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 long-lasting 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.