The Biological Mechanisms of N-3 Polyunsaturated Fatty Acid Treatment in Interferon-Induced Depression

The growing burden of depression is as evidenced by the projection that depression will be the second leading cause of disease or injury in the world by 2020 (WHO). The unsatisfaction of monoamine-based antidepressant therapy and the high occurrence of somatic symptoms and physical illness in patients with depression imply that the serotonin hypothesis is insufficient to approach the etiology of depression. Inflammation is increasingly recognized as contributing to the pathogenesis of depression, and the most strikingly supportive evidence for this inflammation theory is actually the behavioral changes induced by pro-inflammatory cytokines in clinical and animal studies. In fact, as high as 20% to 45% of patients develop major depression in 3 months after starting interferon-alpha (IFN-α) therapy for chronic hepatitis C viral infection. N-3 polyunsaturated fatty acids (PUFAs) play an important role in major depressive disorder. Low n-3 PUFAs levels have been reported in patients with major depressive disorder in our recent meta-analytic review. We and others also demonstrated that n-3 PUFAs have antidepressant effects in double-blind, placebo-controlled trials. N-3 PUFAs might not be more effective than conventional antidepressant medication, which means more than 60% of depressed patients might not experience remission and more than 30% might not show a significant response to n-3 PUFAs. In cellular and animal models, the biological mechanisms of n-3 PUFAs’ antidepressant effects have been found to be associated with their anti-inflammatory effects, which make this current proposal relevant to investigate the therapeutic and mechanistic roles of n-3 PUFAs in interferon-induced depression. This project is composed of both clinical and basic studies and will be conducted collaboratively in China Medical University and King’s College London. The clinical part is an extension of our previous NSC project with a randomized placebo-controlled study to investigate the antidepressant effects of n-3 PUFAs. The biological markers, including cytokine and PUFA levels and genetic variations and expressions of key enzymes for PUFA metabolism, will be built on the clinical trial to approach the roles of PUFAs in the treatment of IFN-alpha-induced depression. To provide the mechanistic insight into how n-3 PUFAs affect neural functioning, the basic part of this project is to look at the effects of n-3 PUFAs on inflammation, signal transduction, and neurotransmissions in cellular models with neurons, astrocytes and microglial cells. Under the grants supported by the National Science Council (NSC) including the Initiative Research Cooperation among Top Universities between UK and Taiwan, the two research teams have been working together in a series of clinical and basic research and publishing several high-impact papers. In London, Dr Pariante’s team will look for the role of n-3 PUFAs on the development of depression, with cytokine/inflammation models in cellular experiments and in clinical settings with patients receiving in IFN-α therapy (Su et al., 2010;Zunszain et al., 2011). In Taiwan, Drs Huang and Su teams will work with a parallel group with HCV patients receiving in IFN-α therapy and the healthy controls, to clarify the effect of n-3 PUFAs and the biological markers on depressive symptoms, and to identify the predictive markers and the biological effects of n-3 PUFAs treatment in human subjects on markers reflecting inflammation and neurotransmission.