Glutamate and Psychiatry ,Ahmed Albehairy ,Psychiatry consultant Ministry of Health , EGYPTReference: Glutamate and Psychiatry in 2012—Up, Up and Away!By Clairélaine Ouellet-Plamondon, MD, FRCPC and Tony P. George, MD, FRCPC | December 12, 2012Dr Ouellet-Plamondon is a Fellow in Schizophrenia and Addiction Psychiatry at the Centre for Addiction and Mental Health in Toronto. Dr George isProfessor of Psychiatry and Co-Director of the Division of Brain and Therapeutics at the University of Toronto.
Introduction• Glutamate is the major excitatory neurotransmitter in the brain.• It is involved in the neuro-circuitry of memory, emotions, and cognition, and is implicated in , depression, anxiety, schizophrenia, and , drug addiction.
Anxiety disorders• Stress is an important risk factor in the genesis of anxiety disorder.
Mood disorders• Monoamine antidepressants are only effective in 50% to 60% of depressed patients, and only about 70% respond after 4 acute treatment steps based on STAR*D algorithms.• !?! Glutamate dysfunction is involved in the limbic and prefrontal circuits of depressed individuals.• An increase of extracellular glutamate during acute and chronic stress and during depression .
Addiction Disorders• The mesocorticolimbic dopamine system is central to our understanding of addiction.• Glutamate modulates dopamine activity and is involved in the development and maintenance of drug dependence, particularly in reinstatement to drug- seeking behavior.
(NAC)• N-acetylcysteine )NAC(, is a glutamate modulator that acts on the glutamate/cysteine exchanger, on cocaine seeking in the early and late stages of the acquisition and maintenance.• NAC dose-dependently decreased the propensity to seek cocaine but had no effect on the reinforcing properties of cocaine.
Schizophrenia• Noncompetitive NMDA-R antagonists such as phencyclidine and ketamine can elicit the positive, negative, and cognitive symptoms of schizophrenia in healthy individuals, ) hypothesis of impaired NMDA-R functioning in psychosis(.
Future Implications of Glutamate in PsychiatryUnderstanding the pathophysiologyof glutamate systems has yieldedtremendous progress,which we hope will translate into noveland exciting neurotherapeutics.
Future Implications of Glutamate in Psychiatry• Anxiety disorder, new drugs that target glutamatergic neurotransmission may be promising on the stress- related anxiety disorders.• N-methyl-D-aspartate receptor )NMDA-R( antagonists )memantine(, NMDA-R partial agonists )D-cycloserine(, and metabotropic glutamate receptors 2 and 3 )mGluR2/3( allosteric modulators )LY354740 and LY544344( may be candidates for the treatment of anxiety disorders.• Presynaptic autoreceptor mGluR2/3 agonists seem to be associated with clinical efficacy.
Future Implications of Glutamate in Psychiatry• Mood disorders, increament of glutamate system may hasten onset of action of antidepressant treatment.• So , ketamine—a nonselective NMDA-R antagonist. In Subanesthetic doses appear to enhance the strength of cortical synapses through NMDA-R– and a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR)-dependent and neurotrophic mechanisms and may rapidly reverse prefrontal cortex–based deficits in depression.
Future Implications of Glutamate in Psychiatry• Ketamin , ketamine infusion experienced a rapid and robust antidepressant response and a rapid diminution in suicidal ideation. In, Depressive symptoms in treatment-resistant depression, ketamine produced rapid reductions in depressive symptoms and had a relatively benign adverse-effect profile.
Future Implications of Glutamate in Psychiatry• In addiction , NAC was effective in decreasing marijuana use in adolescents. NAC was well tolerated and associated with minimal adverse effects.• Pharmacological modulation of the glutamate system may prove to be useful in the control of a range of compulsive behaviors.
Future Implications of Glutamate in Psychiatry• Schizophrenia, A number of compounds licensed for medical conditions, including several NMDA-R and mGluR agents, may have antipsychotic effects, but none has proved overall benefit over risks )adverse effect, tolerability(.• The Cognitive and Negative Symptoms in Schizophrenia Trial )CONSIST( found no beneficial effect of glycine as an add-on treatment in chronic schizophrenia.• Nonetheless, given a clear role for glutamate in the neurobiology of psychosis, it remains an active target for drug development. •