The Dual Advantage of Allopurinol in a Patient With Severe Mania and Gout

The intricate interplay between purine, uric acid, and manic symptoms was explored by Emil Kraepelin, who particularly emphasized the association between hyperuricemia and gout.¹ This case report contributes to evidence supporting the therapeutic effectiveness of allopurinol in managing a complex clinical presentation involving comorbid mania, hyperuricemia, and gout.

Case Report

A 21-year-old man presented to a tertiary care neuropsychiatry facility, having previously experienced 1 episode of mania in 2019. A recurrence of mania occurred after a 4-month planned cessation of psychotropics following 2 years of recovery. The reinitiation of treatment with olanzapine, valproate, and a subsequent trial with a combination of risperidone, trihexyphenidyl, clonazepam, and haloperidol had proved ineffective. Despite these interventions, the patient exhibited only minimal improvement, with persistent aggression, mania, and psychotic symptoms causing significant dysfunction. Incidentally, he was concurrently being treated for hyperuricemia with febuxostat, but the serum uric acid levels remained elevated at 9.2 mg/dL. Physical examination revealed obesity (body mass index of 33.5 kg/m²), and laboratory investigations revealed hypertriglyceridemia (serum triglyceride level of 289 mg/dL) alongside normal thyroid function. Mental status examination indicated dysphoric mood, delusions of grandiosity, poor judgment, and absent insight.

In response to the lack of improvement, allopurinol was initiated at a dose of 200 mg/d and cross tapered with febuxostat due to the additional advantages of allopurinol in managing aggression and mania symptoms. Haloperidol was discontinued. The dose of risperidone was continued at 8 mg/d, while clonazepam was continued with a plan to taper and stop it after 1 month.

Over the subsequent week, the patient reported significant improvement, as evidenced by a 68% reduction in the Young Mania Rating Scale² score (from 22 to 7), a decrease in the Clinical Global Impressions (CGI)-Severity³ score from 5 to 3, and an improvement in the CGI Improvement score from 3 (minimally improved) to 2 (much improved). Objective assessments using the Modified Overt Aggression Scale⁴ showed a reduction from 4 to 0 within 1 week. Serum uric acid levels normalized (2.90 mg/dL) with the administration of allopurinol at 200 mg/d. At 3-month follow-up, the patient remained euthymic, with no residual manic or psychotic symptoms.

Discussion

Increased uric acid level denotes excess purine turnover and diminished adenosinergic transmission.⁵  Adenosine acts as a neuromodulator by acting on A1 and A2A receptors. Adenosine agonists have sedative, anticonvulsant, antiaggressive, and antipsychotic-like effects.⁶

Studies by Machado-Vieira et al⁷ and Akhondzadeh et al⁸ have reported the effectiveness of allopurinol in controlling refractory mania, with randomized, placebo-controlled trials demonstrating reduced symptom severity scores and a lower incidence of extrapyramidal symptoms in the allopurinol group compared to placebo. The underlying mechanism lies in allopurinol’s impact on purinergic neurotransmission, an increasingly implicated factor in mood disorders.^9,10 Adenosine agonists, such as allopurinol, indirectly influence dopamine binding in the ventral striatum and ameliorate manic symptoms. Allopurinol achieves this by inhibiting xanthine oxidase, the enzyme responsible for uric acid production, elevating brain adenosine levels.

This case report from India provides evidence supporting the successful integration of allopurinol in the treatment of mania, particularly in cases with comorbid gout. Allopurinol as an adjunctive therapy may offer other unique advantages in managing comorbid conditions such as hyperuricemia, extrapyramidal sensitivity, aggression, or treatment resistant mania. However, careful patient selection is imperative, and despite promising results, allopurinol still needs to be considered a first-line treatment due to the limited evidence from robust randomized trials. The potential for future research in this field is promising, and allopurinol may emerge as a promising therapeutic modality.

Article Information

Published Online: August 1, 2024. https://doi.org/10.4088/PCC.24cr03713
© 2024 Physicians Postgraduate Press, Inc.
Prim Care Companion CNS Disord 2024;26(4):24cr03713
Submitted: January 27, 2024; accepted April 9, 2024.
To Cite: Suhas S, Das D, Kumar CN. The dual advantage of allopurinol in a patient with severe mania and gout. Prim Care Companion CNS Disord. 2024;26(4):24cr03713.
Author Affiliation: Department of Psychiatry, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India (all authors).
Corresponding Author: Channaveerachari N. Kumar, MD, DPM, Department of Psychiatry, National Institute of Mental Health and Neurosciences (NIMHANS), Hosur Rd, Bengaluru 560029, India (cnkumar1974@gmail.com).
Relevant Financial Relationships: None.
Funding/Support: None.
Patient Consent: Consent was received from the patient to publish the case report, and information has been de identified to protect patient anonymity.