D-Serine: Potential Therapeutic Agent and/or Biomarker in Schizophrenia and Depression?

Abstract

D-Serine is a potent co-agonist at the NMDA glutamate receptor and has been the object of many preclinical studies to ascertain the nature of its metabolism, its regional and cellular distribution in the brain, its physiological functions and its possible clinical relevance. The enzymes involved in its formation and catabolism are serine racemase (SR) and D-amino acid oxidase (DAAO), respectively, and manipulations of the activity of those enzymes have been useful in developing animal models of schizophrenia and in providing clues to the development of potential new antipsychotic strategies. Clinical studies have been conducted in schizophrenia patients to evaluate body fluid levels of D-serine and/or to use D-serine alone or in combination with antipsychotics to determine its effectiveness as a therapeutic agent. D-serine has also been used in combination with DAAO inhibitors in preclinical investigations, and interesting results have been obtained. Genetic studies and postmortem brain studies have also been conducted on D-serine and the enzymes involved in its metabolism. It is also of considerable interest that in recent years clinical and preclinical investigations have suggested that D-serine may also have antidepressant properties. Clinical studies have also shown that D-serine may be a biomarker for antidepressant response to ketamine. Relevant to both schizophrenia and depression, preclinical and clinical studies with D-serine indicate that it may be effective in reducing cognitive dysfunction.

The Intersection of Serine Metabolism and Cellular Dysfunction in Retinal Degeneration

“…Initially, it was discovered in the brain but has more recently been studied in the neural retina [13]. D-serine, formed by the racemization of L-serine by serine racemase (SRR) [13], functions as a neurotrophic factor and as a co-agonist for N-methyl-D-aspartate receptors (NMDARs) [37]. In the brain, NMDARs normally bind glutamate and glycine, but data suggests preferential or higher affinity binding to D-serine in the retina [13,38].…”

“…Irrespective of NMDAR functions, the importance of D-serine is evidenced by pathologies that are directly linked to D-serine irregularities. D-serine insufficiency has been associated with psychiatric and neurodevelopmental disorders [37]. Supplementation with D-serine has proven to mitigate some of the symptoms of psychosis [37].…”

“…D-serine insufficiency has been associated with psychiatric and neurodevelopmental disorders [37]. Supplementation with D-serine has proven to mitigate some of the symptoms of psychosis [37]. Patients with DR, by contrast, suffer from increased SRR activity and over production of D-serine, which elicits an excitotoxic effect on RGCs and ultimately contributes to cell death [40].…”

d-Amino acids and kidney diseases

“…Using kidney tubular cell lines (HK-2) and primary cultures of kidney tubular cells, one study suggested the toxic mechanism of higher doses of d-serine as the induction of cell cycle arrest, pro-inflammatory response, and apoptosis via effector molecules of ER stress [40]. Higher doses of d-serine have been used in some clinical studies in schizophrenia and cerebellar ataxia [41,42], as a potential activator of NMDAR. In these studies, potential side-effects such as proteinuria and abnormal kidney values were sporadically reported, although the causal relationship remains unclear [43,44].…”

Amino acids and acylcarnitines as potential metabolomic markers of schizophrenia: new approaches to diagnostics and therapy

“…Îñíîâûâàÿñü íà ïîëîaeèòåëüíûõ êëèíè÷åñêèõ ðåçóëüòàòàõ ñ ãëèöèíîì, áûëà ïðîâåäåíà ñåðèÿ èññëåäîâàíèé ñ àëüòåðíàòèâíûì àãîíèñòîì ãëèöèí-ñàéòà, D-ñåðèíîì [62]. Ïåðâîíà÷àëüíîå êëè-íè÷åñêîå èññëåäîâàíèå âêëþ÷àëî 29 ïàöèåíòîâ, ëå÷èâøèõñÿ â òå÷åíèå 6 íåä ëèáî D-ñåðèíîì, ëèáî ïëàöåáî.…”