04. The Potential Procognitive Effects of Modafinil in Major Depressive Disorder:A Systematic Review

Text version

Let’s look at an article with a very tempting title, although the results are disappointing and yet interesting. So, the title, “The Potential Procognitive Effects of Modafinil in Major Depressive Disorder: A Systemic Review.” It turns out that there were not enough studies for a good meta-analysis on this topic. However, the authors provided us a useful literature review, first of all, antidepressant effects on cognition in major depression. Vortioxetine even has an FDA indication for this. When I saw that, I thought that it was going to be a niche in order to market because of the competition with the serotonergic antidepressant tight market. However, most of the authors of the papers submitted to the FDA were working for the manufacturer. Between that and the fact that it is not better than others, I dismissed vortioxetine in this role.

Then, duloxetine has 2 studies that show an improvement in cognitive function. Maybe duloxetine was being considered for an FDA indication. However, the authors of 1 of the articles on this subject were employed by Eli Lilly. The other article, by Dr. Herrera-Guzman and colleagues, was not associated with the industry. They found that duloxetine and other SSRIs were equivalent on attention and executive function. So, no advantage of duloxetine in this study that was not industry connected. Then, there is desvenlafaxine, which has an open trial but no control group. Lastly, bupropion and escitalopram in another study were both associated with equal improvement in cognition. In general, it looks like anything that is an effective treatment for depression is likely to improve cognition as well.

What about stimulants for depression as monotherapy? Roger McIntyre and colleagues reviewed it and found that, sure enough, there are supportive data for dextroamphetamine, methylphenidate, and lisdexamfetamine. However, overall, they found the studies were of poor quality, and they said we should leave the question open about whether stimulants can be useful as monotherapy for depression. Moreover, do not forget the FDA caution: One should not combine lisdexamfetamine with SSRIs or SNRIs due to an increased risk of serotonin syndrome.

Modafinil has multiple studies showing efficacy as monotherapy for depression, but the problem is that side effects are frequent. Thirty-four percent of patients, for example, got a headache in trials for narcolepsy. Ten to 30 percent got insomnia in trials for major depression, and 10% had nausea. So, it is not an unmitigated panacea. I would not think of using it instead of an antidepressant in major depression, for example, although one could consider it. Since modafinil improves cognitive performance in nondepressed subjects, you might be thinking of trying it yourself. Things like reaction time, reasoning, attention, learning, planning, decision making all have shown benefit from modafinil in nondepressed subjects.

This brings us finally back to the authors of the review, this new review that found not enough data for meta-analysis. So, they wondered, could the cognitive benefits show up when modafinil was used in major depression? Furthermore, they found the evidence too scant to conclude anything.

In summary, there are a few studies on modafinil’s effect on cognition and depression, but not enough to do a meta-analysis. Nevertheless, I hope this little literature review was useful. Overall, it reminds us that modafinil has a potential role in the treatment of depression, either as an adjunct or as monotherapy. That is literature we are not examining directly here, but we should be aware of it.

Abstract

The Potential Procognitive Effects of Modafinil in Major Depressive Disorder: A Systematic Review

Sophie R Vaccarino, Shane J McInerney, Sidney H Kennedy, Venkat Bhat

Objective: To assess the efficacy of modafinil, a wakefulness-promoting drug, in major depressive disorder (MDD), with a specific focus on the putative procognitive effects of modafinil.

Data sources: A database search of MEDLINE, PsycINFO, and Embase was conducted. No date limits were applied (the end date of the search was October 26, 2018), and only articles in English were included. The following search terms were used: modafinil, depression, depress*, major depressive disorder, cognition, cognitive dysfunction, and cogniti*.

Study selection: Studies included were placebo-controlled or open-label trials of modafinil in MDD populations. Participants had to be diagnosed with MDD via DSM-IV or DSM-5 criteria, and no other interventions other than standard antidepressant treatment could be used in the trial. Overall, 540 articles were screened, 22 full-text research articles for inclusion criteria were assessed, and 12 studies were included in this review.

Data extraction: Two independent reviewers extracted data and assessed the quality of publications.

Results: Modafinil was associated with improvements in executive functioning after 4 weeks of open-label adjunctive treatment in currently depressed participants. Furthermore, in a placebo-controlled study of remitted MDD participants, modafinil led to rapid improvements in episodic and working memory after a single dose. There were contradictory findings on the subjective effects of modafinil on concentration.

Conclusions: Modafinil shows preliminary evidence of alleviating specific cognitive symptoms in MDD patients, especially in the short term. However, more research using placebo-controlled longitudinal designs is needed to assess the benefits of modafinil, as there are very few studies addressing modafinil and cognition in MDD.

Reference

Vaccarino, S. R., McInerney, S. J., Kennedy, S. H., & Bhat, V. (2019). The Potential Procognitive Effects of Modafinil in Major Depressive Disorder: A Systematic Review. The Journal of Clinical Psychiatry, 80(6).