Drug-induced mania and parkinsonism in substance use disorder patient: A case report

Abstract

This case report investigates mania and parkinsonism induced by olanzapine and disulfiram in a patient with substance use disorder. DSM-5 criteria were used for the diagnosis of drug-induced parkinsonism, and movement disorder severity was assessed with the Simpson–Angus Scale. After initiating olanzapine and disulfiram therapy, the patient developed extrapyramidal symptoms and manic features. Naranjo scale indicated a probable drug reaction (score = 7), while Hartwig Severity Assessment (Level 4) suggested that hospitalization was required and these reactions were nonpreventable. The case underscores the need for vigilant monitoring and tailored treatment in patients with psychiatric conditions.

Introduction

Substance use disorder poses multifaceted challenges for clinicians, especially when comorbid psychiatric and neurologic symptoms intersect and complicate treatment strategies. Psychotropic agents such as olanzapine, an atypical antipsychotic and disulfiram, a pharmacotherapy for alcohol dependence, are frequently employed to manage psychotic, affective, or substance-related symptoms in this vulnerable population. However, both medications carry the risk of iatrogenic neuropsychiatric and motor side effects, including paradoxical manic episodes and drug-induced parkinsonism (DIP). Importantly, these adverse effects may mask or mimic primary psychiatric conditions, making diagnosis difficult and increasing the likelihood of inappropriate treatment modifications.[1]

Olanzapine is widely appreciated for its efficacy in managing psychosis and mood disorders, including acute mania and bipolar depression. While it is typically considered mood stabilizing, there have been rare but well-documented instances where olanzapine paradoxically precipitates manic symptoms, even in patients without prior mood disorders. In addition to its mood-related effects, olanzapine can induce extrapyramidal symptoms (EPSs), including DIP, particularly when administered at higher doses or over extended durations. Although atypical antipsychotics generally carry a lower EPS risk than first-generation neuroleptics, olanzapine’s dopamine D₂ receptor antagonism in the striatum can nonetheless precipitate rigidity, bradykinesia, and tremor. The presentation can closely resemble idiopathic parkinsonism disease and may persist long after cessation of the offending agent.[2]

Concurrently, disulfiram, a long-standing agent used in abstinence-based treatment for alcohol dependence, possesses neurotoxic potential. Epidemiological data show that disulfiram exposure is associated with a three-fold increase in the risk of DIP, independent of concurrent neuroleptic use, with greater risk evident in those receiving multiple prescriptions. Mechanistically, disulfiram’s metabolite N, N-diethyldithiocarbamate may induce oxidative damage to basal ganglia structures, resulting in rigid-akinetic syndromes. Some case reports further describe reversible frontal dysfunction and magnetic resonance imaging (MRI) changes in basal ganglia consistent with disulfiram neurotoxicity.[3] This case involves a patient with long-standing substance use disorder who, following concurrent administration of olanzapine and disulfiram, developed acute manic symptoms alongside extrapyramidal features consistent with DIP. The dual pharmacologic insult-olanzapine’s paradoxical mood activation and dopaminergic blockade, compounded by disulfiram’s basal ganglia neurotoxicity produced a clinical picture that obscured differentiation between primary mood disorder, substance-induced withdrawal, and medication side effects. The overlapping etiologies highlight the critical need for systematic monitoring, including detailed psychiatric evaluation, movement assessment, and perhaps neuroimaging. Vigilant clinical observation, dose modulation, and cautious polypharmacy are essential to identify and mitigate iatrogenic effects.

Case Report

We present a 22-year-old male patient, who was previously diagnosed with substance use disorder spanning 4 years. Approximately 3 months before seeking medical assistance, he displayed sudden symptoms including irritation, anger toward family, increased talkativeness, sleep difficulties, and confrontations with neighbors, persisting for about 1 week. During this period, he experienced an altered mental state and spent a significant amount of money on alcohol, which led concerned neighbors to urge him to seek help. Consequently, he was transferred to a de-addiction facility where physical restriction was the primary intervention without medication.

After about 3 weeks into the rehabilitation program, he experienced a seizure episode, leading to discharge. After discharge, he continued to display irritability, engage in conflicts, and exhibit grandiosity, frequently asserting remarkable achievements. He then left home and drove to Tirumala to purchase a car, but sustained a head injury after falling. MRI scan was taken and showed no substantial abnormalities. Following the head injury, he received a treatment regimen of olanzapine 30 mg QD, clobazam 5 mg BID, propranolol SR 40 mg QD, disulfiram 250 mg QD, and zolpidem 10 mg QD resulting in improved mood and other symptoms.

However, 3 days before admission, he experienced EPSs including increasing body tremors, rigidity, dystonia, akathisia, difficulties swallowing food with profuse salivation, slurred speech, and a vacant stare, without complaints of vomiting, fever and pain. This comprehensive patient history emphasizes the case’s complexity, highlighting the need for a thorough clinical evaluation and effective care of the presenting symptoms.

Clinical findings

On admission, a general examination revealed a respiratory rate of 16 breaths/min, blood pressure of 150/110 mmHg, and a pulse rate of 115 beats/min. Muddy conjunctiva was noticed. Systemic examination indicated cogwheel rigidity +, coarse tremor +, bilateral plantar silent response, and a Glasgow Coma Scale score of E4, V4, and M6 indicated a patient is responsive. The power in all four limbs was intact at 5/5, with normal respiratory and cardiovascular systems. Local examination identified enlargement in the left temporoparietal region of the head, accompanied by the existence of Meyerson’s sign. Both MRI and computed tomography scans indicated no notable abnormalities. Laboratory examination results included a complete blood count revealing an increased total count of 15,970 mm3. Serum electrolytes indicated an increased potassium level of 6.0 mmol/L and showed suggestive of hyperkalemia. The serum ammonia level was 50.7 μmol/L. Urinalysis was positive for sugar and ketones. Liver, thyroid, and renal profiles were within normal norms. Based on the reported clinical data, the patient was diagnosed with drug-induced mania and EPSs. The constellation of symptoms, together with the test results, highlighted the complexity of the case, highlighting the need for further study and tailored care to address both the manic and extrapyramidal aspects.

Diagnostic assessment

The patient was initially placed on a treatment regimen consisting of olanzapine at a dosage of 30 mg twice daily, along with disulfiram administered at 250 mg once daily. Subsequent to the initiation of this regimen, the patient manifested symptoms indicative of EPS, specifically DIP, and concurrent manic features. To quantify the severity of the movement disorder, the Simpson–Angus Scale (SAS) was employed, revealing a score of 11. This score on the SAS was indicative of a clinically significant degree of movement disorder. The elevated score emphasized the presence of notable extrapyramidal manifestations, aligning with the observed DIP, and underscored the necessity for a nuanced therapeutic approach to address both the manic and movement disorder components of the patient’s presentation.

The causality evaluation was done with Naranjo Causality Assessment Scale.[4] A score of 7 signified a probable association between the drug and the adverse event [Table 1]. The severity of this case was evaluated using Hartwig Severity Evaluation Scale,[5] and the findings indicated that Level 4 severity (it denotes that the patient’s reaction was warranted for admission). Using the Schumock and Thornton Scale,[6] it was determined that these reactions were not preventable.

Table 1.

Naranjo Adverse Drug Reaction Probability Scale scores of the study patient

Questions	Yes	No	Do not know	Score for this case
Are there previous conclusive reports on this reaction?	+1	0	0	+1
Did adverse event appear after the suspected drug was given?	+2	−1	0	+2
Did the adverse reaction improve when the drug was discontinued or a specific antagonist was given?	+1	0	0	+1
Did the adverse reaction appear when the drug was read ministered?	+2	−1	0	0
Are there alternative causes that could have caused the reaction?	−1	+2	0	+2
Did the reaction reappear when a placebo was given?	−1	+1	0	0
Was the drug detected in any body fluid in toxic concentrations	+1	0	0	0
Was the reaction more severe when the dose was increased or less severe when the dose was decreased?	+1	0	0	0
Did the patient have a similar reaction to the same or similar drugs in any previous exposure?	+1	0	0	0
Was the adverse event confirmed by any objective evidence?	+1	0	0	+1
Total score				7

Discussion

Olanzapine, an atypical antipsychotic, produces its therapeutic effects by antagonizing both serotonin and dopamine receptors, reaching optimal antipsychotic efficacy at a D₂ receptor blockade of 60%–70%, typically achieved with doses around 10 mg per day. However, doses exceeding this threshold, blocking up to 80% of D₂ receptors, may lead to EPSs. Olanzapine’s impact on serotonin contributes to the reduction of negative symptoms in schizophrenia, such as lack of pleasure in activities, diminished emotional expression, limited speech, reduced motivation, and difficulty maintaining focus. Still, taking it can lead to some serious side effects, like uncontrollable movements, muscle stiffness, a rare but dangerous reaction called neuroleptic malignant syndrome, and constant restlessness.[7]

Olanzapine’s lower risk of side effects compared to first-generation antipsychotics is attributed to its decreased affinity and rapid dissociation from D₂ receptors. Samidorphan, which blocks μ-opioid receptors, has been approved to help reduce weight gain linked to the use of olanzapine. Despite its relatively low rate of EPS, higher doses, particularly ≥7.5 mg, may still result in this side effect, reaching statistical significance at doses of 12.5 mg.[8]

Disulfiram, commonly used in alcohol dependence treatment, is hypothesized to induce mania through the dopamine hypothesis. Disulfiram inhibits dopamine-beta-hydroxylase, which converts dopamine to noradrenaline, leading to increased dopamine levels associated with psychotic and manic symptoms. Clinicians encountering patients with a dual diagnosis should be vigilant for the potential of disulfiram-induced mania, altering the management approach accordingly. While disulfiram generally has a tolerable safety profile, it can still cause side effects and interact with other medications, some of which may be severe or even fatal. Common but less serious side effects include headaches, drowsiness, tiredness, and an unusual taste in the mouth, often described as metallic or unpleasant breath odor. Serious psychiatric effects are extremely rare but have been documented. These may involve symptoms such as psychosis, confusion, mutism, head-banging behaviors, memory loss, and, in rare instances, stupor. Typically, these issues subside once the medication is stopped and short-term antipsychotic treatment is provided.[9]

Conclusions

This case report illustrates a patient developing EPS and mania following the initiation of an olanzapine and disulfiram regimen. The temporal relationship between olanzapine introduction and EPS, with significant symptom improvement upon withdrawal, supports the hypothesis of olanzapine as the cause of EPS and disulfiram as the cause of mania. The presentation underscores the importance of careful dose escalation, systematic monitoring, and periodic examination to prevent adverse drug reactions. This emphasizes the significance of a tailored and vigilant approach to medication management in complex cases involving dual diagnoses. The clinical presentation, extensive observation, and meticulous examination played crucial roles in establishing these diagnoses. The timely detection and management of both EPS through discontinuing olanzapine and switching to a different antipsychotic may lower the risk of EPS. For disulfiram-induced mania, the first step is the immediate discontinuation of disulfiram to prevent further episodes and treat the patient with mood stabilizers is essential to control manic symptoms. Supportive care, including psychiatric evaluation, further monitoring, and possible adjustments to the patient’s substance use treatment plan, are also necessary. The key to successful treatment in such cases lies in early recognition, appropriate pharmacological interventions, and ongoing monitoring to mitigate risks and ensure the best possible outcome for the patient.

Declaration of patient consent

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

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.