Mood disorders and complementary and alternative medicine: a literature review
Naseem Akhtar Qureshi1 and Abdullah Mohammed Al-Bedah2
1General Administration for Research and Studies, Sulaimania Medical Complex, Riyadh, Saudi Arabia
2National Center for Complementary and Alternative Medicine, Ministry of Health, Riyadh, Saudi Arabia
Correspondence: Naseem Akhtar Qureshi, General Administration for Research and Studies, Sulaimania Medical Complex, PO Box 2775, Riyadh 11176, Saudi Arabia, Tel +96 61 473 5038, Email moc.evil@meesanihseruq
Author information ►Copyright and License information ►
Copyright © 2013 Qureshi and Al-Bedah, publisher and licensee Dove Medical Press Ltd
This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.
Neuropsychiatr Dis Treat. 2013; 9: 639–658.
Published online 2013 May 14. doi: 10.2147/NDT.S43419
This article has been cited by other articles in PMC.
Mood disorders are a major public health problem and are associated with considerable burden of disease, suicides, physical comorbidities, high economic costs, and poor quality of life. Approximately 30%–40% of patients with major depression have only a partial response to available pharmacological and psychotherapeutic interventions. Complementary and alternative medicine (CAM) has been used either alone or in combination with conventional therapies in patients with mood disorders. This review of the literature examines evidence-based data on the use of CAM in mood disorders. A search of the PubMed, Medline, Google Scholar, and Quertile databases using keywords was conducted, and relevant articles published in the English language in the peer-reviewed journals over the past two decades were retrieved. Evidence-based data suggest that light therapy, St John’s wort, Rhodiola rosea, omega-3 fatty acids, yoga, acupuncture, mindfulness therapies, exercise, sleep deprivation, and S-adenosylmethionine are effective in the treatment of mood disorders. Clinical trials of vitamin B complex, vitamin D, and methylfolate found that, while these were useful in physical illness, results were equivocal in patients with mood disorders. Studies support the adjunctive role of omega-3 fatty acids, eicosapentaenoic acid, and docosahexaenoic acid in unipolar and bipolar depression, although manic symptoms are not affected and higher doses are required in patients with resistant bipolar depression and rapid cycling. Omega-3 fatty acids are useful in pregnant women with major depression, and have no adverse effects on the fetus. Choline, inositol, 5-hydroxy-L-tryptophan, and N-acetylcysteine are effective adjuncts in bipolar patients. Dehydroepiandrosterone is effective both in bipolar depression and depression in the setting of comorbid physical disease, although doses should be titrated to avoid adverse effects. Ayurvedic and homeopathic therapies have the potential to improve symptoms of depression, although larger controlled trials are needed. Mind-body-spirit and integrative medicine approaches can be used effectively in mild to moderate depression and in treatment-resistant depression. Currently, although CAM therapies are not the primary treatment of mood disorders, level 1 evidence could emerge in the future showing that such treatments are effective.
Keywords: complementary and alternative medicine, mood disorders, Ayurveda, homeopathy, integrative medicine
Treating mood disorders has become complex, given the many changes over the years in epidemiological trends, etiological models, classification systems and symptom clusters, diagnosis and diagnostic tools, types of interventions, and outcome studies. Despite psychopharmacological advances during the past six decades, the management of major depression and other mood disorders continues to challenge mental health providers. Many patients with mood disorders who are dissatisfied with conventional treatment seek other interventions, in particular complementary and alternative medicine (CAM). In general, CAM is safe and cost-effective, has limited comparative efficacy to modern allopathic treatments, and is well tolerated by patients with physical and mental disorders.1 This evidence-based review summarizes recent advances in the use of CAM for mood disorders, mainly in the adult population.
A search of the PubMed, Medline, Google Scholar, and Quertile databases was done using the key phrases “complementary and alternative medicine” and “integrative medicine combined with mood disorders and major depression”, and relevant articles published over the past two decades (1992–2012) in the peer-reviewed English language journals were retrieved. Other keywords, including “botanicals”, “phytomedicine”, “nutrients”, “herbs”, “dietary supplements”, “vitamins”, “fatty acids”, “folate”, “hormones”, “exercise”, “meditation”, “yoga”, “Ayurveda”, “homeopathy”, and “mind-body-spirit” were combined with “major depression” and “mood disorders” for more specific searches. More than 30,000 articles were retrieved using this method. Many articles were excluded, including articles without abstracts (n = 529), papers not published in the English language (n = 840), full articles not being available (n = 215), and duplication of articles across searches (n = 12,120), along with many papers unrelated to the topic under consideration (n = 16,046). Only 250 papers were retained for further review. Thirty-seven articles that described single cases and small case series (less than five subjects) were also excluded. In total, the authors selected 213 articles, which included open-label clinical trials, randomized controlled trials, systematic reviews, and meta-analyses addressing use of CAM in the management of major depression and other mood disorders. Eight references were added during revisions of this manuscript and one citation was deleted (see Figure 1).
Mood disorders are common mental health problems, afflicting 154 million people around the world.2 Major depression is currently the third leading cause of disability worldwide. Major depression is preferentially associated with female gender, with manic disorders distributed equally between males and females. Major depression is more common among people of low socioeconomic status, those with low education, those who are unmarried, separated, or divorced, those from a rural background, and those without intact families.3 Major depression has adverse consequences, including increased absenteeism from work, reduced productivity, disruption of family life, and increased health care utilization and costs. Smoking, drug abuse, sexual dysfunction, crime, violence, and suicidal behavior are further consequences for many sufferers.4–6 In addition, mood disorders are the most common cause of premature mortality, acceleration of aging, and reduced life expectancy.7
Mood disorders exist in many forms, including unipolar depression, bipolar depression, mania, mixed syndromes, and subsyndromes, and these conditions can co-occur with other psychiatric and physical disorders.8–10 Comorbid conditions complicate not only the diagnosis but also the management, prognosis, and outcome of major depression.11
Psychopharmacological and nondrug therapies are effective in many patients with mood disorders. However, 30%–40% of patients with major depression become resistant to these treatments as a result of medical comorbidity, unavailability of appropriate services, and poor adherence with available therapies. These difficult-to-treat patients need specialized treatment strategies.12,13 The two major classifications of mental disorders provide a comprehensive view of mood disorders, but these have now been divided into more than 30 diagnostic categories.14,15 Major depression has a definite onset, is strongly influenced by biological and psychosocial factors,3,16,17 and is also related to personality disorders.18 Preclinical studies in animals and basic neurobiological research in human subjects have provided biological insights into the pathogenesis of major depression, and have helped in the development of drugs now used in major depression and other mood disorders.19,20
Nondrug interventions have also been developed to treat major depression, in view of the influence of psychosocial factors.21 Dacher described four healing systems, ie, homeostatic, conventional, mind-body, and spiritual.21 Sarris has also described an antidepressant-lifestyle-psychological-social model for treating depression that integrates conventional drug treatments with CAM, lifestyle changes, and psychosocial techniques.22 A combination of biological and psychosocial treatment produces better outcomes and reduces the rates of relapse and suicide.23 From a psychopharmacological perspective, there have been many controlled trials in mood disorders consistently reporting that 30% of patients achieve full remission, 30% are partial responders, and the rest are nonresponders.24,25 However, application of these results in the real-world setting is problematic because of the criteria used to select patients for entry into these trials. In a naturalistic study of 4000 patients with chronic depression and comorbid psychiatric or medical conditions treated with citalopram up to 60 mg/day, the remission rate was 27% and the response rate was 47%. When nonresponders were augmented or switched to another antidepressant, 30% remitted.26 According to Bambauer et al, patients with treatment-resistant depression attributable to nonadherence with medication27 need augmentation strategies.12,13 Patients with treatment-resistant depression are also at higher risk for relapse.28,29
Complementary and alternative medicine
Increasing attention is being paid worldwide to more traditional medical systems, including Ayurveda, yoga, naturopathy, Unani medicine, Siddha, and homeopathy.30 Use of CAM therapies in various illnesses is on the rise.31 Perron et al found that barriers to conventional treatment have contributed to the increased use of CAM in mentally ill patients.31 Another study found that use of CAM was unaffected by the perceived effectiveness of conventional treatment or compliance with medication among persons with bipolar disorder.32 There are now more than 120 CAM treatments available (Table 1), all of which involve body, mind, and spiritual concepts. This classification of various therapies, and designated by mind, body, or spirit, is perceived as strict compartmentalization, but many of the therapies mentioned have double or triple designations in terms of our theoretical understanding of diagnosis, treatment, and causal mechanisms. Another reason for increasing use of CAM is the positive findings of studies in patients with major depression.33 Many clinical trials of CAM are presently under way worldwide, and are expected to yield positive results in patients with major depression and other mood disorders.
Complementary and alternative treatment modalities34–36
Role of CAM in mood disorders
Complementary and alternative medicine is the most practiced but least researched form of treatment because of the complexities inherent in assessment of its effectiveness in major depression and other mood disorders. These complexities include solo versus adjunctive treatments, the multiple facets of depression, design and methodological issues, and use of herbs with unknown bioactive ingredients. To address this conundrum, the Canadian Network Group has developed guidelines for the use of CAM in adults with major depression, suggesting efficacy using light therapy for seasonal affective disorder, St John’s wort for mild to moderate depression (level 1 evidence), and omega-3 fatty acids, yoga, exercise, sleep deprivation, and S-adenosylmethionine for major depression.37 Level 1 evidence is that obtained from at least one appropriately designed randomized controlled trial. The American Task Force has also reported promising results with regard to omega-3 fatty acids, St John’s wort, folate, S-adenosylmethionine, acupuncture, light therapy, exercise, and mindfulness psychotherapies in major depression.38 This report recommends the undertaking of more rigorous and larger studies in the future, and that each CAM treatment must be evaluated separately in adequately powered controlled trials. They suggested that further focus is needed on clinical, research, and educational initiatives with regard to CAM in psychiatry, and cautions that the greatest risk of pursuing CAM is possible delayed use of other well established treatments.38 Dutch researchers have also developed a protocol for ensuring safe and effective use of CAM in the mental health setting.39
Dietary supplements as CAM therapies
Over-the-counter dietary supplements (nutraceuticals) are used extensively by patients with depression, and are categorized as nutrients, herbal and dietary supplements, and traditional and nontraditional methods.40 Nutraceuticals have also been used to promote mental and physical health, to prevent illness, and to treat diseases, with substantial benefits.40 Nutraceuticals, in particular S-adenosylmethionine, have benefited patients with major depression and other mood disorders. This compound provides methyl and sulfate groups used in the synthesis of deoxyribonucleic acid, proteins, phospholipids, neurotransmitters, and the antioxidant, glutathione, that are disturbed in people with mood disorders.41 In a critical review of the literature, Brown et al reported the results of 48 studies and found S-adenosylmethionine to be safe and effective for the treatment of depression.42 A recent review further supports the use of this compound in mild-to-moderate depression, reporting that eight of 14 studies (57%) produced positive results.43 Interestingly, like selective serotonin reuptake inhibitors (SSRIs), neither S-adenosylmethionine nor St John’s wort have been associated with an increased risk of suicide.43 Several researchers have appraised the clinical and pharmacological benefits of S-adenosylmethionine in depression and as an adjunct in treatment-resistant depression.44–46 In a double-blind randomized study of patients with depression who were nonresponders to SSRIs, Papakostas et al reported preliminary beneficial effects from S-adenosylmethionine augmentation with good tolerability. S-adenosylmethionine appears to be a safe adjunctive treatment for patients with major depression who do not respond to SSRIs, but this needs confirmation in clinical trials.47 S-adenosylmethionine alone or combined with other supplements has been shown to alleviate depression associated with musculoskeletal disease,48,49 liver disease,50,51 Parkinson’s disease,52 and human immunodeficiency virus/acquired immune deficiency syndrome.53 S-adenosylmethionine acts similarly to noradrenergic antidepressants, but with fewer side effects.44
In a randomized clinical study of 30 women with postpartum depression, 1600 mg/day of S-adenosylmethionine resulted in a 70% reduction in symptoms of depression and anxiety compared with a 50% reduction in the placebo group by day 30.54 S-adenosylmethionine is safe to use during pregnancy and breast-feeding. Infants naturally have 3–7 times higher S-adenosylmethionine levels than adults.55 This is because they need more S-adenosylmethionine for methylation of the developing brain, especially the myelin sheaths critical for conduction of electrical impulses. A secondary analysis of clinical trial data for S-adenosylmethionine administered to patients with major depression nonresponsive to SSRIs found a positive impact on symptoms of depression and related cognitive dysfunction.56 In summary, the primary and adjunctive role of S-adenosylmethionine in patients with major and treatment-resistant depression is gaining solid ground.
Herbs and mood disorders
Numerous herbs are known to contain bioactive substances, although the clinical significance of these needs further investigation.57 Research in phytomedicine has been generating considerable amounts of new data on the chemical, pharmacological, and clinical aspects of herbs in mood disorders.58,59
St John’s wort
St John’s wort contains two bioactive substances, ie, hyperforin and hypericin, and has been used effectively in the treatment of major depression.57 Although initial reports of its use were hampered by inadequate concentrations of hyperforin,60 subsequent comparative, randomized, double-blind, placebo-controlled trials using better standardized St John’s wort (Kira® [LI-160 extract], 1800 mg/day, Klosterfrau Healthcare Group, Germany; Remotiv®, Flordis Natural Medicines, Australia; or Ze 117®, 500 mg/day Zeller AG, Switzerland) found it to be as effective as imipramine 150 mg/day and fluoxetine 20 mg/day for all severity levels of depression, but with fewer gastrointestinal side effects.61,62 A widely cited randomized, multicenter, placebo-controlled study of inpatients with depression given St John’s wort Kira® (LI-160 extract) 900 mg/day for 4 weeks, then increased to 1200 mg/day for another 4 weeks, found Kira® (LI-160 extract) to be no better than placebo. However, this negative result could be explained by the use of subtherapeutic doses of the bioactive substances in St John’s wort.63 The greater severity and resistant nature of depression might also have contributed to lack of effectiveness, but this is unlikely, given the results from Phase II of the study.64 In another study of severely depressed patients given Kira® (LI-160, 900–1500 mg/day), sertraline (50–100 mg/day), or placebo, found that neither sertraline nor St John’s wort showed more efficacy than placebo.65 In a randomized, placebo-controlled multicenter study of outpatients with mild-to-moderate depression, Kira® (LI-160 extract) and fluoxetine did not differ significantly with regard to efficacy measures except for remission rates (24% for Kira® [LI-160 extract], 28% for fluoxetine, and 7% for placebo). It was concluded that Kira® (LI-160 extract) and fluoxetine were no more effective than placebo in the short-term treatment of mild-to-moderate depression.66 The results of this study are supported by other researchers.67
In another randomized study of patients with major depression, Kira® (LI-160 extract, 900 mg/day) was more effective than fluoxetine (20 mg/day) and showed a trend towards superiority over placebo.68 The remission rates were higher for Kira® (LI-160 extract) compared with fluoxetine and placebo.68 A reanalysis of earlier data suggested that patients’ beliefs regarding treatment may have a stronger effect on clinical outcome than the actual medication received, depending on what treatment patients thought they were receiving and what they actually received.69 Recent well controlled studies, meta-analyses, and consensus guidelines support the efficacy of St John’s wort in patients with mild-to moderate-depression in particular.33,37,43,70,71
In another double-blind, randomized, placebo-controlled, long-term trial, Kasper et al70 reported the beneficial effects of Hypericum extract (WS® 5570, Dr. Willmar Schwabe Pharmaceuticals, Germany) in adult outpatients who had recovered from an acute episode of moderate depression. Patients treated with WS® 5570 showed more favorable time courses to resolution of symptoms and greater overall improvement than those randomized to placebo. Used as long-term maintenance therapy, WS® 5570 was reported to have a prophylactic effect in patients with early-onset depression and in those with a high degree of chronicity. WS® 5570 also showed a beneficial effect in preventing relapse after recovery from acute depression.70
St John’s wort has also been used in primary care psychiatric settings and in patients with seasonal affective disorder, and examined with regard to relapse rates in those who responded, all with good results. For example, Szegedi et al reported that 71% of patients with moderate-to-severe depression treated in primary care responded to 900 mg/day Hypericum extract WS® 5570, and that 900–1800 mg/day was as effective as paroxetine 20–40 mg/day, but without side effects.72 Patients with mild seasonal affective disorder have also been reported to benefit from Kira® (LI-160 extract).37,73 With regard to relapse, reanalysis of data from 154 patients with mild-to-moderate depression treated with St John’s wort (STW 3-VI; Laif®, Steigerwald Arzneimittelwerk GmbH, Germany) 900 mg, citalopram 20 mg, or placebo once daily found that relapse rates were highest in the citalopram group, followed by the St John’s wort and placebo groups, with no difference in the severity of relapse.74 Further, the duration of response was longest for the St John’s wort group, intermediate for the citalopram group, and shortest for the placebo group. Researchers concluded that 3-VI had the longest duration of response and was more effective than citalopram and placebo in decreasing relapse and recurrence rates.74 However, in a 12-week study of minor depression, St John’s wort (Cederroth International, Sweden, 810 mg/day) was not superior to citalopram 20 mg/day or placebo, and the authors called for more research to identify better treatment options for patients with minor depression.75 In a review of commonly used botanicals in the treatment of anxiety and mood disorders, St John’s wort (5 of 7 trials), black cohosh (all studies reviewed), and ginseng (1 trial) have been reported to improve symptoms of depression and anxiety in menopausal and postmenopausal women.76
St John’s wort is generally used as a second-line option, except in women with a history of response to low doses of an SSRI.57 St John’s wort has potential side effects that increase with higher doses. These include phototoxic rash, SSRI-like effects, serotonin syndrome, and induced mania.77 The side effect profile and dropout rates in the range of 0%–5.7% for patients receiving St John’s wort are not different from placebo, and have been reported to be similar to those of tricyclic antidepressants and slightly lower than those of the SSRIs.77 A study that reanalyzed data from four clinical trials found that St John’s wort extract (WS® 5570) was associated with fewer adverse events than SSRIs.78 Nevertheless, St John’s wort reduces circulating levels of a large number of drugs, including digoxin, warfarin, and oral contraceptives, because it induces cytochrome P450 (CYP) 3A4 and CYP 1A2 enzymes as well as P-glycoprotein in the intestinal wall.77,79 According to one study, the information available on websites selling St John’s wort is not of good quality and consumers should bear this in mind when considering buying the product.80 Another study that evaluated safety information provided in the labeling of St John’s wort products found that the majority of producers failed to address safety issues adequately.81 Health care providers and consumers will benefit if the US Food and Drug Administration and similar regulatory bodies elsewhere re-examine the labeling requirements for dietary supplements.81
The use of medicinal herbs had been widespread across many cultures since ancient times. A recent university student survey83 found that most herb use was self-prescribed (60%) and undisclosed to health providers (75%), 34% of users took herbs to treat a mood disorder, 13% of herb users were taking concurrent prescription medication, and those who took both herbs and prescription medications had higher depression and anxiety scores than other herb users. Detailed patient interviews are necessary to prevent adverse herb-drug interactions.82
Rhodiola rosea, recommended in many conditions, including irregular menopause,83,84 has also been reported to be effective in the treatment of mild-to-moderate depression.85 One trial used a standardized extract of Rhodiola rosea (SHR-5, Swedish Herbal Institute, Sweden) at doses of 340 mg and 680 mg daily for six weeks with no reports of side effects.85 A systematic review has also supported the antidepressant effects of Rhodiola rosea.86 Its mechanism of action in major depression is thought to be via beta-endorphins, tryptophan, and serotonin in the brain.57,88 Rosiridin is the bioactive ingredient of Rhodiola rosea, which is reported to inhibit monoamine oxidases A and B and may also be useful in dementia.83
Having no addictive potential, Rhodiola rosea is a mild stimulant, so should be taken in the morning to avoid sleep problems. It may induce temporary vivid dreams and mild nausea. It also binds with the estrogen receptor, so women with a personal or family history of estrogen-sensitive breast cancer should exercise caution in using Rhodiola rosea, although this issue needs further study.88 Products containing 3% rosavins and 1% salidrosides were found to be effective in a randomized controlled trial, and may be used to enhance the clinical effectiveness of Rhodiola rosea.57 Panossian et al provide detailed information on its traditional use, chemical composition, pharmacology, side effect profile, and clinical efficacy.84
Saffron and other herbs
A systematic review of herbs used in major depression and other mood disorders identified nine clinical trials that met all eligibility criteria.89 Three of these trials found saffron stigma extract to be more effective than placebo and equivalent in effect to fluoxetine and imipramine. Two studies found that saffron petal extract was significantly more effective than placebo and was equivalent to fluoxetine and saffron stigma extract. Lavender was found to be less effective than imipramine, but the combination of lavender and imipramine was significantly more effective than imipramine alone. When compared with placebo, Echium extract was found to decrease depression scores markedly at week 4, although this effect had disappeared by week 6. According to this review, saffron, lavender, Echium, and Rhodiola rosea when used alone or in combination with antidepressants showed good results in mild-to-moderate depression.89 Another critical review that identified 21 phytomedicines and 66 clinical trials involving 11 phytomedicines reported positive results of the aforementioned herbs in mild-to-moderate depression, anxiety, and sleep disorders.90 In a clinical trial of Free and Easy Wanderer Plus (FEWP, Golden Flower, People’s Republic of China; a Chinese herbal extract formula), fluoxetine, and placebo, 150 patients with post-stroke depression showed significant improvement with both FEWP and fluoxetine compared with placebo.91 At the end of the trial, subjects on FEWP showed greater improvement than those on fluoxetine at week 2 and performed better than patients receiving fluoxetine in activities of daily living. This study suggests that FEWP can be used safely with few side effects in patients with post-stroke depression.91
Caution is important when using herbs and dietary supplements. Rai et al92 analyzed the heavy metal content in nine plant species used for the preparation of herbs in India and found that most samples had a heavy metal content exceeding the upper limits set by the World Health Organization. Further, heavy metals and organochlorine pesticides have been found in some dietary supplements in the US.93 In traditional Chinese medicine (Table 2), cases of heavy metal poisoning has been reported by several investigators.94 There is a large body of literature concerning the heavy metal content of herbal supplements used in CAM, including mercury, lead, chromium, cadmium, arsenic, cobalt, and pesticides, including dioxin.95–100 Quality control measures, including standardized doses and regulations, are needed for herbal products used for health reasons.40
Herbal medicinal products: contaminants and adverse effects93–101
Vitamins in mood disorders
Vitamins B and D, folate, and trace elements are essential for the functioning of neurons, and have been shown to afford protection against certain types of mental disorders, particularly depression.101 These nutrients become depleted in the body for many reasons, including poor nutrition, chronic disease, old age, stress, and polymorphism. Low vitamin B12, vitamin D, and folate levels are also associated with poor memory and cognitive dysfunction.102,103 Folic acid and folate from the diet are converted into L-methylfolate in the body. In a randomized, double-blind, placebo-controlled trial, 123 patients with major depression and schizophrenia maintained on standard psychotropic medications were given augmentation therapy of methylfolate 15 mg/day or placebo. The investigators reported significant improvement in clinical and social symptoms with methylfolate compared with placebo.104 However, treatment with folate or vitamin B12 alone has been associated with mixed results in depression. Geriatric patients with depression and cognitive dysfunction showed benefit when tricyclic antidepressants were augmented with vitamin B complex (B1, B6, and B12) and folate.105 Nonresponse to antidepressants has been linked with low levels of folate. A study of 127 patients on fluoxetine supplemented with folate 400 mg/day or placebo reported a 94% response rate to fluoxetine plus folate compared with a 61% response to fluoxetine plus placebo.106 However, a recent placebo-controlled study found little support for B12 (100 μg/day) with folate (400 μg/day) supplementation in community-dwelling adults already taking conventional antidepressants.107 Another placebo-controlled trial of folate plus vitamin B12 supplementation given to older patients with depression also yielded negative results.108
In summary, clinical trials of vitamin B and folate have yielded equivocal results in patients with major depression. Although methylfolate and vitamin B have favorable safety profiles, allergic reactions may occur using these substances. Folate and vitamin B reduce homocysteine levels, so may be cardioprotective. However, combination of these vitamins may cause restenosis of stents in men by stimulating endothelial proliferation, although this effect has not been seen in women.109
Low levels of vitamin D have been identified in patients with major depressive and other mood disorders, but vitamin D supplementation in these patients has produced inconsistent results.110 Supplemental use of vitamin D (800 International Units; IU) produced no positive results in a study of prevention of winter-time blues in elderly women.111 In a placebo-controlled study, obese men and women with major depressive disorder were given high doses of vitamin D (20,000 or 40,000 IU) or placebo per week for one year. Depression scores were higher in patients with low serum 25-hydroxyvitamin D (<40 nmol L) levels than in those with normal levels of 25-hydroxyvitamin D (≥40 nmol L), and participants given the vitamin D supplement showed significant improvement in depression compared with those in the placebo group.112 However, a recent placebo-controlled study of vitamin D3 supplementation in patients with low or high levels of 25-hydroxyvitamin D found that levels of 25-hydroxyvitamin D was significantly lower in patients with depression and that supplementation with vitamin D3 was not associated with improvement in symptoms compared with placebo.113 Similarly negative results were reported for another placebo-controlled trial in elderly women with symptoms of depression given vitamin D3 supplementation at 400 IU/day and calcium.114 However, a recent review suggests that the suicide risk associated with vitamin D deficiency might be reduced by supplementation with vitamin D.115
Other nutrients commonly used in CAM include omega-3 fatty acids, choline, 5-hydroxy-L-tryptophan, inositol, and N-acetylcysteine. These substances are important in functioning of the neural networks involved in mood regulation.
Omega-3 fatty acids in mood disorders
Fish-derived omega-3 fatty acids provide eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which help to maintain fluidity of the cell membrane, reduce inflammatory eicosanoids, and prevent the release of proinflammatory cytokines.57,116 Alpha linoleic acid also converts differentially into omega-3 fatty acids, EPA, and DHA. However, omega-6 fatty acids from domesticated animals and cultivated vegetables is consumed in much larger quantities than omega-3 fatty acids. Therefore, cell membranes acquire increasing proportions of omega-6 fatty acids that adversely affect membrane fluidity and flexibility.57,116 In contrast, supplementation of omega-3 fatty acids from fish oil in liquid or capsule form maintains cell membrane fluidity. Substitution of omega-6 fatty acids for omega-3 fatty acids in the cell membrane has been associated with unipolar and bipolar depression, which is thought to be due to loss of membrane fluidity and flexibility. The latter results in disturbance of membrane proteins, such as enzymes, receptors, ion channels, and neurotransmitters, which in turn increases levels of inflammatory eicosanoids and proinflammatory cytokines.57,116 In fact, a study of 12 women with bipolar disorder found that those treated with omega-3 fatty acid supplements showed significant improvement in membrane fluidity and flexibility.116 However, a review of the relevant literature on use of omega-3 fatty acids in depression yielded mixed results, although this could have been due to methodological differences between studies, the lower proportions of EPA and DHA used in those studies, and patient selection bias.117 In another review of 19 relevant studies, 13 reported a positive effect of omega-3 fatty acids in patients with depression, whereas six studies found no such association.118 In addition, a meta-analysis of relevant studies reported that >60% EPA (out of the total of EPA and DHA, where dose range of 200–2200 mg/day of EPA in excess of DHA) had a positive impact on symptoms of depression compared with studies that used doses containing <60% of total EPA and DHA.119 Finally, a placebo-controlled trial of adding omega-3 fatty acids to citalopram in patients with depression found significant improvement in depression scores compared with a placebo plus citalopram group, although there was no improvement in the speed of the initial antidepressant response.120
An increased risk of suicide, commonly associated with depression, has been linked with omega-3 fatty acid deficiency.121 A case-controlled study at autopsy compared omega-3 fatty acid levels in the orbitofrontal cortex of patients with major depressive disorder (n = 15) and age-matched controls (n = 27). Lower DHA levels were found in the orbitofrontal cortex of 32% of female patients and 16% in male patients,122 suggesting that lower levels of DHA could be a marker of increased suicide risk in patients with depression. Several other clinical trials support the adjunctive role of EPA and DHA in the treatment of both unipolar and bipolar depression.123–125 Omega-3 fatty acids are both safe during infant development and effective for the treatment of major depression in pregnant women. Notably, low fish consumption and omega-3 fatty acids have been linked with depression more in women than in men.126 Finally, a placebo-controlled study of 45 patients with bipolar disorder given omega-3 fatty acids ± cytidine found no significant effect on symptoms of depression compared with the placebo group.127 Cytidine, a pyrimidine, was reported to have antidepressant-like effects in preclinical studies. In summary, further research is needed before recommending use of omega-3 fatty acids as monotherapy in patients with major depressive and other mood disorders.
Omega-3 fatty acids also have a preventive role. Interestingly, a lower lifetime prevalence of bipolar II disorder has been associated with greater consumption of seafood.128,129 Further, a small open-label study of bipolar I patients (n = 10) who were given EPA at a daily dose of 1.5–2.5 g found that eight of ten (80%) had a 50% decrease in depression scores.130 Subsequently, a randomized controlled trial has substantiated the adjunctive role of omega-3 fatty acids (6.2 g EPA plus 3.4 mg DHA and 1–2 g ethyl-EPA) in patients with bipolar II disorder receiving conventional mood stabilizers.131 A randomized controlled study of patients with bipolar disorder and rapid cycling who were receiving conventional treatment found that those given EPA 6 mg/day showed no significant difference in depressive or manic symptoms after four months of intervention than the group receiving placebo.132 These negative results might be due to the use of EPA without DHA and inclusion of patients with resistant rapid cycling. Thus, patients with dysphoria and rapid cycling should be given higher doses of EPA and DHA, probably 8–10 g/day.133 A recent meta-analysis of five pooled databases related to use of omega-3 fatty acids in bipolar patients found a significant reduction in symptoms of depression, although scores for mania were unaffected, thus supporting the adjunctive role of omega-3 fatty acids in the treatment of symptoms of depression in bipolar patients.134
Pregnant women often have depleted omega-3 fatty acid stores and are at higher risk for postpartum depression and bipolar depression.135 Almost all psychotropic medications carry a risk of side effects in pregnant women and may also adversely affect fetal and infant development. CAM therapies are safe alternatives in pregnant women with major depression. In randomized studies that used fixed doses136 or a range of doses (0.5, 1.4, 2.8 g/day) with no placebo controls,137 EPA and DHA (3–8 g/day) were found to be effective in pregnant women with major depression and postpartum depression, with no adverse effects on the fetus. However, researchers have suggested that these studies of omega-3 fatty acids need to be repeated in a larger sample of pregnant women with depression.136–137 S-adenosylmethionine, St John’s wort, bright light therapy, acupuncture, and exercise have also been reported to improve symptoms of depression in women.138 Further studies are needed to delineate specific CAM therapies useful in premenstrual syndrome, premenstrual dysphoric disorder, antepartum and postpartum depression, lactation, and transition through menopause.138–139
Omega-3 fatty acids are also safe for use in children and adolescents with bipolar disorder. An 8-week open-label study of 20 children (aged 6–16 years) with bipolar disorder given EPA 1290 mg/day and DHA 4300 mg/day found that 35% of children had more than a 50% decrease in Young Mania rating scores,140 consistent with results in pediatric depression.141 Two-thirds of patients did not show improvement, indicating that omega-3 fatty acids are ineffective in pediatric bipolar disorder. However, larger studies are needed to confirm this. Pediatric bipolar disorder is a difficult condition to treat, and some pediatric bipolar patients may benefit from CAM therapies. One review has reported that omega-3 fatty acids and lecithin/choline have potential utility as CAM in pediatric bipolar disorder. S-adenosylmethionine and inositol have some data supporting their efficacy in the treatment of depressive symptoms. Some data suggest these compounds may be useful adjunctive treatments, but few data are available to support their use as stand-alone therapy in pediatric bipolar disorder.142 Another small open-label trial of a multinutrient supplement (EMPower™) found that 70% of pediatric completers with bipolar spectrum disorder demonstrated a significant decrease in both depression and mania scores between baseline and the final visit (P < 0.05). Gastric discomfort was the only reported side effect. These researchers suggested that randomized, placebo-controlled trials of EMPower are warranted and feasible.143 Evidently, omega-3 fatty acid treatment was associated with a very modest improvement in symptoms of mania in children with bipolar disorder. The most commonly observed side effects of omega-3 fatty acids in children are nausea, heartburn, stomach pain, belching, bloating, and diarrhea attributable to higher doses and use of unrefined fish oil preparations. Bleeding episodes due to reduction in platelet aggregation and triggering of mania are other side effects of high doses of omega-3 fatty acids. Use of omega-3 fatty acids should be strictly avoided in patients on anticoagulant therapy and antidiabetic medications. Some omega-3 fatty acids found in fish oil can increase low-density lipoprotein cholesterol, which is bad for the heart.57
Choline in bipolar disorder
Choline has been used effectively in ameliorating symptoms of mania. A small, open-label study of six patients with treatment-resistant rapid cycling bipolar disorder and stabilized on lithium found that addition of free choline 2000–7200 mg/day resulted in improvement of manic symptoms, although the impact on depression was variable.144 A randomized controlled trial of oral choline in rapid cycling bipolar patients treated with lithium reported significantly decreased purine levels in the brain over a 12-week period, which was related to the anti-manic effects of choline.145 Oral administration of exogenous choline increased synthesis of phospholipids in the cell membrane and corrected the mitochondrial component of diathesis in patients with bipolar disorder inadequately meeting the demand for increased adenosine triphosphate production.145 Thus, choline supplementation in small studies was effective for improving manic symptoms in bipolar patients, although larger studies are needed before recommending use of oral choline in the treatment of mania in bipolar I disorder.
Inositol in bipolar disorder
Inositol, a glucose isomer precursor of phosphatidyl inositol linked to the second messenger system, has been found to be more effective than placebo in the treatment of depression and other psychiatric illnesses, including panic disorder. Doses in the relevant studies have ranged from 12,000 to 20,000 mg/day.146 Inositol, a vitamin-like substance found in many plants and animals, can be produced synthetically. A randomized controlled trial in 24 bipolar patients given inositol or placebo found no significant differences between the treatment groups. However, a trend towards improvement on inositol led researchers to recommend that larger studies be performed.147–148 Another study of 66 bipolar I or II patients with resistant depression examined the benefits of augmenting mood stabilizers with lamotrigine, inositol, or risperidone, and found that the rate of recovery was 23.8% with lamotrigine, 17.4% with inositol, and 4.6% with risperidone.149 Nierenberg et al suggested that patients with treatment-resistant depression are suitable candidates for inositol augmentation. However, at therapeutic doses, inositol frequently causes flatulence and occasionally induces mania.149
5-hydroxy-L-tryptophan in bipolar disorder
5-hydroxy-L-tryptophan is an immediate precursor in the synthesis of serotonin, and deficiency of serotonin can cause major depression. As a dietary supplement, 5-hydroxy-L-tryptophan is used widely as a self-medication for depression, and has replaced L-tryptophan, which caused eosinophilia myalgia syndrome and was taken off the market.150 Use of L-tryptophan and Showa Denko KK have been shown to be the main causes of this syndrome, but 5-hydroxy-L-tryptophan is not associated with such toxicity.150 There is some (albeit limited) support for 5-hydroxy-L-tryptophan 200–300 mg/day being more effective than placebo when given alone in adults with major depression, although the data are better when it is used to augment antidepressants.151 The most common side effects include nausea, vomiting, diarrhea, headache, and insomnia. No case of serotonin syndrome has been reported in subjects taking 5-hydroxy-L-tryptophan alone or in combination with SSRIs. Further, no adverse interactions have been reported between 5-hydroxy-L-tryptophan and the monoamine oxidase inhibitors.152 In their review, Sarris et al found that use of omega-3 fatty acids, S-adenosylmethionine, folic acid, 5-hydroxy-L-tryptophan, inositol, lavender, and traditional Chinese medicines were effective when used to supplement antidepressants and mood stabilizers in mood disorders.134
N-acetylcysteine in bipolar disorder
N-acetylcysteine, a precursor of glutathione, is an important antioxidant in the brain and reduces oxidative stress. Increased oxidative stress and altered glutathione metabolism have been reported in bipolar and major depressive disorder.153 A randomized controlled trial in bipolar patients on mood stabilizers found that those who were given adjunctive N-acetylcysteine 2 g/day showed a significant improvement in depression, mania, quality of life, and social and occupational functioning compared with placebo.154 Dean et al reviewed the literature on the therapeutic effect of N-acetylcysteine in psychiatric disorders, including bipolar disorder, and found it to be beneficial in patients with bipolar depression.155 It is well tolerated by patients with bipolar disorder, although it needs to be taken for 8 weeks (2 g/day) to achieve a positive response.
Hormones in mood disorders
Dehydroepiandrosterone (DHEA) is an androgen produced by the adrenal glands, levels of which tend to decrease during mid-life in men and women. Lower levels of DHEA have been reported in patients with major depression, and use of DHEA has been associated with improved mood. An increase in DHEA sulfate, the primary metabolite of DHEA, has also been associated with improvement in depression and dysthymia.156–157 In a randomized controlled trial, 23 men and 23 women with major or minor mid-life depression were given DHEA 90 mg/day for three weeks, then 450 mg/day for a further three weeks, or placebo for six weeks. A 50% or greater reduction in baseline Hamilton Depression Rating scores was observed in the 23 subjects who took DHEA and in 13 subjects who took placebo. Patients taking DHEA also showed improvement in sexual function.158 DHEA has been used effectively in patients with human immunodeficiency virus/acquired immune deficiency syndrome and subsyndromal depression or chronic dysthymia. Of 145 such patients given DHEA 100–400 mg/day for 8 weeks, 64% showed a more than 50% reduction in depression scores compared with 38% of those given placebo.159 The response was maintained for 8 months of follow-up, and was higher among those with increased levels of DHEA sulfate.159 Arguably, subsyndromal depression and dysthymia are not the same as major depression. In a recent study, DHEA 100 mg/day or placebo was administered to 26 patients with anorexia nervosa, whose assessment included mood symptoms. Patients receiving DHEA experienced significant improvement in mood and body mass index, although there was no difference in bone marrow density. Thus, comorbid depression in patients with eating disorders may benefit from the use of DHEA.160 DHEA should be used in low doses in bipolar patients because it may induce manic-like symptoms, irritation, and bouts of aggression, and increase testosterone and estrogen levels, resulting in an elevated risk of uterine or breast cancer, vaginal bleeding, endometrial hyperplasia, and venous thrombosis.57
Ayurvedic medicine in mood disorders
Ayurvedic medicine is an ancient healing system used in India, which is now practiced worldwide.161 Ayurveda denotes longevity. The theory of Ayurveda is based on balancing the individual’s three constitutional “doshas”, ie, vata, pitta, and kappa, which arise from five elements of ancient philosophy, being fire, water, air, earth, and space.162–163 It is believed that health or sickness depends on the presence or absence of a balanced state. Both intrinsic and extrinsic factors, such as an indiscriminate diet, undesirable habits, not observing the rules of healthy living, seasonal abnormalities, lack of exercise, and misuse of body and mind can result in lack of balance in the body.164 Ayurvedic medicine includes several treatment options, which balance three disturbed doshas (Table 3). Diagnosis is based on a comprehensive history, detailed physical examination, measurement of vital signs including pulse, and relevant laboratory tests.30 Ashwagandha, along with combinations of herbs, such as Amrit kalash and mentat, and antidepressants can be used in depressed patients.30,165–168
Treatment options in Ayurvedic medicine
There has been difficulty in conducting randomized controlled trials in Ayurvedic medicine because most treatments involve multiple herbs, changes in diet and lifestyle, and treatments are individualized and target the entire person.169 Further, the effects of Ayurvedic herbs tend to be mild and slow in onset. Most Ayurvedic herbs do tend to work gradually and with increasing efficacy as the system habituates to consistent dosing. This is often true of herbs that are prescribed for mood disorders. However, the effect of Ayurvedic herbs is not always mild. With accurate tailoring of herbal preparations, herbal therapy can be powerful in effecting change in the balance of body and mind, eg, with mood disorders that often have complex multifactorial origins. Patients who are intolerant to prescription medications fare better with Ayurvedic interventions, including panchakarma detoxification.162 Small preliminary studies of major depression treated with herbs, herbal mixtures, and Rasayanas (a special branch of Ayurveda aiming to rejuvenate and nourish the body at all levels and comprises several products manufactured from a combination of herbs) have demonstrated improvement in depression scores.163 Sharma et al recommended larger controlled studies in major depression.163 Berberine, a traditional alkaloid plant used in Ayurvedic and traditional Chinese medicine, is reported to improve depression.170 Posmontier and Teitelbaum have discussed the use of Ayurvedic medicine to treat postpartum depression.171
Homeopathy in mood disorders
Homeopathy is a traditional medical system that uses a holistic approach. Homeopathy means treating diseases with minute doses of substances which are capable of producing symptoms similar to the disease when taken by healthy people. In homeopathy, the natural law of healing is known as Similia Similibus Curantur, meaning “likes are cured by likes”.163 Homeopathy is practiced in many places around the world. An audit of UK homeopathic clinics revealed that more than 84% of consultees reported improvement in mental health problems, including depression, and improvement in well-being. None of the 273 patients in that study reported deterioration, and use of conventional medicines was reduced in 25% of patients.172 Homeopathic medicines have been shown to be safe in high dilutions.57 In a systematic review of homeopathic studies in depression, Pilkington et al concluded that the different kinds of homeopathy, such as individualized prescribing, limited list prescribing, and standardized complexes used in these studies make interpretation of results more difficult.173 According to one study,174 the most commonly treated conditions in the practice of homeopathy were depression and anxiety disorders. Positive outcomes were most frequently observed in irritable bowel syndrome (73.9%), depression (63.6%), and anxiety (61.0%). Which components of the treatment were most responsible for the outcomes is unclear.174 A systematic review of randomized placebo-controlled studies (25 eligible studies from an initial pool of 1431) of homeopathic treatments in psychiatry found beneficial effects in several mental health disorders, including functional fibromyalgia and chronic fatigue syndrome. No study of patients with major depression was found in a literature review,175 which called for randomized controlled trials using homeopathic interventions in these disorders.
Mind-body-spirit approaches in mood disorders
There are a large number of mind-body-spirit practices that have been used effectively in major depression.176 It is widely accepted that most conventional antidepressant drugs increase levels of the relevant neurotransmitters, such as serotonin, norepinephrine, and dopamine, in the synapse. Mind-body-spirit approaches are also likely to operate through the same mechanism as antidepressants, and do so in a manner similar to that of psychotherapy. Evidently, psychotherapy-induced neurotransmitter changes are similar to those caused by antidepressants. Common approaches such as yoga, meditation, exercise, and acupuncture are reviewed here.
Pilkington et al reported a positive impact of yoga on depression, although methodological weaknesses make the study results hard to interpret.177 A study of 71 normal adults compared visualization and relaxation techniques with 30 minutes of yoga postures and breathing exercises, and the results indicated that the participants in the yoga group became more energetic and alert with improved mood.178 Kundalini yoga techniques have also been found to be effective in depression.179 In another study, 113 psychiatric inpatients who attended Hatha yoga classes experienced a significant reduction in symptoms of depression. Improvements also occurred in anxiety, depression, hostility, fatigue, and confusion.180 Lavey et al and Weintraub suggest that yoga has a considerable benefit for patients with depression.180–181
In another study, 28 patients with mild depression who participated in two one-hour Iyengar yoga classes showed a significant reduction in depression scores compared with a control group.
Late-life mood disorders and cognitive aging are the most common reasons for using complementary and alternative therapies. The amount of rigorous scientific data to support the efficacy of complementary therapies in the treatment of depression or cognitive impairment is extremely limited. The areas with the most evidence for beneficial effects are exercise, herbal therapy (Hypericum perforatum), the use of fish oil, and, to a lesser extent, acupuncture and relaxation therapies. There is a need for further research involving randomized, controlled trials to investigate the efficacy of complementary and alternative therapies in the treatment of depression and cognitive impairment in late-life. This research may lead to the development of effective treatment and preventive approaches for these serious conditions.
Keywords: acupuncture, art therapy, ayurveda, cognition, complementary medicine, dementia, exercise, gingko, hypericum, late-life depression, omega-3 fatty acids, SAMe, spirituality, yoga
Trends in use of complementary & alternative medicine in the USA
The use of complementary and alternative medicine (CAM) in the USA is increasing rapidly, exceeding a prevalence of 60% in a nationally representative survey conducted by the National Center for Health Statistics in 2002 [1,2]. CAM therapies are defined by the National Center for Complementary and Alternative Medicine as a group of diverse medical and health systems, practices, and products that are not currently considered to be part of conventional medicine . An alternative approach to mental healthcare is one that emphasizes the interrelationship between mind, body and spirit. A national US survey noted a 47% increase in total visits to CAM practitioners, from 427 million in 1990 to 629 million in 1997. These figures surpass the total number of visits to primary care physicians [3,4]. Estimated expenditures for CAM professional services were conservatively estimated at US$21.2 billion in 1997, with at least US$12.2 billion of out-of-pocket expenditures, exceeding out-of-pocket expenditures for all US hospitalizations . In a more recent nationwide survey, 36% of US adults aged 18 years and over use some form of CAM, and aging baby-boomers are expected to accelerate the use of CAM in the coming years .
Despite the increasing use of CAM by individuals, the scientific support for its efficacy is limited. The treatments with the best evidence of effectiveness are St John’s wort (SJW), exercise, cognitive behavior therapy and light therapy (for seasonal depression). There is only some degree of evidence to support the effectiveness of acupuncture, light therapy (for nonseasonal depression), massage therapy, negative air ionization (for winter depression), relaxation therapy, S-adenosyl-L-methionine (SAMe), folate and yoga breathing exercises . The use of CAM therapies is typically associated with higher levels of education, poorer health status, environmentalism, feminism and interest in spirituality and personal growth psychology . CAM users tended to be female, younger, better educated and employed ; however, older adults are also using CAM at increasingly higher rates. Barnes and colleagues noted that nearly 33% of older adults used CAM in the preceding year (2004) . In a survey, 42% of the patients in a managed care organization reported using at least one CAM therapy, most commonly relaxation techniques (18%), massage (12%), herbal medicine (10%) or megavitamin therapy (9%) . Perceived efficacy of CAM was very high, ranging from 98% (energy healing) to 76% (hypnosis). The most commonly used CAM approaches include prayer and megavitamin supplements.
Although some alternative approaches have a long history, many remain controversial owing to less than comprehensive research and poor integration of the Western and Eastern methods of diagnosis and treatment that are often mutually misunderstood and criticized. These practices encompass a diverse range of therapies and techniques but have in common a general lack of acceptance or use in traditional medical settings. However, with the increasing public use of CAM for preventive and therapeutic purposes, including a very active ‘antiaging’ movement, a significant effort is now devoted to the integration of alternative methods of treatment into mainstream healthcare practice and research. The principal uses in older adults include stress reduction, antiaging effects of CAM for prevention of diseases of aging, memory enhancement and treatment of various neuropsychiatric disorders, such as depression, anxiety, insomnia, pain and many other specific indications. Our review is devoted to the description of the existing CAM treatments applied to the care of older adults with neuropsychiatric illnesses that include late-life mood and cognitive disorders.
To identify articles related to this subject, we conducted a systematic search of the MEDLINE database and of Cochrane Database of Systematic Reviews for English articles published in the past 10 years using the following keywords: late life, depression, dementia, memory, cognition, sleep, complementary medicine, omega-3 fatty acids, hypericum, SAMe, acupuncture, ayurveda, massage, energy therapies, therapeutic massage, yoga and herbal remedies, diet, art (music and dance) therapy and spirituality/prayer.
Complementary & alternative medicine use in late-life mood & cognitive disorders
Mood and cognitive impairment are the most frequently occurring psychiatric syndromes in older adults. Depressive symptoms occur in approximately 10–15% of patients in primary care settings. Cognitive disorders are on the rise owing to the ‘graying’ of the population around the world. Mood disturbances are commonly observed in patients with neurodegenerative disorders including probable Alzheimer’s disease (AD), Parkinson’s disease (PD), and post-stroke depression. Depression in later life is a treatable condition. Improvement with treatment occurs in mood symptoms and activities of daily living (ADLs), and in the quality of life of the patients and their caregivers, but not necessarily in memory and other cognitive functions. Clinically, preference is given to therapy with antidepressants that do not have a significant anticholinergic effect. Other treatment strategies include treatment of pain and infection, environmental and behavioral management and professional caregiver training. Despite rigorous research, the response to these therapies remains only modest and partial for most patients . While CAM treatments are widely used by consumers, very little research is available to guide patients and their caregivers, or even practitioners in the field. A 2001 US survey of a nationally representative sample of patients diagnosed with a mood or anxiety disorder reported that 57% of those with anxiety attacks and 54% of those with severe depression were using CAM therapies to treat these conditions (either as primary or as adjunctive medication) . These proportions increased to 66 and 67%, respectively, among those who were seeing a conventional healthcare professional for these conditions . The perceived helpfulness of CAM therapies was similar to that of conventional therapies .
In this article, the literature that pertains to the use of diet and the use of nutritional and herbal supplements, expressive therapies (e.g., art, dance and music), stress reduction, culturally based therapies (e.g., Ayurveda and acupuncture) and spiritual practices is reviewed. Whenever possible, the review of the efficacy provided by positive meta-analyses, followed by one large or several smaller double-blind, placebo-controlled trials, and open trials is also included. This hierarchy of evidence is not available in each of the area of CAM. Although some animal studies are referred to, these are not a reliable indication of efficacy in humans (Table 1).
Complementary and alternative medicine interventions for the treatment of late-life affective and cognitive disorders.
Diet & the use of nutritional & herbal supplements
Adjusting both diet and nutrition may help some people with mental illnesses manage their symptoms and promote recovery. For example, research suggests that eliminating milk and wheat products can reduce the severity of symptoms for some people who have schizophrenia and some children with autism . Similarly, some holistic/natural physicians use herbal treatments, B-complex vitamins, riboflavin, magnesium and thiamine to treat anxiety, depression, drug-induced psychoses and memory loss.
A number of herbs and dietary supplements have demonstrable effects on mood, memory and insomnia . There is a significant amount of evidence supporting the use of Hypericum perforatum (SJW) for depression, and omega-3 fatty acids and gingko biloba for dementia as reviewed below.
St John’s Wort (Hypericum perforatum)
St John’s wort has been extensively studied in Europe, particularly in Germany. A recent meta-analysis of 23 randomized trials (20 were double-blinded) in a total of 1757 outpatients with mild-to-moderate depression found improvement in depressive symptoms in all groups. In 15 placebo-controlled studies, medication was more effective than placebo. In eight treatment-controlled trials, SJW was as effective as tricyclic antidepressants. However, a recent large NIH-sponsored US multisite randomized trial of SJW compared with sertraline and placebo for the treatment of major depression failed to find drug–placebo differences . A recent Cochran database review provided the analyses for a total of 37 trials, including 26 comparisons with placebo and 14 comparisons with synthetic standard antidepressants . The results of placebo-controlled trials demonstrated a marked heterogeneity. In trials restricted to patients with major depression, the combined response rate ratio (RR) for hypericum extracts compared with placebo from six larger trials was 1.15 (95% CI: 1.02–1.29) and from six smaller trials was 2.06 (95% CI: 1.65–2.59). In trials not restricted to patients with major depression, the RR from six larger trials was 1.71 (95% CI: 1.40–2.09) and from five smaller trials was 6.13 (95% CI: 3.63–10.38). Trials comparing hypericum extracts and standard antidepressants were statistically homogeneous. Compared with selective serotonin-reuptake inhibitors (SSRIs) and tri- or tetra-cyclic antidepressants, respectively, RRs were 0.98 (95% CI: 0.85–1.12; six trials) and 1.03 (95% CI: 0.93–1.14; seven trials). Patients given hypericum extracts dropped out of trials owing to adverse effects less frequently than those given older antidepressants (odds ratio [OR]: 0.25; 95% CI: 0.14–0.45); such comparisons were in the same direction, but not statistically significantly different, between hypericum extracts and SSRIs (OR: 0.60; 95% CI: 0.31–1.15). Therefore, current evidence regarding hypericum extracts is inconsistent and confusing. In patients who meet criteria for major depression, several recent placebo-controlled trials suggest that the tested hypericum extracts have minimal beneficial effects while other trials suggest that hypericum and standard antidepressants have similar beneficial effects. The recommended doses include 300 mg three-times daily or 450 mg twice daily. As the preparations available on the market might vary considerably in their pharmaceutical quality, the results of this review apply only to the products tested in the included studies.
Interestingly, hyperforinm, an acylphloroglucinol compound isolated from Hypericum perforatum (SJW), has been used in animal models of AD and has been found to: decrease amyloid deposit formation in rats injected with amyloid fibrils in the hippocampus; decrease the neuro-pathological changes and behavioral impairments in a rat model of amyloidosis; and prevent Aβ-induced neurotoxicity in hippocampal neurons both from amyloid fibrils and Aβ oligomers, avoiding the increase in reactive oxidative species associated with amyloid toxicity. Both effects could be explained by the capacity of hyperforin to disaggregate amyloid deposits in a dose and time-dependent manner and to decrease Aβ aggregation and amyloid formation. Altogether, this evidence suggests that hyperforin may be useful to decrease amyloid burden and toxicity in AD patients, and may be a putative therapeutic agent to fight the disease .
Although it is commonly believed that herbal preparations are safer than the synthetic ones, many of them have limiting side effects. SJW is useful for the treatment of mild-to-moderate depression, but has multiple potentially dangerous and lethal drug interactions owing to its monoamine oxidase inhibition demonstrated in vitro [12,16,17]. In addition, concurrent use of drugs metabolized by the cytochrome CYP450 liver enzyme system may result in altered therapeutic levels due to induction or inhibition of enzymes by SJW that might preclude its use in elderly patients who are taking multiple medications owing to potential drug interactions. Human pharmacokinetic studies have reported induction of CYP 3A/3A4 by reductions of drug concentrations. The drug levels of such medications as carbamazepine, cyclosporine, estrogens and oral contraceptives, as well as statins, may be altered causing potentially dangerous and life-threatening side effects. A significant decrease in cyclosporin levels in transplant recipients (e.g., kidney and heart) taking SJW may result in acute transplant rejection and death .
Other herbal products
Many users of CAM may take a variety of herbal products other than SJW . In primary care settings, 11% of patients with symptoms of anxiety or depression reported using herbal products. Their use was predicted by a diagnosis of major depression, higher education and a lower burden of medical illness . Various herbal products (e.g., Corni fructus, Lycii fructus, Pinelliae rhizome or Rehmanniae radix preparat) are used in the treatment of depression in different parts of the world even though most of them have not been scientifically evaluated . One product has been evaluated in persons with bipolar disorder  and three in rodent models of depression [21,23,24].
Ginkgo biloba leaf extract is among the most widely sold herbal dietary supplements in the USA. Its purported biological effects include: scavenging free radicals; lowering oxidative stress; reducing neural damages, reducing platelets aggregation; anti-inflammation; antitumor activities; and antiaging. Clinically, it has been prescribed to treat CNS disorders such as AD and cognitive deficits. It exerts allergy and changes in bleeding time. While its mutagenicity or carcinogenic activity has not been reported, its components, quercetin, kaempferol and rutin have been shown to be genotoxic. There are no standards or guidelines regulating the constituent components of ginkgo biloba leaf extract nor are exposure limits imposed. Safety evaluation of ginkgo biloba leaf extract is being conducted by the US National Toxicology Program.
Ginkgo biloba has been widely used for many years by people with symptoms attributed to ‘cerebrovascular insufficiency’, despite the lack of evidence of a causal role. Approximately 30 placebo-controlled trials in patients with various types of dementia have been published, with highly inconsistent results. If these studies demonstrated any effect on cognition, it was weak and did not last more than 6months. Cases of hemorrhage were reported, and this means that caution is needed, especially in patients at increased risk of hemorrhage, such as those on ongoing anticoagulant or antiplatelet treatment. In practice, ginkgo biloba extract appears to be little or no different from placebo in the treatment of AD. The recommended doses range widely, but in the recent trial of prevention of AD, gingko biloba at 120 mg twice a day was not effective in reducing either the overall incidence rate of dementia or AD incidence in elderly individuals with normal cognition or those with MCI . Its short-term use is acceptable under some conditions, but the potential risk of bleeding must be seriously considered . Gingko has been reported to reduce depression in dementia patients and counteract sexual side effects of antidepressants [27,28].
Use of nutritional supplements
In addition to herbal remedies, consumers use a variety of nutritional supplements (including vitamins, amino acids and fish oil) that may affect mood and functioning. Although evidence for the use of vitamins, antioxidants and amino acids as sole agents for treatment of psychiatric symptoms is not as strong, there is some preliminary evidence for the use of folate, tryptophan and phenylalanine as adjuncts to enhance the effectiveness of conventional antidepressants in the treatment of depression. SAMe seems to have antidepressant effects, and omega-3 polyunsaturated fatty acids, particularly docosahexaenoic acid, may have mood-stabilizing effects. More research should be conducted on the role of these and other natural products in the prevention and treatment of psychiatric symptoms.
Depression is associated with poor nutrition, with severely compromised cognition and functioning resulting from malnutrition. Early recognition and intervention may prevent poor nutrition in these disorders. For example, the role of L-tryptophan in neuropsychiatric disorders appears to be profound . Tryptophan is an essential amino acid precursor for serotonin synthesis in the brain. Dietary tryptophan supplementation has been used with variable success in psychiatric patients. In a recent study, a 200 mg dose of L-5-hydroxytryptophan (L-5HTP) significantly augmented the prolactin and cortisol response AUC (0–3 h) to 20 mg oral citalopram. The results of this study suggest that an augmented neuroendocrine challenge may be a suitable marker to demonstrate increased 5-HT-mediated responses when exploring novel agents as improved SSRIs . This suggests that it could be useful as an adjunct therapy in the treatment of depression and dementia, but this requires further systematic investigation.
Elevated plasma homocysteine concentrations have been implicated with risk of cognitive impairment and dementia, but it is unclear whether low vitamin B12 or folate status is responsible for cognitive decline or can prevent against it [31,32]. Most studies reporting associations between cognitive function and homocysteine or B-vitamins have used a cross-sectional or case–control design and have been unable to exclude the possibility that such associations are a result of the disease rather than being causal. The homocysteine hypothesis of dementia has attracted considerable interest, since homocysteine can be easily lowered by folic acid and vitamin B12, raising the prospect that B-vitamin supplementation could lower the risk of dementia. Incident dementia is more strongly associated with changes in folate, vitamin B12 and homocysteine, than with previous concentrations. These changes may be linked to other somatic manifestations of early dementia, such as weight loss . However, in a recent trial of high-dose vitamin B in patients with AD, it did not slow cognitive decline in individuals with mild-to-moderate AD . Two other placebo-controlled trials of treatment with B12, folic acid, and B6 showed no advantage of vitamins over placebo at reducing the severity of depressive symptoms or the incidence of clinically significant depression over a period of 2 years in older men . Similarly, a recent Cochrane review found no evidence for short-term benefit from vitamin B6 in improving mood (depression, fatigue and tension symptoms) or cognitive functions. For the older people included in one of the two trials included in the review, oral vitamin B6 supplements improved biochemical indices of vitamin B6 status, but potential effects on blood homocysteine levels were not assessed in either study. This review found evidence that there is scope for increasing some biochemical indices of vitamin B6 status among older people . However, the limited available evidence suggests folate may have a potential role as a supplement to other treatments for depression. It is currently unclear if this is the case both for people with normal folate levels, and for those with folate deficiency . More randomized, controlled trials are needed to explore possible benefits from vitamin B6 supplementation for healthy older people and those with cognitively impairment or dementia.
Omega-3 fatty acids
Other common dietary supplements are fish oil and omega-3 fatty acids. Reductions in cardiovascular risk, depression and rheumatoid arthritis symptoms have been correlated with omega-3 fatty acid intake, and there is increased interest in the use of omega-3 fatty acid supplementation for other psychiatric illnesses and prevention of AD. Omega-3 fatty acids are found principally in fish and seafood although some can be derived from green vegetables. By contrast, omega-6 fatty acids are found in soft margarine, most vegetable oils and animal fat. Omega-6 is plentiful in most modern Western diets while omega-3 is often relatively lacking. A high dietary ratio of omega-6 to omega-3 has been linked to vulnerability to many physical and mental disorders . Reported health benefits include improvements in mood in unipolar and bipolar disorders, as well as dementia .
Following the well-publicized promising results from a placebo-controlled study , there has been a broad interest in the use of omega-3 fatty acids for the treatment of bipolar disorder and depression. There is mounting evidence that dietary supplementation with omega-3 fatty acids may be beneficial in treating a variety of conditions including several psychiatric disorders [39,41], although not all studies are in agreement . Most studies recommend omega-3 essential fatty acids with an eicosapentaenoic acid (EPA):docosahexaenoic acid (DHA) ratio of 7:1.
In a prospective, naturalistic study of 5386 nondemented participants, fish consumption was inversely related to incident dementia. There is one case report of a patient with AD whose agitated behaviors improved after incorporation of fish in his diet. This suggests that omega-3 fatty acids may have a possible role in the prevention and treatment of dementia. To address potential mechanisms, a study documented the effect of DHA on inflammatory markers: AD patients treated with DHA-rich n-3 fatty acid supplementation increased their plasma concentrations of DHA (and EPA), which were associated with reduced release of IL-1β, IL-6 and granulocyte colony-stimulating factor from peripheral blood mononuclear cells . However, in the recent well designed, placebo-controlled trial of the effect of EPA and DHA on mental wellbeing in a double-blind, placebo-controlled trial in the general older population, the study failed to find drug–placebo difference in improving cognition or wellbeing in older adults . In a recent meta-analysis, omega-3 was suggested as an adjunctive treatment for depressive but not manic symptoms in bipolar disorder . Another meta-analysis concluded that available data are insufficient to draw strong conclusions about the effects of omega-3 fatty acids on cognitive function in normal aging or on the incidence or treatment of dementia. However, limited evidence suggests a possible association between omega-3 fatty acids and reduced risk of dementia .
In summary, omega-3 fatty acids may have a role in the treatment of late-life neuropsychiatric disorders. However, given the conflicting data on their efficacy, additional studies are needed before their use can be recommended confidently to patients. These studies should clarify the role and the optimal dose of omega-3 fatty acids or EPA in the treatment of the depression or cognitive decline and address lingering questions regarding the purity of marketed supplements.
S-adenosyl-L-methionine is one of the CAM products that has been studied under rigorous controlled conditions. SAMe is derived from the amino acid L-methionine through the one-carbon cycle and it is a methyl donor involved in the synthesis of the monoaminergic neurotransmitters. SAMe has been investigated for its antidepressant properties in both open [4,47] and randomized, controlled trials . SAMe dosages of 200–1600 mg/day (orally or parenterally) have been shown to be superior to placebo and as effective as tricyclic antidepressants in alleviating depression, although some individuals may require higher doses [47,48]. SAMe may have a faster onset of action than conventional antidepressants and may potentiate the effect of tricyclic antidepressants  or of serotonin reuptake inhibitors . At this time, the recommended doses vary but most commonly used include SAMe 200 mg twice daily, up to 800 mg twice daily. Oral dosages of SAMe up to 1600 mg/day appear to be significantly bioavailable and safe . SAMe has been associated with minor adverse effects (e.g., gastrointestinal symptoms and headaches) . However, as with any antidepressant compound, some cases of mania have been reported in bipolar patients taking SAMe [48,51].
Overall, SAMe appears to be safe and efficacious in the treatment of depression but further controlled studies are required since current evidence comes mostly from open trials or small controlled studies. It may have a role in the management of patients with bipolar disorder but more research is needed, in particular to determine its effective dose and to better assess the risk of switch to mania or hypomania .
Culturally based healing arts
Culturally based healing includes traditional Asian medicine (e.g., acupuncture, shiatsu, and reiki), Indian systems of healthcare (such as Ayurveda and yoga) and Native American healing practices (such as the Sweat Lodge and Talking Circles). All incorporate the beliefs that: wellness is a state of balance between the spiritual, physical, and mental/emotional ‘selves’; an imbalance of forces within the body is the cause of illness; and herbal/natural remedies, combined with sound nutrition, exercise and meditation/prayer, will correct this imbalance.
The Chinese practice of inserting needles into the body at specific points manipulates the body’s flow of energy to balance the endocrine system. This manipulation regulates functions such as heart rate, body temperature and respiration, as well as sleep patterns and emotional changes. Acupuncture has been used in clinics to assist people with substance abuse disorders through detoxification; to relieve stress and anxiety; to treat attention deficit and hyperactivity disorder in children; to reduce symptoms of depression; and to help people with physical ailments. Compared with other empirically validated treatments, acupuncture designed specifically to treat major depression produced results that are comparable in terms of rates of response and of relapse or recurrence. These results warrant a larger trial of acupuncture in the acute- and maintenance-phase treatment of depression . In a recent small study of acupuncture, positive subjective and objective effect was found on mood and wellbeing . However, in the recent Cochrane database review  of seven trials comprising 517 subjects who generally had mild-to-moderate depression, there was no evidence that medication was better than acupuncture in reducing the severity of depression, or in achieving remission.
There are fewer studies of acupuncture for dementia compared with depression or stress. Interestingly, in a recent Chinese study, Zhou and Jin reported acupuncture performed on corresponding scalp regions of the brain regions of AD . A total of 26 patients with clinically diagnosed AD underwent functional MRI (fMRI) while undergoing acupuncture at the four acupoints. fMRI block design paradigm was chosen by electroacupuncture interval stimulation, and the data of fMRI were analyzed by Statistical Parametric Mapping (SPM 99). The results demonstrated that there were right main hemisphere activations (the temporal lobe, such as hippocampal gyrus, insula and some areas of the parietal lobe) and left-activated regions (the temporal lobe, parietal lobule and some regions of the cerebellum). The activated regions induced by these acupoints were consistent with impaired areas in brain for AD patients, which were closely correlated with the cognitive function (the memory, reason, language, executive and so on). The present study provided strong evidence that acupuncture had a potential effect on AD, and in partial revealed the mechanism. In summary, there is insufficient evidence to determine the efficacy of acupuncture compared with medication, or to wait list control or sham acupuncture, in the management of depression. Scientific study design is generally poor and the number of people studied was relatively small. One of the barriers to conducting appropriate studies of acupuncture is the difference in the diagnostic systems in the Western and Chinese medicine, precluding fair comparison.
Ayurveda is a comprehensive natural health-care system that originated in India more than 5000 years ago and has been used for antiaging, memory enhancement, and as nerve tonic, anxiolytic, anti-inflammatory and immunopotentive remedies. It is still widely used in India as a system of primary healthcare, and interest in it is growing worldwide as well. Ayurveda means ‘the science of life’ (Ayur means ‘life’ and Veda means ‘knowledge or science). Ayurvedic medicine is described as ‘knowledge of how to live’. It incorporates an individualized regimen, such as diet, meditation, herbal preparations or other techniques to treat a variety of conditions, including depression, to facilitate lifestyle changes, and to teach people how to release stress and tension through yoga or transcendental meditation. There are some preliminary encouraging results for its effectiveness in treating various ailments, including chronic disorders associated with the aging process. Pilot studies of depression, anxiety, sleep disorders, hypertension, diabetes mellitus, PD and AD yielded positive results [56,57]. However, no extensive, controlled studies of Ayurveda in older adults are available to date.
There is an increasing number of publications on antioxidant, neuroprotective and memory-enhancing properties of various herbal Ayurvedic preparations in rat and mice models of AD [58,59]. The part of the Ayurvedic system that provides an approach to prevention and treatment of degenerative diseases is known as Rasayana, and plants used for this purpose are classed as rejuvenators. Traditional medicinal plants in various countries, particularly in India have been used for centuries for various ailments; however, there has been little scientific effort to validate these anecdotal uses mentioned in the literature.
A number of these traditionally used plant extracts and various Ayurvedic medicines that are highly valued in Ayurveda, have been screened using the National Institute of Mental Health (NIMH) Synthetic Screening Program for scientific validation and the development of new leads of psychotherapeutic compounds using Radioligand Receptor Binding Assays (RRA) [58,59]. The focus was on plants showing the highest displacement of GABA, cholecystokinin (CCK), NMDA, monoamine oxidase and benzodiazopines. A bioactivity-guided fractionation of Terminalia bellerica fruit extract led to the isolation of several pure compounds that retained the original activity of the crude extract for CCK and GABA receptors, with the exception of compound B3EA-6, which exhibited high affinity for the neurokinin receptor.
In young and aging mice models, Anwala churna (50, 100 and 200 mg/kg, per orem) produced a dose-dependent improvement in memory scores. Furthermore, it reversed the amnesia induced by scopolamine (0.4 mg/kg, intraperitoneal) and diazepam (1 mg/kg, intraperitoneal). Interestingly, brain cholinesterase activity and total cholesterol levels were reduced by Anwala churna administered orally for 15 days. Anwala churna may prove to be a useful remedy for the management of AD on account of its multifarious beneficial effects such as its memory improving property, cholesterol-lowering property and anticholinesterase activity.
Ocimum sanctum (OS), a plant widely used in Ayurveda, has been shown to possess anti-inflammatory, antioxidant and cognition-enhancing properties . In rats, the effect of methanolic extract of OS leaves was studied in cerebral reperfusion injury as well as long-term hypoperfusion. OS treatment (200 mg/kg/day for 15 days) significantly prevented long-term hypoperfusion-induced functional and structural disturbances. The results suggest that OS may be useful in treatment of cerebral reperfusion injury and cerebrovascular insufficiency states.
Trasina is a herbal formulation of some Indian medicinal plants classified in Ayurveda, the classic Indian system of medicine, as Medhyarasayanas, or drugs reputed to improve memory and intellect [61,62]. Earlier experimental and clinical investigations have indicated that the formulation has a memory-facilitating action. The effect of trasina was studied in the rodent model of AD simulating some biochemical features known to be associated with AD after subchronic administration for 21 days. Trasina (200 and 500 mg/kg) reversed deficits in acetylcholine after 14 and 21 days of treatment. The findings indicate that the herbal formulation exerts a significant nootropic effect after subchronic treatment that may be due to reversal of perturbed cholinergic function.
Conducting research that compares Ayurveda’s comprehensive treatment approach, Western allopathic treatment, and an integrated approach combining the Ayurvedic and allopathic treatments would shed light on which treatment approach is the most effective for the benefit of the patient.
Yoga & meditation
Practitioners of yoga, the ancient Indian system of healthcare, use breathing exercises, posture, stretch and meditation to balance the body’s energy centers. Mindful physical exercise is a special kind of physical exercise with an additional element that focuses on one’s state of mind. It has recently emerged as a therapeutic intervention for improving the psychosocial wellbeing of individuals. According to IDEA Mind–body Fitness Committee (1997–2001), the mindful physical exercise is characterized by ‘physical exercise executed with a profound inwardly directed contemplative focus’. A physical exercise is considered mindful if:
It has a meditative/contemplative component that is noncompetitive and nonjudgmental;
It has proprioceptive awareness that involves a low-to-moderate level of muscular activity with mental focus on muscular movement;
It is breath centering;
It focuses on anatomic alignment, such as spine, trunk and pelvis, or proper physical form;
It concerns energy centric as awareness of individuals’ flow of intrinsic energy, vital life force, qi and so on .
With the above framework, yoga and qigong are two major streams of mindful physical exercise based on the literature. Yoga is used in combination with other treatments for depression, anxiety and stress-related disorders.
The principle of yoga is to achieve integration of mind, body and spirit. There are 22 types of yoga and many more modifications. The most popular type in the USA is Hatha yoga, a branch of yoga that requires a vast repertoire of physical postures during sitting, standing or lying on the floor, along with specific breathing patterns. Other than physical movement, participants are required to maintain a ‘homeostasis’ of mind and body, which refers to the relaxation of body tension with quieting of thoughts. The qigong exercise is a system of self-practicing physical exercise, which includes healing posture, movement, self-massage, breath work and meditation. All forms of qigong are featured on balance, relaxation, breathing and good posture. The movements of qigong are executed at very low energy expenditure levels. A specific breathing pattern also applies to qigong. Similar to yoga, the breathing style of qigong is slow and deep in order to achieve body relaxation, clearing of mind, and, additionally, maintenance of health. Combining all of the above components, the mindful physical exercise has been shown to provide an immediate source of relaxation and mental quiescence . Scientific evidence demonstrates that medical conditions, such as hypertension, cardiovascular disease, insulin resistance, depression and anxiety disorders, respond favorably to the mindful physical exercises .
Despite a growing body of evidence to show the effects of mindful physical exercises such as qigong, tai chi and yoga on depression [59,65–73], there is a dearth of reviews that have examined mindful physical exercise as to its effects on alleviating depression [74,75]. A recently published review on complementary and alternative treatments in older adults demonstrated that mind–body interventions were effective on treating depression, anxiety and insomnia in ten out of 12 studies reviewed .
The effects of yoga and Ayurveda on geriatric depression were evaluated in 69 patients older than 60 years who were living in a residential home . Participants were stratified by age and gender and randomly allocated to three groups: yoga, Ayurveda or wait-list control. The 15-item Geriatric Depression Scale (GDS) was used to assess depressive symptoms prior to the intervention and after 3months and 6 months postinter-vention. Participation in one of the three groups lasted 24 weeks. The yoga program (7 h 30 min per week) included physical postures, relaxation techniques, regulated breathing, devotional songs and lectures. The Ayurveda group received an herbal preparation twice daily for the whole period. The depression symptom scores of the yoga group at both 3 and 6 months decreased significantly, from a group average baseline of 10.6–8.1 and 6.7, respectively (p < 0.001, paired t-test). The other groups showed no change. Hence, an integrated approach of yoga including the mental and philosophical aspects in addition to the physical practices was useful for institutionalized older persons.
Chen and Tseng reported the results of a pilot study on the health-promoting effects of a silver yoga exercise program for female seniors . Using a one-group, prepost test design, a convenience sample of 16 community-dwelling female seniors was recruited. The silver yoga exercise intervention was administered three times a week, 70min per session, for 4 weeks. Data were collected at baseline and after completion of the 4-week intervention. Results indicated that participants’ body fat percentage and systolic blood pressure decreased, balance and range of motion on shoulder flexion and abduction improved, and sleep disturbance was minimized (all p < 0.05).
In a small randomized pilot study, Butler etal. investigated the effects of meditation with yoga (and psychoeducation) versus group therapy with hypnosis (and psychoeducation) versus psychoeducation alone on diagnostic status and symptom levels among 46individuals with long-term depressive disorders . Results indicate that significantly more meditation group participants experienced a remission compared with controls at 9-month follow-up. Eight hypnosis group participants also experienced remission, but the difference from controls was not statistically significant. Three control participants, but no meditation or hypnosis participants, developed a new depressive episode during the study, although this difference did not reach statistical significance in any case. Although all groups reported some reduction in symptom levels, they did not differ significantly in that outcome. Overall, these results suggest that these two interventions show promise for treating mild-to-moderate depression.
Meditation, spirituality & pastoral care
Some people prefer to seek help for mental health problems from their pastor, rabbi or priest, rather than from therapists who are not affiliated with a religious community. Counselors working within traditional faith communities are increasingly recognizing the need to incorporate psychotherapy and/or medication, along with prayer and spirituality to effectively help some people with mental disorders. Both religiousness and social support have been shown to influence depression outcome, yet some researchers have theorized that religiousness largely reflects social support. In a recent study, religious coping was related to social support, but was independently related to depression outcome. The authors concluded that clinicians caring for older depressives should consider inquiring about spirituality and religious coping as a way of improving depressive outcomes . The protective effects of religion against late-life depression may depend on the broader socio–cultural environment. Religious practice, church attendance or prayer, especially when it is embedded within a traditional value-orientation, may facilitate coping with adversity in later life and stress reduction [80–84].
Clinical effects of meditation impact a broad spectrum of physical and psychological symptoms and syndromes, including reduced anxiety, pain and depression, enhanced mood and self-esteem, and decreased stress. Meditation has been studied in populations with fibromyalgia, cancer, hypertension and psoriasis. While earlier studies were small and lacked experimental controls, the quality and quantity of valid research is growing. Meditation practice can positively influence the experience of chronic illness and can serve as a primary, secondary, and/or tertiary prevention strategy. Health professionals demonstrate commitment to holistic practice by asking patients about use of meditation, and can encourage this self-care activity. Simple techniques for mindfulness can be taught in the clinical setting. Living mindfully with chronic illness is a fruitful area for research, and it can be predicted that evidence will grow to support the role of consciousness in the human experience of disease . Mindfulness-based cognitive therapy (MBCT) is a recently developed class-based program designed to prevent relapse or recurrence of major depression . Although research in this area is in its infancy, MBCT is generally discussed as a promising therapy in terms of clinical effectiveness in treatment and relapse prevention in major depression . No studies of MBCT are available in the elderly.
Relaxation & stress reduction techniques: biofeedback
Learning to control muscle tension and ‘involuntary’ body functioning, such as heart rate and skin temperature, can be a path to mastering one’s fears. It is used in combination with, or as an alternative to medication to treat disorders such as anxiety, panic and phobias. For example, a person can learn to ‘retrain’ his or her breathing habits in stressful situations in order to induce relaxation and decrease hyperventilation. Some preliminary research indicates it may offer an additional tool for treating depression . Although there are no data in geriatric depression, an increasing number of publications use biofeedback for memory training and cognitive enhancement using neurofeedback (NF). NF is an electroencephalographic (EEG) biofeedback technique for training individuals to alter their brain activity via operant conditioning. Research has demonstrated that NF helps to reduce the symptoms of several neurological and psychiatric disorders, with ongoing research currently investigating applications to other disorders and to the enhancement of nondisordered cognition.
Angelakis et al. used EEG peak alpha frequency (PAF) for NF because it has been shown to correlate positively with cognitive performance and to correlate negatively with age . In a pilot double-blind study of NF, training older individuals to increase PAF resulted in improved cognitive performance. The results suggested that PAF NF improved cognitive processing speed and executive function, but that it had no clear effect on memory. Kotchoubey etal. reported the results of two groups of subject comparison, aged 20–28 and 50–64 years, respectively, matched for health status and verbal abilities . Subjects learned to control their slow cortical potentials (SCP) in a feedback paradigm by producing, on command, SCP shifts in either a positive or negative direction. Both groups were able to differentiate significantly between the positivity task and the negativity task, with the differentiation score being only slightly (and not significantly) lower in older than in younger subjects. Older subjects had only explicit, but not implicit, learning deficits. The pattern of consistently more negative SCP shifts produced by elderly subjects may indicate their impaired cortical inhibition probably caused by brain aging. The question remains if biofeedback could be helpful in reducing cognitive deficits associated with aging or dementia.
The underlying principle of this approach is that rubbing, kneading, brushing and tapping a person’s muscles can help release tension and pent emotions. It has been used to treat trauma-related depression and stress. A highly unregulated industry, certification for massage therapy varies widely from state to state. Few studies have been carried out on the effects of massage therapy among older adults. Furthermore, existing studies of massage effects on anxiety, depression and stress have tended to focus on clinic population samples with relatively high levels of distress, rather than community-based samples of people who have not exhibited clinical levels of distress. The potential of massage therapy to promote older adults’ perceptions of wellbeing and reduce perceived stress has not been studied, nor is it known if massage might be superior to guided relaxation in affecting these perceptions. Sharpe et al. reported significant improvements for the anxiety, depression, vitality, general health and positive wellbeing sub-scales of the General Wellbeing Schedule and for Perceived Stress among the massage participants compared with guided relaxation . However, Hirakawa et al. in a study of home massage rehabilitation therapy, did not demonstrate a positive effect on the bed-ridden elderly, either mentally or physically . Cambron etal. reported the side effects of massage therapy in 10% of the massage clients who experienced some minor discomfort after the massage session; however, 23% experienced unexpected, nonmusculoskeletal positive side effects . The majority of negative symptoms started less than 12 h after the massage and lasted for 36 h or less. The majority of positive benefits began immediately after massage and lasted more than 48 h.
Human and other animal studies demonstrate that exercise targets many aspects of brain function providing broad effects on overall brain health. The benefits of exercise have been best defined for learning and memory, protection from neurodegeneration and alleviation of depression, particularly in the elderly populations. Exercise increases synaptic plasticity by directly affecting synaptic structure and potentiating synaptic strength, and by strengthening the underlying systems that support plasticity including neurogenesis, metabolism and vascular function. Such exercise-induced structural and functional change has been documented in various brain regions but has been best studied in the hippocampus .
Emerging evidence suggests that exercise has therapeutic and preventative effects on depression . The prevention and treatment of depression are important areas to define: depression is linked to cognitive decline  and is considered to cause a worldwide health burden greater than that of ischemic heart disease, cerebrovascular disease or tuberculosis . Therapeutic effects of exercise on depression have been most clearly established in human studies. Randomized and crossover clinical trials demonstrate the efficacy of aerobic or resistance-training exercise (2–4 months) as a treatment for depression in both young  and older individuals [98,99]. The benefits are similar to those achieved with anti-depressants . They are also dose dependent: greater improvements are seen with higher levels of exercise .
Furthermore, the therapeutic effects of exercise on depressive symptoms have been demonstrated in conditions of neurodegeneration in humans. Specifically, in a randomized clinical trial, 3 months of exercise intervention improved depressive symptoms in individuals with AD, whereas nonexercising subjects showed worsening of depressive symptoms . In addition to a therapeutic effect, evidence from human studies demonstrate that exercise can provide some protection from the development of depression . A protective effect of sustained exercise (>2 weeks) has been clearly demonstrated in animal models of depression, including stress-induced learned helplessness [101,102]. In addition, a therapeutic effect of exercise on exiting depression has been recently established in an animal model ; this therapeutic effect parallels that observed in human studies. In a recent study of exercise in early AD, cardiorespiratory fitness was modestly reduced in subjects with AD compared with subjects without dementia and was associated with whole-brain volume and white matter volume reductions after controlling for age . In participants with no dementia, there was no relationship between fitness and brain atrophy. Therefore, cardiovascular fitness may moderate AD-related brain atrophy; however, further studies are needed to resolve inconsistent findings.
Although exercise seems to have both preventative and therapeutic effects on the course of depression, the underlying mechanisms are poorly understood. Protective effects of exercise from stress have focused on the hippocampus, where exercise-induced neurogenesis  and growth factor expression  have been proposed as potential mediators, although not without controversy . Other proposed mechanisms include exercise-driven changes in the hypothalamic–pituitary–adrenal axis that regulates the stress response , and altered activity of dorsal raphe serotonin neurons implicated in mediating learned helplessness behaviors . It is important to note that the translatability of animal studies is dependent on the animal model of depression and how well it parallels the human condition–an area that remains under active investigation.
A key mechanism mediating these broad benefits of exercise on the brain is induction of central and peripheral growth factors and growth factor cascades, which instruct downstream structural and functional change. In addition, exercise reduces peripheral risk factors such as diabetes, hypertension and cardiovascular disease, which converge to cause brain dysfunction and neurodegeneration. A common mechanism underlying the central and peripheral effects of exercise might be related to inflammation, which can impair growth factor signaling both systemically and in the brain. Thus, through regulation of growth factors and reduction of peripheral and central risk factors, exercise ensures successful brain function .
Creativity interventions have been shown to positively affect mental and physiological health indicators in older adults. Developing creative coping strategies can enable older adults to adapt more effectively to physical, psychological and psychosocial changes that occur during old age. The process of creating and one’s attitude toward life may be more important than the actual product or tangible outcome. Addams-Price concludes that late-life creativity reflects aspects of late-life thinking: synthesis, reflection and wisdom . From a problem-solving perspective, creativity is an asset in older adulthood, given the number of health, functional and financial limitations likely to occur . Many older adults might not describe themselves as creative and would be reluctant to engage in typical creative endeavors, such as painting or drawing.
Art & music therapy
Drawing, painting and sculpting help many people to reconcile inner conflicts, release deeply repressed emotions, and foster self-awareness, as well as personal growth. Some mental health providers use art therapy as both a diagnostic tool and as a way to help treat disorders such as depression, abuse-related trauma and schizophrenia. Music or sound therapy has been used to treat disorders such as stress, grief, depression, loneliness, and cognitive and functional decline.
The largest study of creativity to date is Cohen’s investigation of the impact of professionally conducted cultural programs on older adults . This study involved 150 treatment and 150 control participants aged 65 years and older, who were matched for health and functioning. Control participants were permitted to engage in their routine activities; however, none of them became involved in rigorous and sustained participation in art programs during the course of the study. The treatment group reported better health 1 year after baseline starting point measures; the control group reported their health was not as good 1 year postbaseline measures . Furthermore, the intervention group reported an average of 9.27 doctor visits per year while the control group reported an average of 13.19 visits per year. Both groups had more visits when compared with baseline, but the control group’s visits increased at a greater rate . Medication use increased at a greater rate in the control group as compared with the intervention group. The average number of medications reported by the intervention group at the 1-year follow-up was 6.97, while the average number of medications reported by the control group at the 1-year follow-up was 8.48. Mental health was positively affected by the intervention as well; an examination of the means revealed that the intervention group revealed significantly lower levels of depression compared with the control group after 1 year. The intervention also group had a self-reported morale score that was significantly higher (higher morale) than the control group (14.07 and 13.07, respectively) 1 year later. In addition to older adults’ enjoyment, the physiological benefits of creativity, combined with the mental health advantages, are key reasons for the use of creative activities in older adults. These findings provide overwhelming support for this notion, linking the engaging nature, physical and mental health benefits of creativity .
Dance & movement therapy
The underlying premise to dance/movement therapy is that it can help a person integrate the emotional, physical and cognitive facets of ‘self.’ A recent study designed a multimodal program aimed at influencing a group of 75 older adult participants’ purpose in life, depression and hypochondriasis, by targeting physical, mental and spiritual wellbeing . Interventions included rhythm and dance exercises; general physical exercises; recreational exercise outdoors; relaxation exercises; a creativity enhancement seminar; a seminar on psychology and philosophy of life; and a seminar on contact with other people and communication. The group sessions were conducted 2 days per week over a period of 4 months. A purpose in life, depression and hypochondria were three parameters of wellbeing that were measured pre- and post-intervention. The purpose in life scale (PIL) measured purpose in life, the GDS assessed depressive symptoms, and the hypochondriasis scale institutional geriatric (HIP) determined the presence of hypochondria. The first day each week consisted of 1 h of some form exercise and a 2 h seminar. The second day each week was comprised of 1 h of relaxation, 1 h of exercise and 2 h of a seminar about stimulating creativity. Significant changes in test scores were observed over time. Mean PIL scores increased from preintervention to postint-ervention, suggesting greater purpose in life, and these scores remained elevated at 6 months postintervention. Scores for the GDS and the HIP decreased from preintervention to postint-ervention, indicating a decrease in depressive symptoms and hypochondriasis, and continued to be significantly reduced 6 months postinter-vention. Outcomes suggested that interventions were successful in improving quality of life as evidenced by an increased purpose in life and decreased depression and hypochondriasis.
Those who prefer more structure or who feel they have ‘two left feet’ gain the same sense of release and inner peace from the Eastern martial arts, such as Tai Chi. There is considerable evidence that Tai Chi has positive health benefits; physical, psychosocial and therapeutic . Furthermore, Tai Chi does not only consist of a physical component, but also sociocultural, meditative components that are believed to contribute to overall wellbeing. Tai Chi exercise is chosen by the elderly for its gentle and soft movements. Besides the physical aspect, the benefits they describe include lifestyle issues, as well as psychological and social benefits [113,114]. Evidence highlights that the improvements in physical and mental health through the practice of Tai Chi among the older adults are related to their perceived level of quality of life . Findings from numerous studies support the belief that the practice of Tai Chi has multiple benefits to practitioners that are not only physical in nature. It is recommended as a strategy to promote successful cognitive and emotional aging.
In summary, late-life mood and cognitive disorders are the most common reasons for using complementary and alternative therapies. The amount of rigorous scientific data to support the efficacy of complementary therapies in the treatment of depression is extremely limited. The areas with the most evidence for beneficial effects are exercise, herbal therapy (Hypericum perforatum), the use of fish oil, and, to a lesser extent, acupuncture and relaxation therapies. There is a need for further research involving randomized, controlled trials into the efficacy of complementary and alternative therapies in the treatment of depression and cognitive impairment in later life, and the development of effective treatment approaches for these serious conditions.
The public health significance of late-life mood and cognitive disorders is rapidly growing with the mounting number of elderly persons. The cost of care for the victims of mental and cognitive illnesses will increase exponentially in the next several decades. The available standard treatments and preventive strategies have only limited efficacy. At the same time, the interest and use of CAM is rising among aging persons. The currently available evidence of the efficacy of CAM interventions is limited owing to the serious methodological limitations and the lack of understanding of Asian medicine. Only true integration of the specific outcomes, increasing the understanding of various approaches and application of this in clinical research will be likely to benefit researchers, clinicians and older adults. The number of studies of various CAM interventions and translational research is steadily rising, and will probably lead to a merger of the methodologies and approaches of the Eastern and Western medicine.
Financial & competing interests disclosure
This work was supported by the NIH grants R01 MH077650 and R-21 AT003480 to Helen Lavretsky. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Papers of special note have been highlighted as:
• of interest
• • of considerable interest
1. Ernst E. Complementary medicine: where is the evidence? J Fam Pract. 2003;52:630–634.[PubMed]
2• . Meeks TW, Wetherell JL, Irwin MR, Redwine LS, Jeste DV. Complementary and alternative treatments for late-life depression, anxiety, and sleep disturbance: a review of randomized controlled trials. J Clin Psychiatry. 2007;68:1461–1471. Comprehensive review of complementary and alternative medicine (CAM) studies in later life depression, anxiety and sleep disturbances.