Anxiety and mood disorders are amongst the most prevalent and disabling of all the psychiatric disorders. Under-diagnosis and current treatments that are often less than adequately effective, contributes to an enormous personal and economic cost to the patient, family and health-care organizations. Although distinctly separate disorders at neuropathological and phenomenological levels, brain-imaging studies in posttraumatic stress disorder (PTSD) and depression have emphasized that both

more »

... s may induce damaging effects on regions of the brain involved in regulating the response to stress. While controversy prevails as to whether these changes represent an adaptive process or are indeed pathological, they are associated with marked changes in memory and other cognitive functions. In depression, a history of prior episodes is correlated with a higher risk of relapse, while poor compliance with antidepressants not only predicts later relapse, it may result in a more rapid shrinkage of the abovementioned brain regions, possibly providing a basis for relapse and treatment resistance. Similarly, even with the introduction of effective medications for PTSD, many patients remain treatment-resistant. Stress in various guises may alter synaptic connectivity in the brain by bolstering glutamatergic excitotoxic mechanisms. Understanding these mechanisms may assist in developing more effective treatment strategies. This paper will review pre-clinical and clinical evidence supporting a role for the glutamatenitric oxide pathway as a putative mediator of the neuropathological changes evident in depression and stress-related disorders, particularly PTSD, and its potential as a novel target for psychotropic activity.