Severe psychiatric disorders, such as schizophrenia, bipolar disorder and depression, are ruining the lives of millions of people worldwide. The kynurenine [kæjnurenin] pathway, unknown to most and difficult to pronounce, is increasingly being viewed as an important component in a multitude of physiological and pathological functions, including psychiatric disorders. So what is this pathway and how can it affect the way we feel and perceive the world surrounding us?

The kynurenine pathway, so called because of the sequential breakdown of compounds collectively known as kynurenines, stems from the dietary amino acid tryptophan. Tryptophan is mostly known as the compound initiating the production of the neurotransmitter serotonin, which is believed to play an important role in depression. Most of the tryptophan in the human body is however not converted to serotonin. As much as 95% of all tryptophan is utilized in the kynurenine pathway, giving rise to a number of compounds with the ability to alter the signaling of neurons in the brain. The pathway is divided into two main arms, branching off from the compound kynurenine. Kynurenic acid (KYNA) is the sole product of one branch. The other branch leads to a number of substances, among them the important quinolinic acid (QUIN). Our understanding is that the flow of kynurenine into one of these branches is increased in a number of disorders.

In the context of psychotic disorders, the compound KYNA has been most extensively studied. KYNA is found in elevated concentrations in patients with schizophrenia and bipolar disorder. Using experiments where researchers either increase or decrease the levels of KYNA in the brain of rodents, it has been shown that KYNA modulates the signaling by several important neurotransmitters in the brain, one of them being dopamine. Dopamine is in turn believed to underlie the development of both psychotic and manic symptoms as observed in schizophrenia and bipolar disorder. Increased levels of KYNA also decreases the levels of glutamate, another neurotransmitter with defect signaling in psychotic disorders. Furthermore, it produces cognitive deficits, such as working memory problems, in experimental animals. Cognition is under the control of both glutamate and acetylcholine neurotransmission, and the receptors for these neurotransmitters are the direct targets of KYNA in the brain. Compromised cognitive function in schizophrenia and bipolar disorder is considered to be a core feature of these disorders, and often presents a large barrier towards normal societal functioning for these patients.
Another compound of the kynurenine pathway, QUIN, is found in normal concentrations in patients with schizophrenia but is believed to play a role in unipolar depression. In two studies investigating patients who attempted suicide, of which approximately half the patients were depressed, researchers found elevated levels of QUIN.

QUIN is a known neurotoxin, involved in tissue destruction following traumatic brain injury or oxygen deprivation. As such, it has been implicated in a number of neurodegenerative disorders. Depression is a psychiatric disorder associated with reduced volume of brain tissue, specifically in regions associated with memory, as well as memory impairment. It is being investigated whether the increased levels of QUIN might cause the reduction in neural tissue and contribute to depressive symptoms. Drugs targeting the kynurenine pathway might hence provide novel opportunities for drug treatment in severe psychiatric disorders, specifically targeting symptoms not responding to the treatment available today in a satisfactory manner. Further research on the role of the kynurenine pathway in psychiatric disorders is therefore of utmost importance to all the people suffering psychiatric disorders today.

Magdalena Kegel is author of the recently published paper, Imbalanced kynurenine pathway in schizophrenia, available for download now in International Journal of Tryptophan Research.