INTRODUCTION: Major depressive disorder is a serious, recurrent, and disabling psychiatric illness. Despite many proven treatments with multiple medications or therapies, approximately 30% of patients fail to achieve remission and are considered to have treatment-refractory depression (TRD). Recently, there has been a growing interest in the use of intravenous (IV) ketamine for the treatment of TRD. There is limited yet increasing evidence to support the use of ketamine, a glutamate receptor antagonist, in the management of depression; however, the lack of data regarding the safety and tolerability of therapy has limited its clinical use. By analyzing a cohort of veterans with TRD and comorbid psychiatric conditions treated with IV ketamine infusions for a 24-month study period, we aim to provide critical information about ketamine's clinical effectiveness and safety.
MATERIALS AND METHODS: Based on a retrospective chart review, we identified eight veterans with TRD receiving treatment with repeated-dose IV ketamine from 2018 to 2020. The magnitude of clinical response was based on the Beck Depression Inventory self-report scale and the Patient Health Questionnaire-9, both measured at the initial patient consultation and before the beginning of each ketamine infusion treatment. Safety analysis included changes to pre- and post-ketamine infusion on vital signs, effects on alertness and sedation, and potential psychosis-like effects. For all outcomes, we estimated a linear mixed-effects model that allowed heterogeneous residual variances for each veteran. The effect of continuous predictor variables was estimated using restricted cubic splines with knot points specified at the 5th, 35th, 65th, and 95th percentiles. All the analyses were conducted using SAS v.9.4, with P < .05 indicating the statistical significance. This study had institutional review board approval: 1220.
RESULTS: During the study period, the median number of ketamine infusions was 15 across a median of 164 days of treatment follow-up with a median time between ketamine infusions of 4 days. For both Beck Depression Inventory and Patient Health Questionnaire-9 scores, there was a statistically significant reduction across infusions (both P < .001), but the strongest reduction occurred before day 40. The change was statistically significant for decreased heart rate (P = .019) but not for systolic blood pressure (P = .612), diastolic blood pressure (P = .942), respiratory rate (P = .822), oxygen saturation (P = .070), and temperature (P = .943). Side effects were reported in six patients (75%); however, the only side effect reported was excessive sedation or dizziness immediately after infusion.
CONCLUSIONS: In this study, repeated-dose IV ketamine infusions over a 24-month study period resulted in a significant reduction in depression scores in a group of veterans with TRD. The rapid onset of significant response, absence of psychosis-like effects or dissociative symptoms despite psychiatric comorbidities, and minimal effects on vital signs support the clinical efficacy and safety of this exciting new treatment option for patients with TRD. Limitations include a 2-year study period, lack of information on long-term effects, and the retrospective nature of the study. Prospective studies of longer duration are needed to assess the long-term efficacy and safety of IV ketamine for TRD.
