Benefits of D-Serine

D-Serine is a non-essential amino acid and dextro isomer of serine with antipsychotic activity. D-serine is a selective full agonist at the glycine site of N-methyl-D-aspartate (NMDA)-type glutamate receptor. Hypofunction of NMDA type of neurotransmission is believed to play a major role in pathophysiology of schizophrenia, therefore, administration of D-serine and subsequent activation of NMDA receptors may alleviate psychotic tendencies.

Use

D-serine has been proposed for use as an adjunct agent with antipsychotics in the treatment of schizophrenia. D-serine added to an antipsychotic regimen for several antipsychotics, but not clozapine, was found to provide significant improvement in all symptoms Tsai et al (1998, 1999), Heresco-Levy et al (2005). A review of many studies concludes that D-serine may modestly improve general psychopathology and negative symptoms of schizophrenia when added to an antipsychotic regimen, but that the effect is modest Tiihonen and Wahlbeck (2006).

Potential benefits

The clinical evidence for cognitive benefits of D-serine is mixed and inconsistent. In a double-blind randomized controlled trial of 35 healthy adults, a single dose of D-serine improved attention compared to placebo. A different study in 50 older adults also showed that D-serine treatment significantly decreased errors on a spatial memory test, but this effect was not compared to placebo and may have been a practice effect. D-serine did not have any effect on working memory, cognitive flexibility, visual attention, or mood scores. All other clinical trials tested the effects of D-serine in people with schizophrenia or those at risk. A few studies showed cognitive benefit with D-serine, while others reported no benefit over placebo. Potential benefit of D-serine for cognitive functions is likely higher for people with suboptimal NMDA receptor activation, such as schizophrenia patients. In older adults with cognitive problems, D-serine may overactivate NMDA receptors, which can damage neurons.

Safety

Based on numerous randomized controlled trials, D-serine is well-tolerated with few side effects. The largest double-blind randomized controlled study of 195 schizophrenia patients reported that D-serine was well-tolerated; mouth sores were more prevalent in the D-serine group, while dizziness and headache were more common in the placebo group. In one small double-blind randomized controlled trial of 35 people at risk for schizophrenia, one participant expressed suicidal thoughts and two participants withdrew because of possible liver problems related to treatment. In this study, the incidence of proteinuria (protein in the urine) was higher in the D-serine group compared to placebo.

Because D-serine activates NMDA receptors, it is likely to interfere with actions of other drugs targeting NMDA receptors, such as memantine, ketamine, dextromethorphan, and nitrous oxide (all are NMDA receptor inhibitors).