Glutamatergic system is intensely researched for potential psychotropic medications. Glutamate (Glu) is the major excitatory neurotransmitter in the brain, Glu neurons project within the cortex and to subcortical regions, such as locus coeruleus, raphe nucleus, and substantia nigra, where they modulate monoaminergic systems.NMDAR is one of the specific types of receptors for glutamate.The overstimulation of NMDA receptors leads to neurodegeneration through a process called excitotoxicity. Antagonism of NMDAR may represent an effective anti- depressant mechanism. Many antidepressants are shown to induce alteration in NMDAR functioning. Acute i.v. administration of the NMDAR non-competitive antagonist Ketamine, results in rapid symptom alleviation in patients with depression and suicide ideation.However, direct NMDAR antagonism may also change dopamine levels leading to psychotic states. Another way to influence NMDAR is via Glycine site on the receptor .
The question is this. Would an antagonist at Glycine site alleviate depression with out the risk of psychotomimetic effects of direct NMDAR antagonism?
Uriel Heresco-Levy, Genia Gelfin, Boaz Bloch, Raz Levin, Shani Edelman, Daniel C. Javitt and Ilana Kremer attempted to answer this question. They used D cycloserine (DCS) (an antibiotic used to treat Tuberculosis) ,a partial agonist at the NMDAR glycine site, with agonist effects predominating at low dose and antagonist effects predominating at high dose.DCS has been assessed in treatment-resistant schizophrenia. At low doses, DCS produced beneficial effects in some studies ; at higher doses it was found to exacerbate psychosis. A previous trial of low dose of DCS was not effective in depression and it appears that higher dose (ie above 500 mg) is required for the antagonistic activity.
26 adult out-patients with Recurrent Major Depressive Disorder, currently resistant to treatment (defined as 20 plus score on the 21-item Hamilton Depression Rating Scale, despite two or more adequate antidepressant medication trials) and been treated for at least 4 wk with a stable clinically determined dose of antidepressant medication, were randomised using a double-blind, placebo controlled parallel group design to receive increasing dose of DCS or placebo.The mean duration of the current episode was 13-14 months.
DCS treatment led to significant improvement in depressive symptoms as measured by HAMD.Seven of 13 (54%) patients assigned to DCS qualified as responders (i.e. 50% HAMD total score reduction) vs. two of 13 (15%) assigned to placebo. Five of 13 (38 %) patients assigned to DCS were also considered remitters (i.e. HAMD total score below 7) vs. two of 13 (15%) assigned to placebo, although this difference was not statistically significant. More patients ( 3 against one in placebo group) withdrew from experimental arm siting discomfort as reason.
Limitations: Small study. Remission rates were not statistically significant.
Conclusion: This study provides proof of concept evidence that antagonistic activity at the NMDAR-associated glycine site can induce antidepressant effects and reduce MDD severity. 54 % of DCS-treated subjects achieved treatment response. This is to be considered against the usually reported 60-65% response rate to the first antidepressant agent in depression. Authors also measured serum glycine levels and comment that treatment targeting NMDAR glycine site may be particularly appropriate in those with high glycine levels.
Summary of the article:
Heresco-Levy U, Gelfin G, Bloch B, Levin R, Edelman S, Javitt DC, Kremer I. Int J Neuropsychopharmacol. 2013 Apr;16(3):501-6.