Several investigators (Stoll and Severus, 1996 and Manji and Lenox, 1998) strongly suggested that the mechanism of action of mood stabilizers is involved in postsynaptic signal transduction processes. Two mood stabilizers (lithium and valproate) appear to treat the same symptoms of patients with bipolar disorder, through different effects on signal transduction in the brain. Recently, Chang et al. (2001) found that lithium and valproic acid have a common action in reducing turnover of arachidonic acid (AA), the major omega-6 polyunsaturated fatty acids (PUFA) in rat brain. Furthermore, a 4-month double-blind, placebo-controlled study, comparing omega-3 PUFAs vs. placebo, in addition to usual treatment, suggested that omega-3 PUFAs may exhibit mood-stabilizing properties in bipolar disorder (Stoll et al., 1999). Thus, PUFAs, as well as lithium and antimanic anticonvulsants, seem to play an important role in the mechanism of mood stabilization by targeting parts of the “arachidonic acid cascade”, which may be functionally hyperactive in mania (Rapoport and Bosetti, 2002).
It has been hypothesized that abnormalities in fatty acid composition may play a role in psychiatric disorders (Horrobin and Bennett, 1999). Maes et al., 1996 and Maes et al., 1999 reported that patients with major depression had a significantly elevated ratio of ecosapentaenoic acid (EPA; 20:5n-3)/docosahexaenoic acid (DHA; 22:6n-3), lower level of EPA and total n-3 PUFAs, in both serum cholesteryl esters and phospholipids when compared to patients with minor depression and normal controls. Similar findings were revealed in terms of fatty acid compositions of the erythrocyte membrane (Adams et al., 1996, Edwards et al., 1998 and Peet et al., 1998). Generally, PUFAs are classified mainly into omega-3 (or n-3) and omega-6 (or n-6) groups. Cerebral cell membranes are composed of certain PUFAs, which cannot be synthesized and must therefore be obtained from the diet. The abnormalities in PUFA composition in cell membranes can alter membrane microstructure, resulting in abnormal signal transduction and immunological regulation. In general, the omega-6 fatty acid, AA is proinflammatory and associated with up-regulation of release of various cytokines. In contrast, the omega-3 fatty acids, EPA and DHA, are anti-inflammatory (Horrobin and Bennett, 1999). Interestingly, patients with bipolar disorder have also been reported to have altered immune functions (Kronfol and House, 1988), including leukocytosis (Kronfol et al., 1988), higher prevalence of thyroid autoantibodies (Lazarus et al., 1986), high rate of immune-related diseases (Tsai et al., 1997), and abnormalities in cytokine levels (Maes et al., 1995, Su et al., 2002, Tsai et al., 1999 and Tsai et al., 2001). Thus, PUFAs also seem to play an important role in the abnormality of psychoimmunology of patients with bipolar disorder.
Despite this evidence from animal studies, psychoneuroimmunology studies, and clinical trials, well-controlled studies on PUFA levels in bipolar manic patients are still sparse. Mahadik et al. (1996) reported the only study that compared PUFA compositions of cultured skin fibroblasts of 12 schizophrenic patients to those of six bipolar patients and eight normal control subjects. They found that there was no difference between bipolar patients and normal subjects. However, their results are difficult to interpret due to various limitations. (1) The sample size is small (n=6) and the aim of their study is to examine the abnormalities of fatty acids in schizophrenic rather than bipolar patients. (2) The clinical status, such as durations of the illness, mood state (mania, depression or mixed), the severity of the symptoms, in these bipolar patients was not well-defined or controlled. (3) No information was given regarding to the use of the mood stabilizing drugs and the antipsychotic drugs, which were also found to influence the PUFA levels ( Horrobin et al., 1997). (4) The PUFA level from fibroblasts (instead of erythrocyte) has not been confirmed to reflect that in the brain ( Neuringer et al., 1984 and Makrides et al., 1994).
To address these issues, we conducted a study on erythrocyte PUFAs in acute manic patients compared with matched normal controls.
