Intravenous ketamine for benzodiazepine deprescription and withdrawal management in treatment-resistant depression: a preliminary report

Abstract

We present the first evidence that sub-anesthetic ketamine infusions for treatment resistant depression (TRD) may facilitate deprescription of long-term benzodiazepine/z-drugs (BZDRs). Long-term BZDR prescriptions are potentially harmful yet common, partly because of challenging withdrawal symptoms. Few pharmacological interventions have evidence for facilitating BZDR discontinuation, and none in patients actively suffering from TRD. In this ambi-directional cohort study, discontinuation of long-term (>6 month) BZDRs was attempted in 22 patients with severe unipolar or bipolar TRD receiving a course of six subanesthetic ketamine infusions over four weeks. We investigated the rates of successful BZDRs deprescription, trajectories of acute psychological withdrawal symptoms, and subsequent BZDRs abstinence during a mean follow-up of 1 year (primary outcome). Clinically significant deteriorations in depression, anxiety, sleep, and/or suicidality during the acute BZDR discontinuation phase were measured by repeated standardized scales and analyzed by latent growth curve models and percent correct classification analysis. Of the 22 eligible patients, all enrolled in this study and 91% (20/22) successfully discontinued all BZDRs by the end of the 4-week intervention, confirmed by urinary analyses. Less than 25% of discontinuers experienced any significant worsening of anxiety, depression, sleep difficulties, or suicidality during treatment. During follow-up (mean [range] duration, 12 [3–24] months), 64% (14/22) of patients remained abstinent from any BZDRs. These preliminary results suggest that ketamine infusions for TRD may facilitate the deprescription of BZDRs, even in patients with active depressive symptoms and significant comorbidity. Further investigation is warranted into this potential novel application of ketamine.

The Montreal model: an integrative biomedical-psychedelic approach to ketamine for severe treatment-resistant depression

“…In this article, we present the Montreal model of ketamine for TRD, a biopsychosocial approach developed gradually over years of real-world clinical experiences and research endeavors. Our aim has been to help bridge the current divide between biomedical and psychedelic models of ketamine while aiding in the interpretation of our recent and upcoming research results ( 12 , 13 , 145 , 164 , 169 ). We have thus endeavored to provide sufficient information for researchers and clinicians from diverse backgrounds to understand our approach, from its theoretical underpinnings up to its session activities and clinical implementation.…”

“…As with the pursuit of lifestyle goals, patients tend to readily engage in such processes when provided with education and support. Our recent results from a cohort study of TRD patients receiving ketamine in our model found that all were willing to attempt BZDR discontinuation, almost all achieved total abstinence during treatment, and the majority remained BZDR-free after an average follow-up of 1 year ( 145 ). These results are particularly noteworthy given our population’s severity, and that only one prior study that has even attempted BZDR discontinuation in patients actively suffering from depression ( 148 ).…”

“…For depression, guidelines only recommend short-term benzodiazepines given evidence for tolerance ( 142 ), potential harms ( 143 ), and questionable long-term efficacy ( 144 ). Nevertheless, approximately half of the patients referred to our service actively receive long-term BZDRs—often at high doses ( 145 ). In many cases, patients report no clear indication for these treatments, nor being adequately informed about their potential harms.…”

“…These results are particularly noteworthy given our population’s severity, and that only one prior study that has even attempted BZDR discontinuation in patients actively suffering from depression ( 148 ). In addition to preclinical and clinical evidence suggesting that ketamine can mitigate psychological BZDR withdrawal symptoms ( 149–151 ), we have found that the initiation of a course of ketamine is an excellent psychological opportunity to undertake rational medication changes ( 145 ).…”