Unusual is an understatement. This just seems ill-conceived to me. You can't eliminate one effect on the brain by introducing other effects on the brain that might have their own consequences for the results.
All this shows is that ketamine while under general anaesthesia is not more efficacious than placebo. Ok then. This just seems like a failed attempt to introduce better blinding to me. I'm not convinced it sheds any light on the mechanism by which ketamine is effective.
Actually, what it shows is both that getting ketamine while under general anaesthesia is roughly as effective as when taken without anaesthesia (40% here vs 45% in [1]), and as effective as just taking anaesthesia (their placebo treatment).
I see. But this seems to cast even more doubt onto the use of general anaesthesia as an active placebo. I mean, usually people waking from it don't feel great because they're very ill or had major surgery. Maybe in the abscence of things like that it could have some antidepressant effect.
Things similar to this have been used as treatment in the distant past of psychiatry as well, when ethics was nowhere to be found. Induced comas and such.
To be precise, the anaesthesia is part of the masking procedure, the placebo is a saline injection that was administered the same way as the ketamine (in practice the ketamine was simply diluted in a saline dose that is then given to the patient).
Of course, getting all those anaesthesia drugs into you could mess up the body chemistry in all sorts of ways that make the ketamine not work, but it is still very surprising that the net effect of this big cocktail of substances is that you get basically the same outcome regardless of treatment method.
Anything that puts you under and also inhibits REM sleep, can have effects against depression. REM sleep is important for memory consolidation, and consolidation of memory is linked to depression in that the reliving and reconsolidation of painful memories is thought to be involved in at least some types of depression.
This is why sleep deprivation can have an acute antidepressive effect, and also why cannabis can have a similar shorter effect in some cases. Usually when there's no tolerance.
I think it's quite possible indeed that something similar happened during this study.
I've never personally done ketamine, but what these studies fail to take into account is the simple fact that for most of these classes of compounds, the subjective psychological experience is the entire mechanism of useful action, and looking purely at the physiological side is missing the forest for the trees. Unfortunately, delving into the subjective with double blinding is damn near impossible, since the whole point of blinding is to remove the subjective aspects of the study.
I know my DMT trips have been so potent of an experience, that if you took that out of the picture and just left the physical aspects, it would be little more than vasoconstriction and elevated heart rate, and I fail to see how that would do anyone any therapeutic good.
I think this was the entire point of this study. The interesting and positive experience is what knocks people out of their depression. It’s not that drug experiences are particularly magical in and of themselves, apparently getting anaesthetised is about as effective. Taking hallucinogens or disassociatives just happens to be a low effort way of having an interesting experience. It helps that it also feels a little transgressive and edgy.
All this shows is that ketamine while under general anaesthesia is not more efficacious than placebo. Ok then. This just seems like a failed attempt to introduce better blinding to me. I'm not convinced it sheds any light on the mechanism by which ketamine is effective.