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Randomized trials have shown that selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) have better safety profiles than classical tricyclic antidepressants (TCAs). However, an increasing number of studies, including meta-analyses, naturalistic studies, and longer-term studies suggested that SSRIs and SNRIs are no less safe than TCAs. We focused on comparing the common side effects of TCAs with those of newer generation antidepressants including SSRIs, SNRIs, mirtazapine, and bupropion. The main purpose was to investigate safety profile differences among drug classes rather than the individual antidepressants, so studies containing comparison data on drug groups were prioritized. In terms of safety after overdose, the common belief on newer generation antidepressants having fewer side effects than TCAs appears to be true. TCAs were also associated with higher drop-out rates, lower tolerability, and higher cardiac side-effects. However, evidence regarding side effects including dry mouth, gastrointestinal side effects, hepatotoxicity, seizure, and weight has been inconsistent, some studies demonstrated the superiority of SSRIs and SNRIs over TCAs, while others found the opposite. Some other side effects such as sexual dysfunction, bleeding, and hyponatremia were more prominent with either SSRIs or SNRIs.