	None of the parameters met statistical significance. The 1.0–2.0 mg/day cariprazine patients had a greater mean decrease in MADRS and CGI scores.	Cariprazine was well tolerated. The mean decrease in depression symptoms with the 1.0-2.0 mg/day dose provides support for further assessment.
Ketter, T. et al. (2018)94	16 week, open-label study on safety and tolerability of cariprazine (3-12 mg/day) with bipolar mania patients. Evaluations for safety included adverse events (AEs); and symptom changes included the total score change of the Young Mania Rating Scale (YMRS). (NCT01059539)	Common serious AEs were mania and depression. 83.3% had TEAEs which included akathisia, headache, constipation, and nausea. At the sixteenth week, the mean YMRS total score decreased by –15.2.	Cariprazine was well tolerated and safe.
Durgam, S. et al. (2016)53	8 week, randomized, double-blind, placebo controlled study with bipolar I patients currently experiencing a major depressive episode, 4 groups, cariprazine (0.75, 1.5, 3.0 mg/day) or placebo. The primary and secondary efficacy parameters were the score change from baseline to the sixth week on the Montgomery-Åsberg Depression Rating Scale (MADRS) and CGI-S. NCT01396447	The cariprazine 1.5mg/day group demonstrated significant improvement of total MADRS score.	Cariprazine at 1.5 mg/day showed statistically significant improvement on MADRS score and CGI-S. This dosage could possibly be an effective dose in treating bipolar I depression.