Cariprazine In Patients Research Articles

Effect of Cariprazine on Anhedonia in Patients with BipolarI Depression: Post Hoc Analysis of Three Randomized Placebo-Controlled Clinical Trials.

Anhedonic symptoms in bipolarI (BP-I) depression are associated with decreased quality of life and impaired functioning. We evaluated the effects of cariprazine in patients with BP-I depression with lower or higher levels of anhedonia at baseline. Data were pooled from three clinical trials (NCT01396447, NCT02670538, NCT02670551) analyzing the effects of cariprazine 1.5 and 3mg/day in adults with BP-I depression. During post hoc analysis, patients were stratified by baseline median Montgomery-Åsberg Depression Rating Scale (MADRS) anhedonia factor score into a lower (score < median) or higher (score ≥ median) anhedonia subgroup. Outcomes included change from baseline to week6 in MADRS total and anhedonia factor score, with the latter also evaluated after adjusting for other depressive symptoms. Between-group differences in change from baseline to week6 were compared using least-squares mean differences (LSMD) analyzed via a mixed-effect model for repeated measures. Median baseline anhedonia factor score was 19, defining the lower (placebo = 211; cariprazine 1.5mg/day = 200, 3mg/day = 212) and higher (placebo = 249; cariprazine 1.5mg/day = 261, 3mg/day = 250) anhedonia subgroups. In the lower subgroup, cariprazine 1.5mg/day but not 3mg/day was superior to placebo in reducing MADRS total (LSMD [95%CI] 1.5mg/day = - 2.61 [- 4.28, - 0.93], P = .0024) and anhedonia factor scores (- 1.70 [- 2.77, - 0.62], P = .0021) at week6. In the higher subgroup, both cariprazine doses were associated with significantly greater reductions than placebo in MADRS total (1.5mg/day = - 3.01 [- 4.84, - 1.19], P = .0012; 3mg/day = - 3.26 [- 5.12, - 1.40], P = .0006) and anhedonia factor scores (1.5mg/day = - 1.97 [- 3.13, - 0.81], P = .0009; 3mg/day = - 2.07 [- 3.26, - 0.89], P = .0006). Anti-anhedonic effects were preserved after adjusting for other depressive symptoms, suggesting the effect was not pseudospecific. Patients in the higher subgroup had higher baseline depression and therefore the lower subgroup may have had a floor effect. Cariprazine demonstrated antidepressant and specific anti-anhedonic effects regardless of baseline anhedonia symptoms in patients with BP-I depression. ClinicalTrials.gov identifiers, NCT02670538, NCT02670551, NCT01396447.

Cariprazine as a maintenance treatment in dual schizophrenia: a 6-month observational study in patients with schizophrenia and cannabis use disorder.

Schizophrenia is often associated with substance use disorders, particularly cannabis use disorder (CUD). However, treatments frequently fail to address both conditions simultaneously. This study aimed to evaluate the antipsychotic effectiveness of cariprazine in patients with both schizophrenia and CUD in a real-world setting. A 6-month observational study was conducted on 58 patients diagnosed with schizophrenia and CUD, treated with cariprazine. Antipsychotic effectiveness was measured using the Positive and Negative Syndrome Scale and the Clinical Global Impression-Schizophrenia Scale, along with the Improvement and Severity scales. Cannabis consumption and addiction severity were assessed using the Cannabis Abuse Screening Test and the Severity of Dependence Scale, while functioning was evaluated with the Sheehan Disability Inventory. Cariprazine treatment resulted in significant improvements in schizophrenia symptoms (Positive and Negative Syndrome Scale change: -47.88 points, P < 0.0001; Clinical Global Impression-Schizophrenia Scale change: -8.26 points, P < 0.0001). Cannabis use and dependence also decreased (Cannabis Abuse Screening Test change: -7.0 points, P < 0.0001; Severity of Dependence Scale change: -7.88 points, P < 0.0001), alongside improvements in functioning (Sheehan Disability Inventory change: -9.48 points, P < 0.0001). These results suggest that cariprazine is effective for both schizophrenia and CUD, though further research is needed to confirm these findings.

Serotonin reuptake inhibitors augmentation with cariprazine in patients with treatment-resistant obsessive-compulsive disorder: a retrospective observational study.

Serotonin reuptake inhibitors augmentation with cariprazine in patients with treatment-resistant obsessive-compulsive disorder: a retrospective observational study.

A review on the pharmacology of cariprazine and its role in the treatment of negative symptoms of schizophrenia.

Management of negative symptoms is one of the most challenging and important unmet needs of schizophrenia treatment. Negative symptoms together with positive symptoms result in significant psychosocial impairment and poor quality of life. Existing studies on atypical antipsychotics reported limited treatment adherence due to higher prevalence of treatment-emergent adverse events, such as diabetes, weight gain, hyperlipidemia, hyperprolactinemia and hypertension. A compound with greater affinity for dopamine D2/D3 receptors may improve negative symptoms, mood, and cognitive impairment associated with schizophrenia. In 2015, the US FDA has approved cariprazine, a partial D2/D3 agonist for treatment of schizophrenia, mania or mixed episodes. Midlands and Lancashire Commissioning Support Unit, UK (2019) has particularly suggested cariprazine for the treatment of predominant negative symptoms of schizophrenia. India's Central Drugs Standard Control Organization (CDSCO) has approved cariprazine in 2021 for the treatment of schizophrenia, manic or mixed episodes associated with bipolar I disorder. A ten-fold greater affinity for D3 receptors and partial agonism to serotonin receptors, along with longer half-life make cariprazine distinct when compared with other atypical antipsychotics. Cariprazine is also reported to have fewer incidents of metabolic and hormonal adverse events, and has been shown to provide better relapse prevention. Recent evidence indicates promising effect of cariprazine in ameliorating negative symptoms as well as psychotic symptoms in patients with schizophrenia. In addition, improved adherence to treatment (adjunctive/monotherapy) with cariprazine in patients having inadequate response to an ongoing antipsychotic treatment has also been clinically established. This review presents the evidence-based safety and efficacy of cariprazine for treatment of predominant negative symptoms of schizophrenia.

Relapse prevention with cariprazine in patients with early-stage schizophrenia

IntroductionRelapse is defined as the return of psychotic symptoms after a period of improvement/stability. Relapse is often associated with the disruptive re-hospitalization of patients. Importantly, relapse history is a strong predictor of subsequent relapses and poorer outcomes. Therefore, relapse prevention in the beginning of the disorder is especially important. Cariprazine, a novel D3-D2 partial agonist, has been effective in preventing relapse compared to placebo in stabilized patients with schizophrenia.ObjectivesTo present the efficacy of cariprazine in preventing relapse in patients with early-stage schizophrenia.MethodsPost-hoc analysis of data from a ˜96 weeks, multicentre, randomized, double-blind, placebo-controlled, parallel-group study in adults with schizophrenia. The study was composed of two parts: a 20-week open-label treatment phase and a double-blind treatment phase up to 72 weeks. During the open-label phase, patients were stabilized with cariprazine 3.0-9.0 mg/day. Then, they were randomized to continue cariprazine (fixed dosing: 3.0, 6.0, or 9.0 mg/day) or receive placebo. Relapse was defined as a deterioration of symptom scores as measured by the Positive Negative Syndrome Scale (PANSS), admission to a psychiatric hospital, exhibiting aggressive behaviour, or risk of suicide. In the present analysis, patients with a schizophrenia diagnosis history of 0-5 years were defined as early-stage patients. Baseline characteristics, and risk ratios (after the double-blind phase) with number-needed-to-treat (NNT) were calculated.ResultsOf 200 patients, 71 (35.5%) met the early-stage criteria: 32 patients in the cariprazine (CAR) and 39 in the placebo (PBO) arm. The mean age was 31.6 years in both groups with an average illness duration of 2.51+/-1.03 years in the CAR and 2.75+/-1.24 years in the PBO arm. 47% of patients in the CAR arm and 77% in the PBO arm were men. The average number of previous hospitalisations was comparable in the two groups (CAR: 2.3; PBO: 2.6), as was the severity of illness: mean PANSS Total score: 89.2 (CAR), 90.4 (PBO). Patients in both groups were highly compliant (pill-count: CAR: 98.2%; PBO: 99.5%). The main reported adverse effects were headache (CAR: 11.3%, PBO: 7.0%), insomnia (CAR: 5.6%, PBO: 4.2%), and increased triglycerides (CAR: 5.6%, PBO: 1.4%), discontinuation due to adverse event was 3.1% in the CAR and 2.6% in the PBO group. Altogether, 9.4% of patients relapsed in the cariprazine group compared to 48.7% on placebo (risk ratio=0.19 (95% confidence interval (CI): 6.3-59.2%, p=0.0041;NNT: 2.5 (95%CI: 1.7-5.1).ConclusionsIn this post-hoc analysis of patients within the first five years of schizophrenia, the relative risk of relapse was 81% reduced with cariprazine with prevention of one additional relapse after each third patient exposed to cariprazine vs placebo. Cariprazine seems to be a good treatment option for early-stage patients for preventing relapse.Disclosure of InterestC. Correll Consultant of: AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Biogen, Boehringer-Ingelheim, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Denovo, Gedeon Richter, Hikma, Holmusk, IntraCellularTherapies, Jamjoom Pharma, Janssen/J&amp;J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Neurelis, Newron, Noven, Novo Nordisk, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Sage, Seqirus, SK Life Science, Sumitomo Pharma America, Sunovion, Sun Pharma, Supernus, Takeda, Teva, Tolmar, Vertex, and Viatris., Z. Dombi Employee of: Gedeon Richter Plc., P. Herman Employee of: Gedeon Richter Plc., Á. Barabássy Employee of: Gedeon Richter Plc.

Safety and tolerability of cariprazine for the adjunctive treatment of major depressive disorder: a pooled analysis of phase 2b/phase 3 clinical trials.

To characterize the safety and tolerability of adjunctive cariprazine in patients with major depressive disorder (MDD) and inadequate response to monotherapy antidepressant treatment (ADT). Post hoc analyses evaluated pooled data from 2 fixed-dose phase 3 cariprazine studies (1.5 and 3 mg/d [approved doses for MDD]). In a separate safety analysis, cariprazine 0.1-4.5 mg/d was evaluated using data from the 2 fixed-dose trials plus 3 flexible-dose studies grouped by modal-daily dose. In the pooled phase 3 studies (placebo = 503, 1.5 mg/d = 502, 3 mg/d = 503), overall cariprazine-treated patients had high rates of study completion (90%). Patients had mostly mild/moderate treatment-emergent adverse events that caused premature discontinuation of 4.3%. Only akathisia, nausea, and insomnia occurred in ≥5% of cariprazine patients (any group) and at twice the rate of placebo; potential dose-dependent responses were observed for akathisia and insomnia. Cariprazine had a neutral metabolic profile, with mean weight increase of <1 kg. Modal-dose results were similar, and both analyses were consistent with the known safety profile of cariprazine across its approved indications. Adjunctive cariprazine therapy was safe and generally well tolerated in patients with MDD who had not obtained an adequate response to ADT monotherapy; no new safety signals were identified.

Therapeutic Appropriateness of Cariprazine in the Management of Schizophrenia: Experts' Opinion using a Delphi Approach.

Schizophrenia is a psychiatric disorder whose therapeutic objectives are aimed at reducing symptoms and improving patient's quality of life. First- and second-generation antipsychotics present numerous side effects. Recently introduced in the treatment of schizophrenia, cariprazine has shown to improve positive and negative symptoms as well as cognitive impairment, with good tolerability. To assess the level of consensus among Italian psychiatrists in relation to the use of cariprazine in the treatment of schizophrenia by using the Delphi technique. A Delphi study was undertaken between January and July 2022. Two questionnaires were consecutively sent to a panel of 97 psychiatrists from all over Italy, of which 81 actively participated, anonymously, in at least one of the two consultations with a sufficiently high response rate (83%). Broad consensus in terms of the efficacy and safety of cariprazine in the treatment of schizophrenia during all phases of the disorder. The young first-episode schizophrenia patient with or without substance abuse seems to be an excellent candidate for cariprazine therapy. In addition, the lack of side effects makes cariprazine a suitable drug for adult and elderly patients with schizophrenia. However, there is still limited experience with the use of cariprazine, along with little knowledge of the most recent real-life data. These results could encourage wider dissemination of evidence-based practices with the final aim of optimizing the clinical use of cariprazine in patients with schizophrenia.

Adjunctive Cariprazine in Patients With Major Depressive Disorder: Post Hoc Analysis of Efficacy by Baseline Antidepressant Response

AbstractIntroductionPatients with major depressive disorder (MDD) often have inadequate response to antidepressant treatment (ADT) requiring augmentation with other treatments. Cariprazine is a D3-preferring D3/D2 and serotonin 5-HT1A receptor partial agonist approved to treat schizophrenia and manic, mixed, and depressive episodes of bipolar I disorder. The efficacy of cariprazine as an adjunctive treatment for patients with MDD and inadequate response to ADT alone has been evaluated in phase 2/3 randomized, double-blind, placebo-controlled trials. Post hoc analyses of one phase 3 trial (NCT03738215) evaluated cariprazine + ADT for improving depressive symptoms in subgroups of patients categorized by 1) the level of response to ongoing ADT at baseline and 2) the number of ADTs associated with inadequate response during the current episode.MethodsPatients were randomized to placebo + ADT (n=254), cariprazine 1.5 mg/d + ADT (n=252), or cariprazine 3 mg/d + ADT (n=253) for 6 weeks of double-blind treatment. Post hoc analyses evaluated change from baseline to week 6 in MADRS total score in subgroups of patients who had ≥25%–&lt;50% or &lt;25% response to ongoing ADT at baseline, and in subgroups of patients who had inadequate response to 1 or ≥2 ADTs in the current episode. Analyses used a mixed-effects model for repeated measures; least squares mean differences (LSMD) versus placebo with 95% confidence interval (95% CI) were calculated.ResultsAt baseline, 65.1% (n=486) of patients had an ADT response level between 25%–&lt;50% and 34.9% (n=261) of patients had an ADT response level &lt;25%. Mean MADRS total score reductions were greater for cariprazine 1.5 mg/d + ADT versus placebo + ADT in both ADT response subgroups (25%–&lt;50% ADT response: -14.8 vs -11.9, LSMD [95% CI]=-2.3 [-4.2, -0.3]; &lt;25% response to ADT: (-14.7 vs -11.7, LSMD [95% CI]=-2.6 [-5.5, 0.3]). For cariprazine 3 mg/d + ADT, mean change in MADRS total score was numerically greater versus placebo in both response subgroups (25%–&lt;50% response=-14.2, LSMD [95% CI]=-1.5 [-3.5, 0.4]; &lt;25% response= -12.3, LSMD [95% CI]=-0.74 [-3.6, 2.1]). Approximately 86% (n=644) and 14% (n=105) of patients in this study had inadequate response to 1 ADT or ≥2 ADTs, respectively, during the current episode. The LSMD (95% CI) in MADRS total score change for cariprazine 1.5 mg/d + ADT versus placebo + ADT was -2.3 (-4.1, -0.6) in the subgroup of patients with 1 previous ADT and -3.2 [-7.1, 0.8]) in the subgroup of patients with ≥2 previous ADTs. For cariprazine 3 mg/d + ADT, the LSMD (95% CI) in MADRS total score change versus placebo was -0.7 (-2.5, 1.0) in the 1 previous ADT subgroup and -4.7 (-8.8, -0.6) in the ≥2 previous ADTs subgroup.ConclusionsIn these post hoc analyses, cariprazine + ADT was associated with greater reductions in MADRS total score versus placebo regardless of the level of response to ongoing ADT at baseline or number of prior ADT failures in the current episode.FundingAbbVie

Safety and Tolerability of Cariprazine for the Adjunctive Treatment of Major Depressive Disorder: A Pooled Analysis of Phase 2B and 3 Clinical Trials

AbstractBackgroundCariprazine has been shown to be efficacious in placebo-controlled clinical trials. In this pooled analysis, the safety of cariprazine in patients with major depressive disorder (MDD) with inadequate response to antidepressants was evaluated using data from placebo-controlled studies of up to 8 weeks’ duration and a long-term open-label safety study.MethodsThe safety, tolerability, and efficacy of cariprazine as an adjunctive treatment for patients with MDD with inadequate response to antidepressant alone was assessed in five placebo-controlled studies (two 6-week fixed-dose studies [NCT03738215; NCT03739203] and three 8-week flexible-dose studies [NCT00854100; NCT01715805; NCT01469377]) and one 26-week open-label flexible-dose study (NCT01838876). Fixed doses of cariprazine 1.5 and 3 mg/d and flexible doses of 0.1-4.5 mg/d were evaluated. Safety assessments included adverse event (AE) reporting, clinical laboratory tests, weight and other vital signs, and suicide evaluation with Columbia-Suicide Severity Rating Scale (C-SSRS). Pooled analyses of the incidence of safety endpoints overall and within each treatment arm were performed using the most frequent (modal) daily dose taken by patients during the study.ResultsA total of 2,222 MDD patients with an ongoing antidepressant received treatment with cariprazine, representing 370 patient-years of exposure in placebo-controlled and open-label studies. In the placebo-controlled studies, 1,969 patients were randomized to cariprazine (dose range, 0.1–4.5 mg/d) and 1,108 patients were randomized to placebo. Overall, treatment-emergent AEs occurred in 61% of cariprazine- and 48% of placebo-treated patients; discontinuation due to an AE occurred with 6% of cariprazine- and 2% of placebo-treated patients. The 2 AEs that occurred in at least 5% of cariprazine-treated patients and at a rate at least twice the rate in placebo-treated patients were akathisia (cariprazine=11%; placebo=2%) and restlessness (cariprazine=6%; placebo=2%). Changes in metabolic parameters, including shifts in fasting glucose and lipid parameters, were similar in cariprazine- and placebo-treated patients. In the long-term safety study, mean weight change was 1.6 kg over 6 months. In the placebo-controlled and long-term studies, other safety endpoints including laboratory and C-SSRS assessments of suicidality were generally consistent with the safety profile of cariprazine in approved indications of bipolar disorder and schizophrenia.ConclusionCariprazine is generally safe and well-tolerated in MDD patients with inadequate response to antidepressant monotherapy. Safety analysis of 2,222 cariprazine-treated patients with MDD revealed no new safety signals, and the data is consistent with the currently approved prescribing information.FundingAbbVie

Categorical Improvement in Depressive Symptom Severity: Results From a Randomized Controlled Trial of Cariprazine for Adjunctive Treatment of MDD

AbstractBackgroundPatients with major depressive disorder (MDD) often do not respond to antidepressant (ADT) monotherapy alone and may require adjunctive treatment to provide adequate symptom relief. Cariprazine (CAR) 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 of bipolar I disorder. Post hoc analysis of data from a randomized controlled trial evaluated clinically relevant improvements in depressive symptom severity with adjunctive cariprazine in patients with MDD and inadequate response to ADT monotherapy.MethodsPost hoc analysis evaluated data from a randomized, double-blind, placebo-controlled MDD trial (NCT03738215) in patients treated with CAR (1.5 mg/d or 3 mg/d) + ADT or placebo + ADT; the primary outcome was change from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Post hoc analysis evaluated category shifts from baseline to week 6 in MADRS severity (normal &lt;6, mild 7–19, moderate 20–34, severe ≥35). MADRS severity shifts were reported as the percentage of patients with no change or worsened severity, 1 category improvement, ≥1 category improvement, and ≥2 category improvement. Examples of categorical shifts in depressive symptoms at week 6 include change from severe at baseline to moderate (1 category improvement) and change from severe at baseline to mild (2 category improvement).ResultsOf the 751 patients in the intent-to-treat (ITT) population (CAR: 1.5 mg/d=250, 3.0 mg/d=252; placebo=249), baseline MADRS severity was mild in 1.5%, moderate in 64%, and severe in 35%. Fewer CAR + ADT patients compared to placebo + ADT had no change or worsened MADRS severity at week 6 (CAR: 1.5 mg/d=32%, 3.0 mg/d=33%; placebo=42%). Approximately 68% of patients treated with CAR + ADT demonstrated a MADRS severity improvement of 1 category or greater by week 6 (CAR: 1.5 mg/d=68%, 3.0 mg/d=67%; placebo=58%). A greater percentage of patients in the CAR 1.5 mg/d group also had a 2 or greater category improvement versus CAR 3.0 mg/d or placebo 6 (CAR: 1.5 mg/d=28%, 3.0 mg/d=17%; placebo=19%).ConclusionsIn this post hoc analysis, CAR + ADT was associated with a greater proportion of patients with improvements in depressive symptom severity categories compared with placebo + ADT. These results may suggest that CAR + ADT is associated with clinically meaningful depressive symptom improvement in MDD patients.FundingAbbVie

Successful high dose antipsychotic treatment with cariprazine in patients on the schizophrenia spectrum: Real-world evidence from a Spanish hospital setting.

Real-world evidence fills in an important gap by providing data on the effectiveness and tolerability of new medications in everyday patients. In this data collection form a Spanish hospital, the effectiveness and tolerability of cariprazine were evaluated in 14 patients who were admitted to the hospital due to an acute episode of schizophrenia or schizoaffective disorder. The collected data included demographic characteristics, history of disorder and previous treatment, and details of cariprazine therapy such as dosing, side effects and measurements of effectiveness via scales. Difference between admission and discharge on the Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impression-Severity (CGI-S) scale scores were evaluated using the Wilcoxon Signed-Rank test. Significant improvement was detected in nearly all patients (one patient dropped out) as measured by the BPRS Total, Negative symptom, Positive symptom, and Hostility scores. At admission, patients were markedly-moderately ill and at discharge the severity was reduced to borderline ill and normal according to the CGI-S. The CGI-Improvement scale also indicated very much and much improvement at discharge. Importantly, patients left the hospital with high doses of cariprazine, i.e., 7.5 mg/day or even 9.0 mg/day, but this did not cause safety problems; cariprazine well-tolerated as only a few patients experienced side effects such as akathisia. The results provide novel evidence regarding the tolerability and effectiveness of cariprazine in high doses patients on the schizophrenia spectrum.

Efficacy and safety of cariprazine augmentation in patients treated with clozapine: a pilot study.

Cariprazine, a novel antipsychotic drug, is a partial agonist of dopamine D2/D3 receptors with preferential binding to the D3 receptor. There has been an increasing interest in cariprazine augmentation to clozapine; however, the evidence thus far has been only limited to case reports and case series. To evaluate the efficacy and safety of the augmentation of clozapine with cariprazine in patients with sub-optimal treatment response. Demographic and clinical information of the study population were collected from the electronic records and PANSS scale administered at baseline and 3 months. Tolerability and discontinuation reasons where applicable were also recorded. Ten patients (four men and six women) with a mean age of 36.5 years (range = 26-45) were included. Reasons for cariprazine initiation included inadequate treatment response, persistent negative symptoms and/or tolerability issues with clozapine or previous augmentation options. Two patients discontinued cariprazine within the first 6 weeks due to restlessness and poor response, respectively. There was a significant reduction in the median total PANSS score from baseline to 3 months (from 59 to 22.5, p < 0.05), median positive PANSS score (from 11.5 to 5.5, p < 0.05) and in the median negative PANSS score (from 15.5 to 3, p < 0.05) which correspond to a 48%, 33.8% and 65.8% mean score reduction, respectively. This is the first pilot study evaluating the effectiveness of clozapine augmentation. The preliminary evidence suggests that this may be a safe and effective practice in patients failing to adequately respond to or tolerate clozapine and/or previous augmentation strategies.

Cariprazine in the Treatment of Bipolar Disorder: Within and Beyond Clinical Trials.

Bipolar disorder (BD) is chronic psychiatric disorder associated with significant impairment in psychosocial functioning and quality of life. Although current pharmacological treatments for BD have improved its clinical management, many patients do not achieve remission, particularly those suffering from bipolar depression. In addition, available treatments are associated with a myriad of potential adverse effects, which highlights the need for novel therapeutic agents that can be effective for both phases of the illness with a reduced side effect burden. Cariprazine is a novel antipsychotic that is a dopamine D2/D3 partial agonist with a preference for D3 receptors. In this review, we examine the pharmacological properties, clinical efficacy and tolerability profile of cariprazine in patients with BD, taking into account the latest clinical trials data. We also review post hoc analyses addressing clinically relevant subgroups and symptom domains in BD. Current evidence suggests efficacy for cariprazine 3–12 mg/day in the treatment of acute manic and mixed episodes; for bipolar depression, the efficacy of cariprazine appears to be dose-related, with doses of 1.5–3 mg/day beneficial as monotherapy. Cariprazine is overall well-tolerated by patients in both manic and depressive episodes. Its most common side effects relative to placebo include akathisia, extrapyramidal symptoms and nausea. There are no metabolic concerns reported with cariprazine use. In summary, the latest evidence suggests that cariprazine is an effective and safe treatment option for BD.

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

[This corrects the article DOI: 10.2147/NDT.S301225.].

Evaluation of MADRS Severity Thresholds in Patients With Bipolar Depression

AbstractIntroductionThe Montgomery-Åsberg Depression Rating Scale (MADRS) is commonly used for the assessment of depressive symptom changes in patients with major depressive disorder (MDD) or bipolar depression. Categories of depression severity that correspond to ranges of MADRS total score have been previously reported in patients with MDD, but it appears that MADRS severity ranges have not been reported for patients with bipolar I disorder. The objective of this study was to evaluate MADRS total score ranges that correspond with different grades of depression severity in patients with bipolar I depression.MethodsData were pooled from 3 randomized, double-blind, placebo-controlled, 6- or 8-week trials of cariprazine in patients with bipolar I depression. MADRS severity ranges were evaluated using an anchor-based approach with the clinician-rated, 7-category Clinical Global Impression-Severity (CGI-S) scale. CGI-S has previously been used to determine severity thresholds in MDD. Correlations between MADRS total score and CGI-S score were assessed in the pooled dataset at week 6; placebo and active treatment arms were pooled together. Youden index from receiver operating characteristic (ROC) curves was used to determine the optimal threshold for MADRS total score corresponding to each CGI-S severity level.ResultsThe pooled dataset included 1523 patients with bipolar depression. Mean CGI-S scores were highly correlated with mean MADRS total scores at week 6 (r=.87; P&lt;.0001), with MADRS total scores increasing with CGI-S severity. Using the ROC curves, MADRS total score ranges corresponding to each CGI-S severity category were estimated as follows: score of 0-6 for “normal, not at all ill”, 7-12 for “borderline mentally ill”, 13-18 for “mildly ill”, 19-23 for “moderately ill”, 24-36 for “markedly ill”, 37-39 for “severely ill”, and 40 or greater for “extremely ill”. Area under the curve (AUC) values for these cutoffs ranged from 0.930 to 0.997, representing outstanding sensitivity and specificity.ConclusionsUtilizing data from 3 recent clinical trials of subjects with bipolar depression, we were able to identify MADRS severity thresholds. These empirical findings may help clinicians to understand and contextualize MADRS results from bipolar clinical research and apply to their patients in practice.FundingAbbVie Inc.

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

BackgroundLong-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).MethodsPost 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.ResultsIn 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%.ConclusionAkathisia, 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 RegistrationStudies registered with ClinicalTrials.gov (NCT00404573, NCT01104779, NCT00694707, NCT01104766, NCT01104792, NCT00839852, and NCT01412060) and EudraCT (2012–005485-36).

Evaluation of MADRS severity thresholds in patients with bipolar depression

BackgroundThe Montgomery-Åsberg Depression Rating Scale (MADRS) is commonly used to assess depression symptom changes in clinical trials; however, the score itself can be difficult to interpret without clinical context. Categories of depression severity corresponding to MADRS total score have not been established for bipolar depression, which was the objective of this study. MethodsData were pooled from 3 randomized, double-blind, placebo-controlled trials of cariprazine in patients with bipolar I depression; placebo and cariprazine arms were pooled. An anchor-based approach was used to map MADRS total score to the clinician-rated, 7-category Clinical Global Impression of Severity scale (CGI-S). Spearman's correlation coefficient was used to assess associations between MADRS total and CGI-S scores. Optimal MADRS severity thresholds for each CGI-S category was determined via Youden index using receiver operating characteristic (ROC) analyses. ResultsUsing data from 1523 patients with bipolar depression, mean MADRS total scores were positively correlated with mean CGI-S scores at week 6 (r = 0.87; P<.0001). Using ROC curves, MADRS severity thresholds corresponding to each CGI-S category were estimated with high sensitivity and specificity: 0–6 for “normal, not at all ill”, 7–12 for “borderline mentally ill”, 13–18 for “mildly ill”, 19–23 for “moderately ill”, 24–36 for “markedly ill”, 37–39 for “severely ill”, and ≥40 for “extremely ill”. ConclusionsUtilizing data from 3 clinical trials of patients with bipolar depression, MADRS severity thresholds were identified. These empirical findings may help clinicians contextualize MADRS results from bipolar clinical research and apply to their practice. Trial Registrationclinicaltrials.gov NCT01396447, NCT02670538, NCT02670551.

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 (E max)‐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.

Efficacy of cariprazine across symptom domains in patients with acute exacerbation of schizophrenia: Pooled analyses from 3 phase II/III studies

Schizophrenia affects various symptom domains, including positive and negative symptoms, mood, and cognition. Cariprazine, a dopamine D3/D2 receptor partial agonist and serotonin 5-HT1A receptor partial agonist, with preferential binding to D3 receptors, is approved for the treatment of adult patients with schizophrenia (US, Europe) and mania associated with bipolar I disorder (US). For these investigations, data were pooled from 3 positive, 6-week, double-blind, placebo-controlled, phase II/III trials of cariprazine in patients with acute exacerbation of schizophrenia (NCT00694707, NCT01104766, NCT01104779); 2 trials were fixed-dose and 1 trial was flexible-dose. Post hoc analyses evaluated mean change from baseline to week 6 in Positive and Negative Syndrome Scale (PANSS) -derived symptom factors (positive symptoms, negative symptoms, disorganized thought, uncontrolled hostility/excitement, anxiety/depression) and PANSS single items for cariprazine (1.5–9.0 mg/d) versus placebo. P values were not adjusted for multiple comparisons. At week 6, statistically significant differences versus placebo were seen for cariprazine on all 5 PANSS factors (P < 0.01 all). Effects sizes ranged from 0.21 (anxiety/depression) to 0.47 (disorganized thought). Dose-response analysis from the fixed-dose studies found significant differences for all cariprazine doses (1.5, 3.0, 4.5, and 6.0 mg/d) versus placebo in PANSS total score, and in negative symptom and disorganized thought factor scores (P < 0.001). Differences between cariprazine and placebo were also statistically significant on 26 of 30 PANSS single items (P < 0.05). In these post hoc analyses, cariprazine was effective versus placebo in improving all 5 PANSS factor domains, suggesting that it may have broad-spectrum efficacy in patients with acute schizophrenia.

Efficacy of cariprazine on negative symptoms in patients with acute schizophrenia: A post hoc analysis of pooled data

Although currently approved antipsychotics exert efficacy on positive symptoms of schizophrenia, treatments for negative symptoms remain a major unmet need. Post hoc analyses were used to investigate the possible efficacy of cariprazine in patients with moderate/severe negative symptoms of schizophrenia and no predominance of positive symptoms. Data were pooled from 2 randomized, double-blind, placebo- and active-controlled cariprazine studies in patients with acute schizophrenia (NCT00694707, NCT01104766). Analyses included data from a subset of patients with a Positive and Negative Syndrome Scale factor score for negative symptoms (PANSS-FSNS) ≥24, PANSS factor score for positive symptoms (PANSS-FSPS) ≤19, and scores of ≥4 on ≥2 of 3 PANSS items (blunted affect [N1], passive/apathetic social withdrawal [N4], lack of spontaneity/flow of conversation [N6]). Changes from baseline to week 6 in PANSS-FSNS were evaluated in the following treatment groups: placebo (n = 79), cariprazine 1.5–3 (n = 94) and 4.5–6 mg/d (n = 66), risperidone 4 mg/d (n = 34), or aripiprazole 10 mg/d (n = 44). Significant differences were observed versus placebo for cariprazine (1.5–3 mg/d, P = .0179; 4.5–6 mg/d, P = .0002) and risperidone (P = .0149), but not aripiprazole (P = .3265), and versus aripiprazole for cariprazine 4.5–6 mg/d (P = .0197). After adjusting for positive symptom changes, differences versus placebo remained statistically significant for cariprazine (1.5–3 mg/d, P = .0322; 4.5–6 mg/d, P = .0038) but not for risperidone (P = .2204). PANSS-FSNS response (≥20% reduction from baseline) rates were significantly higher with cariprazine (1.5–3 mg/d = 54.3%, P = .0194; 4.5–6 mg/d = 69.7%, P = .0001) than placebo (35.4%). In patients with acute schizophrenia and moderate/severe negative symptoms, cariprazine was associated with significantly greater improvement in negative symptoms compared with placebo and aripiprazole, warranting further exploration of the efficacy of cariprazine on negative symptoms.