Fighting the Winter Blues with DHEA

Fighting the winter blues with DHEA

This is the sixth in a series of posts on complementary and alternative therapies for depressed mood. Previous posts reviewed the evidence for SAMe, bright light exposure therapy, omega-3 fatty acids, and folate. The topic of this post is dehydroepiandrosterone (DHEA) a molecule that plays many key roles in the human body and brain that has been extensively investigated for its antidepressant and cognitive enhancing benefits.

Multiple mechanisms of action

Dehydroepiandrosterone (DHEA) is a prohormone (i.e. a precursor of both male and female sex hormones) that occurs naturally in the body and brain and plays key roles in mood regulation and the body’s stress response, and has general neuroprotective, antiinflammatory and anti-oxidant effects.  DHEA and a related molecule (DHEA-S) are both manufactured in the adrenal cortex and testes, and are later converted to androgens and estrogens–the male and female sex hormones–in peripheral tissues. DHEA-S is the sulfonated form of DHEA and the most abundant steroid hormone in the body. The antidepressant mechanism of DHEA has not been fully elucidated but may involve androgen receptors, estrogen receptors, or well defined neurotransmitter systems including serotonin, GABA, NMDA and norepinephrine. Estrogen manufactured from DHEA affects the synthesis and binding of serotonin at multiple receptors sites. A recent study found that elevated DHEA-S serum levels correlated with higher rates of response to SSRI antidepressants consistent with research findings that supplementation with DHEA has antidepressant benefits and significantly enhances antidepressant efficacy (Hough et al 2017).

Promising research findings when taken alone or together with an antidepressant

Research findings show that DHEA supplementation alone may reduce the severity of depressed mood and can be safely used in conjunction with antidepressants increasing their efficacy. Blood levels of DHEA decline with normal aging. An early study found that physiological replacement doses of DHEA (ie, 30 to 90mg/day, a dose range corresponding to DHEA serum levels that are normal in people younger than age 40) may improve mood in middle-aged or elderly depressed patients (Wolkowitz et al. 1997).

This above findings are consistent with the findings of a small randomized placebo-controlled trial in which individuals with mid-life onset depression experienced significant and sustained improvements in mood following several weeks of supplementation with DHEA (Schmidt et al 2005).  In the study 46 moderately depressed adults were randomized to DHEA 90mg/day for three weeks followed by DHEA 450mg/day in three equal doses, for three weeks versus placebo. None of the patients used antidepressants concurrently. A 50% or greater reduction in depressive symptoms was observed in the majority of patients in the DHEA group, which also reported improvements in baseline sexual functioning. Significantly, most patients who responded to DHEA remained asymptomatic at 12 months follow-up.

Two systematic reviews support that DHEA is an effective monotherapy for depressed mood and may be safely combined with antidepressants augmenting their efficacy (Peixoto et al 2018; Peixoto et al 2014). Research findings on DHEA in depressed mood are limited by the small size of many studies, differences in dosages used, and heterogeneous study designs.

DHEA for depressed mood in HIV/AIDS, Alzheimer’s disease and schizophrenia

DHEA may also be an effective treatment of depressed mood individuals with HIV/AIDS. In one study depressed HIV positive patients experienced significant improvements in mood and fatigue when taking DHEA 200 to 500mg/day (Rabkin 2000). Serum testosterone levels and CD4 T-cell counts were not affected. Psychotic or demented patients often experience significant co-morbid depressed mood. In addition to its established antidepressant benefits, emerging findings suggest that DHEA may also reduce symptoms of psychosis, anxiety and cognitive impairment all of which can occur together with depressed mood.

Research findings suggest that DHEA supplementation may reduces the rate of cognitive deterioration in Alzheimer’s disease (Knopman 2003), and may improve anxiety and negative psychotic symptoms (i.e., apathy, withdrawal, paucity of thought) in individuals diagnosed with schizophrenia. In a double-blind placebo-controlled study 30 inpatients diagnosed with schizophrenia treated with DHEA 100mg/day in addition to their antipsychotic medications experienced significant improvements in depressed mood, anxiety and negative psychotic symptoms (Strous 2003). For unclear reasons, women improved more than men.

Safety issues

Most individuals who take DHEA at doses that have been shown to reduce the severity of depressed mood report few mild adverse effects. Case reports show that DHEA can cause hirsutism (i.e. abnormal hair growth) and acne and can interfere with normal blood clotting. DHEA may promote cancer in women who have a history of estrogen receptor positive breast cancer, and should be avoided in this population. However, a metabolite of DHEA called 7-keto-DHEA is not converted into androgens or estrogens and can probably be safely used in this population. Preliminary findings suggest that DHEA supplementation may increase the risk of prostate cancer in men with early or undetected prostate cancer (Arnold 2005).

Bottom line

At dosages established to be effective against depressed mood DHEA has few adverse effects. Combining DHEA with psychiatric medications is a safe and reasonable integrative approach in depressed individuals who fail to respond–or have a partial response–to antidepressant therapy, and in depressed individuals with co-occurring anxiety, psychosis or cognitive symptoms. The beneficial effects of DHEA on libido and sexual functioning is a significant added benefit of DHEA in view of the high percentage of depressed individuals who report reduced libido due to depressed mood or the side effects of antidepressants. Finally, DHEA should be considered when depressed mood occurs together with anxiety, psychosis and cognitive impairment including in patients diagnosed with schizophrenia and Alzheimer’s disease. .

Further research is needed to replicate the findings reported in this post, evaluate the efficacy of DHEA as a monotherapy for severe depressed mood, further elucidate the mechanism for a synergistic or independent antidepressant effect of DHEA and determine optimal safe dosing strategies.

Omega3s have established mood enhancing benefits and boost the effectiveness of antidepressants

This is the fifth in a series of posts on non-pharmacologic treatments of depressed mood. Previous posts briefly reviewed research findings on S-adenosylmethionine (SAMe) and folate. This post is offered as a concise review of omega-3 essential fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), in the treatment of depressed mood.

Multiple mechanisms

Epidemiologic studies have found an inverse relationship between consumption of fish and other foods high in omega-3 fatty acids and the prevalence of depression suggesting that individuals who consume foods richer in omega-3s are at reduced risk of developing depressed mood. Human and animal studies point to several mechanisms of action underlying the antidepressant effects of omega-3 fatty acids, including increased CNS serotonin activity, anti-inflammatory effects, suppression of phosphatidyl-inositol second messenger activity, and possibly increased heart rate variability.

In addition to the above mechanisms, another proposed mechanism of action that may be similar to that of antidepressants, including SSRIs and older so-called ‘tricyclic’ antidepressants, involves the suppression of pro-inflammatory cytokine release by immune cells, resulting in beneficial changes in the brain that manifest as improved mood (Maes 1998). Evidence in support of an anti-inflammatory mechanism of omega-3s is consistent with the observation that increased production of pro-inflammatory cytokines takes place in the initial or “acute phase” of severe depressed mood (Maes 1996). Further, animal studies show that direct administration of pro-inflammatory cytokines into the brain causes dysregulation in serotonin metabolism that mirrors changes observed in depressed individuals. Reports that Omega-3 fatty acids may reduce the incidence of coronary artery disease by influencing the production of pro-inflammatory cytokines in the heart may help to explain the observed correlation between heart disease and major depressive disorder.

Research highlights

Findings of studies on antidepressant effects of omega-3s when used alone or when taken adjunctively with an antidepressant are highly inconsistent, however, over time there has been a trend toward more positive findings of well designed placebo-controlled trials. In some studies patients who had previously been refractory to antidepressants improved significantly when Omega-3s were added to their antidepressant.  Most studies support that EPA has greater antidepressant efficacy than DHA both alone and when used in combination with an antidepressant. There is still no consensus on an effective antidepressant dose of EPA; however, it is probably at least 2gm/day typically taken in divided doses with food for optimal absorption.

Findings on DHA in depressed are highly inconsistent possibly reflecting complex relationships between ratios of Omega-3s and other fatty acids (i.e., Omega-6) in the blood and brain and associated anti-inflammatory effects. In a small double-blind study on the efficacy of DHA alone for severe depressed mood patients treated with DHA 2g/day versus a placebo improved at the same rate (Marangell 2003). However, a subsequent DHA augmentation pilot study found an inverse correlation between dose and antidepressant response, with patients receiving 1gm/day reporting significantly greater improvement in depressive mood symptoms compared to individuals taking DHA at doses of 2gm/day and 4gm/day ( Mischoulon 2008). The authors speculated that an optimal ‘therapeutic window’ may take place when a dose of DHA or EPA results in changes in ratios of omega-3s (which have anti-inflammatory effects) to omega-6 fatty acids (which are pro-inflammatory) in the blood needed to achieve an ‘optimal’ balance between pro- and anti-inflammatory forces.

A meta-analysis of studies on omega-3 supplementation alone found consistent anti-depressant benefits of omega-3 supplementation in individuals diagnosed with major depressive disorder, in depressed individuals who were not diagnosed with MDD, but not in women diagnosed with prenatal depression, or in children and adolescents (Grosso et al 2014). A meta-analysis of 241 placebo-controlled studies on EPA, DHA or combined EPA/DHA augmentation of antidepressants found greater benefits with EPA and combined EPA/DHA; however, the authors reported that their findings were limited by methodological flaws in many studies, heterogeneous study designs, small study sizes, short study duration and (in some cases) evidence of publication bias (Martins 2009).

The above findings support the use of EPA in combination with antidepressants, including bipolar depressed patients and patients who are refractory to antidepressants. It remains unclear whether EPA (or specific ratios of EPA to DHA or other fatty acids) has an independent antidepressant effect or possibly enhances the efficacy of antidepressants via second messenger systems in a manner that is similar to the postulated mechanism for lithium augmentation (Nemets 2002).

Unanswered questions

Many questions about fatty acid composition, optimal dosing strategies and treatment duration have not been answered. Confirmation of the size of an augmentation effect in individuals taking antidepressants and further clarification of the antidepressant mechanism(s) of action of essential fatty acids will require large, long-term placebo-controlled trials designed to answer these questions.

Side effects and safety issues

Gastrointestinal side effects have been reported and Omega-3s may interfere with glucose metabolism in diabetic patients (Glauber 1988). There is one case report of increased bleeding risk when Omega-3 fatty acids are used together with coumadin (Buckley 2004).

Bottom line

Supplementation with EPA may enhance response to available antidepressants. EPA may be safely used in combination with antidepressants and other psychotropic medications. Omega-3s have established cardiovascular benefits and are well tolerated. The majority of people who take EPA at dosages recommended for depressed mood report mild or no adverse effects. On the basis of available data, depressed patients should be encouraged to take EPA (1 to 2g/day) as an augmentation strategy in conjunction with their current antidepressant regimen. Diabetics and individuals taking Coumadin or other anticoagulant medications should consult with their physician before considering taking omega-3s. 

Bright light exposure may improve seasonal depressed mood: more studies are needed

Regular morning exposure to bright light may improve seasonal depressed mood

This is the third post in a series on non-pharmacologic treatments of depressed mood. Previous posts provided brief reviews of the evidence for S-adenosylmethionine (SAMe) and folate. This post is offered as a concise discussion of bright light exposure therapy as a treatment of depressed mood. In addition to commenting on findings of individual studies I comment on the disparity in meta-analysis findings and the resulting debate on the efficacy of bright light therapy.

Mechanism of action is probably multi-factorial 

The mood enhancing benefits of bright light are probably related to many mechanisms of action that affect regulation of the synthesis of melatonin and neurotransmitters, especially the monamine neurotransmitters serotonin, dopamine and norepinephrine. Recent theoretical work suggests that the beneficial effects of light on the body and brain may be consistent with meridian theory in Chinese medicine (Cocilovo 1999).

Many studies support that exposure to bright light (10,000 lux) in the early morning, for one to two hours daily over several weeks (10,000 lux) has therapeutic effects in moderately or severely depressed patients. This effect is especially robust in patients who report recurring seasonal depressed mood changes–so-called seasonal affective disorder (SAD).

Small studies, short duration and methodological differences limit findings

Many studies report that morning exposure and evening exposure to bright light are probably equally effective in seasonal depressed mood however there are reports of insomnia with evening exposure. In addition to artificial full-spectrum bright light, exposure to natural sunlight, especially in the early morning, also has a significant anti-depressant effect, and may reduce the length of hospital stays in severely depressed bipolar inpatients (Benedetti 2001). Findings of a randomized double-blind study (89 total subjects) suggest that bright light delivered transcranially by LED inserted into the ear canals may have both antidepressant and anti-anxiety benefits in individuals diagnosed with seasonal affective disorder (Jurvelin 2014).

Findings of a small randomized trial suggest that bright light therapy may be an effective alternative to antidepressants in pregnant depressed women (Epperson 2004). In another study depressed patients who exercised regularly improved more when exposed to bright light than ordinary room light (Partonen 1998). A study published in the Journal of Affective Disorders in 2018 found that individuals diagnosed with seasonal affective disorder randomized to bright full spectrum exposure vs narrow spectrum low intensity blue light reported equivalent improvements in depressed mood symptoms (Meesters 2018).

Meta-analyses report conflicting findings

Although the above studies and many other controlled studies published in the peer-reviewed medical journal literature have reported beneficial effects of bright light exposure on seasonal depressed mood–and in some cases non-seasonal depressed mood, the conclusions of meta-analyses are inconsistent. For example, in an early meta-analysis Golden et al (Golden 2005) reported on large therapeutic benefits (i.e., a large ‘effect size’) of bright light exposure vs sham. The authors concluded that bright light exposure or dawn simulation for seasonal depressed mood, and bright light exposure (but not dawn simulation) for non-seasonal depression has comparable efficacy to conventional antidepressants (Golden 2005).  However, a more recent meta-analysis using more stringent selection criteria found only equivocal evidence in support of bright light exposure for depressed mood (Martensson 2015) arguing that findings of most studies are limited by small size, short duration and methodological differences in terms of light intensity, exposure duration, light source and wavelength examined, etc. Martensson et al also pointed out that selection bias in the Golden et al meta-analysis had led to unsubstantiated claims on the basis of 3 very small studies reporting positive outcomes.

Side effects can include headaches, insomnia and nausea

Some patients exposed to bright morning light 10,000 lux on a regular basis report transient side effects including mild jitteriness or headaches, and mild nausea. Sporadic cases of hypomania have been reported, especially in winter depressives or Bipolar patients exposed to early morning bright light. Almost two thirds of patients who use bright light exposure therapy in the evening report insomnia. Because of the risk of insomnia with evening bright light exposure, everyone who considering the use of bright light exposure to treat depressed mood should do so in the morning only.

Bottom line

Despite decades of research on full spectrum bright light (and more recently, dim blue light) exposure as a treatment of seasonal depressed mood, there is still no consensus among researchers on the antidepressant efficacy of this therapy. The wide disparity in reported outcomes reflects methodological differences in study designs, and suggests that factors that influence response to bright light exposure may not yet be adequately characterized. These factors may include the relative intensity of light, exposure duration, timing of exposure, frequency of exposure and wavelength. In addition, variation between individuals undergoing bright light therapy such as genetic, epigenetic and other poorly characterized inter-individual differences may help explain the disparity in response. Large prospective studies identifying and controlling for these factors are needed to elucidate the complex mechanisms of light therapy and to clarify its potential antidepressant effects.

Folate in the form of l-methyl folate enhances antidepressant response

This is the third post in a series on complementary and integrative treatments of depressed mood. The previous post reviewed the evidence for SAMe (S-adenosylmethionine). In this post I briefly review the evidence for folate in depressed mood. Future posts will take a look at omega-3 fatty acids, vitamin D, the supplement DHEA and other non-pharmacologic approaches to fighting the winter blues.

Antidepressant mechanism of action

The mechanism of action by which folate affects mood has not been definitively established however its antidepressant effects are probably related to the central role this vitamin plays in the synthesis of neurotransmitters involved in mood regulation, including serotonin, dopamine and norepinephrine. Specifically, folate is a co-factor in the re-methylation of homocysteine into S-adenosylmethionine, required steps in synthesis of serotonin, dopamine and norepinephrine.

Folate in the diet is converted in the body to l-methylfolate, the only form of this vitamin that can cross the blood-brain barrier and contribute to neurotransmitter synthesis. It has been suggested that a significant percentage (perhaps as many as 75%) of individuals who fail to respond to antidepressants (so-called refractory depressed mood or treatment-resistant depression) may have a genetic mutation in the enzyme required for conversion of dietary folate into l-methylfolate, resulting in abnormal low levels of l-methylfolate in the brain and correspondingly low levels of neurotransmitters involved in mood regulation. Emerging research findings suggest that individuals with treatment-resistant depression respond better when high dose folate in the form of l-methylfolate (7.5 to 15mg/day) is added to their antidepressant regimen (Duprey 2016).

Folate enhances antidepressant response

Findings from controlled trials support that folate is an effective adjunctive treatment of depressed mood. One study found that the efficacy of fluoxetine (Prozac) and other antidepressants is significantly enhanced by the addition of daily folate. In another study the response of depressed patients treated with a SSRI antidepressant taken together with l-methylfolate (0.5-1mg/day) was as much as 30% greater than patients treated with a SSRI only (Papakostas 2004). An early systematic review of three controlled studies involving a total of 247 subjects concluded that “folate may have a potential role as a supplement to other (i.e., antidepressant) treatments” of depressed mood however findings were inconsistent (Taylor 2003). Patients who took folate 1mg with an antidepressant experienced incrementally greater reductions in depressed mood compared to those taking an antidepressant alone. However, one study included in the review failed to show a differential effect when folate was combined with trazodone, a widely used antidepressant. The significance of these findings was limited by small number of studies done and small study size. Shelton et al (Shelton 2013) provide a review of more recent research findings, which support that l-methylfolate augmentation is safe and results in statistically significant improvement in response compared to individuals taking an antidepressant alone (Shelton 2013).

Bottom line

In view of the high incidence of treatment non-response to antidepressants, the fact that the majority of non-responders may lack the enzyme required to convert dietary folate into its active form (i.e. l-methylfolate) needed for neurotransmitter synthesis, and consistent positive findings of l-methylfolate augmentation in this population, taking l-methyl folate together with an antidepressant is a reasonable integrative approach for managing depressed mood.

Fighting the Winter Blues with SAMe

Fighting the winter blues with complementary and alternative therapies

This is the second in a series of posts on complementary and alternative (CAM) approaches to depressed mood. As I write I am thinking of many of my own patients who find themselves struggling more as the days grow shorter. This post is about S-adenosyl-methionine (SAMe), a widely used natural supplement with an established track record for treating depressed mood.  Future posts will review the evidence for other natural supplements, mind-body approaches, exercise, and a variety of other complementary and alternative approaches you can use to fight the winter blues.

How SAMe works to improve depressed mood

SAMe is a naturally occurring molecule in bacteria, plants, and animals and plays many important roles at the level of genes, immune function, and amino acid metabolism. In humans, SAMe is an important methyl donor, an essential step in the synthesis of several neurotransmitters from amino acids in the diet. The antidepressant effects of SAMe are probably related to multiple mechanisms of action including increased brain levels of serotonin, dopamine, and norepinephrine. The synthesis of these neurotransmitters by SAMe requires vitamin B12 and folate. Many depressed individuals are deficient in B vitamins thus individuals taking SAMe for depressed mood will benefit from taking vitamin B12 and folate (especially in the form of l-methyl-folate) concurrently. In addition to the effects of SAMe on the above neurotransmitters, it has been suggested that antidepressant effects of SAMe are mediated by anti-inflammatory effects, changes in neuronal membrane fluidity, increased rate of serotonin turnover, inhibition of norepinephrine reuptake, and beneficial synergistic effects of SAMe on dopamine activity. Antidepressant effects of SAMe may also be mediated by anti-inflammatory effects and changes in neuronal cell membrane fluidity.

Research findings show efficacy comparable to antidepressants

SAMe has been widely used for decades to treat depressed mood and osteoarthritis in many European countries where it is available on a prescription basis in oral form, as an intramuscular injection, or for intravenous use. SAMe degrades rapidly when exposed to air and stable oral preparations posed manufacturing challenges for many years. Thus, many early studies investigated the antidepressant efficacy of SAMe administered intramuscularly or intravenously. Early studies reported that effective antidepressant doses of SAMe are significantly smaller when administered intravenously, and showed that few patients receiving SAMe intravenously had adverse effects.

In the U.S., SAMe is available in oral form only and can be purchased as an over-the-counter tablet in pharmacies and health food stores. Shelf-life can be prolonged by refrigeration and protecting SAMe from degradation in blister packs. e-counter supplement in pharmacies and health food stores. Oral SAMe is available in two different forms. Oral forms of SAMe are combined with other molecules to reduce the rate of oxidative degradation and extend shelf life. The butane-disulfonate is available as an enteric-coated tablet and may have significantly greater bioavailability and longer shelf life than the tosylate form.

The standard maintenance regimen of oral SAMe for depressed mood is between 800 and 1600 mg/day in two to four divided doses. A common dosing strategy is to start SAMe at a dose of 200mg twice daily, and gradually increase to 400mg twice daily, monitoring for side effects and therapeutic response. Absorption is improved when SAMe is taken on an empty stomach (i.e., before meals).

Advantages of SAMe compared to prescription antidepressants

Most currently available antidepressants have a delayed onset of action thus consistent improvement in mood may be noticeable only after four to six weeks of daily use. In contrast, SAMe has a relatively rapid onset of action, usually within one week of starting treatment. Another important advantage of SAMe is the absence of clinically significant interactions with prescription medications and relatively few side effects compared to antidepressants.

In addition to its mood enhancing effects, there is evidence that augmentation with SAMe 400mg twice daily in individuals who are not responding to antidepressant therapy, may improve memory and other cognitive problems that often accompany depressed mood (Levkovitz 2012)

SAMe enhances response to antidepressants

Meta-analyses of placebo-controlled studies support that SAMe when used as a monotherapy is as effective as many widely prescribed antidepressants (Hardy et al 2003; Sharma et al 2017). Studies published in peer-reviewed medical journals support that combining SAMe with an SSRI antidepressant or venlafaxine (a serotonin-norepinephrine reuptake inhibitor) improves overall response and may accelerate response rate equivalent to results achieved when augmenting an SSRI antidepressant with bupropion or venlafaxine. The mechanism of action by which SAMe augments the effects of widely used prescription antidepressants in cases where a patient has become non-responsive, may involve re-externalizing neurotransmitter receptors that have been internalized by the nerve cell membrane during prolonged exposure to an antidepressant.

Findings of a landmark study published in the American Journal of Psychiatry provided “preliminary evidence that SAMe can be an effective, relatively well-tolerated, and safe adjunctive treatment strategy for SSRI non-responders diagnosed with major depressive disorder (Papakostas 2010).” Individuals included in the study continued on recommended doses of commonly prescribed antidepressants including paroxetine, citalopram, duloxetine and other, while also taking SAMe. The authors noted that significantly more patients treated with adjunctive SAMe experienced clinical improvement and remission compared to matched patients receiving a placebo. The significance of findings was limited by small study size (73 total patients), the short duration of the study (6 weeks), failure to include a comparison group taking an antidepressant only.

Combining SAMe with an SSRI or other antidepressant is an integrative approach that improves outcomes while permitting a reduction in the dose of the conventional antidepressant by as much as 30% in some cases. The advantages of reducing the dose of a conventional antidepressant include fewer side effects and improved adherence to treatment. In addition to improving the efficacy of antidepressants, there is evidence that the adjunctive use of SAMe may reduce sexual side effects frequently caused by SSRIs and other antidepressants.

Safety issues

Although SAMe is well tolerated, transient anxiety, insomnia, gastrointestinal side effects, dry mouth, and dizziness have been reported. With continued treatment, most side effects resolve within days or a few weeks. Although many studies (including those reviewed above) show that SAMe may be safely used in conjunction with antidepressants, as SAMe affects serotonin synthesis, taking it together with another supplement or medication that increases CNS serotonin may cause serotonin syndrome, a potentially serious syndrome characterized by anxiety, agitation and insomnia. Please consult with your physician before taking SAMe together with an SSRI antidepressant or another medication that increases brain levels of serotonin. Rare cases of hypomania have been reported in patients diagnosed with Bipolar Disorder and it is advisable to avoid SAMe if you have been diagnosed with bipolar disorder.

Safe and Effective Non-medication Ways to get Through the Winter Blues

Dealing with depression over the holidays

Many people who struggle with chronic depressed feel more depressed as the holidays approach, the weather gets colder, and the days get shorter. If you currently take an antidepressant but you are having disappointing results or side effects, and you’re interested in learning about evidence-based non-pharmacologic treatments of depressed mood, research findings show that select natural supplements and other complementary and alternative (CAM) approaches may help you feel and function better.

Complementary and alternative therapies for depressed mood

This is the first in a series of blog posts on complementary and alternative (CAM) treatments of depressed mood. This post is offered as an overview of natural supplements and other CAM approaches widely used to treat depression. Future posts will focus on specific CAM modalities including natural supplements such as St. John’s wort (Hypericum perforatum) S-adenosyl-methionine (SAMe), 5-hydroxytryptophan, Omega-3 fatty acids, mind-body approaches, acupuncture, EEG-biofeedback, and others. In addition to reviewing the evidence for particular CAM modalities, I will comment on emerging research findings for combining specific natural supplements or other CAM modalities with antidepressants aimed at improving response or mitigating adverse effects.

Available mainstream treatments often fail to alleviate depressed mood

Depression is one of the most serious and costly health problems facing the world today. Because of the high incidence of suicide and other medical or mental illnesses in depressed individuals, depression is regarded as the leading cause of death and disability from adolescence through middle age. Although available mainstream treatments such as medications and psychotherapy are often beneficial, existing conventional approaches fail to alleviate depressed mood in many cases. These problems have resulted in ongoing debate over the efficacy and safety of antidepressants in the medical community and in the public at large.

Research findings on the efficacy of antidepressants are inconsistent and disappointing. Several independent analyses have concluded that most trials of antidepressants sponsored by pharmaceutical companies fail to show significant response differences between antidepressants and placebos. It is estimated that in United States, the U.K., and West European countries more than two thirds of depressed patients never receive adequate treatment with antidepressants. This is due to both inadequate screening of depressed mood by physicians and under-reporting by patients. Over half of all patients who take antidepressants are not treated by psychiatrists and have never been formally diagnosed with depression. Among those who are diagnosed and receive recommended doses of antidepressants, between 40% and 70% fail to respond.

Select CAM modalities have been validated as effective treatments of depression

Several non-pharmacologic treatment modalities used to treat depression and other mental health problems have been empirically investigated in well designed placebo-controlled studies and fulfill biomedical criteria for efficacy and safety but are not in widespread use in Western countries because of economic, social or ideological factors, including limited post-graduate training in the evidence-based use of complementary and alternative (CAM) therapies in mental health care, and widespread prescribing of antidepressants by physicians. Many CAM modalities are widely used to treat or self-treat depressed mood, and–as is true for widely used antidepressants–CAM therapies have limitations and drawbacks. However, select natural products and other non-pharmacologic treatments have been substantiated by consistent positive findings from large, well-designed placebo-controlled, double-blind studies, and in some cases, systematic reviews and meta-analyses.

Examples of empirically validated CAM treatments of depressed mood include St. John’s Wort, S-adenosyl methionine (SAMe), the amino acid 5-hydroxytryptophan (5-HTP), a form of the B vitamin folic acid, the essential fatty acid ecosapentanoic acid (EPA), and to a lesser extent, the amino acid Acetyl-L-carnitine and the pro-hormone dehydroepiandrosterone (DHEA). Placebo-controlled double blind studies and meta-analyses show that SAMe has equivalent or superior anti-depressant efficacy compared to tricyclic antidepressants. In contrast CAM therapies with a known biological mechanism of action, mindfulness, mind-body approaches, and other CAM modalities that do not have a clearly defined biological mechanism of action, have not been as rigorously examined by Western science, and therefore have relatively weaker empirical evidence supporting claims of efficacy.

Integrative strategies may be more effective than single conventional or CAM treatments

In addition to the use of single CAM therapies, emerging research findings support that taking an antidepressant while engaging in a mind-body practice, exercising, using bright light exposure therapy, or taking certain natural product supplements may accelerate the rate of treatment response or improve overall outcomes. This is the perspective of integrative mental health care, which is the focus of all my posts.

You can find out more about CAM and integrative treatments of depression by reading my e-book “Depression: The Integrative Mental Health Solution.”

Essential Oils and Aromatherapy for Anxiety

Prescription anti-anxiety medications are limited by safety problems

Prescription medications used to treat generalized anxiety include the benzodiazepines such as diazepam and clonazepam, and SSRI antidepressants such as paroxetine and sertraline.  Chronic benzodiazepine use is associated with dependence, sedation and mental slowing. The SSRI antidepressants often interfere with normal sexual functioning and cause weight gain.

Wide use of herbals in response to a need for safer, more effective anti-anxiety medications

Beneficial effects of the essential oils or aqueous extracts of certain herbals including English Lavender (Lavandula angustifolia), Passion flower (Passiflora incarnata) and other herbals used to treat anxiety include a general calming effect achieved in the absence of sedation, and avoidance of the risk of tolerance or dependence with prolonged use. The differences between many anti-anxiety drugs and herbals are related to the fact that calming effects of the essential oils of Lavender and other fragrant herbals are mediated by many underlying mechanisms and do not act only on GABA/benzodiazepine receptors in the brain. The limited efficacy and safety concerns associated with many conventionally prescribed anti-anxiety medications have stimulated animal research on several plant-derived molecules that have many mechanisms of action and may lead to safer, more effective anti-anxiety medications (De Sousa et al 2015)

Inconsistent findings on Lavender

Oral preparations and essential oils (e.g., used in massage or aromatherapy) derived from several species of Lavender and other fragrant herbs are widely used to treat anxiety however research findings are inconsistent. Very few placebo-controlled studies have been done on different preparations of Lavender for anxiety, most studies are small or methodologically flawed and reported findings are often inconclusive. A review of randomized clinical trials reported that oral preparations of Lavender may be more effective than aromatherapy or topical application of the essential oil (Perry 2012).

Different effects from aromatherapy using Lavender or Rosemary

Some studies report significant anxiety-reducing effects in response to Lavender or Rosemary aromatherapy. A randomized controlled trial evaluated changes in electroencephalographic activity and subjective emotional states in 40 adults exposed to Lavender or Rosemary aromatherapy. Individuals receiving lavender aromatherapy showed increased activity in the beta frequency range (12 to 30 cycles per second) and reported decreased overall anxiety. Patients receiving rosemary aromatherapy showed decreased frontal alpha and beta power and reported diminished anxiety and increased alertness. These findings show that lavender aromatherapy promotes a relaxed drowsy state, while Rosemary aromatherapy promotes a relaxed alert state. Although other essential oil preparations are sometimes used to treat anxiety, there is not enough evidence to support their use.

Promising findings for Passion flower

Passion flower (Passiflora incarnata) contains an active ingredient called chrysin that has been demonstrated to bind to benzodiazepine receptors in the brain resulting in a general calming effect. Although Passion flower extract is commonly used to treat anxiety, few double blind placebo-controlled studies have been done. In one small study, Passion flower extract 45 drops per day and oxazepam (a benzodiazepine) were equally effective in reducing generalized anxiety. Patients taking oxazepam reported significant impairments in job performance at doses that lowered anxiety however there were no reports of performance impairment among patients taking effective doses of Passion flower extract. Another study reported similar findings when comparing Passion flower with the SSRI sertraline in patients with generalized anxiety (Yeung & Hernandez 2018).

Few safety issues

Different species of Lavender are well tolerated and are not associated with serious adverse effects or toxic interactions. Mild transient adverse effects irritation to the skin and a mild photo-sensitive rash, have been reported when Lavender and other essential oils are applied topically. There are a few reports that Lavender may increase the risk of bleeding when used together with an anticoagulant. Because of potential synergistic interactions, individuals taking an anti-seizure medication or a benzodiazepine should exercise caution when using the essential oil of Lavender or other calming herbals.

Healing Touch and Therapeutic Touch for Anxiety and Stress

Ancient healing techniques but unknown mechanism 

Non-contact and so-called ‘energy’ healing techniques have been used in all world regions for thousands of years. Although widely used to treat a range of medical and mental health problems, research findings are difficult to interpret because of problems inherent in measuring a putative mechanism of action and quantifying outcomes. From a Western scientific perspective non-contact and hands-on healing techniques are referred to as ‘biofield therapies’ based on the assumption that an energetic principle exists in humans and all life forms, imbalances in ‘energy’ manifest as diverse physical or emotional symptoms, and the skillful manipulation of ‘energy’ by healers can correct such imbalances restoring good health. To date, Western style research studies have not been able to demonstrate a mechanism underlying Healing Touch, Therapeutic Touch or other biofield therapies. It has been suggested that failure to empirically confirm a mechanism of action may reflect the limitations of current science which lacks methods capable of verifying the role of quantum mechanics or other postulated non-local phenomena that may play a role in energy therapies.

Research findings are mixed

In Healing Touch (HT) the practitioner does not actually have physical contact the patient but positions the hands above different parts of the body with the intention of facilitating healing. In contrast, in Therapeutic Touch (TT) the practitioner uses gentle touch. Most studies done on Healing Touch (HT) and Therapeutic Touch (TT) are small pilot studies or small open trials in individuals who report anxiety or other mental health problems in the context of chronic pain, cancer or other medical conditions. TT may have beneficial effects in chronically anxious patients, and in non-demented elderly nursing home patients, but there is limited evidence for anxiety reducing effects of TT in healthy adults. The findings of two early studies using sham healers in the control group suggest that both contact and non-contact healing reduces state anxiety in patients hospitalized for heart problems. Unfortunately, neither study adequately controlled for anxiety reducing effects of medications taken by some patients.

Findings of two small open studies suggest that patients who receive HT therapy experience significant reductions in emotional and physical symptoms of trauma. A small double-blind sham-controlled trial did not find significant differences in self-reported levels of stress in students treated by Healing Touch practitioners compared to students treated by sham practitioners. In one 4 week study 3rd year nursing students assigned to one weekly session of HT plus music versus music only reported significant reductions in transient and chronic stress and improved sleep. However, among 1st year students, no significant differences between stress levels in the HT and control group were reported.

Negative results of controlled studies raise the question of a general beneficial effect or possibly a threshold anxiety level above which HT is ineffective, or a placebo effect related to the quality or frequency of contact between the HT practitioner and the patient. It has been suggested that different outcomes reflect different skill levels of healers who participate in different studies (Ferguson 1986). Because of the heterogeneity in study designs, small study sizes, and methodological limitations of studies on biofield therapies, systematic reviews of published studies report that HT and TT sometimes improve overall quality of life but report inconclusive findings on outcomes studies of both modalities in the treatment of anxiety, other mental health problems and medical disorders that have been investigated (Anderson & Taylor 2011; Robinson & Biley 2007). An important exception is TT for cancer as many cancer patients who receive regular TT experience improvements in overall health and emotional well-being.

High perceived effectiveness

Despite the absence of compelling empirical evidence for Healing Touch, patient satisfaction surveys show that most patients complaining of anxiety or pain who receive HT treatments report significant subjective benefits. For example, in one small open study on the perceived effectiveness of Healing Touch, 40% of patients reported that calming effects lasted more than 2 weeks following the end of treatment, and 60% experienced feelings of “spiritual well-being” lasting at least 2 weeks after treatment ended. The significance of these findings is difficult to interpret because established rating scales were not used to grade symptom severity before and after the trial.

In sum, research findings suggest that Healing Touch has general beneficial effects on stress and anxiety associated with pain and some medical disorders as well as trauma, however small sample sizes, inadequate controls and potential biases preclude generalizations about the clinical benefits of HT and TT for anxiety. Despite the paucity of empirical evidence for HT, TT and other energy therapies, consistent patient reports show that biofield therapies often result in significant improvement in life quality and help improve the individual’s ability to cope with chronic stress and anxiety.

You can find information about energy therapies and other complementary and alternative treatments of stress and anxiety in my e-book “Anxiety: The Integrative Mental Health Solution.”

Acupuncture of Anxiety: A Safe and Effective Therapy

Acupuncture has diverse mechanisms of action

Animal and human studies suggest that the beneficial effects of acupuncture on health including mental and emotional functioning are related to different mechanism of action including changes in neurotransmitters involved in emotional regulation such as serotonin, and others; modulation of the autonomic nervous system; and changes in immune function. Some researches have argued that the placebo effect plays a significant role in clinical response to acupuncture, however sham-controlled studies do not support this hypothesis.

Research findings support acupuncture as a treatment of anxiety

Acupuncture and acupressure are widely used to treat anxiety in both Asia and Western countries. Extensive case reports from the Chinese medical literature suggest that different acupuncture protocols are reduce the severity of  generalized anxiety and panic attacks (Lake & Flaws 2001).

In a small double-blind sham-controlled study 36 mildly depressed or anxious patients were randomized to an acupuncture protocol traditionally used by Chinese medical practitioners to treat anxiety versus a sham acupuncture protocol (i.e. acupuncture points believed to have no beneficial effects). All patients received three treatments. Heart rate variability (HRV) and mean heart rate were measured at 5 and 15 minutes following treatment. Resting heart rate was significantly lower in the treatment group but not in the sham group, and changes in HRV measures suggested that acupuncture may have changed autonomic activity resulting in reduction of overall anxiety. The significance of these findings is limited by the absence of measures of baseline anxiety before and after treatment.

In another double-blind study 55 healthy adults (i.e., who had not been previously diagnosed with an anxiety disorder) were randomized to a bilateral auricular (i.e. a school of acupuncture in which only points on the ears are treated) acupuncture protocol called the “shenmen” point—a protocol believed to be effective against anxiety (the so-called “relaxation” point)—versus a sham acupuncture point. In all subjects acupuncture needles remained in place for 48 hours. The “relaxation” group was significantly less anxious at 30 minutes, 24 and 48 hours compared to the other two groups, however there were no significant inter-group differences in blood pressure, heart rate or electrodermal activity (Wang 2001).

Reviews report mainly positive findings

An early narrative review of controlled studies, outcomes studies and published case reports on acupuncture as a treatment of anxiety and depressed mood was published by the British Acupuncture Council. Sham-controlled studies yielded consistent improvements in anxiety using both regular (i.e. body) acupuncture and electro-acupuncture. The authors remarked that significant differences existed between protocols used in both regular and electro-acupuncture suggesting that acupuncture may have general beneficial effects or possibly placebo effects. Although most controlled studies reviewed reported a general anxiety-reducing effect of acupuncture, the reviewers regarded these findings as inconclusive because of study design problems including the absence of standardized symptom rating scales in most studies, limited follow-up, and poorly defined differences between protocols used in different studies.

A recently published systematic review (Amorim 2018) compared findings of studies on traditional (body) acupuncture, ear acupuncture (ariculotherapy) and electro-therapy in the treatment of anxiety. Some studies included in the review reported that acupuncture enhances response to prescription anti-anxiety medications and may also reduce medication side effects. The authors found good evidence that different styles of acupuncture reduce symptoms of anxiety in general, and recommended additional sham-controlled studies to help determine whether certain protocols are more beneficial than others.

For more information about complementary and alternative treatments of anxiety read my e-book “Anxiety: The Integrative Mental Health Solution.”

Few mild adverse effects

Uncommon transient adverse effects associated with acupuncture include bruising, fatigue and nausea. Very rare cases of pneumothorax (i.e. a potentially life-threatening condition caused when an acupuncture needle results in the collapse of a lung) have been reported.

Heart Rate Variability (HRV) Biofeedback for Anxiety Conditions

Several mechanisms are involved

Abnormal low heart rate variability (HRV) is associated with both medical and psychiatric disorders. HRV biofeedback is a recently developed technique that aims to modulate HRV in ways that have beneficial effects on mental and emotional functioning. The magnitude and specific characteristics of HRV are related to the body’s ability to adapt to stress. Low HRV generally corresponds to relatively greater susceptibility to stress. HRV is probably related to several underlying mechanisms that work together to ensure the healthy ‘adaptive’ functioning of the body’s cardiovascular system. Abnormal HRV signifies that the body’s stress response is not optimal resulting in potentially more harmful effects of chronic stress and increased risk of stress-related medical or mental disorders such as heart disease, depressed mood, generalized anxiety, panic disorder and post-traumatic stress disorder (PTSD). HRV biofeedback is a technique that has grown out of this insight, and aims to optimize HRV so that individuals can better manage stress and have fewer and less severe diseases caused by chronic stress.

Regular HRV biofeedback training reduces stress and improves general well-being

Findings of a few studies done to date suggest that chronically anxious patients who undergo HRV biofeedback training experience significant improvements in general emotional well-being and reduced baseline anxiety. In one study healthy adults (45 total subjects) were randomized to an emotional self-management program versus a wait list group that received no treatment (McCraty 1998). Significant reductions in cortisol levels and increased coherence in heart rate variability were found in individuals in the experimental group but not in the comparison group. The experimental group reported significant decreases in measures of guilt, hostility, burnout, anxiety and stress. These psychological changes correlated with significant reductions in serum cortisol levels and beneficial increases in measures of coherence in heart rate variability.

In one 4-month controlled trial the most of a group of 29 police officers who trained in biofeedback techniques based on HRV reported significantly greater improvements in baseline anxiety compared to 36 officers who were assigned to a wait-list group and received no treatment. In another study (McCraty 2009) that enrolled 75 correctional officers, those individuals randomized to a group that received training in emotional self-regulation and HRV biofeedback reported significant reductions in overall stress, had a more positive outlook, and had significant reductions in physiological indices of stress including reduced cortisol levels, reduced resting heart rate and blood pressure. Individuals in the treatment group had significant increases in productivity, motivation and perceived support.

Findings of a 5-week open study suggest that daily HRV biofeedback training, vigorous physical activity and mindfulness meditation may be equally effective for stress reduction in healthy adults (Van der Zwan 2015).

More studies are needed

Large long-term prospective sham-controlled studies are needed to confirm the magnitude and type of physiological and psychological benefits of HRV biofeedback, and to optimize HRV biofeedback protocols addressing different medical and mental health problems.