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Background Circadian rhythm disturbances have been reported in patients with major depressive disorder (MDD). Among these is an increased phase angle between peak cortisol concentration and dim-light melatonin onset (DLMO). The aim of this study was to evaluate changes in chronobiologic parameters of sleep in patients with MDD receiving adjunctive brexpiprazole. Methods This was an interventional, multicenter, open-label, flexible-dose, exploratory study in patients with MDD and inadequate response to antidepressant treatment who were experiencing sleep disturbances. Patients received adjunctive brexpiprazole 2–3 mg/day for 8 weeks. Outcome measures included cortisol and melatonin levels, used to calculate phase angle, and the Biological Rhythms Interview of Assessment in Neuropsychiatry (BRIAN). Results The mean (standard error) phase angle between peak cortisol and DLMO increased by 108 (61) minutes from baseline to Week 8 (n = 9). BRIAN Total score changed (improved) by –14.6 (4.6) points from baseline to Week 8 (n = 9). Change in phase angle and BRIAN Total score showed a moderate-to-high correlation (Pearson coefficient: 0.68; 95% confidence limits: 0.04, 0.93; p = 0.040). Limitations This study is limited by its small sample size, and its single-arm, open-label design. Conclusions The findings provide a preliminary indication that the phase angle between peak cortisol and DLMO is of interest as a potential biomarker for depression and therapeutic response. Adjunctive brexpiprazole may represent a strategy for correcting circadian dysfunction in patients with MDD and inadequate response to antidepressant treatment. ClinicalTrials.gov identifier: NCT01942733.

Background Patients with major depressive disorder (MDD) who do not adequately respond to antidepressant treatment (ADT) may benefit from adjunctive atypical antipsychotics; however, certain agents target specific symptoms of depression and not the full syndrome. The aim of this analysis was to examine the effects of brexpiprazole, adjunct to ADT, on the core symptoms of MDD, defined using Montgomery–Asberg Depression Rating Scale (MADRS) items. Methods This was a post hoc analysis of data from two 6-week, randomized, double-blind studies of adjunctive brexpiprazole in patients with MDD and inadequate response to ADTs (n = 1056). Efficacy was assessed using the MADRS core symptom subscale (MADRS6) and individual items (apparent sadness, reported sadness, inner tension, lassitude, inability to feel, and pessimistic thoughts). Results At Week 6, adjunctive brexpiprazole showed a greater effect than adjunctive placebo on the MADRS6 (within-group Cohenʼs d effect sizes: brexpiprazole, 1.05; placebo, 0.71; p Limitations This was a post hoc analysis of studies that were not designed for this purpose. Correction for multiple comparisons was not performed. Conclusions Brexpiprazole, as adjunct to ADT, produced a statistically significant and clinically meaningful improvement on the core symptoms of MDD. Brexpiprazole is thought to exert its effects in MDD by treating the core symptoms of the disease.

Background Anxiety symptoms are prevalent in major depressive disorder (MDD) and are associated with greater illness severity, suicidality, impaired functioning and poor response to antidepressant treatment (ADT). The efficacy and safety of brexpiprazole – a serotonin-dopamine activity modulator – as adjunctive treatment in patients with MDD was recently evaluated in two phase 3 studies. We here present a post-hoc analysis of the efficacy of adjunctive brexpiprazole in patients with MDD and symptoms of anxious distress, defined using proxies for DSM-5 criteria. Methods Eligible patients were randomized to 2 mg brexpiprazole+ADT or placebo+ADT (NCT01360645); or 1 mg brexpiprazole+ADT, 3 mg brexpiprazole+ADT, or placebo+ADT (NCT01360632), respectively. Patients were defined as having anxious distress if they had ≥2 of the symptoms tension (MADRS item 3 score ≥3), restlessness (IDS item 24 score ≥2), concentration (MADRS item 6 score ≥3), or apprehension (HAM-D item 10 score ≥3). Primary efficacy endpoint was change in MADRS total score from baseline to Week 6. Results 55% of the patients had anxious distress at baseline. Adjunctive brexpiprazole showed greater improvement than adjunctive placebo on the primary efficacy endpoint in both patients with (least square mean difference to placebo+ADT: 2 mg+ADT: −2.95, p=0.0023; 3 mg+ADT: −2.81, p =0.0027); and without anxious distress (1 mg+ADT: −2.37, p =0.0093; 3 mg+ADT: −2.23, p =0.0131). Brexpiprazole in patients with anxious distress was not associated with an increased incidence of activating adverse events (e.g., akathisia). Conclusions Adjunctive brexpiprazole 2–3 mg may be efficacious in reducing depressive symptoms and is well tolerated, in patients with MDD and anxious distress.

Background Past studies suggest that brexpiprazole is an effective adjunctive treatment for major depressive disorder and schizophrenia; however, no studies have examined brexpiprazole for bipolar depression. In this study, we examined the effects of brexpiprazole on mood, cognition, and quality of life in outpatients with bipolar depression. Methods Twenty-one adults with bipolar disorder (most recent episode depressed) and scoring at least a 25 on the Montgomery-Asberg Depression Rating Scale (MADRS) were recruited. Brexpiprazole was titrated up to 4 mg/day over the 8-week period. Depressive symptoms were measured using MADRS and Inventory of Depressive Symptomatology Self-report (IDS-SR30). Manic symptoms were measured using Young Mania Rating Scale, quality of life with the Quality of Life in Bipolar Disorder (QOLBD), and cognition with Rey Auditory Verbal Learning Test, Stroop Color Word Test, and Trail Making Test. Results MADRS and IDS-SR30 scores decreased from baseline at weeks 4 and 8. YMRS and cognitive scores did not change significantly. QOLBD scores increased from baseline to week 8. Limitations A limitation to this study is the open-label design. Conclusion To our knowledge, this is the first study to examine the effects of brexpiprazole on bipolar depression. We found a significant reduction in depressive symptoms and an increase in quality of life.

Background Major depressive disorder (MDD) is a debilitating psychiatric illness with a high cost burden. This analysis evaluates the cost-effectiveness of adjunctive brexpiprazole versus comparator branded adjunctive treatment for MDD and background antidepressant therapy (ADT) alone from a US payer perspective. Methods An economic model was developed to assess the cost-effectiveness of brexpiprazole versus comparator adjunctive treatment and ADT alone on total direct medical costs using a 6-week cycle time frame for a total of 48 weeks, with treatment response and remission as primary outcomes. The model consisted of 3 parts, 1 to represent the acute treatment phase and 2 to represent the maintenance stage. Results In the base-case analysis, brexpiprazole as reference treatment resulted in cost per additional responder ranging from $19,442–$48,745 and cost per additional remitter ranging from $27,196–$71,839 versus comparator treatments over 48 weeks. Sensitivity analyses showed treatment with brexpiprazole was more costly, but more clinically effective in all probabilistic simulations. Limitations This representation of disease natural history over 48 weeks may not account for all possible health states. Resource utilization on treatment was estimated using the resource use data from previous trials, and may overestimate medical costs compared to the real-world setting. Treatment comparators were limited to branded therapies, and head-to-head studies were not available to obtain data inputs. Conclusion Compared to other branded adjunctive therapies, brexpiprazole increases response and remission at 6 weeks; medical care cost savings were observed with the use of brexpiprazole. These findings may assist clinicians and formulary decision makers when selecting treatment for MDD.

BackgroundMajor depressive disorder (MDD) is a common, debilitating disorder with substantial socioeconomic burden. Many patients with MDD experience symptoms that impair functioning and productivity, often negatively affecting work or educational pursuits. This Phase 3b open-label study evaluated adjunctive brexpiprazole in young adults with MDD, who were in work or study.MethodsYoung patients (18–35 years) with MDD (inadequate responders to 1–3 antidepressant treatments [ADT] for their current episode) received brexpiprazole 1–3mg/day (target dose, 2mg/day) adjunctive to the same stable dose of ADT for 12 weeks.ResultsDepressive symptoms improved during treatment with adjunctive brexpiprazole (primary endpoint, least squares [LS] mean change from baseline in Montgomery-Åsberg Depression Rating Scale [MADRS] total score, −18.1 [p