Structural neuroimaging studies in patients with mood
disorders have demonstrated regional volumetric
reductions in various grey matter areas. These changes
have also been observed in post-mortem
neuropathological studies, in which region- and layerspecific
reductions in number, density, and/or size of
neurons and glial cells have been reported. It is becoming
evident that these abnormalities may be associated with
phenomena of cellular plasticity. These are described as
the capacity of neuronal and glial cells to resist or adapt to
environmental stressors (cellular resilience), which may
translate into the ability to undergo re-modeling of
synaptic connections (synaptic plasticity) and/or cell
regeneration (neurogenesis). Increasing evidence suggests
that abnormal activity of the glutamatergic system of
neurotransmission, partly regulated via glucocorticoids
and stress mechanisms, might be involved in the
pathogenesis of impairments in cellular neuroplasticity
observed in subjects with mood disorders.
The glutamatergic neurotransmission involves a
complex system of receptors that includes ionotropic
(namely NMDA, AMPA, or Kainate receptors) and
metabotropic receptors. Importantly, dysfunctional
glutamatergic neurotransmission can result in
activation/deactivation of intracellular cascades
associated with trophic support, and neuronal or glial
death. These changes may be partially mediated by an
increased NMDA receptor throughput, predisposing the
cell to neurotoxicity-related events. Thus, it is proposed
that decreases in glutamate neurotransmission in such
systems may result in enhancement and maintenance of
neural connectivity mechanisms, which are essential for
healthy affective functioning.
It remains unclear what aspects of glutamatergic
modulation (i.e., direct inhibition of the release of
glutamate, direct effects at the ionotropic and/or
metabotropic receptors) are necessary to mediate the
antidepressant effects. Therefore a series of clinical
studies of candidate glutamatergic drugs available for
human utilization were investigated in the treatment of
mood disorders at the Mood and Anxiety Disorders Unit,
National Institute of Mental Health (Bethesda MD, US).
Riluzole, an inhibitor of glutamate release, was tested in
an open-label study with 19 treatment-resistant depressed
patients (53% of them were classified as having stage 2
treatment resistance or greater) who received riluzole
monotherapy at a mean dose of 169 mg/day for 6 weeks.
In a separate study, subjects with bipolar depression were
administered Riluzole in combination with lithium and
treated for 8 weeks. A study designed to assess possible
antidepressant effects of memantine, a selective noncompetitive
NMDA receptor antagonist, was conducted in
a double-blind, placebo-controlled study in subjects with
major depression: 32 subjects were randomly assigned to
receive memantine (5–20 mg/day) or placebo for 8 weeks.
Ketamine, an NMDA receptor antagonist primarily used
for the induction and maintenance of general anesthesia,
was investigated in a randomized, double blind, placebocontrolled,
crossover study, and the speed of onset was
also assessed. Eighteen subjects with treatment-resistant major depression received an intravenous infusion of
either ketamine hydrochloride (0.5 mg/kg) or placebo on
2 test days, one week between dosing.
The results of these studies will be presented for
discussion. These studies validate the need to better
understand the role of the glutamatergic
neurotransmission in the pathophysiology of mood
disorders. This neurotransmitter system and the associated
intracellular signaling cascades may represent a viable
target for the development of new antidepressant
interventions for the treatment of these devastating
illnesses.