Wednesday, 21 August 2013

D-cycloserine -- An Old Drug Getting A New Life

D-cycloserine is a drug that was once frequently used in the treatment of tuberculosis, nowadays it is less frequently used, probably, in part, due to how rare tuberculosis is nowadays in developed countries like Australia. Nowadays D-cycloserine is generating some interest as a potential treatment for certain psychiatric disorders such as major depressive disorder (MDD) and schizophrenia.1,2 This is because D-cycloserine, much like the non-cyclic form of this amino acid, D-serine, (the related [sort of a mirror image of D-serine] amino acid, L-serine, which is also what the body synthesises D-serine from, is found in animal and vegetable proteins) has been found to bind to the so called glycine site on the NMDA glutamate receptor. The NMDA receptor is one of the receptors for the very important amino acid neurotransmitter, glutamate (also known as glutamic acid). The NMDA receptor primarily serves as an excitatory receptor, that is, it increases the activity of the cells on which it is expressed.

This receptor has been implicated in several of the major psychiatric disorders that have plagued our society for generations such as schizophrenia, bipolar disorder, major depressive disorder and anxiety disorders. In order to be activated, however, the NMDA receptor requires two events to occur simultaneously: the neurotransmitters, glutamate or aspartate (aspartic acid) must bind to the so called glutamate site on the receptor and the neurotransmitter glycine, or similar amino acid neurotransmitters such as D-alanine or D-serine need to bind to the so called glycine site on the receptor. What's so special about D-cycloserine, however, is that it serves as a partial agonist at the glycine site on the NMDA receptor. This means that when it binds to the glycine site, provided glutamate or aspartate is already bound to the glutamate site, a smaller response is seen than if D-serine, D-alanine or glycine had bound to the same glycine site. Hence because the glycine sites on the NMDA receptor are never completely occupied by the glycine, D-serine and the D-alanine obtained from the diet (after some chemical processing) [this is because there are so many NMDA receptors found in the body that it’s impossible for these neurotransmitters to occupy them all] at lower concentrations of D-cycloserine in the blood it (D-cycloserine) occupies the non-occupied glycine sites on the NMDA receptor and hence leads to an overall increase in the activity of the NMDA receptor. At higher concentrations, however, D-cycloserine competes with glycine, D-serine and D-alanine for the binding with the glycine site on the NMDA receptor and hence it displaces some of these amino acid neurotransmitters and hence since it produces a less full response than these amino acid neurotransmitters  it causes a net reduction in NMDA receptor activity.

The way how this relates to psychiatric illnesses like schizophrenia and major depressive disorder is that it is believed that in schizophrenia the NMDA receptor is underactive and hence by potentiating its activity it is hoped that low doses of D-cycloserine (which translates to low concentrations in the blood when the drug is absorbed by the body) may be of therapeutic benefit in patients with schizophrenia. Whereas in major depressive disorder the NMDA receptor is believed to be overactive and drugs that attenuate its activity have been shown to elicit rapid and robust antidepressant effects and hence it is hoped that high doses of D-cycloserine (or high concentrations) might likewise elicit rapid and robust antidepressant effects without some of the psychotomimetic (psychosis [a state characterised by hallucinations, delusions, etc.]-mimicking) effects of NMDA antagonists (blockers) like ketamine.1,2

Its efficacy in treating schizophrenia seems to be very limited, however, probably because the difference between doses that potentiate the activity of the NMDA receptor and doses that inhibit the activity of the NMDA receptor is rather small and the maximum potentiation of NMDA receptor that D-cycloserine is capable of is significantly less than that of glycine site full agonists (compounds that manage [with the help of glutamate/aspartate binding at the glutamate site] to produce full activation of the NMDA receptor) like glycine and hence it is easy to inadvertently give a patient a dose that overall inhibits NMDA activity hence exacerbating the symptoms of schizophrenia.1 

Whereas in treating major depressive disorder D-cycloserine appears to be rather effective, even in previously treatment-resistant cases probably because it’s been discovered that not only do NMDA antagonists produce antidepressant activity but so do NMDA agonists (activators) like glycine and glutamate.2

There is some evidence in rats to suggest that D-cycloserine might be helpful in the treatment of cocaine addiction.3


Reference List:

  1. Goff DC, Cather C, Gottlieb JD, Evins AE, Walsh J, Raeke L, et al. Once-Weekly D-Cycloserine Effects on Negative Symptoms and Cognition in Schizophrenia: An Exploratory Study. Schizophr Res [Internet]. 2008 Dec [cited 2013 Aug 22];106(2-3):320–7. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2628436/
  2. Heresco-Levy U, Gelfin G, Bloch B, Levin R, Edelman S, Javitt DC, et al. A randomized add-on trial of high-dose d-cycloserine for treatment-resistant depression. The International Journal of Neuropsychopharmacology. 2013;16(03):501–6. Available from: http://journals.cambridge.org/action/displayAbstract?fromPage=online&aid=8852104
  3. Thanos PK, Bermeo C, Wang G-J, Volkow ND. D-cycloserine facilitates extinction of cocaine self-administration in rats. Synapse [Internet]. 2011 [cited 2013 Aug 22];65(9):938–44. Available from: http://onlinelibrary.wiley.com/doi/10.1002/syn.20922/abstract

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