Depressed Mood
Adenosine & Depression
Adenosine & Cortisol
Increased cortisol has been consistently linked to depression since the 1980s and reproduced in recent studies: PMID 30844940. The apparent effect of cortisol on adenylosuccinate synthase and proposed effect of adenylosuccinate on CRH receptors ties this association to adenosine deficiency and is consistent with the ECT's proposed mechanism of action above.
Not Sufficient
However, clinical response to benzodiazepines (BZD), likely adenosine deaminase inhibitors, argues against adenosine as being the primary mediator of depression, since chronic BZD use is associated with worsened depressed mood PMID 32459725 and increased, rather than decreased risk of suicide PMID 9408553, review 28257172. This suggests that the primary modulator of depression is downstream from adenosine: potentially inosine. IMG
Inosine & Depression
Several antidepressants have purine-similar chemical structures or substructures. Citalopram, venlafaxine, and duloxetine all share a general chemical structure roughly analogous to inosine, since the propensity of amine groups is to donate electrons to surrounding atoms, making the methyl-amine similar to inosine's carbonyl group.
Other Antidepressants
Other antidepressants, notably MAOIs, stimulants, and bupropion, share guanine-similarity: expected to inhibit PNP (similar to stimulants of abuse), increasing Io, Xo, and Go as precursors. IMG
Metformin
Metformin is guanine-similar, and would therefore be expected to have antidepressant properties via similar mechanism: evidence of this property is emerging (RCT PMID 35120288, Sys. Review PMID 36185927). Simultaneous improvement in cognition attributable to metformin PMID 24862430 is consistent with the proposed role of xanthine in autistic thought process. IMG
Sildenafil
Previously noted sildenafil's similarity to IMP: here we report mild anti-depressant effect 27283174
Inosine in psychiatry and neurology 34504414
Uric Acid
Symptomatic depression is associated with lower uric acid levels 28917195, 22040815 meta 28620773, 26445247, 26579881, sometimes attributed to increased oxidative stress 24336428, lower than other cognitive disorders 22040815, whereas bipolar is associated with higher uric acid levels, sometimes suggested that only bipolar is purinergic 32686367. Relatively higher uric acid levels are associated with less risk of antidepressant treatment, less risk of depression hospitalization 28845530, and lower LOS if hospitalized 32130258. Neuroimaging changes associated with depression are correlated with uric acid dip 29865782. Lower levels correlate with worse symptoms 23105889, 26984307: improvements in uric acid dip correlate with clinical response over a 12 week study 23105889. Symptomatic remission is associated with resolution of uric acid dip 28917195, 22040815 meta 28620773, 26579881. Antidepressant treatments affect uric acid level: duloxetine different than paroxetine 16964316. Treating uric acid level may treat depression 32130258. In the context of elevated CRP, the association flips 34650110.
Uric acid cannot be the single agent involved: mixed states 26369921 33418368 demonstrate simultaneous depressive and manic features within the same individual