In a 12-week, 3-arm, placebo-controlled study, patients with stable bipolar disorder were treated with EPA 1 g/d (n = 24), EPA 2 g/d (n = 25), or placebo (n = 26) and their usual maintenance regimen; patients in the groups that received EPA experienced small but significant improvements in measures of depressed mood on the HAM-D (1 g: d = 0.90; 2 g: d = 0.50), compared with those in the placebo group, but a significant effect on mania was not achieved on the YMRS.16 In a subsequent larger study (N = 121), patients with rapid cycling bipolar disorder did not experience improvements in the frequency or severity of manic symptoms on the YMRS while taking purified EPA (6 g/d) in combination with at least 1 mood stabilizer.17
A systematic review identified 5 placebo-controlled trials for v-3s in bipolar disorder that met strict inclusion criteria for methodological quality. Only 1 study included in the review in which v-3s were taken as an adjunct to a mood stabilizer showed a significant differential beneficial effect on depressive but not manic symptoms.18 The reviewers commented on the uneven quality of published studies and cautioned that it is premature to draw conclusions about the effectiveness of v-3s for bipolar disorder pending large, well-designed, placebo-controlled studies.
Results of 2 small open-label studies have recently been published that suggest beneficial effects of v-3s in both phases of pediatric bipolar disorder. In a small open-label study, 20 children and adolescents who met DSM-IV-TR criteria for bipolar disorder and had a YMRS score of greater than 15 were given 1290 to 4300 mg of fish oil. There were significant reductions on the YMRS (d = 0.90) and the brief psychiatric rating scale (BPRS; d = 0.83) compared with baseline.19
In a 6-week open-label study, 18 children and adolescents with bipolar I or II disorder were treated with purified v-3s (DHA 1560 mg/d and EPA 360 mg/d). The results showed significant reductions in clinician-rated mania and depression relative to baseline.20 While large placebo-controlled studies are needed to confirm these findings, preliminary data suggest that v-3s may be effective when combined with mood stabilizers in the depressive phase of bipolar illness but may not significantly improve symptoms of mania or rapid cycling.
Although v-3s are generally well tolerated, some patients report nausea, loose stools, and fishy-smelling “burps.” GI adverse effects may be reduced by taking v-3s with meals. Cod liver oil contains high levels of vitamins A and D, and long-term use or inappropriate high doses can result in vitamin toxicity. Mild anticoagulant effects may occur with use of v-3s. Rare cases of increased bleeding time but not increased bleeding have occurred when v-3s were used concurrently with aspirin or anticoagulants.21 Patients treated with v-3s should be advised to use pharmaceutical-grade preparations to avoid contamination from heavy metals, polychlorinated biphenyls, and organochlorines.
Preliminary findings suggest that oral or intravenous magnesium may be an effective adjuvant to mood stabilizers in patients with acute mania or rapid cycling bipolar disorder. In an early open-label trial lasting 32 weeks, 4 of 9 rapid cycling bipolar patients who took oral magnesium (40 mEq/d) experienced improvement similar to that seen in patients who received maintenance lithium therapy.22
In a subsequent case series, 10 patients with severe treatment-resistant agitated manic bipolar disorder who received a continuous intravenous magnesium sulfate infusion (200 mg/h) for 7 to 23 days while continuing to take psychotropic medications (lithium, haloperidol, and clonazepam) showed significant improvement in functioning on the clinical global impression (CGI) scale.23 Several of these patients remained stable while taking lower doses of conventional medications. Five patients experienced bradycardia that promptly resolved when magnesium flow was reduced.
There is evidence that oral magnesium augmentation may improve the antimanic effectiveness of mood stabilizers in patients with stable bipolar disorder. In a small controlled trial, 20 men with bipolar disorder were randomized to verapamil (80 mg qid) plus oral magnesium oxide (320 mg/d) or to verapamil and a placebo. Results showed that patients treated with verapamil and magnesium oxide had significant improvement on the BPRS from baseline compared with patients who were treated with verapamil and a placebo (P = .015).24
Large placebo-controlled studies are needed to confirm the safety and efficacy of intravenous and oral magnesium before either therapy can be recommended for bipolar patients.
Emerging evidence suggests that some bipolar patients may be genetically susceptible to mood swings when select amino acids are not present in the diet.25 The results of 2 small placebo-controlled trials suggest that certain branched-chain amino acids (leucine, isoleucine, and valine) may provide rapid improvement in patients with acute mania—possibly by interrupting synthesis of norepinephrine and dopamine.26,27 In one study, 25 patients with bipolar disorder were randomized to a special tyrosine-free amino acid drink (60 g/d) or to placebo. Compared with patients who had received placebo, the patients in the active-treatment group experienced significant reductions in mania within 6 hours that were sustained with repeated administration of the amino acid drink and lasted at least 1 week after the study ended.27 Improvements in mania were not observed in the placebo group.
Preliminary findings suggest that restricting or excluding l-tryptophan from the diet may increase the susceptibility to depressive mood swings in bipolar patients. Rapid tryptophan depletion has been shown to induce transient depressive symptoms in patients with major depressive disorder whose symptoms are in remission. A rapid reduction of up to 80% in plasma tryptophan level can be accomplished by administering an oral tryptophan-free amino acid solution.
In a small, 7-day, double-blind, placebo-controlled, pilot study, 23 acutely manic bipolar patients who were given sodium valproate (starting at 1000 mg/d) were randomized to receive either a daily tryptophan-free amino acid drink or a placebo drink.28 Compared with patients in the placebo group, patients who received the amino acid drink had better scores on the YMRS and CGI scale on days 3, 5, and 7. However, there was a high intolerance rate and only 17 patients completed the study (23% drop-out rate). Larger studies are needed to replicate these preliminary findings and address intolerance issues.
Dr Lake is in private practice in Monterey, Calif. He chairs the International Network of Integrative Mental Health and is the author of the Textbook of Integrative Mental Health Care (New York: Thieme Medical Publishers, Inc; 2007) and Integrative Mental Health: A Therapist’s Handbook (New York: WW Norton and Company; 2009). He reports no conflicts of interest concerning the subject matter of this article.
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