Treatment of Comorbid Bipolar Disorder and Epilepsy With Valproate

SIR: We report the use of valproate monotherapy for the short- and long-term treatment of epilepsy comorbid with bipolar disorder.

Epilepsy and bipolar disorder are major public health problems in the United States, with estimates of lifetime prevalence ranging from 5.0% to 8.0% and 1.0% to 1.6%, respectively.^1,2 Epilepsy is associated with significant morbidity and mortality and is estimated to cost $1.8 billion/year in the United States.¹ Bipolar disorder is associated with a significant mortality risk; 11% of patients die by suicide.² To our knowledge, there are no reports regarding the treatment of comorbid bipolar disorder and epilepsy in the literature.

More than ever before, discoveries in the basic and clinical sciences are linking epilepsy and bipolar disorder. First, the kindling model of epileptogenesis³ has been applied to bipolar disorder to explain the progressive increase in illness severity and a shift from episodes caused by stress to spontaneous episodes.⁴ Second, many new anticonvulsants are being studied for treatment of bipolar disorder (e.g., valproate, carbamazepine, lamotrigine, gabapentin, topiramate, tiagabine, and vigabatrin). Patients with bipolar disorder are being managed by some neurologists, primary care physicians, and psychiatrists. Third, some patients have both epilepsy and a mood disorder. Although the prevalence of interictal bipolar disorder has not been formally assessed, clinical reports suggest a prevalence of bipolar disorder in patients with epilepsy between 0.1% and 4.3%.⁵ Fourth, anticonvulsants are often associated with cognitive and behavioral side effects.⁶

The standard mood stabilizer treatments for bipolar disorder include lithium, valproate, and carbamazepine. Valproate was found to be efficacious as lithium in a double-blind placebo-controlled randomized trial⁷ and is the newest mood stabilizer approved by the Food and Drug Administration for bipolar disorder. A recent report also suggests that anticonvulsants have broader overall efficacy than lithium, particularly for the following: patients with irritable rather than euphoric mania; patients having mania concurrent with depression (mixed); patients with manic episodes 4 or more times per year (rapid cycling); and patients with comorbid substance disorders.²

Case Reports

Patient 1. C.C. is a 56-year-old Caucasian woman with bipolar disorder for 5 years who was brought to the emergency room by family after a “seizure.” On physical examination, her vital signs were stable; she was alert and oriented to place, month, and day but not date; and a neurologic exam including fundoscopic examination was normal. Laboratory test results were unremarkable. Emergent MRI was unremarkable. During preparation for an EEG, she had a generalized tonic-clonic seizure and was started on intravenous phenobarbital and phenytoin. The EEG that was subsequently done revealed background slowing and no epileptogenic foci; the slowing was attributed to the phenobarbital and phenytoin. She was diagnosed by the neurologist (G.D.R.) with a complex partial seizure with secondary generalization on the basis of her clinical information, normal examination, and age of onset.⁸

Three days later she was seen by the neurologist because of severe agitation. She was not on a mood stabilizer, and recently she had had disorganized speech, difficulty answering questions, and agitation, and had made paranoid statements. Her agitation intensified even though she was seizure free at the time. The phenobarbital was discontinued to eliminate the chance it was causing behavioral side effects,⁶ and valproate (Depakote, Abbott Laboratories, North Chicago, IL) was initiated at 1,000 mg po tid for 1 day and then 1,000 mg po bid. Her agitation and other symptoms subsided. The phenytoin was discontinued during the hospitalization. She has remained stable for 12 months since discharge.

Patient 2. J.G. is a 49-year-old Caucasian woman with a 26-year history of bipolar disorder. She had been stable clinically on lithium 600 mg po bid long-term, but wished to discontinue it because of weight gain, slowed mentation, and hypothyroidism. Her other medications were levothyroxine for hypothyroidism and enalapril for hypertension. She suffered a generalized tonic seizure and was started on phenytoin 300 mg po daily. After a second seizure 1 week later despite a phenytoin level of 15, she was briefly hospitalized for a medical evaluation. On physical exam at the hospital, she was alert and oriented, with pressured speech, euphoric mood, and grandiose thoughts. Neurologic examination was normal. Laboratory (including thyroid-stimulating hormone), MRI, and EEG evaluations were unremarkable.

After discussion between her neurologist and psychiatrist (D.M.H.), the patient was started on valproate (Depakote) at 750 mg po bid (20 mg/kg per day) because of its favorable cognitive and behavioral side effects profile.⁶ On discharge, her diagnosis was generalized seizure disorder. On follow-up 1 week later, her mood symptoms had stabilized and she had had no seizure recurrence. Over the next 6 months, she remained stable on valproate, enalapril, and levothyroxine.

Comment

These case reports illustrate the successful management of comorbid epilepsy and bipolar disorder with valproate monotherapy. The favorable side effect profile of valproate facilitates short-term stabilization by rapid oral or intravenous loading.⁹ To our knowledge, there are no reports regarding the treatment of comorbid bipolar disorder and epilepsy in the literature. More systematic controlled trials in larger populations are needed to evaluate the efficacy, safety, and cost-effectiveness of valproate monotherapy for patients with comorbid epilepsy and bipolar disorder and to identify predictors of response.

The preparation of this manuscript was supported by an honorarium from Abbott Laboratories.