Switching to monotherapy after failure with a first antidepressant resulted in no significant difference in efficacy and tolerability among bupropion, sertraline, and venlafaxine. In treatment-resistant depression, augmentation of previous treatment with bupropion did not result in significant differences in remission compared with switching to bupropion monotherapy, augmentation with aripiprazole, or augmentation with buspirone. Switching to bupropion monotherapy or augmentation with bupropion was associated with significantly higher incidence of anxiety, decreased appetite, dry mouth, and increased blood pressure, but lower incidence of increased appetite, increased weight, somnolence, akathisia, and laboratory test abnormality compared to augmentation with aripiprazole. Augmentation therapy with bupropion or aripiprazole may be a cost-effective option relative to switching to bupropion in treatment-resistant depression. Among the monotherapies, switching to vortioxetine appeared to be the most cost-effective option relative to other medications such as agomelatine, bupropion, venlafaxine, or sertraline; bupropion, venlafaxine, and sertraline monotherapies were not significantly different from one another in terms of cost-effectiveness.