|April 2001||Letters to the Editor|
Accelerated Weight Loss After Treating Refractory Depression With Fluoxetine Plus Topiramate: Possible Mechanisms of Action?
Because most of the psychotropic drugs increase appetite and can cause weight gain, the pharmacological management of obese patients with psychiatric disorders remains a challenge. We present a case of psychopharmaco-tailored and patient-centred management of an obese patient with refractory depression (body mass index [BMI]: weight [89 kg] / height [1.6m2] = 34.8). A 42-year-old woman with a 26-year history of chronic recurrent depressive episodes presented with a past partial or unsatisfactory response to various antidepressant drug treatments and combination or augmentation strategies. These included the tricyclic antidepressants (TCAs) imipramine and clomipramine; also used were paroxetine, sertraline, moclobemide, phenelzine, lithium, T3, psychotherapy, and typical antipsychotics (thioridazine and pimozide). It is, however, very important to note that she did not comply with some of these treatments: because she noticed weight gain, she did not agree to dose increases and also discontinued medications before reaching an optimum dose, although at certain periods in her life, clinical improvement appeared to be partially satisfactory.
She was commenced on fluoxetine because this selective serotonin reuptake inhibitor (SSRI) is reported to decrease appetite and can cause weight loss (1,2). Her initial 17-item Hamilton Depression Rating Scale (HDRS) score was 34. Fluoxetine was initiated at a dose of 20 mg daily, which was gradually increased over 8 weeks to the maximum tolerated dose of 50 mg daily. There was minimum weight loss (1.5 kg) over this time, and the clinical improvement (depressive psychopathology) was mild (HDRS score, 27).
Therefore, we decided to augment fluoxetine with topiramate, for the following 3 reasons: topiramate is a potential mood stabilizer with a possible antidepressant efficacy (3); there is no potential pharmacokinetic interaction between topiramate and fluoxetine, because they are metabolized via different liver CYP-450 enzymes (1,4); and the obesity remained a medical problem that possibly contributed to the patient’s depression, while topiramate has a desirable side effect of weight loss, even for weight gain induced by psychotropic drugs (4). The patient was commenced on topiramate 25 mg at bedtime, and the dose was gradually increased up to 250 mg daily to response over 14 weeks. There was significant improvement of depressive psychopathology at week 14 (HDRS score, 8). It is interesting to note that the clear and significant improvement of depressive psychopathology coincided with significant reduction in the patient’s weight at week 14 (weight loss was gradual, with a total loss of 30 kg and a new weight of 59 kg). She reported no significant change in eating pattern and habits or in food consumption. She did not feel tired or fatigued but, rather, more energetic and active, and she started exercising to maintain the weight loss. Reported side effects included mild hand tremor, sedation, and nausea.
The precise mechanism of action of the antidepressant efficacy of fluoxetine plus topiramate and the mechanism of action of the accelerated augmentation of the weight loss remain unclear. However, fluoxetine appears to decrease appetite and weight, which may be related to its actions on 5-HT2C receptors (5). It is possible that topiramate may directly or indirectly (via first or second messenger systems) augment 5-HT2C receptor function and further contribute to weight loss. Unfortunately, a Medline search failed to yield any data on the serotonin-receptor–binding profile of topiramate that would confirm our hypothesis. It is also possible that dopamine, noradrenaline, or glutamate systems may be involved in the accelerated weight-loss mechanism of action observed with this combination.
Such a combination may nevertheless be considered in a sequential way for patients with refractory depression who have a BMI of over 30 or who are clinically judged to be at a risk of developing medical disorders due to obesity. Because this is a case report, the outcome cannot be generalized until further confirmatory controlled studies have been conducted.
1. Edwards JG,
Anderson I. Systematic review and guide to selection of selective serotonin
re-uptake inhibitors. Drugs 1999;57:507–33.
SM Dursun MD, PhD, FRCPC