Valproic acid (VPA) is a mood stabilizer widely used for bipolar disorder and behavioral dysregulation that is commonly associated with hyponatremia. Hyperkalemia, however, has been reported only once in association with its use.¹ We present the case of a young man with bradycardia and Jacobs syndrome, in which a clear, dose-dependent relationship between VPA and hyperkalemia was observed. This finding is clinically relevant, as hyperkalemia may exacerbate conduction abnormalities in patients with cardiac conditions.²

Case Report

A 24-year-old man with intellectual developmental disorder in the context of Jacobs syndrome presented with episodes of aggression, impulsivity, irritability, and low frustration tolerance. His medical history was notable for sinus bradycardia, with no other relevant comorbidities. In September 2024, while taking VPA 1,500 mg/d, quetiapine 100 mg/d, diazepam 20 mg/d, and pregabalin 225 mg/d, his routine laboratory testing revealed a normal potassium level of 4.5 mmol/L with otherwise unremarkable results.

Due to worsening behavioral symptoms through the end of the year, his treatment was adjusted to VPA 2,000 mg/d, quetiapine 300 mg/d, diazepam 30 mg/d, and pregabalin 225 mg/d, resulting in clinical improvement. In January 2025, routine laboratory testing showed a potassium level of 5.6 mmol/L (above the hospital laboratory reference limit of 5.1 mmol/L) and no abnormalities in other parameters, namely complete blood count, renal function, glucose, creatine kinase, and uric acid. There was no evidence of hemolysis of the sample, dietary changes including foods with high potassium content, trauma, excessive exercise, new medications, or supplements. He remained asymptomatic, with a normal electrocardiogram.

Given the potential cardiac risk posed by hyperkalemia in a patient with baseline bradycardia, VPA was reduced to 1,500 mg/d. His potassium level was rechecked after 1 month, according to outpatient laboratory availability, and normalized at 4.9 mmol/L. However, behavioral deterioration led to psychiatric reassessment, and VPA was increased again to 2,000 mg/d, with maintenance of the remaining treatment. Subsequent testing showed an increase of his potassium level to 5.3 mmol/L, once more with no other laboratory or clinical abnormalities. Following this result, VPA was reduced to 1,750 mg/d, and cariprazine 3 mg/d was introduced to the medication regimen, resulting in clinical improvement and normalization of potassium to 4.3 mmol/L. This level remained stable at 4.4 mmol/L 4 months later.

Discussion

This is, to our knowledge, the second published case linking VPA to hyperkalemia and the first demonstrating a reproducible, dose-dependent relationship. Other potential causes of hyperkalemia, such as potassium-raising drugs, renal dysfunction, hemolysis, leukocytosis, thrombocytosis, diabetes, muscle injury, or dietary history for potassium intake or supplements, were excluded.³

The underlying mechanism remains unclear, with previous hypotheses suggesting impaired renal potassium excretion due to decreased mineralocorticoid function or abnormal tubular potassium reabsorption induced by VPA.^1,4 Regardless, this association carries clinical significance, particularly for patients with baseline cardiac conditions. In this case, although the patient remained asymptomatic with normal electrocardiogram findings, the potential for exacerbation of his arrhythmia justified dose adjustment.

Clinicians should consider monitoring serum potassium levels in patients treated with VPA, especially those with preexisting cardiac conditions. Awareness of this rare but potentially life-threatening adverse effect is crucial for safe long-term management. Further investigation is needed to elucidate the pathophysiological mechanisms underlying VPA-induced hyperkalemia.

Article Information

Published Online: April 9, 2026. https://doi.org/10.4088/PCC.25cr04124
© 2026 Physicians Postgraduate Press, Inc.
Prim Care Companion CNS Disord 2026;28(2):25cr04124
Submitted: October 29, 2025; accepted December 30, 2025.
To Cite: Silva FS, Braz IS. Dose-dependent valproic acid–induced hyperkalemia. Prim Care Companion CNS Disord. 2026;28(2):25cr04124.
Author Affiliations: Department of Psychiatry, Unidade Local de Saúde de Santa Maria, Lisbon, Portugal (Silva, Braz).
Corresponding Author: Francisco S. Silva, MD, Serviço de Psiquiatria e Saúde Mental, Piso 4, Unidade Local de Saúde Santa Maria–Avenida Professor Egas Moniz, 1649-035 Lisbon, Portugal ([email protected]).
Patient Consent: Informed consent was obtained from the patient for publication of this case report, and information, including dates, has been de-identified to protect patient anonymity.
ORCID: Francisco S. Silva: https://orcid.org/0000-0001-7943-4562; Inês S. Braz: https://orcid.org/0000-0001-6289-3324