Major Depressive Disorder

Major depression is one of the most common mental disorders in the United States and is a leading cause of disability worldwide.1,2

Major depressive disorder (MDD) is a chronic, heterogeneous disorder that causes changes in an individual’s mood, thoughts, and behavior.3


It is estimated that 5% of the world’s population is living with depression.2 According to the National Institute of Mental Health, 8.4% of all U.S. adults (approximately 21 million people) had at least one major depressive episode in 2020.1 These episodes occurred at a higher rate among adult females (10.5%) compared to adult males (6.2%). The most affected age group was individuals aged 18-25, with 17.0% experiencing at least one episode, as compared to 9.1% of those aged 26-49, and 5.4% of those over age 50. Multiracial individuals (those who reported having two or more races) had the highest prevalence of major depressive disorder (15.9%), followed by individuals who reported being White (9.5%), Hispanic/Latino (7.0%), Black/African American (6.0%), Asian (4.2%), and Native American or Alaska Native (4.2%).

The risk for MDD is estimated to be 2- to 4-fold higher among first-degree family members of individuals with MDD, compared to the general population.3 Though MDD may first appear at any age, the incidence of first episodes increases significantly with puberty. The incidence of MDD in the U.S. appears to peak for individuals in their 20s, though it is not uncommon for individuals to experience a first major depressive episode later in life.


In order to meet diagnostic criteria for MDD, an individual has to have at least 5 symptoms, including at least 1 of the 2 core symptoms, during the same 2-week period and they must represent a change from previous functioning.3 The core symptoms, which must be present for most of the day, nearly every day, are depressed mood and loss of interest or pleasure. The other diagnostic symptoms, which must be present nearly every day, are:

  • Significant weight loss (when not dieting) or significant weight gain, or change in appetite
  • Insomnia or hypersomnia
  • Psychomotor agitation or retardation
  • Fatigue or loss of energy
  • Feelings of worthlessness or excessive or inappropriate guilt
  • Diminished ability to think or concentrate, or indecisiveness
  • Recurrent thoughts of death or suicidal ideation

Note: Nearly every day does not apply to weight change or thoughts of death or suicide

Symptoms of a depressive episode (≥2 weeks) must cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.3 The episode should not be attributable to the effects of a substance or another medical condition​​, and cannot be better explained by other psychotic, delusional, or other specified or unspecified schizophrenia spectrum disorders. Additionally, the diagnosis of MDD requires that the patient has never had a manic or a hypomanic episode.


While in recent years considerable advances have been made to understand the genetic risk factors associated with depression, its fundamental etiology remains poorly understood. Known risk factors are female sex, childhood history of abuse, family history and recent life stressors; however, we have yet to determine exactly how genetics influence environmental risk factors and vice versa.4 The genetic component to depression is thought to contribute 30-40% of variance, while non-genetic / environmental factors are thought to have an influence of 60-70%.5

Numerous hypotheses have implicated different physiologic systems in depression, based on observed variations in function, including:6

  • Structural and functional abnormalities in neural circuitry
  • Chronic stress and hyperactivity of the hypothalamic-pituitary-adrenal axis
  • Biogenic monoamines, such as serotonin
  • Inflammation, indicated by pro-inflammatory markers such as C-reactive protein (CRP), interleukin (IL)-6, IL-1 and tumor necrosis factor alpha (TNF-α)
  • Neuropeptides such as substance P
  • Hormone dysregulation, including thyroid hormones, estrogen dysregulation, and vasopressin.

Research continues regarding these factors in relation to the pathogenesis of MDD.

Navigating MDD

Timely diagnosis and management of MDD is important to improve the heavy personal, societal,  and economic burden of MDD. In 2018, the incremental economic burden of adults with MDD in the U.S., including costs related to suicide and workplace costs, was $326.2 billion.7

MDD also increases the risk for other diseases:

  • Individuals with MDD may be 40% to 100% more likely to develop coronary artery disease.8,9
  • The odds ratio for obesity ranges from 1.37-1.71 among individuals with MDD.10
  • The comorbidity of MDD and metabolic syndrome has also been well recognized, though risk estimates have varied greatly across studies.11

A variety of validated tools are available for screening, diagnosis, and monitoring of MDD.12,13 Measurement based care (MBC) facilitates symptom monitoring, can improve collaborative care efforts as well as treatment response, and can increase satisfaction with care.14

After a patient is diagnosed with MDD, the goal of treatment during the acute phase of illness is to achieve symptom remission and improve the patient's functioning.12 During the continuation phase of treatment, patients’ symptoms (including signs of relapse), side effects, adherence, and functional status should be monitored. Maintenance treatment is also recommended, particularly for patients with residual symptoms, previous episodes, and ongoing psychosocial stressors. Treatments for depression may include pharmacotherapy; depression-focused psychotherapy; the combination of medications and psychotherapy; other somatic therapies such as electroconvulsive therapy, transcranial magnetic stimulation, or light therapy; or complementary or alternative therapies.12 Pharmacological treatment may not be appropriate for all patients with MDD.