Alcohol Dependence Drug the Next Anti-Anxiety Med?

Disulfiram, a US Food and Drug Admiistration (FDA)–approved medication for the treatment of chronic alcohol dependence, shows promise as a potential anxiolytic, early research suggests.

Japanese researchers, headed by Akiyoshi Saitoh, PhD, professor in the Department of Pharmacy, Tokyo University of Science, compared the reactions of mice that received a classic anxiolytic agent (diazepam) to those that received disulfiram while performing a maze task and found comparable reductions in anxiety in both groups of mice.

Moreover, unlike diazepam, disulfiram caused no sedation, amnesia, or impairments in coordination.

"These results indicate that disulfiram can be used safely by elderly patients suffering from anxiety and insomnia and has the potential to become a breakthrough psychotropic drug," Saitoh said in a press release.

The study was published online March 7 in Frontiers in Pharmacology.

Inhibitory Function

Disulfiram inhibits the enzyme aldehyde dehydrogenase (ALDH), which is responsible for alcohol metabolism. Recent research suggests that disulfiram may have broader inhibitory functions.

In particular, it inhibits the cytoplasmic protein FROUNT, preventing it from interacting with two chemokine receptors (CCR2 and CCRs) that are involved in cellular signaling pathways and are associated with regulating behaviors, including anxiety, in rodents, the authors write.

"Although the functions of FROUNT-chemokines signaling in the immune system are well documented, the potential role of CNS-expressed FROUNT-chemokine-related molecules as neuromodulators remains largely unknown," they write.

The researchers had been conducting preclinical research on the secondary pharmacologic properties of disulfiram and "coincidentally discovered" its "anxiolytic-like effects." They investigated these effects further because currently used anxiolytics — ie, benzodiazepines — have unwanted side effects.

The researchers utilized an elevated plus-maze (EPM) test to investigate the effects of disulfiram in mice. The EPM apparatus consists of four arms set in a cross pattern and are connected to a central square. Of these, two arms are protected by vertical boundaries, while the other two have unprotected edges. Typically, mice with anxiety prefer to spend time in the closed arms. The mice also underwent other tests of coordination and the ability to navigate a Y-maze.

Some mice received disulfiram, others received a benzodiazepine, and others received merely a "vehicle," which served as a control.

Disulfiram "significantly and dose-dependently" increased the time spent in the open arms of the EPM, compared with the vehicle-treated group, at 30 minutes after administration (F [3, 30) = 16.64, P < .0001], suggesting less anxiety. The finding was confirmed by a Bonferroni analysis that showed a significant effect of disulfiram, compared with the vehicle-treated group, at all three doses.

20 mg/kg	i. p.: t = 0.9894, P > .05
40 mg/kg	i. p.: t = 3.863, P < .01
80 mg/kg	i. p.: t = 6.417, P < .001

A Student's t-test analysis showed that diazepam likewise had a significant effect, compared to the vehicle (t = 5.038, P < .001).

Disulfiram also "significantly and dose-dependently" increased the percentage of open-arm entries (F [3, 30] = 14.24, P < .0001). The Bonferroni analysis showed this effect at all three doses.

20 mg/kg	i. p.: t = 0.3999, P > .05
40 mg/kg	i. p.: t = 2.693, P > .05
80 mg/kg	i. p.: t = 5.864, P < .001

Diazepam similarly showed a significant effect, compared to the vehicle condition (t = 3.733, P < .005).

In particular, the 40 mg/kg dose of disulfiram significantly increased the percentage of time spent in the open arms at 15, 30, and 60 minutes after administration, with the peak effect occurring at 30 minutes.

The researchers examined the effect of cyanamide, another ALDH inhibitor, on the anxiety behaviors of mice and found no effect on the number of open- arm entries or percentage of time the mice spent in the open arm, compared with the vehicle condition.

In contrast to diazepam, disulfiram had no effect on the amount of spontaneous locomotor activity, time spent on the rotarod, or activity on the Y-maze test displayed by the mice, "suggesting that there were no apparent sedative effects at the dosages used." Moreover, unlike the mice treated with diazepam, there were no increases in the number of falls the mice experienced on the rotarod.

Glutamate levels in the prelimbic-prefrontal cortex (PL-PFC) "play an important role in the development of anxiety-like behavior in mice," the authors state. Disulfiram "significantly and completely attenuated increased extracellular glutamate levels in the PL-PFC during stress exposure" on the EPM.

"We propose that DSF inhibits FROUNT protein and the chemokine signaling pathways under its influence, which may suppress presynaptic glutamatergic transmission in the brain," said Saitoh. "This, in turn, attenuates the levels of glutamate in the brain, reducing overall anxiety."

Humanity's Most Common Affliction

Commenting for Medscape Medical News, Roger McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, Canada, and head of the Mood Disorders Psychopharmacology Unit, noted that there is a "renewed interest in psychiatry in excitatory and inhibitory balance — for example, ketamine represents a treatment that facilitates excitatory activity, while neurosteroids are candidate medicines now for inhibitory activity."

McIntyre, who is the chairman and executive director of the Brain and Cognitive Discover Foundation, Toronto, and was not involved with the study, said it is believed "that the excitatory-inhibitory balance may be relevant to brain health and disease."

McIntyre also pointed out that the study "highlights not only the repurposing of a well-known medicine but also exploiting the potential brain therapeutic effects of immune targets that indirectly affect inhibitory systems, resulting in potentially a safer treatment for anxiety — the most common affliction of humanity."

Also commenting for Medscape Medical News, Wilfrid Noel Raby, PhD, MD, a psychiatrist in private practice in Teaneck, New Jersey, called disulfiram "grossly underused for alcohol use disorders and even more so when people use alcohol and cocaine."

Raby, who was not involved with the study, has found that patients withdrawing from cocaine, cannabis, or stimulants "can respond very well to disulfiram [not only] in terms of their cravings but also in terms of mood stabilization and anxiolysis."

He has also found that for patients with bipolar disorder or attention-deficit/hyperactivity disorder with depression, disulfiram and low-dose lithium "can provide anxiolysis and mood stabilization, especially if a rapid effect is required, usually within a week."

However, Raby cautioned that "it is probably not advisable to maintain patients on disulfiram for period long than 3 months consecutively because there is a risk of neuropathy and hepatopathology that are not common but are seen often enough." He usually interrupts treatment for a month and then resumes if necessary.

The research was partially supported by the Tsukuba Clinical Research and Development Organization (T-CReDO) from the Japan Agency for Medical Research and Development (AMED). The authors and Raby have disclosed no relevant financial relationships. McIntyre reports receiving research grant support from CIHR/GACD/National Natural Science Foundation of China (NSFC); speaker/consultation fees from Lundbeck, Janssen, Alkermes, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, AbbVie, and Atai Life Sciences. McIntyre is a CEO of Braxia Scientific Corp.

Front Pharmacol. Published online March 7, 2022. Full text

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