Switching from Inadequate Adjunctive or Combination Treatment Options to Brexpiprazole Adjunctive to Antidepressant: An Open-Label Study on the Effects on Depressive Symptoms and Cognitive and Physical Functioning

Maurizio Fava, Takao Okame, Yuki Matsushima, Pamela Perry, Emmanuelle Weiller, Ross A Baker, Maurizio Fava, Takao Okame, Yuki Matsushima, Pamela Perry, Emmanuelle Weiller, Ross A Baker

Abstract

Background: Approximately 50% of patients with major depressive disorder do not respond adequately to their antidepressant treatment, underscoring the need for more effective treatment options. The objective of this study was to investigate the effect of adjunctive brexpiprazole on depressive symptoms in patients with major depressive disorder who were not responding to adjunctive or combination therapy of their current antidepressant treatments with several different classes of agents (NCT02012218).

Methods: In this 6-week, open-label, phase 3b study, patients with major depressive disorder who had an inadequate response to ≥1 adjunctive or combination therapy, in addition to history of ≥1 failure to monotherapy antidepressant treatment, were switched to adjunctive brexpiprazole. Efficacy was assessed by change from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale total score. Patient functioning was assessed using the Sheehan Disability Scale and the Cognitive and Physical Functioning Questionnaire. Safety and tolerability were also assessed.

Results: A total of 51/61 (83.6%) patients completed 6 weeks of treatment with adjunctive brexpiprazole. Improvements in depressive symptoms were observed (least squares mean change from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale total score, -17.3 [P < .0001]) as well as improvements in general and cognitive functioning (mean changes from baseline to week 6: Sheehan Disability Scale, -3.1 [P < .0001]; Massachusetts General Hospital-Cognitive and Physical Functioning Questionnaire, -9.2 [P < .0001]). The most common adverse event was fatigue (14.8%); akathisia was reported by 8.2% of patients.

Conclusions: In patients with major depressive disorder who had switched to open-label adjunctive brexpiprazole following inadequate response to previous adjunctive or combination therapy, improvements were observed in depressive symptoms, general functioning, cognitive function, and energy/alertness.

Keywords: adjunctive; antidepressant; brexpiprazole; major depressive disorder; switching.

© The Author 2016. Published by Oxford University Press on behalf of CINP.

Figures

Figure 1.
Figure 1.
Changes in depressive symptoms. (A) Mean change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score. (B) Mean change from baseline in Clinical Global Impression-Severity of Illness (CGI-S) score. All patients received ADT+brexpiprazole 1 to 3 mg/d switched from previous adjunctive or combination treatment; primary antidepressant treatment (ADT) kept constant. Analyzed using mixed model repeated measures on observed cases (OC) data; P value relative to baseline. LS, least squares.
Figure 2.
Figure 2.
Response and remission rates for Montgomery-Åsberg Depression Rating Scale (MADRS) and response rates for Clinical Global Impression-Improvement (CGI-I). (A) Percentage of patients with MADRS response, defined as a ≥50% reduction from baseline in total score. (B) Percentage of patients with MADRS remission, defined as a total score decrease ≥50% from baseline and ≤10. (C) CGI-I response rates, defined as a score of 1 (very much improved) or 2 (much improved). All patients received ADT+brexpiprazole 1–3 mg/d switched from previous adjunctive or combination treatment; primary antidepressant treatment (ADT) kept constant. Analyzed by exact binomial 95% CI on observed cases (OC) data.
Figure 3.
Figure 3.
Changes from baseline in Sheehan Disability Scale (SDS) mean and domain scores. Analyzed using ANCOVA on observed cases (OC) data. LS, least squares.

References

    1. Atkinson MJ, Sinha A, Hass SL, Colman SS, Kumar RN, Brod M, Rowland CR. (2004) Validation of a general measure of treatment satisfaction, the Treatment Satisfaction Questionnaire for Medication (TSQM), using a national panel study of chronic disease. Health Qual Life Outcomes 2:12.
    1. Baer L, Ball S, Sparks J, Raskin J, Dube S, Ferguson M, Fava M. (2014) Further evidence for the reliability and validity of the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ). Ann Clin Psychiatry 26:270–280.
    1. Barnes TR. (1989) A rating scale for drug-induced akathisia. Br J Psychiatry 154:672–676.
    1. Bellani M, Hatch JP, Nicoletti MA, Ertola AE, Zunta-Soares G, Swann AC, Brambilla P, Soares JC. (2012) Does anxiety increase impulsivity in patients with bipolar disorder or major depressive disorder? J Psychiatr Res 46:616–621.
    1. Citrome L. (2010) Adjunctive aripiprazole, olanzapine, or quetiapine for major depressive disorder: an analysis of number needed to treat, number needed to harm, and likelihood to be helped or harmed. Postgrad Med 122:39–48.
    1. Citrome L. (2013) A review of the pharmacology, efficacy and tolerability of recently approved and upcoming oral antipsychotics: an evidence-based medicine approach. CNS Drugs 27:879–911.
    1. Connolly KR, Thase ME. (2011) If at first you don’t succeed: a review of the evidence for antidepressant augmentation, combination and switching strategies. Drugs 71:43–64.
    1. Fava GA, Bech P. (2015) The concept of euthymia. Psychother Psychosom 85:1–5.
    1. Fava M. (2001) Augmentation and combination strategies in treatment-resistant depression. J Clin Psychiatry 62:4–11.
    1. Fava M. (2003) Diagnosis and definition of treatment-resistant depression. Biol Psychiatry 53:649–659.
    1. Fava M, Rush AJ. (2006) Current status of augmentation and combination treatments for major depressive disorder: a literature review and a proposal for a novel approach to improve practice. Psychother Psychosom 75:139–153.
    1. Fava M, Iosifescu DV, Pedrelli P, Baer L. (2009) Reliability and validity of the Massachusetts general hospital cognitive and physical functioning questionnaire. Psychother Psychosom 78:91–97.
    1. Fleurence R, Williamson R, Jing Y, Kim E, Tran QV, Pikalov AS, Thase ME. (2009) A systematic review of augmentation strategies for patients with major depressive disorder. Psychopharmacol Bull 42:57–90.
    1. Gao K, Kemp DE, Fein E, Wang Z, Fang Y, Ganocy SJ, Calabrese JR. (2011) Number needed to treat to harm for discontinuation due to adverse events in the treatment of bipolar depression, major depressive disorder, and generalized anxiety disorder with atypical antipsychotics. J Clin Psychiatry 72:1063–1071.
    1. Goodwin G, Fleischhacker W, Arango C, Baumann P, Davidson M, de Hert M, Falkai P, Kapur S, Leucht S, Licht R, Naber D, O’Keane V, Papakostas G, Vieta E, Zohar J. (2009) Advantages and disadvantages of combination treatment with antipsychotics ECNP Consensus Meeting, March 2008, Nice. Eur Neuropsychopharmacol 19:520–532.
    1. Guy W. (1976) ECDEU assessment manual for psychopharmacology (revised). In: Hamilton anxiety scale (Hamilton M, ed), pp 193–198. US Department of Health, Education, and Welfare publication (ADM) 76–338, Rockville, MD: National Institute of Mental Health.
    1. Hamilton M. (1960) A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56–62.
    1. Johns MW. (1993) Daytime sleepiness, snoring, and obstructive sleep apnea. The Epworth Sleepiness Scale. Chest 103:30–36.
    1. Kessler RC. (2012) The costs of depression. Psychiatr Clin North Am 35:1–14.
    1. Knoth RL, Bolge SC, Kim E, Tran QV. (2010) Effect of inadequate response to treatment in patients with depression. Am J Manag Care 16:e188–e196.
    1. Maeda K, Sugino H, Akazawa H, Amada N, Shimada J, Futamura T, Yamashita H, Ito N, McQuade RD, Mork A, Pehrson AL, Hentzer M, Nielsen V, Bundgaard C, Arnt J, Stensbol TB, Kikuchi T. (2014) Brexpiprazole I: in vitro and in vivo characterization of a novel serotonin-dopamine activity modulator. J Pharmacol Exp Ther 350:589–604.
    1. McElroy SL, Martens BE, Mori N, Blom TJ, Casuto LS, Hawkins JM, Keck PE., Jr (2015) Adjunctive lisdexamfetamine in bipolar depression: a preliminary randomized, placebo-controlled trial. Int Clin Psychopharmacol 30:6–13.
    1. Mendlewicz J. (2009) Sleep disturbances: core symptoms of major depressive disorder rather than associated or comorbid disorders. World J Biol Psychiatry 10:269–275.
    1. Montgomery SA, Åsberg M. (1979) A new depression scale designed to be sensitive to change. Br J Psychiatry 134:382–389.
    1. National Cholesterol Education Program (NCEP) Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) (2002) Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 106:3143–3421.
    1. Nelson JC, Papakostas GI. (2009) Atypical antipsychotic augmentation in major depressive disorder: a meta-analysis of placebo-controlled randomized trials. Am J Psychiatry 166:980–991.
    1. Nierenberg AA, DeCecco LM. (2001) Definitions of antidepressant treatment response, remission, nonresponse, partial response, and other relevant outcomes: a focus on treatment-resistant depression. J Clin Psychiatry 62:5–9.
    1. Papakostas GI. (2009) Managing partial response or nonresponse: switching, augmentation, and combination strategies for major depressive disorder. J Clin Psychiatry 70(Suppl 6):16–25.
    1. Papakostas GI, Culpepper L. (2015) Understanding and managing Cognition in the Depressed Patient. J Clin Psychiatry 76:418–425.
    1. Patton JH, Stanford MS, Barratt ES. (1995) Factor structure of the Barratt impulsiveness scale. J Clin Psychol 51:768–774.
    1. Perroud N, Baud P, Mouthon D, Courtet P, Malafosse A. (2011) Impulsivity, aggression and suicidal behavior in unipolar and bipolar disorders. J Affect Disord 134:112–118.
    1. Rothschild AJ, Raskin J, Wang CN, Marangell LB, Fava M. (2014) The relationship between change in apathy and changes in cognition and functional outcomes in currently non-depressed SSRI-treated patients with major depressive disorder. Compr Psychiatry 55:1–10.
    1. Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, Niederehe G, Thase ME, Lavori PW, Lebowitz BD, McGrath PJ, Rosenbaum JF, Sackeim HA, Kupfer DJ, Luther J, Fava M. (2006) Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 163:1905–1917.
    1. Rush AJ, Trivedi MH, Stewart JW, Nierenberg AA, Fava M, Kurian BT, Warden D, Morris DW, Luther JF, Husain MM, Cook IA, Shelton RC, Lesser IM, Kornstein SG, Wisniewski SR. (2011) Combining medications to enhance depression outcomes (CO-MED): acute and long-term outcomes of a single-blind randomized study. Am J Psychiatry 168:689–701.
    1. Sheehan DV, Harnett-Sheehan K, Raj BA. (1996) The measurement of disability. Int Clin Psychopharmacol 11:89–95.
    1. Simpson GM, Angus JW. (1970) A rating scale for extrapyramidal side effects. Acta Psychiatr Scand Suppl 212:11–19.
    1. Thase ME, Schwartz TL. (2015) Choosing medications for treatment-resistant depression based on mechanism of action. J Clin Psychiatry 76:720–727.
    1. Thase ME, Youakim JM, Skuban A, Hobart M, Zhang P, McQuade RD, Nyilas M, Carson WH, Sanchez R, Eriksson H. (2015. a) Adjunctive brexpiprazole 1 and 3 mg for patients with major depressive disorder following inadequate response to antidepressants: a phase 3, randomized, double-blind study. J Clin Psychiatry 76:1232–1240.
    1. Thase ME, Youakim JM, Skuban A, Hobart M, Augustine C, Zhang P, McQuade RD, Carson WH, Nyilas M, Sanchez R, Eriksson H. (2015. b) Efficacy and safety of adjunctive brexpiprazole 2 mg in major depressive disorder: a phase 3, randomized, placebo-controlled study in patients with inadequate response to antidepressants. J Clin Psychiatry 76:1224–1231.
    1. Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L, Norquist G, Howland RH, Lebowitz B, McGrath PJ, Shores-Wilson K, Biggs MM, Balasubramani GK, Fava M, on behalf of the Star*D Study Team (2006) Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry 163:28–40.
    1. Trivedi MH, Cutler AJ, Richards C, Lasser R, Geibel BB, Gao J, Sambunaris A, Patkar AA. (2013) A randomized controlled trial of the efficacy and safety of lisdexamfetamine dimesylate as augmentation therapy in adults with residual symptoms of major depressive disorder after treatment with escitalopram. J Clin Psychiatry 74:802–809.

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