Over the past 15 years or so, ketamine has on numerous occasions been demonstrated as an effective, rapid salve for symptoms of major depressive disorder. Whereas other pharmacological depression treatments take many weeks to become effective—if they become effective at all—ketamine’s effects are rapid and robust. It’s touted by many as a depression wonderdrug, though some very big questions remain, such as: How does it actually work?
A study published Wednesday in Nature, courtesy of the University of Maryland, NIH, and others, offers some crucial new insights into the ketamine mystery. Chief among them is that the efficacy of ketamine might not be due to ketamine at all. Instead, it would seem that a metabolite of ketamine—that is, a byproduct of the body’s process of chemically decomposing ketamine—is the thing doing the actual depression fighting. Crucially, the metabolite, known as hydroxynorketamine or HNK, is able to do this minus many of the motor and cognitive side effects of ketamine proper.
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Clinically, ketamine is a drug most commonly used for inducing and maintaining anesthesia. Its effects at anaesthetic doses include pain relief, sedation, and memory-formation inhibition. At lower, recreational doses, it produces a strong sense of depersonalization, e.g. checking way the fuck out. Most of ketamine’s effects have been traced to its blockage of the NMDA receptors in the brain, whose functions largely have to do with memory formation.
“Ketamine has a moderately high binding affinity for, and can block the activity of, the NMDA receptor protein (NMDAR),” explains UC San Diego neurobiologist Roberto Malinow in a separate Nature commentary. “This receptor is perhaps best known for its requirement in a phenomenon called long-term potentiation, which occurs widely in the brain, whereby the synaptic connections between neurons are strengthened, enhancing neural signalling. The enhanced signalling produced by LTP underlies the formation of associative memories.”
The assumption has been that it’s this interaction with NMDA receptors that explains ketamine’s antidepressive effects as well, but the current study suggests that might not be the case. Which wouldn’t be all that weird—as Malinow notes, directly linking depression and memory formation is a bit fishy to begin with.
The study explored two variants of ketamine with differing structural forms commonly administered together: (S)- and (R)-ketamine. (S)-Ketamine is three to four times better at inhibiting NMDA receptors than than (R)-ketamine and so it should be better at fighting off depression, at least under current assumptions.
What the University of Maryland researchers found, however, was the opposite. (R)-ketamine had more of an impact on depression symptoms (via mouse models) than (S)-ketamine. Moreover, a third ketamine version, this one an even more potent NMDA inhibitor, wasn’t very antidepressive at all.
So, if not via NMDA receptors, how then is ketamine actually working?
The first clue was in the observation that a lower dose of ketamine is required to produce antidepressive effects in females than males. In scenarios where both male and female brains contained equal concentrations of ketamine, the researchers observed that the female brains had much higher concentrations of the aforementioned HNK metabolite.
To explore the HNK role further, ketamine was tested in brains that had had their ability to convert ketamine to HNK limited. The result was a decrease in antidepressant effects. Finally, just plain HNK was tested, with the by-now expected result being a rapid and sustained decrease in depressive symptoms.
The study represents definite progress, but we’re still quite a ways away from an actual HNK-based depression treatment. For one thing, we don’t really know how HNK works, just that it does. And, again, so far this is all just in mice.
Still, the UMD paper rightly concludes:
“Considering the lack of side effects, and the favourable physiochemical properties of HNKs, these findings have relevance for the development of next-generation, rapid-acting antidepressants.”
