Disulfiram-induced psychosis at a therapeutic dose and in clear sensorium: Two case demonstrations

Abhishek Ghosh; Debasish Basu; C Pradeep; BN Subodh

doi:10.4103/jmhhb.jmhhb_1_19

CASE REPORT

Year : 2019 | Volume : 24 | Issue : 1 | Page : 57-59

Disulfiram-induced psychosis at a therapeutic dose and in clear sensorium: Two case demonstrations

Abhishek Ghosh¹, Debasish Basu¹, C Pradeep², BN Subodh¹
¹ Department of Psychiatry, Drug De-Addiction and Treatment Center, Postgraduate Institute of Medical Education and Research, Chandigarh, India
² VMKV Medical College and Hospital, Salem, Tamil Nadu, India

Date of Web Publication

4-Jun-2020

Correspondence Address:
Abhishek Ghosh
Department of Psychiatry, Drug De-Addiction and Treatment Center, Postgraduate Institute of Medical Education and Research, Chandigarh
India

Source of Support: None, Conflict of Interest: None

Check

DOI: 10.4103/jmhhb.jmhhb_1_19

Abstract

The literature on disulfiram induced psychosis showed, it was either associated with delirium or preceded by a prescription of a higher dose. We report two cases of psychosis in clear sensorium developing in individuals with alcohol dependence without any familial loading following a short duration of a therapeutic dose of disulfiram. Before the onset of psychosis, the patients were abstinent from alcohol for about a month, which made substance-induced psychosis unlikely. Psychosis resolved following discontinuation of disulfiram. Hence, the diagnosis of disulfiram-induced psychosis was considered. A plausible mechanism of such association has been discussed. Disulfiram-induced psychosis though unusual could be disruptive and severe. Close surveillance following disulfiram is important for early identification and management of such condition.

Keywords: Adverse effects, disulfiram, psychosis

How to cite this article:
Ghosh A, Basu D, Pradeep C, Subodh B N. Disulfiram-induced psychosis at a therapeutic dose and in clear sensorium: Two case demonstrations. J Mental Health Hum Behav 2019;24:57-9

How to cite this URL:
Ghosh A, Basu D, Pradeep C, Subodh B N. Disulfiram-induced psychosis at a therapeutic dose and in clear sensorium: Two case demonstrations. J Mental Health Hum Behav [serial online] 2019 [cited 2023 Jun 4];24:57-9. Available from: https://www.jmhhb.org/text.asp?2019/24/1/57/285987

Introduction

After its debut in therapy by Martensen-Larsen in 1948, disulfiram has been used in the treatment of patients suffering from alcohol dependence. Despite a few different pieces of evidence, the efficacy of disulfiram for increasing the rate of abstinence in chronic alcoholism has been undisputed especially when administered under supervision.^[1]

Although regarded as generally safe, there are some serious concerns regarding disulfiram. One of them is psychosis. Disulfiram-induced psychosis was first reported by Liddon and Satran.^[2] In this review, the most significant proportion of subjects with psychosis had concurrent delirium. This article was published nearly 50 years back, and there have been notable changes in prescription pattern and dosage of disulfiram. Subsequently, another study from India reported six subjects with disulfiram-induced psychosis, but all of them had simultaneous mood disorders.^[3] In recent times, there is a couple of case reports on psychosis influenced by co-prescription of disulfiram and methylphenidate, and in the other, the association was confounded by the presence of family history, an occurrence of disulfiram–ethanol reaction at the time of the onset of psychosis.^[4],[5] Association was observed to be dose dependent.^[4],[6],[7]

In this case report, we describe two patients who developed psychotic symptoms without any coexisting delirium succeeding the administration of a therapeutic dose of disulfiram. Informed consents were obtained from both the patients for publication of the case report.

Case Reports

The clinical profiles of both the patients are tabulated in [Table 1]. The narrative description follows.

Table 1: Clinical profile of the subjects

Click here to view

Case 1

A 32-year-old male, dependent on alcohol for the past 10 years, presented to an unregistered medical practitioner who prescribed him disulfiram following 2 weeks of abstinence from alcohol. After 2 weeks on a regular dose of disulfiram 250 mg/day, he developed a suspicion that someone was trying to harm him and was conspiring against his family. Furthermore, he would accuse others discussing him with malicious intent. He would remain firm in these beliefs and was not amenable to logical explanation. In response, he turned homebound and religious to escape and set aside imaginary imminent danger. He continued to be fearful and confined himself indoor and would stop interacting with family, friends, and neighbors. He ended going to his workplace and would only come out of his room to use the toilet. He would have insomnia and poor self-care. His family stopped administering disulfiram within 5 days of the appearance of delusions, and he was brought to a specialized treatment facility. The mental status examination in the walk-in-clinic showed the presence of delusion of persecution and reference. He was prescribed olanzapine at the dose of 5 mg/day. Suspiciousness and fearfulness began to resolve rapidly and remitted entirely by the end of 2 weeks. Olanzapine was discontinued over another 2 weeks. Liver function test was done. His aspartate transaminase (AST) and alanine transaminase levels were 45 U/L and 41 U/L, respectively. Bilirubin and albumin levels were also within the normal range.

Case 2

A 33-year-old graduate, dependent on alcohol for the past 9 years and with at least four failed detoxification attempts in the past, was admitted to the de-addiction center. He was diagnosed with alcohol-induced Grade II fatty liver with an AST level of 142 U/L, though his bilirubin, albumin, and other enzyme levels were within normal range. Written informed consent was obtained and he was started on disulfiram following 2 weeks of abstinence and while he was at the hospital. He went home on 250 mg/day dosage and maintained well with supervised disulfiram for a month. After a month, he had an abrupt onset persecutory delusion against his close friends and a relative. He was extremely aggressive and also threatened to kill his relative with a knife accusing him of having an illicit affair with his wife. He was roaming around almost nude and ran away when he was tried to be confined. His mood was reported to be labile. He was brought to the outpatient department. On examination, he was aggressive and had delusion of persecution. Disulfiram was stopped and symptoms remitted after 48 h. He was prescribed olanzapine 5 mg and continued for another 2 months.

None of these patients had a history of other drug use. The history was corroborated from the family members as well. Urine chromatographic immunoassay was done for the second patient and it was negative for cannabinoids, amphetamine, barbiturates, benzodiazepines, cocaine, and morphine. Neither of these patients had expressed enduring sadness. Neither of them did express ideas of guilt, pessimism, or worthlessness. They did not have either perceptual or cognitive disturbances. Both of them were well oriented to time, place, and person during the entire period. None of the physical or psychological symptoms of withdrawal were present. Neither of them had any past or family history of psychosis. For both the patients, computed tomography of the brain was normal. Disulfiram was never reintroduced. Psychotic symptom did not reappear subsequently.

Discussion

We have demonstrated an account of a middle-aged alcohol-dependent male patient who did not have any family history of psychosis and was abstinent from alcohol for about a month and had developed psychotic symptoms after the administration of therapeutic dosage of disulfiram. The first patient was taking disulfiram on his own, whereas for the second patient, it was supervised by the family members. There was no reason to believe, they took higher than the prescribed dose. Moreover, in our patient, psychosis was not associated with any concomitant confusional state or mood disorder and subsided following discontinuation of disulfiram. Although olanzapine was prescribed; simultaneously, the pace of improvement in psychosis could not be better accounted by its effect.

Naranjo adverse drug reaction probability scale^[8] was administered to both the patients. It classifies the probability that an adverse event is related to drug therapy and is based on a list of weighted questions.^[8] The scale examines ten important factors before implicating the drug in question. In both these patients, the total score was 6. Hence, disulfiram could be regarded as the probable cause of psychosis in our patient [Table 2].

Table 2: The Naranjo adverse drug reaction probability scale scores in both the cases

Click here to view

Two hypotheses can be speculated behind this association. The two toxic metabolites of disulfiram are diethyldithiocarbamate (DDC) and its metabolite carbon disulfide. DDC chelates copper, thus impairing the activity of dopamine beta-hydroxylase (DBH), an enzyme that catalyzes the metabolism of dopamine to norepinephrine. In this way, DDC causes accumulation of dopamine, increasing concentrations of dopamine in the mesolimbic system, and this has been implicated in psychosis. There is also a second possibility of direct disulfiram-associated neurotoxicity because of abnormal metal accumulation from the chelation of copper by DDC in the central nervous system, leading to free radical formation and neuronal oxidative stress.^[9]

It must be kept in mind that only a minority of individuals who are exposed to disulfiram develop psychosis. Hence, it would be intuitive to conjecture about the vulnerability of disulfiram psychosis. First, as disulfiram is primarily metabolized by CYP3A4 isoenzyme which is well known for its wide variability in activity due to the presence of functional polymorphisms, it would be worthwhile to examine the association between CYP3A4 “high metabolizers” and psychosis. Second, the association of DBH polymorphism with psychotic symptom has been extensively studied in the literature.^[10] Interestingly, the inhibition of DBH by DDC which is purported to be the primary mechanism behind the development of psychosis following disulfiram would become crucial if an individual already has the “low-activity” variant of the enzyme. Therefore, a low-activity DBH allele might predispose an individual to disulfiram psychosis.

Finally, we would like to reiterate disulfiram-induced psychosis is a rare entity, and an apprehension of such an event must not deter a clinician to prescribe disulfiram, where it is otherwise indicated. However, a clinician should exercise caution and recognize the risk of psychosis in the first few weeks of disulfiram prescription.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1.	Berglund M, Thelander S, Salaspuro M, Franck J, Andréasson S, Ojehagen A, et al. Treatment of alcohol abuse: An evidence-based review. Alcohol Clin Exp Res 2003;27:1645-56.
2.	Liddon SC, Satran R. Disulfiram (Antabuse) psychosis. Am J Psychiatry 1967;123:1284-9.
3.	Murthy KK. Psychosis during disulfiram therapy for alcoholism. J Indian Med Assoc 1997;95:80-1.
4.	Grau-López L, Roncero C, Navarro MC, Casas M. Psychosis induced by the interaction between disulfiram and methylphenidate may be dose-dependent. Subst. Abus 2012;33:186-8.
5.	de Melo RC, Lopes R, Alves JC. A case of psychosis in disulfiram treatment for alcoholism. Case Rep Psychiatry 2014;2014:561092.
6.	Mohapatra S, Rath NR. Disulfiram induced psychosis. Clin Psychopharmacol Neurosci 2017;15:68-9.
7.	Das N, Mahapatra A, Sarkar S. Disulfiram induced psychosis: Revisiting an age-old entity. Asian J Psychiatr 2017;30:94-5.
8.	Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. Amethod for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-45.
9.	Vaccari A, Ferraro L, Saba P, Ruiu S, Mocci I, Antonelli T, et al. Differential mechanisms in the effects of disulfiram and diethyldithiocarbamate intoxication on striatal release and vesicular transport of glutamate. J Pharmacol Exp Ther 1998;285:961-7.
10.	Park JK, Kim JW, Lee HJ, Chung JH, Ha EY, Oh DJ, et al. Dopamine beta-hydroxylase gene polymorphisms and psychotic symptoms in schizophrenia. Am J Med Genet B Neuropsychiatr Genet 2007;144B: 944-5.