ADVANCES IN PHARMACOLOGY: ANTIDEPRESSANT-INDUCED WEIGHT GAIN

Medicine and Health Rhode Island, Oct 2005 by Kachur, Sarah Grace, Hannan, Christine L, Ward, Kristina E

Weight gain is a common concern when treating patients with antidepressant medications. The actual effects of antidepressant medications on weight are difficult to quantify because depression is often characterized by changes in appetite, energy and physical activity. The propensity of an antidepressant medication to induce weight gain may be due in part to its neuropharmacologic effects; however, the mechanism for weight gain caused by antidepressants cannot be fully explained. Changes in weight vary between classes of antidepressants, and between agents within each class.

Weight gain is a frequent adverse effect of tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs). The antidepressant action of MAOIs results from the irreversible inhibition of two monoamine oxidase enzyme isoforms, MAO-A and MAO-B. Serotonin and epinephrine have a high affinity for the MAO-A isoenzyme, while dopamine, telemethylhistamine, and phenylethylamine have a high affinity for the MAO-B isoenzyme. Of the MAOIs, phenelzine has been most associated with weight gain; however, this conclusion is based primarily on case reports.1 Another MAOI, tranylcypromine, may cause weight loss due to structural similarities to amphetamines.1

TCAs inhibit neurotransmitter re-uptake at several sites, including serotonin, adrenergic and histamine receptors. The nonselective pharmacologic actions of TCAs are the likely cause of carbohydrate cravings, increased appetite, and alterations in the regulation of body fat stores.2,3 Although all TCAs are associated with weight gain, amitriptyline is associated with a higher likelihood of weight gain than other agents within the class.1,2

Selective serotonin reuptake inhibitors (SSRIs) have a more selective and potent effect on serotonin than the less selective activity of TCAs. However, the mechanism of antidepressant action is not entirely understood and is due to effects other than the reuptake of serotonin at the neurosynapse. 4 An increase in serotonin availabiliy should decrease carbohydrate intake and reduce cravings,3 but this effect is unpredictable and poorly documented. Slight pharmacological differences between SSRIs result in varying affinities for serotonin, histamine and dopamine receptors, further complicating the association between SSRIs and weight. In clinical trials, SSRIs have been associated with both weight gain and weight loss.

COMPARATIVE WEIGHT CHANGES BETWEEN SSRIs

The largest trial prospectively comparing the metabolic effects of SSRIs was conducted by Maina et al.5 Patients with obsessive-compulsive disorder were randomized to treatment with clomipramine, citalopram, fluoxetine, fluvoxamine, paroxetine or sertraline for 2.5 years. Over the course of the trial, mean body weight increased by 1.58 kg (2.5%) compared to baseline, with 14.5% of patients experiencing significant weight gain (increase of 7% or more from baseline). Patients in the clomipramine group experienced the highest mean percentage weight increase (4.86%) and the highest proportion of significant weight gain (34.8%); this is consistent with the known adverse effects of TCAs. Fluoxetine patients experienced initial weight loss, and were the only treatment group to not experience significant weight gain over the course of the trial. The lowest proportions of patients experiencing significant weight gain were 8.7% and 4.5%, in the fluoxetine and sertraline groups, respectively. Trial results are summarized in the table below.

In another prospective trial evaluating long-term weight change, depressed patients were randomized to fluoxetine, sertraline, or paroxetine for 26 to 32 weeks.6 There was a small mean decrease in weight (0.2%) among fluoxetine patients and a small mean increase in weight (1.0%) among sertraline patients; neither change was statistically significant. Paroxetine-treated patients experienced a significant increase in weight compared with baseline (3.6%). From baseline to endpoint, 25.5%, 6.8% and 42% of paroxetine, fluoxetine and sertraline patients, respectively, experienced 7% or greater weight gain (P = 0.016 paroxetine vs fluoxetine, P = 0.003 paroxetine vs sertraline).

When fluoxetine was compared to placebo for the prevention of relapse after acute treatment of depression, fluoxetine was associated with significantly more weight gain than placebo over one year.7 After twelve weeks of acute treatment, fluoxetine was associated with slight weight loss (mean -0.35 kg, P

Newer, non-SSRI antidepressants have variable effects on weight. A pooled analysis of trials comparing nefazodone to SSRIs demonstrated that nefazodone is associated with fewer instances of significant (≥ 7%) weight loss in the acute phase (6-8 weeks) of treatment.8 During the long-term treatment phase (16-44 weeks), fewer nefazodone than SSRI patients experienced significant (≥ 7%) weight gain (8.3% vs. 17.9%, P = 0.003 for any point during treatment and 6.9% vs. 13.8%, P = 0.007 at endpoint). There was no difference between groups in the incidence of significant weight loss (≥ 7%) during long-term treatment. Fewer instances of weight loss during the acute phase and weight gain during long-term therapy suggest that nefazodone causes less weight variability than SSRIs.