Here’s another one to file under “What we don’t know about brain chemistry”. That’s a roomy category for sure, which (to be optimistic about it) leaves a lot of room for discovery. In that category are the observations that ketamine seems to dramatically help some people with major depression. It’s an old drug, of course, still used in some situations as an anesthetic, and also used (or abused) by people who wish to deliberately derange themselves in dance clubs. Chemists will note the chemical resemblance to phencyclidine (PCP), a compound whose reputation for causing derangement is thouroughly deserved. (Ketamine was, in fact, a “second-generation” version of PCP, many years on).
Both of these compounds are, among other things, NMDA receptor antagonists. That had not been considered a high-priority target for treating depression, but you certainly can’t argue with results (not, at least, when you know as little about the mechanisms of depression as we do). There are better compounds around, fortunately:
AZD6765, an inhibitor of the N-methyl-D-aspartate (NMDA) receptor, a glutamate signaling protein involved in cellular mechanisms for learning and memory, was originally developed as a treatment for stroke. It was shelved in 2000 by the drug’s manufacturer, AstraZeneca, after phase 2 trials failed to show signs of efficacy. In the decade that followed, however, small clinical reports started to emerge showing that ketamine, an analgesic that also blocks the NMDA receptor, produced rapid responses in people who didn’t benefit from any other antidepressants. And unlike most therapies for major depression, which usually take weeks to kick in, ketamine’s mood-lifting effects could be seen within two hours, with a therapeutic boost that often lasted for weeks following a single infusion. Ketamine treatment also came with a number of debilitating side effects, though, including psychosis and detachment from reality. Fortunately for AstraZeneca, the company had a cleaner drug on its shelves that could harness ketamine’s benefits with fewer problems.
Note that AZD6765 (lanicemine) has a rather simple structure, further confirmation (if anyone needed any) that things this size can be very effective drugs. Here’s the clinical study that Nature Medicine news item refers to, and it makes clear that this was a pretty tough patient cohort:
This double-blind, placebo-controlled, proof-of-concept study found that a single intravenous infusion of a low-trapping nonselective NMDA channel blocker in patients with treatment-resistant MDD rapidly (within minutes) improved depressive symptoms without inducing psychotomimetic effects. However, this improvement was transitory. To our knowledge, this is the first report showing rapid antidepressant effects associated with a single infusion of a low-trapping nonselective NMDA channel blocker that did not induce psychotomimetic side effects in patients with treatment-resistant MDD.
More specifically, patient depression scores improved significantly more in patients receiving AZD6765 than in those receiving placebo, and this improvement occurred as early as 80 min. This difference was statistically significant for the MADRS, HDRS, BDI, and HAM-A. These findings are particularly noteworthy, because a large proportion of study participants had a substantial history of past treatment that was not efficacious. The mean number of past antidepressant trials was seven, and 45% of participants had failed to respond to electroconvulsive therapy.
The problem is the short duration. By one evaluation scale, the effects only lasted about two hours (by another less stringent test, some small effect could still be seen out to one or two days). Ketamine lasts longer, albeit at a cost of some severe side effects. This doesn’t seem to be a problem with high clearance of AZD6765 (its PK had been well worked out when it was a candidate for stroke). Other factors might be operating:
These differences could be due to subunit selectivity and trapping blockade. It is also possible that the metabolites of ketamine might be involved in its relatively sustained antidepressant effects, perhaps acting on off-site targets; a recent report described active ketamine metabolites that last for up to 3 days. It is also important to note that, although trapping blockade or broadness of antagonist effects on the NMDA subunit receptors might be key to the robustness of antidepressant effects, these same properties might be involved in the dissociative and perceptual side effects of ketamine. Notably, these side effects were not apparent at the dose of AZD6765 tested.
If that last part is accurate, this is going to be a tricky target to work with. I doubt if AZD6765 itself has a future as an antidepressant, but if it can help to understand that mode of action, what the downstream effects might be, and which ones are important, it could lead to something very valuable indeed. The time and effort that will be needed for that is food for thought, particularly when you consider the patients in this study. What must it be like to feel the poison cloud of major depression lift briefly, only to descend again? The Nature Medicine piece has this testimony:
(David) Prietz, 48, a scheduling supervisor at a sheet-metal manufacturer in Rochester, New York, who has been on disability leave for several years, started to feel his head clear from the fog of depression within days of receiving AZD6765. After his second infusion, he vividly began noticing the fall foliage of the trees outside his doctor’s office—something he hadn’t previously appreciated in his depressed state. “The greens seemed a lot greener and the blue sky seemed a lot bluer,” he says. Although the lift lasted only a couple months after the three-week trial finished and the drug was taken away, the experience gave Prietz hope that he might one day get better. “I can’t recall feeling as well I did at the time,” he says.
Fall foliage for Algernon? I hope we can do something for these people, because as it is, a short-duration effect is scientifically fascinating but emotionally cruel.