Valproate-induced hyperammonemia: A case report

INTRODUCTION

Valproate is a commonly prescribed drug for conditions such as epilepsy, bipolar affective disorder (BAD), and prophylaxis for migraine. As an anticonvulsant and mood stabilizer, it is generally well tolerated but can produce a variety of adverse effects, including gastrointestinal upset, increased appetite, weight gain, tremors, pancreatitis, and, infrequently, valproate-induced hyperammonemia (VIH).¹ VIH may occur in individuals with normal liver function, even at therapeutic doses and serum levels of valproate.^2,3 Most cases are asymptomatic or present with non-specific neuropsychiatric symptoms, often leading to underdiagnosis. Symptoms can range from mild cognitive disturbances to severe neurological impairment that can be life-threatening. In psychiatric practice, valproate-induced delirium may be mistaken for psychosis or worsening of mania, which can lead to a delay in diagnosis and management.^4,5 Recognizing the possibility of hyperammonemia and initiating prompt evaluation are key to preventing morbidity.

CASE REPORT

A 58-year-old male, known case of BAD with a total duration of illness of 20 years, with multiple manic as well as depressive episodes in the past, presented during a manic phase to our facility for the past 7 days following poor treatment compliance. The episode was characterized by decreased need for sleep, irritability, overtalkativeness, grandiosity, and absconding behavior. Upon admission, he was initiated on Tab. sodium valproate (1500 mg/day) (as per weight, re-initiated for rapid control of aggression), Tab. risperidone (4 mg/day), Tab. lorazepam (6 mg/day), all in divided doses along with Tab. trihexyphenidyl (2 mg/day).

On day 2, he developed increased irritability, restlessness, disorientation, slurred speech, and ataxia. Therefore, all psychotropics were stopped. Serum ammonia and valproate levels were sent, suspecting VIH.

Laboratory investigations revealed a markedly elevated serum ammonia level of 140 μmol/L and a subtherapeutic serum valproate level of 33.73 μg/mL, measured on day 3 of admission, 24 hours after valproate discontinuation. Liver enzymes and renal function were within normal range, and the Magnetic Resonance Imaging (MRI) Brain was unremarkable, ruling out any structural brain lesion.

Supportive treatment in the form of lactulose (30 mL) night dose and L-carnitine (200 mg) twice daily supplementation was given for 2 weeks.

The patient showed significant clinical improvement within 72 hours of cessation of valproate. Improvement in cognitive functions was assessed by Mini Mental State Examination. One week later, with re-emergence of manic symptoms, valproate was reintroduced at a reduced dose of 500 mg/day, under strict clinical vigilance, which was gradually built up to 1200 mg on an outpatient basis with serum valproate level monitoring. The Young Mania Rating Scale was applied to monitor manic symptoms. Frequent serum ammonia level monitoring could not be performed due to resource constraints, but rechallenge was successful. Currently, the patient is stable on 1200 mg valproate. Objective scales for adverse drug reactions, though not applied initially, could be considered for future follow-ups.

DISCUSSION

Several mechanisms have been proposed for VIH. One possibility is that propionate, a metabolite of valproate, lowers hepatic levels of N-acetyl glutamate, which is essential for activating carbamoyl phosphate synthetase I (CPS I). Reduced CPS I activity interferes with the urea cycle, impairing the normal disposal of ammonia and leading to its build-up in the blood.⁵

Another proposed pathway involves depletion of hepatic carnitine stores by valproate. Carnitine deficiency hampers the beta-oxidation of fatty acids, which in turn reduces the production of acetyl-CoA. Since acetyl-CoA is required for proper urea cycle function, its reduction can also contribute to hyperammonemia.⁵ Additional hypotheses include stimulation of mitochondrial glutamine transport by valproate, causing the kidneys to take up more glutamate and release more ammonia, as well as reduced uptake of glutamate by astrocytes, which may result in neuronal damage and cerebral swelling.^5,6 Furthermore, deficiency of ornithine transcarbamylase enzyme is the most common inherited cause of hyperammonemia, and valproate therapy can worsen the pre-existing hyperammonemia in such cases.^5,7

Clinicians need to be vigilant and consider hyperammonemia in all patients with worsening of mental status after receiving valproate, as it may be misdiagnosed as deterioration in psychiatric state, especially in patients with mood disorders.

Antipsychotics and benzodiazepines can also cause or worsen delirium, especially at higher doses and longer-acting antipsychotics, due to their anticholinergic action and cardiovascular effects.⁸ However, in this case, a strong temporal link between symptom onset and valproate initiation, along with normal liver function, biochemical confirmation of hyperammonemia, and rapid reversal upon drug cessation, strongly supports the diagnosis of VIH.

Management includes immediate cessation of valproate, which is the foremost and critical step. L-carnitine and lactulose have been recommended as adjunctive treatments. L-carnitine supplementation helps restore depleted carnitine stores, promotes mitochondrial β-oxidation of fatty acids, and reduces the build-up of toxic valproate metabolites.⁸ Lactulose is also commonly used, particularly in cases with significant encephalopathy. It acidifies the contents of the colon, converting ammonia (NH₃) into ammonium (NH₄⁺), which is less readily absorbed. This process also creates an osmotic effect that increases bowel movements, aiding in the removal of ammonia from the body.⁹

While earlier studies recommend discontinuation as the mainstay of treatment,^4,5 emerging evidence indicates that rechallenge may be feasible in selected patients.^1,10 Review of literature suggests a variety of rechallenge regimens, including 200 mg two times a day, titrated up to 500 mg two times a day; 1000 mg daily, titrated up to 750 mg two times a day; and a 2750 mg divided dose (1250 mg in the morning, 1500 mg at bedtime).^1,10 In this case, reintroducing valproate at a lower dose with close monitoring was both effective and safe.

Notably, the challenges faced in the case were a non-specific symptom presentation in the background of normal liver function tests and serum valproate levels, along with the difficulties faced in monitoring ammonia levels repeatedly in a resource-limited setting.

CONCLUSION

Hyperammonemia should be considered in valproate-treated patients presenting with delirium or altered mental status. One should not misdiagnose this condition as a worsening psychiatric condition. Serum ammonia, in addition to liver and kidney function tests, should be assessed. Early identification and discontinuation of valproate can result in rapid clinical recovery. Rechallenge with valproate at lower doses, with close monitoring, can be successful and safe in selected patients.