Can a Simple Amino Acid Treat Schizophrenia?
25 June 2013. D-serine, a simple compound that boosts glutamate signals, might reinvigorate the effort to treat schizophrenia by this pathway, according to a report published May 31 in Proceedings of the National Academy of Sciences. Led by Joseph Coyle of Harvard Medical School in Boston, Massachusetts, the study supports the idea that underactive glutamate signaling generates the brain disturbances characteristic of the disorder, and argues that these may be fixed in adulthood. One line of glutamate drug development came to an end last year when Eli Lilly and Company abandoned its metabotropic glutamate receptor compound (see SRF related news story), so this study may inject some hope into this area.
The study expands upon the groupís previous work with mice designed to have underachieving glutamate systems, achieved by giving them sluggish N-methyl-D-aspartate (NMDA) receptors. Activating NMDA receptors requires not only glutamate, but also a cofactor, one of which is D-serine. But these mice lack serine racemase, an enzyme that makes D-serine, which lowers their D-serine levels and results in underactive NMDA receptors and cognitive deficits (Basu et al., 2009). The new study further probes the consequences of going without D-serine in the brain and turns up a series of anomalies that already have links to schizophrenia.
First author Darrick Balu and colleagues focused on the dentate granule cells of the hippocampus, a region long suspected in schizophrenia. There they found decreased signals flowing through NMDA receptors of dentate granule neurons in the serine racemase mice compared to controls. They found less plasticity there, too, as measured by long-term potentiation (LTP), which depends on NMDA receptor activation. Similar to what has been found in postmortem brains in schizophrenia, the dentate granule neurons in the mutant mice exhibited sparser dendritic spines and reduced expression of spine-promoting molecules miR-132 and brain-derived nerve growth factor (BDNF) compared to controls. The researchers also found diminished signaling downstream of NMDA receptor activation in the Akt/mTOR pathway, which may also contribute to dendrite outgrowth (and is linked to schizophrenia suspect molecules such as DISC1 [see SRF related news story] and the dopamine D2 receptor [see SRF related news story]). The pattern of anomalies there suggested a damaged mechanism for protein synthesis.
This list of perturbations could be remedied in adulthood by adding back D-serine, the researchers found. Injecting the adult mice under the skin for 20 days not only restored hippocampal D-serine levels to normal, but also rescued the deficits in LTP, BDNF expression, and Akt/mTOR signaling. The researchers do not report whether there were changes in dendrite structure, however. Moving to behavior, the researchers found that these mice had impaired fear conditioning when treated with saline but not when treated with D-serine: serine racemase knockouts receiving D-serine remembered as well as wild-type mice that a certain sound or place predicted an electric shock.
The study provides convergent evidence supporting the glutamate hypothesis of schizophrenia (see SRF Hypothesis and SRF Webinar). But maybe more interestingly, it suggests that a longstanding deficit in NMDA receptor function may be remedied in adulthood, similar to recent findings about neuregulin (see SRF related news story). If the human brain retains sufficient plasticity in adulthood, this may bode well for clinical trials of D-serine currently underway (see SRF related news story).óMichele Solis.
Balu DT, Li Y, Puhl MD, Benneyworth MA, Basu AC, Takagi S, Bolshakov VY, Coyle JT. Multiple risk pathways for schizophrenia converge in serine racemase knockout mice, a mouse model of NMDA receptor hypofunction. Proc Natl Acad Sci U S A. 2013 May 31. Abstract
Comments on Related News
Related News: Boosting NMDA Receptors Improves Symptoms, Cognition in SchizophreniaComment by: Hugo Geerts
Submitted 20 October 2013
Posted 20 October 2013
I recommend the Primary Papers
The group around Dr. Hsien-Yuan Lane has published a number of papers on clinical trials in schizophrenia patients with agents that act on co-agonist sites of the NMDA-receptor. This time they report on the beneficial effects of augmentation therapy with high-dose benzoate, a D-amino acid oxidase inhibitor, on a number of clinical scales (about 25 subjects/treatment arm). The effect is substantial (effect sizes between 1.16 on the PANSS negative and 1.69 on the PANSS positive subscale). For instance, this effect size is about twice the value seen in clinical trials with bitopertin, a glycine transporter-1 inhibitor in a larger Phase II study (Umbricht et al., 2010). Only one dose of benzoate has been tested, so the issue of a possible inverse U-shape response that has been observed earlier for a similar target and supported by theoretical-mechanistic insights has not been addressed in this study. They took great care in balancing the treatment arms with regard to the type of basal antipsychotic medication and found that haldol and risperidone were particularly receptive for benzoate augmentation therapy.
Of interest is the observation that benzoate is a food additive (E210-E213) with an impressive record of safety, opening up the possibility of an easier treatment approach of lower levels of the drug be achieved using food strategies. It might therefore be of interest to test lower levels of benzoate as well.
Antipsychotics are often considered deleterious or neutral at best for cognitive improvement, so this augmentation study suggests that benzoate is able to reverse this trend of worsening. In addition, there were no correlations between changes in PANSS positive or EPS changes and changes in both PANSS negative or cognitive outcome. This suggests that the observed effect of the compound is unlikely to be indirectly due to an improvement in PANSS positive symptoms or motor side effects, suggesting a genuine impact on the negative or cognitive subscales.
With regard to cognition, from the MATRICS subscale, the authors only found speed of processing and visual learning and memory to be significantly improved with the active treatment. However, this is one of the few trials in which the global composite score increased more with treatment than the placebo, despite the possible practice effect. Nevertheless, it underscores the difficulty of improving all seven domains of the cognitive MATRICS scale.
With the caveat of low numbers in the treatment arm, this study has to be recommended because it once again suggests a path forward for glutamatergic strategies. The glutamatergic system is currently the focus of much research in psychiatric indications (such as ketamine in depression). However the major problem, unlike older dopaminergic and neuromodulatory strategies, is finding a balance between excitation and inhibition in the human brain, and the feedback mechanism that operates, that makes it sometimes difficult to find the best dose-range for any treatment paradigm. The authors of this paper, however, show that this is possible.
Umbricht D, Yoo K, Youssef E, Dorflinger E, Martin-Facklam M, Bausch A, Arrowsmith R, Alberati D, Marder S, Santarelli L. Glycine Transporter Type 1 (GLYT1) Inhibitor RG1678: Positive
Results of the Proof-of-Concept Study for the Treatment of Negative Symptoms in Schizophrenia. Neuropsychopharmacology. 2010; 35:S320-321.
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Related News: Boosting NMDA Receptors Improves Symptoms, Cognition in Schizophrenia
Comment by: Michael McFarland
Submitted 5 November 2013
Posted 11 November 2013
Sodium benzoate combined with ascorbic acid produces benzene, a known carcinogen. I hope that another D-amino acid oxidase inhibitor can be found easily.
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Related News: New Antipsychotic Drug? Bypassing the NMDA Receptor With mGluR5
Comment by: Foster Olive
Submitted 5 June 2015
Posted 7 June 2015
These exciting findings represent a paradigm shift in current theories and drug development efforts for neuropsychiatric disorders. The ability of this novel mGluR5 PAM to produce behavioral effects independent of secondary NMDA receptor activation has implications that extend into numerous areas of neuroscience. Recent work by our laboratory and others indicates that mGluR5 PAMs facilitate the extinction of drug-seeking behavior in rodent models of addiction and reverse cognitive deficits associated with high levels of methamphetamine intake. The work by Conn and colleagues opens the door to exciting new directions for future research and drug development efforts in neuroscience and neuropsychiatry.
Gass JT, Olive MF. Positive allosteric modulation of mGluR5 receptors facilitates extinction of a cocaine contextual memory. Biol Psychiatry. 2009 Apr 15; 65(8):717-20. Abstract
Reichel CM, Schwendt M, McGinty JF, Olive MF, See RE. Loss of object recognition memory produced by extended access to methamphetamine self-administration is reversed by positive allosteric modulation of metabotropic glutamate receptor 5. Neuropsychopharmacology. 2011 Mar; 36(4):782-92. Abstract
Gass JT, Trantham-Davidson H, Kassab AS, Glen WB, Olive MF, Chandler LJ. Enhancement of extinction learning attenuates ethanol-seeking behavior and alters plasticity in the prefrontal cortex. J Neurosci. 2014 May 28; 34(22):7562-74. Abstract
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