Food preferences that influence the consumption of EFAs may be directly re- lated to observed differences in the rate of depression when industrialized coun- tries are compared with those in more traditional cultures. Countries where fish is a mainstay of the average diet are characterized by significantly lower rates of major and postpartum depression (Hibbeln 1998). Epidemiological data suggest an inverse relation between the consumption of food sources rich in omega-3 fatty acids and the prevalence of major depression. Cross-national studies show a decrease in the prevalence of major depression, postpartum depression, and depressive symptoms as the per capita consumption of fish increases (Hibbeln 2002). In Japan, where fish consumption is very high, only 0.12% of the popu- lation experiences depressed mood in a given year. In contrast, New Zealanders, who consume relatively little fish, reported a 6% annual rate of depression and a high suicide rate. Most epidemiological data are consistent with the hypothesis that fish consumption has a general protective effect on mood (Silvers and Scott 2002; Tanskanen et al. 2001); however, some studies have not confirmed this association (Hakkarainen et al. 2004). Although epidemiological studies show apparent correlations between dietary preferences and prevalence rates of de- pression, definitive proof of a causal association between low levels of the EFAs found in fish oil or other foods and depression can only be obtained through controlled studies.
Accumulating laboratory evidence suggests a plausible link between the di- etary ratio of omega-6 to omega-3 EFAs and the incidence of depression. One study found a positive correlation between the severity of depression and the ra- tio of AA (an omega-6 fatty acid) to EPA in erythrocytes (Adams et al. 1996). Another study reported increased production of proinflammatory cytokines in the initial acute phase of major depression (Maes et al. 1996). The clinical sig-
nificance of these findings is supported by the observation that direct adminis- tration of the same cytokines into the brain causes a dysregulation in serotonin metabolism that is consistent with changes observed in depressed individuals. Furthermore, both tricyclic antidepressants and selective serotonin reuptake in- hibitors are known to suppress the release of certain proinflammatory cytokines by immune cells, consistent with the hypothesis that conventional antidepres- sants perform a similar function in the brain, thereby positively affecting de- pressed mood (Maes et al. 1997a). The finding that omega-3 EFAs reduce the incidence of coronary artery disease by modulating the production of proin- flammatory cytokines in the heart may help to explain the observed relation be- tween the risk of heart disease and major depressive disorder (Hibbeln 1995).
Findings to date from randomized, controlled trials on omega-3 EFAs in the treatment of depression are inconsistent. A published case report claimed rapid dramatic improvement in a severely depressed, suicidal patient whose depression had been refractory to multiple antidepressant trials, including lithium augmen- tation (Puri et al. 2002). That patient showed sustained improvement in mood over a 9-month period while taking EPA (4 g/day) alone. No adverse effects were reported.
Three controlled studies have yielded promising results for pure EPA in the form of ethyl ester EPA as an adjunctive treatment in refractory major depressive disorder. A small double-blind study (n = 36) comparing monotherapy with DHA 2 g/day and placebo for 6 weeks showed no statistical difference in de- pression response rates (Marangell et al. 2003). However, three other double- blind, placebo-controlled trials found that purified ethyl ester EPA or combina- tions of purified EPA and DHA resulted in significant improvement in the se- verity of depressed mood compared with placebo (Nemets et al. 2002; Peet and Horrobin 2002; Su et al. 2003). One study demonstrated significant improve- ments in depressed mood in response to combinations of EPA and DHA at dos- ages as high as 9.6 g/day (Su et al. 2003). Researchers in another small double- blind trial concluded that depressed patients taking EPA 1 g/day were more likely to improve compared with a placebo group, but that higher doses of EPA did not result in an improved response (Peet and Horrobin 2002). Another con- trolled trial compared two groups of adults with uncomplicated depression (i.e., no comorbid medical or psychiatric disorders) treated with a placebo versus pu- rified ethyl ester EPA (2 g/day) while continuing their antidepressant medica- tions (Nemets et al. 2002). No patients included in the study met criteria for re- fractory depression, and all but one had experienced complete remission with previous trials of conventional antidepressants. Ratings using the Hamilton Rat- ing Scale for Depression (Ham-D) were taken at the start of the study and weekly thereafter. Average baseline scores were 18 or higher. By week 2, Ham- D scores were significantly different between the placebo and EPA groups, and by the end of the study, EPA-treated patients showed a mean reduction of 12.4
points, compared with only 1.6 points in patients receiving a placebo. Overall, 6 of the 10 patients assigned to the EPA group showed a 50% reduction in Ham- D scores, compared with only 1 of 10 patients in the placebo group. EPA had a significant effect on several core depressive symptoms, including insomnia and feelings of guilt and worthlessness. There were no reports of significant adverse effects in either group, and only one patient dropped out (placebo group) be- cause of worsening depression. The authors noted that the results did not clarify whether EPA had an independent antidepressant effect or augmented antide- pressants via second-messenger systems in a manner similar to the postulated mechanism for lithium augmentation. Confirmation of the significance of a pri- mary antidepressant effect and clarification of the mechanism of action of EPA will require long-term, prospective studies that include arms assigned to receive antidepressants alone, omega-3 fatty acids alone, or combined antidepressants and omega-3 fatty acids and a broader range of depression subtypes.
A trial is currently being conducted that will determine whether adding EPA to citalopram (Celexa) will accelerate treatment response (“PUFA Aug- mentation in Treatment of Major Depression,” available at: www.clinicaltri- als.gov/ct/show/NCT00067301?order=1). All patients in the study (N = 60) will receive citalopram, and one-half will be randomized to EPA or placebo. The study is expected to be completed in mid-2006.
Bipolar Disorder
Case reports and the findings of one small double-blind trial suggest that omega- 3 EFAs improve depressive and manic symptoms in bipolar patients, possibly by inhibiting the activity of CNS phospholipases and thereby reducing the release of unsaturated EFAs from nerve cell phospholipids and by limiting the produc- tion of specific prostaglandins (e.g., prostaglandin E1) that are known to be as-
sociated with mania or depression. It has been postulated that lithium, dopamine antagonists, and serotonin-blocking agents are effective in treating mania through a similar mechanism of action that corrects overactivity in cell mem- brane signal transduction processes.
Until now there have been no large studies on the efficacy of omega-3 EFAs in the treatment of bipolar disorder, and all studies conducted to date have been designed to assess the efficacy of omega-3 EFAs in combination with mood-sta- bilizing medications and not alone. However, findings from one small double- blind study (Stoll et al. 1999) suggest that bipolar disorder patients taking omega-3 fatty acids alone remained in remission significantly longer than matched patients receiving only a placebo. In this 4-month placebo-controlled, double-blind study, 30 bipolar patients were treated with a combination of omega-3 EFAs (6.16 g EPA plus 3.36 g DHA for a total dosage of 9.5 g/day) or placebo (olive oil) in combination with their usual mood-stabilizing medica-
tions (including lithium, valproic acid, carbamazepine, and others). Post hoc analysis determined that 4 out of 8 patients who took only omega-3 fatty acids remained in remission significantly longer than 3 patients who received only placebo. Furthermore, among the remaining 22 patients taking mood-stabiliz- ing drugs, those treated with omega-3 EFAs performed significantly better on all outcome measures compared with patients in the placebo arm. In another 4- month double-blind, placebo-controlled study, 120 bipolar patients were ran- domized to omega-3 EFAs (ethyl ester EPA) 6 g/day or placebo in combination with their conventional mood stabilizers (Keck et al. 2002). The response rates in the omega-3 EFA and placebo groups were not significantly different.
Schizophrenia
Case reports (Puri et al. 2002; Su et al. 2001) and small double-blind trials (Laugharne et al. 1996; Mellor et al. 1995; Peet et al. 1996) have demonstrated sustained improvements in positive and negative symptoms in chronic schizo- phrenic patients who consume certain omega-3 EFAs and are not being treated with conventional antipsychotic medications. Findings of a small 4-month open study suggest that combining EPA and DHA with antioxidant vitamins reduces the severity of positive and negative symptoms and improves overall quality of life (Arvindakshan et al. 2003). Findings of studies evaluating the putative antip- sychotic efficacy of omega-3 EFAs as an adjunctive treatment for schizophrenia have been inconsistent. In a 12-week controlled trial, schizophrenic patients randomized to adjunctive EPA experienced greater reductions in psychotic symptoms compared with those who received only DHA or placebo while con- tinuing on a conventional antipsychotic (Peet et al. 1996). All patients remained on conventional antipsychotics throughout the study. In a large 3-month con- trolled study (n =115), patients with schizophrenia refractory to conventional antipsychotics were randomized to ethyl ester EPA 1, 2, or 4 g/day or placebo while remaining on conventional drugs (Peet et al. 2002). Those taking EPA 2 g/day concurrently with clozapine experienced the most significant and sus- tained improvements; however, a differential effect was not observed in patients who combined EPA with other antipsychotic drugs. The finding of a specific augmentation effect with clozapine is consistent with Horrobin’s membrane phospholipid hypothesis (see above). In another controlled study, sustained re- ductions in psychotic symptoms and tardive dyskinesia were observed after 3 months of augmentation with purified EPA (ethyl ester EPA 3 g/day) (Emsley et al. 2002). However, another double-blind, placebo-controlled study found no differences in response between EPA (3 g/day) and placebo in a group of 87 schizophrenic patients concurrently taking antipsychotic medications (Fenton et al. 2001). In contrast to the studies discussed earlier, these patients were treated for residual psychotic symptoms and were not treated while in the early, acute phase of illness.