New study uncovers biological differences between psychiatric disorders

In psychiatric disorders, rather than producing serotonin, tryptophan is instead sequestered through and metabolized along the kynurenine pathway, yielding metabolic by-products such as kynurenic acid, quinolinic acid, and 3-hydroxykynurenine, according to a recent study.

Moreover, different psychiatric conditions have different level profiles of these metabolites. The neurotoxic quinolinic acid, for example, seems to be preferentially synthesized in mood disorders, such as major depressive (MDD) and bipolar (BD) disorder, but not in schizophrenia (SZ).

“Tryptophan, the main precursor of the kynurenine pathway, is decreased across all mental disorders considered. This likely reflects its relative importance in these disorders, particularly in the context of serotonin bioavailability,” the researchers said. “Decreased bioavailability of tryptophan is at least partially responsible for the depleted levels of serotonin found in MDD.”

A systematic search of three online databases returned 101 studies eligible for meta-analysis, comprising 10,912 participants (median age, 25 years). More than half (n=5,856) had psychiatric disorders, while 5,056 were controls. Most of the studies measured metabolites in plasma, as opposed to serum. [Mol Psychiatry 2020;doi:10.1038/s41380-020-00951-9]

In patients with MDD, tryptophan (g, –0.51; p<0.001), kynurenine (g, –0.26; p<0.001), and kynurenic acid (g, –0.37; p=0.001) were all significantly suppressed, while levels of quinolinic acid and 3-hydroxykynurenine were unaltered. The ratios of kynurenic acid to quinolinic acid (p<0.001), kynurenine (p=0.003), and 3-hydroxykynurenine (p<0.001) were all also significantly reduced in MDD.

In BD, levels of only tryptophan (g, –0.56; p<0.001) and kynurenic acid (g, –0.44; p<0.001) were significantly attenuated; the resulting ratio between kynurenic acid and quinolinic acid was likewise lowered (p<0.0001). No such impacts were observed for the other metabolites and ratios.

“In mood disorders, kynurenic acid is lower, and the ratios of kynurenic acid to kynurenine, and of kynurenic acid to 3-hydroxykynurenine are decreased compared to healthy subjects, suggesting an imbalance between the putatively neuroprotective kynurenic acid and the neurotoxic quinolinic acid, with a preponderance of quinolinic acid,” the researchers explained.

“Quinolinic acid, however, is not increased in mood disorders, thus it is not possible to say if this imbalance is due to a decrease in kynurenic acid … [solely or] in tandem with an increase in quinolinic acid,” they added.

In SZ, on the other hand, while bioavailable tryptophan was also lowered (g, –0.24; p=0.04) and its metabolism likewise shifted away from serotonin toward kynurenine, there was no strong evidence supporting an imbalance between the kynurenic and quinolinic acids.

Taken together, these findings suggest that “a differential pattern exists between mood disorders and SZ, with a preferential metabolism of kynurenine to the potentially neurotoxic quinolinic acid instead of the neuroprotective kynurenic acid in mood disorders but not in SZ,” the researchers said.

“Further studies are required to examine the individual characteristics that modulate kynurenine metabolism in these disorders and to investigate potential treatment options,” they added.