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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, mixed, or hypomanic episodes. An MDD episode is defined by the criteria listed in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision (DSM-IV-TR).1 Depression is associated with significant functional disability, morbidity, and mortality. Individuals with MDD experience significant and pervasive symptoms that can affect mood, thinking, physical health, work, and relationships. Unfortunately, suicide may be a result of MDD that has not been diagnosed and treated adequately.

The true prevalence of MDD in the United States is unknown. The National Comorbidity Survey Replication found that 16.2% of the population studied had a history of MDD in their lifetime, and more than 6.6% had an episode within the past 12 months.2 Women are twice as likely as men to experience MDD. Although MDD may begin at any age, the average age of onset is the mid-20s.1 MDD patients may also suffer from anxiety disorders and substance-use disorders.2


The exact cause of MDD is unknown, but appears to be multifactorial. There are biologic, psychological, and social theories that attempt to explain depressive disorders, however, none of them do so completely.

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.

Stress: Depression can occur in the absence or presence of major life stressors. However, there is an association between life stressors and depression. In addition, when a genetic predisposition accompanies significant life stress chances for depression increase.

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.3-4 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 (down regulation) of beta 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.3-4

While such models of depression are useful in conceptualizing the mechanisms behind antidepressant activity, they most likely represent an oversimplification of the actual pathophysiology 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.5

Clinical Presentation and Diagnosis

MDD patients typically present with a ...

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