In terms of the meaningfulness of its pro-cognitive properties, a recent meta-analysis found that while vortioxetine improves performance in the DSST, it didn’t help patients on 3 other cognitive tests. These include the Stroop test (a measure of cognitive control), the TrailMaking Test B (executive function), and the Rey Auditory Verbal Learning Test (delayed recall) (Rosenblat JD et al, Int J Neuropsychopharmacol 2015;19(2).pii: pyv082.doi:10.1093/ijnp/pyv082). As a smart pill, vortioxetine’s effects seem limited to one specific test—which doesn’t improve our confidence in its efficacy.
Finally, are the cognitive benefits of vortioxetine—however modest they may be—a direct pro-cognitive effect? Or do they indirectly follow from vortioxetine’s role as an antidepressant, thus implying that it won’t perform better than any other treatment that eases depression? This question has not yet been fully answered, although one manufacturer-sponsored trial claims that the higher DSST scores were independent of its antidepressant effect (Mahableshwarkar AR et al, Neuropsychopharm 2015;40(8):2025–2037). Similar claims have also been made for duloxetine (Greer TL et al, Dep Res Treat 2014. Published online 2014 Jan 19. doi: 10.1155/2014/627863), but other antidepressants simply haven’t been studied for their cognitive benefits.
TCPR Verdict: Will Brintellix make your patients “Brintellectuals”? The FDA is skeptical, and so are we.
Ketamine is not FDA approved for depression, but rather for preoperative general anesthesia. And it doesn’t act on serotonin, norepinephrine, or dopamine; instead, it’s an antagonist of the NMDA subtype of the glutamate receptor. It has long had illicit popularity in the party and rave scene under the nickname “special K.” Of relevance to psychiatrists, ketamine has been touted as a potential fast-acting miracle antidepressant, and many clinicians are already offering it off-label to their patients in pop-up ketamine clinics. Should you jump on the ketamine bandwagon?
The ketamine antidepressant data
As of late 2015, nearly a dozen randomized clinical trials of intravenous ketamine for the treatment of depression had been published (DeWilde KE et al, Ann NY Acad Sci 2015;1345:47–58). These include some placebo-controlled trials, in addition to some open-label trials and a few trials with an active control (usually midazolam [Versed]). All showed, on average, a statistically significant response—defined as a 50% reduction in MADRS or Hamilton Rating Scale for Depression (HAM-D) symptom scores—within 24 hours. Response rates have ranged from 40% to 70%. Some studies used only a single dose, with an antidepressant effect lasting up to 72 hours (even longer in some studies), while others involved repeated IV administrations over 2 weeks. The typical ketamine dose was 0.5 mg/kg given over a 40-minute period—as opposed to the anesthetic dose, which ranges from 1.0–4.5 mg/kg IV usually given over one minute.
Other studies have found that single infusions reduce suicidal ideation at 4 and 24 hours post-infusion (Price RB et al, Biol Psychiatry 2009;66:522–526). Investigators are now trying to identify subgroups who are more likely to respond to ketamine. There aren’t enough data yet to predict response, but some potential positive indicators include a family history of alcoholism, comorbid anxiety, or an elevated body mass index (Niciu MJ et al, J Clin Psychiatry 2014;75:e417–423).
Ketamine in the office?
So if it provides such rapid relief to some people who have been refractory to other treatments, why hasn’t ketamine caught on? One major hurdle, of course, is the fact that it’s an intravenous medication, making it much more complicated to prescribe than a pill. Because of potential, though rare, side effects such as an acute hypertensive crisis, the IV infusion should take place in a medical office equipped with vital sign monitoring, airway equipment, oxygen, and a crash cart. Some even advise the presence of a trained anesthesiologist (Sisti D et al, Curr Psychiatry Rep 2014;16:527). These requirements likely explain the high outof-pocket costs (up to $500–$750 per infusion) for this off-label procedure at the handful of ketamine clinics that have popped up nationwide over the last few years. Other potential adverse effects, like an uncomfortable dissociative experience, as well as long-term cognitive impairment and the risk of diversion or recreational abuse of ketamine, must be considered.
Furthermore, no one really knows how long to provide the treatment. In the 2-week trials described above, which involved 6 infusions, relapse rates were as high as 55% to 89% in the month following treatment (Newport DJ et al, Am J Psychiatry 2015;172:950–966). No “maintenance” strategy has been described, and no other medications have been shown to extend ketamine’s antidepressant effect.
Finally, it’s still not clear that the standard 0.5 mg/kg intravenous dose is the “best” dose. This dose was chosen, in part, because it produces few side effects; these are typically transient dissociative symptoms (“I feel like I’m floating”) or hallucinations during the infusion. While these effects are short-lived, they have also been positively associated with a treatment response (Luckenbaugh DA et al, J Affect Disord 2014;159:56–61). Thus, dissociative effects may predict—or may even be responsible for—the antidepressant effect. If this is true, it may be hard to find a dose that minimizes unpleasant psychoactive effects while also producing a robust antidepressant effect. Then again, some practitioners are deliberately using higher doses of ketamine, sometimes in intramuscular or oral forms, in order to induce a psychedelic state, which they see as a necessary component of healing (Dakwar E et al, Drug Alc Depend 2014;136:153–157).
Pharmaceutical companies have eagerly embraced the ketamine story, in hopes of developing a similar drug without ketamine’s reputation and its pesky DEA Schedule III designation. But the options are limited. AstraZeneca tested one compound, lanicemine, but quietly backed out after it failed a Phase IIb trial in 2015. Another compound called GLYX-13 (recently renamed rapastinel), a partial agonist at another site on the NMDA receptor, has been effective in reducing HAM-D scores relative to placebo at some doses, and further research is ongoing. Other labs are studying the tuberculosis drug Dcycloserine, another NMDA modulator, as well as other agents. The closest thing to ketamine in the commercial pipeline is Janssen’s intranasal S-ketamine (an enantiomer of ketamine), currently in phase II trials.
Of course, if you want to explore this territory on your own, IV ketamine is readily available. It can be compounded into oral, sublingual, and intranasal forms. But its use in depression remains strictly off-label and, at this time, must be seen as experimental. As more data become available and protocols are published and refined, it may be worth your time and effort to add it to your repertoire.
TCPR Verdict: Ketamine looks promising for extremely rapid relief of depression—but the effects are short-lived, and any antidepressant that requires a crash cart nearby is not likely to become a blockbuster.