Family history of alcohol dependence and antidepressant response to an N‐methyl‐D‐aspartate antagonist in bipolar depression

Luckenbaugh DA, Ibrahim L, Brutsche N, Franco‐Chaves J, Mathews D, Marquardt CA, Cassarly C, Zarate CA Jr. Family history of alcohol dependence and antidepressant response to an N ‐methyl‐ d ‐aspartate antagonist in bipolar depression. Bipolar Disord 2012: 14: 880–887. Published 2012. This article is a U.S. Government work and is in the public domain in the USA.

Objectives: Both ketamine and ethanol are N ‐methyl‐ d ‐aspartate (NMDA) receptor antagonists. Ketamine has rapid antidepressant properties in major depressive disorder (MDD) as well as bipolar depression. In individuals with MDD, a positive family history of alcohol dependence (FHP) was associated with greater improvement in depressive symptoms after ketamine administration compared to individuals whose family history of alcohol dependence was negative (FHN). This study investigated whether FHP influences ketamine’s antidepressant and perceptual effects in individuals with bipolar depression.

Methods: A post hoc analysis was conducted on 33 subjects with DSM–IV bipolar disorder (BD) type I or II depression pooled from two previously published studies. All subjects had undergone a double‐blind, randomized, crossover trial of a single intravenous infusion of ketamine (0.5 mg/kg) combined with lithium or valproate therapy. Subjects were rated at baseline; at 40, 80, 120, and 230 min; and at days 1, 2, 3, 7, 10, and 14 post‐infusion. The primary outcome measure was Montgomery‐Åsberg Depression Rating Scale (MADRS) scores. Patients were categorized as FHP when they reported at least one first‐degree relative with alcohol dependence. Measures of psychosis, dissociation, and dysphoria were also collected.

Results: After ketamine infusion, subjects with FHP showed significantly greater improvement on MADRS scores than FHN subjects. In addition, patients with FHP had attenuated psychotomimetic and dissociative scores compared to FHN patients.

Conclusions: FHP appears to predict a more sustained antidepressant response to ketamine in individuals with BD. Family history of alcoholism may be an important consideration in the development of glutamatergic‐based therapies for depression.