Atypical antidepressants, including bupropion (Wellbutrin), mirtazapine (Remeron), nefazodone (Serzone), trazodone (Desyrel), and vilazodone (Viibryd), offer unique mechanisms of action. Bupropion weakly inhibits dopamine and norepinephrine reuptake, aiding depression treatment and smoking cessation, with a low risk of sexual dysfunction. Mirtazapine enhances serotonin and norepinephrine neurotransmission, leading to sedation, increased appetite, and weight gain. As a result, it helps treat major depressive disorder, particularly in patients with insomnia or poor appetite. Nefazodone and trazodone are weak serotonin reuptake inhibitors and sedating agents. Nefazodone is used for major depressive disorder, while trazodone is commonly used for treating insomnia. Vilazodone combines serotonin reuptake inhibition with 5-HT_1a receptor partial agonism, similar to SSRIs' adverse effect profile. It also helps treat major depressive disorder.
Monoamine oxidase inhibitors (MAOIs) such as phenelzine (Nardil) and selegiline (Emsam) inhibit monoamine oxidase, either irreversibly or reversibly, causing increased neurotransmitter accumulation. Due to dietary restrictions and drug interactions, they are last-line agents typically indicated for patients unresponsive or intolerant to other treatments. Adverse effects include hypertension from tyramine-containing foods, drowsiness, orthostatic hypotension, blurred vision, dry mouth, and constipation.

Serotonin-dopamine activity modulators (SDAMs) like aripiprazole (Abilify), brexpiprazole (Rexulti), dopamine type 2 (D2), and serotonin 2A (5HT_2A) receptor antagonists like quetiapine (Seroquel), and SSRIs such as fluoxetine-olanzapine combinations are adjuncts in major depressive disorder. Despite off-label use for major depression without psychotic features, they carry risks of weight gain and metabolic syndrome.
Other agents: Newer agents like vortioxetine (Trintellix) use a multi-modal approach. Vortioxetine inhibits 5-HT₃ and 5-HT₇ receptors and serotonin reuptake while being a 5-HT_1a agonist, resulting in nausea, constipation, and sexual dysfunction. It is classified as a serotonin modulator and treats major depressive disorder, particularly in patients with cognitive symptoms or inadequate response to SSRIs.
Combination strategies involving atypical antipsychotics with antidepressants are used for partially responsive patients, with the significant risks being weight gain and metabolic syndrome.