N-acetylcysteine (NAC) is an amino acid with strong antioxidant properties that has been used to treat a range of inflammatory disorders.29 Emerging findings suggest that NAC may reduce symptoms of depressed mood but not mania in patients with stable bipolar disorder when it is combined with mood stabilizers.
In a 24-week, placebo-controlled trial, 75 patients with stable bipolar I or bipolar II disorder received 1 g of NAC twice daily as an adjunct to their usual medication. Compared with patients who received placebo in combination with their regular mood stabilizer regimen, patients in the NAC group had significant improvements in bipolar depression on the Montgomery Asberg Depression Rating Scale and the Bipolar Depression Rating Scale, with strong effect sizes of 1.04 and 0.83, respectively. Nonsignificant improvements were found over baseline for symptoms of mania.30
Choline is a necessary precursor for synthesis of acetylcholine (Ach); abnormally low CNS Ach levels may underlie some cases of mania.31 Findings of a small controlled trial suggest that phosphatidylcholine (15 to 30 g/d) may reduce the severity of mania and depressed mood in bipolar patients.32
Folic acid may be an effective adjuvant therapy when combined with lithium carbonate in unipolar and bipolar depression. In an early 1-year placebo-controlled study, 102 patients with unipolar or bipolar depression receiving maintenance lithium therapy were randomized to folate 200 µg/d or placebo.33 Patients in the folic acid group (n = 41) had significantly lower Beck Depression Inventory scores than those in the control group, with a strong effect size of 1.07.
At the start of the trial, a significant percentage of patients had low serum folate levels. In those whose plasma folate levels increased to 13 ng/mL (roughly twice the mean of pretrial levels), there was a significant decrease in symptom severity during the trial year. The researchers speculated that the therapeutic benefits of folate supplementation in folate-deficient individuals with affective disorders might be related to the essential role of folate in serotonin synthesis. Abnormally low levels of folate are also associated with mania. Forty-five inpatients with acute mania had significantly lower red blood cell folate levels than socioeconomically matched controls, but there was no significant difference in serum folate levels.34 Pending replication by larger studies, these preliminary findings suggest that reduced tissue and CNS levels of folate may be associated with bipolar illness and not dietary deficiency or reduced absorption.
Proprietary multinutrient formula
A proprietary nutrient formula containing 36 separate constituents, including chelated minerals, vitamins, and trace elements, may reduce symptoms of mania, depressed mood, and psychosis in bipolar patients when taken alone or used as an adjunct to conventional mood-stabilizing medications.35-39 Beneficial clinical outcomes in bipolar disorder may result from correction of hereditary metabolic errors in genetically predisposed individuals when select micronutrients are deficient or absent in the diet.37
In one case series, 11 patients with bipolar disorder who completed a 6-month protocol consisting of 32 capsules daily in 4 divided doses had clinical response with strong effect sizes (HAM-D: 1.70; YMRS: 0.83) and were able to reduce their conventional mood stabilizers by half and improve clinically.37 In another case series, 13 of 19 bipolar patients who continued taking the nutrient formula remained stable after they discontinued conventional mood stabilizers.40 Some patients stopped taking the formula because of nausea and diarrhea, and 3 patients resumed conventional mood stabilizers because of recurring manic symptoms. An analysis of self-reported data from 682 adults with bipolar disorder who were taking the proprietary nutrient formula reported significant and sustained clinical improvements over a 6-month period.41 Serious safety concerns have been reported when the nutrient formula is taken with conventional medications, including toxic levels of certain mood stabilizers.38 Pregnant women and women who are breast-feeding should avoid use of this formula because of its potentially toxic high vitamin A content.
St John’s wort (Hypericum perforatum) has been evaluated extensively as the treatment of major depressive disorder, with mixed results.42 To date, no studies have been conducted on St John’s wort in the depression phase of bipolar disorder. Emerging findings suggest that St John’s wort may be effective adjunctive treatment in combination with mood stabilizers in patients with the seasonal variant of bipolar disorder (ie, seasonal affective disorder). In an open study, 169 self-referred patients with a history of seasonal mood changes but without a formal DSM-IV diagnosis of bipolar disorder were randomized to a standardized St John’s wort preparation or to St John’s wort plus early morning bright light exposure.43 Both groups experienced significant reductions in anxiety and insomnia; however, the group that received both St John’s wort and bright light therapy experienced greater diminution of insomnia.
Adverse effects with St John’s wort are infrequent and include mild GI distress, rashes, and fatigue. St John’s wort can result in a photosensitive rash and should not be used by patients who are likely to experience prolonged exposure to sunlight. There are case reports of serotonin syndrome with the concurrent use of St John’s wort and an SSRI; therefore, this combination should be avoided.44
Case reports of mania induction with St John’s wort have resulted in limited use of this herbal for the treatment of both major depressive disorder and bipolar disorder.45,46 Interactions between St John’s wort and conventional drugs are mediated by the induction of cytochrome P-450 3A4, which results in increased metabolism and decreased absorption of widely used drugs, including digoxin, anticoagulants, antiretrovirals, oral contraceptives, statins, and cyclosporine.47
Reserpine, an alkaloid derivative of Rauwolfia serpentina, is used in ayurvedic medicine to treat hypertension and symptoms that resemble the Western diagnoses of psychotic disorders and bipolar disorder. Early studies suggested that reserpine may be an effective adjunctive treatment in severe refractory cases of bipolar disorder or schizoaffective disorder.
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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