As previously discussed, mirtazapine can be more sedating at lower doses. Mirtazapine has a high affinity for the H1 (histamine) receptor. This histamine blockade is thought to increase appetite and sedation. Weight gain with mirtazapine can be advantageous or a negative for some patients. One may ask, does weight gain follow a similar dose-dependent effect?
Unfortunately, mirtazapine works in many mechanisms and weight gain associated with its use is thought to be due to more than its antihistaminergic effects. It is thought that mirtazapine causes an activation of the TNF- cytokine system. One study conducted in Germany found a significant increase in weight gain, plasma TNF concentrations, and serum leptin levels. This is also seen in prior studies of patients taking clozapine. In general, plasma TNF-levels and circulating soluble TNF receptors are found to be positively correlated with body weight and can be seen in significantly higher levels in obese individuals.
Leptin levels appear to have a different relationship with bodyweight in humans than in animals. Animals with leptin deficiency are often found to be severely obese. However, in obese individuals, leptin levels are often increased and there is thought to be leptin resistance. When compared to venlafaxine, mirtazapine led to more weight gain and increased plasma concentrations of TNF and leptin. Venlafaxine did not cause a significant increase in weight, and some patients lost weight. Plasma levels of TNF and leptin remained unchanged in patients receiving venlafaxine.
While more research needs to be done to determine the exact trigger of the TNF-cytokine system activation in patients being treated with mirtazapine, it is unlikely that weight gain associated with mirtazapine is an adverse effect that is dose-dependent or will go away over time with continued use.
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