Adjunctive brexpiprazole in patients with major depressive disorder and anxiety symptoms: an exploratory study

Abstract Background Major depressive disorder (MDD) with concurrent anxiety symptoms may signal a difficult‐to‐treat patient. Brexpiprazole is a serotonin–dopamine activity modulator: a partial agonist at 5‐HT1A and dopamine D2 receptors at similar potency, and an antagonist at 5‐HT2A and noradrenaline alpha1B/2C receptors. The objective of this Phase IIIb study was to explore effectiveness, safety, and tolerability of brexpiprazole adjunctive to antidepressant (ADT) monotherapy in patients with MDD and anxiety symptoms (NCT02013531). Methods Patients with MDD, Hamilton Anxiety Rating Scale (HAM‐A) total score ≥ 20, and inadequate response to current ADT received open‐label brexpiprazole 1–3 mg day−1 (target dose 2 mg day−1) + ADT for 6 weeks. Efficacy endpoints included change from baseline at Week 6 in Montgomery–Åsberg Depression Rating Scale (MADRS) total score, HAM‐A total score, and Sheehan Disability Scale (SDS). Safety and tolerability assessments included adverse events (AEs). Results Of 37 participants enrolled, 32 (86.5%) completed the study. Baseline mean (SD) MADRS total score was 30.1 (5.1); mean HAM‐A total score was 26.9 (5.0). Improvements from baseline were observed at Week 6 for least squares mean change in MADRS total score (−19.6, p < .0001 vs. baseline), HAM‐A total score (−17.8, p < .0001) and mean (SD) SDS mean score [−3.6 (2.6)]. Brexpiprazole was well tolerated. The most frequent treatment‐emergent AEs were increased appetite (13.5%) and diarrhea, dry mouth, and dizziness (all 10.8%). Conclusions These open‐label results support the anxiolytic effects of adjunctive brexpiprazole in the treatment of patients with MDD.


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Fifth Edition , which included the addition of criteria for a "with Anxious Distress" specifier for MDD (American Psychiatric Association, 2013).
Evidence-based guidance on treatment strategies for patients with MDD and concurrent anxiety symptoms is scarce. Several large studies have reported that patients with MDD and anxiety symptoms have poorer treatment outcomes than patients who are not anxious (Wiethoff et al., 2010;Farabaugh et al., 2012;Fava et al., 2008;Ionescu et al., 2014). Although monotherapy with antidepressant treatments (ADTs) can be effective in treating MDD with anxiety symptoms, patients may be less likely to experience sustained response or remission (Ionescu et al., 2014). Subgroup analyses of short-term, larger studies have indicated that augmentation with an antipsychotic is an effective strategy in the treatment of MDD with anxiety symptoms (Bandelow et al., 2014;Trivedi et al., 2008). Pooled analysis from two double-blind, placebo-controlled studies in patients with MDD and inadequate response to ADTs demonstrated that augmentation with aripiprazole improved Montgomery-Åsberg Depression Rating Scale (MADRS) total score in a subgroup with baseline Hamilton Rating Scale for Depression (HAM-D) anxiety/somatization factor score ≥ 7 (Trivedi et al., 2008). Quetiapine extended-release (XR) augmentation has also been reported to improve MADRS total score in subgroups of patients with MDD and inadequate response to ADTs, with anxious depression defined as baseline HAM-D anxiety/somatization factor score ≥ 7, and alternatively as baseline Hamilton Rating Scale for Anxiety (HAM-A) ≥ 20 (Bandelow et al., 2014).
Brexpiprazole is a serotonin-dopamine activity modulator that is a partial agonist at serotonin 5-HT 1A and dopamine D 2 receptors at similar potency, and an antagonist at 5-HT 2A and noradrenaline alpha 1B/2C receptors (Maeda et al., 2014). In two pivotal Phase III, double-blind, placebo-controlled studies, brexpiprazole 2 and 3 mg day −1 + ADT significantly improved the MADRS total score versus placebo over 6 weeks in patients with MDD and inadequate response to ADTs (Thase et al., 2015a(Thase et al., , 2015b. The tolerability profile observed with brexpiprazole in these short-term studies was consistent with its receptor pharmacology. Brexpiprazole has low intrinsic activity at D 2 receptors (Maeda et al., 2014), which may reduce the potential for activating side effects.
The objective of this Phase IIIb study (ClinicalTrials.gov NCT02013531) was to explore the effectiveness, safety, and tolerability of brexpiprazole + ADT in patients with MDD and anxiety symptoms who had an inadequate response to their current ADT.  (Sheehan et al., 1998) and clinical examination. During the current episode, participants must have had an inadequate response, defined as <50% reduction in symptoms selfreported via the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ; Chandler et al., 2010), to adequate trials of between one and three ADTs. During the 6 weeks prior to screening, participants must have received treatment at an adequate dose with one of the following single selective serotonin reuptake inhibitors (SSRIs) or serotonin noradrenaline reuptake inhibitors (SNRIs): escitalopram 10-20 mg day −1 , fluoxetine 20-40 mg day −1 , paroxetine controlled-release (CR) 25-50 mg day −1 , sertraline 50-200 mg day −1 , duloxetine 40-60 mg day −1 , or venlafaxine extendedrelease (XR) 75-225 mg day −1 . Eligible participants had a Hamilton Depression Rating Scale 17-item (HAM-D-17;Hamilton, 1960), total score ≥ 18, and HAM-A (Hamilton, 1959) total score ≥ 20 at both screening and baseline.

| Study participants
Key exclusion criteria included treatment during the current episode with an antipsychotic as adjunctive to an ADT for ≥3 weeks, electroconvulsive therapy (ECT) or transcranial magnetic stimulation; previous inadequate response to ECT or transcranial magnetic stimulation; previous vagus nerve stimulation or implantation of deep brain stimulation; new-onset psychotherapy within 42 days prior to screening; hospitalization within 4 weeks prior to screening; other psychiatric diagnosis; hallucinations, delusions, or psychotic symptoms in current episode; serious risk of suicide; substance abuse or dependence; and significant medical condition, or abnormal laboratory tests or electrocardiogram (ECG).
If clinically appropriate, participants taking neuroleptics, monoamine oxidase inhibitors, benzodiazepines, or hypnotics were required to discontinue these medications during the screening period. Treatment with other psychotropic or investigational agents, CYP2D6 inhibitors (other than fluoxetine, paroxetine, and duloxetine), CYP3A4 inhibitors or inducers, and barbiturates was discontinued at least 24 hr before the first dose of study medication. Short-term use of oral benzodiazepines (maximum dose: lorazepam 2 mg week −1 or oxazepam 30 mg week −1 ) or nonbenzodiazepine sleep aids (maximum 7 days) was allowed during the study to manage symptoms, if necessary. Anticholinergics (maximum 4 mg day −1 benztropine or equivalent) or propranolol (maximum 60 mg day −1 ) were permitted for management of extrapyramidal symptoms (EPS), if required. Concomitant medication was to be avoided for at least 12 hr prior to efficacy and safety assessments.

| Study design
This was an open-label, flexible-dose study conducted in 12 centers in the USA between November 2013 and June 2014. The study comprised a 2-21-day screening phase, during which participants received stable-dose, open-label SSRI, or SNRI treatment, a 6-week treatment phase during which open-label brexpiprazole (target dose 2 mg day −1 ) was added to the current ADT, and a 30-day follow-up phase (Fig. 1).
The study was conducted in compliance with the International Conference on Harmonization Good Clinical Practice guidelines. The protocol was approved by an institutional review board or independent ethics committee at each center. All participants provided informed consent to participate and none required surrogate consent.

| Statistical analysis
No formal sample size calculations were performed. The safety population comprised all participants who took at least one dose of brexpiprazole, while the efficacy population included only participants in the safety population with an efficacy assessment both at baseline and on at least one occasion postbaseline.
The primary efficacy endpoint was change from baseline at Week 6 in MADRS total score. Other efficacy endpoints included change from baseline at Week 6 in CGI-S score, HAM-A total score, HAM-D-17 total score, KSQ total and symptom subscale scores, SDS mean and individual item scores, MGH-CPFQ total score, and BIS-11 total score, and CGI-I score at Week 6. Responder rate was defined as the proportion of participants with ≥50% reduction from baseline in MADRS total score at Week 6; or a CGI-I score of 1 or 2 at Week 6. Remission rate was defined as the proportion of participants with MADRS total score ≤10 and a reduction from baseline of ≥50% in MADRS total score at Week 6.
Analysis of the primary efficacy endpoint was based on actual observations recorded at each visit, and no missing data were imputed (observed cases). A mixed model repeated measures (MMRM) analysis was fitted with an unstructured variance covariance structure, in which change from baseline in MADRS total score was the dependent variable. The model included fixed class effect terms for visit, baseline score, and the interaction term of score-by-visit. Point estimates and associated two-sided 95% confidence intervals (CIs) were calculated.
The null hypothesis of zero mean change from baseline at Week 6 was tested at a significance level of .05. As this was an exploratory trial, no methods to control type I error rate were warranted. Change from baseline at Week 6 in CGI-S score and HAM-A total score were analyzed in the same way as the primary efficacy endpoint. The other efficacy endpoints were summarized using last-observation-carriedforward data.
Changes from baseline at last visit were reported for fasting metabolic parameters and EPS scale scores. Mean (standard deviation [SD]) change in body weight at Week 6 was derived from observed case data.
F I G U R E 1 Study design. All participants received stable-dose, open-label SSRI or SNRI treatment throughout the screening phase. Brexpiprazole was initiated at a dose of 0.5 mg day −1 , and was increased to 1 and 2 mg day −1 at Weeks 1 and 2, respectively. Thereafter, the dose could be decreased at any time to 1 mg day −1 or increased at study visits to 3 mg day −1 , as required. All participants discontinued brexpiprazole at the end of the treatment phase, and were contacted by telephone to monitor safety at the end of the 30-day follow-up phase. ADT, antidepressant; ET, early termination; MDD, major depressive disorder; SNRI, serotonin noradrenaline reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor 3 | RESULTS

| Participants
We enrolled 37 participants, of whom 32 (86.5%) completed the study. Of the five participants who discontinued the study, three were lost to follow-up, one withdrew consent, and one became pregnant and was discontinued. All 37 participants were included in the safety population; one participant was excluded from the efficacy population because they did not have an efficacy assessment both at baseline and on at least one occasion postbaseline.
Participants who completed the study received brexpiprazole at a mean dose of 2.1 mg day −1 in addition to their current ADT.
Mean (SD) duration of the current episode of MDD was 13.6 (18.0) months, while the median was 8.9 months. Most of the participants (32, 86.5%) had experienced recurrent episodes of depression.
During the current episode, 32 participants (86.5%) reported an inadequate response to one ADT, while five participants (13.5%) had an inadequate response to at least two ADTs. None of the participants had been treated with an antipsychotic during the current episode.
Baseline depression and anxiety rating scale scores confirmed that the participant population had moderate-to-severe depression and anxiety symptoms (Table 1).

| Efficacy
Mean HAM-D-17 total score improved from baseline at Week 6, as did MGH-CPFQ total score and BIS-11 total score (Table 2). Mean KSQ total score improved over the 6-week treatment period; reductions were seen in all symptom subscale scores: anxiety, depression, somatic symptoms, and anger-hostility (Table 2). Mean (SD) SDS mean score improved by 3.6 (2.6) points from baseline at Week 6, while individual item scores for social life, family life, and home responsibilities, and work and school life also improved at Week 6 ( Fig. 3

| Safety and tolerability
Treatment-emergent adverse events (TEAEs) were reported by 75.7% (28/37) of the participants (Table 3); however, none of the TEAEs resulted in discontinuation of brexpiprazole. The most frequently reported TEAEs were increased appetite, diarrhea, dry mouth, and dizziness. Most of the TEAEs were considered by the investigators to be mild or moderate in severity, while two were considered to be severe (arthralgia; neck pain). One participant experienced a serious AE (pneumonia) after completion of brexpiprazole treatment. There were no clinically significant changes from baseline at the last visit in mean fasting metabolic parameters ( F I G U R E 3 Mean (SD) change from baseline at Week 6 in SDS mean score and individual items (efficacy population). Mean scores at baseline were 6.5 for mean score (calculated as mean of three item scores), 6.7 for social life, 6.4 for family life and home responsibilities, and 6.3 for work and school life. Range 0-10, higher scores indicate greater impairment. SD, standard deviation; SDS, Sheehan Disability Scale an increase in body weight of ≥7% from baseline at Week 6; one of these participants reported weight gain as a TEAE. Mean (SD) increase in body weight from baseline (screening) at Week 6 was 1.6 (2.4) kg. One female participant had an elevated serum prolactin level at Week 6. In the ECG evaluations, two subjects had new-onset QT interval >450 ms; three subjects had increases of 30-60 ms in QT interval corrected by Bazett's formula; and two participants had increases of 30-60 ms in QT interval corrected by Fridericia's formula.
There was no worsening in mean EPS scale scores. Mean (SD) changes from baseline at the last visit were as follows: −0.2 (0.9) for SAS total score, 0 (0) for AIMS total score, and 0 (0.2) for BARS total score. Treatment-emergent suicidal behavior and ideation recorded on the C-SSRS comprised one incidence of emergence of suicidal ideation and one incidence of worsening suicidal ideation.

| DISCUSSION
In this exploratory, 6-week, open-label study, symptoms of depression and anxiety improved in participants with MDD with concurrent anxiety who had an inadequate response to previous ADT monotherapy, following treatment with brexpiprazole at a mean dose of 2.1 mg day −1 adjunctive to their current ADT. Mean reductions from baseline of 20 points in MADRS total score (primary endpoint, p < .0001 vs. baseline) and 16 points in HAM-D-17 total score were observed at Week 6, together with high response (69.4%) and remission (47.2%) rates, indicating substantial improvements in symptoms of depression. These findings were supported by a reduction from baseline in CGI-S to a mean score of 2.2 at Week 6, consistent with borderline depression and a mean CGI-I score of 1.9 at Week 6, indicative of much improved status over baseline. Anxiety symptoms also improved substantially during the treatment period with a mean 18-point reduction in HAM-A total score.
In addition to improvements in clinician-rated depression and anxi- It is recognized that patients with MDD and anxiety symptoms may have more severe illness and may require a more intensive treatment approach (Wiethoff et al., 2010;Ionescu et al., 2014). The results from this study suggest that brexpiprazole + ADT may be an appropriate treatment option for the difficult-to-treat patients with MDD and anxiety. The efficacy of brexpiprazole + ADT in treating patients with MDD and an inadequate response to ADT has previously been demonstrated in two double-blind, placebo-controlled Phase III studies (Thase et al., 2015a(Thase et al., , 2015b. Patients entered into the Phase III studies were not selected for a high level of anxiety as evidenced by mean baseline HAM-A total scores of 16-18. In these studies, reductions from baseline at Week 6 in mean HAM-A total score were greater in the 2 and 3 mg brexpiprazole + ADT groups than those in the placebo groups. In this study, mean HAM-A total score at baseline was 27, indicating a population with a high level of anxiety. Improvements in depression and anxiety symptoms were seen as early as 1 week after initiation of brexpiprazole, and followed a similar time course. T A B L E 3 Adjunctive brexpiprazole treatment-emergent adverse events (safety population, n = 37)

Number of participants, n (%)
At least one TEAE 28 (75. Brexpiprazole was well tolerated in this population, consistent with previous studies (Thase et al., 2015a(Thase et al., , 2015b. No participants discontinued due to TEAEs or reported serious AEs during treatment with brexpiprazole + ADT. The most frequently reported TEAE was increased appetite (five participants, 13.5%). Mean weight gain over the 6-week treatment period (1.6 kg) was comparable to that reported with brexpiprazole in previous short-term studies (Thase et al., 2015a(Thase et al., , 2015b. Brexpiprazole did not have clinically relevant adverse effects on metabolic parameters in this short-term study. The incidence of EPS-related TEAEs was low, and no worsening of EPS-related symptoms was observed using objective EPS rating scales. Few activating TEAEs were reported, with only akathisia (two participants, 5.4%) having an incidence ≥5%. This finding is clinically important since activating side effects associated with second-generation antipsychotics (Trivedi et al., 2008) may limit their use in an anxious population.
Overall, the tolerability profile of brexpiprazole observed in this study reflected its receptor pharmacology.
This study has several limitations, including the open-label design, lack of a placebo or active comparison group, short duration of the treatment phase, heterogeneity of ADTs, and the small number of participants. Use of low-dose benzodiazepines during the treatment period was rare; however, this may have affected the outcomes for a small number of participants. In addition, we are unable to conclude whether the improvements in anxiety symptoms were direct effects of brexpiprazole, or whether they occurred secondary to improvements in depressive symptoms.

| CONCLUSION
In conclusion, the results of this exploratory study support the effectiveness of brexpiprazole + ADT in the treatment of depression in patients with both MDD and a high level of anxiety symptoms, a newly recognized, clinically important specifier for MDD designated "Anxious Distress" by DSM-5 (American Psychiatric Association, 2013). The findings support the pivotal, double-blind, placebo-controlled studies (Thase et al., 2015a(Thase et al., , 2015b showing efficacy of brexpiprazole + ADT in the treatment of MDD in patients with an inadequate response to ADT monotherapy.