Clomipramine

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.

The weight gain associated with mirtazapine may be due to its activity at histamine receptors.9 In a long-term continuation of a trial of acute treatment, patients continued treatment with mirtazapine, amitriptyline, or placebo for up to two years.10 Weight gain was more common with amitriptyline (22%) than mirtazapine (13%) patients, but significantly more mirtazapine than placebo patients experienced weight gain. In a four-week study of healthy subjects, those treated with mirtazapine experienced a significant increase in body weight from baseline (mean increase 3.64 lb.), suggesting that the weight gain caused by mirtazapine is independent of the weight changes associated with recovering depression.11 This trial also quantified the changes in total cholesterol, LDL and triglycerides associated with mirtazapine treatment.11 After four weeks of therapy, mirtazapine-treated subjects experienced a significant increase in total cholesterol (mean increase 7.6 mg/dL) and nonsignificant increases in LDL and triglyceride levels compared to baseline, while no significant changes were noted in placebo-treated patients. Among treated patients, weight increase was linearly associated with increasing total cholesterol. The results of this short-term trial suggest that weight and cholesterol changes associated with mirtazapine occur independent of depression recovery.

A small, open-label trial compared the effects of mirtazapine and venlafaxine on weight.12 During the four weeks of treatment, mirtazapine-treated patients experienced a mean weight gain of 2.4 kg while venlafaxine-treated patients had a mean loss of 0.4 kg. A twelve-week trial did not detect weight change with either venlafaxine- or fluoxerine-treated patients.13 In another trial, weight changes in elderly patients treated with venlafaxine or citalopram for six months were not clinically significant.14 More research is needed to clarify the effects of venlafaxine on weight, although the agent is most likely not associated with significant weight gain or loss.

Bupropion is generally associated with weight loss. In an eight-week trial comparing sustained release (SR) bupropion 150-400 mg/day to sertraline 50-200 mg/day, bupropion patients experienced a mean 1.06 kg decrease in weight from baseline to endpoint compared with 0.79 kg decrease for sertraline and a 0.21 kg increase for placebo; these differences were not statistically significant.15 During an eight-week placebo-controlled trial, bupropion SR 300 mg/day and 400 mg/day caused weight loss greater than 5 pounds in 14% and 19% of patients, respectively, compared with 6% of placebo patients. Weight loss of greater than 10 pounds occurred in 2%, 6% and 2% of bupropion 300 mg, 400 mg and placebo patients.2

DISCUSSION

Because of the difficulty separating the effects of antidepressant medications from the effects of depression, the true effects of SSRI and non-SSRI antidepressants on weight have yet to be completely understood. In general, SSRIs and other newer antidepressants have a more favorable metabolic profile than TCAs or MAOIs. Among SSRIs, paroxetine is associated with weight gain early in therapy but the long-term effects are undear. Fluoxetine may cause short-term weight loss that resolves with continued treatment. Other SSRIs are either weight-neutral or the effects have yet to be determined. Nefazodone appears less likely to cause weight gain dun SSRIs. Bupropion is often associated with weight loss while mirtazapine is associated with weight gain and the effects of venlafaxine remain unclear.

Several factors predict the development of weight gain with antidepressants. Combination therapy with multiple antidepressants or an antidepressant and concomitant antipsychotic may increase the risk of weight gain, but the adverse effects may counter each other (e.g., bupropion and an SSRI).2 Patients with appetite suppression or altered eating habits caused by depression are more likely to experience weight change upon treatment. The relationship between higher daily dose and risk of weight gain has not been evaluated.

When selecting an antidepressant, the clinician must balance the risk of weight change with the potential benefits of treatment. Slight increases in weight upon initial treatment may resolve with continued therapy, but significant weight change may decrease medication compliance.

REFERENCES

1. Cantu TG, Korek JS. Monoamine oxidase inhibitors and weight gain. Drug Intell Clin Pharm 1988;22:755-79.

2. Fava M. Weight gain and antidepressants. J Clin Psychiatry 2000;61 (suppl 1):37-41.

3. Harvey BH, Bouwer CD. Neuropharmacology of paradoxic weight gain with selective serotonin reuptake inhibitors. Clin Neuropharmacol 2000;23:90-7.

4. Vaswani M, Linda FK, Ramesh S. Role of selective serotonin reuptake inhibitors in psychiatric disorders. Prog Neuropsychopharmacol Biol Pychiatry 2003;27:85-102.

5. Maina G, Albert U, Salvi V, Bogetto F. Weight gain during long-term treatment of obsessive-compulsive disorder. J Clin Psychiatry 2004;65:1365-1371.

6. Fava M, Judge R, Hoog SL, Nilsson ME, Koke SC. Fluoxetine versus sertraline and paroxetine in major depressive disorder. J Clin Psychiatry 2000;61:863-7.

7. Michelson D, Amsterdam JD, Quitkin FM, Reimherr FW, Rosenbaum JF, et al. Changes in weight during a 1-year trial of fluoxetine. Am J Psychiatry 1999;156:1170-6.

8. Sussman N, Ginsberg DL, Bikoff J. Effects of nefazodone on body weight. J Clin Psychiatry 2001;62:256-260.

9. Stimmel GL. Mirtazapine: an antidepressant with noradrenergic and specific serotonergic effects. Phamacotherapy 1997;17:10-21.

10. Montogmery SA, Reimitz PE, Zivkov M. Mirtazapine versus amitriptyline in the long-term treatment of depression. Int Clin Psychopharmacol 1998;13:63-73.

11. Nicholas LM, Ford AL, Esposito SM, Ekstrom RD, Golden RN. The effects of mirtazapine on plasma lipid profiles in healthy subjects. J Clin Psychiatry 2003;64:883-9.

12. Kraus T, Haack M, et al. Body weight, the tumor necrosis factor system, and leptin production during treatment with mirtazapine or venlafaxine. Pharmacopsychiatry 2002;35:220-5.

13. Silverstone PH, Ravindran A. Once-daily venlafaxine extended release compared with fluoxetine in outpatients with depression and anxiety. J Clin Psychiatry 1999;60:22-8.

14. Allard P, Gram L, et al. J. Efficacy and tolerability of venlafaxine in geriatric outpatients with major depression. Int J Geriatr Psychiatry 2004;19:1123-30.

15. Croft H, Settle E, et al. A placebo-controlled comparison of the antidepressant efficacy and effects on sexual functioning of sustained-release bupropion and sertraline. Clin Ther 1999;21:643-58.

SARAH GRACE KACHUR, PHARMD, CHRISTINE L. HANNAN, PHARMD, AND KRISTINA E. WARD, PHARMD

At time of writing, Sarah Grace Kachur and Christine Hannan were Doctor of Pharmacy students at the University of Rhode bland College of Pharmacy.

Sarah Grace Kachur, PharmD, is a clinical pharmacist at Advanced Pharmacy Concepts in North Kingstown, RI.

Christine Hannan, PharmD, is a pharmacy practice resident at Palmetto Health Richland in Columbia, SC.

Kristina E. Ward, PharmD, is Director, Drug Information Services and Clinical Assistant Professor at the University of Rhode Island College of Pharmacy.

CORRESPONDENCE:

Sarah G. Kachur, PharmD

Advanced Pharmacy Concepts

1130 Ten Rod Rd.

Bldg D Suite 206

North Kingstown, RI 02852

E-mail: skachur@apc-rx.com

Copyright Rhode Island Medical Society Oct 2005
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