Tryptophan is an essential amino acid (i.e. an amino acid that comes from one's diet). It is of interest for the subject of depression, as it is used by the body to produce serotonin, a target for many of the "first-line" anti-depressants that are widely prescribed (a key type of antidepressant being selective serotonin reuptake inhibitors). However, most of the tryptophan we consume is not converted in serotonin, but is rather broken down along the kynurenine pathway. A number of the metabolites formed along this pathway may have neuroprotective or neurotoxic effects, and there is evidence that they may be altered in patients with major depression, which may in turn be associated with alterations in relevant brain regions.
A recent article from work we did at UCC examined a number of these metabolites in blood samples from patients with prolonged major depression. We examined blood samples taken before ketamine treatment and at repeated times after three ketamine injections, spaced one week apart. (Although the anti-depressant effects of ketamine are very rapid, they also fade after a week or so, and so repeated injections are sometimes given for a number of weeks). We found that kynurenic acid, which is thought to be neuroprotective, was reduced in patients with major depression compared to healthy controls. However, although the antidepressant effects were soon evident in most of these patients (in terms of their depressive thoughts and feelings), ketamine did not lead to clear changes in kynurenine pathway metabolites.
Our results seem to suggest that depressive symptoms may be improved by ketamine, even in the absence of kynurenine pathway change. Perhaps other biological factors are more important, such as neurotrophins (proteins that are crucial for neuronal growth and development). Nor should we ignore the potential effects of ketamine on the psyche; the disassociative effects of ketamine may create a psychological "distance from the self", not unlike the effects of mindfulness meditation. Nonetheless, the observed differences in kynurenic acid in patients with depression is indicative of how depression is associated with changes in tryptophan metabolism beyond serotonin.
New research is being published regularly in this area, including in leading glamour journals, looking at more mechanistic preclincial work as well as research in patients. We will hopefully gain more understanding in the coming years into how this drug works. Such an understanding may help to develop more targeted drugs in future.
Allen, A. P., Naughton, M., Dowling, J., Walsh, A., O'Shea, R., Shorten, G., ... & Dinan, T. G. (2018). Kynurenine pathway metabolism and neurobiology of treatment-resistant depression: Comparison of multiple ketamine infusions and electroconvulsive therapy. Journal of Psychiatric Research. doi: https://doi.org/10.1016/j.jpsychires.2018.02.011
Depression treatment: ketamine
I felt a funeral, in my brain
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