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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. MDD exhibits a genetic pattern and if accompanied by significant life stressors, chances for depressive episodes increase.

Classic views for the cause of MDD focus on the deficiency of neurotransmitters such as norepinephrine (NE), serotonin (5-HT), and dopamine (DA) and/or abnormal functioning of these 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. Glutaminergic neurotransmission via the N-methyl-D-aspartate (NMDA) pathway has also been shown to play a critical role in the neuropathology of depression, which is the target of the intranasal medication for treatment-resistant depression, esketamine (Spravato).

Although 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. The diagnosis of MDD requires the presence of at least five depressive symptoms present nearly every day for a minimum of a 2-week period. These symptoms must cause clinically significant impairment in one's ability to function at home, work, or school. One of these symptoms must include depressed mood or loss of interest or pleasure.

TABLE 60-1Clinical Presentation of Major Depressiona

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