Use of Disulfiram for Treatment of Alcohol Addiction in Patients With Psychotic Illness

To the Editor: I commend Robertson and colleagues for investigating the effect of medication-assisted treatment (MAT) on behavioral health treatment utilization and criminal justice outcomes among alcohol-dependent adults with serious mental illness who interface with the criminal justice system (1). Their study, published in the July 2018 issue of the Journal, considered three medications that are approved by the U.S. Food and Drug Administration for treatment of alcohol use disorder: acamprosate, naltrexone, and disulfiram. I agree with the authors that MAT is underutilized in this population, and their results reveal the benefits of this treatment modality with respect to psychiatric hospitalizations, emergency department visits, and adherence to psychotropic medications. However, I would caution against providers selecting disulfiram when deciding what medication(s) to prescribe for the treatment of alcohol use disorder in patients with psychotic disorders.

Disulfiram irreversibly inhibits aldehyde dehydrogenase, leading to the accumulation of acetaldehyde when alcohol is ingested. The unpleasant disulfiram-ethanol reaction experienced by someone who consumes alcohol while on this medication serves as a deterrent against alcohol use. Disulfiram’s metabolite diethyldithiocarbamate inhibits another enzyme, dopamine beta-hydroxylase, which is responsible for conversion of dopamine into norepinephrine in noradrenergic neurons; this inhibition increases dopamine concentrations in the mesolimbic system. There are multiple case reports in the literature (2) describing an association between use of disulfiram (either alone or in combination with other medication) and psychosis, and inhibition of dopamine beta-hydroxylase is thought to underlie this phenomenon. For this reason, psychosis is listed as a contraindication in the disulfiram package insert.

To counter this point, Robertson et al. may cite evidence in the literature that disulfiram does not appear to lead to an exacerbation of symptoms in patients with psychotic disorders. One such study referenced by Robertson et al. (3) showed that the percentage of subjects with psychotic illness who experienced worsening psychiatric symptoms while taking 125–500 mg/day was very low. However, that same study revealed that 76% of subjects reported using alcohol while on disulfiram and that only 28% reported experiencing the disulfiram-ethanol reaction when they consumed alcohol. The reason for this is likely attributable to the dose of disulfiram being administered. Dosages in excess of 1 g/day are often needed to achieve a level of enzyme inhibition necessary for the disulfiram-ethanol reaction to occur when alcohol is consumed. It is unclear what effect high-dose disulfiram has on psychotic illness, as the studies investigating disulfiram and psychosis involved dosages that did not exceed 500 mg/day. Thus, it is hard to say with certainty whether higher doses of disulfiram (doses that are often required to achieve effect) are safe in patients with psychotic disorders.

In light of the concern that disulfiram may exacerbate psychotic illness, and given that other medications (naltrexone and acamprosate) are considered to be superior to disulfiram in the treatment of alcohol addiction (4), providers would do well to follow APA’s current practice guideline for the pharmacological treatment of alcohol use disorder (5) and offer naltrexone and/or acamprosate as first-line pharmacotherapy, especially for patients with psychotic illness.