Wednesday, June 7, 2023
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Doctoral candidate, Department of Clinical Psychology, University of North Carolina at Chapel Hill
Professor, Department of Psychiatry, Harvard Medical School, Cambridge, Massachusetts; Psychiatrist-in-Chief, Massachusetts General Hospital, Boston, Massachusetts
As reviewed by Kathryn Connor, MD,[1] of Duke University Medical Center, Durham, North Carolina, there is considerable evidence to suggest that poor nutrition is a risk factor for obesity, hypertension, and atherosclerosis and a contributor to such physical disease states as coronary heart disease, cancer, diabetes, and dental caries and erosion. She also stated that there is growing interest in the hypothesis that nutritional deprivation may contribute to psychiatric disorders as well, with the implication that enhanced nutrition may exert a salutatory influence on mental health. This hypothesis was the topic of discussion at the American Psychiatric Association 2004 Annual Meeting in New York, NY, with experts reviewing the potential uses of nutritional supplements, including omega-3 fatty acids, folate, and chromium, in the treatment of psychiatric disorders. A highlight of this review is presented below.
According to Jerry Cott, PhD,[2] of the US Food and Drug Administration, the observation that omega-3 fatty acids have mood stabilizing properties has generated research into the utility of omega-3 as a treatment for a variety of psychiatric disorders.
Dr. Cott explained that the essential fatty acids omega-3 and omega-6 are taken in through diet and compete with each other for the same elongation enzymes. Omega-6 eventually leads to arachidonic acid and eicosanoids, which promote inflammation, platelet clotting, and the production of prostaglandins. Omega-3 also leads to the production of eicosanoids, but the eicosanoids that are derived from omega-3 -- eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) -- actually possess anti-inflammatory properties and decrease platelet stickiness.
When the proportion of omega-6 acids eaten to omega-3 acids eaten reaches 20:1, the enzyme used by both fatty acids for elongation favors omega-6. Although the precise mechanism through which this affects mental health is unclear, it has been hypothesized that depletion of DHA causes a change in neurotransmitter receptors and that depletion of omega-3 fatty acids generally contributes to serotonergic dysregulation.[3] Furthermore, explained Dr. Cott, the depletion of DHA may result from consuming large amounts of foods that contain corn and soy oils, which consist of omega-6 and are present in processed, high-fat foods. Fish oil, on the other hand, contains high levels of omega-3.
According to Dr. Cott, countries in which individuals consume a large amount of fish appear to have populations at lower risk for affective disorders. For example, Magnusson and colleagues[4] reported an unexpectedly low prevalence of seasonal affective disorders in Iceland and suggested that this was due to unique genetic features of the Icelandic population. Cott and Hibbeln,[5] in response, proposed that perhaps this finding was due to the high content of fish in the Icelandic diet (225 lbs per person per year) rather than the result of genetic protection again depression per se. This interpretation is consistent with results from a cross-national study conducted by Hibbeln in which it was observed that higher seafood consumption was associated with a lower prevalence of major depression.[6]
Results from the Hibbeln cross-national study are paralleled by an epidemiologic study of Finnish adults in which it was observed that the likelihood of having depressive symptoms was significantly higher among individuals who ate fish infrequently (less than once per week) than among those who were frequent fish consumers (more than once per week).[3] Of note, this finding that was observed for women but not for men.
The role of omega-3 fatty acids in depression is also supported by the finding that adding E-EPA (ethyl-eicosapentaenoic acid) to standard antidepressant pharmacotherapy is efficacious in potentiating antidepressant effects. For example, in a 12-week, double-blind, placebo-controlled study, Peet and Horrobin[7] found that adding 1 g/day of E-EPA to ongoing antidepressant medication resulted in significant decreases in depression among patients who had remained depressed despite having had an adequate trial of an antidepressant. In a 4-week, double-blind, placebo-controlled study conducted by Nemets and colleagues,[8] it was observed that adding 2 g/day of E-EPA to maintenance antidepressant therapy resulted in significant decreases in depression.
The utility of omega-3 fatty acids as a treatment for bipolar disorder was suggested by a 4-month, double-blind, placebo-controlled study conducted by Stoll and colleagues.[9] The mood stabilizing drugs lithium carbonate and valproate have inhibitory effects on neuronal signal transduction systems, leading some researchers to speculate that overactive signal transduction mechanisms may be involved in bipolar disorder. Given that omega-3 fatty acids are also associated with a dampening of signal transduction, the authors hypothesized that omega-3 fatty acids may be useful in the treatment of bipolar disorder. In this investigation, 30 patients with bipolar disorder were randomized to receive either placebo (n = 16) or 9.6 g/day of omega-3 fatty acids (n = 14), in addition to usual treatment. Olive oil tablets served as placebo; omega-3 fatty acids were in the form of tablets containing EPA and DHA derived from fish oil. Four patients in each group were not taking any mood stabilizing medication, and 40% of the sample had rapid-cycling bipolar disorder, characterized by 4 or more mood episodes in the year prior to study entry.
Results indicated that patients who had received the omega-3 fatty acids stayed well significantly longer, showed a significant decrease in depressive symptoms, demonstrated significant clinical improvement, and displayed significant increases in global functioning compared with patients who had received placebo. A similar pattern of results regarding duration of time staying well was observed for the subgroup of 8 patients who received omega-3 or placebo monotherapy.
The role of omega-3 fatty acid in the treatment of other psychiatric disorders appears to depend on the particular illness under investigation. For instance, Noaghiul and Hibbeln[10] observed that countries in which there was greater seafood consumption displayed lower lifetime prevalence rates of bipolar I disorder, bipolar II disorder, and bipolar spectrum disorder. However, there was no correlation between lifetime prevalence rates of schizophrenia and seafood consumption.
Furthermore, results from treatment studies investigating the efficacy of omega-3 fatty acids in patients with schizophrenia have been mixed. For instance, Peet and Horrobin[11] found that the addition of E-EPA was efficacious in attenuating depressive symptoms and, to a modest extent, psychotic symptoms among severely ill patients with schizophrenia who were already receiving antipsychotic medication, but Fenton and colleagues[12] found no effect of adding 3 g/day of E-EPA to chronically ill patients with schizophrenia already being treated with antipsychotic medication.
Fux and colleagues[13] also failed to observe an effect for the addition of 2 g/day of adjunctive EPA for patients with obsessive-compulsive disorder who were receiving pharmacotherapy with selective serotonin reuptake inhibitors (SSRIs).
In contrast, promising results were observed for omega-3 fatty acids in borderline personality disorder and hostility. Zanarini and Frankenburg[14] conducted an 8-week, double-blind, placebo-controlled study of 1 g/day of E-EPA among females diagnosed with borderline personality disorder. Placebo, in this case, consisted of mineral oil. Participants receiving E-EPA demonstrated significantly greater decreases in hostility scores and depression ratings compared with those in the placebo group, and no clinically relevant side effects were noted.
In a large, cross-sectional observational study conducted by Iribarren and colleagues,[15] it was observed that consumption of DHA and fish rich in omega-3 fatty acids was associated with decreased levels of hostility in an urban sample of young adults.
In sum, emerging data suggest that omega-3 fatty acids, such as EPA, may play a role in the etiology of certain mood disorders -- for example, major depression and bipolar disorders -- and may be useful treatments for major depression, depression in the context of bipolar disorder, and borderline personality disorder. Cross-sectional data suggest that omega-3 fatty acids may also be helpful in decreasing hostility, but in the absence of clinical data from treatment outcome studies of omega-3 as an intervention for hostility, one should be cautious in evaluating the therapeutic potential for this indication. On the other hand, the role of omega-3 fatty acids in the management of psychosis appears less compelling.
The role of folate in depression was reviewed by Jonathan Alpert, MD, PhD, of Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.[16] According to Dr. Alpert, research has shown that depression is associated with low serum or red cell folate levels[17] and patients with low plasma folate respond less well to antidepressant treatment.[18] The precise role of folate in depression is unknown, although it has been suggested that folate may be indirectly involved in the synthesis of the monoamines.[17]
Several studies have been conducted to examine the efficacy of adding folate to antidepressant pharmacotherapy. For instance, Coppen and Bailey[19] conducted a double-blind, placebo-controlled, 10-week study of 127 depressed adults with normal folate levels. Patients were assigned to receive either 500 mcg/day of folic acid or placebo in addition to 20 mg fluoxetine daily. Patients who received the combination of folate plus fluoxetine demonstrated a significant increase in plasma folate and had a significantly better response than did patients who received fluoxetine plus placebo. Of note, this effect was observed for women but not men.
Alpert and colleagues[20] evaluated the efficacy of adjunctive leucovorin (folinic acid) in an open trial among a group of patients with treatment-resistant depression. The sample consisted of 22 adults who had demonstrated partial response or nonresponse to an SSRI or venlafaxine after 4 or more weeks of treatment. Oral leucovorin 15 mg/day was added to patients' stable antidepressant regimen for 2 weeks; this was increased to 30 mg/day for an additional 6 weeks. At the end of the trial, modest but significant decreases in depression were observed, and effects were observed for both women and men. Leucovorin was also well-tolerated.
Jonathan Davidson, MD, of Duke University Medical Center, Durham, North Carolina, presented data on the utility of chromium picolinate for atypical depression.[21] As reviewed by Dr. Davidson, insulin inhibits the reuptake of norepinephrine and enhances the blood-brain transport of tryptophan, a precursor of serotonin. Chromium potentiates the action of insulin by enhancing the ability of insulin to bind to its receptors and promoting glucose uptake. Insulin resistance, which has been implicated in such conditions as type II diabetes, is ameliorated by administration of chromium picolinate. These observations led Dr. Davidson and his colleagues to hypothesize that administration of chromium may also have implications for atypical depression, which is associated with insulin resistance and is characterized by hypersomnia, interpersonal rejection sensitivity, increased appetite, and weight gain.
To test this hypothesis, they conducted a double-blind, placebo-controlled trial of chromium picolinate in 15 patients with atypical depression.[22] Patients were randomized to 8 weeks of treatment in a 2:1 chromium to placebo ratio. The initial starting dose was 400 mcg/day and was increased to 600 mcg/day after 2 weeks. Eleven of the 15 patients were women.
Results indicated that 7 of 10 (70%) patients in the chromium group met response criteria, defined in advance as a drop of at least 66% on the HAM-D from baseline to final visit, compared with 0 out of 5 (0%) patients in the placebo group. This difference was statistically significant, and response was seen early in a number of the cases. Three patients in the chromium group failed to demonstrate any improvement. Trends were also observed for the efficacy of chromium on the Symptom Checklist-90 (SCL-90) scores for anxiety, hostility, interpersonal sensitivity, paranoia, and psychoticism. Overeating and fatigue also improved among a subset of patients in the chromium group. Chromium picolinate was well-tolerated over the course of the study.
It is well known that poor nutrition is related to conditions such as obesity and hypertension and may play a contributing role in coronary artery disease and diabetes, to name just a few physical disease states. Converging lines of evidence from epidemiologic studies, clinical samples, and treatment outcome studies suggest that nutrition may play a role in mental health as well and offer intriguing hypotheses about the etiology and treatment of certain psychiatric conditions, particularly those that involve dysregulated affect -- for example, major depression, bipolar disorder, and borderline personality disorder. Emerging data regarding the role of omega-3 fatty acids and folate in mood disorders and the putative antidepressant efficacy of chromium suggest that nutritional supplementation may be a helpful strategy in the management of psychiatric disease states. Future studies are needed to evaluate the reliability of initial findings and to investigate the long-term safety of these compounds within various subpopulations of psychiatric patients.
