Michael Posternak, MD.
Psychiatrist in private practice, Boston, MA
Dr. Posternak has disclosed that he has no relevant financial or other interests in any commercial companies pertaining to this educational activity.
You may have been hearing a lot of buzz about vortioxetine (Trintellix) and cognition. The FDA recently allowed a labeling change with this antidepressant that mentions specific benefits in cognitive symptoms of depression. Depressed patients tell us all the time how bad their memory is, and their concerns are valid. On average, depression impairs cognition to a similar degree as 24 hours of sleep deprivation (Mahableshwarkar AR et al, Neuropsychopharm 2016;41(2):2961).
Clearly, any antidepressant that improves cognition would be welcome. But we’ve seen other antidepressants that claim novel benefits, yet fail to offer anything unique upon closer scrutiny. So, does vortioxetine really help cognition, and if it does, is it any better than other antidepressants in this regard? Or is this nothing more than a marketing campaign seeking to carve out a new niche for vortioxetine in a crowded antidepressant field? To sort out these questions, we took a close look at the data.
Vortioxetine for depression Vortioxetine was approved by the FDA for depression in September 2013. Originally called Brintellix, its name was later changed to Trintellix to avoid confusion with the blood thinner, Brilinta.
For major depression, vortioxetine has established efficacy at daily dosages of 5 mg, 10 mg, and 20 mg in most, but not all, trials. It has also demonstrated efficacy in anxious and elderly patients. Impressively, vortioxetine outperformed the European antidepressant agomelatine in a large, double-blind switch study of patients who failed to respond to an SSRI (Montgomery SA et al, Hum Psychopharmacol 2014;29(5):470–482).
Vortioxetine is well-tolerated, with the most commonly reported side effects being nausea, headaches, and dizziness. There is no evidence of ECG changes, it does not seem to cause weight gain, and it may be associated with lower rates of sexual side effects than SSRIs, at least at doses of 5 mg or 10 mg (Jacobsen PL, CNS Spectr 2016;2(5):367–378).
OK, so far so good. What about the cognitive data?
Cognitive data Vortioxetine has a complex mechanism of action. It is a 5-HT3, 5-HT7, and 5-HT1D receptor antagonist, a 5-HT1B receptor partial antagonist, a 5-HT1A agonist, and an inhibitor of the 5-HT transporter. If that doesn’t scream “Cognitive enhancer!” to you, don’t worry: It doesn’t to anyone else, either. Lab researchers first noted vortioxetine’s cognitive-enhancing properties after testing the drug on rats. After this finding, Takeda Pharmaceuticals, the makers of vortioxetine, began to monitor cognition methodically in each of their antidepressant trials. More recently, it was discovered that vortioxetine induces neurogenesis in mice—which, if replicated, could go a long way toward explaining its putative cognitive benefits (Felice D et al, Front Pharmacol 2018;12(9):204).
Takeda didn’t have much precedent to work with, and they chose the Digit Symbol Substitution Test (DSST) as their primary assessment tool for cognition. The DSST has been around for over a century and is one of the most commonly used tests in neuropsychology. It measures attention, memory, and processing speed, all areas that are impacted by depression.
What exactly is the DSST? A picture is worth 1,000 words, and with one peek at the test you’ll understand exactly how it works. You have to match random symbols with digits as fast as you can. It takes about 2 minutes to administer in practice, and you can check it out at https://tinyurl.com/yc9oo62k. As a frame of reference for DSST performance, most depressed patients match 30 to 60 symbols correctly in 90 seconds (mean of 43). Mean scores in healthy adults are 70 in 20-somethings and 49 in those over age 60 (Hoyer WJ et al, Psychol Aging 2004;19(1):211–214).
The first evidence that vortioxetine improved cognition in humans came from a study of depressed, geriatric patients, all of whom were free of early signs of dementia. The mean age of the sample was just over 70 years. In this study, 453 subjects were randomized in a double-blind manner to vortioxetine 5 mg, duloxetine 60 mg, or placebo. Both medications treated depression, and both improved verbal learning memory compared to placebo, but only vortioxetine led to significant improvement on the DSST, which suggested that it may confer unique benefits in processing speed and executive function (Katona C et al, Int Clin Psychopharmacol 2012;27(4):215–223).
Following this, Takeda conducted a full-court press with a series of large-scale, placebo-controlled trials looking at vortioxetine’s effects on cognition. Results on the DSST were positive in 3 out of 5 randomized, controlled trials involving 1,813 depressed patients (Buane BT et al, Int J Neuropsychopharmacol 2018,21(2):97– 107). It consistently outperformed duloxetine, which was non-significantly better than placebo in terms of DSST results. In the negative studies, vortioxetine trended in a positive direction but ultimately failed to reach statistical significance, possibly because Takeda used a much smaller sample size than in the positive trials (Vieta E et al, J Affect Disord 2018;227:803–809).
All of those studies were industry-sponsored, but the methodologies were sound and there were no statistical manipulations that might have led to commercial bias. To their credit, Takeda chose to compare against duloxetine, which had the best cognitive data among antidepressants at the time.
Other antidepressants have not fared as well when run through the DSST. Those were, in order from the least to the most impairing class: SSRIs, MAOIs, and tricyclics. In 9 randomized, controlled trials conducted before the vortioxetine era, these antidepressants failed to improve or actually worsened cognition on this measure. Unfortunately, none of these studies evaluated bupropion, an antidepressant that also has favorable cognitive data (Gualtieri CG et al, MedGenMed 2007;9(1):22).
Could vortioxetine’s cognitive effects simply be due to its antidepressant benefits? Path analysis shows the two effects are independent. For example, one study found that 76% of vortioxetine’s cognitive benefits are independent of its antidepressant effects (Mahableshwarkar AR et al, J Clin Psychopharmacol 2015;76(5):583– 591). In contrast, the independence of duloxetine’s cognitive effects was estimated at 50%.
To give you a better sense of what vortioxetine’s cognitive benefits look like in real life, they’re about equal to a 50 mg dose of caffeine, or a shot of espresso. Caffeine improves the DSST performance in healthy volunteers with a medium effect size, about the same as the effect seen with vortioxetine in depressed patients (Jaeger J, J Clin Psychopharmacol 2018;38(5):513–519). Does that translate into functional improvement? The DSST is a strong predictor of functioning, but so far only one study has looked at this outcome, and it found a large effect for vortioxetine and a negligible one for duloxetine (Mahableshwarkar, 2016).
TCPR Verdict: Takeda Pharmaceuticals has set a new bar for antidepressant research by lining its antidepressant up against one with the best cognitive evidence to date, duloxetine, and rising above it. One key question remains: Will patients actually feel sharper on vortioxetine, and will it, for example, allow them to return to work sooner? Maybe that’s a lot to ask, but given its favorable side effect profile, lack of discontinuation syndrome, and clear cognitive benefits, vortioxetine has emerged as a reasonable first-line option for any depressed patient with cognitive complaints.