Neuropharmacology of paradoxic weight gain with selective serotonin reuptake inhibitors.

It has been suggested that weight gain associated with tricyclic antidepressants (TCA) reflect actions on dopamine (DA) and histamine receptors. However, a definitive cause is purely assumptive given the nonselective pharmacology of these agents. The selective serotonin reuptake inhibitors (SSRIs), as well as agents like dexfenfluramine (DFF), have emphasized the pivotal role of serotonin (5HT) in reducing carbohydrate (CHO) intake, and have provided a more selective tool with which to study appetite regulation. It would be expected that all SSRIs should exert a similar anorectic action. However, recent reports provide evidence to the contrary. Despite their claimed selectivity, SSRIs still interact, either directly or indirectly, with various critical neurotransmitter systems. In addition, although the anorectic action of fluoxetine (FLX) is well recognized, long-term follow-up studies in depressed patients and in obese nondepressed patients reveal that its weight-reducing effects are transient, even leading to a gain in body weight. Similarly, paroxetine (PRX) and citalopram (CTP) have also been associated with weight gain. These latter observations are unexpected because PRX and CTP are highly potent and selective SSRIs. A neuropharmacologic rationale for the apparent paradoxic effects of SSRIs on appetite not a review of neuronal regulation of appetite is presented in this article. As with the regulation of feeding, paradoxic weight gain observed with SSRIs appears to rest on the interaction of 5HT with multiple mechanisms, with the extent of weight gain observed being dependent on subtle, yet important pharmacologic differences within the group. Finally, the neurobiology of depressive illness itself, and of recovery from it, is a major contributing factor to individual response to these drugs.

Phasic craving for carbohydrate observed with citalopram.

The serotonin selective reuptake inhibitors (SSRIs) have clinically and ancedotally been associated with nausea and weight loss as a side effect of their action. The tricyclic antidepressants have been linked to carbohydrate (CHO) craving and weight gain in patients with major depressive disorders. This side effect has been attributed to the strong anti-histaminergic actions of these agents and is recognized as a causal factor of non-compliance in a substantial percentage of patients. CHO craving is an important feature and complication of the treatment of depression and is often ignored. A total of 18 patients were treated with the SSRI citalopram in our mood disorder clinic. In eight cases there was a significant increase in CHO craving together with weight gain shortly after initiation of treatment. The craving for CHO took on a phasic presentation. These cases are presented, together with data on the change in mood and anxiety symptom rating scales. Our observations appear paradoxical, given that serotonin (5-HT) typically mediates a reduction in CHO intake and that citalopram displays potent and select 5-HT-enchancing actions. However, the receptor binding profile of citalopram may predict a risk for inducing this adverse event. These, together with serotonergic, dopaminergic, histaminergic and other possible mechanisms are discussed. A profound influence on patient acceptability was observed, suggesting that the impact on compliance needs to be considered.