Maintenance of antidepressant and antisuicidal effects by D-cycloserine among patients with treatment-resistant depression who responded to low-dose ketamine infusion: a double-blind randomized placebo–control study


Increasing evidence supports a rapid antidepressant and antisuicidal effect of a single subanesthetic dose of ketamine infusion for treatment-resistant depression (TRD). Maintaining the initial clinical response after ketamine infusion in TRD is a crucial next-step challenge. D-cycloserine (DCS), a partial agonist of the glycine co-agonist of the N-methyl-D-aspartate (NMDA) glutamate receptor, is potentially effective as a depression augmentation treatment. However, whether DCS maintains the antidepressant and antisuicidal effects of ketamine infusion remains unknown. In all, 32 patients with TRD (17 with major depression and 15 with bipolar depression) who responded to ketamine infusion with an average 17-item Hamilton Depression Rating Scale (HAMD) score of 9.47 ± 4.11 at baseline were randomly divided to 6-week DCS treatment (250 mg for 2 days, 500 mg for 2 days, 750 mg for 3 days, and 1000 mg for 5 weeks) and placebo groups. Depression symptoms were rated at timepoints of dose titration and weekly. During the 6-week treatment, the total scores of HAMD did not differ between the DCS and placebo groups. The results remained consistent when stratified by disorder. A mixed model analysis indicated that the DCS group exhibited lower scores of HAMD item 3 (suicide) compared with the placebo group throughout the follow-up period (p = 0.01). A superior maintenance of the antisuicidal effect of ketamine was observed in the DCS group than in the placebo group. DCS may be therapeutically beneficial for patients with TRD who responded to ketamine infusion but have a residual suicidal risk.

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We express our gratitude to all patients who kindly participated in this study. We thank all research assistants, physicians, pharmacists, and nursing staffs at D020 Unit of Taipei Veterans General Hospital for their assistance during the study process, without whom this work could not have been possible. We thank Mr I-Fan Hu for his support and friendship. The participation of Dr Krystal was supported by the US Department of Veterans Affairs via its support for the VA National Center for PTSD, the US National Institute on Alcohol Abuse and Alcoholism (P50AA12870, M01RR00125), and the US National Center for Advancing Translational Science (UL1 RR024139). None of the aforementioned funding organizations had any role in the study design, data collection, analysis, interpretation of result, writing of the report, and the ultimate decision to submit the paper for publication.

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Correspondence to John H. Krystal or Tung-Ping Su.

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