According to former Food and Drug Administration scientist Jerry Cott, PhD, omega-3 fatty acids are the most exciting development in psychiatry in the last 40 years. Several new studies show that omega-3s can reduce symptoms and disabilities associated with depression, schizophrenia, and bipolar disorder.

ANAHEIM, CA—Omega-3 fatty acids are, “the most exciting thing that’s happened in psychiatry in 40 years,” said Jerry Cott, PhD, of the Food and Drug Administration’s Center for Drug Evaluation and Research.

Speaking at the annual Nutracon conference on advances in nutraceutical development and research, Dr. Cott said recent discoveries of the benefits of these essential fatty acids in depression, bipolar disorder and schizophrenia, “will lead to a whole new way of treating mental disorders.”

That’s no small assertion coming from a researcher who spent much of his career as chief of the National Institute of Mental Health’s psychopharmacology research program. While research is still at an early stage, the available data suggest “there’s much hope for the future.”

Indeed, there is something to the notion that fish is “brain food.” Omega-3s, abundant in oily cold-water ocean fish, are integral to proper neuronal function.

Neuronal cell membranes normally have high concentrations of omega-3 fatty acids, particularly docosahexaenoic acid (DHA), as well as arachidonic acid (AA). These two fatty acids each comprise roughly 25% of the total membrane phospholipid content. Deficiency of omega-3s, especially DHA, impairs neuronal membrane function and has been linked to depression, aggression, bipolar cycling, and schizophrenia.

There is a strong link between increased prevalence of depression and decreased omega-3 intake (Hibbeln JR, et al. Lancet 1998; 351:1213). Patients with major depression have significantly increased AA relative to eicosapentaenoic acid (EPA) and DHA in both plasma and in red blood cell membranes. Fatty acid content in red cell membranes is thought to mirror that of the neurons (Peet M, et al. Biol Psychiatry 1998; 43:315–319).

The mechanism by which omega-3 deficiency contributes to depression is not entirely clear, but Dr. Cott pointed out that neurotransmitter receptors are embedded in the phospholipid membranes. The shape of these receptors is dependent on the fatty acids that structure the membrane. In other words, different fatty acids create different receptor shapes, and this influences the kinds of signals passing through the neurons.

Powerful Adjunct for Depression

Omega-3s are an effective adjunct to antidepressant drugs, especially in patients in whom conventional therapy is insufficient. In one recently published trial, 70 patients with persistent depression despite “adequate” pharmacotherapy were randomized to placebo or EPA at a dose of 1, 2 or 4 g per day for 12 weeks. EPA proved better than placebo on the HAM-D, Montgomery-Asberg Depression Rating Scale and Beck Depression Inventory. Among those completing the trial according to protocol, 69% of the EPA 1 g group had 50% reductions of HAM-D scores, compared with only 25% of those on placebo (Peet M, Horrobin DF. Arch Gen Psych 2002; 59:913–919).

A second trial randomized 20 patients with major depression to 4 weeks of adjunctive therapy with EPA or placebo, and revealed significant benefits from EPA by week 3 (Nemets B, et al. Am J Psychiatr 2002; 159(3):477–479). It remains to be seen whether EPA or DHA have antidepressant effects independent of concurrent drug therapy. But given the evidence of neuronal membrane DHA depletion in depression, there is reason to think they would.

Omega-3s could also prevent post-partum depression (PPD). Without supplementation or a high seafood diet, maternal omega-3 levels decline steadily during pregnancy and lactation. In a recent analysis of data from 14,532 women in 41 studies worldwide, low DHA in breast milk and low seafood consumption both predicted increased prevalence of PPD. The inverse was also true: increased DHA in breast milk and increased seafood intake predicted lower PPD prevalence (Hibbeln JR, et al. J Affect Disord 2002; 69(1–3):15–29).

As Effective as Lithium, Valproate

Some of the most promising work has been in treatment of bipolar disorder (BPD). Andrew Stoll and colleagues at Brigham & Women’s Hospital, Boston, found that a fish oil DHA/EPA combination, 15 g/d, produced marked mood stabilization as an adjunct to drug therapy for patients with refractory BPD, including rapid cyclers. Over the 4-month trial, 2 of 14 omega-3 patients relapsed, compared with 9 of 16 in the placebo-treated group. HAM-D, Global Assessment Scale and Clinical Global Impression ratings all favored the fish-oil (Stoll AL, et al. Arch Gen Psych 1999; 56:407–412).

Dr. Cott said Dr. Stoll’s group recently won an NIH grant to replicate the study in a much larger cohort. He added, “the magnitude of change we see with omega-3s in BPD is as large as what we see with lithium or valproate.”

New Promise for Schizophrenia

Omega-3s are also proving effective in management of schizophrenia, apparently owing to their antioxidant effects. Compared with normal controls, schizophrenic patients show increased levels of lipid peroxidation products in cerebrospinal fluid and plasma (Mahadik SP, et al. Schizophr Res 1996; 19:1–17; Mukerjee S, et al. Schizophr Res 1996; 19:19–26; Mahadik SP, et al. Biol Psychiatr 1998; 43:674–679). These changes are consistently associated with lower levels of omega-3s and other polyunsaturated fatty acids in brain and erythrocyte cell membranes.

In a study of 20 chronic schizophrenics with primarily negative symptomatology (alogia, flat affect, anhedonia, apathy, motor retardation), 6 weeks of treatment with marine-derived EPA, 10 g/d, led to significant improvements in negative symptoms as rated by the Positive and Negative Symptoms Scale (PANSS). The improvements correlated with increased red cell membrane omega-3 content (Laugharne JD, et al. Lipids 1996: 31(suppl):s163–s165).

Dr. Cott suggested that supplementation with omega-3s as well as antioxidants like vitamins E and C, and β-carotene in early stages of schizophrenia could prevent the oxidative damage associated with deterioration of neurologic and behavioral function.