Key Points
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.
Diagnostic Criteria and Clinical Characteristics
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):
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 or pleasure in most activities; present most of the day, nearly every day.
Weight or appetite change: significant weight loss (not due to dieting) or weight gain (eg, change >5% of body weight in 1 month) and/or significant change in appetite (increase or decrease) present almost daily. Note: can be a failure to make expected weight gain in children.
Sleep disturbance: insomnia or hypersomnia; present nearly every day.
Psychomotor disturbance: observation made by others of psychomotor retardation or agitation; present nearly every day.
Fatigue: loss of energy or fatigue; present nearly every day.
Worthlessness or guilt: feelings of worthlessness and/or excessive or inappropriate guilt; present nearly every day.
Concentration or indecision: subjective report or observation made by others of difficulty thinking or concentrating and/or indecisiveness; present nearly every day.
Suicide: recurrent morbid ideation or recurrent suicidal ideation with or without a specific plan or a suicide attempt.
Course
Depression falls on a continuum of severity ranging from sad mood to diagnosable depressive disorders.
MDD is highly recurrent (over 80% of depressed individuals experience more than one episode) and often chronic (up to 25% of individuals with MDD have a protracted episode).
Median duration of MDD ranges from 19 to 22 weeks across multiple episodes in adults, and mean duration ranges from 26 to 36 weeks in children and adolescents.
Remission is defined as a relatively brief period of symptom improvement after the onset of a major depressive episode (MDE) for at least 3 consecutive weeks but not longer than 4 months; the neurobiology of the MDE is assumed to be active; a return to the MDE before recovery is termed a relapse.
Recovery is defined as a period of symptom improvement lasting at least 4 months after the onset of an MDE; the neurobiology of the MDE is assumed to be resolved; the development of an MDE after recovery is termed a recurrence.
Seasonal affective disorder is a course specifier indicating that depressive episodes occur at a particular time of the year, for at least 2 years, with no episodes occurring during nonseasonal periods.
Age at onset
Earlier age of onset for the first MDE is associated with increased risk for recurrence.
Sex differences
Prevalence rates of MDD are approximately twice as high in females; sex differences emerge after puberty.
Subtypes
Atypical depression is characterized by weight gain, appetite increase, and hypersomnia.
Melancholic depression includes pervasive anhedonia or lack of mood reactivity and at least three of the following symptoms: distinct quality of mood, mood worse in the morning, terminal insomnia, psychomotor disturbance, significant anorexia or weight loss, and excessive guilt.
Sleep
Electroencephalographic (EEG) sleep abnormalities characterize 40% to 60% of outpatients and up to 90% of inpatients with an MDE. Persistence of these abnormalities into remission is associated with increased risk for relapse or recurrence.
Screening and Counseling
There is only limited evidence from family studies for the role of genetic factors in antidepressant medication response.
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