Weight Issues with Depression and Antidepressant Medications
Primary Psychiatry. 2005;12(10):19-20
Dr. Clayton is professor of psychiatric medicine at the University of Virginia in Charlottesville.
Disclosure: Dr. Clayton is a consultant to and on the advisory boards of Boehringer-Ingelheim, Eli Lilly, GlaxoSmithKline, Pfizer, Vela, and Wyeth; is on the speaker’s bureaus of and receives honorarium from Eli Lilly, GlaxoSmithKline, Pfizer, and Wyeth; and receives grants and/or research support from Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Forest, GlaxoSmithKline, Neuronetics, Pfizer, and Wyeth.
Many psychiatric illnesses are associated with changes in weight. For example, major depressive disorder can be associated with decreased appetite and resultant weight loss, or increased appetite and subsequent weight gain. In addition, many of the medications used to treat these disorders (as well as others) are also associated with changes in weight. Many patients require the use of multiple medications to achieve remission; however, combination therapy may contribute to greater weight gain. Among women, weight gain is the most undesirable medication side effect and often leads to medication non-adherence or discontinuation.1 Additional harmful effects of weight gain include negative health consequences, issues of self-esteem, and reduced quality of life.
In women with depression, weight gain that continues despite response to antidepressant therapy may represent either a residual symptom of depression or a side effect of the antidepressant medication. The reverse may also be a problem, as excessive weight gain itself may lead to depression in women. Rates of weight-related adverse effects appear to be fairly consistent within antidepressant classes, but vary across classes of antidepressants.
Possible explanations for weight gain with antidepressants include an effect of recovery from the depression, stimulation of appetite, a metabolic effect, or a reduction in motor activity with the therapeutic effect on depression or anxiety.2 The most likely mechanisms of weight gain with the antidepressants are antagonism of the serotonin-2C, histamine-1, or dopamine-2 receptors; affects on leptin; and/or increased prolactin levels.2 Indirect inhibition of dopamine neurotransmission via serotonergic stimulation may also lead to increased appetite.
Antidepressants and Weight Change
The assessment of weight changes in the context of depression can be complicated, as depressive symptoms typically involve mood, motivation, appetite, and activity level.2 Studies do not provide the definitive information patients and physicians want, as the design of medication trials generally is not adequate to demonstrate clinical significance. In addition to limited trial duration, other considerations include lack of placebo controls, absence of data analysis to account for baseline body mass index (BMI), failure to control for concomitant use of weight-affecting agents, and limited analysis of mean changes in weight versus percentage of patients with a change of ≥7% from baseline body weight (considered clinically significant). For example, in short-term depression trials (generally 8–12 weeks), all selective serotonin reuptake inhibitors (SSRIs) are typically weight neutral, or associated with modest weight loss. However, long-term use of SSRIs (1 year) is reported to be associated with weight gain (15% to 20%),3,4 although in some controlled studies, the change is comparable to placebo.5 Weight changes with the serotonin norepinephrine reuptake inhibitors appear similar. One explanation is that a comparable percentage of patients in long-term treatment gain weight as lose weight, leading to the appearance of weight neutrality. However, for the women who gain ≥7% of their baseline body weight, this is a negative outcome. The issue of baseline BMI may also affect the percentage of women gaining ≥7% of their baseline body weight; patients who begin a trial underweight may be more likely to demonstrate an increase in body weight, as fewer actual/absolute pounds must be gained in this group to meet the weight gain criteria than in those who enter a trial overweight.
Mirtazapine has been associated with the opposite pattern; potential weight gain in the acute treatment period (18%),6 without significant further increase in long-term treatment (Table). Thirteen percent of subjects receiving mirtazapine gained weight in a 20-week continuation phase. This weight gain was more than those on placebo, but less than with amitriptyline (22%).7 Younger women appear to be at greatest risk for weight gain with mirtazapine.6 Bupropion is associated with short-term weight loss, which is maintained in the long term. This weight loss differs significantly from placebo at 1 year of treatment.8 Nefazodone does not differ from placebo (9% and 11% respectively) in the percentage of patients who experience clinically significant effects on mean body weight (≥7% increase) in long-term treatment studies as compared to the tricyclic antidepressant (TCA), imipramine (25%) or SSRIs (18%).3 Monoamine oxidase inhibitors also appear to be associated with significant weight gain.9 However, the worst offenders are the TCAs,10 with immediate onset of weight gain at a rate of 1.3–2.9 lbs/month over the course of 6 months.11
Consider weight concerns with the initiation of therapy, as medication non-compliance secondary to weight gain is common. Monitor weight at baseline and throughout treatment, but do not rely on patient self report. Treat to remission in order to rule out weight gain as a residual symptom of depression. Once weight gain is identified, early intervention can limit the negative effect. Keep in mind that some medications can increase appetite, such as TCAs, SSRIs (after 3 months), and mirtazapine, so restriction of intake despite an increase in appetite can limit weight gain. Early behavioral interventions of caloric restriction (including alcohol) and increased exercise may be helpful with the medications that contribute to early weight gain. Nutrition/dietary referral may aid some patients. Evaluation for other medical or psychiatric conditions, or concomitant medication effects (eg, hypothyroidism, eating disorders, antipsychotic medications) that may affect weight is important. Changing to another antidepressant less likely to cause weight gain may also be of benefit, and may be necessary to ensure patient adherence to treatment. Although no medication is approved to limit or counteract the effects of antidepressants on weight, purported antidotes for weight gain include bupropion,12 psychostimulants,13 topiramate,14 and thyroid supplementation,15 generally requiring higher doses for an anorexic effect. The primary effect noticed with these added medications is that of appetite suppression. If weight gain develops, associated with response after treatment resistance, monitoring of general health concerns is important. Lipids, cardiovascular status, and glucose metabolism should be routinely followed. For most patients, remission of depressive symptoms, overall good health, and quality of life are possible. PP
1. Jamerson B, Ashton AK, Houser RL, et al. Antidepressant compliance and side effects: results from a patient survey. Poster presented at: The 154th Annual Meeting of the American Psychiatric Association; May 2001; New Orleans, LA.
2. Sussman N, Ginsberg D. Rethinking side effects of the selective serotonin reuptake inhibitors: sexual dysfunction and weight gain. Psychiatr Ann. 1998;28(2):89-97.
3. Mackle M, Kocsis J. Effects on body weight of the SSRI citalopram. Poster presented at: The 37th Annual Meeting of the American College of Neuropsychopharmacology; December 1998; Las Croabas, Puerto Rico.
4. Sussman N, Ginsberg D. Weight effects of nefazodone, bupropion, mirtazapine, and venlafaxine: a review of available evidence. Primary Psychiatry. 2000;7(5):33-48.
5. Stahl SM. Placebo-controlled comparison of the selective serotonin reuptake inhibitors citalopram and sertraline. Biol Psychiatry. 2000;48(9):894-901.
6. Thase ME, Nierenberg AA, Keller MB, Panagides J; Relapse Prevention Study Group. Efficacy of mirtazapine for prevention of depressive relapse: a placebo-controlled double-blind trial of recently remitted high-risk patients. J Clin Psychiatry. 2001;62(10):782-788.
7. Montgomery SA, Reimitz, Zivkov M. Mirtazapine versus amitriptyline in the long-term treatment of depression: a double-blind placebo-controlled study. Int Clin Psychopharmacol. 1998;13(2):63-73.
8. Croft H, Houser TL, Jamerson BD. Effect on body weight of bupropion sustained-release in patients with major depression treated for 52 weeks. Clin Ther. 2002;24(4):662-672. Erratum in: Clin Ther. 2002;24(9):1481.
9. Rabkin J, Quitkin F, Harrison W, Tricamo E, McGrath P. Adverse reactions to monamine oxidase inhibitors. Part I. A comparative study. J Clin Psychopharmacol. 1984;4(5):270-278.
10. Fava M. Weight gain and antidepressants. J Clin Psychiatry. 2000;61(suppl 11):37-41.
11. Berken GH, Weinstein DO, Stern WC. Weight gain. A side-effect of tricyclic antidepressants. J Affect Disord. 1984;7(2):133-138.
12. Jain AK, Kaplan RA, Gadde KM, et al. Bupropion SR vs. placebo for weight loss in obese patients with depressive symptoms. Obes Res. 2002;10(10):1049-1056.
13. Ryan DH. Use of sibutramine and other noradrenergic and serotonergic drugs in the management of obesity. Endocrine. 2000;13(2):193-199.
14. Teter CJ, Early JJ, Gibbs CM. Treatment of affective disorder and obesity with topiramate. Ann Pharmacother. 2000;34(11):1262-1265.
15. Krotkiewski M. Thyroid hormones and treatment of obesity. Int J Obes Relat Metab Disord. 2000;23(suppl 2):S116-S11