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Pathologic rejection sensitivity is the most common feature of depression with atypical features. While monoamine oxidase inhibitors (MAOI) studies suggested that MAOIs might be useful first-line agents in treatment of depression with atypical features, dietary restrictions, high rates of side effects, such as weight gain and sexual dysfunction, and significant drug-drug interactions make MAOIs less attractive in practice. Hence, the advent of the more user-friendly selective serotonin reuptake inhibitors (SSRIs) had significant appeal. The literature is clear that phenelzine is a superior choice over imipramine for the treatment of depression with atypical features, particularly if onset is early and the course is very chronic. Prior to starting an MAOI, the patient must be educated about the content of and rationale for the tyramine-free diet and dangerous medications, such as SRIs and meperidine. The selegiline patch has the side effects of other MAOIs.