Treatment-resistant bipolar disorder can be one of the most challenging conditions to manage. There is a need to develop more effective treatment strategies, including complex regimens of combination therapy. Clozapine has been used to treat bipolar disorder that has been nonresponsive to lithium and anticonvulsant therapy, but it appears to be less effective in treating the depressed phase of the illness (1). Lamotrigine has recently been shown to possess efficacy in the treatment of bipolar depression without increasing the rate of switching into mania (2, 3). We report here a case of a patient with bipolar I disorder who was partially responsive to lithium and divalproex whose treatment was augmented with lamotrigine and clozapine.
Mr. A, a 46-year-old man with bipolar I disorder, was referred for follow-up care after hospitalization for 7 months for treatment of mania accompanied by grandiose delusions. During hospitalization he was treated with 300 mg/day of quetiapine, 1200 mg/day of lithium (serum level=1.1 meq/liter), and 2000 mg/day of divalproex (serum level=65 μg/ml). He had previously been unresponsive to adequate trials of carbamazepine, fluoxetine, nortriptyline, amitriptyline, protriptyline, tranylcypromine, bupropion, methylphenidate, l-thyroxine, risperidone, olanzapine, and cognitive behavior psychodynamic psychotherapy. Since life charting suggested that Mr. A was due to cycle into severe depression, lamotrigine therapy was begun and titrated to 150 mg/day over 8 weeks. His depression disappeared after 21 days of treatment.
After a 5-day period of euthymia Mr. A cycled into mania, which led to the initiation of clozapine treatment, starting at 25 mg/day and gradually increasing to 450 mg/day. After augmentation of divalproex and lamotrigine therapy with clozapine, his mood stabilized. Lithium and quetiapine treatment were then gradually discontinued. Previous side effects, which included tremors, weight gain, and listlessness, subsided with the discontinuation of lithium. After 5 months of treatment Mr. A elected to decrease his dose of clozapine to 200 mg/day because of excessive daytime fatigue; he subsequently relapsed into a mild 2-month depression that disappeared after clozapine therapy was resumed. Adjunctive methylphenidate, 20 mg b.i.d., was used to manage his persistent fatigue. Despite the side effects of excessive salivation and daytime fatigue, he has tolerated the combination of divalproex, lamotrigine, and clozapine and remained without symptoms of mania for 7 months, after a 34-year history of periodic mania and a 10-year history of continuous circular cycling.
This case suggests that complex regimens of combination therapy can be safe and effective in the treatment of patients with complex, lifelong histories of treatment-resistant bipolar I disorder. The use of divalproex, lamotrigine, and clozapine in this patient was reasonably well tolerated. Controlled trials are needed to more definitely explore the safety and efficacy of combination therapy in the treatment of bipolar disorder.