In contrast to mirtazapine, the selective serotonin reuptake inhibitors (SSRI), serotonin–norepinephrine reuptake inhibitors (SNRI), Monoamine oxidase inhibitors (MAOI), and some Tricyclic antidepressants (TCA) increase the general activity of the 5-HT2A, 5-HT2C, and 5-HT3 receptors leading to a host of negative changes and side effects, the most prominent of which including anorexia, insomnia, nausea, and diarrhea, among others. Its reduced incidence of sexual dysfunction (such as loss of libido and anorgasmia) could be a product of negligible binding to the serotonin transporter (as is generally the cause of sexual dysfunction with most SSRIs) and antagonism of the 5-HT2A receptors; however, Mirtazapines high affinity towards and inverse agonism of the 5-HT2C receptors may greatly attenuate those pro-sexual factors (as evidenced by the pro-sexual effects of drugs like m-CPP and Lorcaserin which agonize 5-HT2C receptors in a reasonably selective manner). As a result, it is often combined with these drugs to reduce their side-effect profile and to produce a stronger antidepressant effect.Mirtazapine does not have pro-serotonergic activity and thus does not cause serotonin syndrome. This is in accordance with the fact that it is not a serotonin reuptake inhibitor or monoamine oxidase inhibitor (MAOI), nor a serotonin receptor agonist. There are no reports of serotonin syndrome in association with mirtazapine alone, and mirtazapine has not been found to cause serotonin syndrome in overdose. However, there are a handful of case reports of serotonin syndrome occurring with mirtazapine in combination with serotonergic drugs like SSRIs, although such reports are very rare, and do not necessarily implicate mirtazapine as causative.
Side effects
A 2011 Cochrane review found that, compared with other antidepressants, it is more likely to cause weight gain and sleepiness, but it is less likely to cause tremor than tricyclic antidepressants, and less likely to cause nausea and sexual dysfunction than SSRIs.Very common (≥10% incidence) adverse effects include constipation, dry mouth, sleepiness, increased appetite (17%) and weight gain (>7% increase in <50% of children).Common (1–10% incidence) adverse effects include weakness, confusion, dizziness, fasciculations (muscle twitches), peripheral edema (swelling, usually of the lower limbs), and negative lab results like elevated transaminases, elevated serum triglycerides, and elevated total cholesterol.Mirtazapine is not considered to have a risk of many of the side effects often associated with other antidepressants like the SSRIs, and may actually improve certain ones when taken in conjunction with them. (Those adverse effects include decreased appetite, weight loss, insomnia, nausea and vomiting, diarrhoea, urinary retention, increased body temperature, excessive sweating, pupil dilation and sexual dysfunction.) In general, some antidepressants, especially selective serotonin reuptake inhibitors (SSRI), can paradoxically exacerbate some peoples depression or anxiety or cause suicidal ideation.