A systematic review of ketamine for the treatment of depression among older adults

Introduction Depression is the second most prevalent mental health disorder among older adults after anxiety disorders. It effects 7% of the general older population globally 5.6% of US older adults. Suicide rates also increase between ages of 60-90 in both men and women around the world. A large body of literature shows increased association of late life depression with increased morbidity and mortality in this age group. Evidence for depression as a risk factor for physical and cognitive decline that results in lower quality of life and function among older adults underlines the importance of early recognition and prompt treatment of this serious condition. The most common modalities currently used for treatment of late life depression include pharmacotherapy, psychotherapy and electroconvulsive therapy (ECT). Pharmacotherapy mostly consists of antidepressants targeting the monoaminergic system. Ketamine has recently emerged as a novel, rapid acting option for treatment resistant depression in adults. Ketamine is a N-methyl-D-aspartate (NMDA) receptor antagonist, which has been used primarily as an anesthetic since the 1960s. In 1990s preclinical studies demonstrated the role of NMDA receptor antagonists in treatment of depression, which was later confirmed in a pilot clinical study. Berman et al administered subanaesthetic doses of Ketamine (0.5mg/kg) vs. placebo to 7 study participants which resulted in robust decreases in Hamilton Depression Rating Scale scores within 4 hours of the infusion in all participants. The effect was sustained for 3 days followed by diminution of the scores and relapse of symptoms. This rapid onset anti-depressant effect of ketamine compared to conventional antidepressants attracted considerable interest and these findings have since been reliably replicated in multiple different studies, using different protocols and routes of administration of ketamine. This systematic review evaluates randomized controlled trials completed in the older adult population with depression to appraise the efficacy and tolerability of ketamine specifically in this population. Methods The authors followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) On November 09, 2019 the authors conducted a comprehensive search of multiple databases: PubMed (through November 09, 2019), MEDLINE (Ovid ALL 1946 to November 08, 2019), Embase (Ovid 1974 to 2019 November 08), PsycINFO (Ovid 1806 to October Week 4 2019), Web of Science Core Collection (through November 09, 2019), and Cochrane Central Register of Controlled Trials (Issue 11 of 12, November 2019). The search strategy was filtered for human studies in PubMed, MEDLINE, and Embase using controlled vocabulary terms in the search strategy. On December 13, 2019 an updated search was completed. The search repeated the controlled vocabulary terms and free text terms. Results A total of 1699 citations were deduplicated to 1005 and uploaded to Covidence for screening by two separate screeners. Two studies were found to meet the inclusion criteria for this review. The first study showed a significant reduction in depression symptoms with use of repeated subcutaneous ketamine administration among older adults with depression. The second study failed to achieve significance on its primary outcome measure but did show a decrease in MADRS scores with intranasal ketamine. This study also showed a higher response and remission rates in esketamine group when compared to the placebo group. Both the studies showed relapse in symptoms after a week of last treatment, but the benefits were better sustained with repeated treatments. The adverse effects from ketamine generally lasted only lasted a few hours and abated spontaneously without any additional intervention. No cognitive adverse effects were noted in either trial from the use of ketamine. Conclusions The current evidence for use of ketamine among older adults with depression indicates some benefits with one positive and one negative trial. Although one of the trails did not achieve significance on primary outcome measure, it still showed benefit of ketamine in reducing depressive symptoms. Both studies show longer sustenance of antidepressant effects at higher doses and with repeated treatments. One of the studies showed better ketamine efficacy in younger old subjects (65 to 74 years) when compared to older old (³75 years) subjects. Ketamine was well tolerated in both studies with adverse-effects being mild and transient. Additionally, there were no negative cognitive effects of ketamine noted among any of the study participants. Based on the limited current evidence, it is our opinion that ketamine shows some benefit in relieving depressive symptoms in older adults. However, there is dearth of randomized controlled trials and we need more well designed studies to arrive at a reliable conclusion regarding ketamine's benefit in treating depression among older adults. Funding None