What are Depression and Depressive Disorders?

Depression is a mood state characterized by low mood and a loss of interest in previously pleasurable activities. If a depressed mood is persistent and severe enough to interfere with normal day-to-day function, it may meet the criteria for diagnosis as a depressive disorder.

Major depressive disorder, or major depression, is the main type of depressive disorder. When episodes of major depression are chronic and recurring, the condition is called persistent depressive disorder. Other types of depressive disorders include premenstrual depressive disorder, substance- or medication-induced depressive disorder, and depressive disorder due to another medical condition.

It has long been thought depression results from a neurotransmitter imbalance, but more recent evidence suggests underlying causes such as chronic low-level inflammation, dysregulation of the stress response, altered brain cell function, and imbalance in the gut microbiome are important contributors. Some natural interventions such as omage-3 fatty acids, saffron extract, acetyl-L-carnitine, and probiotics have been shown to target these underlying mechanisms, supporting healthy brain function and mood.

What are the Risk Factors for Depressive Disorders?

• Gender — women are about twice as likely to experience depression as men
• Age — adolescents and young adults are more likely to develop depression than older adults, and the risk is especially high in gender- and sexual-minority, racial- and ethnic-minority, and economically disadvantaged youth
• Family history of depression — the risk of major depression is three times greater among those who have a first-degree relative with major depression
• Maltreatment during childhood, including neglect and abuse
• Adverse life events, such as unemployment, financial hardship, divorce, grief and loss, and catastrophic world events such as natural disasters
• Chronic or severe stress
• Loneliness
• Certain personality traits, including shyness, agreeableness, and moodiness
• Sleep disorders, including sleep apnea
• Other psychiatric disorders, such as substance use disorders, anxiety disorders, and post-traumatic stress disorder (PTSD)

Depression frequently co-occurs with chronic diseases: stroke survivors and people with chronic diseases like heart disease, cancer, diabetes, and respiratory disease are up to four times more likely than others to have depression, and the co-occurrence of depression worsens their prognosis.

What are the Signs and Symptoms of Major Depressive Disorder?

• Persistent depressed mood
• Loss of interest and pleasure
• Change in appetite or body weight
• Over- or under-sleeping
• Slowness or agitation
• Fatigue
• Inability to concentrate or make decisions
• Thoughts of death or suicide

What are Conventional Medical Treatments for Depressive Disorders?

• Cognitive behavioral therapy
• Drug therapy
  • First-line antidepressants:
    • selective serotonin reuptake inhibitors (SSRIs)
      • eg, fluoxetine (Prozac) and citalopram (Celexa),
    • serotonin-norepinephrine reuptake inhibitors (SNRIs)
      • eg, duloxetine (Cymbalta) and venlafaxine (Effexor), and
    • atypical antidepressants
      • eg, bupropion (Wellbutrin) and mirtazapine (Remeron)
  • Second-line antidepressants, including:
    • tricyclic antidepressants
      • eg, amitriptyline (Elavil) and clomipramine (Anafranil)
    • monoamine oxidase inhibitors (MAOIs)
      • eg, tranylcypromine (Parnate) and phenelzine (Nardil)
    • Atypical antipsychotics:
      • eg, aripiprazole (Abilify) and quetiapine (Seroquel)
• Neurostimulation techniques
  • Electroconvulsive therapy
  • Vagus nerve stimulation
  • Repetitive transcranial magnetic stimulation
  • Ablative neurosurgery

What are Some Emerging Treatments for Depressive Disorders?

• Agomelatine, a synthetic version of melatonin
• Ketamine (Ketalar, an intravenous medication) and esketamine (Spravato, an intranasal derivative of ketamine approved for use in treatment-resistant depression)
• Investigational neurostimulation techniques
• Transcutaneous auricular vagus nerve stimulation
• Magnetic seizure therapy
• Transcranial electrical stimulation
• Deep brain stimulation

What Dietary and Lifestyle Changes May Be Beneficial for Depressive Disorders?

• Eat a healthy, well-balanced, anti-inflammatory diet (eg, Mediterranean-style diet)
• Get regular exercise — consider a structured program to keep you motivated
• Get enough sleep
• Meditation techniques, including mindfulness meditation

What Natural Interventions May Be Beneficial for Depressive Disorders?

• Omega-3 fatty acids. The omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) reduce inflammation, promote healthy nerve function, and have been shown to reduce symptoms of depression.
• Vitamin D. Vitamin D deficiency has been linked to depression, and supplements have been found to have a positive impact on depression symptoms.
• Probiotics. Certain probiotic strains have been shown to improve mood in those with depression.
• Zinc. Low zinc levels have been correlated with depression, and zinc supplements have been shown to reduce symptoms of depression when used alone or with antidepressants.
• Saffron. Saffron extract has been found to reduce depressive symptoms in those with other health problems and improve the effectiveness of antidepressants.
• St. John’s wort. Multiple clinical trials have shown St. John’s wort can reduce symptoms of depression.
• Acetyl-L-carnitine. Acetyl-L-carnitine promotes healthy brain cell function and has been found to reduce depression symptoms.
• Dehydroepiandrosterone (DHEA). DHEA contributes to mood modulation, is neuroprotective, has anti-stress activity, and has been reported to reduce depressive symptoms.
• B complex vitamins. Clinical trials have shown supplementing with B vitamins can lower levels of perceived stress, improve mood, and reduce depressive symptoms.
• L-tryptophan and 5-hydroxytryptophan (5-HTP). L-tryptophan has been found to reduce depression symptoms and 5-HTP, a byproduct of tryptophan metabolism, may improve the effectiveness of antidepressants.
• Other natural interventions such as N-acteylcysteine, rhodiola, lemon balm, lavender, and SAMe may help reduce symptoms of depression.

“Depression” is an amorphous term often applied to a spectrum of mental health conditions ranging in severity from mild to very severe and debilitating. Depression may refer to a normal mood state or a manifestation of a pathological psychiatric condition. When depressive symptoms fit certain criteria, they may be classified as distinct conditions such as major depressive disorder or persistent depressive disorder. While most people experience depressed mood from time to time, depressive disorders are generally distinguished by their severity and persistence.^1-3

Depressive disorders are among the most common mental health conditions in the United States.⁴ Depression has been ranked among the leading causes of disease burden worldwide by the World Health Organization (WHO).^5-7 In the United States, more than one in five adults experience a major depressive disorder at some point in their lifetime.⁴ Despite its high prevalence, depression often goes undiagnosed and untreated.^8,9

Depression is associated with a wide range of other chronic conditions and often co-occurs with cancer, stroke, heart disease, diabetes, chronic obstructive pulmonary disease, multiple sclerosis, chronic pain, and many other medical ailments.^10,11 In addition, patients with depression commonly experience other psychiatric conditions such as anxiety.¹² The overlap between depression and other health conditions can make it difficult to identify a primary diagnosis and initiate the appropriate treatment.^10,11,13 Although medical and psychotherapeutic interventions are available, approximately one-third of depression patients fail to respond to conventional treatments.¹⁴

In this protocol, you will learn about the different types of depression and the underlying causes of depressive disorders and why they are often so challenging to successfully treat. You will also learn about the important role of diet and lifestyle strategies in a comprehensive treatment approach, as well as many integrative therapies that have demonstrated similar efficacy to antidepressant medications. These include probiotics, herbal supplements like saffron and St. John’s wort, and nutritional supplements like omega-3 fatty acids, vitamin D, and zinc.

Most people experience depressed moods from time to time, usually in response to disappointments, losses, or other negative life events. A depressed mood generally comes in waves that tend to be associated with thoughts or reminders of triggering life events, pass when the situation improves, and may be interrupted by periods of positivity and humor.¹⁵ In depressive disorders, dark moods are more severe and may even include thoughts of suicide, are often unrelated to immediate circumstances, are persistent or recur in episodes lasting weeks to months or longer, and are associated with diminished ability to function in multiple realms of life, including work, school, and relationships.⁸ Throughout this protocol, the term “depression” will be used to indicate clinical depressive disorders rather than transient depressed moods.

Depressive disorders are defined by the Diagnostic and Statistical Manual of Mental Disorders, fifth edition, or DSM-5, published by the American Psychiatric Association. The main types of depression delineated in DSM-5 include those listed below, although there are several subtypes and qualifiers with some of these conditions³:

• Major depressive disorder
• Persistent depressive disorder (dysthymia)
• Premenstrual dysphoric disorder
• Substance/medication-induced depressive disorder
• Depressive disorder due to another condition
• Disruptive mood dysregulation disorder (a childhood disorder, not covered extensively in this protocol)

Major Depressive Disorder

Major depressive disorder (also called major depression or clinical depression) is characterized by one or more episodes lasting at least two weeks in which depressed mood is experienced most of the day nearly every day. A loss of interest and ability to experience pleasure is a key feature of major depression. Major depression interferes with the ability to function in day-to-day life, and often affects self-care. Other possible symptoms include an increase or decrease in appetite and body weight; increase or decrease in sleep; mental and physical agitation; fatigue; feelings of guilt or worthlessness; and inability to think clearly, concentrate, or make decisions. Many people with major depressive disorder have recurring thoughts of suicide, may have a suicide plan, or may have attempted suicide.^5,8,15

In order to be diagnosed with major depressive disorder, a patient must exhibit at least five of the aforementioned symptoms, and one must be persistent depressed mood or loss of interest and pleasure.⁵ Episodes of major depressive disorder may be categorized as mild, moderate, or severe, depending on degree of disability and duration of symptoms.⁸

Major depression is more likely to occur in women than men. People in their mid-teens, 20s, and 30s are more susceptible than those in other age groups. Approximately 40% of individuals with major depressive disorder have their first episode before age 20 and many depression patients experience recurrent episodes throughout their life.^5,15

Persistent Depressive Disorder

Persistent depressive disorder (aka dysthymia) is a chronic form of depression diagnosed when episodes of major depression occur over a period of at least two years, with intervals of remission lasting no longer than two months. The number and severity of symptoms and degree of functional impairment may fluctuate. In addition to depressed mood most of the time on most days, patients with persistent depressive disorder exhibit at least two of the following symptoms: changes in appetite, body weight, and sleep; fatigue or lack of energy; low self-esteem; difficulty concentrating and making decisions; and feelings of hopelessness.^5,15

Premenstrual Dysphoric Disorder

Premenstrual dysphoric disorder is a form of depression that occurs in synchrony with the menstrual cycle. Women with this disorder have depressive symptoms severe enough to cause distress and limit functioning during a part of most of their cycles, beginning sometime after ovulation, easing within a few days of the onset of menses, and subsiding completely or near-completely in the week following menstruation. Premenstrual dysphoric disorder is marked by mood swings, irritability or anger, feelings of hopelessness or dislike for oneself, and anxiety or tension, as well as other typical depressive symptoms such as low interest in usual activities, difficulty concentrating, low energy level, changes in appetite and sleep habits, and a sense of being overwhelmed. In addition, physical symptoms like bloating, breast swelling or tenderness, muscle and joint pain, and weight gain may accompany mood symptoms.^15,16

Substance- or Medication-induced Depressive Disorder

Substance- or medication-induced depressive disorder is characterized by the same symptoms as major depression, but the onset correlates with beginning, or withdrawing from, a medication or substance that can cause depression. Some substances and medications that can trigger depression during their use or withdrawal include alcohol, psychedelics such as phencyclidine (PCP), opioids, sedatives and insomnia drugs, anti-anxiety medications, and stimulants like amphetamines and cocaine.¹⁶

Depressive Disorder Due to Another Medical Condition

Depression can result from the physiologic effects of certain medical conditions. It can be very challenging to distinguish a condition-related depression from major depression, since depression is both a common symptom and contributing factor in numerous physical illnesses.¹⁰ Some conditions known to cause depression include hypothyroidism, stroke, traumatic brain injury, Parkinson disease, and Huntington disease.¹⁶ The relationship between other chronic diseases and depression is often more complicated, but it is important to note that depression frequently co-occurs with conditions such as heart disease, diabetes, respiratory diseases, cancer, and dementia.^10,17

Other Depressive Disorders

This diagnostic category refers to people who have never met the diagnostic criteria for major depressive disorder yet experience debilitating depressive episodes that include fewer than five symptoms or remit in less than two weeks. In particular, people experiencing disabling depressed mood and at least one other depressive symptom for two weeks or longer can be diagnosed with having a “depressive episode with insufficient symptoms,” which is sometimes referred to as subthreshold depression.^5,15,16 Recognizing subthreshold depression is important because of its high prevalence, possible prodromal relationship with major depression, and substantial negative impact on function, health, and mortality, especially in the elderly.¹⁸

Depression is approximately twice as common in women than men; in general, adolescents and young adults have a higher chance of developing major depression than older adults.⁸ In the United States, Native American and white adults are more likely to have major depression than Hispanic, African-American, and Asian adults, and those with lower incomes are at greater risk than those with higher incomes.⁴ In adolescents, the risk of depression is higher among sexual minorities (gay, lesbian, bisexual, transgender), racial and ethnic minorities, and economically disadvantaged youth.¹⁹ In addition, the following risk factors for major depression have been identified:

• Family history of depression
  • Risk of major depression is three times greater among people who have a first-degree relative with major depression⁵
• Maltreatment during childhood, including neglect and abuse^20,21
• Adverse life events, such as unemployment, financial hardship, divorce, grief and loss, and catastrophic world events such as natural disasters⁸
• Chronic or severe stress²²
• Loneliness²³
• Certain personality traits, including shyness and introversion, agreeableness, and neuroticism (moodiness with a tendency to feel emotions such as worry, fear, anger, frustration, envy, guilt, loneliness, and depressed mood)²⁰
• Sleep disorders²⁴
• Other psychiatric disorders, such as substance use disorders, anxiety disorders, and post-traumatic stress disorder (PTSD)⁴

Depression is a complex disorder with numerous contributing and proposed causes. Genetic factors, including those affecting neurotransmitter metabolism and receptor expression and function, are moderately heritable (up to 45%) and may account for some of the risk. Interestingly, genetics appear to have a stronger influence on depression risk in women than men.²⁰ Environmental and experiential circumstances, including during childhood, also contribute significantly to depression susceptibility; depression risk correlates with factors such as traumatic life events, physical illness, and chronic stress.^491,492

The exact ways that genetics and the environment interact and contribute to depression is a topic of ongoing research. It is likely that there are multiple complex interactions between a variety of mechanisms, including those described below.

Neurotransmitter Imbalance (The Monoamine Hypothesis)

The monoamine hypothesis of depression originated with research in the 1950s that found that an MAO-inhibiting drug had beneficial effects on mood in depressed tuberculosis patients. This marked the beginning of the modern field of psychopharmacology.⁴⁹³

According to the monoamine hypothesis, there is depletion of, or decreased signaling by, monoamine neurotransmitters (serotonin, norepinephrine, and dopamine) in depressed patients.⁴⁹⁴ This is thought to affect nerve activation in regions of the brain involved in emotional processing, memory, learning, and motivation, resulting in depressed mood and diminished cognitive function.³⁵ In practice, in the context of depression, the monoamine hypothesis is primarily a “serotonin hypothesis” since it is to this neurotransmitter that depression and its symptoms are most commonly attributed. Additionally, most antidepressant medication prescriptions are for selective serotonin reuptake inhibitors (SSRIs).^495-497

However, even after decades of neuropsychiatric research, the monoamine hypothesis of depression remains supported only by an inconsistent and increasingly tenuous evidence base.^{36,495,496,498} Nevertheless, much of the general public and even clinicians remain convinced that antidepressant medications are effective for depression and that they work by correcting neurotransmitter imbalances.^126,496

Multiple practical problems plague the monoamine-centric paradigm of depression. An oft-highlighted conceptual challenge is that while SSRI medications rapidly and reliably elevate synaptic levels of serotonin, therapeutic effects are only observed after a period of two or more weeks, suggesting that monoamines are not by themselves causative.³⁶ Furthermore, response to antidepressant treatment is unpredictable, and the majority of patients experience only a partial response.^499,500 In fact, multiple analyses of trial data have established that the benefits derived from antidepressants are not clinically meaningful when compared with placebo.^126,143,501 These are just a few of the many difficulties presented by the existing evidence base for antidepressants. All of this information should be considered in the context of the adverse effect profile of these medications, which ranges from inconvenient to potentially fatal.¹⁴⁴

Interestingly, antidepressants have been shown to shift negative emotional processing towards positive emotional processing, but in a way that is imperceptible to the patient. These cognitive effects precede effects on mood itself. This discovery opens a new avenue of inquiry into the potential usefulness of antidepressants.^495,502

Nevertheless, the most common medications for clinical depression target the monoaminergic systems. The three primary monoamine neurotransmitters and their proposed connections with depression are reviewed briefly below.

Serotonin. Serotonin signaling occurs in much of the nervous system and brain and is concentrated in the limbic system, a network of brain structures involved in processing emotions and memories as well as generating sensations of pleasure that reinforce behaviors.³⁷ In addition, serotonin participates in cognition and regulation of appetite, sleep, and temperature.³⁸ Low serotonin levels, low brain responsiveness to serotonin, and abnormal serotonin metabolism in individuals with depression have been reported.^20,39 Selective serotonin reuptake inhibitors (SSRIs), which enhance serotonin signaling, are widely used in first-line treatment of depression.²⁰

Norepinephrine. Norepinephrine, the main neurotransmitter of the sympathetic nervous system, increases nerve excitability generally and activates the stress response.^40,41 Like serotonin, norepinephrine is involved in many brain functions including attention, learning, memory, mood, sleep, and appetite.^20,42 Antidepressant medications that increase norepinephrine levels, called serotonin-norepinephrine reuptake inhibitors (SNRIs), are also used in first-line treatment of depression.²⁰ It is well known that acute stress increases norepinephrine signaling, but chronic stress and stress-induced depression are associated with damage to neurons that produce norepinephrine and changes in norepinephrine receptor function in key regions of the brain. SNRI medications may work by restoring normal norepinephrine levels and balancing norepinephrine receptor function.^20,41

Dopamine. Dysregulation of dopamine signaling may play an important though less-recognized role in depression. Dopamine participates in learning and memory, and mediates feelings of pleasure and motivation.⁴³ Deficits in dopamine signaling in specific brain regions may be associated with depression and are thought to contribute particularly to the loss of interest, pleasure, and motivation that are hallmark symptoms of depression.⁴⁴ Older antidepressants called monoamine oxidase inhibitors (MAOIs) increase dopamine levels, as well as levels of serotonin and norepinephrine, by blocking their breakdown.⁴³

Stress

Stressful events and high levels of perceived stress often precipitate depressive episodes. Many people with depression, especially those who have experienced early childhood stress, have been found to have increased signaling along the hypothalamic-pituitary-adrenal (HPA) axis.⁴⁵ The HPA axis regulates the output of the stress hormone cortisol, and in the sympathetic nervous system, initiates the acute “fight-or-flight” stress response. The HPA axis and sympathetic nervous system are closely interconnected and together manage the body’s reactivity to stressful stimuli. Hyper-responsiveness to stress appears to be an important underlying factor in the development of depression, as well as the connections between depression and chronic metabolic problems such as cardiovascular disease, type 2 diabetes, metabolic syndrome, and cognitive impairment.^46,47

Inflammation

Depression is correlated with a number of inflammatory diseases, including chronic viral and bacterial infections, allergies and asthma, autoimmune conditions, neurological and cardiovascular diseases, obesity, and diabetes.²² It is estimated that 30–50% of people with depression exhibit an increased inflammatory tendency.⁴⁸ These individuals have been found to have higher levels of immune cells and immune activation, C-reactive protein, and inflammatory cytokines such as interleukin-2 (IL-2) and IL-6, and generally have more severe depression than those without increased markers of inflammation.^49,50 Some evidence suggests antidepressant medications may have anti-inflammatory effects that contribute to their therapeutic benefits, and anti-inflammatory medications are currently being explored for their potential to improve the effectiveness of antidepressant therapy (see section titled “Novel and Emerging Therapies”).⁵¹

Inflammation causes increased production of cell-damaging free radicals, which can disrupt the synthesis of monoamine neurotransmitters by oxidizing tetrahydrobiopterin, a common cofactor needed for their synthesis.⁵² Inflammation also activates enzyme pathways that increase production of neurotoxins, alters signaling along neural networks by increasing glutamate release in the brain, and may contribute to decreased neuronal growth and plasticity by reducing production of a growth factor called brain-derived neurotrophic factor (BDNF).^52,53 Furthermore, evidence suggests stress-induced inflammation may exacerbate neuroinflammation by compromising the integrity of the blood-brain barrier, which selectively controls the microenvironment of the brain.⁴⁸

While stress is a known trigger of inflammatory signaling, inflammatory cytokines in turn activate the stress response, and a heightened inflammatory response to stressful circumstances has been noted in both individuals with depression and those at high risk of depression. The integration of stress and immune function is thought to have evolved as a mechanism to help injured and infected organisms avoid or escape danger.⁵⁴ Depressive behaviors induced by inflammation may even have served important functions, such as allowing energy to be conserved and redirected toward fighting infection and healing wounds, avoiding psychological or emotional re-injury, and soliciting help from others. ^46,54 However, in the context of modern life, these adaptive strategies have become problematic, with rampant immune dysregulation and long-term psychosocial stress inducing an unabating depressed state that itself contributes to chronic illness and death.⁵⁴

Impaired Neuroplasticity and Neurogenesis

The formation of new nerve cells from stem cells in the brain (neurogenesis) and the ability of neurons to grow and form new connections (neuroplasticity) may be diminished in individuals with depression. Neurogenesis and neuroplasticity are regulated by growth factors, including BDNF.^55,56 BDNF levels are lower and epigenetic changes related to the BDNF gene have been noted in people with depression.³⁶ Suppressed levels of monoamines, neuroinflammation, and stress may all contribute to diminished levels of BDNF and reduced neurogenesis and neuroplasticity.^5,36,52,56 Evidence suggests medical and psychotherapeutic treatment of depression, when effective, increase BDNF levels and result in greater neuroplasticity and neurogenesis.^5,35,36 In addition, exercise has been shown in multiple studies to raise plasma BDNF levels, and accumulating evidence indicates signaling molecules released by muscles during exercise cross the blood-brain barrier and promote its production in the brain.^57-59

Brain Atrophy

Patients with depression have consistently been found to have substantial reductions in volumes of the hippocampus (part of the limbic system) and medial prefrontal cortex regions of the brain, affecting both emotional regulation and cognition.^5,35,60 This appears to be due not only to decreased density of neurons, but also diminished numbers of glial cells, a type of brain cell that provides structural, metabolic, and functional support to neurons.³⁵ The degree of atrophy in these brain regions reflects the duration and severity of depression, and impacts neural networks responsible for such basic brain functions as introspection and rumination, discriminating salient from background stimulation, attention, and working memory (short-term memory related to immediate activities).⁶¹ High levels of the stress hormone cortisol, brain oxidative stress, neuroinflammation, and low levels of neurotransmitters may contribute to neuron and glial cell death, and ultimately, brain atrophy.^22,36,60,62

Microbiome Dysbiosis

The bidirectional communication network between microorganisms (or microbes) of the digestive tract and the brain is the basis of the concept of the microbiota-gut-brain axis.^63,64 Intestinal microbes, especially bacteria, produce signaling molecules that support digestion, preserve gut barrier function, regulate immune function and the inflammatory response, and modulate metabolism.⁶⁵ In the brain, the microbiome appears to affect mood and cognition through complex signaling that alters neurotransmitter release and function, levels and activity of BDNF, circadian systems, and activation of the stress response.^63,66 Gut microbial imbalance may contribute to depression by dysregulating circadian control and the HPA axis, increasing neuroinflammation, altering neurotransmitter signaling, and reducing neuroplasticity and neurogenesis.^63,66,67

Patients with depression have been found to have lower numbers and diversity in their gut microbiota compared with healthy controls.⁶⁷ This may be significant because diversity and abundance are key characteristics of a healthy microbiome.⁶⁵ Not only does a compromised microbiome likely contribute to poor mental health, it is also clear that stress, anxiety, and depression can have negative impacts on the microbiome.⁶⁵ Therapies for depression that target the microbiome, such as dietary interventions, probiotic supplements, and fecal microbial transplant, have shown promise in preclinical and early clinical research.^64,67

It is estimated that nearly half of people with depression have at least one chronic non-psychiatric condition.⁶⁸ In addition, stroke survivors and people with chronic diseases, including heart disease, cancer, diabetes, and respiratory disease, are up to four times more likely to have depression compared to those without such conditions, and the co-occurrence of depression worsens their prognosis.^10,13,68 Many chronic diseases can cause symptoms that overlap with those of depression, blurring distinctions and complicating diagnosis and treatment.¹⁰ Underlying mechanisms that may link depression to other ailments include stress, systemic immune-inflammation dysregulation, and altered microbiome.^7,10,69,70

Individuals with mental health disorders such as anxiety disorders and schizophrenia have a higher risk of depression as well. Furthermore, depression worsens the prognosis for people with other psychiatric illnesses.⁷¹

The following are some of the many chronic non-psychiatric diseases that frequently co-occur with depression:

• Cardiovascular disease. Cardiovascular disease and depression are strongly linked, and their relationship appears to be bidirectional.⁷² It is estimated that major depression increases the risk of cardiovascular disease and death by about 80%.⁷³ The complex mechanisms linking depression to cardiovascular disease are likely to include genetic, biological, psychosocial, and behavioral factors, with stress playing a substantial role.^72,74
• Cerebrovascular disease. Post- stroke depression is a well-documented phenomenon and is associated with greater disability and increased likelihood of death.⁷⁵ Cognitive impairment and dementia are also closely linked to depression, possibly due to changes in brain structure and neuroplasticity.^17,76
• Diabetes and obesity. People with diabetes are about twice as likely to suffer from major depression as people without diabetes. In addition, up to 25% of diabetics suffer from depressive symptoms. Distress related to diabetes may contribute to high rates of depression; however, depression also increases the risk of diabetes, suggesting they are linked by underlying mechanisms.⁷⁷ This same type of bidirectional relationship exists between obesity and depression, and may reflect common mechanisms such as systemic inflammation and microbiome imbalance.⁷⁸
• Neurological disease. Chronic neurodegenerative conditions such as Parkinson disease, Huntington disease, and Alzheimer disease are highly correlated with depression. Findings such as neurotransmitter deficits, dysregulated HPA axis signaling, neuroinflammation and oxidative stress, and impaired glial cell function are shared mechanisms in these conditions.⁷⁹
• Digestive disorders. Chronic digestive problems have been associated with major depression. Irritable bowel syndrome, for example, is associated with a 2.7-fold increase in depressive disorders compared with healthy controls.⁸⁰ On the other hand, individuals who self-report having depression or anxiety are twice as likely to have irritable bowel syndrome as those reporting no mood problems.⁸¹ Chronic constipation, dyspepsia, and inflammatory bowel disease are also common in depressed patients.^82-84 Factors affecting gut-brain communication, such as serotonin signaling and the microbiome, are disturbed in digestive and mood disorders.^78,85
• Chronic pain. As many as 85% of people with chronic pain disorders, such as fibromyalgia and migraines, also suffer from depression.^86-88 Interestingly, individuals with depression also appear to have a greater likelihood of developing chronic pain syndromes, suggesting bi-directionality due to a common mechanism, possibly rooted in chronic or extreme stress and reduced neuroplasticity.^86,88
• Cancer. The prevalence of major depression is up to four times higher in cancer patients than the general population and is a predictor of worse outcomes. It is thought that psychological distress related to having cancer is an underlying factor.⁸⁹ In addition, having depression has been associated with greater risk of cancer.⁹⁰
• Allergic and autoimmune disease. Allergic conditions including asthma and atopic dermatitis and autoimmune diseases including multiple sclerosis, rheumatoid arthritis, and celiac disease have all been found to correlate with depression, which can complicate their course.^91-94
• Chronic fatigue. Chronic fatigue syndrome and major depression share many symptoms and often co-occur. It is thought stress and neuro-inflammatory pathways are mechanisms linking them.^95,96

Diagnosing major depressive disorder involves screening through careful history-taking to identify risk factors, ruling out other causes for depressive symptoms, and the use of diagnostic surveys.

Screening

The U.S. Preventive Services Task Force (USPSTF) and American Academy of Family Physicians recommend screening all adults for depression during routine health visits.¹⁰⁷ It is especially important for those at high risk of depression—those who have a prior depressive episode, family history of depression, recent major stressful event, one or more chronic medical conditions, cognitive impairment or dementia, or anxiety or substance abuse—to undergo a screening process with their healthcare provider.⁶⁸ In addition, because depression can manifest as physical symptoms, it is important to screen patients presenting to their healthcare provider with multiple physical complaints, vague complaints, or unexplained physical symptoms.⁶⁸

Screening questions and surveys can help distinguish ordinary variations in mood from major depressive disorder, which is severe or enduring enough to interfere with realms of life such as work, school, and relationships.¹⁵ When depression is suspected, it is critical to also evaluate the risk of suicide.¹⁵ The two-item and nine-item Patient Health Questionnaires (PHQ-2 and PHQ-9) are the most widely used screening tools. Some healthcare providers use PHQ-9 following a positive result on PHQ-2 before proceeding with the diagnostic process.¹⁰⁷

Table 1: PHQ-2 Depression Screening Tool

Over the past two weeks, how often have you been bothered by the following problems?	Not at all	Several days	More than half the days	Nearly every day
Little interest or pleasure in doing things	0	1	2	3
Feeling down, depressed, or hopeless	0	1	2	3

Scoring: a score of 3 or higher is considered a positive result and indicates the need for further evaluation.^68,107

Table 2: PHQ-9 Depression Screening Tool

Over the past two weeks, how often have you been bothered by the following problems?	Not at all	Several days	More than half the days	Nearly every day
Little interest or pleasure in doing things	0	1	2	3
Feeling down, depressed, or hopeless	0	1	2	3
Trouble falling or staying asleep, or sleeping too much	0	1	2	3
Feeling tired or having little energy	0	1	2	3
Poor appetite or overeating	0	1	2	3
Feeling bad about yourself, or that you are a failure or have let yourself or your family down	0	1	2	3
Trouble concentrating on things such as reading the newspaper or watching television	0	1	2	3
Moving or speaking so slowly that other people could have noticed, or the opposite: being so fidgety or restless that you have been moving around a lot more than usual	0	1	2	3
Thoughts that you would be better off dead, or hurting yourself in some way	0	1	2	3

Scoring: a score of 1–4 indicates minimal depression; 5–9 indicates mild depression; 10–14 indicates moderate
depression; 15–19 indicates moderately severe depression; 20–27 indicates severe depression.^68,107

Ruling Out Other Causes

Depressed mood is a common symptom in a broad array of medical conditions, including cardiovascular, neurological, hormonal, metabolic, infectious, autoimmune, and psychiatric ailments.^15,107 Substance abuse disorders may be particularly difficult to distinguish from depression, and the close relationship between anxiety and depression can make accurate diagnosis complicated.⁶⁸ Nutritional deficiencies, especially of B vitamins or iron, are also associated with depressive symptoms.¹⁰⁷

Although there are no blood tests for diagnosing depression, the following may help rule out other causes of depression:

• Complete blood count (CBC)¹⁵
• Ferritin¹⁰⁸
• Basic chemistry, including electrolytes, glucose, liver enzymes, blood urea nitrogen (BUN), and creatinine¹⁰⁷
• Vitamin B12 and folate¹⁵
• Homocysteine¹⁰⁹
• Thyroid stimulating hormone (TSH)¹⁵
• Testosterone in men¹⁵

Cortisol testing may be helpful in assessing stress-related depression. Cortisol levels in saliva, blood, urine, and hair have been shown to be reliable markers of adrenal cortisol output and may be useful in detecting dysfunctional HPA axis signaling.^45,110-112

Urine neurotransmitter tests are widely available and promoted as a method of assessing mood disorders and guiding treatment. Levels of neurotransmitters in urine reflect their levels in peripheral blood; however, it is not yet clear whether these levels are correlated with brain neurotransmitter levels or clinical disorders like depression.^113,114

It is important to note that certain medications may cause depressive symptoms, including some blood pressure lowering drugs, corticosteroids, and progesterone implants, as well as interferon alfa-2b (Intron-A, used to treat some viral infections and some cancers), montelukast (Singulair, an asthma medication), finasteride (Propecia or Proscar, used to treat non-cancerous prostate enlargement and male-pattern hair loss), isotretinoin (Accutane, used to treat severe acne), and varenicline (Chantix or Champix, used to assist in smoking cessation).^115,116 Drug-induced depression should be ruled out before diagnosing depression.

Diagnostic Criteria

According to the DSM-5, in order to be diagnosed with major depressive disorder, a patient must exhibit at least five of the following symptoms at the same time for two weeks or longer¹⁰⁷:

• Depressed mood most of the day, nearly every day, as indicated by either subjec­tive report (eg, feels sad, empty, hopeless) or observation made by others (eg, appears tearful). (Note: In children and adolescents, can be irritable mood.)
• Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either subjective account or observation).
• Significant weight loss when not dieting, or weight gain (eg, a change of more than 5% body weight in a month), or decrease or increase in appetite nearly every day. (Note: In children, consider failure to make expected weight gain.)
• Insomnia or hypersomnia (excessive sleeping) nearly every day.
• Mental or physical agitation or slowness nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down).
• Fatigue or loss of energy nearly every day.
• Feelings of worthlessness or excessive or inappropriate guilt (which may be delu­sional) nearly every day (not merely self-reproach or guilt about being sick).
• Diminished ability to think or concentrate, or indecisiveness, nearly every day (either by subjective account or as observed by others).
• Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or specific plan for committing suicide.

Furthermore, either persistent depressed mood or loss of interest and pleasure must be one of the five symptoms; the symptoms must cause clinically significant distress or impairment in social, occupational or other important areas of function; and, the episode must not be attributable to the physiologic effects of a substance or another medical condition.¹⁰⁷

Severity of depression is determined by its duration and degree of disability it causes. The Hamilton Rating Scale for Depression (HAM-D) is used by healthcare providers to assess depression before, during, and after treatment, and the Beck Depression Inventory (BDI) is widely used for self-assessing depression symptoms.¹¹⁷ Many other depression rating scales have been developed and validated for their ability to measure major depression. Tools specific to children, adolescents, and the elderly are also available. It is vital for healthcare providers to assess suicide risk in patients with depression by questioning them about thoughts or plans to harm themselves or others and previous suicide attempts.¹⁵

Since the emergence of evidence suggesting a biological basis (in addition to a psychological basis) for major depressive disorder, pharmaceutical companies have been developing and promoting medications targeting neurotransmitter activity.¹²⁴ Despite the number and variety of approved drugs, it is estimated up to 70% of people with major depression receiving evidence-based treatment with antidepressants continue to experience depressive symptoms, and over a third of cases are deemed treatment-resistant after having not responded to two or more drug trials.¹²⁸

Psychotherapeutic interventions such as cognitive behavioral therapy (CBT) have proven efficacy as stand-alone treatment for mild depression and alongside drug therapy in moderate-to-severe cases.⁵ Neurostimulation therapies have a long history of effective use and may be a reasonable option for some patients, particularly those with treatment-resistant depression.¹²⁹

Cognitive Behavioral Therapy

Cognitive behavioral therapy (CBT) is a type of psychotherapy in which patients develop cognitive and behavioral strategies for changing harmful or counterproductive patterns of thinking and acting. Brain imaging studies suggest individuals with depression treated with CBT experience changes in signaling in brain regions involved in emotional regulation and cognitive function.^130,131 Including CBT or other types of psychotherapy in depression treatment results in a higher chance of recovery.¹³²

CBT has been shown to be as effective as antidepressant medications when used as a first-line intervention for major depression, and has also been shown to reduce symptoms in those with subthreshold depression.^133,134 Although it is widely accepted that those with severe depression require drug treatment, controlled trials and meta-analyses have found CBT results in similar response and remission rates as antidepressant medications, regardless of the severity of depression.^135,136 CBT works faster and has fewer side effects than antidepressant drugs, and has demonstrated efficacy even in patients who have not responded to drug therapy.¹³⁷ Meta-analyses of controlled clinical trials have found CBT can produce lasting benefits in depression patients, whether delivered in individual therapy, group therapy, or therapist-guided self-help formats.^134,138

Pharmacologic Approaches

Antidepressants. Antidepressants are the most commonly used treatment for clinical depression. In fact, antidepressants are among the most commonly prescribed drugs in the world, and the majority of antidepressant prescriptions are for SSRIs.^5,125 There are a number of individual drugs within the SSRI and other classes of antidepressants, each with slightly different mechanisms of action and side effects. Taking into account the symptom expression, co-occurring health issues, tolerance of side effects, and other individual factors will help in selecting among the many drug options and increasing the chance of a positive response.¹²⁴

SSRIs and several other newer classes of antidepressants have better safety profiles than older antidepressants and are modestly effective, with treatment response rates ranging from 15–55%.¹⁴² Unfortunately, clinical trial data have failed to demonstrate clear, clinically-meaningful superiority over placebo for most available antidepressant medications.^126,143,144 However, drugs in these classes remain first-line treatment for depression.^5,142,145

• Selective serotonin reuptake inhibitors (SSRIs). SSRIs increase the activity of serotonin by interfering with its being taken up by a transport molecule after its release into the synapse. These medications can cause adverse side effects such as headache, digestive upset, insomnia, fatigue, anxiety, sexual dysfunction, and weight gain.¹²⁴ Examples of drugs in this class are:
• Fluoxetine (Prozac)
• Paroxetine (Paxil)
• Sertraline (Zoloft)
• Citalopram (Celexa)
• Escitalopram (Cipralex or Lexapro)
• Serotonin-norepinephrine reuptake inhibitors (SNRIs). SNRIs increase the activities of serotonin and norepinephrine (also called noradrenaline) by interfering with their transport once they are released. The side effect profile of SNRIs is similar to SSRIs but also includes dry mouth and increased blood pressure.¹²⁴ Drugs in this class are:
• Venlafaxine (Effexor)
• Desvenlafaxine (Pristiq)
• Duloxetine (Cymbalta)
• Levomilnacipran (Fetzima)
• Atypical antidepressants
• Bupropion (Wellbutrin), a norepinephrine-dopamine reuptake inhibitor (NDRI), increases the activities of norepinephrine and dopamine by inhibiting transport molecules. Bupropion causes side effects such as headache, agitation, insomnia, sweating, appetite loss, and weight loss.¹²⁴
• Mirtazapine (Remeron) increases the actions of norepinephrine and serotonin on nerve endings. Mirtazapine can cause sedation, increased appetite, and weight gain.¹²⁴
• Trazodone (Oleptro) has complex actions affecting serotonin, norepinephrine, and histamine. Possible side effects of trazodone include sedation, nausea, and, rarely, priapism (painful, persistent erection of the penis).^124,146
• Vortioxetine (Trintellix) and vilazodone (Viibryd) are recent additions to the antidepressant arsenal. They affect serotonin metabolism and receptor function, and have been associated with side effects such as nausea, diarrhea, insomnia, and dizziness.^124,147

Second-line antidepressants include tricyclic antidepressants (TCAs) (ie, amitriptyline [Elavil], clomipramine [Anafranil], and doxepin [Silenor]) and MAOIs (ie, tranylcypromine [Parnate] and phenelzine [Nardil]). Partly because they are less selective in their actions, these older classes of antidepressants cause many adverse side effects, some of which are dangerous. Their use has largely been replaced by newer options; however, they have higher response rates than many first-line antidepressants and are still prescribed in some cases of treatment-resistant depression.^5,124

Augmentation. Many patients with depression do not respond to first- or second-line antidepressants. Unfortunately, the course of illness is more severe and risk of suicide higher for these patients.¹²⁸ There are several treatment options for those who do not have an adequate response after four to eight weeks of antidepressant therapy: increase the dose, switch to a different antidepressant, combine antidepressants, or use another type of medication to augment the effect of the antidepressant.^128,153

Augmentation strategies are usually used after two failures with antidepressants. Atypical antipsychotics such as aripiprazole (Abilify), quetiapine (Seroquel), olanzapine (Zyprexa), and brexpiprazole (Rexulti) are the most common drugs used in augmentation strategies.¹⁵³ While there is mounting evidence that augmenting antidepressant therapy with atypical antipsychotics can increase treatment efficacy, these drugs add another layer of problematic side effects; in particular, atypical antipsychotics can cause metabolic disturbances leading to weight gain and increased risks of heart disease and type 2 diabetes.^128,153

Neurostimulation Therapies

Electroconvulsive therapy (ECT). ECT is the oldest type of neurostimulation therapy and has been used to treat depression for over 75 years. It is currently used to treat severe and recurrent major depressive disorder that is unresponsive to drug therapies. ECT is performed under general anesthesia and involves applying a mild electrical current to specific brain regions via electrodes placed on the scalp. The electrical stimulation causes a seizure that is thought to be important to its therapeutic effect; however, ECT’s exact mechanism of action is still unknown.¹⁵³

Patients undergoing ECT typically receive treatments three times per week for 2–4 weeks, for a total of 6–12 treatments, followed by long-term drug therapy. Although ECT is associated with remission rates as high as 80%, the majority of patients experience relapse. In some cases, ECT is continued for six months, and possibly longer as a maintenance therapy.¹⁵³

ECT is associated with serious side effects, including confusion and memory deficits that may be brief or protracted, dangerous sustained seizure, and transient changes in heart rhythm and increased blood pressure. Nevertheless, ECT is one of the most effective treatment options for treatment-resistant major depression, and its potential benefits outweigh its risks in some cases.¹⁵³

Vagus nerve stimulation (VNS). VNS is an invasive therapy in which an electrode placed around the vagus nerve is connected to an electrical impulse generator implanted in the chest wall.¹²⁹ The vagus nerve is a major nerve connecting the brain to the rest of the body, particularly the gut, and helps regulate normal resting body functions. Although the mechanisms underlying the antidepressant effect of VNS have not been established, one contributing factor may be its ability to reduce inflammation. The vagus nerve has been shown to communicate with the immune system by activating the cholinergic anti-inflammatory pathway and thereby inhibiting production of inflammatory cytokines.¹⁵⁹ It also appears to modulate the gut microbiome in part through its effects on immune signaling.^160,161

VNS has been found to induce long-term remission in some depression patients who have not responded to other forms of treatment, including ECT.^162,163 In one study, approximately half of patients treated with VNS had a clinical response (defined as a 50% or greater reduction in depression scores) and nearly 40% were in remission after two years.¹⁶⁴ As an add-on to drug treatment in patients with highly treatment-resistant depression, VNS has been shown to have faster and longer lasting positive impacts on depression and quality of life than drug treatment alone.^165,166 Surgery-related infection is the most common complication; others include vocal cord and facial muscle weakness, changes in heart rhythm, cough, hoarseness, and throat pain.¹⁶⁷ VNS is approved for use in those with major depression who have been unresponsive to at least four antidepressant interventions.¹⁶⁵

Repetitive transcranial magnetic stimulation (rTMS). rTMS is a noninvasive neurostimulation technique in which a magnetized coil placed on the scalp generates an electrical current that passes through the brain’s cortex. rTMS is performed daily for several days to weeks, and does not require anesthesia.¹²⁹ In some cases, therapy is continued through periodic maintenance sessions.¹⁶⁸ rTMS specifically targeting the dorsolateral prefrontal cortex of the brain has been shown to have positive effects in patients with major depression that is unresponsive to other types of treatment.^169-171 Findings from animal research suggest rTMS may increase neuroplasticity and improve cognitive function.¹⁶⁹ It has even been found to be safe and effective in pregnant and elderly patients.¹⁷² Although its ability to induce long-term remission is not known, its safety and fast action have led to calls for its inclusion as a first-line intervention.¹⁶⁸

Ablative neurosurgery. Ablative neurosurgery is a rarely used technique for intractable major depression in which neural connections in specific brain regions are surgically cut. The seriousness of potential harm, coupled with the irreversible nature of this approach, limit its use to the most chronic, debilitating, and intractable cases.¹²⁹

Emerging Medications

Agomelatine. Agomelatine (Valdoxan) is a synthetic version of the neurohormone melatonin. Like melatonin, agomelatine activates MT1 and MT2 receptors, which play an important role in regulating circadian cycles and serotonin signaling, affecting sleep, mood, and cognition. In addition, agomelatine interacts with 5-HT2C serotonin receptors. When 5-HT2C receptors are activated by serotonin, the result is inhibition of dopamine and norepinephrine signaling; on the other hand, agomelatine interacts with 5-HT2C receptors as a neutral antagonist, preventing their over-activation without suppressing their normal function.¹⁷³ Meta-analyses of controlled trials have found agomelatine is similar in efficacy to other antidepressant drugs, but is more tolerable than most, mainly due to its lower likelihood of causing sexual side effects and weight gain.^142,174-176 Possible adverse side effects include headache, dizziness, sleepiness, fatigue, and digestive upset. Its long-term safety is yet to be explored, but rare cases of liver toxicity have been reported.¹⁷⁷ Agomelatine is approved for treating depression in Europe and Australia, but not in the United States.

Ketamine and esketamine. Ketamine (Ketalar) is a drug with wide ranging effects on the central nervous system due to its inhibition of glutamate receptors, known as N-methyl D-aspartate (NMDA) receptors, in the brain.¹⁷⁸ Ketamine rapidly enhances neuronal activity in some brain regions and may ultimately reverse depression-related brain atrophy and diminished neuroplasticity.¹⁵³ Although approved for use as a general anesthetic, ketamine has recently attracted interest for its effects in psychiatric disturbances, including substance use, depression, and anxiety disorders.

Ketamine, used intravenously in sub-anesthetic doses, has been reported to trigger rapid and long-term antidepressant effects.¹⁷⁹ Multiple clinical trials have found an intranasal version of ketamine, called esketamine (Spravato), increased response and remission when used alone or in combination with oral antidepressants in patients with treatment-resistant depression.^128,180 This led to esketamine’s approval by the US Food and Drug Administration (FDA) in 2019 for use in patients with treatment-resistant depression.¹⁸¹ It was the first antidepressant with a new mechanism of action to be approved by the FDA in 30 years.¹⁸⁰

Ketamine is typically administered in single intravenous doses. In most patients, substantial antidepressant effects are noted within four hours and may last a week or longer.^153,178,179 Esketamine is also administered in single doses under the supervision of a certified healthcare provider.¹⁸² As with ketamine, esketamine’s effects come on within hours of administration and have been reported to last four weeks or longer.¹⁸³ Despite their increasing use, the long-term safety and effectiveness of ketamine and esketamine are still being explored.^181,184 For example, ketamine is known to raise blood pressure for a few hours after administration, and may pose a safety risk in patients with high blood pressure or aneurysm.¹⁸⁵ In addition, ketamine and esketamine can cause drowsiness, dizziness, and blurred vision, as well as altered perceptions and hallucinations that many find intolerably uncomfortable.^153,183 Due to the potential for dissociation and perceptual changes, patients administered esketamine must be monitored by a qualified healthcare provider for at least two hours after receiving a dose.¹⁸²

Anti-inflammatory drugs. Cytokine inhibitors (eg, etanercept [Enbrel] and infliximab [Remicade]) and non-steroidal anti-inflammatory drugs (eg, aspirin and celecoxib [Celebrex]) are categories of anti-inflammatory drugs being investigated for their possible use in depression treatment, mainly as adjuncts (add-ons) to antidepressant drugs.

An uncontrolled trial that included 24 depression patients who had not responded to four weeks of SSRI treatment found the addition of 160 mg aspirin per day resulted in a 52.4% response rate and a 43% remission rate.²¹⁰ Controlled trials have been less promising: one trial found aspirin did not improve the effectiveness of either the SNRI duloxetine or the SSRI escitalopram,²¹¹ and another found the combination of 160 mg aspirin per day plus the SSRI citalopram led to severe anxiety and physical restlessness in eight of the 10 participants receiving this combination.²¹² Further research indicates aspirin does not have a role in preventing depression.^213,214 Several randomized controlled trials found that celecoxib, as an adjunct to antidepressant therapy, improved symptom reduction in patients with depression, but its possible association with increased cardiovascular risk must be taken into consideration.²¹⁵

Findings from clinical trials using cytokine inhibitors have not been consistently positive, but a growing body of evidence suggests there may be a subset of depression patients with elevated inflammatory cytokine levels, such as those with co-occurring autoimmune or other inflammatory conditions, who are likely to benefit from the addition of cytokine-blocking agents to their treatment regimen.^216-218 More research is needed to clarify the potential utility of these drugs in these patient groups.

Investigational Neurostimulation Techniques

Transcutaneous auricular vagus nerve stimulation (tVNS), in which electrical stimulation is applied through the skin at a location behind the ear, is a non-invasive variation on VNS. A meta-analysis of four randomized controlled trials with a combined total of 222 subjects with major depression found tVNS, applied twice daily or at least five days per week for 2–4 weeks, effectively reduced depression symptoms.²¹⁹

Magnetic seizure therapy is a non-invasive technique involving the application of a magnetic field across the head in high enough intensity to induce a seizure. Like ECT, magnetic seizure therapy is performed under general anesthesia at a series of sessions over several days or weeks. Magnetic seizure therapy may be somewhat less effective than ECT, but appears to cause fewer general and cognitive side effects.¹²⁹

Transcranial electrical stimulation involves the use of a battery-operated device that delivers weak electrical impulses via electrodes placed on the scalp, earlobes, behind the ears, or on the face.¹²⁹ Transcranial electrical stimulation devices are widely available and appealing because they are non-invasive and self-administered. One form of transcranial electrical stimulation, called transcranial direct current stimulation, has shown some positive effects in patients with major depressive disorder.²²⁰ However, more remains to be learned about whether and how this neurostimulation method works and its long-term consequences on mood and cognitive function.^129,220

Other non-invasive neurostimulation techniques under investigation include^129,221,222:

• Focal electrically administered seizure therapy
• Transcranial low-voltage pulsed electromagnetic fields
• Trigeminal nerve stimulation
• Low field magnetic stimulation
• Transcranial focused ultrasound

Deep brain stimulation (DBS) is a highly invasive neurostimulation therapy being investigated for possible use in patients with severe treatment-resistant depression. In DBS, electrodes are surgically placed in specific deep regions of the brain (below the cortex) and pulses of electricity are administered to alter the activity of neurons in these brain regions.¹²⁹ DBS is gaining interest and showing clinical promise in patients with treatment-resistant major depression.^223-225 Its mechanism of action is still not completely understood: in addition to activating local neurons, DBS also appears to stimulate neurogenesis and neuroplasticity and may slow the progression of neurodegenerative conditions such as Parkinson disease (for which DBS is approved) and Alzheimer disease.²²⁶ Surgical complications are a risk associated with DBS, and, although most side effects are reportedly mild, about 50% of individuals receiving DBS experience some stimulation-related side effects.²²⁵

Diet

Evidence consistently supports the notion that healthy dietary patterns with low inflammatory potential are associated with better mental health and less depression risk. The Mediterranean diet and similar diets that limit inflammatory foods (like those high in saturated fats, trans fats, and processed sugars) and emphasize anti-inflammatory foods (like fruits and vegetables and other plant-based unprocessed foods high in phytonutrients, mono- and poly-unsaturated fats, and fiber) have been associated with reduced risk of depression.^231-240

A meta-analysis of 16 randomized controlled trials with over 45,000 participants combined, most of which included participants with depressive symptoms but not major depression, found dietary interventions can effectively reduce symptoms of depression, and women may benefit more than men.²⁴¹ One trial included 67 individuals with moderate-to-severe depression who were randomly assigned to receive nutritional counseling or general social support for 12 weeks. The purpose of nutritional counseling was to improve adherence to a Mediterranean-like diet, high in whole grains, vegetables, fruit, legumes, low-fat unsweetened dairy products, nuts, fish, lean meat and poultry, eggs, and olive oil. Those in the nutritional support group had more improvement in depression symptoms and a higher rate of remission (32%) compared with those in the social support group (8%).²⁴² Another important trial included 76 young adults with high levels of depression symptoms and poor dietary habits assigned to either a three-week dietary intervention or no intervention. Those in the dietary intervention group received guidance encouraging adherence to a more Mediterranean-style diet and discouraging consumption of refined carbohydrates, sugar, soft drinks, and fatty or processed meat. Not only did those in the diet intervention group have decreased depression scores at the end of the trial, their improvement in mood was sustained three months after the trial ended.²⁴³

Exercise

Physical activity has well established benefits on mood and depression, while being sedentary worsens mental and physical health.^244-246 The efficacy of exercise in depression is comparable to that of antidepressant medications and CBT, yet has additional benefits on fitness and physical health.²⁴⁷ Exercise has been shown to be beneficial in patients with major depression as well as conditions associated with depression such as alcohol and substance use disorders,²⁴⁸ cardiovascular disease,²⁴⁹ neurodegenerative diseases,²⁵⁰ and other psychiatric illnesses.²⁵¹

Aerobic exercise, strength training, and mind-body exercise (such as yoga, tai chi, and qigong) have all been found to improve depression.^252-254 A meta-analysis of 11 trials with a total of 455 participants with major depression found aerobic exercise, for an average of 45 minutes three times weekly for nine weeks, reduced symptoms by 21%.²⁵⁵ A meta-analysis of nine clinical trials with a combined total of 366 participants found both high-intensity interval training (HIIT) and moderate intensity continuous training can be beneficial in patients with depression and other psychiatric disorders, but HIIT may have a stronger effect.²⁵⁶ A meta-analysis of 15 trials with a total of 596 older adult participants found, among the different types of exercise, mind-body exercise had the greatest positive impact on depression in this demographic.²⁵⁷ Furthermore, multiple randomized controlled trials have shown mind-body exercise can reduce depression and anxiety severity in adults of all ages.²⁵⁸

Despite the wealth of evidence that exercise can play a substantial role in treating depression, depression itself is an obstacle to self-care. Structured exercise programs that provide ongoing supervision, support, and motivation are more likely to engage patients with depression and increase the chance of successful adherence.²⁵⁹

More information is available in our Exercise Enhancement protocol.

Chronotherapy

Circadian signaling between the brain’s master “clock” and cells throughout the body regulates biological cycles that impact every aspect of physiology and health, modulating metabolism, temperature regulation, appetite, sleep, cognition, behavior, social activity, and mood.^260,261 Circadian rhythms become disrupted due to factors such as nighttime activity or light exposure, atypical eating patterns, alcohol overconsumption, shift work, and travel through time zones.²⁶² Circadian disruption is a common feature of many chronic and metabolic diseases, as well as mood disorders.²⁶² In people with major depression, circadian desynchronization has been noted to manifest as altered sleep patterns, increased core temperature, and blunted circadian changes.^263,264

Chronotherapy involves modifying or limiting exposure to environmental stimuli that affect circadian rhythms. The goal of chronotherapy is to restore normal circadian control and synchronize rhythmic cycles.²⁶⁵ In depression treatment, chronotherapy strategies include bright light therapy, sleep deprivation (also called wake therapy), and sleep phase advance. Evidence from clinical research suggests combinations of these therapies with or without antidepressants may have positive impacts on depression.²⁶⁶

Bright light therapy generally involves use of white light at an intensity of 2,000–10,000 lux for 30 to 120 minutes per day. Although it is best known as a first-line treatment for seasonal depression, multiple controlled trials indicate bright light therapy can reduce depressive symptoms and improve sleep quality in healthy subjects and patients with non-seasonal major depression.²⁶⁵ One sleep deprivation method involves awakening well before usual rising time one morning followed by normal awakening the next morning, in a set of three for a total of six mornings. Another method involves total sleep deprivation for one night, followed by morning light therapy. Sleep phase shifting usually involves normalizing bedtime over a period of weeks. Sleep deprivation and phase shifting are generally done together to treat sleep and mood disorders.²⁶⁷

Chronotherapy has been found to be helpful in cases of moderate-to-severe treatment-resistant depression, and some evidence suggests those with evening chronotypes (a preference to function and conduct activities in the evening) and whose mood is best in the evening may be more likely to benefit.²⁶⁸ A meta-analysis of 16 studies noted chronotherapies improve depression more quickly than antidepressants, psychotherapy, or exercise, reducing symptoms by 50% or more in 33% of patients after 5–7 days.²⁶⁹ In one open study, 35 hospitalized patients with moderately severe major depression underwent chronotherapy as follows: sleep deprivation via 4 a.m. awakening on three mornings with simultaneous light therapy of increasing intensity from 4 a.m. to 8 a.m., alternating with three nights of uninterrupted sleep with one hour of bright light therapy in the morning; a sleep phase shift of one hour earlier was targeted. Participants experienced improvements in depression and energy after the first night and throughout the 6-day trial, and were successful in shifting bedtime to 30–40 minutes earlier. Participants given glasses to filter out blue light during light therapy did slightly worse than those exposed to full spectrum white light.²⁷⁰ In another trial, 27 patients underwent one night of total sleep deprivation followed by morning light therapy; this chronotherapy program led to improvement in depression after one week that was sustained three months after the end of treatment.²⁷¹ In one study, 29 adolescents with major depression underwent a four-day chronotherapy intervention that included one night of sleep deprivation followed by three days of sleep phase advancement (going to bed earlier) and morning bright light therapy. The intervention led to symptom reduction of 50% or more in 26 subjects (84%) and remission in 24 (77%), and the benefits were sustained one month after treatment.²⁷²

Meditation

Mindfulness meditation, which emphasizes focused attention on the present moment, has been shown to be helpful in reducing the severity of major depression.^254,273,274 Having a regular practice at home may also reduce the risk of relapse.²⁷⁵ Research suggests mindfulness training may have lasting positive effects on stress resilience that may reduce the risk and symptoms of depression.^276,277 Other types of meditation, such as breathing-based and mantra-based meditation practices, have also been found to improve depression symptoms.^278,279 Studies in healthy volunteers and subjects with major depression suggest meditation may alter signaling and connectivity in regions of the brain involved in depression and anxiety.^280,281

Omega-3 Fatty Acids

The long-chain polyunsaturated omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are important components of nerve cell membranes, affecting their fluidity and ability to send and receive signals.²⁸² They are also used in the body to produce anti-inflammatory metabolites, as well as endocannabinoids, compounds that regulate nerve function by interacting with cannabinoid receptors. These effects have been correlated with improvement in major depression.^283,284 Preclinical research further suggests EPA and DHA enhance neuroplasticity.²⁸⁵

Eating moderate amounts of fatty fish, the main dietary source of EPA, DHA, and other omega-3 fatty acids, may reduce the risk of depression.^284,286 In people with depression and other psychiatric illnesses, higher levels of omega-3 fatty acids have been correlated with less severe symptoms.^287,288

Numerous randomized controlled trials using supplements with EPA and DHA in proportions of 2:1 or 3:1 and at doses of 1–2 grams per day have found positive effects on depression.^289,290 Omega-3 fats may also have metabolic benefits in patients with depression and metabolic disorders such as type 2 diabetes, obesity, and cardiovascular disease.^291-294 Based on the abundance of evidence, the International Society for Nutritional Psychiatry Research recommends the use of EPA in the treatment and prevention of major depression.²⁹⁵ The unique role of DHA in supporting emotional health should also be recognized. DHA is the most prevalent fatty acid in the central nervous system. Not only is DHA incorporated into nerve cell membranes, where it is necessary for normal structure and function, it is also a critical component of other brain cells that use it to support neuronal growth and formation of nerve connections. Furthermore, DHA is a source for critical anti-inflammatory molecules called resolvins and protectins.^284,296

Vitamin D

A number of observational studies have noted an association between low vitamin D levels and depression risk,^297-299 and several studies have noted a link between vitamin D deficiency and suicidality.^300,301 Furthermore, low vitamin D status may also be associated with cognitive impairment in depression patients.³⁰² The connection between vitamin D and depression may be related to vitamin D’s immune-regulating anti-inflammatory effects, ability to promote neuroplasticity and neurogenesis, and its influence on neurotransmitter levels.^299,303

A randomized placebo-controlled trial with 18,353 participants aged 50 years and older (16,657 of whom had never had depression and 1,696 of whom had had depression but had not been treated for at least two years) found taking 2,000 IU vitamin D daily for a median of 5.3 years did not reduce the risk of developing depression or clinically relevant depressive symptoms.³⁰⁴ However, the methodology and rigor of this study has been questioned.³⁰⁵ Moreover, vitamin D has been found to be effective in reducing symptoms in patients with depression in clinical trials using doses from 2,800 to 5,600 IU daily for 1–12 months.²⁹⁹ A meta-analysis of four randomized controlled trials with a combined total of 948 patients with major depression found vitamin D supplementation can have a substantial positive impact on depression symptoms.³⁰⁶ Another meta-analysis that included nine studies found vitamin D supplementation can reduce depression symptoms and improve some markers of inflammation and oxidative stress in patients with a variety of psychiatric diagnoses.³⁰⁷

Vitamin D has broader health benefits and may reduce depression in those with other chronic conditions. In one trial, subjects with type 2 diabetes and mild-to-moderate depressive symptoms treated with 4,000 IU vitamin D daily had greater improvement in mood, as well as markers of metabolic health, compared with those treated with placebo after 12 weeks.³⁰⁸ An open-label trial found 10,000 IU vitamin D daily for 12 months reduced depressive symptoms in 35 patients with multiple sclerosis. Blood tests showed subjects’ vitamin D levels were deficient or borderline-deficient at the beginning of the study and became sufficient during the course of the study. In addition, higher vitamin D levels were correlated with lower scores on depression tests throughout the study.³⁰⁹

Probiotics

The gut microbiome has a close relationship with the brain and plays a fundamental role in regulating mood and cognitive function. People with depression have been found to have reduced gut microbial abundance and diversity, a pattern associated with poorer health in general.⁶³ Eating probiotic-rich fermented foods was correlated with lower risk of major depression in one study.³¹⁰

Multiple clinical trials, reviews, and meta-analyses indicate probiotic supplements can be effective in treating depression.^311-315 In an 8-week trial that included 110 patients being treated with antidepressant drugs for mild-to-moderate depression, those receiving a probiotic with 10 billion colony forming units (CFUs) of combined Lactobacillus helveticus R00052 and Bifidobacterium longum R00175 had greater reductions in scores on a test for depression than those receiving placebo.³¹⁶ These same probiotic strains have previously been shown to reduce psychological distress in healthy volunteers.³¹⁷ A placebo-controlled trial that enrolled 90 subjects with mild-to-moderate depression found taking a probiotic supplement providing 1 billion CFUs of L. plantarum, along with 200 mg SAMe, daily for six weeks effectively reduced depression symptom scores as well as depression-related anxiety and cognitive changes.³¹⁸ A probiotic supplement with 2 billion CFUs per day each of L. acidophilus, L. casei, and B. bifidum reduced depression symptoms and improved some markers of insulin resistance, oxidative stress, and inflammation better than placebo in 40 subjects with major depression after eight weeks.³¹⁹

The addition of a probiotic supplement containing Clostridium butyricum, at 60 mg per day, to standard antidepressant therapy resulted in a 70% response rate and 35% remission rate in an open trial in 40 patients with treatment-resistant depression.³²⁰ Another small open trial in treatment-resistant depression patients found the addition of a mixed probiotic with a total of 20 billion CFUs of L. acidophilus, B. bifidum, and Streptococcus thermophilus, plus 1,600 mg per day magnesium orotate, to antidepressant therapy led to improvement in depression and quality of life scores in eight of 12 participants (67%) after eight weeks.³²¹

Probiotics may reduce depressive symptoms in patients with other chronic conditions. A placebo-controlled trial that included 54 participants with type 2 diabetes and coronary heart disease showed taking a mixed probiotic with 2 billion CFUs each of L. acidophilus, L. reuteri, L. fermentum, and B. bifidum, along with 200 mcg selenium, daily for 12 weeks decreased depression scores and improved metabolic markers.³²² Similarly, a placebo-controlled trial in 44 post-heart attack patients found 1.6 billion CFUs L. rhamnosus per day for 12 weeks reduced depression, decreased markers of inflammation and oxidative stress, and improved quality of life.³²³ Findings from other clinical trials suggest probiotics may reduce symptoms of depression in patients with irritable bowel syndrome.^324,325

In a noteworthy clinical trial, 155 healthy individuals and 156 patients with major depression were studied to identify differences in bacterial landscapes and metabolic signatures of their gut microbiome and fecal metabolites.⁴⁸⁹

Trial participants had notable differences in the abundance of three bacteriophages (viruses that infect bacteria), 50 fecal metabolites, and 47 bacterial species. The bacterial species were mainly classified in one of the three genera (taxonomic category): Bacteroides, Blautia, and Eubacterium. Bacterial species in these genera are diverse but can play critical roles in the body including regulating inflammation.^489,490 Those in the major depression group had significantly increased abundance of Bacteroides and significantly decreased abundance of Blautia and Eubacterium.

Based on these findings, the authors suggest certain species in these genera might be responsible for the inflammatory imbalances commonly seen in major depression patients. Importantly, this research helps pave the way for using gut microbiome signatures in the assessment of major depression.

Zinc

Zinc has a multitude of functions in the body, including reducing oxidative stress, modulating neurotransmitter receptor function, and regulating gene expression.^326,327 Importantly, zinc may inhibit neuronal NMDA glutamate receptors, which are dysregulated in those with depression, and raise BDNF levels, which can promote neuroplasticity.^328,329 A meta-analysis of nine studies found low zinc intake was associated with increased depression risk.³³⁰ In addition, people with depression have been reported to have lower zinc levels compared with non-depressed individuals, and zinc deficiency has been correlated with increased depression severity and treatment resistance.^328,331 Zinc supplementation has been found to improve depression as a stand-alone therapy and in conjunction with antidepressant therapy, even in cases of treatment-resistant depression.^329,332

A controlled trial in 50 overweight and obese subjects found symptoms of depression were correlated with lower blood BDNF levels, and supplementing with 30 mg zinc daily for 12 weeks increased BDNF levels and reduced depression symptoms more effectively than placebo.³³³ In 30 healthy young women, adding 7 mg zinc to a daily multivitamin supplement for 10 weeks led to lower scores assessing anger and hostility compared with the multivitamin alone.³³⁴ A 12-week trial that included 44 participants with major depression found those receiving zinc sulfate (providing 25 mg elemental zinc per day) in addition to their usual SSRI had greater improvement in depression compared with those receiving placebo plus SSRI.³³⁵ This same dose of zinc was found to be more beneficial than placebo for lowering depression scores in a trial with 14 patients with major depression being treated with SSRIs or tricyclic antidepressants.³³⁶ In 60 patients with treatment-resistant depression, adding 25 mg zinc daily to treatment with the tricyclic antidepressant imipramine (Tofranil) for 12 weeks led to a more rapid and robust treatment response compared with placebo.³³⁷

Saffron

Saffron (Crocus sativus) and its active constituents have been widely studied for their effects on depression. Saffron’s antidepressant effects may be due to its anti-inflammatory action, ability to raise dopamine levels, and interactions with endogenous opioid receptors.³³⁸ Multiple controlled clinical trials and meta-analyses have shown saffron extract, typically at a dose of 30 mg per day, is more effective than placebo and comparable to antidepressant drugs for improving mild-to-moderate depression.^339-342 One meta-analysis that included findings from 21 controlled trials found saffron extract can reduce self-reported depression and anxiety scores and improve sleep quality.³⁴³

In a placebo-controlled trial in 40 patients with major depression, combined treatment with antidepressant therapy plus 30 mg crocin (an active compound from saffron) per day for four weeks was more effective for reducing symptoms than antidepressant therapy alone.³⁴⁴ In 54 patients with type 2 diabetes and mild-to-moderate combined depression and anxiety, mood symptoms and sleep improved more after taking 30 mg saffron extract daily for eight weeks compared with placebo.³⁴⁵ In 139 patients with persistent depression despite treatment with antidepressant drugs, adding a standardized saffron extract, at a dose of 28 mg per day, for eight weeks reduced practitioner-assessed depression scores, but not self-assessment score, better than placebo.³⁴⁶

Saffron extracts have been shown to lower depression symptoms in overweight women,³⁴⁷ healthy women with menopausal symptoms,³⁴⁸ patients with HIV/AIDS in substance abuse recovery,³⁴⁹ individuals with metabolic syndrome,³⁵⁰ patients with coronary artery disease,³⁵¹ and those with fibromyalgia syndrome. Placebo-controlled clinical trials further show saffron, when used in conjunction with antidepressants, may mitigate antidepressant side effects related to sexual function in both men and women.^352,353

St. John’s wort

Multiple clinical trials have shown St. John’s wort ( Hypericum perforatum) can reduce symptoms of major depression with a similar efficacy to first-line antidepressant therapy, but with fewer adverse side effects.^354-357 One meta-analysis including 35 randomized controlled trials with a combined total of 6,993 participants confirmed St. John’s wort’s benefits in mild-to-moderate depression; however, little is known about its effects in severe depression.³⁵⁸

Some active compounds from St. John’s wort have a weak inhibitory effect on monoamine oxidase, an enzyme that breaks down neurotransmitters, while other constituents have anti-inflammatory and free radical-scavenging effects.^359,360 It is thought its antidepressant properties are related to synergistic effects of multiple active compounds.³⁶¹ Standardized extracts typically contain 0.1–0.3% hypericin and up to 6% hyperforin.³⁶²

Extracts of St. John’s wort, particularly those high in hyperforin, can promote increased detoxification activity in the intestinal wall and liver, which can impact metabolism of a number of drugs; therefore, individuals who take medications and want to add St. John’s wort will be safest using low-hyperforin preparations and carefully monitoring conditions for which they take medications.³⁶²

Acetyl-L-Carnitine

Acetyl-L-carnitine is a form of the amino acid L-carnitine, which is important for normal mitochondrial energy metabolism. Acetyl-L-carnitine readily crosses the blood-brain barrier and enhances neuronal mitochondrial metabolism.³⁶³ It is thought to have brain-protective effects related to anti-inflammatory and antioxidative stress mechanisms, and promote neuroplasticity.^364,365 Acetyl-L-carnitine levels in the blood have been reported to be lower in depressed than non-depressed subjects, and levels were noted to drop with decreasing age of depression onset and increasing severity; patients with treatment-resistant depression and a history of childhood trauma had the lowest levels.³⁶⁶

A meta-analysis of 12 randomized controlled trials with a combined total of 791 participants found acetyl-L-carnitine was more effective than placebo and had similar efficacy to widely-prescribed antidepressant drugs for reducing depression symptoms.³⁶⁷ A 7-week placebo-controlled trial in 80 elderly patients with subthreshold depression found acetyl-L-carnitine was as effective as the antidepressant fluoxetine for reducing symptoms, but symptomatic improvements were more rapid with acetyl-L-carnitine than fluoxetine.³⁶⁸ Acetyl-L-carnitine in doses of 1,500 mg per day has been found to reduce depression symptoms and pain and improve quality of life in patients with fibromyalgia syndrome more effectively than placebo and similarly to duloxetine (Cymbalta).^369,370

Dehydroepiandrosterone

Dehydroepiandrosterone (DHEA) is an adrenal hormone that can be used to produce testosterone and estradiol. It also has immune-modulating and metabolic effects independently of its role as a sex hormone precursor.³⁷¹ DHEA contributes to mood modulation, is neuroprotective, and has anti-stress activity.³⁷² Patients with depression have been found to have low DHEA-sulfate (DHEA-s) levels, and the ratio of cortisol:DHEA-s has been suggested to be a measure of stress hormone activity in depression.³⁷³ Persistent disturbance of the cortisol:DHEA ratio during remission from depression may be an indicator of recurrence risk.³⁷⁴

In a randomized controlled trial that included 17 participants with midlife-onset non-major depression, taking 90 mg DHEA daily for three weeks resulted in greater improvement in depression symptoms compared with placebo.³⁷⁵ Similarly, a placebo-controlled trial involving 46 participants with major or non-major midlife-onset depression also noted the antidepressant effect of DHEA.³⁷⁶ In another trial, 22 participants with major depression, some of whom were being treated with antidepressant therapy, received either 90 mg DHEA per day for six weeks or placebo. Compared with the control group, more participants in the DHEA group experienced a treatment response, defined as a 50% reduction in depression symptoms.³⁷⁷ DHEA has also been reported to reduce depressive symptoms in patients with schizophrenia³⁷⁸ and HIV/AIDS.³⁷⁹

B Vitamins

The vitamin B complex consists of nine water-soluble B vitamins that have related roles as cofactors in a diverse array of biochemical reactions, and are necessary for normal cellular metabolism and energy production.³⁸⁰ Vitamins B1 (thiamine), B3 (niacin), B6 (pyridoxine), B9 (folate), and B12 (cobalamin) are needed for normal nerve function, and deficiencies have been linked to depression.³⁸¹ Adequate amounts of the trio of methylators, B6, B9, and B12, are required for the conversion of homocysteine into S-adenosyl methionine, or SAMe, a form of methionine involved in the synthesis of many critical biomolecules, including neurotransmitters. Deficiencies of any of these three B vitamins can raise homocysteine levels. High homocysteine levels have been associated with increased risk of depression, as well as cardiovascular, neurological, and other chronic diseases.¹⁰⁹

Clinical trials have shown supplementing with B vitamins can lower levels of perceived stress and improve mood in healthy individuals.³⁸² Long-term folate and B12 supplementation has been found to reduce the risk of relapse in individuals with major depression, and may help prevent the onset of major depression in people at high risk.³⁸³ In patients with major depression and a genetic mutation that causes disruption in homocysteine metabolism, taking a multivitamin-mineral supplement with the metabolized forms of B vitamins reduced homocysteine levels and was more effective than placebo at reducing depression symptoms, resulting in a 42% remission rate after eight weeks.³⁸⁴ A combination of 200 mg L-tryptophan, 8 mg B6, and 8 mg B3 per day taken between meals was found to reduce symptoms better than placebo in a 7-day trial that included 30 young adults with severe depression symptoms that did not reach the threshold for a major depression diagnosis.³⁸⁵

Although findings from studies in patients with depression have been mixed, placebo-controlled trials indicate folate, particularly in the form methylfolate, may improve the response to antidepressant therapy.^386,387 Vitamin B12 supplementation has also been found to reduce symptoms in patients being treated with antidepressants: in a trial that included 73 patients taking antidepressants for major depression, 100% of participants who received intramuscular injections of 1,000 mcg B12 weekly for six weeks had 20% or greater improvement in depression scores, while only 69% of those not receiving B12 had the same degree of improvement.³⁸⁸ In a placebo-controlled trial in 51 hospitalized patients with major depression, the addition of 300 mg B1 per day to antidepressant therapy led to faster symptom reduction.³⁸⁹

L-Tryptophan and 5-Hydroxytryptophan

L-tryptophan, the amino acid precursor to serotonin in the intestines and brain, is an important mediator of communication between the gut and the central nervous system.^38,390,391 L-tryptophan is also a precursor to melatonin and vitamin B3, as well as several other metabolites. Altered tryptophan metabolism that enhances production of inflammatory metabolites may be a contributing factor in depression risk and connect depression to other chronic conditions.^392-394 Some evidence suggests stress can disrupt normal tryptophan metabolism, interfering with serotonin production and leading to increased inflammation and risk of depression.^395,396 L-tryptophan levels have been noted to diminish with age.³⁹⁷

A meta-analysis of studies found patients with major depression have lower levels of circulating tryptophan.³⁹⁸ Increased tryptophan intake is associated with reduced depressive symptoms and increased sociability, and randomized controlled trials indicate supplementing with up to 3 grams L-tryptophan daily may improve positive mood in healthy adults.^399-402 Genetic factors that influence tryptophan metabolism appear to determine in part individual responsiveness to L-tryptophan supplementation.⁴⁰³

5-hydroxytryptophan (5-HTP) is a byproduct of tryptophan metabolism and the immediate precursor to serotonin. Supplementing with 5-HTP instead of L-tryptophan may avoid the production of other L-tryptophan metabolites and may bypass the rate-limiting step in the conversion of tryptophan to serotonin. Randomized controlled trials have found 5-HTP, mainly in doses of 200–300 mg per day, is more effective than placebo and comparable to first-line antidepressants in treating major depression.^404,405 Some evidence suggests 5-HTP may also increase responsiveness to antidepressant therapy.⁴⁰⁶ 5-HTP can cause digestive upset but has not been linked to serotonin syndrome or serious adverse effects.^406,407

N-acetylcysteine

N-acetylcysteine (NAC) is a derivative of the amino acid cysteine. As a source of cysteine, it helps build levels of glutathione, which is needed to metabolize toxins and reduce oxidative stress throughout the body. NAC has important functions in the brain, decreasing oxidative stress and neuroinflammation, enhancing mitochondrial activity, modulating dopamine and glutamate signaling, and promoting neuroplasticity.⁴⁰⁸

A controlled trial in 252 participants with major depression compared standard of care plus 2,000 mg NAC daily with standard of care plus placebo. Among those with the most severe depression, NAC use resulted in statistically significant improvement in symptoms beginning at week six and continuing until the end of the study. In addition, NAC users had greater improvement in functional impairment at a follow-up four weeks after the end of the trial.⁴⁰⁹ Another trial found 1,800 mg NAC per day reduced symptoms of depression and anxiety in bipolar or major depression patients with elevated baseline levels of C-reactive protein, a marker of systemic inflammation.⁴¹⁰ In a trial of 35 female youths with a history of non-suicidal self-injury, treatment with NAC in doses that were gradually increased to 3,600 mg per day reduced depression symptoms and self-injurious behaviors.⁴¹¹ NAC has been found in multiple clinical trials to reduce depressive symptoms in patients with depression and other psychiatric and neurological conditions.⁴¹²

Rhodiola

Rhodiola (Rhodiola rosea) is a plant that flourishes in northern climates and has been used medicinally as an adaptogen. Adaptogens are therapeutics that increase stress resilience and have been used historically to treat fatigue, build stamina, and promote longevity.⁴¹³ Preclinical evidence indicates rhodiola modulates neurotransmitter signaling and normalizes the stress response. It also has anti-inflammatory and oxidative stress-reducing effects that may contribute to its antidepressant activity, and has been shown to inhibit depression-like signaling in brains of healthy volunteers.^414-416

A controlled trial in 89 patients with mild-to-moderate depression found rhodiola extract, in doses of 340 mg and 680 mg daily, reduced depression symptoms compared with placebo after 42 days. Although the overall effects of the two dosages were similar, those receiving the higher dose were noted to have experienced a marked improvement in self-esteem, which was not observed in those receiving the lower dose.⁴¹⁷ In a randomized controlled trial, 100 patients with mild-to-moderate depression were treated with the SSRI sertraline plus either 300 mg per day rhodiola, 600 mg per day rhodiola, or placebo. After 12 weeks, those receiving the higher dose of rhodiola had the greatest symptom improvement.⁴¹⁸ In addition, results from a number of open trials add to the evidence that rhodiola has meaningful antidepressant activity.⁴¹⁹ In a 12-week comparison trial in 57 patients with mild-to-moderate depression, a dose-escalation of rhodiola extract (ranging from 340–1,360 mg daily) led to slightly lower likelihood of improvement than sertraline, relative to placebo, but caused fewer adverse side effects.⁴¹⁶

Lemon Balm (Melissa officinalis)

Lemon balm is a perennial herb in the mint family; it is native to southern Europe, Asia Minor, and Africa. Lemon balm has been used historically to treat mood disorders, including depression and anxiety, and for managing stress and promoting restful sleep.^420,421 Contemporary preclinical research has shown that lemon balm possesses some pharmacological properties that may partly explain its ability to influence mood. Extracts of lemon balm have been shown in vitro to inhibit monoamine oxidase A (MAO-A),⁴²² an action that can modulate the metabolism of monoamine neurotransmitters involved in mood regulation.

In a small pilot study, 45 adults with major depression were randomized to fluoxetine, lemon balm, or another herb, English lavender (Lavandula angustifolia).⁴²¹ Subjects’ mood was assessed at baseline, two, four, and eight weeks using the HAM-D. Lemon balm and lavender were both as effective as fluoxetine in reducing subjects’ HAM-D scores over the course of the study. The authors of this study acknowledged the preliminary nature of this work: “Although in our study effects of M. officinalis and L. angustifolia was equal to fluoxetine, a meta-analysis has revealed that these effects [are comparable to those attributable to the] placebo effect.¹²⁶ Regarding to this controversy, larger trials with longer duration of follow up and including placebo group are needed to evaluate the long-standing safety and efficacy of these herbal medications.”

An earlier randomized placebo-controlled trial evaluated the effects of lemon balm on mood and sleep disorders in 80 subjects with chronic stable angina. Participants were randomized to receive either 3 grams lemon balm or placebo daily for eight weeks. Mood was assessed using a standardized questionnaire. At the end of the study period, subjects taking the lemon balm had significant reductions in scores for depression, anxiety, stress, and sleep disturbance compared with those taking placebo.⁴²³ Another small trial found lemon balm helped relieve depression in people with insomnia. In this study, lemon balm was combined with another herb, Nepeta menthoides, and the combination improved mood-related scores more than placebo after four weeks of treatment.⁴²⁴

Lavender (Lavandula angustifolia)

Lavender is a common herb in the Mediterranean region; its pleasant scent makes it a popular ingredient in perfumes and essential oil infusions. Lavender aromatherapy has been shown to alleviate depressive symptoms in preliminary research. Oral supplementation with lavender preparations, as extracts, teas, or tinctures, has been shown to ameliorate depression symptoms in a few small studies.⁴²⁵

In a single-blind clinical trial, 60 elderly subjects were assigned to consume lavender tea twice daily or no treatment for two weeks. Mood scores were assessed using standardized questionnaires. Scores for depression declined significantly in the lavender tea group compared with those who did not consume any lavender tea.⁴²⁶ In a trial that enrolled 318 adults with mixed anxiety and depression, a lavender extract (Silexan, 80 mg daily) improved scores on a standardized depression rating scale significantly more than placebo after 70 days of treatment.⁴²⁷ In a separate open-label trial in which this same extract was studied in people reporting anxiety and restlessness, depression scores decreased significantly from baseline after six weeks of treatment.⁴²⁸

In another trial, 45 adults with major depression were randomized to receive a lavender tincture (1:5 extract in 50% alcohol) plus placebo, lavender tincture plus the antidepressant imipramine, or imipramine plus placebo for four weeks. The combination of lavender plus imipramine was found to be more effective than imipramine alone in reducing depression, but lavender alone was less effective than imipramine alone. The researchers concluded that “The main overall finding from this study is that [lavender] tincture may be of therapeutic benefit in the management of mild to moderate depression as adjuvant therapy.”⁴²⁹

S-adenosyl methionine

S-adenosyl methionine (SAMe) is an important source of single-carbon methyl groups needed for the synthesis of many critical biomolecules, including neurotransmitters and hormones. The production of SAMe from the amino acid methionine requires adequate amounts of folate and vitamin B12, which act as cofactors in that chemical reaction. SAMe levels have been found to be reduced in people with depression.⁴³⁰

Findings from clinical trials examining the use of SAMe for depression have been mixed, and most studies of SAMe in the context of depression have suffered from low methodological quality, design flaws, or small sample size.⁴³¹ A systematic review of the research from 2005 and two meta-analyses published in 2003 and 1994 all found evidence supportive of SAMe’s antidepressant effect^432-434; however, more recent trials have been unable to clearly corroborate these findings.⁴³¹

In a placebo-controlled trial that included 49 patients with mild-to-moderate depression, 800 mg SAMe per day for eight weeks led to substantial reductions in depression symptoms, particularly in those with milder depression; however, due to the small number of participants in the study and a very strong placebo response, the improvements seen with SAMe were not statistically significant.⁴³⁵ Similarly, SAMe added to antidepressant therapy in patients who did not respond sufficiently to medication alone led to improvements that were clinically meaningful but not statistically significant due to a 50% response rate in those receiving placebo.⁴³⁶

A 2016 systematic review of eight trials that included a combined total of 934 subjects found SAMe had similar efficacy to certain antidepressant therapies, but the overall quality of evidence was weak.⁴³⁷ A 12-week randomized controlled trial in which 189 patients with major depression were given either 1,600–3,200 mg SAMe per day, 10–20 mg escitalopram per day, or placebo found all three were equally effective⁴³⁸; however, a second analysis of these findings revealed that SAMe was superior to placebo in men but not women.⁴³⁹ A potential influence of gender could partly explain the inconsistency of findings from clinical trials over the years.

Overall, the available evidence is insufficient to allow conclusions to be drawn as to the efficacy of SAMe in the treatment of depression. Adjunctive therapy with SAMe in people taking antidepressants might be effective, but higher-quality studies are needed to clarify the degree of benefit, if any.^431,440

SAMe is contraindicated in patients with bipolar disorder since it has been reported to induce mania in some cases.⁴⁴¹

Creatine

Creatine is an organic acid made from the amino acids glycine, arginine, and methionine and is found in meat and fish. It plays a critical role in modulating energy production in highly active cells, such as muscle and brain cells. Low dietary intake of creatine has been correlated with increased risk of depression, and altered brain creatine metabolism has been identified as a potential factor in depression.^442,443

A randomized controlled trial in 52 women with major depression found combined treatment with escitalopram plus creatine monohydrate, at 3 grams daily for one week followed by 5 grams daily for seven weeks, led to better treatment responsiveness than escitalopram plus placebo.⁴⁴⁴ A follow-up study found creatine supplementation also increased formation of nerve connections in the brain.⁴⁴⁵ In an open trial in 15 women with treatment-resistant depression, adding 5 grams creatine monohydrate plus 100 mg 5-HTP daily for eight weeks decreased depression symptom scores by 60%.⁴⁴⁶ An open trial in five adolescent girls with major depression that was unresponsive to fluoxetine found the addition of 4 grams creatine daily for eight weeks led to symptom score reductions of 56%.⁴⁴⁷ However, a controlled trial in 18 depressed women who were unresponsive to antidepressant therapy after three weeks found the addition of 5 or 10 grams creatine daily was no more effective than placebo at improving the response rate.⁴⁴⁸ Further studies with creatine are necessary to elucidate whether it offers benefit over placebo in patients with major depression.

Inositol

Inositol (sometimes referred to as myo-inositol) is a sugar alcohol derived from glucose in the body. It is found in many plant and animal foods. Inositol is stored in cell membranes in the form of phosphatidylinositol and its derivatives. In the central nervous system, inositol helps regulate neuronal signaling: activation of neurotransmitter receptors on a nerve cell stimulates delivery of inositol from the cell membrane into the cell where it modulates signal perpetuation via neurotransmitter release.⁴⁴⁹ Brain levels of inositol have been reported to be lower in individuals with depression, and may normalize as a result of successful therapy.^449,450 Oral inositol supplementation may help normalize brain inositol levels.^449,451

A randomized controlled trial in 28 participants with depression found 12 grams inositol per day for four weeks was more effective than placebo for reducing symptoms.⁴⁵² Inositol has also been found to reduce depression symptoms marginally better than placebo in several controlled trials.⁴⁵³ However, researchers have failed to find a benefit from inositol compared with placebo in depressed patients being treated unsuccessfully with SSRIs.^454,455

Magnesium

Magnesium has many important functions in the brain, including participating in regulation of nerve signal transmission.⁴⁵⁶ Some studies have reported higher magnesium intake and serum levels are associated with lower likelihood of depression and decreased depressive symptoms.^457,458 Several uncontrolled trials have found magnesium supplementation is effective for reducing depressive symptoms.⁴⁵⁹ In one crossover trial that included 126 patients with mild-to-moderate depression, supplementing with 248 mg elemental magnesium (as magnesium chloride) per day for six weeks resulted in a significant reduction in symptoms compared with no treatment.⁴⁶⁰ Although most placebo-controlled trials have found magnesium’s therapeutic effect is not different from placebo,⁴⁵⁹ one trial noted 500 mg magnesium oxide daily for eight weeks reduced symptoms significantly more than placebo in 60 depressed patients with magnesium deficiency.⁴⁶¹

It is thought that magnesium’s poor ability to cross the blood-brain barrier may be responsible for its weak performance in clinical trials.⁴⁶² In cell and animal research, magnesium L-threonate, a magnesium salt that more readily permeates the central nervous system, has been found to raise brain magnesium levels, improve brain structure and function, prevent nerve damage due to toxicity or low oxygen levels, and reduce symptoms of neurological diseases.^463-468 In a study in rats, magnesium L-threonate reduced depression-like symptoms and improved memory more than other forms of magnesium.⁴⁶⁹

Taurine

The central nervous system is a site of high concentrations of the amino acid taurine, which reduces brain oxidative stress, stimulates nerve growth and development, and participates in regulation of nerve signal transmission.⁴⁷⁰ Diminished levels of taurine, along with aspartate, glycine, and gamma aminobutyric acid (GABA), have been noted in the brains of animals with experimentally-induced depression.⁴⁷¹ One research group identified an antidepressant action of taurine in diabetic laboratory animals, and noted taurine supplementation reversed diabetes-related decreases in GABA signaling and BDNF production, prevented brain atrophy, and improved memory.^472,473 Taurine has also been reported to decrease depression-like symptoms in animals exposed to chronic stress by regulating stress hormone levels and promoting nerve growth, nerve survival, and formation of new nerves.⁴⁷⁴ In a randomized controlled trial, 86 patients being treated for a first psychotic episode were given 4 grams taurine or placebo daily along with standard medical treatment for 12 weeks; those receiving taurine had greater improvement in psychiatric symptoms, including depression symptoms, as well as overall functioning.⁴⁷⁵