Richard G. Petty

Weight Loss with Topiramate

TO THE EDITOR: The novel anticonvulsant topiramate has demonstrated efficacy in the treatment of adults with epileptic disorders.1,2 Although systematic, controlled studies are yet to be reported, there is preliminary evidence that topiramate is an effective mood stabilizer3,4 and may also mitigate pathologic weight gain.4-6 This latter action may be of value in the management of weight gain induced by novel (atypical) antipsychotic agents.7,8 We report a patient whose significant weight gain during olanzapine therapy was normalized by topiramate. Case Report. A 32-year-old white woman (height 5’8”) with a 16-year history of Diagnostic and Statistical Manual of Mental Disorders, 4th edition9– defined schizoaffective disorder had experienced intermittent binge eating, with weight fluctuations of up to 9 kg, since age 20. A routine medical examination diagnosed mild hypothyroidism at age 28, which had been successfully treated with levothyroxine. The patient had persistently normal thyroid indices until initiation of treatment with olanzapine 20 mg/d at age 29. She had previously been treated with several antipsychotic agents, including clozapine, with only modest success. At the initiation of olanzapine, the patient weighed 63.6 kg, with a body mass index (BMI) of 21.3. Over the next three years, she gained 36 kg, without evidence of fluid retention. After olanzapine initiation, the patient reported a recurrence of binging episodes, primarily of carbohydrates, occurring each afternoon and at night. She received monthly counseling on the roles of diet and exercise in weight management; these interventions, however, proved ineffective. During the first year of olanzapine treatment, the woman gained an average of 1 kg per month (total 12.2 kg). This weight gain continued during the second year, with an average gain of 0.6 kg per month (total 6.8 kg). During the third year, the patient’s rate of weight gain increased to an average of 1.5 kg per month (total 17.3 kg). At 90.9 kg, she experienced decreased control of her hypothyroidism. As a result, her endocrinologist increased the levothyroxine dosage to maintain normal thyroid-stimulating hormone concentrations. Her final weight at the end of the three-year period was 100 kg, raising her BMI to 33.5. Despite good control of psychotic symptoms, the patient reported mood swings, depression, and subjective distress regarding her weight gain. In view of the clinical features, she was treated with topiramate for both mood stabilization and to aid in weight normalization. At topiramate initiation, the woman continued to be unable to implement any nonpharmacologic interventions to lose weight. Concomitant medications included olanzapine and levothyroxine, which remained at stable doses throughout the topiramate trial. Topiramate was initiated at 25 mg/d and titrated up to 150 mg/d within two weeks. Within the first four weeks of treatment with topiramate, the woman reported a dramatic decrease in binging episodes to two to four times per month, which remained at this frequency throughout treatment. The patient lost an average of 2.3 kg per week during the initial eight weeks of treatment. After 10 weeks, the topiramate dosage was decreased to 75 mg/d due to difficulty in concentration. She remained on this dosage for an additional 32 weeks and lost a total of 30.9 kg. Her weight loss reached a plateau at 32 weeks and remained unchanged from week 32 to week 42. She subsequently requested topiramate discontinuation. The patient experienced a significant reduction in mood swings, crying, and depression during topiramate treatment. After topiramate discontinuation, she initiated behavior modification efforts to maintain her weight loss, ostensibly because she now felt that it was realistic to maintain her reduced weight, in contrast to her previous feelings of hopelessness concerning weight management. The woman began to monitor her caloric intake, participated in aerobic exercise, and initiated behavior modification techniques (trigger avoidance, food substitution) to control her binge eating. Six months after topiramate discontinuation, she had maintained an average weight of 70.5 kg (BMI 23.6) while continuing to receive olanzapine 20 mg/d. Both her psychotic and mood symptoms remained under excellent control. Discussion. This case report provides preliminary evidence that may support a pharmacologic intervention for antipsychotic-induced weight gain in someone who was initially unwilling, or unable, to follow conventional diet strategies. Shapira et al.10 have hypothesized that topiramate’s antagonism of kainate/AMPA glutamate receptors subtypes may cause appetite suppression, leading to a reduction in binge-eating behavior, which is precisely what we observed. The patient tolerated topiramate for an extended period of time (>10 mo) achieving a steady, continued weight loss for 32 weeks. Controlled clinical trials are needed to determine the efficacy and safety of combining topiramate with antipsychotic agents.

Olanzapine: a 5-year perspective.

Olanzapine is a novel antipsychotic, approved for the acute and maintenance treatment of schizophrenia and bipolar I disorder. Despite the publicity regarding reported adverse events with the novel antipsychotics, such as weight gain and Type II diabetes mellitus, olanzapine remains a useful and important medicine. It is a selective monoaminergic antagonist with high-affinity binding to a number of receptors thought to be implicated in some psychotic and mood symptoms. The complex pharmacology of olanzapine has lead to studies exploring its use in treating substance abuse, aggression/violence, borderline personality disorder, schizotypal personality disorder, obsessive–compulsive disorder and as a neuroprotective agent in schizophrenia. As the pharmacology of olanzapine and other novel antipsychotics becomes better understood, future effective treatment strategies are likely to match an individual’s genetic makeup and receptor profiles to the most compatible agent.