Paradoxical Agitation in Adolescent Male on Valproate

To the Editor:

Valproate is widely used in the management of mixed and manic states of bipolar disorder, pediatric epilepsy, and migraine headache (Erol et al.). Valproate has no approved United States Food and Drug Administration (FDA) indications for use in children and adolescents, although it is often used off label in the treatment of impulsive aggression and irritability in this population (Kavoussi and Cocarro 1998). Although valproate is used in the management of these illnesses, there is one report of an adult patient who developed agitation during treatment with valproate. We describe a paradoxical reaction in an adolescent boy with new-onset mood symptoms, who developed agitation and aggression directly related to the use of valproate.

Case Report

Mr. J, a 17-year-old male with no past psychiatric history, was hospitalized for disorganized thinking and speech and paranoia. The patient had been spending most of the day in bed and had not attended school for 2 years. More recently, he had not been attending to activities of daily living (ADLs), was refusing to leave the house, and believed that people were watching his home. Laboratory reports, neuroimaging, and physical examination were unremarkable, and he had no family history of psychiatric disorders. His intelligence quotient was 87.

Mr. J was treated with increasing doses of quetiapine over 4 weeks, reaching a total daily dose of 600 mg. During this time, Mr. J's disorganized thought processes and speech and paranoia steadily improved, but he remained irritable. Valproate 250 mg was started and titrated up to 1000 mg daily over a 2 week period reaching a plasma level of 88 μg/mL. While on valproate, Mr. J's irritability worsened with new episodes of aggressive behavior, which included posturing toward staff and threatening peers. His sensorium remained clear and there were no other signs of delirium. Ammonia, chemistries, and liver function tests were within normal ranges.

Concern that valproate might have worsened Mr. J's irritability and agitation led to tapering and discontinuation of valproate. Following the taper and washout of valproate, Mr. J's aggression and agitation resolved. On discharge Mr. J was calm and cooperative with organized thought process.

Discussion

This is the second reported case of valproate being associated with a new onset of agitation and aggression in a patient being treated for a mood disorder and the first in a pediatric patient. Among adult patients with psychiatric disorders, Sobhan et al. reported the case of a 39-year-old man with schizoaffective disorder who exhibited increasing agitation and aggression associated with the use of valproate (Sobhan et al 2001). This patient had steadily worsening aggression as the valproate was increased to a maximum dose of 2500 mg daily, with a blood level of 79 μg/mL, which resolved with discontinuation of the medication. Mood stabilizers reduce affective lability and thus may decrease irritability and aggression (Barzman et al. 2005). A double-blind, placebo-controlled crossover study demonstrated that divalproex reduced impulsive aggression as well as mood lability in youth 10–18 years of age (Donovan et al 2000). Further, divalproex was associated with overall diminution in aggressive symptoms and overall improvement in global functioning in youth with impulsive aggression (Barzman et al. 2005).

Although rare, there have been case reports citing unexpected reactions to valproate in the treatment of patients with epilepsy. In a study of 88 pediatric patients being treated for epilepsy with valproate, the most common behavioral symptoms were irritability and changes in sleep. Of these 88 subjects, 56 (63.6%) showed behavioral changes (Herranz et al. 1982). Bellman also reported a 14-year-old boy who became psychotic after being placed on valproate for treatment of complex tonic clonic seizures (Bellman and Ross 1977).

The cause of paradoxical reactions to valproate is not understood. One hypothesis is that this effect may be linked to the drug's effect on the γ-aminobutyric acid (GABA) system. Potentiation of GABA neurotransmission has been linked to delirium, hyperactivity, and other abnormal behavioral reactions.

There are several limitations that must be considered. The first of these is inherent in the case report method; the association noted may be coincidental. Second, rechallenging the patient on valproate would have strengthened the argument that valproate caused paradoxical agitation in this patient. However, because of clinical circumstances, this was not feasible.

Conclusions

In conclusion, this is the first report of valproate being associated with new onset of irritability and aggression in an adolescent with a primary psychiatric disorder. Valproate is a commonly used treatment in the management of pediatric mood disorders. Paradoxical agitation may be a rare side effect of valproate, and should be considered when new onset or worsening of agitation occurs during its use.