How to control weight gain when prescribing antidepressants

Causes of weight gain

Serotonin. Appetite is controlled by cultural, psychological, neurochemical, and metabolic factors. Among neurochemical factors, serotonin helps regulate appetite and is the neurotransmitter most often manipulated in depression treatment.

Serotonin receptor agonists such as fenfluramine and dexfenfluramine have an acute anorexigenic effect. In rats, 5-HT2c receptor agonism decreases eating behavior, and mice lacking 5-HT2c receptors are obese.²⁰ This may explain why SGAs or antidepressants that block 5-HT2c pose the greatest risk of weight gain.

SSRI or SNRI treatment might increase serotonin in the synaptic cleft, allowing 5-HT2c receptor down-regulation that is slower than—but similar in effect to—the acute 5-HT2c blockade caused by the SGAs.²¹ Weight gain from SSRI use reflects on these medications’ multiple serotonergic mechanisms. Serotonin appears to regulate carbohydrate intake and can increase food intake.²²

Nefazodone and trazodone block 5HT2a receptors potently, and the norepinephrine (nefazodone only) and serotonin reuptake pumps (both agents) less potently. Differences in their mechanism (nefazodone increases norepinephrine) and lack of 5-HT2c blockade might be responsible for their reported weight neutrality.

Tricyclics block differing ratios of norepinephrine and serotonin reuptake pumps, resulting in postsynaptic serotonergic and adrenergic receptor desensitization and, later, down-regulation. TCAs with higher serotonin reuptake blockade may increase weight through this desensitization.

TCAs also affect appetite by blocking histaminergic (H1) pathways. Drugs with high affinity for blocking H1 receptors have been associated with carbohydrate craving¹⁸ and low satiety rates that allow increased calorie intake. TCAs have antimuscarinic, antihistaminic, and alpha adrenoceptor-blocking actions, all of which may contribute to weight gain.

In theory, beta-3 adrenergic receptors in adipose tissue may play a role in weight control by converting fat into heat and energy, especially in response to norepinephrine. TCAs or SNRIs that favor a noradrenergic profile may promote weight loss or neutrality. The relatively weight-neutral selegiline patch, which avoids first-pass metabolism and active adverse metabolites, also may use this mechanism.²³

Mirtazapine blocks presynaptic alpha-2 and postsynaptic 5HT2a, 5HT2c, and 5HT₃ serotonin receptors as well as H1 histamine receptors. Both 5HT2c and H1 blockade result in weight gain, the drug’s most apparent adverse effect. This mechanism is similar to that of the SGA olanzapine.

TNF-α. Obese persons have increased plasma levels of TNF-α and its soluble receptor (sTNF-R p75), which may induce insulin resistance. Activation of the TNF-α system, such as by amitriptyline or mirtazapine, may promote weight gain.²⁴

Preventing weight gain

Early intervention is key to preventing drug-related weight gain and treating obesity. Provide informed consent and psychoeducation when prescribing antidepressants. In patients at metabolic risk, consider using weight-neutral or weight-loss agents (Table 2),^4-16 and monitor for weight gain (Table 3). At-risk patients have:

• abdominal obesity (waist circumference >40 inches [102 cm] in men, >35 inches [88 cm] in women, or waist-to-hip ratio >0.9 in women and >1.0 in men)
• hyperlipidemia
• elevated body mass index (BMI [overweight=BMI 25 to 30 kg/m², obesity=BMI >30 kg/m²])
• hypertension
• diabetes mellitus or impaired glucose tolerance
• history of stroke or cardiovascular disease
• family history of obesity, hypertension, diabetes, or hyperlipidemia.

Use SGA guidelines? Consider following modified American Diabetes Association guidelines for metabolic monitoring of patients treated with SGAs.²⁵ We suggest that you follow SGA guidelines as a default when using mirtazapine—which is pharmacodynamically the most similar to SGAs—and TCAs. For patients taking other antidepressants, we recommend that you:

• measure blood pressure and weight, and calculate BMI often
• instruct patients to weigh themselves at home at least weekly in the morning and to report gains >5 lbs.

An overall 10-lb weight gain is clinically significant in most patients and calls for a management plan. Abdominal girth often increases as part of metabolic syndrome. If you choose to measure this variable and are uncomfortable reaching around patients while measuring, allow patients to apply the tape measure themselves.

Lab tests. Obtain fasting glucose and lipid levels at baseline for most patients and then quarterly in those with initial weight gain, medical comorbidities, or family history of hypertension, hypercholesterolemia, or diabetes. Many clinicians also screen for hypothyroidism and anemia, and these tests may be added. For patients without metabolic risk factors taking SSRIs and SNRIs, start quarterly draws if weight increases rapidly by >5 lbs or if BMI approaches ≥30 kg/m². Tracking fasting triglycerides can serve as a sentinel for metabolic syndrome, which sometimes occurs before substantial weight gain or hyperglycemia.