記住我
In patients with major depressive disorder (MDD), anxiety symptoms are frequent, indicative of a more severe form of depression, and have a detrimental impact on patients' functioning and quality of life.1–4 The presence of anxiety symptoms in MDD is associated with a decreased likelihood of response to antidepressant treatment (ADT)2,5 and is a common reason for clinicians to prescribe an adjunctive antipsychotic to help improve patient outcomes.6
To help identify and treat patients with anxiety symptoms in MDD, an anxious distress specifier was added to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).7 The DSM-5 and its subsequent text revision (DSM-5-TR) define anxious distress in MDD as the presence of at least two of the following symptoms during a depressive episode: feeling keyed up or tense, feeling unusually restless, difficulty concentrating because of worry, fear that something awful may happen, and feeling that the individual might lose control of himself or herself.8,9
Brexpiprazole is an atypical antipsychotic that acts as a partial agonist at serotonin 5-HT1A and dopamine D2 receptors, and an antagonist at 5-HT2A receptors as well as noradrenaline α1B and α2C receptors, all with subnanomolar affinity.10 In 4 phase 3 clinical trials in patients with MDD (with or without symptoms of anxiety) who had inadequate response to ADTs, adjunctive brexpiprazole showed efficacy in reducing overall depressive symptoms, as measured by change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score, among other outcomes.11–14 In one of these trials, adjunctive brexpiprazole was prospectively evaluated in the subgroup of patients with DSM-5 anxious distress and was found to be efficacious on MADRS total score.13 Although the DSM-5 anxious distress specifier was not directly assessed in the other trials, the efficacy of adjunctive brexpiprazole on MADRS total score was demonstrated post hoc in pooled analyses of subgroups that met proxies for the DSM-5 anxious distress specifier.15,16
Adjunctive treatments can be used in MDD to target specific symptoms that remain after ADT, as well as to improve overall efficacy.17,18 While adjunctive brexpiprazole has shown efficacy on overall depression severity in the subgroup with anxious distress, an understanding of the effects of adjunctive brexpiprazole on specific depressive symptoms in patients with anxious distress would be valuable to clinicians to allow for targeted treatment. Considering early improvement of certain symptoms may also be useful to help identify patients who will later have a broad benefit from adjunctive brexpiprazole, thereby guiding treatment optimization. In addition, the effect of adjunctive brexpiprazole on functioning in patients with MDD and anxious distress has not yet been evaluated; functioning is a clinically meaningful treatment goal that is of considerable importance from the patient perspective.19,20
The aims of this post hoc analysis were to examine the efficacy of ADT + brexpiprazole versus ADT + placebo on individual MADRS depressive symptoms and on functioning in patients with and without anxious distress (using proxy criteria) and to determine whether treated patients continue to meet proxy anxious distress criteria over time, using pooled data from three randomized controlled trials. Whereas previous research has considered the efficacy of ADT + brexpiprazole in patients with anxious distress using the same proxy criteria, the present analysis included a much larger patient sample (derived from the full brexpiprazole phase 3 clinical program) than a preliminary analysis by McIntyre et al15 and considered different outcomes (individual MADRS items and functioning) to a more recent analysis in the full sample by Thase et al.16
MATERIALS AND METHODS Study Design and PatientsThe analysis included data from three similarly designed, short-term, randomized, double-blind, placebo-controlled, parallel-group, phase 3 studies of adjunctive brexpiprazole in patients with MDD and inadequate response to ADTs (ClinicalTrials.gov identifiers: NCT01360645, NCT01360632, NCT02196506).11–13 A fourth study was not used because it did not include all of the rating scales needed to determine the presence of anxious distress per the proxy definition used.14 The studies were conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonization Good Clinical Practice guideline, and local regulatory requirements. Study protocols were approved by relevant institutional review boards and independent ethics committees, and all patients provided written informed consent before enrolment, after procedures, and possible adverse effects had been explained. The studies were conducted at multiple sites in North America and Europe (including Russia) between June 2011 and May 2016.
Detailed study designs have been previously published.11–13 In brief, the studies enrolled male and female outpatients aged 18 to 65 years with a DSM-IV-TR diagnosis of single or recurrent, nonpsychotic MDD21; a current depressive episode of ≥8 weeks in duration (with or without symptoms of anxiety); an inadequate response (defined as <50% improved) to an adequate trial of 1 to 3 prior ADTs during the current episode; and a Hamilton Depression Rating Scale (HAM-D17)22,23 total score of ≥18. Patients who presented with suicidal ideation or behavior, had substance abuse or dependence, or who had specified DSM-IV-TR comorbidities were excluded.
Eligible patients were administered an investigator-determined, open-label ADT (escitalopram, fluoxetine, paroxetine controlled-release, sertraline, duloxetine, or venlafaxine extended-release) together with single-blind placebo for 8 weeks, to identify patients with inadequate response to ADT under clinical trial conditions. Inadequate response to ADT was defined as persistent symptoms without substantial improvement based on depression rating scale score thresholds. Patients who met the criteria for inadequate response were eligible for randomization to 6 weeks of double-blind treatment with fixed-dose adjunctive brexpiprazole (1, 2, or 3 mg/d, depending on the study) or adjunctive placebo, while continuing the same ADT. Brexpiprazole was started at 0.5 mg/d, titrated to 1 mg/d after 1 week, and titrated to the allocated dose after 2 weeks. Treatment adherence was determined by tablet counting; patients with less than 80% adherence were considered for discontinuation. Antipsychotics (other than the study drug), antidepressants (other than those prescribed as part of the study), mood stabilizers, and anticonvulsants were prohibited during the studies. Short-term use of oral benzodiazepines (maximum 6 mg/d lorazepam or equivalent) for treatment-emergent anxiety/agitation and nonbenzodiazepine sleep aids (up to 7 days) for insomnia were permitted.
Definition of Anxious DistressIn this post hoc analysis, patients were stratified according to the presence or absence of anxious distress at baseline (the randomization visit). Two of the included studies were initiated before the publication of the DSM-5 in 2013, meaning that these studies did not include a specific assessment for the DSM-5 anxious distress specifier. Consequently, previously established proxy criteria for the specifier were applied to all three studies. The proxies were developed by linking each feature of the specifier to a specific rating scale item (selected from rating scales that were administered in the brexpiprazole studies), and assigning an a priori clinically meaningful cutoff.15 Thus, anxious distress was defined as the presence at baseline of at least two of the following symptoms: (1) feeling keyed up or tense: MADRS item 3 (inner tension) score of ≥3; (2) feeling unusually restless: Inventory of Depressive Symptomatology Self-Report item 24 (feeling restless) score of ≥2; (3) difficulty concentrating because of worry: MADRS item 6 (concentration difficulties) score of ≥3; and (4) fear that something awful may happen: HAM-D17 item 10 (psychic anxiety) score of ≥3.15,16 No proxy was found for “feeling that the individual might lose control of himself or herself,” and therefore patients were classified as having anxious distress if they met criteria for at least 2 of 4, rather than 2 of 5, symptoms.
Outcome MeasuresChange in MADRS total score from baseline to week 6 of the randomized treatment phase was the primary efficacy endpoint of each study. The MADRS is a clinician-rated measure of the severity of 10 depressive symptoms, each of which is rated on a 7-point scale from 0 (least severe) to 6 (most severe).24 The MADRS was administered at baseline (before dosing at the randomization visit) and at weekly intervals in the randomized treatment phase. The present post hoc analysis investigated change in MADRS individual item scores; change in MADRS total score has previously been reported in patients with and without anxious distress.16
Change in Sheehan Disability Scale (SDS) mean score from baseline to week 6 was a key secondary efficacy endpoint in each study. The SDS is a patient-rated measure of functional disability on 3 items (work/studies, social life, and family life), each of which is rated on an 11-point scale from 0 (not at all disrupted) to 10 (extremely disrupted).25,26 The SDS mean score was calculated as the mean of the 3 individual item scores (or the mean of 2 scores if the work/studies item was not rated).27 The SDS was administered at baseline, week 3 and week 6 of the randomized treatment phase.
Data AnalysisPatient data were pooled for two adjunctive brexpiprazole doses of interest: 2 mg/d (data from two studies) and 2 to 3 mg/d (data from three studies), representing the recommended-to-maximum brexpiprazole doses for the adjunctive treatment of MDD in different countries.28,29 Data were similarly pooled for patients who received adjunctive placebo, for the 2 mg analysis (data from two studies) and the 2 to 3 mg analysis (data from three studies). Analyses were performed in a modified intention-to-treat (efficacy) sample, defined as all patients randomized per final protocols who received at least one dose of double-blind medication and who had a baseline and at least one postbaseline MADRS total evaluation in the randomized treatment phase.
Patient baseline demographic and clinical characteristics were summarized using descriptive statistics. For MADRS items, SDS mean, and SDS items, least squares mean changes from baseline were calculated, with nominal P values (no adjustment for multiplicity) and Cohen d effect sizes (ES),30 using a mixed model for repeated measures (MMRM) with trial site, treatment group, visit, and treatment group-by-visit interaction as factors and baseline-by-visit interaction as a covariate. An observed cases dataset was used with no imputation for missing data, consistent with the primary efficacy assessments in the individual studies. An unstructured covariance was used by default; if the MMRM failed to converge then covariance structures with fewer parameters including heterogeneous Toeplitz, heterogeneous compound symmetry, Toeplitz, and compound symmetry were sequentially explored until the MMRM converged. Finally, the proportion of patients who changed anxious distress status (with/without) from baseline to week 6 was determined for patients who completed the studies. Ratios of response rate (brexpiprazole/placebo) were calculated, with 95% confidence intervals (CIs) and P values.
Analyses were performed using SAS Enterprise Guide 8.2 (SAS Institute, Inc, Cary, NC).
RESULTS PatientsThe efficacy sample comprised 746 patients in the 2 mg analysis and 1162 patients in the 2 to 3 mg analysis. Of these patients, 450 (60.3%) in the 2 mg analysis and 670 (57.7%) in the 2 to 3 mg analysis met the proxy criteria for anxious distress at baseline.
Compared with patients without anxious distress (descriptive statistics), the subgroup of patients with anxious distress had a greater proportion of females, a longer duration of current episode, more severe illness (higher MADRS total score), and slightly worse functioning (higher SDS mean score) (Table 1). Age, body mass index, proportion of White patients, and number of prior ADT failures in the current episode were similar among patients with and without anxious distress.
TABLE 1 - Baseline Demographic and Clinical Characteristics and Assigned ADTs Stratified by the Presence or Absence of Anxious Distress at Baseline Variable 2 mg Analysis 2–3 mg Analysis Patients With Anxious Distress Patients Without Anxious Distress Patients With Anxious Distress Patients Without Anxious Distress ADT + Placebo (n = 219) ADT + Brexpiprazole (n = 231) ADT + PlaceboEfficacy sample.
*Three patients in the 2 mg analysis and 5 patients in the 2 to 3 mg analysis (all ADT + brexpiprazole) were missing prior ADT information.
BMI, body mass index; CR, controlled-release; SD, standard deviation; XR, extended-release.
Between ADT + brexpiprazole and ADT + placebo treatment groups, baseline demographic and clinical characteristics were generally similar for patients with anxious distress, and for patients without anxious distress (Table 1).
Efficacy on MADRS Item ScoresMean changes in MADRS item scores over 6 weeks are presented in Figure 1. In patients with anxious distress, ADT + brexpiprazole 2 mg showed greater improvements than ADT + placebo (P < 0.05) on 6 of 10 MADRS items at week 6: apparent sadness (ES = 0.41), reported sadness (ES = 0.36), reduced appetite (ES = 0.43), lassitude (ES = 0.42), inability to feel (ES = 0.44), and pessimistic thoughts (ES = 0.23). In patients with anxious distress, ADT + brexpiprazole 2 to 3 mg showed greater improvements than ADT + placebo (P < 0.05) on 8 MADRS items at week 6: apparent sadness (ES = 0.30), reported sadness (ES = 0.32), inner tension (ES = 0.19), reduced sleep (ES = 0.18), reduced appetite (ES = 0.32), lassitude (ES = 0.36), inability to feel (ES = 0.32), and pessimistic thoughts (ES = 0.22).
FIGURE 1: Mean change in MADRS item scores from baseline to week 6 of treatment with adjunctive brexpiprazole (2 or 2–3 mg) or adjunctive placebo, stratified by the presence or absence of anxious distress at baseline. *P < 0.05, **P < 0.01, ***P < 0.001 versus ADT + placebo; MMRM. BSL, mean baseline score; LS, least squares; SE, standard error.
On the items apparent sadness, reported sadness, lassitude, and pessimistic thoughts, ADT + brexpiprazole showed improvements versus ADT + placebo (P < 0.05) as early as weeks 1 to 2 in patients with anxious distress, which were maintained to week 6, for both doses (see Fig. S1, Supplemental Digital Content 1, https://links.lww.com/JCP/A900, which provides by-week changes from baseline in MADRS item scores).
In patients without anxious distress, ADT + brexpiprazole 2 mg showed greater improvement than ADT + placebo (P < 0.05) on one MADRS item at week 6: inability to feel (ES = 0.24). ADT + brexpiprazole 2 to 3 mg showed greater improvements than ADT + placebo (P < 0.05) on 5 MADRS items at week 6: inner tension (ES = 0.20), reduced appetite (ES = 0.22), lassitude (ES = 0.19), inability to feel (ES = 0.19), and pessimistic thoughts (ES = 0.22).
Efficacy on SDS Mean and Item ScoresMean changes in SDS mean and item scores over 6 weeks are presented in Figure 2. In patients with anxious distress, ADT + brexpiprazole showed greater improvement in SDS mean score than ADT + placebo (P < 0.05) at week 6, in the 2 mg analysis (ES = 0.23) and the 2 to 3 mg analysis (ES = 0.21). Considering SDS items in patients with anxious distress, ADT + brexpiprazole showed greater improvements than ADT + placebo (P < 0.05) over 6 weeks on social life (2 mg analysis, ES = 0.29; 2–3 mg analysis, ES = 0.26) and family life (2 mg analysis, ES = 0.24; 2–3 mg analysis, ES = 0.26), but not work/studies.
FIGURE 2: Mean change in SDS mean and item scores from baseline to week 6 of treatment with adjunctive brexpiprazole (2 or 2–3 mg) or adjunctive placebo, stratified by the presence or absence of anxious distress at baseline. *P < 0.05, **P < 0.01, ***P < 0.001 versus ADT + placebo; MMRM. BSL, mean baseline score; LS, least squares; SE, standard error.
In patients without anxious distress, improvements in SDS mean and item scores were similar between treatment groups.
Anxious Distress Status ChangesIn the 2 mg analysis, 231 of 366 patients (63.1%) in the ADT + brexpiprazole group met the proxy criteria for anxious distress at baseline, compared with 68 patients (18.6%) at week 6. Corresponding values in the ADT + placebo group were 219 of 380 (57.6%) at baseline and 85 (22.4%) at week 6. Among patients with anxious distress at baseline, treatment with ADT + brexpiprazole 2 mg reduced the likelihood of having anxious distress at week 6 versus ADT + placebo (P = 0.0060) (Table 2).
TABLE 2 - Proportion of Patients Who Changed Anxious Distress Status (With/Without) From Baseline to Week 6 Treatment Group Anxious Distress at Baseline N Anxious Distress at End of Study n (%) RR (95% CI) P 2 mg analysis ADT + placebo Yes 219 No 151 (68.9) 1.17 (1.04–1.30) 0.0060 ADT + brexpiprazole 231 182 (78.8) ADT + placebo No 161 Yes 17 (10.6) 1.52 (0.83–2.78) 0.18 ADT + brexpiprazole 135 19 (14.1) 2–3 mg analysis ADT + placebo Yes 327 No 229 (70.0) 1.14 (1.04–1.25) 0.0048 ADT + brexpiprazole 343 267 (77.8) ADT + placebo No 256 Yes 25 (9.8) 1.48 (0.87–2.51) 0.16 ADT + brexpiprazole 236 26 (11.0)P values derived from the Cochran-Mantel-Haenszel test controlling for study and trial site. This analysis included only those patients with data at baseline and week 6 (ie, patients who did not complete the study were not analyzed).
CI, confidence interval; RR, ratio of response rate (brexpiprazole/placebo).
In the 2 to 3 mg analysis, 343 of 579 patients (59.2%) in the ADT + brexpiprazole group met the proxy criteria for anxious distress at baseline, compared with 102 patients (17.6%) at week 6. Corresponding values in the ADT + placebo group were 327 of 583 (56.1%) at baseline and 123 (21.1%) at week 6. Among patients with anxious distress at baseline, treatment with ADT + brexpiprazole 2 to 3 mg reduced the likelihood of having anxious distress at week 6 versus ADT + placebo (P = 0.0048) (Table 2).
DISCUSSIONIn this pooled analysis, adjunctive brexpiprazole demonstrated efficacy on various individual MADRS items in a difficult-to-treat sample of patients with MDD who met proxy criteria for anxious distress. The specific items on which efficacy was observed for adjunctive brexpiprazole 2 mg or 2 to 3 mg were the 6 core depressive symptoms (ie, apparent sadness, reported sadness, inner tension, lassitude, inability to feel, and pessimistic thoughts),31 as well as the noncore symptoms of sleep and appetite, all of which had P < 0.05 versus adjunctive placebo in patients with anxious distress. Between-group ES for these items were 0.18 to 0.44, which are considered “small to moderate” by convention32; however, clinical meaningfulness should be assessed at the individual-patient level, and ES of this magnitude have previously corresponded to improved response rates in patients with inadequate response to ADT.16,33 Thus, adjunctive brexpiprazole has effects on a relatively broad range of depressive symptoms in patients with unresolved symptoms of depression and anxious distress, while also allowing clinicians to target specific symptoms as-needed. On the items of apparent sadness, reported sadness, lassitude, and pessimistic thoughts, adjunctive brexpiprazole had an effect from weeks 1 to 2 onward (ie, during titration) in patients with anxious distress. Early monitoring of these items may help identify patients who will benefit from adjunctive brexpiprazole on a broader range of items at week 6, thereby guiding treatment optimization.
Whereas the presence of anxiety symptoms typically reduces the chances of response and remission on ADT,2,5 improvements with adjunctive brexpiprazole were generally larger in patients with anxious distress than in those without anxious distress. This may reflect the observed presence of more severe symptomatology (MADRS total score) at baseline in patients with anxious distress, possibly allowing more room for improvement on average. Nonetheless, this observation may help advance precision medicine, because patients with anxious distress can be identified early, and adjunctive brexpiprazole is particularly efficacious in this population.
Adjunctive brexpiprazole improved anxious distress as well as improving depression versus adjunctive placebo, as shown by a reduced likelihood of patients still having anxious distress after 6 weeks of treatment, and by efficacy for the 2 to 3 mg dose on the MADRS item of inner tension, which was used as a proxy for the DSM-5 anxious distress specifier item of feeling keyed up or tense. Specifically, after treatment with adjunctive brexpiprazole, almost 80% of patients with anxious distress at baseline did not have anxious distress at week 6. This result aligns with a previous post hoc analysis showing benefits for adjunctive brexpiprazole on the HAM-D Anxiety/somatization factor,16 and an open-label study showing benefits for adjunctive brexpiprazole on the Hamilton Anxiety Rating Scale.34 Thus, it seems that adjunctive brexpiprazole may be clinically valuable for the treatment of both depressive symptoms and anxious distress in patients with MDD.
Adjunctive brexpiprazole did not separate from placebo on the items of suicidal thoughts or concentration difficulties in patients with anxious distress, as previously reported for the total sample across 4 clinical trials.33 The lack of effect on suicidality can be attributed to the exclusion of patients with suicidal ideation or behavior, meaning that the sample had minimal suicidal thoughts at baseline, with limited room for improvement. Of note, anxiety symptoms in depression are generally associated with increased suicidal ideation.1,2,4 Regarding concentration, the lack of difference between adjunctive brexpiprazole and adjunctive placebo over a period of 6 weeks may reflect the short-term nature of the studies (see the work/studies discussion in the next paragraph) or indicate that brexpiprazole does not affect this aspect of cognition, either positively or negatively.
Adjunctive brexpiprazole showed improvement in functioning versus adjunctive placebo in patients with anxious distress, as measured by SDS mean score and the SDS items of social life and family life. There was no separation from adjunctive placebo on the SDS work/studies item, which is consistent with other studies of various adjunctive treatments in MDD.35 The lack of benefit on work/studies is likely to be explained by the short duration of the present studies (6 weeks), because patients with depression, especially those with inadequate response to ADT, are prone to persistent impairment in occupational functioning.36–38 This persistent impairment may be attributed to residual cognitive symptoms, such as impaired attention, executive function, and verbal memory, as well as the adverse effects of antidepressant medications.38–40
With regard to dosing, the effects of the brexpiprazole 2 mg and 2 to 3 mg doses were generally similar, although a greater number of MADRS items had P < 0.05 versus placebo in the 2 to 3 mg analysis, likely reflecting the larger sample size. The target dose for the adjunctive treatment of MDD is 2 mg/d28,29; however, individual patients may benefit from an increase to 3 mg in regions where this dose is permitted.
Previous analyses have demonstrated that adjunctive brexpiprazole is generally well tolerated by patients with or without anxious distress.15,16 The overall incidence of adverse events in previous studies was higher among patients with anxious distress than patients without anxious distress, regardless of treatment group, but there were no clinically meaningful differences in the rates of specific adverse events according to the presence or absence of anxious distress.16 The most common adverse event with ADT + brexpiprazole was akathisia, with an incidence of 10.3% in the subgroup with anxious distress and 8.5% in the subgroup without anxious distress (corresponding values for ADT + placebo were 3.6% and 2.0%).16 Other treatment-emergent adverse events with incidence ≥5% with ADT + brexpiprazole and greater incidence than with ADT + placebo in the subgroup with anxious distress were restlessness, weight increase, and somnolence, and in the subgroup without anxious distress was weight increase.16
The efficacy of brexpiprazole in patients with anxious distress can be attributed to aspects of its receptor binding profile. Brexpiprazole acts as a partial agonist at serotonin 5-HT1A receptors10; clinical studies of other 5-HT1A receptor partial agonists show that such activity can improve anxiety symptoms.41 Brexpiprazole acts as an antagonist at noradrenaline α1B and α2C receptors10; other drugs that target the noradrenergic system have shown benefits on symptoms of anxiety.42 Brexpiprazole's partial agonism at dopamine D2 receptors10 is not thought to play a key role in the treatment of nonpsychotic anxiety symptoms.43
This study is limited by its post hoc nature and because there were no corrections for multiple comparisons, meaning that results should be considered exploratory. The analysis used proxies for the DSM-5 anxious distress specifier, with the particular limitations that proxies could only be found for 4 of 5 aspects of the specifier and that 2 of the proxies (MADRS inner tension and concentration difficulties items) were subsequently used to assess efficacy. The included trials assessed short-term treatment (6 weeks), and further research is needed to determine the long-term efficacy, safety, and tolerability of adjunctive brexpiprazole in patients with and without anxious distress. The majority of the sample was White (>80%), and care should be taken when extrapolating results to other races. Finally, because the analysis used data from clinical trials, patient selection criteria (eg, exclusion of patients with suicidality or certain comorbid psychiatric conditions) and other restrictions (eg, concomitant medication use) limit the generalizability of the results to a broader patient population.
In conclusion, adjunctive brexpiprazole is efficacious in reducing core depressive symptoms, sleep, and appetite, as well as improving functioning, in patients with MDD and anxious distress who have inadequate response to ADTs. Furthermore, adjunctive brexpiprazole reduces the likelihood of patients meeting anxious distress criteria following treatment.
ACKNOWLEDGMENTSWriting support was provided by Chris Watling, PhD, assisted by his colleagues at Cambridge—a Prime Global Agency (Knutsford, United Kingdom), and funded by Otsuka Pharmaceutical Development & Commercialization Inc and H. Lundbeck A/S.
AUTHOR DISCLOSURE INFORMATIONR.S.M. has received research grant support from CIHR/GACD/National Natural Science Foundation of China and the Milken Institute and speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Neurawell, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, AbbVie, and Atai Life Sciences. He is a CEO of Braxia Scientific Corp. S.B., F.T., and M.B. are full-time employees of Otsuka Canada Pharmaceutical Inc. Z.Z. is a full-time employee of Otsuka Pharmaceutical Development & Commercialization Inc. E.M.M. was a full-time employee of Lundbeck Canada Inc at the time of this work. M.M. was a full-time employee of Otsuka Pharmaceutical Development & Commercialization Inc at the time of this work.
This work was supported by Otsuka Pharmaceutical Development & Commercialization Inc (Princeton, NJ) and H. Lundbeck A/S (Valby, Denmark). The authors affiliated with the sponsors were involved in the design of the study, the analysis and interpretation of data, the writing and reviewing of this article, and the decision to submit the article for publication.
DATA AVAILABILITY STATEMENTTo submit inquiries related to Otsuka clinical research, or to request access to individual participant data (IPD) associated with any Otsuka clinical trial, please visit https://clinical-trials.otsuka.com/. For all approved IPD access requests, Otsuka will share anonymized IPD on a remotely accessible data sharing platform.
REFERENCES 1. Fava M, Alpert JE, Carmin CN, et al. Clinical correlates and symptom patterns of anxious depression among patients with major depressive disorder in STAR*D. Psychol Med. 2004;34:1299–1308. 2. Fava M, Rush AJ, Alpert JE, et al. Difference in treatment outcome in outpatients with anxious versus nonanxious depression: a STAR*D report. Am J Psychiatry. 2008;165:342–351. 3. Zimmerman M, Chelminski I, Young D, et al. A clinically useful self-report measure of the DSM-5 anxious distress specifier for major depressive disorder. J Clin Psychiatry. 2014;75:601–607. 4. McIntyre RS, Woldeyohannes HO, Soczynska JK, et al. The prevalence and clinical characteristics associated with Diagnostic and Statistical Manual Version-5‐defined anxious distress specifier in adults with major depressive disorder: results from the International Mood Disorders Collaborative Project. Ther Adv Chronic Dis. 2016;7:153–159. 5. Brown TM, DiBenedetti DB, Danchenko N, et al. Symptoms of anxiety and irritability in patients with major depressive disorder. J Depress Anxiety. 2016;5:237. 6. McIntyre RS, Weiller E. Real-world determinants of adjunctive antipsychotic prescribing for patients with major depressive disorder and inadequate response to antidepressants: a case review study. Adv Ther. 2015;32:429–444.
留言 (0)