A few years ago here, I wrote about an interesting hypothesis involving the TrkB receptor and the action of antidepressant drugs. The short form of that one is that TrkB is important in the signaling and action of the BDNF neuronal growth factor, and BDNF in turn has been the subject of several theories about major depression. The claim was that the BDNF/TrkB complex produces a small molecule binding site that accommodates many known antidepressant molecules, a use for them that their developers never anticipated, and that this might be a main mode of their actions in vivo. The same group believes that this might be a mechanism for efficacy of psychedelic drugs in treating some major depression patients as well, although this seems to require endogenous BDNF to be present, while some other ligands might be able to work without it. Here’s a recent review of the overall idea, and another is here.

That’s a bold statement on a therapeutic area of great interest, so I wanted to highlight some recent papers that bear on it. This recent J. Med. Chem. paper describes a phenotypic screen for antidepressant compounds using the “chronic unpredictable mild stress” rodent model. They identified a few compounds with what is for antidepressants unusually fast onset - typically in humans you need weeks of dosing to start seeing effects (and indeed, this is what this paper noted with the widely used antidepressant fluoxetine). The authors went on to do compound optimization using rodent assays, and found a compound (their B11) that seemed promising.

Further evaluation in neuronal cellular assays showed that the compound seemed to have notable growth-factor-like effects (similar to BDNF treatment, in fact), and brain tissue from treated mice seemed to confirm this. B11 treatment in fact upregulated BDNF levels within 15 minutes of treatment, and a set of further experiments (not detailed here for reasons of time!) all pointed to this being its likely mechanism of antidepressant action. The authors report that preclinical selectivity studies show no particular activities on a number of other CNS targets, and also say that toxicity testing has been performed in rats and dogs up to 1g/kg (!)

So that would make a person very interested in seeing what this or a related compound would do in human patients! I would hope that this is in the works. The authors are all from a pharma company in Chengdu, so there is a reasonable possibility that we might see something like this. But if not them, then it’ll be someone (or something!) else, because this hypothesis is too interesting not to be investigated.

Meanwhile, this recent paper zooms back out in this area to propose another related idea. The authors are also working the neuroplasticity-as-therapy idea for depression and other disorders, but they are proposing hypoxia (!) as a common thread. In their view, the hallucinogenic states brought on by hypoxia at high altitude or in near-death experiences might be setting off the same downstream neuronal adaptability mechanisms as those seen with hallucinogenic drugs themselves. There actually has been research in controlled intermittent hypoxia as a neurological therapy, which is something I hadn’t known. Here’s an overview. (As a personal note, if this is true then I’ve been through some seminars that might have done me a lot of good. . .)

The hypoxia folks are also referencing BDNF pathways in their proposed mechanisms of action, and it’s not clear to me (and I’m sure that it’s not clear to anyone!) whether these TrkB approaches are a way to jump right through that without having to experience hypoxia or whether hypoxia provides added benefits that a TrkB-BDNF targeted approach would lack. Either way, as wooly as some of this is, I’m very glad to see such approaches being studied. Our treatment of depression (and many other cognitive disorders) is very rudimentary and has huge room for improvement. Show some real, reproducible benefit and let’s talk!