Affective disorders are widely distributed disorders with severe social and economic effects. Strong evidence underlines that effective treatment helps to restore function and quality of life. Unfortunately, patients with major affective disorders respond variably and, at times, unpredictably to different treatments, which underline the need of alternative approaches. Due to the action of most modern antidepressant drugs, serotonergic mechanisms have traditionally been suggested to play major roles in the pathophysiology. However, recent clinical evidence strongly suggests involvement of neurodegenerative pathology in the disease. Since there is accumulating evidence that the novel neurotransmitter NO acts as a neuromodulator, and participate in several sub-cellular processes, such as cellular memory and neuronal toxicity, nitrergic pathways may have an important role in hippocampal degenerative pathology and cognitive deficits seen in patients with affective disorders.

A few clinical and several pre-clinical studies, strongly suggests involvement of the nitric oxide (NO) signalling pathway in these disorders (Harvey 1996). Several of the conventional neurotransmitters, including serotonin, glutamate and GABA, are intimately regulated by NO (Wegener et al. 2000). Interestingly, distinct classes of antidepressants (Imipramine, Tianeptine, Citalopram and Paroxetine) have been found to modulate the NO level in the living rat hippocampus in clinically relevant doses (Wegener et al. 2003). Moreover, our recent work, using selective inhibitors of phosphodiesterase 5, indicate that the whole NO signalling pathway may play a major role in the behavioural and neurochemical effects observed.

The NO system is therefore a potential target for antidepressant and anxiolytic drug action in acute therapy as well as in prophylaxis.