In one case series, 6 acutely manic inpatients with bipolar disorder or schizoaffective disorder who had previously been refractory to lithium and an antipsychotic improved significantly when reserpine was substituted for the antipsychotic; in some cases, the lithium dosage was reduced. The results showed improved tolerance to conventional pharmacological treatment, and the patients remained stable on this combination regimen. None of the patients became depressed and none reported significant adverse effects.48 Preliminary findings suggest that R serpentina may be an effective and safe adjuvant to lithium in the treatment of acute mania.
In a retrospective review of treatment-refractory, acutely psychotic, agitated inpatients, 50% of 36 patients who received reserpine (0.5 to 5.5 mg/d) following a nonblinded protocol in combination with antipsychotics or antipsychotics plus lithium experienced moderate to dramatic improvement.49 Three of the responders had full clinical symptom remission, and 8 patients were evaluated as having no psychosis at the time of maximum response. These early findings have not been replicated by large placebo-controlled studies.
Reserpine has relatively few and minor adverse effects when used at dosages of less than 0.2 mg/d; the main adverse effect is nasal congestion.50 However, use of reserpine in the United States and other Western countries is restricted because of safety concerns that include nausea, vomiting, gastric ulceration, cramps and diarrhea, erectile dysfunction, hypotension, and bradycardia. Western-trained psychiatrists are also cautious about reserpine because of the increased risk of depressed mood and suicide, although most reports of suicide have come from early uncontrolled studies with dosages as high as 0.5 mg/d.51
Conclusions and caveats
Conventional pharmacological treatments of bipolar disorder have limited effectiveness and a record of significant unresolved safety issues. These factors have resulted in high rates of nonresponse, partial response, and nonadherence. In this context, many patients with bipolar disorder use CAM therapies alone or in combination with prescription medications in the absence of FDA approval and in spite of a paucity of research evidence for the majority of nonconventional treatments—often without disclosing this information to their physician. These trends underscore the urgent need to objectively evaluate the research evidence so that psychiatrists and other mental health professionals can knowledgeably advise patients about appropriate, safe uses of CAM and integrative therapies.
The use of CAM therapies as stand-alone treatments for mania or depressed mood in bipolar disorder is not supported by strong evidence (see Table 2 for provisional guidelines). Questions remain about the appropriate off-label use of select CAM treatments in bipolar disorder. Thus, decisions on whether to recommend CAM or integrative therapies to patients should be based on reviews of available data on efficacy and safety of these products.
While acknowledging the limited efficacy and unresolved safety issues of mood stabilizers and atypical antipsychotics, it is my view that conventional pharmacological therapies should be considered as first-line treatments of severe symptoms of mania and depressed mood in bipolar patients. By the same token, current limited evidence for CAM and integrative modalities used to treat bipolar disorder argues for a conservative treatment philosophy employing nonconventional therapies, pending additional findings needed to further substantiate both safety and efficacy. Well-documented limitations and benefits of both conventional and CAM therapies suggest it is prudent and reasonable to take a middle-ground approach when treating bipolar patients; in other words, to follow a conservative treatment philosophy that emphasizes conventional pharmacological management while remaining rigorously open-minded to the use of select natural products as adjuvants when appropriate on a case-by-case basis (Table 2).
Psychiatrists and other mental health professionals should stay abreast of current research findings on natural products and other CAM therapies (eg, exercise, biofeedback, yoga, mind-body therapies) in order to judiciously and appropriately educate and advise patients regarding safety and efficacy findings. Integrative treatments using select natural products reviewed in this article add to the established armamentarium of conventional treatments of bipolar disorder and should be considered when formulating a treatment plan for bipolar disorder.
When recommending any conventional, alternative, or integrative treatment for bipolar disorder (or any psychiatric disorder), the clinician’s first task is to carefully examine the evidence supporting all available treatment choices. Conventional, alternative, and integrative therapies whose safety and efficacy are not supported by strong research evidence should not be recommended as first-line treatments of severe symptoms of bipolar mania or depressed mood.
Because of the potentially serious consequences of inappropriate treatment or undertreatment of bipolar disorder, patients should be discouraged from self-medicating with over-the-counter natural products or combinations of natural products and mood stabilizers for which safety and efficacy are not supported by solid research evidence. Keep in mind that all natural products reviewed in this article should be regarded as “off-label” because they are not currently endorsed by the FDA for the treatment of bipolar disorder or other psychiatric disorders. Therefore, it is important to review potential risks and benefits of any natural product therapies and to obtain and fully document informed consent when recommending these therapies.
To minimize safety issues, it is incumbent on the clinician to advise all bipolar patients who elect to use a natural product to use only quality brands of select natural products following a critical appraisal of the evidence and only under the supervision of a medical or naturopathic physician. When discussing CAM treatment options with patients, it is important to keep in mind that the literature is incomplete with regard to safety of most natural product supplements in young children, pregnant and breast-feeding women, and patients with significant liver or kidney disease. Maximum safe dosages have not been clearly established for these populations, and conservative dosing strategies should be used with close monitoring for treatment-emergent adverse effects. Before recommending any natural product to a patient with bipolar disorder, the clinician should be familiar with important safety considerations summarized in Table 1.
With these general comments and caveats in mind, Table 2 summarizes provisional guidelines for the use of CAM and integrative therapies in patients with bipolar disorder. Emerging evidence supports the use of select natural products as safe and efficacious adjuvants to conventional mood stabilizers in treating the manic phase of bipolar illness. In contrast to the manic phase of bipolar illness, there is less evidence for CAM or integrative therapies for bipolar depressed mood.
Large placebo-controlled studies on all CAM and integrative treatments discussed in this article are needed to establish safety, efficacy, and optimal dosing strategies before general treatment recommendations in bipolar disorder can be strongly endorsed. However, pending further research, there is sufficient evidence for provisional treatment guidelines for using select natural products reviewed in this article as adjuvant therapies in combination with mood stabilizers.
[Editor's Note: Originally presented as an independent educational activity under the direction of CME LLC, this article was published by Psychiatric Times (2011;28:58-63. Please click here for a pdf of the article and author's financial disclosures). The ability to receive CME credits has expired. The article is presented here for informational purposes.]
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.
1. Elkins G, Rajab MH, Marcus J. Complementary and alternative medicine use by psychiatric inpatients. Psychol Rep. 2005;96:163-166.
2. Simon GE, Cherkin DC, Sherman KJ, et al. Mental health visits to complementary and alternative medicine providers. Gen Hosp Psychiatry. 2004;26:171-177.
3. Kessler RC, Soukup J, Davis RB, et al. The use of complementary and alternative therapies to treat anxiety and depression in the United States. Am J Psychiatry. 2001;158:289-294.
4. Dennehy EB, Gonzalez R, Suppes T. Self-reported participation in nonpharmacologic treatments for bipolar disorder. J Clin Psychiatry. 2004;65:278.
5. Andreescu C, Mulsant BH, Emanuel JE. Complementary and alternative medicine in the treatment of bipolar disorder—a review of the evidence. J Affect Disord. 2008;110:16-26.
6. Keaton D, Lamkin N, Cassidy KA, et al. Utilization of herbal and nutritional compounds among older adults with bipolar disorder and with major depression. Int J Geriatr Psychiatry. 2009;24:1087-1093.
7. Cohen J. Statistical Power Analysis for the Behavioral Sciences. 2nd ed. Hillsdale, NJ: Lawrence Erlbaum Associates, Inc, Publishers; 1988.
8. Benjamin AB. A unique consideration regarding medication compliance for bipolar affective disorder: exercise performance. Bipolar Disord. 2007;9:928-929.
9. Lakhan SE, Vieira KF. Nutritional therapies for mental disorders. Nutr J. 2008;7:2.
10. Pompili M, Serafini G, Del Casale A, et al. Improving adherence in mood disorders: the struggle against relapse, recurrence and suicide risk. Expert Rev Neurother. 2009;9:985-1004.
11. Culver JL, Arnow BA, Ketter TA. Bipolar disorder: improving diagnosis and optimizing integrated care. J Clin Psychol. 2007;63:73-92.
12. Fleck DE, Keck PE Jr, Corey KB, Strakowski SM. Factors associated with medication adherence in African American and white patients with bipolar disorder. J Clin Psychiatry. 2005;66:646-652.
13. Ghaemi SN, Lenox MS, Baldessarini RJ. Effectiveness and safety of long-term antidepressant treatment in bipolar disorder. J Clin Psychiatry. 2001;62:565-569.
14. Altamura AC, Goikolea JM. Differential diagnoses and management strategies in patients with schizophrenia and bipolar disorder. Neuropsychiatr Dis Treat. 2008;4:311-317.
15. Stoll AL, Severus WE, Freeman MP, et al. Omega 3 fatty acids in bipolar disorder: a preliminary double-blind, placebo-controlled trial. Arch Gen Psychiatry. 1999;56:407-412.
16. Frangou S, Lewis M, McCrone P. Efficacy of ethyl-eicosapenta-enoic acid in bipolar depression: randomised double-blind placebo-controlled study. Br J Psychiatry. 2006;188:46-50.
17. Keck PE Jr, Mintz J, McElroy SL, et al. Double-blind, randomized, placebo-controlled trials of ethyl-eicosapentanoate in the treatment of bipolar depression and rapid cycling bipolar disorder. Biol Psychiatry. 2006;60:1020-1022.
18. Montgomery P, Richardson AJ. Omega-3 fatty acids for bipolar disorder. Cochrane Database Syst Rev. 2008;2:CD005169.
19. Wozniak J, Biederman J, Mick E, et al. Omega-3 fatty acid monotherapy for pediatric bipolar disorder: a prospective open-label trial. Eur Neuropsychopharmacol. 2007;17:440-447.
20. Clayton EH, Hanstock TL, Hirneth SJ, et al. Reduced mania and depression in juvenile bipolar disorder associated with long-chain omega-3 polyunsaturated fatty acid supplementation. Eur J Clin Nutr. 2009;63:1037-1040.
21. Sarris J, Schoendorfer N, Kavanagh DJ. Major depressive disorder and nutritional medicine: a review of monotherapies and adjuvant treatments. Nutr Rev. 2009;67:125-131.
22. Chouinard G, Beauclair L, Geiser R, Etienne P. A pilot study of magnesium aspartate hydrochloride (Magnesiocard) as a mood stabilizer for rapid cycling bipolar affective disorder patients. Prog Neuropsychopharmacol Biol Psychiatry. 1990;14:171-180.
23. Heiden A, Frey R, Presslich O, et al. Treatment of severe mania with intravenous magnesium sulphate as a supplementary therapy. Psychiatry Res. 1999;89:239-246.
24. Giannini AJ, Nakoneczie AM, Melemis SM, et al. Magnesium oxide augmentation of verapamil maintenance therapy in mania. Psychiatry Res. 2000;93:83-87.
25. Kaplan BJ, Crawford SG, Field CJ, Simpson JS. Vitamins, minerals, and mood. Psychol Bull. 2007;133:747-760.
26. Barrett SP, Leyton M. Acute phenylalanine/tyrosine depletion: a new method to study the role of catecholamines in psychiatric disorders. Primary Psychiatry. 2004;11:37-41.
27. Scarna A, Gijsman HJ, McTavish SF, et al. Effects of a branched-chain amino acid drink in mania. Br J Psychiatry. 2003;182:210-213.
28. Applebaum J, Bersudsky Y, Klein E, Rapid tryptophan depletion as a treatment for acute mania: a double-blind, pilot-controlled study. Bipolar Disord. 2007;9:884-887.
29. Dodd S, Dean O, Copolov DL, et al. N-acetylcysteine for antioxidant therapy: pharmacology and clinical utility. Expert Opin Biol Ther. 2008;8:1955-1962.
30.Berk M, Copolov DL, Dean O, et al. N-acetyl cysteine for depressive symptoms in bipolar disorder—a double-blind randomized placebo-controlled trial. Biol Psychiatry. 2008;64:468-475.
31. Leiva DB. The neurochemistry of mania: a hypothesis of etiology and rationale for treatment. Prog Neuropsychopharmacol Biol Psychiatry. 1990;14:423-429.
32. Stoll AL, Sachs GS, Cohen BM, et al. Choline in the treatment of rapid-cycling bipolar disorder: clinical and neurochemical findings in lithium-treated patients. Biol Psychiatry. 1996;40:382-328.
33. Coppen A, Chaudhry S, Swade C. Folic acid enhances lithium prophylaxis. J Affect Disord. 1986;10:9-13.
34. Hasanah CI, Khan UA, Musalmah M, Razali SM. Reduced red-cell folate in mania. J Affect Disord. 1997;46:95-99.
35.Kaplan BJ, Crawford SG, Gardner B, Farrelly G. Treatment of mood lability and explosive rage with minerals and vitamins: two case studies in children. J Child Adolesc Psychopharmacol. 2002;12:205-219.
36. Kaplan BJ, Fisher JE, Crawford SG, et al. Improved mood and behavior during treatment with a mineral-vitamin supplement: an open-label case series of children. J Child Adolesc Psychopharmacol. 2004;14:115-122.
37. Kaplan BJ, Simpson JS, Ferre RC, et al. Effective mood stabilization with a chelated mineral supplement: an open-label trial in bipolar disorder. J Clin Psychiatry. 2001;62:936-944.
38. Popper CW. Do vitamins or minerals (apart from lithium) have mood-stabilizing effects? J Clin Psychiatry. 2001;62:933-935.
39. Simmons M. Letter to the Editor. J Clin Psychiatry. 2002;64:338.
40. Simmons M. Nutritional approach to bipolar disorder. J Clin Psychiatry. 2003;64:338.
41. Gately D, Kaplan BJ. Database analysis of adults with bipolar disorder consuming a micronutrient formula. Clin Med Psychiatry. 2009;4:3-16. http://la-press.com/article.php?article_id=1384. Accessed January 10, 2011.
42. Freeman MP, Fava M, Lake J, et al. Complementary and alternative medicine in major depressive disorder: the American Psychiatric Association Task Force report. J Clin Psychiatry. 2010;71:669-681.
43. Wheatley D. Hypericum in seasonal affective disorder (SAD). Curr Med Res Opin. 1999;15:33-37.
44. Sarris, J, Kavanagh DJ, Byrne G. Adjuvant use of nutritional and herbal medicines with antidepressants, mood stabilizers and benzodiazepines. J Psychiatr Res. 2010;44:32-41.
45.Moses EL, Mallinger AG. St. John’s wort: three cases of possible mania induction. J Clin Psychopharmacol. 2000;20:115-117.
46. Fahmi H, Huang C, Schweitzer I. A case of mania induced by hypericum. World J Biol Psychiatry. 2002:3:58-59.
47. Izzo AA. Drug interactions with St. John’s wort (Hypericum perforatum): a review of the clinical evidence. Int J Clin Pharmacol Ther. 2004;42:139-148.
48. Bacher NM, Lewis HA. Lithium plus reserpine in refractory manic patients. Am J Psychiatry. 1979;136:811-814.
49. Berlant JL. Neuroleptics and reserpine in refractory psychoses. J Clin Psychopharmacol. 1986;6:180-184.
50. Curb JD, Schneider K, Taylor JO, et al. Antihypertensive drug side effects in the Hypertension Detection and Follow-up Program. Hypertension. 1988;11(3, pt 2):1151-1155.
51. Lemieux G, Davignon A, Genest J. Depressive states during Rauwolfia therapy for arterial hypertension: a report of 30 cases. Can Med Assoc J. 1956;74:522-526.