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

Substance use disorders, particularly alcohol dependence, are highly prevalent in individuals diagnosed with bipolar disorder (BD) (1). In addition, the presence of substance abuse or alcoholism significantly affects the course and prognosis of BD (2–6). Recent evidence from diverse studies suggests that glutamatergic dysfunction may be involved in the pathophysiology of both BD (7, 8) and alcoholism (9–11), as well as both disorders concomitantly (12). Furthermore, the glutamatergic system, particularly the N-methyl-D-aspartate (NMDA) receptor complex, has been investigated as a putative target for the development of novel treatments for both disorders (7, 13–18). For mood disorders, much of the recent work in this area has centered on ketamine, an NMDA receptor antagonist with rapid (within hours) antidepressant effects in both major depressive disorder (MDD) and bipolar depression. Notably, both ketamine and ethanol are NMDA receptor antagonists and show dose-related similarities with regard to their subjective effects in healthy subjects—an effect that appears to be mediated by positive family history of alcohol dependence (FHP) (19, 20). In healthy subjects undergoing ketamine infusion, individuals with FHP showed an attenuated response in terms of perceptual alterations and dysphoric mood compared to those with a negative family history of alcohol dependence (FHN) (20). Alcohol-dependent patients also appear to have a blunted behavioral affect in response to ketamine, suggesting cross-tolerance between alcohol and ketamine (19). Relative to healthy subjects, ketamine administration in recovering ethanol-dependent patients was associated with reduced psychotomimetic symptoms and dysphoric mood (11). A previous study from our laboratory examined whether FHP would mediate the subjective and behavioral effects of ketamine in individuals with MDD. Indeed, consistent with the extant literature, we found that treatment-resistant MDD patients with FHP had fewer dysphoric and psychotomimetic effects in response to ketamine administration than MDD patients with FHN. In addition, we found that FHP patients had a significantly better initial antidepressant response to ketamine (21). Thus, in patients with MDD, FHP predicted a differential response to the perceptual disturbances, dysphoric effects, and antidepressant effects associated with ketamine. To date, no studies have investigated the link between FHP and ketamine’s antidepressant properties in patients with bipolar depression. Nevertheless, identifying predictors of robust treatment response could improve research efforts to develop glutamatergic modulators for the treatment of mood disorders. Thus, this study sought to determine whether the dysphoric, psychotomimetic, and antidepressant effects associated with ketamine are altered in FHP individuals with bipolar depression; the study combines samples from two recently published controlled studies investigating the antidepressant properties of ketamine in individuals with bipolar depression (7, 8). The relationship between personal history of alcohol dependence and ketamine’s effects was also examined.