Key Takeaways
Extended Takeaways
- When selecting treatment for cognitive symptoms in major depressive disorder, prioritize evidence from placebo-controlled trials with objective cognitive endpoints, as many positive signals in this review came from small open-label studies and several cognitive gains were moderated by improvement in depressive severity.
- Vortioxetine showed the most consistent signal across studies, with 10 mg/d and 20 mg/d superior to placebo after 8 weeks in improving global cognition and the largest effects on the DSST (d = 0.51 for 10 mg and d = 0.52 for 20 mg), supporting its use when executive functioning, processing speed, or attention are prominent concerns.
- Functional improvement did not reliably track with medication choice alone: vortioxetine improved functional capacity in one 8-week trial (N = 508, P < .001) but not in 2 smaller studies, suggesting clinicians should monitor cognition and day-to-day functioning separately rather than assume one will normalize with the other.
- Among SNRIs and related agents, placebo-controlled support was strongest for levomilnacipran, which improved attention and reaction time over 8 weeks in severely depressed patients and appeared to work best in those with greater baseline cognitive impairment.
- Bupropion may be a practical option when memory and processing speed are the main targets, as 8 weeks of treatment improved memory measures in severe and moderate major depressive disorder samples and one randomized study linked change in immediate verbal memory to psychosocial functioning.
- Non-antidepressant augmentation remains exploratory but clinically interesting: lisdexamfetamine improved executive functioning without improving composite cognition, modafinil improved only one executive task after 4 weeks, erythropoietin improved recall and recognition memory over 8 weeks with effects maintained across 14 weeks, and intranasal insulin showed no cognitive benefit after 12 weeks.
