Among SSRIs and SNRIs, paroxetine might be one of the worst for provoking long-term weight gain; a study showed an average increase of 2.73 kg over a 4-month period.6
Theoretically, SNRIs have the ability to increase noradrenergic tone. This might be associated with nausea and a decline in appetite or it might generally curb appetite. These agents likely will cause less future weight gain. SNRIs typically induce more noradrenergic tone at increasingly higher dosages. There may be a dose-response curve in this manner. Levomilnacipran likely is the most noradrenergic of the SNRIs; recent regulatory studies suggest no statistically significant weight gain over the long term.7
Sedating antidepressants
Mirtazapine has receptor-blocking effects on noradrenergic α-2 and serotonergic 5-HT2a and 5-HT2c receptors. Additionally, histamine blocking of H1 receptors can contribute to additional weight gain, similar to what is seen with some SGAs. H1 antagonism dampens satiety response, resulting in increased caloric intake. In that case, or when specific SGAs are used for managing depression, appetite increases (H1 antagonism) and metabolism slows (possibly 5-HT2c antagonism, muscarinic receptor antagonism, etc.), thus allowing for greater adipose tissue growth and leptin insensitivity.
In a meta-analysis, mean weight increased by 1.74 kg (P < .0001) in the first 4 to 12 weeks of mirtazapine treatment, with greater variability in periods >4 months.6 Among the more novel antidepressants released since the era of tricyclic antidepressants (TCAs) or monoamine oxidase inhibitor, mirtazapine might have the greatest weight gain potential.
Trazodone and nefazodone block 5-HT2a and 5-HT2c receptors, as well as serotonin reuptake transporters. Compared with trazodone, nefazodone has a more potent effect on 5-HT2a receptor antagonism and a less potent effect on 5-HT2c receptors, and also mildly inhibits uptake of norepinephrine—meaning that this drug might have less weight gain potential. These medications are not used frequently for treating depression, but trazodone is used as an adjunctive agent for insomnia. Used even at off-label low dosages, trazodone exerts H1-histaminic and α-1 adrenergic antagonistic properties, decreasing the level of consciousness and allowing sedation and somnolence. Because of its fast onset and relatively short duration of action, it can improve depression symptoms by promoting restful sleep as well as by facilitating monoamine neurotransmission. It also might add to weight gain because of its pharmacodynamic receptor profile.
Tricyclic antidepressants
Amitriptyline can be associated with release of tumor necrosis factor-alpha, which is implicated in causing weight gain. Many TCAs block H1 (amitriptyline, imipramine, clomipramine), likely causing weight gain. Most TCAs antagonize muscarinic receptors as well. The more noradrenergic TCAs could curb appetite (nortriptyline, desipramine, protriptyline) similar to SNRIs, therefore countering some of the weight gain drive.
As an example, in a meta-analysis examining weight gain with antidepressants, amitriptyline was associated with weight gain of 1.52 kg above baseline in the acute period (4 to 12 weeks) and 2.24 kg above baseline at 4 to 7 months.6 These results of the acute phase should be viewed cautiously because the authors reported high heterogeneity among these studies, and the possibility of publication bias (Egger test, P < .0001). In the same meta-analysis, the even the more noradrenergic nortriptyline was associated with an increase of 2.0 kg on average over baseline during acute treatment, with that number dropping to 1.24 kg over baseline at ≥4 months.6
Newer antidepressants
Vilazodone is a weak SSRI that aggressively partially agonizes pre-synaptic and post-synaptic 5-HT1a receptors in the CNS. This dual site 5-HT1a action is somewhat unique among antidepressants. This type of agent sometimes is called multimodal,8 or could be considered an “SSRI +” antidepressant. These drugs are SSRIs at the core but have additional 5-HT receptor modulating capabilities. Vilazodone has a favorable weight gain profile, as suggested in a 52-week trial reporting 1.7 kg gain over 52 weeks, compared with an average of 6.8 to 10 kg for long-term SSRI therapy.9
Vortioxetine is a stronger SSRI that also partially agonizes presynaptic 5-HT1a receptors. In addition, it antagonizes 5-HT1d, 5-HT3, and 5-HT7 receptors, giving it a unique pharmacodynamic profile.10 Vortioxetine also had minimal impact on drug-induced weight gain in 52-week studies, with data from 2 trials indicating either minimal weight gain in 6.1% of patients (mean increase of 0.41 kg over 52 weeks)11 or gain that was not statistically significant.12
Levomilnacipran is unique in that it has the most aggressive norepinephrine reuptake inhibition of all SNRIs.13 Again, increased noradrenergic tone might curb appetite and caloric intake. Many SNRIs cause low-grade nausea, which could account for decreased appetite. Long-term, 52-week data for this drug also shows minimal proclivity for weight gain, with the trial participants reporting a slight decrease of 4.34 kg on average from baseline.14
Continue to: Addressing weight gain