Clinical Efficacy of Ketamine for Treatment-resistant Depression total information

Clinical Efficacy of Ketamine for Treatment-resistant Depression total information

Abstract

Depression is a common psychiatric disorder affecting more than 300 million people worldwide. According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), the diagnosis of depression requires at least two weeks of either low mood or anhedonia as well as four or more other symptoms such as appetite or weight changes, insomnia or hypersomnia, psychomotor agitation or retardation, loss of energy, inability to concentrate, feelings of worthlessness or excessive guilt, and suicidality. Selective serotonin reuptake inhibitors (SSRIs) target the monoaminergic system and are the commonest drugs used for treating depression, but have certain limitations, such as their delayed onset of action. Ketamine liquid supplier, a non-competitive NMDA receptor antagonist, has shown in several randomized controlled trials (RCTs) promising results with rapid antidepressant effects, especially in patients with severe treatment-resistant depression (TRD), which is depression that has not responded to more than two antidepressants. In this review, the clinical efficacy of ketamine in TRD has been discussed, with emphasis placed on the evidence from RCTs.

Introduction & Background

Depression is a common psychiatric disorder affecting more than 300 million people worldwide, leading to a considerably reduced quality of life and increased risk of suicide, while posing a tremendous economic burden (more than 200 billion dollars in the US). According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), the diagnosis of a Major Depression Episode (MDE) requires five or more symptoms to be present within a two-week period [5]. One of the symptoms should be either a depressed mood or anhedonia. The secondary symptoms of MDE are appetite or weight changes, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue or loss of energy, diminished ability to think or concentrate, feelings of worthlessness or excessive guilt, and suicidality. Currently, the most commonly used antidepressant drugs are selective serotonin reuptake inhibitors (SSRI), which primarily target the monoaminergic system [6]. An important limitation of SSRIs is their delayed onset of action, as they take about two weeks to start having an effect and can even worsen pre-existing anxiety and suicidality during this time period, especially in younger populations [7-8]. In addition, 35% of patients fail to respond to treatment altogether [9]. Recent evidence implicates the glutamatergic system in the pathogenesis of depression and thus agents that aim to modify this system, have generated immense interest. Specifically, ketamine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, has particularly been in the spotlight due to its rapid antidepressant effects and particularly in patients with treatment-resistant depression (TRD), who are significantly less likely to respond to another antidepressant and are at higher risk of functional disability. TRD refers to depression that does not respond to more than two antidepressants. The aim of this review is to discuss the clinical efficacy of ketamine for TRD, by appraising the available evidence and specifically randomized controlled trials (RCTs), which evaluated the effects of ketamine in patients with TRD.

Clinical efficacy

In a two-site, parallel-arm RCT, Murrough et. al. compared the efficacy of a single infusion of ketamine to an active placebo-control, the anesthetic midazolam, in 73 patients with TRD. At 24 hours, the mean Montgomery-Åsberg Depression Rating Scale (MADRS) score was significantly lower in the ketamine compared to the midazolam group, by 7.95 points (14.77 vs 22.72; P < 0.001), while the likelihood of treatment response (more than 50% reduction from baseline MADRS) was significantly greater for ketamine compared to midazolam (response rates 64% and 28% respectively; P < 0.006). Ketamine’s benefits were maintained for up to seven days post-infusion, at which point significant differences in MADRS compared to midazolam were no longer observed.