The Study of Polymorphisms and Expressions in Genes of Omega-3 Fatty Acid Metabolism Enzymes in the Patients with Major Depressive Disorder

Background. With the unsatisfaction of monoamine-based pharmacotherapy and the high comorbidity of physical illness in depression, the serotonin hypothesis seems to fail in approaching the aetiology of depression. Based upon the evidence from epidemiological data, case-control studies of PUFAs levels in human tissues, and antidepressant effect in clinical trials, phospholipid polyunsaturated fatty acids (PUFAs) is enlightening a promising path to discover the unsolved of depression. N-3 (or omega-3) PUFAs play an important role in major depressive disorder, as shown by epidemiological studies, case-control studies of PUFAs levels in human tissues, and clinical trials of their antidepressant effect. For example, we and others have reported the antidepressant effect of n-3 PUFAs in double-blind, placebo-controlled trials. In the animal model, we also have reported that n-3 PUFAs have a preventing effect against depression-like behaviours induced by the forced swimming test. Theoretically, DHA deficit is associated with dysfunctions of neuronal membrane stability and transmission of serotonin, norepinephrine and dopamine, which might connect to aetiology of depression. On the other hand, EPA is important in balancing the immune function by reducing membrane arachidonic acid (AA, an n-6 PUFA) and prostaglandin E2 (PGE2) synthesis. Interestingly, animals fed with high AA diet can increase PGE2 levels and induce sickness behaviour of anorexia, low activity, change in sleep pattern and attention, which are similar to somatic symptoms of depression in human. There are several important Questions to Answer in regard with the PUFA hypothesis of depression. Firstly, although case-control studies revealed that depressive patients had lower levels of n-3 PUFAs, the abnormal findings in individual PUFA of DHA, EPA or AA are not consistent. Secondly, the levels of n-3 PUFAs are determined by their metabolic enzymes, e.g. phospholipase A2 (PLA2) or cyclo-oxygenase 2 (COX2). However, the association study of polymorphisms of PLA2 or COX2 genes in depression is lacking. Thirdly, the mechanism of the antidepressant effect of n-3 PUFAs has never been studied in gene expression in human. Method. This project will be carried out in 3 years. The first part is a case-control cross-section study to clarify the effects of levels of DHA, EPA and AA, and polymorphisms of the genes coding cPLA2, COX2, serotonin transporter (5HTTLPR) and tryptophan hydroxylase-2 (TPH-2), on depression symptom clusters (Core, Activity, Sleep, Anxiety, Somatics and Delusion), in 100 patients with major depressive disorder and 100 normal controls. The second part aims to identify the effects of n-3 PUFAs on peripheral gene expression in patients with depression. We will enrol 20 patients with major depressive disorder to receive open-labelled n-3 PUFAs 3 gram per day for 8 weeks. The response and remission of n-3 PUFAs’ antidepressant effect will be evaluated by Hamilton Rating Scale of Depression. The changes of gene expression of PLA2, COX-2, serotonin transporter and TPH-2 will be examined by real-time RT-PCR and compared with that of 20 normal controls. The Anticipated Results are: 1). The polymorphisms of genes coding PLA2 or COX2 have effects on the compositions of individual PUFAs and specific symptom clusters of depression. Specifically, individuals with BanI G/G genotype of cPLA2 might have higher levels of AA, lower levels of EPA, more somatic symptoms and higher risk of depressive disorders. EPA levels might have effects on somatic symptoms, while DHA levels might have a effect on core depressive symptoms; 2) PUFAs treatment might increase the gene expressions of 5-HTT and TPH-2, and reduce the gene expressions of cPLA2 and COX2. Under the grants supported by the National Science Council (NSC) for the eight consecutive years, our research team has been involved in a series of research on n-3 PUFAs in depressive disorders and has earned its internationally renowned reputation. If successful, the conducting of this proposal will lead to a successful integration of knowledge to understand phospholipid hypothesis of depression.