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R E V I E W S
Mood disorders major depressive disorder (http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=608516
Web End =MDD ) and bipolar disorder (http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=125480
Web End =BPD ) are serious, debilitating, life-shortening illnesses that affect millions of people worldwide. The lifetime risk for any mood disorder in the United States is 20.8%, and onset typically begins in childhood or adolescence1. Mood disorders are chronic illnesses characterized by multiple episodes of symptom exacerbation, residual symptoms between episodes and functional impairment24. The World Health Organizations (WHO) Global Burden of Disease project ranked MDD as the fourth leading cause of disability in 1990, and predicts that by 2020 it will become the second leading cause of disability worldwide5.
Although most patients with mood disorders receive some benefit from available treatments6,7, the largest
open-label study examining the effectiveness of pharmacological treatment of MDD conducted so far (STAR*D)7
found that less than one-third of patients achieved remission with an adequate trial of a standard antidepressant after up to 14 weeks of treatment. Furthermore, it was not until the completion of two antidepressant trials and nearly 24 weeks of treatment that half of the patients with MDD in the STAR*D study remitted. Similarly, many patients with BPD do not respond to existing medications8, particularly during depressive episodes6,9.
A major obstacle to developing more effective treatments for mood disorders has been our limited understanding of their pathophysiology, and of the mechanisms underlying the efficacy of existing treatments. Mood
disorders arise from the complex interaction of multiple genes and environmental factors, and the phenotypic expression of the disease includes not only mood disturbance, but also a range of cognitive, motor, autonomic, endocrine and sleep/wake abnormalities. To date, the monoaminergic (that is, serotonergic, noradrenergic and dopaminergic) systems in the brain have received the greatest attention in neurobiological studies of mood disorders. These systems project widely to limbic, striatal and prefrontal cortical neuronal circuits that are implicated in the behavioural and visceral manifestations of mood disorders (reviewed in REFS 1012).
However, there are limitations to current monoamine theories related to mood disorders. For example, most antidepressants exert their initial effects by increasing the intrasynaptic levels of serotonin and/or noradrena-line. Nevertheless, meaningful improvement in core depressive symptoms emerges only after several weeks of antidepressant administration, suggesting that downstream...