Disulfiram-induced psychosis still an important clinical entity: A case series

Abstract

Disulfiram, an FDA-approved medication for treating alcohol dependence syndrome (ADS), is often used surreptitiously, resulting in severe adverse drug reactions such as disulfiram-induced psychosis (DIP). DIP presents diagnostic challenges, despite being perceived as common; however, there is limited literature available on DIP in India. We describe four cases with a history of psychosis in the background of disulfiram exposure. Our four male patients, aged 30–46 years old, had a history of ADS ranging from 7 to 16 years. They developed DIP after 5–15 days of exposure to disulfiram in doses ranging from 500 to 750 mg. In all cases, disulfiram was administered surreptitiously based on advice from non-experts. Predominant symptomatology included delusion, followed by perceptual disturbances. Naranjo adverse drug reaction probability scale was applied to establish disulfiram as the probable cause of psychosis in all cases. All patients responded to disulfiram discontinuation and a brief period of low-dose antipsychotic therapy within 7 days. The probability of DIP should be explored in a case of ADS presenting with an acute psychotic episode. Disulfiram, though an effective agent, should be used cautiously in selected cases at the recommended dose. Awareness building among family members may prevent and aid in the early detection of DIP.

Disulfiram, an aldehyde dehydrogenase inhibitor, is the first FDA-approved medication for alcohol dependence syndrome (ADS) treatment (in 1951).[1] Although the use of disulfiram is uncommon for treating ADS, it is known to cause several mild-to-severe adverse drug reactions (ADRs). Disulfiram-induced psychosis (DIP) is one such uncommon but serious ADR. Most of the cases of DIP had been reported before the 21^st century. There are only a handful of reports (predominantly from Western nations) concerning DIP in the last two decades, maybe owing to its decreased utilization. There are only a few case reports and a follow-up study related to this clinical entity from India.[2,3,4] While a systematic review on disulfiram ethanol reaction (DER) exists, India has only documented three case reports of DIP, with no reported case series. This series describes four patients who developed psychotic symptoms with disulfiram. Notably, all cases in this unique series involve surreptitious administration of disulfiram. Informed consent was obtained before the preparation of the reports.

CASE REPORTS

Case 1

A 46-year-old male with a history of ADS for 12 years presented with fearfulness, suspiciousness, hearing voices not heard by others, and irrelevant talk for 5 days. The patient’s wife had given disulfiram 250 mg tablet thrice a day without the knowledge of the patient. For the first 2 days, the patient had taken alcohol and had two episodes of mild DER characterized by nausea, itching, and flashes. Thus, he stopped taking alcohol on 3^rd day. However, on the 5^th day, he developed acute-onset fearfulness that some people were trying to harm him and people were talking about him. On the 8^th day, the family stopped disulfiram. There was no history of other substance use. On presentation, he was in clear sensorium and had a pulse rate of 94/min and mild tremors in his outstretched hands, without other signs of autonomic hyperactivity or disorientation. His mental status examination (MSE) revealed increased psychomotor activity, irritable effect, delusion of persecution and reference, and elementary-type auditory hallucinations. He was started on olanzapine 5 mg and was up-titrated to 10 mg. Family members were counseled about disulfiram. A complete resolution of psychotic symptoms was noticed within 1 week, and olanzapine was discontinued after 2 weeks without recurrence of psychotic symptoms in follow-up.

Case 2

A 30-year-old married male with a family history of psychosis in his father, married but separated with alcohol use in a dependence pattern for 7 years with no history of other substance use except tobacco, presented with acute-onset irrelevant speech, muttering, and laughing to himself, and fearfulness for 10 days. History revealed that the patient was given two tablets of disulfiram 250 mg daily surreptitiously by family members, as suggested by a local physician, for the last 25 days. Initially, he experienced nausea and vomiting due to concurrent alcohol intake. Subsequently, he abstained from alcohol for 20 days. Psychotic symptoms began around 15 days after starting disulfiram. Upon presentation, his pulse rate was 80/min, and no tremors or disorientation were noted. The patient was admitted, and tablet olanzapine 5 mg was initiated. Symptoms were completely improved within 1 week of the inpatient stay. He was on olanzapine for 1 month, gradually tapered off in the next follow-up. No psychotic symptoms were observed in subsequent three-month follow-ups.

Case 3

A 40-year-old married male, a carpenter by occupation, presented with acute-onset aggressive behavior, restlessness, fearfulness, and auditory hallucinations for 3 days. He had a family history of ADS in a first-degree relative and a personal history of alcohol dependence for the last 5 years. The patient was maintaining complete abstinence from alcohol for 3 months following admission to a deaddiction facility 3.5 months ago. There was no history of other substance use except tobacco. About a week before the current presentation, he expressed an urge to drink after attending a social gathering. Hence, family members consulted a local pharmacist who prescribed the tablet disulfiram 250 mg thrice daily. Five days into disulfiram use, he developed psychotic symptoms, such as muttering, auditory hallucinations, suspiciousness, and irritability, and sought professional assistance after 7 days. On physical examination, the patient was oriented to time/place/person with no tremor, pulse 90/min, and BP 130/84 mmHg. MSE findings were increased psychomotor activity, irritable affect, 2^nd person auditory hallucinations (commenting type), half-formed delusion, impaired judgment, and grade 1 insight. Upon admission, disulfiram was stopped. The patient received lorazepam 2 mg twice daily and 2 mg risperidone for 5 days, leading to full symptom resolution within the hospital stay. Risperidone was then gradually discontinued.

Case 4

A 31-year-old male, a four-wheeler dealer by profession, had a 16-year history of ADS with no history of other substance use. Two days after discharge from a rehab, he relapsed. As advised by a rehab staff, his mother started him on ayurvedic medication without his knowledge. After consuming alcohol alongside the medicine, he experienced mild DER symptoms, including sweating, redness of the eyes, palpitations, and vomiting. Consequently, his alcohol intake became less frequent and decreased in amount. Around 2 weeks after the initiation of medication, the patient developed behavioral abnormalities, characterized by suspiciousness and fearfulness, believing some of his family members were trying to harm him. He was brought to the emergency department and kept under observation. During the examination, the patient was in clear consciousness, oriented, and had a mild tremor, with a pulse of 102/min and BP of 100/64 mmHg. He received lorazepam 8 mg in tapering dose and tablet olanzapine 5 mg. There was a significant improvement in symptoms within 2 days, and he was seen in follow-up after 1 week, with complete resolution of symptoms. Olanzapine was stopped after 1 week.

DISCUSSION

Common side effects of disulfiram include fatigue, mild drowsiness, headache, garlic or metallic taste, allergic dermatitis, and peripheral neuropathy.[5] Rare but serious adverse effects of disulfiram include fulminant hepatitis, hepatic failure, and psychosis.[6] DER can manifest as mild symptoms such as facial flushing, nausea, vomiting, sweating, tachycardia, and hypotension, while severe reactions may include acute heart failure, myocardial infarction, arrhythmias, and severe hypotension.

In this series, an attempt has been made to discuss psychosis following disulfiram administration. Naranjo adverse drug reaction probability scale was used to evaluate the likelihood of medication involvement (i.e. disulfiram) in the observed adverse event (psychosis). A score of 6 in all cases indicates disulfiram as the probable cause of the psychosis.[7]

Our four patients were male, in the age range of 30–46 years, having a history of ADS for 7–16 years. They developed DIP after 5–15 days of disulfiram exposure in a dose range of 500–750 mg. Delusion of persecution was the predominant psychotic symptom followed by auditory hallucination. All the cases responded to disulfiram discontinuation and a brief period of low-dose antipsychotic therapy within 7 days.

DIP is thought to result from disulfiram’s toxic metabolites, diethyldithiocarbamate (DDC), which impair dopamine beta-hydroxylase (DBH) activity by chelating copper. This leads to dopamine accumulation in the mesolimbic system, potentially causing psychosis. Another emerging hypothesis suggests disulfiram-associated neurotoxicity, stemming from carbon disulfide (another toxic metabolite) and abnormal metal accumulation due to copper chelation in the central nervous system, leading to neuronal oxidative stress and free radical formation.[2] A case report from India revealed disulfiram-induced encephalopathy following surreptitious administration of disulfiram along with its subcutaneous implantation over the right iliac fossa.[8]

A case study from India reported that two patients receiving disulfiram developed psychotic symptoms.[3] Both patients had developed psychotic symptoms after 2 weeks of disulfiram therapy and were not associated with altered sensorium, like all the cases in the present case series. Psychotic symptoms remitted completely after discontinuing disulfiram and a short course of antipsychotic therapy. A systematic review from India found that three out of 10 patients developing psychosis following disulfiram administration had comorbidities and family history of psychosis (seen in one of our cases).[9]

Similarly, a comprehensive review of published English literature (1960–2017) by Das et al.[10] enlisted 17 cases and found delusion of persecution to be the most common psychotic symptom. In 16 of these cases, psychosis subsided after the withdrawal of disulfiram within an average of 7.5 days after discontinuing disulfiram. These findings are consistent with our observations in all four cases.

In cases of DIP, diagnostic challenges may arise from inaccuracies in the timeline of alcohol use and the influence of comorbid substance use. In addition, when disulfiram administration is unsupervised, challenges include estimating dosage and confirming the presence of disulfiram in the various nashamukti medications used. The main alternative diagnoses for the psychotic symptoms observed in all four cases encompass delirium tremens, alcoholic withdrawal hallucinosis, and acute and transient psychosis (ATPD), posing primary diagnostic challenges in our case series.

The onset of delirium tremens (DT) typically occurs within 48–72 hours of the last alcohol intake and resolves within 5 days. Except for case 3, symptoms in this study emerged after 3 days, persisting for 8 days in that case. Mild or no withdrawal symptoms were observed during examination, ruling out DT diagnosis in all four cases.

In all cases except for case 3, persecutory delusion was the primary symptom, which is inconsistent with alcoholic hallucinosis (AH), where predominant auditory hallucinations typically accompany delusions. In addition, AH usually manifests within hours to a day or two of alcohol abstinence. However, in this case series, the absence of psychotic symptoms after a minimum of 10 days of alcohol abstinence rules out the possibility of withdrawal hallucinosis.

While distinguishing between ATPD and DIP can be challenging, our cases present compelling arguments for the latter. First, disulfiram’s known potential to induce psychosis lends credibility to this diagnosis. Second, there is a clear temporal relationship between disulfiram initiation and the emergence of psychotic symptoms. Furthermore, none of the patients had a history of psychotic symptoms before disulfiram use. Third, we speculate that the swift resolution of symptoms may stem from disulfiram discontinuation rather than the typical antipsychotic effect, which often requires more time for a full response. Notably, all patients remained stable even after discontinuing antipsychotic medications, reinforcing the likelihood of DIP in our cases.

One striking commonality among all the cases was the surreptitious administration of disulfiram as advised by unregistered practitioners. Many traditional medicine preparations used for treating ADS, such as seen in case 4, contain disulfiram in a higher-than-usual prescribed dose, leading to uncommon but serious adverse effects such as psychosis, hepatotoxicity, and neuropathy.[11] These preparations are usually available in powder form in plastic packets resembling traditional medicines.

This case series underscores the consequence of unsupervised and uninformed administration of disulfiram, highlighting the potential risks of psychosis. Increasing awareness among family members is crucial to prevent and detect such uncommon but serious adverse effects early. However, clinicians should not hesitate to prescribe the medication in the recommended doses when indicated, like patients who wish to achieve abstinence from alcohol and in whom family members or caregivers are available for supervision of Disulfiram use.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.