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Key Points

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  • Disease summary:

    • Major depressive disorder (MDD) is a common and debilitating mood disorder associated with high morbidity and mortality.

    • It is estimated that 10% to 20% of the general population will experience clinical depression during the lifetime; rates differ by age (0.3%-2.5% for children, 10%-20% for adolescents and adults), gender (with women having about twice the risk compared to men), and ethnicity (with higher rates in non-Hispanic Whites).

    • MDD is characterized by both clinical and etiologic heterogeneity, involving a complex interplay among genetic, biologic, personality, cognitive, interpersonal, and environmental factors.

  • Differential diagnosis:

    • Unipolar depression must be distinguished from bipolar disorder, bereavement, and mood disorders due to general medical conditions, substance use, or toxin exposure.

  • Monogenic forms:

    • No single gene cause of MDD is known to exist.

  • Family history:

    • There is a two- to threefold increased risk for the illness among first-degree relatives of probands with MDD. Family history of MDD is also associated with early age of onset and recurrence.

  • Twin studies:

    • Heritability estimates for MDD based on monozygotic versus dizygotic twin concordance differences exhibit a modest heritable contribution of 37%, with a greater estimated contribution of 42% for women versus 29% for men. Evidence suggests that 31% to 42% of variance in liability to depression can be explained by additive genetic effects, 58% to 67% by individual specific environmental effects, and 0% to 5% by shared environmental effects.

  • Environmental factors:

    • Strong evidence supports a link between stressful life events and the onset and maintenance of depression in both children and adults. Childhood trauma is associated with increased risk for early-onset depression and alterations in the hypothalamic-pituitary-adrenal (HPA) axis that are characteristic of depression.

  • Genome-wide associations:

    • No studies have identified specific genetic variants that achieved genome-wide significance. Such studies require large-scale samples, with several thousand cases to study main effects and several tens of thousands of cases to investigate gene × gene or gene × environment interactions. Such large-scale samples have not been recruited into genome-wide association studies (GWASs) of MDD.

  • Pharmacogenomics:

    • Although evidence suggests that genes implicated in pharmacokinetics or pharmacodynamics of antidepressant medications may predict response, replication of findings has been hampered by heterogeneity among samples across studies and because treatment outcome is likely determined by a combination of genetic variants exerting only modest unique effects.

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Diagnostic Criteria and Clinical Characteristics

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Diagnostic Criteria for Unipolar Major Depressive Disorder

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Diagnostic evaluation should include five or more of the following symptoms, including depressed mood and/or anhedonia, present for at least two consecutive weeks and causing clinically significant distress or impairment in important areas of functioning (eg, social, occupational, self-care):

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  • Depressed mood: either subjective report (eg, feeling sad or empty) or observation made by others (eg, appears tearful); present most of the day, nearly every day. Note: can be irritable mood in children and adolescents.

  • Anhedonia: either subjective report or observation made by others of markedly diminished interest ...

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