Polyunsaturated fatty acids (PUFA) include omega-3 and omega-6. Omega-3 fatty acids include eicosapentaenoic acid (EPA) and docosahexaenoic (DHA), which together are important ingredients in fish oil. EPA and DHA are essential for normal brain development and are the most widely sold dietary supplements in the U.S., surpassing even multivitamins. Possible links between PUFA and serious psychiatric disorders have been investigated for more than two decades.58 Some studies have suggested that the geographical prevalence of schizophrenia or affective disorders correlates with fish consumption; a lower fish consumption was associated with a higher prevalence of bipolar disorder, but the results for schizophrenia were less clear.59,60 Some studies have reported that PUFA levels are reduced in individuals with bipolar disorder, but a study of DHA levels in women who gave birth to children who developed psychotic disorders found DHA levels to be elevated.61 Confounding factors such as smoking make the interpretation of these studies difficult.59-60

Mechanism of Action

PUFA are essential ingredients in cell membranes and are thought to affect signal transduction pathways. They are known to inhibit phospholipase A-2 and cyclo-oxygenase and thought to modulate oxidative stress62-63, but their precise mechanism of action in psychiatric disorders is not known.

Use in Schizophrenia

At least seven double-blind adjunct treatment trials have been carried out, four with positive findings and three negative. All used between 1g and 4g of EPA and lasted 12 to 16 weeks. The three negative studies involved 69, 87, and 115 patients, both first-episode and chronic; one of the studies reported positive symptom improvement only for the patients on clozapine.64-66 The first three positive studies were smaller (n=30, 40, and 45). They were noteworthy because one showed EPA as superior to DHA;67 another reported 6 out of 14 patients maintained on EPA without antipsychotics;67 and, the third claimed “remarkable” symptom improvement in chronic patients.68 However, a meta-analysis of all six studies concluded that “omega-3 EPA did not alleviate the symptoms of schizophrenia.”59 In perhaps the most interesting of the positive studies, young people thought to be at ultra-high risk for developing psychoses were randomized to 1.2g/day of omega-3 fatty acids or placebo for 12 weeks. Nine months after completion of the trial, 2/41 individuals (5%) in the omega-3 group but 11/40 individuals (28%) in the placebo group had transitioned to a psychotic disorder.69 SMRI is supporting a five-year follow-up of the individuals in this trial as well as a large (n=320) replication of this study and a study using omega-3 fatty acids to try to prevent the recurrence of schizophrenia in individuals who have recovered from their initial episodes.

Use in Bipolar Disorder

At least three double-blind, placebo-controlled adjuvant trials have utilized omega-3 to treat adult bipolar disorder. A study of 30 bipolar patients, both types I and II, used 9.6mg/day of EPA and DHA and reported a “striking difference in relapse rates and response” for patients on omega-3 compared to placebo.70 A study of 75 patients with bipolar depression, using EPA 1g or 2g for 12 weeks, reported a significant improvement in depression for patients on either dose compared to placebo.71 However, a study of 121 bipolar patients (59 depressed, 62 rapid cyclers) reported no marked effect of EPA 6g/day for 4 months.72 In addition, an open-label study of 12 bipolar depressed patients, using EPA 1.5–2g/day for up to 6 months, reported an improvement in depressive symptoms.73 Finally, an open-label study of 18 children with juvenile bipolar disorder reported improvement in manic and depressive symptoms using a combination of EPA and DHA for 6 weeks.74


The possible role of omega-3 in treating schizophrenia is unclear. As a recent Cochrane Review summarized it: “There is currently still no reason for clinicians to either encourage or discourage the use of polyunsaturated fatty acids. If a person with schizophrenia wishes to use one then, perhaps, an omega-3 preparation should be the preferred option.”75 For bipolar disorder, especially the depressed symptoms, omega-3 appears to be more promising. One meta-analysis of ten studies of omega-3 for treating depression also suggests the same conclusion.76 We have performed, but not yet published, a meta-analysis of omega-3 in depression and found DHA-predominant preparations to be without clinical efficacy; however, preparations that contain at least 50% or more EPA are consistently superior to placebo in treating depression. Since omega-3 supplements are widely available and apparently without serious side effects, they are probably worth trying.