1. Glutamate and Psychiatry
,Ahmed Albehairy
,Psychiatry consultant
Ministry of Health , EGYPT
Reference: Glutamate and Psychiatry in 2012—Up, Up and Away!
By Clairélaine Ouellet-Plamondon, MD, FRCPC and Tony P. George, MD, FRCPC | December 12, 2012
Dr Ouellet-Plamondon is a Fellow in Schizophrenia and Addiction Psychiatry at the Centre for Addiction and Mental Health in Toronto. Dr George is
Professor of Psychiatry and Co-Director of the Division of Brain and Therapeutics at the University of Toronto.

2. 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.

3. Anxiety disorders
• Stress is an important risk factor in the
genesis of anxiety disorder.

4. Stress and Anxiety disorders

5. 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 .

6. 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.

8. (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.

9. 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(.

10. Future Implications of
Glutamate in Psychiatry
Understanding the pathophysiology
of glutamate systems has yielded
tremendous progress,
which we hope will translate into novel
and exciting neurotherapeutics.

11. 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.

12. 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.

13. 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.

14. 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.

15. 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.
•

16. THANK
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