Rigorous Trial Design Is Essential to Understand the Role of Opioid Receptors in Ketamine’s Antidepressant Effect

In addition to N-methyl-d-aspartate receptor antagonism, ketamine produces opioid system activation. The objective of this study was to determine whether opioid receptor antagonism prior to administration of intravenous ketamine attenuates its acute antidepressant or dissociative effects.

Empirical evidence has only weakly supported antidepressant treatment for patients with co-occurring depression and alcohol dependence. While some studies have demonstrated that antidepressants reduce depressive symptoms in individuals with depression and alcohol dependence, most studies have not found antidepressant treatment helpful in reducing excessive drinking in these patients. The authors provide results from a double-blind, placebo-controlled trial that evaluated the efficacy of combining approved medications for depression (sertraline) and alcohol dependence (naltrexone) in treating patients with both disorders. A total of 170 depressed alcohol-dependent patients were randomly assigned to receive 14 weeks of treatment with sertraline (200 mg/day [N=40]), naltrexone (100 mg/day [N=49]), the combination of sertraline plus naltrexone (N=42), or double placebo (N=39) while receiving weekly cognitive-behavioral therapy. The sertraline plus naltrexone combination produced a higher alcohol abstinence rate (53.7%) and demonstrated a longer delay before relapse to heavy drinking (median delay=98 days) than the naltrexone (abstinence rate: 21.3%; delay=29 days), sertraline (abstinence rate: 27.5%; delay=23 days), and placebo (abstinence rate: 23.1%; delay=26 days) groups. The number of patients in the medication combination group not depressed by the end of treatment (83.3%) approached significance when compared with patients in the other treatment groups. The serious adverse event rate was 25.9%, with fewer reported with the medication combination (11.9%) than the other treatments. More depressed alcohol-dependent patients receiving the sertraline plus naltrexone combination achieved abstinence from alcohol, had delayed relapse to heavy drinking, reported fewer serious adverse events, and tended to not be depressed by the end of treatment.

The major problem with the oral formulation of naltrexone for heroin dependence is poor compliance (adherence). Long-acting sustained release formulations of naltrexone (implantable and injectable) might help to improve compliance and, thus, increase the efficacy of abstinence-oriented treatment of heroin dependence with naltrexone. There have been several implantable and injectable formulations of naltrexone developed within the last decade. It was demonstrated that some of them are effective and relatively well tolerated medications for relapse prevention in heroin addicts. However, advantages and disadvantages of these new medications have never been systematically analyzed. Long-acting sustained release formulations of naltrexone are well tolerated and more effective for relapse prevention in heroin addicts than the oral ones.