SYMPOSIA

Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org
Abstracts of the Invited Speakers
The purpose of this study is to show the usefulness of the tests in the literature and to compare the advantages and disadvantages in
terms of structural validity and first sight validity.
Key words: Anxiety, anxiety models
Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S68-9
[PS-10]
Symposium Title: Will glutamatergic modulators be a target for the future therapy of depression?
Ketamine and other glutamate modulators as potential antidepressants
Serdar Dursun, Glen Baker, Nick Mitchell
Neurochemical Research Unit, University of Alberta, Edmonton, Canada
E-mail: Dursun@ualberta.ca
Depression is seen as a complex neuropsychiatric disorder affecting integrated pathways connecting discrete cortical, subcortical, and
limbic regions and their associated neurotransmitter and molecular mediators. One episode of major depression is a strong predictor of
future episodes, and more than 50% of individuals who have an episode of major depression experience a recurrence.
Unfortunately, currently approved pharmacological treatments for depression require several weeks for onset of efficacy. Despite
advances in the understanding of the psychopharmacology of depression and the introduction of several novel classes of antidepressants
in the last 3-4 decades, patient response to any given pharmacological approach continues to be unsatisfactory.
Although almost all of the prescription drugs currently available as antidepressants have effects on noradrenaline (NA) and/or
5-hydroxytryptamine (5-HT), it is obvious that other factors are also important in the etiology and pharmacotherapy of depression and
that the monoamines cannot be considered in isolation. Perhaps the most exciting system and that for which there is now substantial
translational evidence for a role in depression is that involving glutamate. Ample evidence indicates that glutamate homeostasis and
neurotransmission are disrupted in major depressive disorder but the nature of these disruptions and the mechanisms by which they
contribute to the syndrome are unclear. Likewise, the specific effects of existing antidepressants on glutamate are unclear, as is the
potential of drugs directly targeting glutamatergic neurotransmission to act as novel antidepressant medications. However, these are
areas of active research and some exciting results have been obtained.
This presentation will review the current knowledge of the contribution of the N-methyl-D-aspartate (NMDA) receptor, one of the several
types of glutamate receptors, to depression and its treatment. Several lines of evidence, in humans and in animal models, support
the contention that neurotransmission via the NMDA receptor is dysregulated in depression. Drugs targeting the NMDA receptor as
antagonists have shown antidepressant properties in both clinical and preclinical studies. Nevertheless, other effects of such medications,
including both cognitive side effects and their psychotomimetic properties, complicate such an application and represent a challenge to
the development of clinically useful agents.
There is a recent hypothesis that the therapeutic effects of monoaminergic antidepressants and the NMDA receptor antagonist ketamine
may be mediated by increased alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-to-NMDA glutamate receptor activity
in critical neuronal circuits. It has been hypothesized that ketamine directly mediates this receptor activity, whereas monoaminergic
antidepressants work indirectly and gradually; this may explain, in part, the lag of onset of clinical improvement of several weeks that
is observed with traditional antidepressants. Ketamine (intravenous) is the first medication reported to produce rapid, relatively longlasting
antidepressant efficacy. Although the precise antidepressant mechanisms of action of ketamine remain unclear, there is preclinical
evidence to suggest that both AMPA and NMDA receptor subtypes are involved. In terms of neuroanatomical sites of action, it has been
shown that the subgenual cingulate cortex (Sg CG) is overactive in depression while the dorsal frontal regions and posterior cingulate are
underactive and that successful treatment normalizes the pattern. There is also evidence from functional magnetic resonance imaging
(fMRI), which has demonstrated that the effect of ketamine resembles the pattern of normalisation after successful antidepressant
treatment, i.e., in healthy volunteers there is decreased orbitofrontal cortex (OFC)–Sg CG blood oxygen level-dependent (BOLD) signal
response and increased BOLD signal response in the dorsolateral prefrontal cortex (PFC) (Brodmann area 8) and the posterior cingulate
region. These findings suggest that an overactive Sg CG may be the dysfunctional organising region in depression.
Key words: Ketamine, rapid antidepressant efficacy, glutamate, NMDA receptor
Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S69
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