One medication stood out as the most effective in a meta-analysis of alcohol use disorders with depression, but few patients are taking it.
One medication stood out as the most effective in a meta-analysis of alcohol use disorders (AUD) with depression, but few patients are taking it.
One medication rose to the top in a new network meta-analysis of AUD with depression. But first, the specs on the study...
This network meta-analysis included 66 randomized controlled trials that tested 18 categories of medications in 5,890 patients who had an alcohol use disorder and either major depression or depressive symptoms.1
For remission of an alcohol use disorder, only 3 medications reached statistical significance:
2. Anticonvulsants (Carbamazepine, topiramate, tiagabine)
3. Naltrexone with an SSRI
The odds ratio for remission was much higher with disulfiram, although the spread of the data was also wider as indicated by the standard deviations in the graph. This difference held up to sensitivity analysis, where studies that might have skewed the results were removed.
For days abstinent from alcohol, only 2 medications reached statistical significance:
Baclofen is a muscle relaxant that has mixed results in AUD when studied independent of depression. It has no measurable reinforcing properties, but there have been rare reports of baclofen abuse.
The odds ratio for days abstinent from alcohol was higher for disulfiram compared to baclofen. This finding also held up to sensitivity analysis.
The final outcome in this study was change in depressive symptoms. Here there were no clear winners, at least in the US. The “noradrenergic” medications appeared effective as a group. However, this group included only venlafaxine and and the non-US medication viloxazine, and nearly all of that efficacy was attributable to viloxazine, a norepinephrine reuptake inhibitor. Mirtazapine did show promise, but only in a secondary analysis that included only studies that looked at full episodes of depression, rather than subsyndromal cases.
Studies like this cannot explain why disulfiram works well in depression, but I will venture a guess from clinical experience. Patients with depression are often unable to take action toward things that are good for them, from bathing to eating healthy to sobriety. They want to stop drinking, but struggle with ruminative thoughts that never arrive at an executable plan. Disulfiram brings that indecision to a halt and relieves them of the internal struggle. These patients are unlikely to drink on disulfiram because their actions are driven more by anxious-avoidance than by impulse.
On the other hand, disulfiram’s efficacy may not be unique to depression. The drug worked well in general AUD in several prior analyses.
In the 1930s, workers who were exposed to disulfiram at a rubber factory became very sick after drinking alcohol. This led to the first clinical use of disulfiram in the 1940s and its FDA approval for alcohol cessation in 1951. However, today only 200,000 people take it in the US, which is about 1% of all patients with AUD.
The reason for disulfiram’s decline may have to do with its unique mechanism. Disulfiram induces an immediate hangover reaction when combined with alcohol through a drug interaction. It blocks the enzyme that metabolizes acetaldehyde, the toxin responsible for alcohol’s hangover effect. With heavy drinking or high doses of disulfiram, this effect can be fatal. When disulfiram was first released, it was thought that patients had to experience this effect for it to work, and they were advised to drink on it. That practice ended when a few patients died from it, but it also left a stain on disulfiram’s reputation.
Oncologists do not withhold life-saving medications from patients with cancer because they are potentially toxic. Yet disulfiram appears under-utilized in psychiatry, even while alcohol-related fatalities have soared to become the #1 cause of death in middle aged adults. Although fatalities are extremely rare with disulfiram, physicians may feel a greater weight of responsibility for those deaths than they do when patients die from alcohol. An oncologist, however, would not feel this way when a patient dies from cancer.
As a review of disulfiram’s safety put it, “Deaths from the disulfiram-alcohol (ethanol) interaction have not been reported in recent years, possibly because the dosages used are lower than those used 40 years ago, and patients with cardiac disease are now excluded from treatment.”2
Today, most physicians prefer the lower dose of disulfiram 250 mg/day. This produces a less toxic interaction with alcohol, and works just as well as 500 mg/day dose. Actually, placebo worked just as well as disulfiram in the blinded studies, because simply warning a patient that the interaction is toxic will help them achieve sobriety even when the pill is a placebo.
Patients must be alcohol free for 12 hours before starting disulfiram, and the disulfiram-alcohol interaction persists for up to 2 weeks after stopping disulfiram.
Disulfiram is contraindicated in patients with severe coronary artery disease or heart failure, as there have been cases of sudden death after starting it in these patients. Relative contraindications include liver disease (disulfiram can elevate LFTs, as can naltrexone), psychotic disorder (there are rare cases of psychosis or confusional states on disulfiram), and active alcohol use (in past 12 hours). When used in absence of alcohol, common side effects include fatigue and headache. Check for drug interactions in the p450 system before starting it.
Bottom Line: Don’t overlook disulfiram, but know how to use it safely in AUD.
Dr Aiken is Instructor in Clinical Psychiatry at the Wake Forest University School of Medicine and the Director of the Mood Treatment Center in Winston-Salem, NC. He is Editor in Chief of The Carlat Psychiatry Reportand Bipolar Disorder Section Co-Editor for Psychiatric Times.
1. Li J, Wang H, Li M, et al. Efficacy of pharmacotherapeutics for patients comorbid with alcohol use disorders and depressive symptoms-A bayesian network meta-analysis. CNS Neurosci Ther. 2020;26(11):1185-1197.
2. Chick J. Safety issues concerning the use of disulfiram in treating alcohol dependence. Drug Saf. 1999;20(5):427-435.