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Depression is a chronic state of low mood often associated with hopelessness, apathy, and fatigue. Unlike sadness, depression is a disorder that persists for weeks or months and interferes with daily life.

Our evidence-based analysis on depression features 37 unique references to scientific papers.

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Summary of Depression

Overview | Causes | Symptoms | Diagnosis | Treatments


Depression is a state of low mood, often associated with hopelessness and apathy.[1] It's not simply sadness, although that may be part of it. Sadness can be a normal temporary response to upsetting events, while depression is more rooted in symptoms that persist for weeks or months and interfere with daily life.

The most common depressive disorder is major depressive disorder (MDD), a condition that affects nearly 322 million people worldwide[2] and is one of the largest contributors to global disability. The World Health Organization (WHO) estimates that the number of people living with depression increased by nearly 20% from 2005 to 2015.

Although estimated to be more common in females[3] and adults, depressive symptoms are frequently found in both sexes and all age groups.[4] Depression often first manifests in young adulthood or teenage years but may not be formally diagnosed until much later.


The causes of depression are complex: brain dysfunction, genetics, environment, biology, age, and psychological factors can all play a role.

One of the first major theories was that depression was caused by low levels of serotonin, a neurotransmitter that notably helps regulate mood.[5] However, more recent studies have contradicted this theory.[6] Some showed that selective serotonin reuptake inhibitors (SSRIs), a type of antidepressant drug, increased serotonin levels instantly, but improvements in patients with depression took weeks.[7] Others showed that using drugs to deplete serotonin in healthy individuals simply caused irritation or temporary insomnia, not depression.[8] 

This has led some researchers to suggest that antidepressants work by mechanisms other than upping serotonin, such as increasing brain-derived neurotrophic factor (BDNF), a molecule associated with brain growth.[9] Because of this, BDNF levels have been proposed as a better observable variable than serotonin levels to indicate the efficacy of antidepressants. But changes in BDNF levels don’t appear to occur uniformly across all antidepressants.[10]

Today, the serotonin hypothesis has lost much of its credibility with neuroscientists and psychiatrists. Several new biological theories of depression have emerged and gained traction, exploring the roles of neuroinflammation,[11] neurotoxicity (more precisely, excitotoxicity[12]), hypothalamic-pituitary-adrenal (HPA) axis dysfunction,[13] and circadian-rhythm abnormalities.[14]

Additionally, observational studies have linked depressive symptoms to nutrient deficiencies[15] and seasonal decreases in sunlight exposure. Unfortunately, in either case, it is difficult to assess whether these links are causal because other variables might be at play. For instance, less sunlight is associated with less exercise, and both are associated with worse sleep.[16] In turn, less exercise[17] and worse sleep are associated with lower mood.[18][19][20]


Symptoms of depression can vary. Below are some of the more common ones. As you can see, diagnosing depression can be tricky, because opposite symptoms can manifest in different people, such as sleeping too much for one and the inability to sleep for another.

  • Aches and pains

  • Anxiety

  • Cramps

  • Digestive problems

  • Fatigue

  • Guilt

  • Headaches

  • Hopelessness

  • Inability to sleep

  • Irritability

  • Loss of appetite

  • Loss of interest in favorite activities

  • Overeating

  • Sadness or emptiness

  • Sleeping too much

  • Thoughts of death or suicide

Personality can factor in also. Some people may become withdrawn and hesitant to socialize, having feelings of guilt and worthlessness, while some may be excessively irritable and hostile. The common thread, again, isn't necessarily sadness but may be mild anhedonia — a diminished ability to feel pleasure.


⚠️ Caution: Don’t self-diagnose

Though diagnosing depression often involves patient-completed questionnaires, it is a much more involved process than our summary may suggest, so don’t self-diagnose. If you suspect you’re depressed, get the opinion of a mental health clinician or your primary care doctor.

By far, the most common way to measure depression is with questionnaires designed to rate the severity of known symptoms of depression. There are other approaches, such as behavioral assessments and neuroimaging, but those are much less common in research.

Mood disorders are difficult to diagnose, notably because they cannot be assessed objectively. To diagnose depression, doctors need to weigh subjective symptoms, such as anxiety, fatigue, insomnia, and low appetite.

Not only are those symptoms subjective, but not everyone living with depression will have them all, and the severity will also differ from person to person.[21] One person with depression may suffer from narcolepsy, serious fatigue, loss of interest, and some anxiety, while another may suffer from serious anxiety, very little fatigue, and insomnia.

Different depression assessment questionnaires can be completed by the patient or the clinician.

Common patient-completed questionnaires include the Beck Depression Inventory-II (BDI-II)[23] and the self-reported 30-item Inventory of Depressive Symptomatology (IDS-SR30).[23] 

Common clinician-completed questionnaires include the Hamilton Depression Rating Scale (HDRS)[24] and the Montgomery-Åsberg Depression Rating Scale (MADRS).[25]

According to the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM–5), the main types of depressive disorders are:

  • Depressive disorder due to another medical condition

  • Disruptive mood dysregulation disorder

  • Major depressive disorder, including major depressive episode)

  • Other specified depressive disorder

  • Persistent depressive disorder (dysthymia)

  • Premenstrual dysphoric disorder

  • Substance/medication-induced depressive disorder

  • Unspecified depressive disorder

These may be further classified by “specifiers”, such as peripartum onset (e.g., postpartum depression), seasonal pattern (e.g., seasonal affective disorder), melancholic features, mood-congruent or mood-incongruent psychotic features, anxious distress, and catatonia (e.g., abnormal movement).


Depression is a complex mental disorder, and there are several barriers to measuring and treating it. Taming it may require long-term work with a trained professional who has good judgment and tries various interventions to see what works best for you.

The subjectivity and variability of depression symptoms from person to person make it hard to establish robust, generalized theories and find treatments that work for everyone. In this section, we will cover some treatments that have shown the most promise as treatment options.


The table below displays an analysis of human studies and indicates how supplements may affect depression.

If you are using an antidepressant, consult your physician before taking any supplement, especially a methylation agent, such as S-adenosyl methionine (SAMe), L-methylfolate, trimethylglycine (betaine), or choline.

Diets & foods

Some trends have emerged across trials investigating dietary interventions’ effects on depressive symptoms. Several align with a Mediterranean-type diet.

Increases in fruits and vegetables, nuts and seeds, and fish appear to be beneficial.[26] Decreases in processed meats, refined carbohydrates, and other highly processed foods have also been associated with greater mental well-being.[27]


Exercise seems to perform at least comparably with the current medical standard of care for mild-to-moderate depression,[28][29] but further work is needed to clarify which types of exercise are most effective.

Observational evidence has indicated that those who meet the Centers for Disease Control and Prevention’s (CDC) guidelines for both aerobic and muscle-strengthening exercise[30] had the lowest prevalence of depressive symptom severity.[31] 

The CDC recommends:

  • 75–150 minutes a week of vigorous-intensity aerobic physical activity, or an equivalent combination of moderate- and vigorous-intensity aerobic activity

  • 2 or more days a week of muscle-strengthening activities


The primary treatment for depression is cognitive-behavioral therapy (CBT),[32] which has shown consistent benefits in many trials.[33] There is still much uncertainty about the extent of its effects, however, and it can be inaccessible to many people due to cost and lack of information.[34]


Today, antidepressants (chiefly SSRIs) are still the first-line treatment for depression, even though they’ve been controversial since becoming available.

A 2008 meta-analysis concluded that although antidepressants were statistically more effective than a placebo in reducing symptoms of depression, their benefits were not clinically meaningful, because the size of the reduction did not meet the guidelines set by researchers.[35]

In 2018 the largest meta-analysis of antidepressants to date combined 522 controlled trials and found that antidepressants led to a small reduction in symptoms of depression. But they were also associated with higher study dropout rates as a result of adverse events.[36]

Some authors have disputed these results,[37] suggesting the benefits are smaller and the risks higher, due to many of the analyzed trials suffering from poor study design, poor choice of statistical analysis methods, and potential publication bias[38] (meaning studies with positive results, considered more interesting, are more likely to be published).

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Human Effect Matrix

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The Human Effect Matrix looks at human studies to tell you what supplements affect Depression.

Full details on all Depression supplements are available to Examine members.
Grade Level of Evidence
Robust research conducted with repeated double-blind clinical trials
Multiple studies where at least two are double-blind and placebo controlled
Single double-blind study or multiple cohort studies
Uncontrolled or observational studies only
Level of Evidence
? The amount of high quality evidence. The more evidence, the more we can trust the results.
Supplement Magnitude of effect
? The direction and size of the supplement's impact on each outcome. Some supplements can have an increasing effect, others have a decreasing effect, and others have no effect.
Consistency of research results
? Scientific research does not always agree. HIGH or VERY HIGH means that most of the scientific research agrees.
grade-a Notable Very High See all 28 studies
Fish oil supplementation has been noted to be comparable to pharmaceutical drugs (fluoxetine) in majorly depressed persons, but this may be the only cohort that experiences a reduction of depression. There is insufficient evidence to support a reduction of depressive symptoms in persons with minor depression (ie. not diagnosed major depressive disorder)
grade-a Notable Very High See all 9 studies
30mg saffron daily (both petals and stigma) appear to be effective in reducing depressive symptoms in persons with major depressive disorder, and the potency has been noted to be comparable to reference drugs (fluoxetine and imipramine).
grade-b Notable Very High See all 8 studies
Curcumin seems to be more effective than placebo in reducing symptoms of depression. It may take 2-3 months to see any outcomes. Skepticism is warranted though, as the studies comparing curcumin to placebo were not well designed and produced effect sizes not too far apart, even though the differences were statistically significant.
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