Life Extension

Depression is a state of psyche characterized by a spectrum of negative feelings ranging in scope from minor unhappiness to overwhelming despair. Though generally associated with emotional or psychological symptoms, depression can be accompanied by severe pain or other physical symptoms as well; depression is capable of dramatically influencing the lives of those it affects.

Recent data estimate the overall prevalence of depression at about 11.1% of the American population, or nearly 35 million individuals (CDC 2010), and predictive models suggest that up to 50% of the population will experience at least one episode of depression during their lives (Andrews 2005).

The framework underlying the pathogenesis of depression is complex and variable among individuals; both psychological and biological factors influence a person’s state of mind at any given time. For example, emergent research links depression with several metabolic phenomena, including inflammation, insulin resistance, and oxidative stress. Intriguing preliminary data also suggest that mitochondrial dysfunction plays a previously unappreciated role in depression. Moreover, the role of hormones in depression is considerable, including stress hormones (glucocorticoids) and sex hormones (testosterone, estrogen). Many people affected by depression may be suffering from hormonal imbalances that are significantly contributing to their symptoms (Howland 2010).

The mainstream medical establishment relies heavily upon psychoactive drugs that manipulate brain chemistry as the frontline treatment (ICSI 2011). Unfortunately, the success rate of pharmacologic intervention for depression is a mere 50% or less and these medications are fraught with potential side effects, including a proclivity to increase suicidal ideation with some anti-depressant drugs (Prescrire Int. 2011).

Life Extension, on the other hand, acknowledges and appreciates the complex nature of depression and advocates a comprehensive management strategy that includes proactive lifestyle changes, behavioral therapy, hormone restoration, and targeted nutritional support to complement conventional antidepressant treatment and balance brain chemistry holistically.

Types of Depression and Associated Symptoms

Although depression is a clearly defined disorder with mental and physical symptoms, unlike other disorders, doctors cannot diagnose it using a blood panel or other form of lab test. Instead, they use carefully developed clinical guidelines as defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM).

Depression is distinguished into various forms. The most common are major depressive disorder and dysthymic disorder.

Major depressive disorder (major depression): Major depressive disorder can be very disabling, preventing the patient from functioning normally. A combination of symptoms sabotages the patient’s ability to sleep, study, work, eat, and enjoy formerly pleasurable activities. Some people may experience only a single episode, while others experience recurrent episodes.

Dysthymic disorder (dysthymia): Dysthymia, also known as chronic mild depression, lasts longer than two years. Symptoms are not disabling or as severe as those of major depression, however the patient finds it difficult to function normally and does not feel well. A person with dysthymia may also experience periods of major depression.

Psychotic depression: Psychotic depression is a severe depressive illness that includes hallucinations, delusions, or withdrawal from reality.

Postpartum depression (postnatal depression): Postpartum depression, also known as postnatal depression (PND), affects 10% to 15% of all women after giving birth. This is not to be confused with the “baby blues,” which a mother may feel briefly after giving birth. The development of a major depressive episode within a few weeks of giving birth likely indicates PND. Sadly, many of these women go undiagnosed and suffer for long periods without treatment and support.

Seasonal affective disorder (SAD): The incidence of SAD increases along with the distance from the equator. A person who develops a depressive illness during the winter months with symptoms that go away during spring or summer may have SAD. Accumulating evidence points to vitamin D deficiency as a contributing factor in SAD and in other forms of depression (Parker 2011).

Bipolar disorder (manic-depressive illness): A patient with bipolar disorder experiences (oftentimes extreme) highs (mania) and lows (depression) in mood. The frequency at which an individual reverts from mania to depression, and vice-versa, determines where they lie on the bipolar spectrum – a diagnostic tool used to measure the severity of bipolar disorder.

Diagnosing Depression

A diagnosis of clinical depression requires that the patient experience at least five of the nine symptoms below, as described by the DSM, for most of the day, nearly every day, for at least two weeks. One of the symptoms must be either a constant feeling of sadness, anxiety, and emptiness, or loss of interest in formerly pleasurable activities.

If any of these symptoms affects your relationships and your ability to function at home or work, consult with a health care practitioner qualified to assess and treat depression.

Emotional Symptoms

  • Constant or transient feelings of sadness, anxiety, and emptiness
  • Feeling restless; may experience irritability
  • Feeling hopeless
  • Feeling worthless or guilty for no reason; suicidal thoughts may occur
  • Loss of interest in activities or hobbies once enjoyed; may lose interest in sex

Physical Symptoms

  • Disturbed sleep patterns; may sleep too little or too much
  • Low energy; fatigue
  • Significant weight loss or gain due to a change in eating habits; either loss of appetite or eating too much
  • Difficulty concentrating, remembering details, or making decisions

Causes of Depression

Research spanning the last 20 to 30 years has examined a range of influences that contribute to depression. These include genetics, brain chemistry, early life trauma, negative thinking, one’s personality and temperament, stress, and difficulty relating to others (Liu 2010). Moreover, emerging scientific research suggests that metabolic phenomenon such as inflammation, oxidative stress, and hormonal imbalances can cause or exacerbate depression as well (Maes 2011; Wolkowitz 2011).

Impaired Stress Response

When a person experiences stress—whether it’s physical or emotional, internal or external—the body copes through a complex system of adaptive reactions. This response involves the release of glucocorticoids, or stress hormones, which stimulate adaptive changes throughout the body.

A stress response is designed to help us confront or escape danger by redirecting blood flow to the muscles, dilating the pupils, inhibiting digestion, and releasing stored fatty acids and glucose (blood sugar) to be used by the muscles. This process is known as the fight-or-flight response.

The fight-or-flight response originates in the brain. When the hypothalamus, the brain’s “control tower,” perceives a threat, it sends chemical signals to the brain’s pituitary gland, also known as the master hormone gland. The pituitary gland then sends chemical signals to the adrenal glands, which sit atop the kidneys. The adrenal glands then release the stress hormone cortisol, which triggers many of the physiological responses to danger.

Almost all animals share the fight-or-flight response, as it is paramount for survival. Although we were designed to undergo this response on only an occasional basis, modern humans cope with relentless stress. Such things as financial worries, deadline pressures at work or school, emotional challenges, excessive caloric intake, poor diet, obesity, inactivity, and environmental toxins chronically activate the hypothalamic-pituitary-adrenal axis, keeping us in a perpetual fight-or-flight response. The result is an increased rate of cardiovascular disease, diabetes, and mood disorders such as depression and anxiety.

The relationship between chronic stress, depression, and anxiety is complex, but incredibly powerful. For instance, the chronic elevation of glucocorticoids (primarily cortisol) caused by chronic stress actually changes the physical structure of the brain.

Chronic exposure to glucocorticoids shifts dendrites, the branches of neurons that receive signals from other neurons, into less functional patterns. Research links this phenomenon with alterations in mood, short-term memory, and behavioral flexibility (Joëls 2011). Glucocorticoids blunt the brain’s sensitivity to serotonin, the mood-regulating neurotransmitter most often associated with depression. (van Riel 2003; Karten 1999). Chronic stress also increases one’s susceptibility to neuronal damage and impairs neurogenesis, the process by which new neurons are “born” (Joëls 2011).

Interestingly, emerging research suggests that drugs used to treat anxiety and depression may stabilize mood not only by acting on neurotransmitters, but also by regulating the brain’s receptors for stress hormones. (Anacker 2011) These new findings strongly support the importance of controlling the stress response in order to alleviate mood disorders. Indeed, several genetic and epidemiological studies have linked excessive stress, and the inability to adapt efficiently to stress, with increased rates of anxiety and depression (Ströhle 2003; Binder 2010; Bennett 2008).

Fortunately, a number of relaxation techniques and coping styles can improve depression, further emphasizing the role of stress in depression. These approaches include Mindfulness-Based Stress Reduction (McCown 2010), meditation (Newberg 2010), biofeedback (Katsamanis 2007), progressive muscle relaxation (Dusek 2008) and an integrative health approach that combines relaxation, nutrition, and exercise (Dusek 2009).

Recent studies suggest some of these techniques influence genetic activity regulating depression (Dusek 2008). Brain imaging techniques show meditation significantly affects neurotransmitter levels and the activity of various parts of the brain that facilitate relaxation (Newberg 2010).

Traumatic events and Post-Traumatic Stress Disorder

Research establishes that trauma, such as the sudden loss of a family member, sexual abuse, or war-related traumas, contributes significantly to prolonged periods of depression. The effects are more pronounced when the trauma occurs in childhood; childhood trauma can considerably alter the structure and function of the brain, increasing susceptibility to depression and anxiety later in life (Nemeroff 2003).

Social network and personal relationships

Lack of meaningful social contact with others has been linked to depression, while evidence increasingly shows that close personal relationships and social networks positively affect mood and health (Grav 2011). Loving relationships, social connection and support, work-related passion and recognition, and a good marriage help prevent depression (Kiecolt-Glaser 2010; Coughlin 2010). Interestingly, it also has been shown that while a good marriage benefits both men and women, it seems to be more important for men from an overall health standpoint.

Neurotransmitter imbalances

Magnetic resonance imaging (MRI) shows that the areas of the brain that orechestrate thinking, sleep, mood, appetite, and behavior function abnormally in depressed patients compared to non-depressed individuals. In addition, an imaging technique called single-photon emission computed tomography (SPECT) shows changes in brain blood flow and neurotransmitter activity in the depressed person’s brain. (Yang 2008 Joensuu 2007) Although imaging technology can identify neurotransmitter imbalances, it cannot reveal why depression has occurred.

Comorbid Conditions

Depression is more common in those with HIV/AIDS (Wolff 2010), heart disease (Liu 2010), stroke (Morris 2011), cancer (Jayadevappa 2011), diabetes (Stuart 2011), Parkinson's disease (Hemmerle 2011), and many other illnesses. Research shows a person with both depression and a serious illness is more likely to experience severe symptoms and find it harder to adapt to the medical condition. Studies also show that treating depression in this population may improve symptoms of the co-occurring illness in some instances.

Additionally, people dependent on alcohol or narcotics are significantly more likely to be depressed (Shibasaki 2011).

Mainstream Medicine Overlooks Factors that Contribute to Depression

The mainstream view on the cause of depression relies largely on the monoamine hypothesis - a theory proposing that deregulation in neurotransmitter signaling is the sole cause of depression. This has been the grounds for the primary utilization of antidepressant drugs in the management of depression for decades. However, this theory fails to take into account various other well-studied causes, and partly explains the poor success rate of antidepressant medications.

Conventional medicine overlooks several important biological factors that influence depression, thereby undermining the likelihood that a holistic strategy will be employed to thoroughly manage a patient’s depression.

If left unchecked, aberrations among these underappreciated factors may work together to create metabolic and neurochemical imbalances that provoke mood changes and initiate depression.

Critical omissions from conventional assessment of depression include:

  • Hormonal imbalances
  • Nutritional deficiencies
  • Oxidative stress and mitochondrial dysfunction
  • Insulin resistance and chronic inflammation

Hormonal influences

Balanced and youthful concentrations of hormones can help control depression, and astute clinicians often find hormonal imbalances in patients with depression. Because a wide range of hormones can influence depression, it is important to discern which hormone(s) may be an underlying factor when considering depression.

For example, thyroid function directly affects metabolism and brain function, and low thyroid activity can contribute to depression. Conventional medicine relies on overly broad thyroid lab ranges, failing to recognize many cases of sub-optimal thyroid function.

Overt hypothyroidism has been shown to perturb serotonin signaling in the brain, which can contribute to depression (Stipcevic 2009). Furthermore, because the brain requires sufficient thyroid hormones to function optimally, a low thyroid hormone status can contribute to overall loss of function and degeneration in the brain, including the areas of the brain that govern mood (Davis 2007). Hashimoto’s thyroiditis, an autoimmune thyroid disease, can cause a person’s metabolism to swing between overly active to overly depressed. These swings can mimic the symptoms of bipolar disorder and cause misdiagnosis and inappropriate treatment (Chang 1998; Kupka 2002; Cole 2002; Frye 1999).

Sex hormones also influence mood and depression. Women are more susceptible to anxiety than men and also experience more depression when they are pregnant, postpartum, premenstrual and menopausal than at other times in life. These general observations have piqued the interest of scientists and given rise to an expanding body of research linking depression with sex hormone imbalances.

By now, it is well known that most steroid hormones (e.g., pregnenolone, estrogen, progesterone, testosterone, and DHEA) are neurologically active. In fact, the brain contains large numbers of receptors for DHEA, estrogen, and progesterone. These hormones affect many functions in the brain, including the regulation of mood.

Accordingly, a number of studies link hormonal imbalances to various depressive disorders (Cunningham 2009; Parcells 2010; Bloch 2011; Sundermann 2010). In the follicular phase of menses, when estrogen levels are high, women produce more serotonin and experience an improved mood. When estrogen decreases during the premenstrual period, serotonin levels drop, contributing to the negative mood and personality shifts associated with PMS (Kikuchi 2010).

Likewise, the drop in estrogen during menopause is associated with reduced serotonin production and a negative impact on mood and cognition. This is evidenced by the fact that SSRIs have been shown to improve mood and cognitive function in menopausal women (Cubeddu 2010).

In addition, testosterone deficiency has been linked with depression in men, which is not surprising since testosterone plays an important role in brain function, including mood regulation (Zitzmann 2006; Delhez 2003). In studies, select populations of men were more likely to be depressed if their total and/or free testosterone levels are low; these included those with heart disease, HIV/AIDS, and the elderly (Jankowska 2010; Zarrouf 2009).

Medical research acknowledges the link between hormonal imbalances and depression; however, conventional doctors rarely evaluate and address hormone status when treating depression. Instead, they frequently dismiss such imbalances as a normal part of aging, while in truth, restoring youthful hormonal status may effectively combat multiple health deficits associated with aging, including mood imbalances.

The role of hormones in treating depression will be examined more closely in the section of this chapter entitled “Hormone Restoration”.

Nutritional deficiency or insufficiency

Nutrition plays an essential role in brain function, and poor nutrition significantly increases one’s risk for depression. Dietary nutrients influence nervous system function in multiple ways. Important dietary nutrients include:

  • B-complex vitamins: B-complex vitamins serve as cofactors for the production of neurotransmitters. Inadequate levels of B-vitamins, especially folate, vitamin B12, niacin, and vitamin B6, can disrupt neurotransmitter synthesis. This not only may lead to mood alterations, but also can impact overall brain function, memory, and cognition.
  • Optimal balance of omega-3 and omega-6 fatty acids: Fatty acids are critical components of nerve cell membranes and play an important role in neuronal communication. Fatty acid imbalances can impair the transmission of messages between nerve cells, leading to cognitive deficits and mood alterations, including depression (Yehuda 2005).
  • Vitamin D activity: A vitamin-D insufficiency, which is very common even among dedicated supplement users (Faloon 2010), is linked with seasonal depression. Recent evidence suggests that it also may contribute to general depression through its considerable influence on genetic activity, its ability to control inflammation, and other mechanisms.

It is important to remember that optimal brain function necessitates all of these nutritional aspects be addressed simultaneously.

Oxidative Stress and Mitochondrial Dysfunction

Brain tissue is particularly susceptible to oxidative damage due to its high concentrations of phospholipids and the exhaustive metabolic rate among neurons. A growing body of research suggests that oxidative stress contributes to depression and other brain-related disorders (Hovatta 2010). This is thought to result from either an increase in damaging reactive oxygen species, a decrease in antioxidant defense mechanisms, or a combination of the two. These mechanisms become especially important with advancing age (Wolkowitz 2011).

Newer research sheds light on the critical role of mitochondria and neurotransmission and mood regulation. Mitochondria are the “powerhouses” in each cell that generate energy. In an intriguing study, researchers measured the content of mitochondrial DNA within white blood cells in aging patients who were depressed, and in an age-matched group who were not depressed. The subjects with depression had significantly fewer mitochondria than non-depressed controls, leading researchers to suggest, “mitochondrial dysfunction could be a mechanism of geriatric depression” (Kim 2011). In a similar study, greater numbers of mitochondria in peripheral cells were associated with improved cognitive function in healthy elderly women (Lee 2010).

Preliminary research suggests that two nutrients, coenzyme Q10 and acetyl-L-carnitine, which support mitochondrial function, may influence depression. A small study of 35 depressed patients in comparison to 22 healthy volunteer controls showed that plasma CoQ10 levels were significantly lower in the depressed patients. Levels were also lower in treatment-resistant patients, as well as those with chronic fatigue (Maes, 2009).

Several studies of geriatric depression have investigated acetyl-L-carnitine (Pettigrew 2000). One study compared treatment with acetyl-L-carnitine to the medication amisulpride, an antipsychotic medication commonly used to treat depression. In 204 patients with chronic depression, both acetyl-L-carnitine and the pharmaceutical drug improved symptoms (Zanardi, 2006). Acetyl-L-carnitine also has been found to relieve depression and improve quality of life in patients with liver disease (Malaguarnera 2011), and to ease depressive symptoms significantly in patients with fibromyalgia (Rossini 2007).

Another nutrient, pyrroloquinoline quinine (PQQ), is an enzyme involved in the generation of new mitochondria and the maintenance of antioxidant defense systems (Chowanadisai 2010; Rucker 2009; Tachaparian 2010). Supplemental PQQ has been shown to increase mitochondrial activity levels and to be neuroprotective in animal models (Bauerly 2011; zhang 2006; Zhang 2009). Since fewer mitochondria have been observed in depressed patients (Kim 2011), PQQ may be supportive in this population.

Insulin Resistance

Recent data suggest a direct link between insulin resistance and depression. In a small clinical study, treatment of depressed patients with the insulin-sensitizing drug pioglitazone alleviated depression while simultaneously improving their cardio-metabolic risk profiles (Kemp 2011). Evidence suggests that another popular glucose control agent, metformin, may influence psychiatric health as well (Ohaeri 2011). Individuals who are overweight, have suboptimal glucose control, or have diabetes with concurrent depression may find that losing weight and gaining control over their glucose levels eases their depressive symptoms.

Scientific literature indicates that for optimal health, fasting glucose levels should fall between 70 and 85 mg/dL, and 2-hour postprandial (2 hours after a meal) glucose levels should not exceed 120 mg/dL.

Chronic Inflammation

Several studies support the role of inflammation and immune system deregulation in depression. Studies have found elevated levels of inflammatory cytokines (signaling molecules with which immune cells communicate) in patients suffering from major depression (Tsao et al 2006), late-life depression (Craddock et al, 2006), and in patients who do not respond to SSRIs (O’Brien 2007). These cytokines include the interleukins IL-1beta and IL-6, as well as the cytokines INF-gamma and TNFalpha.

Studies show an association between the systemic inflammation marker C-reactive protein (C-RP) and major depression (Cizza 2009). Moreover, elevated CRP levels are associated with a number of other significant health problems such as cardiovascular disease. Life Extension suggests that women target a CRP blood level of less than 1.0 mg/L and men target a level of less than 0.55 mg/L.

In prospective studies involving patients being treated with recombinant cytokines for immune-related conditions, depression is observed to develop after inflammation initiates several other undesirable metabolic cascades. This has lead some researchers to identify depression as a late-stage consequenceof chronic inflammation (Dantzer 2011).

Research innovations suggest that future antidepressant medications may be anti-inflammatory in nature (Christmas 2011).

Conventional Medical Approaches – Challenges and Benefits

As mentioned earlier, mainstream medicine typically relies on antidepressants as first line treatment for depression (ICSI 2011). However, in many cases, this first line treatment is meant with failure. The result is a diagnosis of “treatment resistant depression”, and, if severe enough, more drastic measures will be undertaken in attempt to alleviate depressive symptoms. Instead of addressing the multiple other potential contributors to depression mentioned in the protocol, conventional physicians opt to appease treatment resistant depression with procedures like electroconvulsive therapy, which happens to cause memory loss.

Sadly, though research has given rise to promising new modalities for relieving depression, such as transcranial magnetic stimulation, mainstream medicine has yet to advance past the archaic model of psychiatric medicine that has been in place for decades.

This section of the protocol will discuss typical conventional treatment options and also introduce some promising new techniques that are quickly gaining the attention of patient-minded clinicians.

Medications Typically Used to Treat Depression

Several classes of medications may be employed to treat depression; depending on the patients symptoms and history medications from the following classes are typically utilized.

Most antidepressant medications work by altering signaling within the brain. They do so by manipulating the level of neurotransmitters in the synaptic junction, the finite space between two neurons in which signaling molecules are released and reabsorbed to facilitate neuronal communication.

While antidepressants may temporarily improve mood, they do so in a way that is somewhat artificial and unlikely to be effective for an extended time. There is disturbing evidence that some antidepressants may cause the brain to adapt to their presence, requiring increasing dosage and leading to withdrawal symptoms upon cessation.

Moreover, an underrecognized condition known as antidepressant discontinuation syndrome may arise in as many as 20% of patients upon abrupt discontinuation of an antidepressant medication. This phenomenon is likely the result of the brain having adapted to the medication, and now being deprived of it, malfunctions for a time until it can readapt to the lack of the drug. Symptoms of antidepressant discontinuation syndrome include flu-like symptoms, insomnia, nausea, hyperactivity, and sensory disturbances, among others (Warner 2006).

  1. Selective serotonin reuptake inhibitors (SSRIs) are one of the most popular class of antidepressants. Fluoxetine (Prozac®), citalopram (Celexa®), and sertraline (Zoloft®) are all SSRIs. They tend to have the fewest side effects of antidepressant drugs. Primary side effects are decreased sexual desire and delayed orgasm. Other side effects—digestive symptoms, headaches, insomnia and anxiousness—often decrease over time (Wilson 2004).
  1. Serotonin and norepinephrine reuptake inhibitors (SNRIs) include duloxetine (Cymbalta®), venlafaxine (Effexor®), and desvenlafaxine (Pristiq®). The side effects for these medications are similar to those of SSRIs.
  1. Atypical antidepressants are norepinephrine and dopamine reuptake inhibitors (NDRIs) such as bupropion (Wellbutrin®), trazadone (Desyrel®), and mirtazapine (Remeron®). They have a different mechanism of action and side-effect profile than other antidepressants. For example, NDRIs generally do not cause sexual dysfunction as a side effect; however, they can increase blood pressure and risk of a seizure. Other minor effects include loss of appetite, headaches, dry mouth, nervousness, anxiety, stomach pain, constipation, insomnia, and more.
  1. Older antidepressants include the tricyclic antidepressants amitriptyline, amoxapine, desipramine (Norpramin®), doxepin, imipramine (Tofranil®), nortriptyline (Pamelor®), protptyline (Vivactil®), trimiptyline (Surmontil®); and the monoamine oxidase inhibitors (MAOIs) tranylcypromine (Parnate®) and phenelzine (Nardil®). Doctors do not use these medications frequently because they tend to have more frequent and severe side effects. For example, tricyclic antidepressants can cause an abnormal heart rhythm and drowsiness. MAOIs can increase the risk of severe reactions to foods, drinks and other medications, as well as significantly increase blood pressure, which may lead to a heart attack or stroke. Other side effects of both these classes of medication include constipation, headaches, anxiety, and dry mouth.

Electroconvulsive Therapy

A long-standing treatment still used in conventional medicine is electroconvulsive therapy, or ECT. It is most often reserved for people with suicidal ideation, psychotic depression, or those who have not responded to other treatments. It is reportedly effective in up to 90 % of patients, which is why it is still available (Schneider 2007), although it is important to question the extent of the benefit and how long the effects last.

ECT is associated with short-term memory loss, and it appears that some aspects of memory may be affected for an extended time (Lisanby 2000). Moreover, ECT may negatively influence other realms of cognition unrelated to memory; in fact, one group of reviewers stated that “…clinicians should take the non-memory cognitive effects of ECT into account, and patients should be informed of their existence before they sign consent for ECT” (Calev 1995).

Cognitive Behavioral Therapy

Cognitive behavioral therapy (CBT) is a non-pharmacologic means of therapy often employed to relieve depression. CBT is typically initiated if primary treatment with antidepressant medications fail, but it is sometimes used as part of first-line treatment alongside antidepressants.

CBT is centered upon the belief that depression is closely linked with negative thinking (i.e. thought patterns that negatively reinforce depressed mood). The goal of CBT is to help the patient recognize and replace negative thinking with more positive, constructive thoughts. CBT has been studied in various settings and has shown efficacy both independently and in combination with other conventional treatment regimens.

A recent review of studies using CBT in treatment resistant depression found that CBT performed as well as pharmacotherapy when used in conjunction with a primary medication, or in cyclical fashion involving switching from pharmacotherapy to CBT and back again (Inoue 2010). This same review also pointed out that when a patient with treatment resistant depression switched antidepressants, greater relief was attained when the switch was accompanied by CBT. A 2010 clinical trial revealed that CBT effectively relieved depression and/or anxiety in patients with chronic obstructive pulmonary disease (Hynninen 2010).

CBT is also effective in young people with depression, and may be preferable over psychotropic drugs for some parents since it lacks harsh side effects. In one trial, CBT was compared to stand-of-care (pharmacotherapy) in children ages 8 – 15. CBT was superior to pharmacotherapy in several aspects, including patient alliance to treatment (Weisz 2009). Moreover, CBT may have an overall cost advantage versus pharmacotherapy (Weisz 2009).

Life Extension suggests that every patient with depression talk with a qualified healthcare provider about cognitive behavioral therapy as an adjuvant, or alternative to pharmacotherapy.

Physical activity

Research supports the use of exercise, primarily aerobic or weight training, as a preventive and adjuvant treatment (used in conjunction with medication) of mood disorders and depression. Some studies have found exercise alone is as effective as medication for relieving depression (Freeman, 2010) and that exercise can reduce depression recurrence rates (Babyak et al 2000). A recent study looked at 202 adults with major depression who either participated in 4 months of exercise, took the medication sertraline, or took a placebo. A one-year follow up showed that exercise was as effective as the medication at relieving depression and that exercise during the follow-up period extended the benefits (Hoffman et al 2011).

Light Therapy

Research shows morning light therapy from a light-therapy lamp is effective at treating seasonal affective disorder (seasonal depression), and that it is equally or possibly even more effective than antidepressants, in this type of depression (Freeman, 2010). A study of 98 patients with seasonal depression illustrated this. Depressed subjects were randomly assigned to 8 weeks of therapy with light in the morning (30 minutes, 10,000 lux, and a placebo pill) or 30 minutes of dim light (100 lux and 20 mg of fluoxitine), with both groups experiencing a 67 % response rate (Lam et al 2006).

Light therapy for non-seasonal depression is not well established, although results are promising; light therapy may be more helpful as an adjuvant treatment than as a stand-alone treatment.

Transcranial Magnetic Stimulation

Interestingly, a new procedure called transcranial magnetic stimulation (TMS), which uses magnetic fields to stimulate nerve cells in the brain, is widely researched and showing promising results as a treatment for depression. The FDA has approved TMS for people who have not responded to medication, and it is often compared to the controversial electroconvulsive therapy (ECT). However, it is a possible alternative to ECT, as it is more humane and causes fewer adverse effects.

A recent study of 190 patients with major depression treated with TMS showed a clinically significant improvement in symptoms (George 2010). In a recent review, TMS was concluded to be as effective as cognitive behavioral therapy or pharmacotherapy for relieving depression (Schutter 2011).

TMS is becoming more widely available in hospitals and private practices; however because it is relatively new, it is important to ask how long the treatment has been offered, how many patients have been treated, and what the success rates are.

Dietary Considerations for Depression

Dietary factors should always be addressed when managing depression, as evidence demonstrates that various aspects of diet can affect the disorder.

Individuals with depression may consume too many inflammatory omega-6 fatty acids and saturated fats, so increasing consumption of omega-3's and decreasing consumption of trans-fats, saturated fat, and excess omega-6 fatty acids is recommended (McNamara 2008).

Omega-3 fatty acids (Lin, 2007) and folate (Tolmunen 2004) both appear to be very important in mood management. Although the role of these nutrients in the diet is important, one should augment the diet with supplements as described below for maximum benefit in addressing symptoms of depression or in trying to prevent a recurrence. As described later in this protocol, omega-3 fatty acids have been shown to decrease susceptibility to depression and may help as an adjuvant therapy. Foods high in omega-3's include deep-water fish such as salmon, mackerel, sardines, and tuna, as well as flax seeds, and some nuts (e.g., walnuts).

Evidence suggests that limiting sugar intake to control blood sugar levels is another important approach to depression. This would include addressing hyperglycemia (high blood sugar), hypoglycemia (low blood sugar), or reactive hypoglycemia (low blood sugar that occurs within 4 hours of eating). Reactive hypoglycemia may be more common in people who are not overweight. To address high or low blood sugar, it is important to limit or avoid sugar and refined carbohydrates, eat small meals 4–6 times per day, eat a balance of healthy proteins, fats, and complex carbohydrates, and decrease caffeine. The nutrients magnesium and chromium and practicing relaxation techniques also help manage hypoglycemia.

Evidence also suggests that an anti-inflammatory Mediterranean Diet may help prevent or manage depression (Sanchez-Villegas 2006). A Mediterranean diet, which is rich in omega-3 fatty acids and polyphenolic antioxidants, could serve as a foundation to which targeted dietary supplements are added for maximum response. The diet generally includes good quantities of fish, vegetables, unrefined grains, beans or legumes, fruit, and olive oil. It includes moderate amounts of dairy (mostly cheese and yogurt) and red wine, and limits meats to small portions.

Complementary Therapies for Depression

Hormone Restoration

Although some physicians routinely screen for underlying hormonal disorders and/ or imbalances as part of depression management, many use hormonal therapy in protocols for depression, most typically do not. Instead, they may consider hormonal imbalances a normal part of aging. Also, many ascribe to the philosophy of looking at studies of averages of population data as opposed to individual cases for potentially beneficial therapeutic programs, which can cause patients who may benefit from hormone restoration to go untreated.


Thyroid dysfunction may be a significantly underappreciated cause of depressive symptoms. In one study, thyroid disorders were associated with a 22% higher likelihood of depression in women (Fuller-Thomson 2011).

Studies have shown that treating subjects within so-called “normal” thyroid hormone levels may still be beneficial. In one such pilot study invloving 17 female patients with depression, 11 (64.7%) saw significant improvement in response to a moderate dose of l-thyroxine (Lojko 2007). Similarly, in a study of 225 subjects with treatment resistant depression, augmenting primary antidepressant therapy with thyroid hormone was found to be roughly as effective as adding a second antidepressant medication for providing relief of symptoms (Fang 2011).

Life Extension suggests maintaining a TSH (thyroid stimulating hormone) of 1 – 2 µIU/mL (typical lab normal range 0.45- 4.5 µIU/mL) to avoid the consequences of subclinical thyroid dysfunction, which may include depression. To learn more about sub-optimal thyroid function and how it may be impacting your life read our Thyroid Regulation protocol.


DHEA is an important steroid hormone often referred to as a neurosteroid because it serves a variety of functions in the brain. DHEA levels decrease with age and stress, and people with depression often have low levels of DHEA. In one study, blood samples from women with a history of depression contained lower levels of select neurosteroids, including DHEA, than women with no depression history (Girdler 2011). Interestingly, experiments showed the women with a history of depression may metabolize progesterone differently than healthy women, reflecting an adaptive effort by the body to compensate for low neurosteroid levels.

A number of studies have examined the role of DHEA in depression, with very encouraging results. DHEA has been shown to modulate serotonin levels in the brains of laboratory animals (Karishma 2002; Abadie 1993). DHEA has also performed well in human trials. DHEA therapy significantly benefited patients with HIV/AIDS and depression (Rabkin 2006). In a randomized, placebo-controlled, double-blind study, researchers studied the effects of 90 mg DHEA daily for 3 weeks and 450 mg daily for 3 weeks as a stand-alone treatment for both mild and severe depression. They found that DHEA therapy resulted in a significant improvement in symptoms compared with the placebo (Schmidt 2005).


Studies indicate that some depressed men have low levels of testosterone (Barrett-Connor 1999; Schweiger 1999). In addition, several clinical trials have shown that testosterone replacement therapy, usually transdermal testosterone gel, can relieve depression in men with low testosterone, metabolic syndrome, and HIV/AIDS (Giltay 2010; Shores 2009; Zarrouf 2009; Pope 2003).

Aging men should maintain their free testosterone level in the youthful range of 20–25 pg/ml to stabilize mood and avert other age-related diseases, such as cardiovascular disease and metabolic syndrome. Men interested in restoring their hormone levels should read Life Extension's Male Hormone Restoration protocol.


Estrogen is critically important for brain function and linked to depression, especially in perimenopausal or postmenopausal women (Grigoriadis 2002). Women using estrogen replacement therapy to alleviate menopause symptoms appear to experience reduced depression (Miller 2002). In some older women being treated for depression, estrogen replacement therapy may actually improve the effects of conventional antidepressants (Schneider 2001).

Estrogen is thought to prevent depression through its association with serotonin regulation in the brain (Osterlund 2010; Joffe 1998; Rubinow 1998). Animal studies show that estrogen may facilitate the effects of antidepressants by modulating serotonin receptors. This suggests that an estrogen imbalance may dampen the efficacy of antidepressant medications (Bethea 1998; Kendall 1982).

Further evidence suggests that estrogen promotes neuroplasticity, the process by which the brain adapts structurally and functionally to new stimuli (Barha 2010; Osterlund 2010). Disturbances in neuroplasticity may lead to recurrent depression (Vidailhet 2010).

Women interested in learning more about the benefits of restoring their hormone levels should read Life Extension's Female Hormone Restoration protocol.


Melatonin is a hormone produced in the pineal gland in the brain; it is involved in sleep-wake function and other circadian rhythms. Melatonin decreases with age and some studies link low levels of melatonin with symptoms of depression.

A double-blind placebo-controlled pilot study of perimenopausal and post-menopausal women who took 3 mg of melatonin at bedtime for 6 months showed significant improvement in depressive symptoms (Bellipanni 2001). Recently, another well-controlled preliminary study looked at 33 participants with major depression and early morning waking who took 6 mg of melatonin for 4 weeks. The results suggested improvement in sleep and depressive symptoms (Serafty 2010).

Studies of the medication agomelatine, which acts upon melatonin receptors in the brain, support melatonin's influences on depression (Green 2011). Some studies suggest that this drug may be as effective as venlafaxine, fluoxetine, and sertraline in relieving depression (Hickie 2011).

Nutrients to Balance Brain Chemistry

Depression is a multifactorial condition, and efficient relief requires addressing multiple neurochemical and metabolic imbalances that may underlie mood disturbances. The nutrients listed in the protocol are categorized according to their evidence-based mechanisms of action in brain health and mood regulation. The categories are:

  1. Broad-range nervous system function (omega-3 fatty acids, magnesium, saffron extract);
  2. Neurotransmitter synthesis (SAMe, folate, B12 , B6, tryptophan);
  3. Blood-sugar regulation (chromium, green coffee extract);
  4. Antioxidant effects (lipoic acid, NAC, selenium); and
  5. Others (St. John's Wort, vitamin D, zinc, inositol, iron).

Each of these categories is examined below.

Broad-Range Nervous System Effects: Omega-3 Fatty Acids, Magnesium, and Saffron Extract

Omega-3 fatty acids

Omega-3 fatty acids are long-chain polyunsaturated fatty acids found in fish and various oils, such as flaxseed or canola oil (Logan 2003). The brain has a high concentration of polyunsaturated fatty acids, which are found mostly in cell membranes. They affect adaptability of the nervous system, nerve cell conduction and function, and neurotransmitter synthesis (Yehuda 2005; Bourre 1991). Several research models exhibit the influence of omega-3 fatty acids in depression including: (a) dietary studies (Tanskanen 2001); (b) nutritional status studies showing positive effects associated with higher omega-3 to omega-6 fatty acid ratios (Tiemeier 2003); and (c) intervention studies that look at both eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) taken as a stand-alone treatment and as an adjunct to medication (Lin 2007).

One investigation showed that adding the omega-3 fatty acid EPA to conventional antidepressant treatment relieved depressive symptoms (Puri 2001). Among children with depression, supplementation with omega-3 fatty acids demonstrated “highly significant” effects on symptom scores (Nemets 2006). In a review article from 2006, researchers analyzed results from six published studies and found that omega-3 fatty acids can reduce symptoms of depression among adults as well (Williams 2006).

Because they are anti-inflammatory, omega-3 fatty acids also reduce the risk of cardiovascular disease, which is highly associated with depression (Burr 1989; Singh 1997). In fact, the American Heart Association recommends fish oil for both preventing an initial heart attack and for preventing a second attack when one has already occurred.

Omega-3 fatty acids are counterbalanced with the inflammatory omega-6 fatty acids. Typically, Americans consume far too many omega-6's and not nearly enough omega-3's.

The ratio of omega-6 to omega-3 fatty acids is important. You can learn your ratio easily with the Omega Check test. This test can help you assess your risk for depression, heart disease, and other age-related ailments. It can also help you evaluate whether you take enough fish oil or other omega-3 supplements. More information about the importance of maintaining an optimal omega-6 to omega-3 ratio of less than 4:1 can be found in the Life Extension Magazine article entitled “Optimize your Omega-3 Status”.


Magnesium is a cofactor for more than 300 enzymes in the body; it is important for blood-sugar regulation, and has a calming effect on the nervous system (Nadler 1995). Some evidence shows a link between magnesium deficiency and depression (Whittle 2011), and a recent, comprehensive review in the Journal of Medical Hypotheses suggests that magnesium supplementation is a viable approach for depressive symptoms (Eby 2010).

A major hurdle for supplemental magnesium historically has been delivery into the brain. This is a barrier that has limited the ability of typical magnesium supplements to target conditions that arise from within the central nervous system such as depression and anxiety. However, in a recent scientific breakthrough, researchers collaborating from Beijing, Ontario, the University of Texas, and the Massachusetts Institute of Technology have developed a highly advanced form of supplemental magnesium called magnesium-L-threonate.

Magnesium-L-threonate was shown in multiple animal models to not only effectively penetrate deep into the brain, but also to trigger enhancements in learning and memory by optimizing neuronal communication and reinforcing brain structure in key areas of the cortex, the most advanced aspect of the human brain (Slutsky 2010; Abumaria 2011). Since magnesium-L-threonate is readily able to diffuse across the blood brain barrier, while other forms of magnesium are not, it appears to be the ideal form of supplemental magnesium for those with depression of other mood disorders.

Saffron extract

Saffron and its constituents have multiple biochemical activities that help provide supporting evidence for saffron in the treatment of depression. These include serotonin modulation as well as neuroprotective, neuro-hormonal, anti-inflammatory, and oxidative stress reducing functions (Hausenblas 2015; Lopresti 2014; Dorri 2015). In an advanced laboratory study, two saffron compounds, crocin and saffronal, inhibited the activity of enzymes that lower levels of the monoamine neurotransmitters serotonin, norepinephrine, and dopamine in brain synapses (De Monte 2014).

Two randomized controlled trials found 30 mg per day of saffron extract to be as effective for mild-to-moderate depression as 20–40 mg per day of the antidepressant drug fluoxetine (Akhondzadeh Basti 2007; Shahmansouri 2014). In another randomized placebo-controlled trial, 40 patients hospitalized with major depressive disorder were given 15 mg of the saffron extract crocin, twice daily, in addition to antidepressant medication. Patients taking crocin had significantly greater improvement in anxiety and depression scores than those who received placebo plus antidepressant (Talaei 2015).

In a controlled clinical trial, 60 individuals with depression and anxiety were treated with either 50 mg saffron twice daily or placebo for 12 weeks. The saffron group had significantly reduced depression and anxiety symptom scores on standardized questionnaires compared with placebo (Mazidi 2016). In another controlled clinical trial in 40 patients with mild-to-moderate depression, six weeks of treatment with 15 mg saffron extract, twice daily, resulted in a more than 2.7-fold greater reduction in standardized depression symptom scores compared with placebo (Moshiri 2006). A similar study also found treatment for six weeks with 30 mg per day saffron extract was significantly more effective than placebo at improving depression symptoms scores in individuals with mild-to-moderate depression (Akhondzadeh 2005).

One relatively common side effect of SSRIs is sexual dysfunction in both men and women (Montejo-Gonzalez 1997). Two controlled clinical trials, one in men and one in women, found saffron safely and effectively relieved some symptoms of antidepressant-induced sexual dysfunction (Kashani 2013; Modabbernia 2012). One study in women with premenstrual syndrome, a condition often treated with antidepressants, found saffron was significantly more effective than placebo for relieving symptoms, including depression, of this condition (Marjoribanks 2013). In this randomized controlled trial, 50 women received either 15 mg saffron extract or placebo twice daily for two consecutive menstrual cycles. Sixty percent of the saffron group had a 50% or greater reduction in depression symptoms versus 4% in the placebo group. Seventy-six percent of the saffron group experienced a 50% or greater reduction in PMS symptoms versus 8% in the placebo group (Agha-Hosseini 2008).

Supporting Neurotransmitter Synthesis: Tryptophan

L-tryptohan is essential for the brain to synthesize serotonin, and several studies have shown that acute tryptophan depletion can cause depression in humans. In fact, some foreign countries license L-tryptophan as an antidepressant (Murphy 2006).

In one study, healthy women given L-tryptophan for 14 days experienced increased recognition of happy faces and words, and decreased recognition of negative words. The research team concluded L-tryptophan had improved the study participants' supply of serotonin in a manner similar to that of SSRIs (Murphy 2006). In another study of the effects of acute tryptophan depletion on healthy women and on patients with bulimia nervosa, both groups were given amino acid mixtures to decrease their plasma L-tryptophan levels. Both groups experienced an increase in depression. (Kaye 2000) Other studies have found L-tryptophan depletion can lead to recurrence of depression in those who are in remission from depression (Booij 2006) or in those with seasonal depression (Neumeister et al 1998).

Methylation (a biochemical building block process for producing neurotransmitters):

Methylation is a process in which a molecule passes a methyl group to another molecule. Methylation is essential to multiple functions in the body, including the production of neurotransmitters. One can supply raw materials to support methylation reactions by supplementing with S-adenosyl-methionine (SAMe) or by providing metabolic cofactors such as folate, vitamin B12, and vitamin B6. These nutrients are necessary for neurotransmitter production and have other regulating effects.

S-Adenosylmethionine (SAMe)

SAMe, which can be found in almost every tissue in the body, assists with production of creatine, glutathione, taurine, L-carnitine, and melatonin.

Research shows SAMe can benefit depressed patients who do not respond to SSRIs. In a well-controlled, 6-week, double-blind trial, 73 subjects with treatment resistant depression were treated with an SSRI plus placebo, or an SSRI plus 1,600 mg SAMe daily. The group receiving the SAMe experienced significantly better response rates and remission compared to the placebo control group (Papakostas 2010). Intriguingly, the group that received SAMe also displayed improved memory function over those receiving placebo. A smaller 6-week study revealed a response rate of 50% and a remission rate of 43% in subjects taking 800–1,600 mg a day of SAMe as an adjunct to their antidepressants (Alpert 2004).


Research shows that low blood levels of folate are associated with depression (Alpert 2000), and may also be predictive of poor response to antidepressant medication (Fava 1997). Clinical trials have also demonstrated that folic acid both relieves depression on its own and enhances the effect of antidepressants. In one study, patients given 500 mcg folic acid daily in conjunction with fluoxetine experienced a significant improvement in depressive symptoms compared with patients receiving the antidepressant alone; women particularly benefited (Coppen 2000). Because relapse is associated with low serum folate, it is important to maintain folate supplementation for a year following a depressive episode (Morris 2003).

The form of supplemental folate is important since a considerable portion of Americans may have a genetic polymorphism that impairs folate metabolism (Willems 2004). In fact, mutations in the gene (MTHFR) that converts folic acid into the active 5-methyltetrahydrofolate (5-MTHF) are associated with depression (Lewis 2006). Therefore, taking supplemental 5-MTHFdirectly, which can cross the blood-brain barrier, may be more effective in supporting healthy neurotransmission and decreasing potentially neurotoxic homocysteine levels.

Vitamin B12

Vitamin B12 should always be measured in the event of depression (or any other psychological problems) as a vitamin B12 deficiency can be a reversible cause of various neuropsychiatric disorders (Hector 1988). One should also consider whether a vegetarian diet or malabsorption due to celiac disease or gluten enteropathy is a factor in B12 deficiency.

Weaker digestion, reduced absorption of nutrients, and hypochlorhydria (inadequate stomach acid needed to break down proteins that contain vitamin B12) are common in the aging population and associated with a B12 deficiency; B12 levels should be tested in an older person with symptoms of depression. Evidence suggests that the methylcobalamin form of B12may have more beneficial metabolic effects than cyanocobalamin (Sun et al 2005; Bertoglio et al 2010).

Vitamin B6

Vitamin B6 is a cofactor for the production of most neurotransmitters, but it is particularly important for serotonin synthesis (Baldewicz 2000). B6 levels are often low in women taking oral contraceptives and research has shown that B6 supplementation in these women can improve mood. For example, one study showed 22 women who had depression associated with oral contraceptive use and a B6 deficiency saw significant improvement in their symptoms with B6 supplementation (Adams et al 1973).

A more recent study examined blood levels of pyridoxal-5-phosphate (P5P), a metabolically active form of B6, in the blood of 251 elderly individuals living is Massachusetts. The investigators found that deficient levels of P5P doubled the likelihood of depression in this population. Accordingly, when dietary composition was assessed, those with higher daily B6 intakes were less likely to be depressed (Merete 2008).

Blood sugar regulation and insulin resistance: Chromium and Green Coffee Extract

Green Coffee

Recent data link increasing consumption of coffee with decreased risk of depression (Lucas 2011). In fact, this relationship proved to be dose-dependent, meaning that the more coffee study participants drank, the less likely depression would strike them. These findings are corroborated by a similar study conducted in 2010, which supports the link between increasing coffee consumption and decreased depression risk (Ruusunen 2010). Interestingly, this last trial was unable to link caffeine with depression risk, suggesting that other compounds in coffee may be responsible for the mood-elevating effect.

Conventional coffee preparation, which involves roasting the green coffee beans at high temperatures to attain the desired flavor profile, dramatically lowers levels of health-promoting coffee constituents called chlorogenic acids.

Chlorogenic acids have been shown in several studies to aid in controlling blood sugar levels; especially those glucose spikes which occur after a high-carbohydrate meal (Tunnicliffe 2011; Zhang 2011). In a 12-week study, consumption of chlorogenic acid-fortified instant coffee led to a considerable reduction in the absorption of glucose when compared to regular instant coffee (Thom 2007). As elevated glucose levels are common among depressives, chlorogenic acids may help combat some symptoms of depression tied to insulin resistance and irregularities in glucose metabolism.

Green coffee, the primary source of chlorogenic acids, cannot be consumed as a beverage due to its extremely bitter taste. Consuming a green coffee extract standardized to chlorogenic acids is an effective means of obtaining biologically active concentrations of chlorogenic acids.

The potential role of chlorogenic acids in mediating the mood boost associated with coffee consumption, and their thoroughly studied antihyperglycemic properties give rise to promising multimodal depression protection.


Chromium has been studied for its role in regulating blood sugar by facilitating the uptake of glucose into cells, and some research indicates that it may be beneficial in depression as well (McCarty 1994).

In one case series of five patients with minor depression, chromium supplementation led to remission (MacLeod 1999). Two other pilot studies found chromium picolinate supplementation benefited atypical depression (Davidson et al 2003; Docherty et al 2005). Finally, although not studied for seasonal depression, chromium may help regulate blood sugar and cravings for sugar and carbohydrates in relation to seasonal depression.

Antioxidant Effects: N-Acetyl-cysteine, Lipoic acid, vitamins C and E, and Selenium

One of the best-researched antioxidants for depression is N-acetyl cysteine (NAC). NAC is a precursor to glutathione, one of the body's most powerful antioxidants. Research has found glutathione depletion and oxidative stress in people with bipolar depression. Two recent studies showed NAC is a safe and effective adjunctive treatment that improves depression in patients with bipolar disorder (Berk 2011).

Although lipoic acid has not been well studied for depression, it is one of the most effective supplemental antioxidants, since it helps recycle other antioxidants, such as vitamin C (May 2010). It also may benefit blood sugar regulation and neurological function, as evidence shows it can help diabetic neuropathy (Jin et al 2007).

In general, antioxidants may help buffer nerve cell damage in cases of chronic or recurrent depression, although they also serve other roles in brain health. For example, the antioxidant vitamin C is an important cofactor in the synthesis of serotonin, norepinephrine, and adrenal hormones that mediate stress. Vitamin E helps protect nerve cell membranes, and low selenium levels are associated with depression (Hawkes WC, Hornbostel L 1996).

Additional nutrients:


Curcumin is a phytoceutical derived from turmeric, a spice used often in preparation of Indian cuisine. It belongs to a class of compounds called polyphenols, which have been extensively studied and shown to exert an array of health benefits. One of the most intriguing properties of polyphenols, and curcumin in particular, is the ability to positively influence mood (Pathak 2013). Indeed, mounting evidence suggests curcumin might represent an important novel modality for the treatment of depression (Lopresti 2012).

Curcumin appears to modulate several aspects of neurobiology involved in mood and behavior. Experimental evidence from an animal model of depression suggests curcumin can preserve levels of a protein important for healthy neuronal function (brain-derived neurotrophic factor [BDNF]) in a region of the brain called the amygdala, which is involved in mood regulation (Zhang 2014). Curcumin appears to manipulate neurotransmitter signaling as well. In another animal model, mice with neuropathy (who are prone to depression) were treated for 3 weeks with 45 mg/kg of curcumin twice daily (about 583 mg daily for an 80 kg adult human). While these mice normally exhibit depressive-like symptoms, curcumin treatment ameliorated this behavior. Interestingly, the researchers found that curcumin may have eased the rodent’s depression by altering serotonin and gamma-aminobutyric acid (GABA) signaling in their central nervous systems (Zhao 2013). Curcumin also helps relieve pain, which may be helpful for some individuals with depression because pain, especially of chronic nature, is closely – and potentially causally – associated with depression (Finan 2013; Ong 2003; Zhao 2013; Arora 2011). Other studies show that curcumin’s powerful anti-inflammatory properties may also underlie its ability to elevate mood. In an experiment in which rats were exposed to chronic stress for 21 days to induce depressive-like behavior, curcumin administration was shown to significantly reduce signs of depression. This study also showed that curcumin considerably eased inflammation by suppressing activation of nuclear factor-kappaB (NF-?B), a master regulator of inflammation; the researchers concluded that curcumin’s antidepressant effects were due in part to its anti-inflammatory action (Jiang 2013).

Evidence for a potent antidepressant effect of curcumin among animals has been partially confirmed in at least one human study. In a randomized, double-blind, placebo-controlled trial, 40 people with new-onset depression were treated with antidepressants (escitalopram [Lexapro®] or venlafaxine [Effexor®]) together with either curcumin (500 mg per day) or placebo for 5 weeks. Researchers then tracked subjects’ depression severity using several standardized assessments. Although subjects in both groups experienced comparable relief of their depression, those who received curcumin tended to achieve faster relief than those who received a placebo (Bergman 2013).

A plethora of animal data indicate curcumin may be a powerful tool in the treatment of depression, and, as of the time of this writing, additional human studies are ongoing to assess its effects on mood (SHSC 2014). Lastly – and perhaps most importantly – curcumin, unlike conventional antidepressant medications, has an excellent safety and side-effect profile (Gupta 2013; Noorafshan 2013; Whiskey 2013; Henry 2012; Asher 2013).

St. John's Wort

St. John's wort (Hypericum perforatum) is a medicinal herb used to treat neurological and psychiatric disorders, including depression (Nangia M et al 2000). Compared to a placebo, H. perforatum extract is more effective at targeting mild to moderate depression, and reducing symptoms and recurrence rate (Lecrubier Y et al 2002). Its effectiveness is considered comparable to antidepressant medications, but its actions are more complex (Schrader E et al 2000; Szegedi A et al 2005).

St. John's wort's mechanism of action on depression is not entirely understood, even though it is one of the most researched herbs for depression. St. John's wort has been shown to inhibit serotonin and norephinephrine reuptake, thus increasing their availability at the synapse (Nangia M et al 2000). Other investigators found it influences dopamine and GABA activity. Its antidepressant qualities also can be linked to its antioxidant and anti-inflammatory properties that normalize an overactive hypothalamus-pituitary-adrenal axis and stress response (Butterweck 2003).

While additional research is on-going to identify all of the anti-depressant mechanisms of action, experimental models and clinical trials alike have shown that treatment with St. John's wort delivers positive response rates for mild to moderate depression (Can 2011; Kim 1999; Linde 1996).

Unfortunately, potential side effects associated with St. John's Wort deprive many depressives of its benefits.

Vitamin D

Growing evidence suggests that vitamin D significantly affects depression. This is not surprising in seasonal depression, since the skin synthesizes vitamin D in response to sunlight, which is less available in the winter (Namri et al 2009; Shipowick 2009). However, vitamin D has been found to play other roles in depression. For example, in a study of 7,358 patients age 50 and over with a cardiovascular diagnosis and no a history of depression, low vitamin D levels significantly increased the risk of developing depression (May et al 2010).

Studies also find that vitamin D3 (cholecalciferol) supplementation can improve symptoms of depression. One well-controlled study of 441 overweight and obese participants showed an association between low vitamin D levels and depression. High dose vitamin D supplementation (20,000–40,000 IUs per week or 2,800–6,000 IUs per day) for one year improved mood (Jorde 2008). Another pilot study noted significant improvement in depression in six of nine women with low levels of vitamin D upon supplementation (Shipowick 2009).

Vitamin D's effectiveness may be related to the high prevalence of vitamin-D deficiency in the general population, its importance in blood-sugar regulation, and its importance in overall regulation of genetic activity.


Zinc is a trace element known to help regulate the nervous system (Nowak G 2002) and may be specifically related to depression (Levenson 2006). Increasing evidence shows that decreased blood levels of zinc are associated with depression (Maes M et al 1994, 1997; McLoughlin 1990), and, in depressed subjects, lower levels of zinc are associated with worse depression (Nowak et al 1999). One pilot study of 20 depressed patients also showed that 25 mg a day of zinc augmented benefits of antidepressant medication (Nowak et al 2003).

Animal studies show that antidepressants and electroconvulsive shock treatments change zinc concentrations in areas of the brain associated with depression (Nowak G et al 1999). In further animal research, zinc also was shown to enhance antidepressant effects of imipramine (Kroczka B 2001) and influence serotonin levels and activity in several brain regions (Sairanen 2005).


Inositol levels in the brain and cerebrospinal fluid were found to be lower in subjects with depression. One well-controlled trial showed that taking 12 grams a day of inositol helped relieve symptoms in 39 patients with depression (Levine 1995).

Further research on bipolar depression suggests beneficial influences of inositol (Chengappa 2000). A well-controlled but small trial of 17 participants with bipolar depression showed varied responses. Four of nine patients experienced significant improvement with inositol supplementation compared to zero of eight who took a placebo (Evins 2006).

Inositol, a second-messenger precursor, has important cellular communication functions in the nervous system. Interestingly, inositol is also involved with insulin signaling and function. It therefore may have more of an effect on overweight or obese individuals, as well as those who are insulin resistant, such as those with metabolic syndrome or women with polycystic ovarian syndrome (PCOS). These findings require further research and replication.


Emerging research has revealed an important relationship between the gastrointestinal tract and its billions of resident organisms—often referred to as the microbiome—and the brain. This has been termed the “gut-microbiota-brain axis” (Petra 2015; Foster 2015; Forsythe 2010; Forsythe 2013; Dinan 2012; Cryan 2012). Probiotics are organisms which, when consumed in adequate doses, exert a beneficial effect on health (Sanders 2008). Probiotics, which are able to modulate the gut-brain axis, have been shown in preclinical and clinical trials to ameliorate behaviors and symptoms of stress, anxiety, and depression (Bravo 2011; Gareau 2007; Messaoudi, Lalonde 2011).

Lactobacillus helveticus (L. helveticus) R0052 has been researched, in combination with another proprietary probiotic strain, Bifidobacterium longum (B. longum) R0175, as a probiotic for psychological health (Arseneault-Breard 2012; Messaoudi, Violle 2011; Messaoudi, Lalonde 2011). Rats given a daily dose of a combination of L. helveticus R0052 and B. longum R0175 for two weeks had markedly reduced signs of anxiety compared to those treated with a placebo. In fact, the probiotics reduced anxious behaviors to a similar degree as diazepam (Valium), the prescription anti-anxiety medication (Messaoudi, Lalonde 2011; Calcaterra 2014).

In a double-blind randomized clinical trial, 55 healthy volunteers took a supplement containing three billion colony-forming units (CFUs) of the combination of L. helveticus R0052 and B. longum R0175, or placebo, for 30 days. The probiotic treated group had significantly lower scores on anxiety, anger, and depression symptom scales, with particular improvement in symptoms of depression (Messaoudi, Lalonde 2011). Among a subset of 25 participants considered to have low levels of chronic stress based on low urinary cortisol levels, the combination of L. helveticus R0052 and B. longum R0175 appeared to act as a preventive, suggesting it may be able to protect against stress-related diseases (Messaoudi, Violle 2011).



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Depression is a multifactorial condition, and efficient relief often requires addressing multiple neurochemical and metabolic imbalances that may underlie mood disturbances. The nutrients listed in this protocol are categorized according to their evidence-based mechanisms of action in brain health and mood regulation.

Many of these suggestions may serve as adjuvants to conventional therapies for depression. Always consult a qualified healthcare professional before combining any supplements with an antidepressant medication.

Broad-Range Nervous System Effects

Supporting Neurotransmitter Synthesis

Supporting Methylation Reactions

Supporting Blood Sugar Regulation

Antioxidant Effects

Supporting Mitochondrial Health

Hormone Restoration

Men and women with depression should consider restoring their hormone concentrations to youthful levels with the use of natural bioidentical hormones. More information is available in the Male Hormone Restoration and Female Hormone Restoration protocols. A natural, over-the-counter hormone men and women should consider optimizing is:

  • DHEA: 15 – 50 mg daily for women or 25 – 75 mg daily for men

In addition, thyroid hormone irregularities may contribute to depression. Therefore, those with known or suspected thyroid dysfunction should refer to the Thyroid Regulation protocol.

Miscellaneous Mechanisms of Relief

In addition, the following blood testing resources may be helpful:

These statements have not been evaluated by the Food and Drug Administration. These products are not intended to diagnose, treat, cure or prevent any disease.

The information provided on this site is for informational purposes only and is not intended as a substitute for advice from your physician or other health care professional or any information contained on or in any product label or packaging. You should not use the information on this site for diagnosis or treatment of any health problem or for prescription of any medication or other treatment. You should consult with a healthcare professional before starting any diet, exercise or supplementation program, before taking any medication, or if you have or suspect you might have a health problem. You should not stop taking any medication without first consulting your physician.

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