Efficacy of cariprazine in patients with bipolar depression and higher or lower levels of baseline anxiety: a pooled post hoc analysis.

Post hoc analyses evaluated cariprazine, a dopamine D 3 -preferring D 3 /D 2 receptor partial agonist, in patients with bipolar I depression and high baseline anxiety. Data were pooled from two phase 3, randomized, double-blind, placebo-controlled studies in adults with bipolar I disorder and a major depressive episode (NCT02670538, NCT02670551). Cariprazine 1.5 and 3 mg/d were evaluated in patient subgroups with higher and lower baseline anxiety. In patients with higher baseline anxiety, significant differences for cariprazine 1.5 mg/d versus placebo were observed on change in Montgomery-Åsberg Rating Scale (MADRS) total score, Hamilton Anxiety Rating Scale (HAM-A) total score and subscale scores, and rates of MADRS remission ( P < 0.05 all); nonsignificant numerical improvements were observed for cariprazine 3 mg/d versus placebo. In patients with lower anxiety, differences versus placebo were significant for HAM-A (cariprazine 3 mg/d) and MADRS (cariprazine 1.5 and 3 mg/d) total score changes ( P < 0.05 all). Rates of treatment-emergent mania were low and similar for cariprazine and placebo. Cariprazine 1.5 mg/d had consistent effects on anxiety and depression symptoms in patients with bipolar I depression and higher baseline anxiety; tolerability was favorable. Given few proven treatments for this common comorbidity, these preliminary results are promising.

The efficacy of cariprazine on cognition: a post hoc analysis from phase II/III clinical trials in bipolar mania, bipolar depression, and schizophrenia.

OBJECTIVE: To investigate the effect of cariprazine on cognitive symptom change across bipolar I disorder and schizophrenia. METHODS: Post hoc analyses of 3- to 8-week pivotal studies in bipolar I depression and mania were conducted; one schizophrenia trial including the Cognitive Drug Research System attention battery was also analyzed. Outcomes of interest: Montgomery-Åsberg Depression Rating Scale [MADRS], Functioning Assessment Short Test [FAST], Positive and Negative Syndrome Scale [PANSS]). LSMDs in change from baseline to end of study were reported in the overall intent-to-treat population and in patient subsets with specified levels of baseline cognitive symptoms or performance. RESULTS: In patients with bipolar depression and at least mild cognitive symptoms, LSMDs were statistically significant for cariprazine vs placebo on MADRS item 6 (3 studies; 1.5 mg=-0.5 [P<.001]; 3 mg/d=-0.2 [P<.05]) and on the FAST Cognitive subscale (1 study; 1.5 mg/d=-1.4; P=.0039). In patients with bipolar mania and at least mild cognitive symptoms, the LSMD in PANSS Cognitive subscale score was statistically significant for cariprazine vs placebo (3 studies; -2.1; P=.001). In patients with schizophrenia and high cognitive impairment, improvement in power of attention was observed for cariprazine 3 mg/d vs placebo (P=.0080), but not for cariprazine 6 mg/d; improvement in continuity of attention was observed for cariprazine 3 mg/d (P=.0012) and 6 mg/d (P=.0073). CONCLUSION: These post hoc analyses provide preliminary evidence of greater improvements for cariprazine vs placebo across cognitive measures in patients with bipolar I depression and mania, and schizophrenia, suggesting potential benefits for cariprazine in treating cognitive symptoms.

Pharmacokinetics, Safety, and Tolerability of Cariprazine in Pediatric Patients with Bipolar I Disorder or Schizophrenia.

Objective: Cariprazine is a dopamine D3-preferring D3/D2 and serotonin 5-HT1A receptor partial agonist approved to treat adults with schizophrenia and manic/mixed or depressive episodes associated with bipolar I disorder. This sequential-cohort, dose-escalation study was the first to evaluate the pharmacokinetic, safety, and tolerability profile of cariprazine and its two major active metabolites, desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR), in pediatric patients with schizophrenia or bipolar I disorder. Methods: This phase I open-label study enrolled patients with schizophrenia (13-17 years of age) or bipolar I disorder (10-17 years of age). Patients met the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for schizophrenia or bipolar I disorder and had Positive and Negative Syndrome Scale (PANSS) total scores ≥70 or Young Mania Rating Scale (YMRS) total scores ≥20. Patients were assigned to one of four treatment groups to receive 6 weeks of cariprazine treatment through slow titration to 1.5, 3, or 4.5 mg/d or fast titration to 4.5 mg/d. Pharmacokinetics, adverse events (AEs), and various safety parameters were analyzed. Efficacy was evaluated as an exploratory outcome. Results: A total of 50 participants were enrolled. Based on mean trough levels, steady state appeared to be reached within 1-2 weeks for cariprazine and DCAR and within 4-5 weeks for DDCAR. Systemic exposure of cariprazine, DCAR, and DDCAR generally increased approximately in proportion to the increases in dose from 1.5 to 4.5 mg/d. The most frequent treatment-related, treatment-emergent AEs included sedation, parkinsonism, tremor, dystonia, and blurred vision. Improvements from baseline on the PANSS and YMRS were observed throughout treatment. Conclusion: In this first investigation of cariprazine in a pediatric population with schizophrenia or bipolar disorder, pharmacokinetic parameters were consistent with those observed in adults. Cariprazine appeared to be safe and tolerable in children and adolescents.

Minimal Effects of Cariprazine on Prolactin Levels in Bipolar Disorder and Schizophrenia.

Background: Many medications used to treat schizophrenia and bipolar I disorder are linked to hyperprolactinemia. The effects of cariprazine, a dopamine D3/D2 receptor partial agonist, on prolactin levels in patients with schizophrenia or bipolar I disorder were evaluated. Methods: Effects on prolactin were evaluated using pooled data from randomized, double-blind, placebo-controlled studies in patients with schizophrenia (4 studies; 6-week duration; cariprazine 1.5-3 mg/d, 4.5-6 mg/d, and 9-12 mg/d), bipolar mania (3 studies; 3-week duration; cariprazine 3-6 and 9-12 mg/d), and bipolar depression (3 studies; 6- to 8-week duration; cariprazine 1.5 and 3 mg/d). Long-term effects were analyzed using open-label studies in patients with schizophrenia (2 studies; 48-week duration) and patients with bipolar mania (1 study; 16-week duration). Change in prolactin levels (ng/mL) from baseline to study endpoint was evaluated in subsets of sex and prior medication use. Results: In patients with schizophrenia (male, n = 1377; female, n = 558), median prolactin changes were -1.2 for males and -7.4 for females on placebo, and ranged from -4.2 to -3.6 for males and -12.4 to +0.2 for females in the cariprazine-treatment groups. In patients with bipolar mania (male, n = 570; female, n = 395), median prolactin changes were -0.2 for males and -1.1 for females on placebo and ranged from -2.1 to -3.0 for males and 0 to +1.8 for females in the cariprazine-treatment groups. Median decreases were also seen in the long-term studies of schizophrenia (range, -14.6 to -2.0) and bipolar mania (range, -0.8 to +1.9). In patients with bipolar depression (male, n = 485; female, n = 780), median prolactin changes were +0.3 for males and +0.7 for females on placebo and ranged from +0.4 to +0.5 for males and +3.0 to +3.1 for females in the cariprazine-treatment groups. Conclusion: Treatment with cariprazine for schizophrenia or bipolar I disorder was associated with minimal effects on prolactin levels.

Disentangling the symptoms of schizophrenia: Network analysis in acute phase patients and in patients with predominant negative symptoms.

BACKGROUND: The Positive and Negative Syndrome Scale (PANSS) is widely used in schizophrenia and has been divided into distinct factors (5-factor models) and subfactors. Network analyses are newer in psychiatry and can help to better understand the relationships and interactions between the symptoms of a psychiatric disorder. The aim of this study was threefold: (a) to evaluate connections between schizophrenia symptoms in two populations of patients (patients in the acutely exacerbated phase of schizophrenia and patients with predominant negative symptoms [PNS]), (b) to test whether network analyses support the Mohr 5 factor model of the PANSS and the Kahn 2 factor model of negative symptoms, and finally (c) to identify the most central symptoms in the two populations. METHODS: Using pooled baseline data from four cariprazine clinical trials in patients with acute exacerbation of schizophrenia (n = 2193) and the cariprazine-risperidone study in patients with PNS (n = 460), separate network analyses were performed. Network structures were estimated for all 30 items of the PANSS. RESULTS: While negative symptoms in patients with an acute exacerbation of schizophrenia are correlated with other PANSS symptoms, these negative symptoms are not correlated with other PANSS symptoms in patients with PNS. The Mohr factors were partially reflected in the network analyses. The two most central symptoms (largest node strength) were delusions and uncooperativeness in acute phase patients and hostility and delusions in patients with PNS. CONCLUSIONS: This network analysis suggests that symptoms of schizophrenia are differently structured in acute and PNS patients. While in the former, negative symptoms are mainly secondary, in patients with PNS, they are mainly primary. Further, primary negative symptoms are better conceptualized as distinct negative symptom dimensions of the PANSS.

The efficacy of cariprazine on function in patients with bipolar depression: a post hoc analysis of a randomized controlled trial.

INTRODUCTION: Individuals with bipolar depression often experience functional impairment that interferes with recovery. These analyses examined the effects of cariprazine on functional outcomes in patients with bipolar I disorder. METHODS: Prespecified analyses of data from a randomized, double-blind, placebo-controlled pivotal trial of cariprazine in bipolar I depression (NCT01396447) evaluated mean changes from baseline to week 8 in Functional Assessment Short Test (FAST) total score. Post hoc analyses with no adjustment for multiplicity evaluated FAST subscale scores, functional recovery and remission (FAST total score ≤11 and ≤20, respectively), and 30% or 50% improvement from baseline. RESULTS: There were 393 patients with bipolar I disorder (placebo = 132; cariprazine: 1.5 mg/d = 135, 3 mg/d = 126) in the FAST analysis population. Statistically significant differences were noted for cariprazine 1.5 mg/d versus placebo in mean change from baseline in FAST total score (p<.01) and on 5 of 6 subscale scores (p<.05); cariprazine 3 mg/d was significantly different than placebo on the Interpersonal Relationship subscale (p<.05). Rates of functional remission and recovery, and ≥30% or ≥50% improvement were significantly greater for cariprazine 1.5 mg/d versus placebo (p<.05 all); the percentage of patients with ≥30% improvement was significantly different for cariprazine 3 mg/d versus placebo (p<.05). CONCLUSION: At week 8, statistically significant improvements in FAST outcomes were observed for cariprazine versus placebo in patients with bipolar I depression; more consistent results were noted for 1.5 mg/d than 3 mg/d. In addition to improving bipolar depression symptoms, these results suggest that cariprazine may improve functional outcomes.

Safety and Tolerability of Cariprazine in Patients with Schizophrenia: A Pooled Analysis of Eight Phase II/III Studies.

BACKGROUND: Long-term treatment with antipsychotic agents is indicated for patients with schizophrenia, but treatment is associated with adverse events (AEs) that contribute to medication discontinuation and nonadherence. Understanding drug safety profiles is critical to avoid unwanted side effects. Cariprazine is a potent dopamine D3/D2 receptor partial agonist that is approved for the treatment of adults with schizophrenia (EU, US) and acute manic/mixed and depressive episodes associated with bipolar I disorder (US). METHODS: Post hoc analyses were conducted to characterize the safety profile of cariprazine within the recommended 1.5-6 mg/d dose range for schizophrenia; data from 8 short- or long-term clinical trials were analyzed. RESULTS: In the pooled cariprazine-treated safety population (n=2048), the rate of study completion was 52.8%, with withdrawal of consent, insufficient response, and AEs the most common reasons for premature discontinuation. The most commonly reported AEs (>10%) in the overall cariprazine-treatment group were akathisia (14.6%), insomnia (14.0%), and headache (12.1%); most AEs were considered mild (71.0%) or moderate (26.5%). Most akathisia was mild/moderate (97.5%) and >93% of patients remained on treatment; akathisia events were managed by rescue medications (56.3%) or dose reduction (18.3%). The metabolic profile of cariprazine was neutral in patients with short- and long-term exposure; mean weight gain was 1 kg for overall cariprazine, with an AE of weight increased reported for 5.1%. Other AEs of special interest that occurred at >3% for overall cariprazine were extrapyramidal disorder (7.0%), sedation (3.7%), and somnolence (3.1%); prolactin elevation, cognition impairment, sexual dysfunction, suicidality, and QT prolongation occurred at ≤1%. CONCLUSION: Akathisia, the most common cariprazine-related AE, was mild/moderate and resulted in few study discontinuations; symptoms were well managed and most patients remained on treatment. Results of this analysis indicated that cariprazine in the recommended dose range was safe and generally well tolerated in patients with schizophrenia. TRIAL REGISTRATION: Studies registered with ClinicalTrials.gov (NCT00404573, NCT01104779, NCT00694707, NCT01104766, NCT01104792, NCT00839852, and NCT01412060) and EudraCT (2012-005485-36).

Cariprazine and akathisia, restlessness, and extrapyramidal symptoms in patients with bipolar depression.

BACKGROUND: Akathisia is a neuropsychiatric syndrome that is commonly related to the use of dopamine receptor antagonists/partial agonists. The characteristics of cariprazine-related akathisia, restlessness, and extrapyramidal symptoms (EPS) were investigated in patients with bipolar I depression. METHODS: Akathisia-related data from 3 fixed-dose clinical studies of cariprazine 1.5 mg/d and 3 mg/d in bipolar depression were evaluated in pooled post hoc analyses. Outcomes related to treatment-emergent adverse events (TEAEs) included incidence, time to onset, time to resolution, severity, discontinuations, and rescue medication use. RESULTS: The incidence of akathisia was 7.6% for overall cariprazine (1.5 mg/d=5.5%; 3 mg/d=9.6%) and 2.1% for placebo; acute EPS occurred in 4.5% of cariprazine-treated (1.5 mg/d=3.8%; 3 mg/d=5.1%) and 2.1% of placebo-treated patients. Findings were similar for restlessness. Most TEAEs were mild/moderate (>95%), occurred during the first 3 weeks of cariprazine initiation or dose increase, and resulted in few discontinuations (<3%); median time to resolution of an akathisia or EPS TEAE after the last dose of cariprazine was ~1 week. Rescue medication was used by <3% of patients to manage akathisia/EPS events. LIMITATIONS: Post hoc analyses; no active comparator. CONCLUSIONS: In patients with bipolar depression, the incidence of cariprazine-related akathisia was higher than acute EPS or restlessness, with lower cariprazine doses associated with lower incidences of events. Akathisia and EPS TEAEs occurred early in treatment and were mild/moderate in severity. Few patients with akathisia or acute EPS discontinued treatment. Cariprazine-related akathisia and EPS can be minimized with conservative dosing and titration strategies. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT01396447, NCT02670538, NCT02670551.

Efficacy of cariprazine in bipolar I depression across patient characteristics: a post hoc analysis of pooled randomized, placebo-controlled studies.

Patients who experience bipolar depression have diverse demographic and clinical characteristics that have the potential to impact treatment. The efficacy of cariprazine in bipolar I depression was evaluated in patient subgroups defined by baseline demographic and clinical characteristics. Post hoc analyses of data from three randomized, double-blind, placebo-controlled trials in bipolar I depression (NCT01396447, NCT02670538 and NCT02670551) evaluated mean change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total scores for pooled cariprazine 1.5-3 mg/d versus placebo in subgroups defined by demographic and clinical characteristics. The least-squares mean difference in MADRS total score change from baseline was statistically significant for cariprazine 1.5-3 mg/d versus placebo in all patient subgroups analyzed (P < 0.05 all subgroups): demographic characteristics (age, sex, white or black race and obese/nonobese BMI); episode characteristics (defined by current episode duration, number of previous manic/mixed and depressive episodes, and prior bipolar disorder medication use) and disease severity (groups above and below Clinical Global Impressions-Severity and MADRS cutoff scores). Cariprazine 1.5-3 mg/d consistently improved depressive symptoms in all patient subgroups without regard to differences in baseline demographic and clinical characteristics, suggesting broad efficacy across a spectrum of patients with bipolar I depression.

Broad Efficacy of Cariprazine on Depressive Symptoms in Bipolar Disorder and the Clinical Implications.

INTRODUCTION: Bipolar disorder is a complex mood disorder characterized by a chronic and subtle course of fluctuating manic/hypomanic and depressive symptoms. Cariprazine, a dopamine D3-preferring D3/D2 receptor partial agonist with serotonin 5-HT1A receptor partial agonist and serotonin 5-HT2A antagonist properties, is approved to treat manic and depressive episodes of bipolar disorder. Post hoc analyses evaluated efficacy across symptoms in bipolar depression. METHODS: Pooled data were analyzed from 3 phase 2 or 3, randomized, double-blind, placebo-controlled studies of adults with bipolar disorder and a major depressive episode. Mean change from baseline to week 6 in Montgomery-Asberg Depression Rating Scale (MADRS) total score and individual item scores were analyzed in individual dose groups (1.5 mg/d, 3 mg/d) and overall cariprazine (1.5-3 mg/d). Pooled safety was evaluated via adverse events. RESULTS: A significantly greater difference in mean change from baseline in MADRS total score was seen for each cariprazine dose group versus placebo (least squares mean difference vs placebo: 1.5-3 mg/d = -2.6, 1.5 mg/d = -2.8, 3 mg/d = -2.4) (P < .001 all). Significant differences versus placebo were seen on all individual MADRS items except inner tension for the overall cariprazine group (P < .05). Cariprazine was generally well tolerated. CONCLUSIONS: Cariprazine demonstrated broad efficacy across symptoms of depression in bipolar disorder. In previous post hoc analyses, cariprazine also demonstrated broad efficacy across manic symptoms, suggesting that it is effective across the wide range of symptoms on the bipolar spectrum. A 1.5-mg/d starting dose and slow titration resulted in lower rates of some adverse events in the bipolar depression studies versus the mania studies. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT01396447, NCT02670538, NCT02670551.

Evaluation of cariprazine in the treatment of bipolar I and II depression: a randomized, double-blind, placebo-controlled, phase 2 trial.

This double-blind placebo-controlled, fixed/flexible-dose phase 2 trial assessed the efficacy, safety, and tolerability of cariprazine vs. placebo for depressive episodes associated with bipolar I or II disorder. Primary endpoint was change in Montgomery-Åsberg Depression Rating Scale (MADRS) total scores (baseline to week 8), and secondary endpoint was mean Clinical Global Impressions-Improvement score (week 8). Patients were randomized (N = 233) 1:1:1 to placebo, 'low-dose' 0.25-0.5 mg/day or 'high-dose' 1.5-3.0 mg/day cariprazine. Adverse events, laboratory results, vital signs, extrapyramidal symptoms, and suicide risk were monitored. Neither cariprazine group significantly separated from placebo in primary (mixed-effect model repeated measures MADRS least-squares mean differences: low-dose = -0.7, P = 0.7408; high-dose = 0.0, P = 0.9961) or secondary efficacy measures. No new safety signals with cariprazine were observed and common treatment-emergent adverse events (≥5% of cariprazine patients and twice the rate of placebo) included insomnia, akathisia, dry mouth, nausea, weight increased, diarrhea, restlessness, vomiting, musculoskeletal stiffness, migraine, and cough. Metabolic and weight changes were generally similar for cariprazine and placebo. Factors that may have affected the outcome of the trial were identified, which helped to inform the design and conduct of subsequent phase 2b/3 clinical trials of cariprazine in bipolar depression.

A pooled post hoc analysis evaluating the safety and tolerability of cariprazine in bipolar depression.

BACKGROUND: The safety and efficacy of cariprazine, a dopamine D3-preferring D3/D2 receptor partial agonist and serotonin 5-HT1A receptor partial agonist, was evaluated in 4 randomized, double-blind, placebo-controlled trials in patients with bipolar depression. METHODS: Safety and tolerability were evaluated in 2 post hoc analyses. Modal dose analysis: pooled data from all 4 flexible/fixed-dose trials (dose groups: <1.5, 1.5, 3 mg/d). Fixed-dose analysis: pooled data from 2 identically designed fixed-dose trials (1.5 and 3 mg/d dose groups). RESULTS: The modal dose and fixed-dose analyses evaluated data from 1775 and 970 patients, respectively. Cariprazine was generally safe and well tolerated; study completion rates were 78% and 82% in the modal dose and fixed-dose analyses, respectively. In modal dose analysis, treatment-emergent adverse events (TEAEs) occurred in 60% of overall cariprazine- and 55% of placebo-treated patients; nausea (8% vs 3%) and akathisia (7% vs 2%) occurred in ≥5% of cariprazine patients and twice the rate of placebo. Metabolic changes were small and generally similar for cariprazine and placebo; mean increase in glucose was 3.1 mg/dL for cariprazine and 2.6 mg/dL for placebo. Fixed-dose and modal dose findings were generally consistent; values for most metabolic parameters were slightly higher for fixed-dose 3 mg/d versus 1.5 mg/d. LIMITATIONS: Post hoc analyses, modal dose groups, short treatment duration. CONCLUSIONS: In modal dose (0.25-3 mg/d) and fixed-dose (1.5 and 3 mg/d) analyses, cariprazine was generally safe and well tolerated in the treatment of bipolar depression. Slightly improved tolerability was observed with fixed-dose cariprazine 1.5 mg/d versus 3 mg/d. TRIAL REGISTRATION: clinicaltrials.gov NCT00852202, NCT01396447, NCT02670538, NCT02670551.

Efficacy and safety of cariprazine in bipolar I depression: A double-blind, placebo-controlled phase 3 study.

OBJECTIVE: To assess the efficacy, safety, and tolerability of cariprazine in the treatment of the depressed phase of bipolar I disorder in adults (NCT02670538). METHODS: In this phase 3 double-blind placebo-controlled study, adult patients with bipolar I disorder according to the Diagnostic and Statistical Manual - 5th Edition criteria and a current depressive episode were randomized to placebo (n = 167), cariprazine 1.5 mg/day (n = 168) or cariprazine 3.0 mg/day (n = 158). Efficacy parameters were changes in the Montgomery-Åsberg Depression Rating Scale (MADRS) total scores (primary) and Clinical Global Impressions - Severity (CGI-S) scores (secondary) from baseline to Week 6 compared to placebo. A mixed-model for repeated measures was used to estimate the least-squares mean differences (LSMD); P-values were adjusted for multiplicity. Adverse events (AEs), laboratory results, vital signs, and suicide risk were monitored. RESULTS: Cariprazine 1.5 mg/day significantly reduced depressive symptoms on the primary (MADRS LSMD = -2.5; adjusted P = .0417) and secondary (CGI-S LSMD = -0.3; adjusted P = .0417) efficacy parameters vs placebo; differences were not statistically significant for cariprazine 3.0 mg/day. Common treatment-emergent AEs (≥5% in either cariprazine group and at least twice the incidence of placebo) were akathisia, restlessness, nausea, and fatigue. Mean metabolic parameter changes were low and generally comparable among groups; mean weight increases were ≤0.5 kg for all groups. CONCLUSIONS: Cariprazine 1.5 mg/day significantly reduced depressive symptoms in adults with bipolar I depression compared to placebo, but differences were not significant for cariprazine 3.0 mg/day. The safety and tolerability profiles were similar to previous studies of cariprazine.

Relationship Between Plasma Concentrations and Clinical Effects of Cariprazine in Patients With Schizophrenia or Bipolar Mania.

Population pharmacokinetic/pharmacodynamic modeling (via NONMEM) was used to describe longitudinal exposure-response relationships for total cariprazine (sum of cariprazine and its major active metabolites) in 2,558 patients with schizophrenia or bipolar mania. Drug exposure metrics were explored for potential relationships with efficacy and safety end points. Total cariprazine exposures were significantly related to reductions in Positive and Negative Syndrome Scale (PANSS) or Young Mania Rating Scale (YMRS) total scores in schizophrenia or bipolar mania, respectively, via a maximum effect (Emax )-type relationship. Typical steady-state plasma concentrations after 3 and 4.5 mg/day were associated with 50% of maximum typical reductions in PANSS and YMRS total scores, respectively. Time-weighted cariprazine exposures had significant relationships with the probability of common adverse events (AEs). Dose increase was associated with increased efficacy but was also associated with an increase in AEs. Results of these pharmacokinetic/pharmacodynamic analyses support that the recommended dose range (1.5-6 mg/day for schizophrenia and 3-6 mg/day for bipolar mania) provides an appropriate benefit-risk balance between cariprazine efficacy and safety.

Cariprazine efficacy in bipolar I depression with and without concurrent manic symptoms: post hoc analysis of 3 randomized, placebo-controlled studies.

OBJECTIVE: Mixed presentations, defined by simultaneous occurrence of depressive and manic symptoms, are difficult to treat. Antidepressants, although commonly used, have weak evidence of efficacy and may increase risk of mood destabilization. The aim of this pooled post hoc analysis was to evaluate the efficacy of cariprazine in the treatment of bipolar depression with or without concurrent manic symptoms. METHODS: Patients from 3 randomized, double-blind, placebo-controlled studies who met DSM-IV-TR or DSM-5 criteria for bipolar I disorder with a current major depressive episode were identified to have concurrent manic symptoms by baseline Young Mania Rating Scale total score ≥4. Efficacy was assessed in cariprazine 1.5 and 3 mg/day dose groups versus placebo; analyses included the least squares mean change from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score. RESULTS: Of 1383 patients randomized to treatment, 808 (58.4%) had concurrent manic symptoms. For patients with manic symptoms, mean reduction in MADRS total score from baseline to week 6 was significantly greater for both cariprazine 1.5 and 3 mg/day compared with placebo, with least squares mean differences (LSMDs) versus placebo of -2.5 (p = .0033) and -2.9 (p = .0010), respectively; for patients without manic symptoms, the LSMD was significant for 1.5 mg/day (-3.3; p = .0008), but not for 3 mg/day (-1.9; p = .0562). CONCLUSION: The results of this post hoc analysis suggest that cariprazine may be an appropriate treatment option for patients with bipolar I depression with or without manic symptoms, with higher doses potentially more effective in patients with manic symptoms.

Relationship between the timing of relapse and plasma drug levels following discontinuation of cariprazine treatment in patients with schizophrenia: indirect comparison with other second-generation antipsychotics after treatment discontinuation.

OBJECTIVE: To explore the timing of relapse following drug discontinuation and its relationship to estimated plasma levels and elimination half-life by comparing data from a randomized, placebo-controlled discontinuation study of cariprazine with those from similarly designed and conducted randomized control trials of other oral atypical antipsychotics (AAPs). METHODS: Data from a long-term, randomized, double-blind, placebo-controlled relapse prevention study in participants with schizophrenia (NCT01412060) were analyzed. Similarly designed, published studies of other AAPs were used for comparison. Time to drug-placebo relapse separation and relapse rates were estimated from Kaplan-Meier curves and evaluated descriptively. Separation was defined as a sustained difference of ≥5% incidence of relapse between the AAP and placebo curves. RESULTS: The Kaplan-Meier curve for cariprazine showed a time to drug-placebo relapse separation at 6-7 weeks after randomization, compared to the Kaplan-Meier curves for the other AAPs, which showed earlier separation at 1-4 weeks. The placebo relapse rates at 4 weeks after randomization were 5% for cariprazine and 8-34% for other AAPs. Geometric mean values of model-predicted plasma concentrations for total active cariprazine moieties (sum of cariprazine, desmethyl-cariprazine, and didesmethyl-cariprazine) were 20.0 and 6.1 nM at 2 and 4 weeks after discontinuation, respectively. Elimination half-lives of other AAPs and their active metabolites (<4 days) suggest that plasma concentrations would be low or negligible at 2-4 weeks after last dose. CONCLUSION: Discontinuation of cariprazine treatment appeared to be associated with a delayed incidence of relapse compared with other AAPs, which may be due to the longer half-life of cariprazine and its active metabolites.

Cariprazine for the treatment of bipolar mania with mixed features: A post hoc pooled analysis of 3 trials.

BACKGROUND: When bipolar I disorder (BP-I) mania is accompanied by subsyndromal depressive symptoms, a more complicated illness presentation results. To qualify for the mixed features specifier during mania, the DSM-5 requires ≥3 "non-overlapping" depressive symptoms (DS); notwithstanding, concerns of this definition's ecological validity and implications for timely diagnosis remain. METHODS: Herein, patients were pooled from three similarly-designed pivotal trials of cariprazine compared to placebo for BP-I mania (NCT00488618/NCT01058096/NCT01058668) in post hoc analyses of mixed features using three criteria: ≥3 DS (DSM-5), ≥2 DS, and Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≥10. Efficacy of cariprazine compared to placebo was assessed (Week 3) by Young Mania Rating Scale (YMRS) and MADRS scores and rates of mania response and remission. RESULTS: In pooled patients (N = 1037), cariprazine significantly improved mean YMRS scores compared to placebo for each criterion; LSMDs were ≥3 DS = -3.79 (P = .0248), ≥2 DS = -2.91 (P = .0207), and ≥10 MADRS = -5.49 (P < .0001). More cariprazine- than placebo-treated patients met YMRS response and remission criteria, reaching significance for response in ≥2 DS (34% versus 47%; number-needed-to-treat [NNT] = 8, P = .0483) and ≥10 MADRS (31% versus 57%, NNT = 4, P < .0001) and for remission in ≥2 DS (27% versus 39%, NNT = 9, P = .0462), ≥10 MADRS (23% versus 44%, NNT = 5, P < .0001). Depressive symptoms were improved compared to placebo, reaching statistical significance in the MADRS ≥10 subgroup (LSMD = -1.59, P = .0082). LIMITATIONS: Post hoc analysis, MADRS  < 18 entry criterion may have prevented assessment of MADRS changes. CONCLUSIONS: Cariprazine significantly reduced manic and depressive symptoms in patients with mixed features with differential efficacy across the subgroups analyzed herein.

Linking PANSS negative symptom scores with the Clinical Global Impressions Scale: understanding negative symptom scores in schizophrenia.

Understanding how rating scale improvement corresponds to a clinical impression in patients with negative symptoms of schizophrenia may help define the clinical relevance of change in this patient population. We conducted post hoc equipercentile linking analyses of Positive and Negative Syndrome Scale (PANSS) outcomes (e.g., PANSS-Factor Score for Negative Symptoms [FSNS]) with Clinical Global Impressions-Improvement (CGI-I) and -Severity (CGI-S) ratings on data from patients treated with cariprazine (n = 227) or risperidone (n = 229) in a clinical study evaluating negative symptoms in schizophrenia. Patients were prospectively selected for persistent, predominant negative symptoms of schizophrenia (PNS), and minimal positive/depressive/extrapyramidal symptoms. Linking results demonstrated that greater improvement on PANSS-derived measures corresponded to clinical impressions of greater improvement, as measured by the CGI-I, and less severe disease states, as measured by the CGI-S. For example, CGI-S scores of 1 (normal), 2, 3, 4, 5, and 6 (severely ill) corresponded to PANSS-FSNS scores of 7, 13, 19, 24, 29, and 35, respectively. Likewise, CGI-I scores of minimally improved, much improved, and very much improved corresponded to a change from baseline in PANSS-FSNS scores of -27%, -49%, and -100%, respectively. These are important findings for the interpretation of the results of trials in patients with persistent negative symptoms.

Cariprazine Treatment of Bipolar Depression: A Randomized Double-Blind Placebo-Controlled Phase 3 Study.

OBJECTIVE: Cariprazine, a dopamine D3/D2 and 5-HT1A receptor partial agonist, was found to be effective in treating bipolar I depression in a previous phase 2 study. This phase 3 study further assessed the efficacy, safety, and tolerability of cariprazine in bipolar I depression. METHODS: In a double-blind placebo-controlled study, adult participants (18-65 years old) who met DSM-5 criteria for bipolar I disorder and a current depressive episode were randomly assigned to receive placebo (N=158) or cariprazine at 1.5 mg/day (N=157) or 3.0 mg/day (N=165). The primary and secondary efficacy parameters were changes from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) score and Clinical Global Impressions severity (CGI-S) score, respectively. Least squares mean differences were estimated using a mixed model for repeated measures, and p values were adjusted for multiplicity. RESULTS: Both dosages of cariprazine were significantly more effective than placebo in improving depressive symptoms (reducing MADRS total score); the least squares mean differences were -2.5 (95% CI=-4.6, -0.4) for cariprazine at 1.5 mg/day and -3.0 (95% CI=-5.1, -0.9) for cariprazine at 3.0 mg/day. Both cariprazine dosages were associated with lower CGI-S scores compared with placebo, but the differences did not reach statistical significance after adjustment for multiplicity (least squares mean difference, -0.2 [95% CI=-0.5, 0.0] for the 1.5 mg/day group and -0.3 [95% CI=-0.5, 0.0] for the 3.0 mg/day group). Common treatment-emergent adverse events (in at least 5% of participants in either cariprazine treatment group and twice the rate of the placebo group) were nausea, akathisia, dizziness, and sedation. Mean changes in weight and metabolic parameters were relatively small and comparable across groups. CONCLUSIONS: Cariprazine, at both 1.5 mg/day and 3.0 mg/day, was effective, generally well tolerated, and relatively safe in reducing depressive symptoms in adults with bipolar I depression.

The efficacy of cariprazine in negative symptoms of schizophrenia: Post hoc analyses of PANSS individual items and PANSS-derived factors.

BACKGROUND: Negative symptoms in schizophrenia are heterogeneous and multidimensional; effective treatments are lacking. Cariprazine, a dopamine D3-preferring D3/D2 receptor partial agonist and serotonin 5-HT1A receptor partial agonist, was significantly more effective than risperidone in treating negative symptoms in a prospectively designed trial in patients with schizophrenia and persistent, predominant negative symptoms. METHODS: Using post hoc analyses, we evaluated change from baseline at week 26 in individual items of the Positive and Negative Syndrome Scale (PANSS) and PANSS-derived factor models using a mixed-effects model for repeated measures (MMRM) in the intent-to-treat (ITT) population (cariprazine = 227; risperidone = 227). RESULTS: Change from baseline was significantly different in favor of cariprazine versus risperidone on PANSS items N1-N5 (blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, difficulty in abstract thinking) (P < .05), but not on N6 (lack of spontaneity/flow of conversation) or N7 (stereotyped thinking). On all PANSS-derived negative symptom factor models evaluated (PANSS-Factor Score for Negative Symptoms, Liemburg factors, Khan factors, Pentagonal Structure Model Negative Symptom factor), statistically significant improvement was demonstrated for cariprazine versus risperidone (P < .01). Small and similar changes in positive/depressive/EPS symptoms suggested that negative symptom improvement was not pseudospecific. Change from baseline was significantly different for cariprazine versus risperidone on PANSS-based factors evaluating other relevant symptom domains (disorganized thoughts, prosocial function, cognition; P < .05). CONCLUSIONS: Since items representing different negative symptom dimensions may represent different fundamental pathophysiological mechanisms, significant improvement versus risperidone on most PANSS Negative Subscale items and across all PANSS-derived factors suggests broad-spectrum efficacy for cariprazine in treating negative symptoms of schizophrenia.