In adults, the efficacy of paroxetine for depression is comparable to that of older tricyclic antidepressants, with fewer side effects and lower toxicity. Differences with newer antidepressants are subtler and mostly confined to side effects. It shares the common side effects and contraindications of other SSRIs, with high rates of nausea, somnolence, and sexual side effects. Unlike two other popular SSRI antidepressants, fluoxetine and sertraline, paroxetine is associated with clinically significant weight gain. Pediatric trials of paroxetine for depression did not demonstrate statistical efficacy better than placebo and showed an increase in the risk of harmful outcomes, including episodes of self-harm and suicidal thoughts.

Discontinuing paroxetine is associated with a high risk of withdrawal syndrome. Due to the increased risk of birth defects, pregnant women or women planning to become pregnant are recommended to consult with their physician.