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.

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.

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.

Extended release quetiapine fumarate in major depressive disorder: analysis in patients with anxious depression.

BACKGROUND: A pooled analysis was performed on data from two studies evaluating the efficacy of once-daily extended-release quetiapine fumarate (quetiapine XR) monotherapy for patients with major depressive disorder. Through these analyses (based on Hamilton Rating Scale for Depression (HAM-D) and Hamilton Rating Scale for Anxiety (HAM-A) measures), we aim to further evaluate the efficacy of quetiapine XR in depressed patients with high levels of anxiety symptoms. METHODS: Secondary analyses were conducted of pooled individual patient data from two 8-week (6-week randomized phase, 2-week drug discontinuation phase), double-blind, placebo-controlled studies of quetiapine XR (50-300 mg/day). Outcomes included change from randomization at Week 6 in Montgomery Åsberg Depression Rating Scale (MADRS) total score for patients with anxious and nonanxious depression. RESULTS: Of 968 patients included in the analysis, 788 (81.4%) were classified as anxious depressed (defined as HAM-D anxiety/somatization factor score ≥ 7) and 180 (18.6%) were nonanxious. For patients with anxious depression and nonanxious depression, statistically significant differences versus placebo in MADRS total score were recorded for quetiapine XR 150 mg/day (-3.24, P < .001 and -4.82, P < .01, respectively) and 300 mg/day (-3.57, P < .001 and -3.39, P < .05, respectively) at Week 6. In the second analysis using an alternate definition of anxious depression (baseline HAM-A total score ≥ 20), quetiapine XR 150 and 300 mg/day resulted in significant differences versus placebo in MADRS total score reduction in patients with high and lower levels of anxiety. The adverse event (AE) profile was similar irrespective of baseline anxiety levels, although patients with anxious depression reported a somewhat greater incidence of AEs. CONCLUSION: Quetiapine XR monotherapy improved symptoms of depression in patients with higher and lower levels of anxiety.

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.

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).

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.

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.

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.

Long-term safety and tolerability of cariprazine as adjunctive therapy in major depressive disorder.

Lack of treatment response is a critical problem in major depressive disorder (MDD). Cariprazine is a D3-preferring dopamine D3/D2 receptor partial agonist and 5-HT1A partial agonist. This phase 3, multicenter, open-label, long-term (26-week), flexible-dose (1.5-4.5 mg/day) study assessed the long-term safety and tolerability of cariprazine used adjunctively with antidepressant therapy in adult patients with MDD who had either completed a lead-in study (n=311) or had been newly recruited (n=131). A higher percentage of continuing patients (66.2%) than new patients (35.9%) completed the study. The most common reason for discontinuation was adverse events (AEs; 13.9%); 79% of patients experienced a treatment-emergent AE [most common: akathisia (15.9%,) headache (11.6%)]. Serious AEs occurred in 2% of patients; two deaths occurred (one traffic accident, one completed suicide, both considered unrelated to treatment). The mean changes in clinical laboratory, cardiovascular, and ophthalmologic parameters were generally not clinically relevant. The mean (SD) changes from the open-label baseline in Montgomery-Åsberg Depression Rating Scale total score and Clinical Global Impression-Severity score at week 26 were -7.3 (9.5) and -1.0 (1.2), respectively. By week 26, 53.3% of patients were in remission (Montgomery-Åsberg Depression Rating Scale total score≤10). The results suggest that cariprazine was generally safe and well tolerated as adjunctive therapy to treat MDD.

Steady-state pharmacokinetic, safety, and tolerability profiles of quetiapine, norquetiapine, and other quetiapine metabolites in pediatric and adult patients with psychotic disorders.

OBJECTIVE: The aim of this study was to investigate the steady-state pharmacokinetic, safety, and tolerability profiles of immediate-release quetiapine administered by similar dose-escalation regimens in pediatric and adult populations with psychotic or mood disorders. METHODS: Pediatric patients aged 10-17 years were titrated to a quetiapine dose of 200 mg twice daily (b.i.d. on days 5-7, 400 mg b.i.d. on days 11-12, with a final 400-mg dose on day 13. In a separate trial, adult patients aged 18-45 years were titrated to a quetiapine dose of 200 mg b.i.d. on days 4-6, 400 mg b.i.d. on days 10-11, with a final 400-mg dose on day 12. Concentrations of quetiapine and three metabolites (quetiapine sulfoxide, 7-hydroxy quetiapine, and norquetiapine) were quantified in plasma and urine. Adverse events, vital signs, 12-lead electrocardiogram (ECG), and clinical laboratory tests were evaluated throughout the studies. RESULTS: In both pediatric and adult populations, plasma concentrations of quetiapine and norquetiapine increased proportionately as the dose was escalated from 200 mg b.i.d. to 400 mg b.i.d. There were no age-related differences in the dose-normalized quetiapine plasma concentration-time curve (AUC(SS)) and maximum plasma concentration (C(SS,max)). Quetiapine was rapidly absorbed after 200-mg and 400-mg doses in pediatric patients [median t(max) (time to maximum plasma concentration) 1.5 hours, both doses] and adult patients (median t(max) 1.0 hour and 1.2 hours, respectively). The mean quetiapine t(1/2) (terminal elimination half-life) was approximately 6 hours for pediatric and 5 hours for adult patients. Norquetiapine displayed a similar median t(max) and a longer t(1/2) compared with quetiapine. Quetiapine was well tolerated, with no serious adverse events and no unexpected events reported. CONCLUSION: Pediatric and adult populations demonstrated similar pharmacokinetic, safety, and tolerability profiles for quetiapine administered by dose escalation. The predictability in quetiapine concentration profiles for children aged 10 years to adults suggests that no dosage adjustment may be required when treating patients of these ages.

Cariprazine Augmentation to Antidepressant Therapy in Major Depressive Disorder: Results of a Randomized, Double-Blind, Placebo-Controlled Trial.

Cariprazine is an atypical antipsychotic currently under investigation as an adjunctive to antidepressant treatment (ADT) for patients with major depressive disorder (MDD). Here results of an 18- to 19-week randomized double-blind placebo-controlled Phase 3 study evaluating the efficacy of adjunctive cariprazine (1.5-4.5 mg/day[d]) with ADT in participants with previous inadequate response to ADT are presented. ADT response was assessed in an 8-week open-label period; inadequate responders were randomized (N = 530) to open-label ADT plus placebo (n = 261) or cariprazine (n = 269) for the 8-week double-blind phase (NCT01715805). Primary and secondary endpoints were changes at week 8 (cariprazine versus placebo) in Montgomery-Åsberg Depression Rating Scale (MADRS) total score and in Sheehan Disability Scale (SDS) score, respectively, which were analyzed by mixed-effect models for repeated measures. Cariprazine did not significantly improve scores in either compared to placebo, but non-significantly reduced depressive symptoms (MADRS least-squares mean difference [LSMD]: -0.2, P = 0.7948 and SDS LSMD: -0.7, P = 0.2784). Of additional efficacy parameters, cariprazine significantly improved Clinical Global Impressions - Improvement (CGI-I) scores versus placebo (LSMD: -0.2; P = 0.0410). A greater proportion of participants achieved MADRS response with cariprazine vs placebo, but differences were not significant. Cariprazine was generally well-tolerated, and metabolic parameters and body weight changes were not meaningfully different than placebo. Common newly-emergent adverse events included akathisia and restlessness. The lack of significant improvement in depressive symptoms with adjunctive cariprazine and ADT for MDD in inadequate responders contrasts with previously published results, therefore additional studies are needed to understand role of adjunctive cariprazine in MDD.

Efficacy and safety of extended-release quetiapine fumarate in youth with bipolar depression: an 8 week, double-blind, placebo-controlled trial.

OBJECTIVE: Quetiapine is an atypical antipsychotic with demonstrated efficacy in the treatment of adolescent schizophrenia and pediatric bipolar mania. Large, placebo-controlled studies of interventions in pediatric bipolar depression are lacking. The current study investigated the efficacy and safety of quetiapine extended-release (XR) in patients 10-17 years of age, with acute bipolar depression. METHODS: This multicenter, double-blind, randomized, placebo-controlled study investigated quetiapine XR (dose range, 150-300 mg/day) in pediatric outpatients with an American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR) diagnosis of bipolar I or bipolar II disorder (current or most recent episode depressed) treated for up to 8 weeks (ClinicalTrials.gov identifier: NCT00811473). The primary study outcome was mean change in Children's Depression Rating Scale-Revised (CDRS-R) total score. Secondary efficacy outcomes included CDRS-R-based response and remission rates. RESULTS: Of 193 patients randomized to treatment, 144 patients completed the study (75.3% of quetiapine XR group [n=70]; 74.0% of placebo group [n=74]). Least squares mean changes in CDRS-R total score at week 8 were: -29.6 (SE, 1.65) with quetiapine XR and -27.3 (SE, 1.60) with placebo, a between-treatment group difference of -2.29 (SE, 1.99; 95% CI, -6.22, 1.65; p=0.25; mixed-model for repeated measures analysis). Rates of response and remission did not differ significantly between treatment groups. The safety profile of quetiapine XR was broadly consistent with the profile reported previously in adult studies of quetiapine XR and pediatric studies of quetiapine immediate-release (IR). Potentially clinically significant elevations in clinical chemistry values included triglycerides (9.3%, quetiapine XR; 1.4%, placebo group) and thyroid stimulating hormone (4.7%, quetiapine XR; 0%, placebo group). An adverse event potentially related to diabetes mellitus occurred in 3.3% of the quetiapine XR versus no adverse events in the placebo group. CONCLUSIONS: Quetiapine XR did not demonstrate efficacy relative to placebo in this 8 week study of pediatric bipolar depression. Quetiapine XR was generally safe and well tolerated.

Extended release quetiapine fumarate in patients with major depressive disorder: suicidality data from acute and maintenance studies.

OBJECTIVE: To prospectively analyze effects of extended release quetiapine fumarate (quetiapine XR) on suicidality in major depressive disorder (MDD). METHOD: Data were pooled from randomized, acute studies (4 monotherapy; 2 adjunct therapy) in adult patients with a DSM-IV diagnosis of MDD who were considered not to be at high risk of suicide at baseline and were receiving quetiapine XR 50 mg/d (n = 181), 150 mg/d (n = 910), or 300 mg/d (n = 685) or placebo (n = 957). Data from 1 acute monotherapy study in elderly patients receiving quetiapine XR (50-300 mg/d; n = 166) or placebo (n = 172) and maintenance data (up to 52 weeks) for patients receiving quetiapine XR (50-300 mg/d; n = 391) or placebo (n = 385) were also evaluated. Overall incidences and relative risks for suicidality (suicidal behavior/ideation) were assessed by Columbia-type review and classification. The proportion of patients with Montgomery-Asberg Depression Rating Scale (MADRS) item 10 (suicidal thoughts) score ≥ 4 was analyzed. RESULTS: Incidence of suicidality during acute treatment in adults was 1.1%, 0.7%, 0.7%, and 0.7% with quetiapine XR 50 mg/d, 150 mg/d, and 300 mg/d and placebo, respectively. The proportion of patients with MADRS item 10 score ≥ 4 during acute treatment in adults was 1.8% with quetiapine XR (all doses combined) and 2.4% with placebo. In elderly patients, the incidence of suicidality during acute treatment was 0.6% in both treatment groups; the proportion of patients with MADRS item 10 score ≥ 4 was 0% with quetiapine XR (all doses combined) and 1.2% with placebo. During maintenance treatment, the incidence of suicidality was 0.3% (n = 1) and 0.5% (n = 2) for quetiapine XR and placebo, respectively. The proportion of patients with MADRS item 10 score ≥ 4 was 4.1% with quetiapine XR in the open-label stabilization period and 0.3% with quetiapine XR and 0.5% with placebo during the randomized period. CONCLUSIONS: This analysis suggests that there is no evidence of treatment-emergent suicidality with quetiapine XR therapy in patients with MDD considered not to be at high suicide risk at baseline.

Extended release quetiapine fumarate as adjunct to antidepressant therapy in patients with major depressive disorder: pooled analyses of data in patients with anxious depression versus low levels of anxiety at baseline.

OBJECTIVES: To evaluate quetiapine XR in patients with anxious depression, as defined by HAM-A total and HAM-D anxiety/somatisation factor scores. METHODS: Post hoc analyses of pooled data from two 6-week, double-blind, randomised, placebo-controlled studies of adjunctive quetiapine XR (150 or 300 mg/day) in patients with MDD and inadequate response to antidepressants. Patients were stratified in a primary analysis using HAM-A (HAM-A total score at baseline ≥ 20 ["high"] or < 20 ["low"]) and a secondary analysis using HAM-D (anxious depression defined as HAM-D anxiety/somatisation factor score ≥ 7). Outcomes included change in MADRS total score. RESULTS: In patients with high anxiety levels (HAM-A total score ≥ 20), reductions in MADRS total score were -15.20 (P = 0.122) and -15.92 (P < 0.05) for quetiapine XR 150 and 300 mg/day, respectively, vs. placebo (-13.49). In patients with low levels of anxiety (HAM-A total score < 20), both quetiapine XR doses (P < 0.001) improved MADRS total scores vs. placebo. In the secondary analysis, quetiapine XR 150 (P < 0.01) and 300 mg/day (P < 0.001) improved MADRS total score vs. placebo in patients with HAM-D anxiety/somatisation factor score ≥ 7. CONCLUSIONS: Adjunct quetiapine XR demonstrates efficacy in patients with anxious and non-anxious depression, assessed using HAM-A total score, and anxious depression assessed using HAM-D anxiety/somatisation factor score.

A randomized, double-blind study of the efficacy and tolerability of extended-release quetiapine fumarate (quetiapine XR) monotherapy in patients with major depressive disorder.

OBJECTIVES: To evaluate the efficacy and tolerability of once-daily extended release quetiapine fumarate (quetiapine XR) monotherapy in patients with major depressive disorder (MDD). PATIENTS AND METHODS: This was a 10-week (8-week active treatment/2-week post-treatment) randomized, double-blind, placebo- and active-controlled study (D1448C00004). Patients received quetiapine XR 150 mg/day, escitalopram 10 mg/day, or placebo; patients with an inadequate response (<20% improvement in Montgomery-Åsberg Depression Rating Scale [MADRS] total score) at week two received double-dose treatment. The primary end point was week eight change from randomization in MADRS total score. Secondary end points included MADRS response (≥50% improvement) and remission (score ≤8); Hamilton Rating Scale for Depression total and item 1; Hamilton Rating Scale for Anxiety total, psychic, and somatic; Clinical Global Impressions - Severity of Illness total; Pittsburgh Sleep Quality Index (PSQI) global; and Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form percentage maximum total scores. Tolerability was assessed throughout. RESULTS: A total of 471 patients was randomized. No significant improvements in MADRS total score were observed at week eight (last observation carried forward) with either active treatment (quetiapine XR, -17.21 [P=0.174]; escitalopram, -16.73 [P=0.346]) versus placebo (-15.61). There were no significant differences in secondary end points versus placebo, with the exception of week-eight change in PSQI global score (quetiapine XR, -4.96 [P<0.01] versus placebo, -3.37). Mixed-model repeated-measures analysis of observed-case data suggested that the primary analysis may not be robust. Most commonly reported adverse events included dry mouth, somnolence, and dizziness for quetiapine XR, and headache and nausea for escitalopram. CONCLUSION: In this study, neither quetiapine XR (150/300 mg/day) nor escitalopram (10/20 mg/day) showed significant separation from placebo. Both compounds have been shown previously to be effective in the treatment of MDD; possible reasons for this failed study are discussed. Quetiapine XR was generally well tolerated, with a profile similar to that reported previously.

Pooled analysis of adjunct extended-release quetiapine fumarate in patients with major depressive disorder according to ongoing SSRI or SNRI treatment.

This pooled analysis evaluated the efficacy of extended-release quetiapine fumarate (quetiapine XR) adjunct to selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) in patients with major depressive disorder (MDD). Pooled data were analyzed from two 6-week, double-blind, randomized, placebo-controlled trials of adjunct quetiapine XR (150 and 300 mg/day) in patients with MDD and inadequate response to initial antidepressant monotherapy. This post-hoc analysis included evaluation of change from randomization at week 6 in Montgomery Åsberg Depression Rating Scale (MADRS) total scores (primary endpoint), and week 6 MADRS response and remission rates for quetiapine XR as an adjunct to ongoing SSRI or SNRI. In total, 189, 178, and 202 patients received quetiapine XR 150 mg/day+SSRI, 300 mg/day+SSRI, and placebo+SSRI, respectively, whereas 82, 90, and 76 patients, respectively, received quetiapine XR 150 mg/day+SNRI, 300 mg/day+SNRI, and placebo+SNRI. At week 6, quetiapine XR 150 mg/day+SSRI and 300 mg/day+SSRI reduced the MADRS total score from randomization versus placebo+SSRI [least squares mean (LSM) change, -14.70 (P<0.05) -14.72 (P<0.05) vs. -12.59, respectively]. Quetiapine XR 150 mg/day+SNRI (LSM change, -14.68, P<0.01) and 300 mg/day+SNRI (LSM change, -14.99, P<0.01) also reduced the MADRS total score from randomization at week 6 versus placebo+SNRI (-10.77). In conclusion, in patients with MDD and inadequate response to ongoing antidepressant, adjunct quetiapine XR (150 and 300 mg/day) was effective in both SSRI and SNRI subgroups.

Safety, tolerability, and efficacy of quetiapine in youth with schizophrenia or bipolar I disorder: a 26-week, open-label, continuation study.

OBJECTIVE: The purpose of this study was to describe the safety, tolerability, and efficacy of quetiapine monotherapy continued for up to 26-weeks in youth with schizophrenia or bipolar I disorder. METHODS: Medically healthy boys and girls with a baseline Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV-TR) diagnosis of schizophrenia (ages 13-17 years) or a manic episode of bipolar I disorder (ages 10-17 years) who participated in one of two acute, double-blind, placebo-controlled studies of immediate-release quetiapine were potentially eligible to enroll in a 26-week, open-label study. During the open-label study, quetiapine was flexibly dosed at 400-800 mg/day, with options to reduce dosing to 200 mg/day based on tolerability. Safety and tolerability outcomes assessed from open-label baseline to week 26 included adverse events (AEs), metabolic/laboratory parameters, extrapyramidal symptoms, suicidality, and vital signs. RESULTS: Of 381 patients enrolled in the open-label study (n=176, schizophrenia; n=205, bipolar disorder diagnosis), 237 patients (62.2%) completed the 26-week study period (71.0%, schizophrenia; 54.6%, bipolar disorder). The most common AEs reported during the study included somnolence, headache, sedation, weight increase, and vomiting. A total of 14.9% of patients experienced a shift to potentially clinically significant low levels of high-density lipoprotein cholesterol and 10.2% of patients experienced a shift to potentially clinically significant high triglyceride levels. Weight gain ≥ 7% was reported in 35.6% of patients between open-label baseline and final visit. After adjustment for normal growth, 18.3% of study participants experienced clinically significant weight gain (i.e., increase in body mass index ≥ 0.5 standard deviations from baseline). CONCLUSIONS: In this 26-week study, quetiapine flexibly dosed at 400-800 mg/day, with options to reduce dosing based on tolerability, was generally safe and well tolerated in youth. Clinicians should monitor lipid profiles and weight gain in youth with schizophrenia or bipolar disorder during treatment with quetiapine.