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November 11, 2019
Mood disorders are mental health issues that primarily affect a person’s emotional state, in which a person experiences long periods of extreme happiness, extreme sadness, or both.1 In the fifth addition of The Diagnostic and Statistical Manual of Mental Disorders (DSM-5), the list of mood disorders and their diagnostic criteria are exceedingly lengthy; but the most common include major depression, dysthymia, bipolar disorder, seasonal affective disorder (SAD), and depression related to an illness, substance abuse or medication.2 For simplicity of this article, I will refer to these issues collectively as mood disorders unless otherwise indicated.
The 2001-2003 National Comorbidity Survey Replication shows an estimated 9.7% of US adults (anyone over 18) had any mood disorder in the past year, with a higher prevalence in females (11.6%) than males (7.7%); and an estimated 21.4% of US adults will experience a mood disorder at some point in their lives.3 Please note that these figures are a combination of mood disorders; frequently updated individual statistics may be found by accessing the National Institute of Mental Health Statistics website at https://www.nimh.nih.gov/health/statistics/index.shtml.
Depression alone affects more than 300 million people worldwide.4 Bipolar disorder affects more than 60 million, and SAD can affect up to 10% of the population, depending on geographical location.5 The direct and indirect costs of these health issues are immense. For example, in 2008, the World Health Organization (WHO) ranked major depression as the third leading cause of burden of disease worldwide and projected that the disease will rank first by 2030.6 In 2015, it was estimated that bipolar I disorder (BDI) total costs were $202.1 billion (US dollars), an average of $81,559 per affected individual.
Sadly, the aforementioned numbers of afflicted individuals, as well as cost burden, are likely underestimates because many of the individuals that struggle with mood disorders go undiagnosed. At times, they may be reluctant to seek help due to the social stigma associated with these conditions. In practice, mood disorder detection, diagnosis, and management also pose many challenges for clinicians because of various presentations, unpredictable course and prognosis, as well as variable response to treatment.7,8
There is an urgent need for safer and more efficacious alternatives to medications. Medications certainly have their role in mood disorders, when used judiciously. It has been well established in mild to moderate depression, for example, that medications are no more effective than placebo.9 In manic and depressive states of bipolar disorder, the data is mixed on how efficacious medications really are.10
The extensive laundry list of side effects of mood disorder medications is so vast, it makes one’s head spin. In clinical practice, it seems the side effects tend to be so intolerable for patients, they would many times rather suffer from their illness than deal with the negative consequences of the medications. Antidepressants, anxiolytics, stimulants, antipsychotics and mood stabilizers are typically used with mood disorders; but a full discussion of their efficacy and potential side effects is beyond the scope of this article.
To better understand mood disorders and provide more effective treatment interventions, it is beneficial to look at underlying etiologies, risk factors, and genetics (encompassing family history). Each particular mood disorder has its own unique set of etiologies, but commonalities amongst all of them include brain structural changes (not yet well understood) compared to those without mood disorders, neurotransmitter alterations, and hormonal imbalances. Risk factors include low self-esteem, being highly self-critical, traumatic and stressful events (e.g., physical or sexual abuse, loss of a loved one), comorbid mental disorder (e.g., schizophrenia or anxiety disorders), alcohol and recreational drug abuse, chronic illness, and side effects of certain medications (e.g., sleeping pills and anti-hypertensive drugs).11
An enormous risk factor is genetics12 and even epigenetics.13 Research into the role single nucleotide polymorphisms (SNPs) play in mood disorders has exploded in the last 15 years or so and offers promise to help improve people’s lives through nutritional and botanical interventions.14,15 Indeed, even pharmacogenetic testing is finally becoming more mainstream in clinical practice, offering safer, more specific, personalized pharmaceutical options.16-18
A comprehensive, integrative approach to mood disorders works very well in clinical practice.19 This may include all or most of the following: lifestyle and dietary modifications, constitutional homeopathy, botanical medicines, nutraceutical support, psychotherapy, and occasionally pharmaceutical interventions. Again, given space limitations, this article will focus on evidence-based botanical and nutraceutical interventions.
Studies are consistent that up to half of all individuals diagnosed with a mood disorder use one or more complementary and alternative medicine (CAM) therapies.20,21 It has been shown that diet,22 exercise,23 sleep, a strong supportive social network, and low stress environment reduce relapses in mood disorders.24 Even targeting the proverbial “gut microbiome” can have a tremendous positive impact!25,26
Given all of the aforementioned information and dire need of safe and effective alternatives, are there really any nutraceutical and/or botanical interventions that work? The answer is yes, definitely.
Vitamin B12 (cobalamin) is involved in DNA synthesis, red blood cell formation, homocysteine metabolism, and synthesis of S-adenosylmethionine (SAMe). It also is heavily involved in the proper function of the nervous and immune systems.27 Observational studies have shown that as many as 30% of patients hospitalized with depression are deficient in this vitamin.28 Depression can be induced by B12 deficiency, even with normal hematological and blood parameters,29 so a therapeutic intervention of 1000 mcg (1 mg) daily, orally, has been suggested.30 The forms of B12 in these studies have varied.
It has been shown that individuals with psychiatric conditions either have impaired transport across the blood-brain barrier and/or an accelerated catabolism, hence the need for increased requirements.31 When these individuals were treated with a therapeutic trial of B12, clinical improvement was noted.32
Folate is a generic term referring to both natural folates in food and folic acid (the synthetic form used in many supplements and fortified food). Folate is critical in the synthesis of DNA and RNA, several amino acids, methylation reactions, homocysteine and B12 metabolism, and assists in the proper functioning of the central nervous and immune systems.33
Like B12, low red blood cell folate levels have been detected in 15–38% of adults diagnosed with depressive disorders.34 Efficacious doses have ranged from 200 mcg to 15 mg of folic acid, along with medication(s), depending on the mood disorder.35,36 Do note, most trials have been conducted on folic acid, not its biologically active forms of 5-methyltetrahydrofolate (5-MTHF, the major circulating form in the body) and 5,10-methylenetetrahydrofolate. In individuals with methylene-tetrahydrofolate reductase (MTHFR) polymorphisms and/or on medications that inhibit dihydrofolate reductase (by reducing interactions), along with those having compromised gastrointestinal function, folinic acid and 5-MTHF may be the preferred forms.37,38
Vitamin B6 (pyridoxine, pyridoxal and pyridoxamine) and its coenzyme form, pyridoxal 5’-phosphate (PLP), are essential to over 100 enzymes, affecting lipid, amino acid, and carbohydrate metabolism, along with the action of steroid hormones.39 It cannot be synthesized in the body and must be obtained from the diet. In the brain, PLP is necessary to metabolize serotonin from tryptophan and dopamine from L-3,4-dihydroxyphenylalanine (L-Dopa). Other neurotransmitters and amino acids that are PLP-dependent include glycine, D-serine, glutamate, histamine, and γ-aminobutyric acid (GABA).40 PLP also plays a role in the metabolism of homocysteine.41 Typical dose ranges are from 10 to 200 mg/day, but anyone taking more than 200 mg/day should be monitored for neurotoxic symptoms.42
Vitamin D3 (cholecalciferol) is a fat-soluble vitamin that functions as a hormone precursor. It is biologically inactive and must first be hydroxylated in the liver to 25-hydroxyvitamin D (25[OH]D), with further hydroxylation in the kidneys to its active form, 1,25-dihydroxyvitamin D, the form that acts as a steroid. In this form it suppresses prostaglandin action; inhibits p38 stress kinase signaling, tumor angiogenesis, invasion and metastasis; and inhibits NF-κB signaling.43,44
Many studies have seen a correlation between low serum concentrations of 25(OH)D and mood disorders.45 While the exact mechanisms of action haven’t been fully elucidated, vitamin D supplementation has been shown to improve mood in both depression and SAD.46,47 It should be noted that “optimal” serum levels of 25(OH)D are around 40 ng/mL.48,49
Magnesium insufficiency and frank deficiency are rampant in the US and most industrialized nations. More than half of the populous (ages ≥ 4 years) is considered to be under consuming this vital mineral.50 Chronic diseases, medications, decreases in food crop magnesium content, and the availability of refined and processed foods51 have all contributed to this epidemic.
Magnesium is the second most abundant cation in soft tissues (behind potassium) and is a cofactor for more than 300 enzymes. It plays a role in adenosine triphosphate (ATP) production, neuronal activity, cardiac function, electrical properties of cell membranes, has antispasmodic effects, and assists in glutathione synthesis.52,53 In addition to all of these accolades, it has anxiolytic properties, increases stress tolerance, and is a great antidepressant.54-56 The recommended daily allowance (RDA) varies by age and gender, ranging from 360 to 420 mg of elemental magnesium daily.
Zinc, well known for its immune properties, also plays an important role for mood, as it is essential for over 300 enzyme-dependent reactions.57 The RDA for males 19 years and older is 11 mg daily and for females, 8 mg daily. Therapeutically, trials have shown efficacy at much higher doses, although this depends on the condition being addressed. In many of the depression trials, a dose of 25 mg daily of elemental zinc was utilized.58,59 Excessive zinc intake can have toxic effects, as well as deplete copper, so the US Food and Nutrition Board has set the tolerable upper limit for those 19 years or older at 40 mg/day.60
Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are well known for anti-inflammatory affects61,62 via suppression of NF-κB, cyclooxygenase (COX)-2, tumor necrosis factor (TNF)-α, and interleukin (IL)-1β. They also have a solid reputation for assisting those afflicted with mood disorders. Doses of 500 mg to 10 grams of EPA and DHA, with many trials using 1 to 2 grams daily, have been shown to be effective in prevention and treatment of depressive disorders,63-65 with EPA having better data for efficacy than DHA.66 In bipolar disorders, there is strong evidence that omega-3 fatty acids are helpful in depression but not for attenuating mania.67
SAMe is produced in vivo from homocysteine and 5-MTHF, and also is available as a supplement. It is the body’s major methyl-group donor and is vital for membrane function and neurotransmission.68 In divided doses totaling 800 to 1600 mg daily, SAMe has been shown to be just as effective as tricyclic antidepressants with a lower side effect profile.69 It also has been shown to have a beneficial effect in depressed individuals where medication was not fully resolving their symptoms.70 It should be used with caution in bipolar disorder, as it can trigger mania.71
5-Hydroxytryptophan (HTP) is the rate-limiting intermediary in the synthesis of serotonin from L-tryptophan. The dosage of 5-HTP depends on condition, ranging from 50 mg to 3 grams daily in short studies.72-75 Commonly, it is dosed at 50 to 100 mg, one to three times daily, with some of the best evidence at this dose seen in anxiety.76,77 For depression, clinical trials have used 400-900 mg per day in divided doses.78-80 Caution is advised for those on selective serotonin reuptake inhibitors (SSRIs).
N-Acetyl-L-cysteine (NAC) a derivative of L-cysteine, but more stable,81 is well known for its function as an antioxidant and precursor to glutathione,82 acts as a mucolytic,83 has anti-inflammatory properties84 and is the treatment of choice for acetaminophen-induced hepatic necrosis.85 At 1000 mg, two to three times daily, this sulfhydryl molecule also possesses efficacy in numerous neuropsychiatric conditions.86-88 It appears to increase the uptake of cysteine, which activates a reverse transport of glutamate into the extracellular space. Restoring glutamate to the extracellular space inhibits more glutamate release, thereby improving compulsive behaviors.89
Taurine can be synthesized in vivo from cysteine. It stabilizes cell membranes, is an osmoregulator, assists in bile acid conjugation, contributes to cardiac contractility, inhibits platelet aggregation, is an antiarrhythmic and anticonvulsant, and last but not least, also functions as a neurotransmitter.90,91 Albeit, direct clinical trials of taurine on mood disorders may not exist, it has been shown to inhibit the release of excitatory neurons, like glutamate, act as a GABA agonist, inhibit TNF-α, and increase ATP production.92,93
Hypericum perforatum (St. John’s wort) is a highly revered botanical medicine with antibacterial, antiviral, anticancer (in vitro), antioxidant, neuroprotective, anti-inflammatory, and vulnerary (wound healing) properties.94 It is probably most well-known for its antidepressant effects, showing equal efficacy to tricyclic antidepressants and SSRIs, but with higher tolerability.95-97 The constituents hyperforin and adhyperforin appear to modulate the effects of serotonin, dopamine, and norepinephrine, as well as inhibit reuptake of these neurotransmitters. Most studies in individuals with depression, anxiety, and SAD show improvement with 300 mg, three times daily.98,99 Caution should be used in those on medications that interact with cytochrome P450 (CYP1A2, 2C9, 2C19, & 3A4) inducers, monoamine oxidase inhibitors (MAOIs), P-glycoprotein inducers, photosensitizers, and serotonergic agents.100
What doesn’t Curcuma longa (turmeric) do? Its virtues are endless, but one may not be aware of its efficacy in depressive disorders. Studies have shown that just 1000 mg of the herb daily is as effective as 20 mg of fluoxetine; and when used in combination with the medication, response rates for those with major depression rose from 65% to 78%.101 A 2017 meta-analysis showed again, its efficacy in depression.102 It also has been shown to reduce anxiety.103 It is postulated that it inhibits the activity of both monoamine oxidase (MAO)-A and MAO-B, increases the levels of neurotrophic factors (particularly brain derived neurotrophic factor [BDNF]), and modulates the serotonin and dopamine neurotransmission in the brain.104
Rhodiola rosea (rhodiola) is a wonderful plant that thrives in cold regions and high altitudes and is notorious for its ability to increase resistance to physical, chemical, and biological stressors.105 In vitro and animal studies have shown the constituents rhodioloside, salidroside, and tyrosol regulate the activity of serotonin, dopamine, and norepinephrine, as well as inhibit MAO-A.106-108 In depressed individuals, 340 mg one to two times daily has been shown to decrease overall depressive symptoms, emotional instability, insomnia, and somatization.109,110 Typically, dosages range from 200-600 mg daily, depending on the percentage of active constituents. Caution should be used in those with bipolar disorder, who are prone to manic episodes when given antidepressants or stimulants.111
Crocus sativus (saffron) is a well-known, brilliant yellow-red, precious spice that mostly grows in Iran, Greece, Morocco, and India, and is one of the most expensive botanicals in the world.112 It has a long history of traditional use and is considered to be an antispasmodic, thymoleptic, carminative, cognition enhancer, aphrodisiac, and emmenagogue.113 This revered spice also has been shown clinically to benefit attention-deficit/hyperactivity disorder,114 Alzheimer’s disease,115,116 anxiety117 and depression.118
It is theorized that safranal, a carotenoid found in saffron, interacts with the GABAergic system,119 modulates levels of serotonin (possibly by inhibiting reuptake),120 as well as alters levels of dopamine and norepinephrine.121 Standardized extracts containing 2% safranal, 2% crocin and small amounts of picrocrocin (% in studies unspecified), dosed at 15 mg twice daily have been shown to significantly reduce numerous parameters of depression.122-124 It is very safe and has no known drug-herb interactions.125
The use of pharmaceutical hormone replacement therapies (estrogen, progesterone and testosterone) will not be discussed in this article, but the prudent use of dehydroepiandrosterone (DHEA) and pregnenolone will be.
Pregnenolone is a ubiquitously produced endogenous neurosteroid, mostly made in the brain and adrenal glands from cholesterol. It is known as the master steroid hormone, since all steroid hormones, including cortisol, aldosterone, allopregnanolone, DHEA, progesterone, and testosterone, are made from it.126 Pregnenolone is thought to interact with the endocannabinoid (CB1) receptor, exerting antidepressant effects.127 Pregnenolone and its metabolites have also been shown to modulate GABA-A, N-methyl-D-aspartate (NMDA), cholinergic, dopaminergic, and neurotrophic systems, thus affecting neuronal excitability.128,129
In individuals with mood disorders, doses have ranged from 5 to 500 mg daily, with typical dosing of 50 to 100 mg daily. Monitoring serum pregnenolone levels every three to six months is advisable. Studies in both bipolar disorder and depression have shown significant improvements in symptoms.130,131
DHEA is the most abundant neurosteroid hormone in the human, secreted by the adrenal gland and produced in the brain.132 As a precursor to male and female sex hormones, DHEA has been shown to be effective in many health conditions; but germane to this paper, doses of 30 to 500 mg daily have been shown to be helpful in depression and dysthymia.133,134 DHEA-S, the major circulating metabolite of DHEA, is not subject to day-to-day and diurnal changes that DHEA is.135,136 For this reason, DHEA-S should be tested prior to administering the hormone to ensure it may be of benefit, as well as monitored every three to six months. Excessive administration of DHEA can cause acne and hirsutism; and as a precursor to estrogen and testosterone, there is a theoretical risk that long-term use could lead to hormone-sensitive cancers, especially if DHEA-S becomes elevated.
The aforementioned text is not an exhaustive list of safe and effective interventions to mood disorders, but rather a consolidation of what has better evidence clinically, both from published human studies and this author’s personal experience. As with any health condition, individuals should not self-treat, but rather seek out a qualified healthcare professional to discuss their health concerns and options.
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