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J Clin Psychiatry. 2017 Sep/Oct;78(8):1126-1135. doi: 10.4088/JCP.15m10511.

Effectiveness of Supplementary Cognitive-Behavioral Therapy for Pharmacotherapy-Resistant Depression: A Randomized Controlled Trial.

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Center for Clinical Research, Keio University School of Medicine, Shinanomachi 35, Shinjuku-ku, Tokyo 160-8582, Japan.
Center for Clinical Research, Keio University School of Medicine, Tokyo, Japan.
Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan.
Department of Psychiatry, Sakuragaoka Memorial Hospital, Tokyo, Japan.
Preventive Medicine and Public Health, Keio University School of Medicine, Tokyo, Japan.
Department of Neuropsychiatry, Kyorin University School of Medicine, Tokyo, Japan.
Center for the Development of Cognitive Behavior Therapy Training, Tokyo, Japan.



Antidepressant medication is efficacious in the treatment of depression, but not all patients improve with antidepressant medication alone. Despite this treatment gap, limited evidence regarding the effectiveness of supplementing psychotherapy for pharmacotherapy-resistant depression is available. Therefore, we investigated the effectiveness of supplementing usual medication management (treatment as usual [TAU]) with cognitive-behavioral therapy (CBT) in patients with pharmacotherapy-resistant depression seeking psychiatric specialty care.


A 16-week assessor-masked randomized controlled trial with a 12-month follow-up was conducted in 1 university hospital and 1 psychiatric hospital from September 2008 to December 2014. Outpatients aged 20-65 years with pharmacotherapy-resistant depression (taking antidepressant medications for ≥ 8 weeks, 17-item GRID-Hamilton Depression Rating Scale [GRID-HDRS₁₇] score ≥ 16, Maudsley Staging Method for treatment-resistant depression score ≥ 3, and DSM-IV criteria for major depressive disorder) were randomly assigned (1:1) to CBT combined with TAU or to TAU alone. The primary outcome was the alleviation of depressive symptoms, as measured by change in the total GRID-HDRS₁₇ score from baseline to 16 weeks; primary analysis was done on an intention-to-treat basis.


A total of 80 patients were randomized; 78 (97.5%) were assessed for the primary outcome, and 73 (91.3%) were followed up for 12 months. Supplementary CBT significantly alleviated depressive symptoms at 16 weeks, as shown by greater least squares mean changes in GRID-HDRS₁₇ scores in the intervention group than in the control group (-12.7 vs -7.4; difference = -5.4; 95% CI, -8.1 to -2.6; P < .001), and the treatment effect was maintained for at least 12 months (-15.4 vs -11.0; difference = -4.4; 95% CI, -7.2 to -1.6; P = .002).


Patients with pharmacotherapy-resistant depression treated in psychiatric specialty care settings may benefit from supplementing usual medication management with CBT.


UMIN Clinical Trials Registry identifier: UMIN000001218​​.

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