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Major depressive disorder (MDD) is diagnosed when an individual experiences one or more major depressive episodes without a history of manic or hypomanic episodes. An MDD episode is defined by the criteria listed in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5). Depression is associated with significant functional disability, morbidity, and mortality. Individuals with MDD experience symptoms that can affect mood, thinking, physical health, work, and relationships. Unfortunately, suicide may be a result of MDD that has not been diagnosed or treated adequately.


The exact cause of MDD is unknown, but appears to be multifactorial. There are many biologic, psychological, and social theories that attempt to explain depressive disorders, but none of them do so completely. Most individuals have a variety of factors that contribute to the onset and severity of their symptoms.

  1. Genetics: The occurrence of MDD exhibits a genetic pattern. First-degree relatives of MDD patients are more likely to develop MDD compared to first-degree relatives of control individuals.

  2. Stress/Environmental: Depression can occur in the absence or presence of major life stressors or environmental and household stressors. In addition, when a genetic predisposition accompanies significant life stressors, chances for depressive episodes increase.

  3. Neurotransmitter and receptor: Classic views for the cause of MDD focus on the neurotransmitters such as norepinephrine (NE), serotonin (5-HT), and dopamine (DA). The neurotransmitter hypothesis asserts that depression is due to a deficiency of neurotransmitters. The supporting evidence for this hypothesis is that existing antidepressants increase neurotransmitters concentrations. The neurotransmitter receptor hypothesis suggests that depression is related to abnormal functioning of neurotransmitter receptors. In this model, antidepressants exert therapeutic effects by altering receptor sensitivity. Chronic administration of antidepressants causes desensitization (downregulation) of β-adrenergic receptors and various 5-HT receptors. Importantly, the time required for changes in receptor sensitivity corresponds to the onset of action of antidepressant therapy.

While such models of depression are useful in conceptualizing the mechanisms behind antidepressant activity, they most likely represent an oversimplification of the actual pathophysiological process of the disorder. Depression likely involves a complex dysregulation of neurotransmitter systems, and these systems modulate or are modulated by other biologic systems. Thus, the underlying cause of depression may extend beyond dysfunction of the neurotransmitter system.

Clinical Presentation and Diagnosis

Patients with MDD present with a combination of emotional, physical, and cognitive symptoms. Table 60-1 lists the clinical presentation of patients with depression. Symptoms of a major depressive episode develop over days to weeks, but mild depressive and anxiety symptoms may be present for weeks to months prior to the onset of the full syndrome. Left untreated, major depressive episodes may last 6 months or more. A minority of patients experience chronic episodes that can last for at least 2 years. Approximately two-thirds of patients recover fully from major depressive episodes and return to ...

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