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The experience of stress is often utilised in models of emerging mental illness and neurobiological systems are implicated as the intermediary link between the experience of psychological stress and the development of a mental disorder. Chronic stress and prolonged glucocorticoid exposure have potent effects on neuronal architecture particularly in regions that modulate the hypothalamic-pituitary-adrenal (HPA) axis and are commonly associated with psychiatric disorders. This review provides an overview of stress modulating neurobiological and neurochemical systems which underpin stress-related structural and functional brain changes. These changes are thought to contribute not only to the development of disorders, but also to the treatment resistance and chronicity seen in some of our most challenging mental disorders. Reports to date suggest that stress-related psychopathology is the aetiological mechanism of these disorders and thus we review the rapid acting antidepressant ketamine as an effective emerging treatment. Ketamine, an N-methyl D-aspartate (NMDA) receptor antagonist, is shown to induce a robust treatment effect in mental disorders via enhanced synaptic strength and connectivity in key brain regions. Whilst ketamine's glutamatergic effect has been previously examined, we further consider ketamine's capacity to modulate the HPA axis and associated pathways.

While numerous studies have employed magnetic resonance spectroscopy (MRS) to determine in vivo neurometabolite levels associated with mood disorders the findings in both unipolar depression and bipolar disorder have been mixed. Data-driven studies may shed new light on this literature by identifying distinct subgroups of patients who may benefit from different treatment strategies. The objective of the present study was to utilize hierarchical cluster analysis in order to generate new hypotheses with respect to neurometabolic profiling of mood disorder. Participants were 165 young persons (18-30 yrs) with a mood disorder and 40 healthy controls. Neurometabolite levels were recorded via proton-MRS ((1)H MRS). The ratios (relative to creatine) of glutamate (GLU), N-acetyl aspartate (NAA) and myo-inositol (MI) measured within the hippocampus. Self-reported and clinician rated symptoms as well as cognition were also measured. The unipolar depression (N=90) and bipolar disorder (N=75) groups did not significantly differ (from each other or controls) in their levels of GLU, NAA or MI. Cluster analyses derived four subgroups of patients who were distinguished by all three metabolites. There was a pattern of positive association between NAA and GLU, whereby clusters were abnormally increased (clusters 1, 2) or normal (cluster 4) or abnormally decreased (cluster 3) in these neurometabolites. These findings suggest that there are neurometabolic abnormalities in subgroups of young people with mood disorder, which may occur despite diagnostic similarities. Such evidence highlights that the underlying neurobiology of mood disorder is complex and MRS may have unique utility in delineating underlying neurobiology and targeting treatment strategies.

Aberrant glutamate neurotransmission has been implicated in the pathophysiology of bipolar disorder with accumulating evidence from imaging, post-mortem and pathology studies. Studies investigating in vivo changes to the glutamatergic system have not been as consistent and warrant clarification. Studies utilizing proton-magnetic resonance spectroscopy (1H-MRS) have reported increased levels of combined glutamate and glutamine (“Glx”), which have been linked to impairments in N-methyl-d-aspartate (NMDA) receptor function. Similarly, neurophysiological studies utilising mismatch negativity (MMN) as an index of NMDA receptor function, have reported impairments in bipolar disorder. Here, we provide a systematic review of the literature in regards to the concentration of Glx and the magnitude of MMN in bipolar disorder. Separate meta-analyses revealed that bipolar disorder was associated with increased Glx concentration and decreased MMN—both measured frontally. The current findings corroborate previous evidence indicating that bipolar disorder is characterized by a perturbed frontal glutamate system. These observed changes in bipolar disorder might manifest as impairments in neuronal–glial interactions that lead to disrupted neuronal output and ultimately result in the characteristic neurocognitive sequelae associated with this disorder.