Replication of Ketamine's Antidepressant Efficacy in Bipolar Depression: A Randomized Controlled Add-On Trial

Abstract

Background Currently, no pharmacological treatments for bipolar depression exist that exert rapid (within hours) antidepressant or antisuicidal effects. We previously reported that intravenous administration of the N-methyl-D-aspartate (NMDA) antagonist ketamine produced rapid antidepressant effects in patients with treatment-resistant bipolar depression. The present study sought to replicate this finding in an independent sample. Methods In this double-blind, randomized, crossover, placebo-controlled study, 15 subjects with DSM-IV bipolar I or II depression maintained on therapeutic levels of lithium or valproate received a single intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on two test days two weeks apart. The primary outcome measure was the Montgomery-Asberg Depression Rating Scale (MADRS), which was used to rate overall depressive symptoms at baseline, at 40, 80, 110, and 230 minutes post-infusion, and on Days 1, 2, 3, 7, 10, and 14 post-infusion. Results Within 40 minutes, depressive symptoms as well as suicidal ideation significantly improved in subjects receiving ketamine compared to placebo (d=0.89, 95% C.I. = 0.61–1.16 and 0.98, 95% C.I. = 0.64–1.33, respectively); this improvement remained significant through Day 3. Seventy-nine percent of subjects responded to ketamine and 0% responded to placebo at some point during the trial. The most common side effect was dissociative symptoms, which occurred only at the 40-minute time-point. Conclusion This study replicated our previous finding that patients with bipolar depression who received a single ketamine infusion experienced a rapid and robust antidepressant response. In addition, we found that ketamine rapidly improved suicidal ideation in these patients.

Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder

“…Intravenous ketamine (level 3)477, 478 has rapid onset of efficacy and may be considered for patients who are refractory to first and second‐line treatments, as well as for those in need of rapid response.…”

Neurocognitive Effects of Ketamine and Association with Antidepressant Response in Individuals with Treatment-Resistant Depression: A Randomized Controlled Trial

“…We recently reported that ketamine was superior to an anesthetic control condition (the benzodiazepine midazolam) at rapidly reducing depressive symptoms 24 h following a single intravenous (IV) infusion in a two-site randomized controlled trial (response rates to ketamine and midazolam were 64 and 28%, respectively; Murrough et al, 2013a). Randomized controlled trials have also found positive therapeutic effects of ketamine in bipolar depression (Zarate et al, 2012) and posttraumatic stress disorder (PTSD; Feder et al, 2014). Despite the potential of ketamine as a mechanistically novel therapeutic option for patients with TRD, important concerns regarding safety and toxicity remain (Green and Cote, 2009;Morgan et al, 2009).…”

The Treatment of Bipolar Disorder

“…17 Following up leads emerging from insights into the underlying neurobiology is already producing promising results. For example, after evidence of dysfunction in the N-methyl-Daspartate-receptor complex in the glutamatergic system in bipolar disorder, two crossover trials 12,13 found that infusion of the N-methyl-D-aspartate antagonist ketamine produced rapid alleviation of depressive symptoms in bipolar depression. These findings open a new approach to drug development and provide insights into the neurobiology of the disorder.…”