The Use of Natural Products and Supplements in Late-Life Mood and Cognitive Disorders

Introduction

Natural products and supplements are increasingly widely used by aging baby-boomers, mostly for mood, sleep, and cognitive symptoms. Evidence suggests that some supplements may be effective in the treatment of a range of mood and cognitive symptoms in middle-age and older adults. We will review studies of the use of natural products and supplements for geriatric or “late-life” mood and cognitive disorders. The lower inclusion age for these studies generally ranges between 60 and 65 years (1, 2). The use of supplements and natural products falls into a category of complementary and alternative medicine. The National Center for Complementary and Alternative Medicine (NCCAM) defines complementary and alternative medicine (CAM) as “a group of diverse medical and health care systems, practices, and products that are not generally considered part of ‘conventional’ medicine,” with conventional being defined as the approaches used by clinicians in the routine daily practice of Western or allopathic medicine that are within the currently accepted standard of care (3). NCCAM identifies four categories of CAM: mind-body medicine, manipulative or body-based practices, natural products, and other practices. The most recent comprehensive assessment of CAM use in the U.S., conducted as part of the 2007 National Health Interview Survey (NHIS), found 17.7% of Americans had used a nonvitamin/nonmineral natural product (3). It is essential for clinicians to understand the risks and benefits of these products to protect their patients. The list of natural products will not be exhaustive, and instead will focus on those products which have a stronger evidence base.

Omega-3 fatty acids

One of the most widely utilized CAM therapies is use of omega-3 fatty acids. Over 37% of individuals who reported using a nonvitamin/nonmineral natural product in the 2007 NHIS reported using omega-3 (3). Normal human development and cellular function throughout the lifespan depends on omega-3.

Mood disorders

There is evidence to support an inverse relationship between omega-3 and depression. A number of studies show lowered levels of omega-3 in depressed patients (4) and higher suicidal ideation (5–7). Several meta-analyses of the benefit of omega-3 for depression in general adult populations have been published (4, 8, 9).One such comprehensive review found that actual diagnosis of depression predicted a more robust response to omega-3 compared with simply having depressive symptoms, lending support to the hypothesis that omega-3 benefits individuals suffering from a clinical depression (8). Another meta-analysis showed that omega-3 supplementation with ≥60% of eicosapentaenoic acid (EPA) was beneficial to depression (9).

There are no meta-analyses of omega-3 and geriatric depression, but some randomized clinical trials (RCTs) exist. A small RCT of clinically depressed females, age 66–95 years old living in a nursing home, found omega-3 improved depression and quality of life (10). However, another RCT of older adults, age 60–80 years old without clinical depression who had recently suffered a myocardial infarction, showed no benefit from omega-3 on depressive symptoms (11). These findings are consistent with previous studies in general adult populations in which omega-3 did not improve symptoms in those with minor depression (8).

It is plausible that omega-3 would benefit bipolar disorder since deficiencies lead to disruption of neuronal membrane structure, leading to dysfunctional suppression of neuronal transmission and increased bipolar episodes (12). A recent meta-analysis of omega-3 as an adjunctive treatment for general adult populations with bipolar disorder support its use in bipolar depression but not for mania (13). The authors recommended target dosages of at least 1000 mg/day but no more than 3000 mg/day. Therefore, there is evidence to recommend omega-3 for unipolar or bipolar depression.

Cognitive disorders

It is thought that omega-3 may benefit neurodegenerative disorders due to its antioxidant and anti-inflammatory effects. Several meta-analyses support the use of omega-3 to slow cognitive impairment but not for the treatment or prevention of dementia (14, 15). One meta-analysis of omega-3 used in subjects age 58–85 years old with cognitive impairment and no dementia showed improvement in attention and processing speed (15). However, there was no improvement in those older adults who were cognitively normal or who had Alzheimer’s disease (AD) (15).Therefore, omega-3 does not appear to treat dementia but instead may slow the decline in cognitive impairment prior to the development of dementia.

SAMe

S-adenosyl-l-methionine (SAMe) is a naturally occurring compound normally synthesized in the body (16, 17). Initial oral formulations of SAMe were relatively unstable, necessitating parenteral administrations. However, the more recent development of stable oral forms of SAMe has allowed for more widespread testing and use of this compound.

Mood disorders

SAMe is thought to play a role in depression, since it is a necessary cofactor for the synthesis of serotonin, norepinephrine, and dopamine (18). Additionally, cerebrospinal fluid levels of SAMe have been shown to be decreased in depressed patients and levels have been shown to rise in response to treatment (19). Clinical studies support an antidepressant effect of SAMe. Meta-analyses found that SAMe yields results superior to placebo and equivalent to clomipramine, amitriptyline, and imipramine (20, 21). An open trial supports SAMe as an augmentation strategy in patients with incomplete response to conventional antidepressants (22). A small 6-week RCT of oral SAMe found that response and remission rates were significantly higher than placebo (23). Among the trials, oral doses of SAMe ranged from 400–1600 mg/day, with most trials dosing between 800–1600 mg/day. However, dosages up to 3600 mg/day have been used with success and safety in older populations (55–76 years old) (24), lending support to the idea that higher dosages may be needed and are also tolerated. Therefore, the evidence is strong to support the use of SAMe as an antidepressant with parenteral formulation and the support is growing for oral administration.

SAMe is generally well tolerated, but important safety concerns such as increased anxiety, mania, and hypomania have been reported in patients with bipolar disorder (22). Patients with bipolar disorder should not take SAMe without concomitant administration of mood stabilizers coupled with clinical monitoring. There are no studies of SAMe in the geriatric population. SAMe can be beneficial for depression; however the data are lacking for the geriatric population.

Cognitive disorders

SAMe plays an essential role in maintaining neuronal health and may prove to be an effective neuroprotective supplement in AD. There is reduced glutathione S-transferase (GST) activity in AD, and SAMe can exert a direct effect on GST activity, thereby making SAMe an ideal neuroprotective candidate to slow the progression of AD (25). Additionally, a small open-label study of older adults, ages 64–83 years old, with mildly impaired cognition showed parenteral SAMe improved Mini-Mental Status Examination (MMSE) scores over 2 months (26). A more recent study showed SAMe improved recall in depressed participants ages 18–80 years old (27). More trials are needed for the oral formulation of SAMe as well as trials with randomization and placebo control before we can definitely conclude that SAMe improves cognition in the absence of depression.

St. John’s wort

St. John’s wort (SJW) (Hypericum perforatum) is a wildflower that has been used for medicinal purposes for thousands of years. Various standardized extracts of this natural dietary supplement have been studied more recently. Most evidence supports its use as an antidepressant as current data for cognitive disorders come only from animal studies.

Mood disorders

In Europe there have been a number of large positive trials comparing SJW to placebo and standard antidepressants in general adult populations. A recent meta-analysis of 23 randomized trials (20 double-blind), including outpatients with mild-to-moderate depression, found improvement in depressive symptoms compared with placebo (28). Additionally, there is some evidence that SJW may be better tolerated than older SSRIs such as paroxetine (29). Clinical trials have used various divided doses of SJW (600–1800 mg/day), with the most common dose being 300 mg three times daily.

In the U.S., excitement over SJW has been tempered by highly publicized negative clinical trials and associated reviews (30–32). Despite these negative findings, a recently updated systematic review of the evidence base for use of SJW in depression for adults suggests that it is superior to placebo and similarly effective as standard antidepressants for mild to moderate depression (28). A more recent RCT examined adults with severe major depression taking SJW (900–1500 mg), sertraline (100 mg), or placebo over 6 months (33). No significant differences between the groups in depression were found. However, it should be noted that there was a significantly large placebo response. Therefore, the results are mixed, with some evidence to support the use of SJW in adults with mild to moderate depression but not severe depression.

In older adults, the available evidence base for use of SJW as an antidepressant is limited. A small RCT comparing SJW (800 mg extract LoHyp-57) and fluoxetine (20 mg) in moderately depressed older adults (ages unavailable) found equivalent efficacy of these agents in reducing depression over 6 weeks (34). Additionally, a more recent study showed improvement in depressive symptoms with SJW (600 mg extract LI160) in a sample of adults (18–70 years) with atypical depression (35). Therefore, the few studies including older adults support SJW for depression.

SJW is relatively well-tolerated and safe when used alone; however, when taken in combination with other medications, there can be a number of potentially dangerous drug-drug interactions (36, 37). SJW acts as a monoamine oxidase inhibitor (MAOI) as well as an inducer of cytochrome P-450 3A4 liver enzyme system. In summary, for older adults who would prefer a trial of an alternative treatment to treatment with a standard antidepressant SJW can be considered as an alternative natural remedy for mild-to-moderate depression. However, the ideal patient is free of comorbid medical conditions, and all patients using SJW should be informed about potential side effects and drug-drug interactions, as such interactions can have serious, even potentially lethal, consequences.

Ginkgo biloba

Ginkgo biloba leaf extract comes from the Maidenhair tree and is a commonly sold herbal supplement. Its purported biological effects include scavenging free radicals, lowering oxidative stress, reducing neural damage, and reducing platelet aggregation as well as anti-inflammatory, antitumor, and antiaging activities. Its main clinical use targets cognitive disorders and depression co-occurring with neurodegenerative disorders.

Cognitive disorders

Many RCTs of Ginkgo biloba in patients with various types of dementia have yielded contradictory results. Of the studies that revealed cognitive improvement, the effect was minor and did not last more than 6 months. A recent RCT demonstrated the efficacy of once daily dosed Gingko biloba (240 mg extract EGb761) in outpatients aged 50 years or older with mild to moderate AD or vascular dementia over 24 weeks (38). Both types of dementia showed improvement in cognition and neuropsychiatric symptoms compared to placebo. However, evidence does not suggest Gingko biloba to prevent dementia. In a trial of AD prevention in older adults, ages 72–96 years old, 120 mg of Gingko biloba twice a day was not effective in reducing the overall incidence of dementia in the elderly with normal cognition or mild cognitive impairment (39).Therefore, Ginkgo biloba will not prevent the development of AD but may have a minor impact on cognitive decline in those already afflicted with a dementia. In addition to some improvement in neuropsychiatric symptoms, Gingko biloba has also been reported to reduce depression in dementia patients and also counteract sexual side effects of antidepressants (40). However, it should be noted that the data supporting these positive findings come mostly from smaller studies that lacked a placebo control group.

As with other natural products, Ginkgo biloba comes with risks. It is recommended to use caution when using Ginkgo biloba in those who are at increased risk of hemorrhage as it may potentiate bleeding (41). Nevertheless, a short RTC of males using EGb 761 did not show any effect on coagulation or bleeding time (42). The short-term use of Ginkgo biloba is acceptable under some conditions, but the potential risks should be considered.

Huperzine A

Huperzine A comes from a Chinese herb called Huperzia serrata. It has anticholinesterase effects as well as antagonism of the N-methyl-d-aspartate receptor, both of which are thought to have beneficial effects in AD. There are no reports of huperzine A affecting late-life mood disorders.

Cognitive disorders

The results from studies on huperzine A and memory are mixed. There have been multiple studies from China showing the benefit of huperzine A on cognition. The most recent RTC from China showed huperzine A improving activities of daily living and cognitive testing scores in a small sample of individuals ages 60–80 years old with vascular dementia (43). However, a larger clinical trial in the U.S. showed less promising effects when evaluating two dosages of huperzine A versus placebo in individuals with AD who were over 50 years old (44). There was only a modest effect of the higher dosage of huperzine A on cognitive testing. The main side effect that participants described from huperzine A was nausea (44). No long-term studies have evaluated the safety of huperzine A.

Vitamin B

Mood disorders

Low levels of vitamin B12 and vitamin B9 (folic acid) are implicated in depression since they are involved in the production of monoamine neurotransmitters (45). Multiple observational studies have shown that low levels of these vitamins and high levels of homocysteine are risk factors for depression in the elderly; such studies included samples that included mixed populations 20–85 years of age, those older than 65, and those older than 55 (45–47). However, studies evaluating an antidepressant effect of supplementation with vitamins B12 and B9 are mixed. A RCT in Australia showed no benefit from vitamins B12 and B9 supplementation in older adults (60–74 years of age) with mild depressive symptoms (48). Nevertheless, another RCT using vitamins B12 and B9 as well as vitamin B6 prevented the development of depression in a group of adults ages 45.8–76.6 years old who had sustained a stroke (49). A new formulation of vitamin B9, l-methylfolate, has some evidence for having an antidepressant effect as an augmenting agent in small studies of general adult populations (50–53). In conclusion, although low levels of the B vitamins may contribute to mood symptoms, there are limited data available to support an antidepressant effect for vitamins B6, 9, and 12 in older adults.

Cognitive disorders

It is considered standard procedure to check a vitamin B12 level when considering a diagnosis of dementia because it is seen as a reversible cause of cognitive decline (54). Moreover, a cross-sectional study showed various measures of vitamin B12, including methylmalonate, homocysteine, and cystathionine to be associated with episodic memory deficits, slowed perceptual speed, and decreased total brain volume in a sample of adults ages 65 years and older (55). Interestingly, data have related elevated homocysteine levels to amyloid and glutamate toxicity and cognitive decline in animal studies (56). Additionally, vitamin B3 (niacin) deficiency, also referred to as pellagra, leads to the classic triad of dementia, dermatitis, and diarrhea. Therefore, it is logical that B vitamin supplementation should benefit cognition.

However, the evidence does not support a robust response in cognition with B vitamin supplementation. A multicenter RCT of adults over 50 years old with mild to moderate AD and normal vitamin B12 and B9 levels showed no benefit in cognition with supplementation (56). Another RCT in China failed to show an improvement with supplementation in cognition with older participants, age 60 years or older, with either AD or vascular dementia and normal vitamin levels (57). However, the evidence appears to be more promising in individuals without cognitive impairment. A recent RCT of older adults, ages 60–74 without dementia and normal vitamin B12 and 9 levels, showed a benefit in immediate and delayed recall with supplementation (58). The evidence does not support vitamin B supplementation in treating dementia when levels are normal, but some data support supplementation improving cognition prior to development of dementia. Additionally, such use of supplemental vitamins may come at a risk: the Iowa Women’s Health Study demonstrated an increase in mortality with the use of various dietary supplements, including vitamin B6 and B9 (59). This study supports the fact that is important for patients and clinicians to acknowledge that being natural is not always safer than “conventional” medicine.

Conclusion

Late-life mood and cognitive disorders are among the most common reasons for older adults to use CAM practices (Table 1). Despite the growing use of natural supplements and vitamins by an aging U.S. population, there is an urgent need to establish the efficacy and safety in well-designed rigorous RCTs. In addition, clinicians can offer important information for those patients who are less comfortable with “conventional” medicine and prefer alternative “natural” therapies, such as advising of drug-drug interactions. Gaining knowledge in CAM safety and efficacy and interactions with traditional medicine interventions is important for patients who are using these products and for clinicians who are treating them.