Definition and Etiology

Depression is a descriptive term often misused as a diagnostic label. Its misapplication can lead to diagnostic errors and mismanagement. Depression is more aptly used to describe a symptom-behavior complex that can be the predominant clinical manifestation of a heterogeneous group of disorders including major depressive disorder (MDD), bipolar disorder (BPD), substance-induced mood disorders, and mood disorder due to a general medical condition.

The symptoms of MDD are nonspecific and, therefore, are easily confused with a long list of other psychiatric and medical illnesses. Accurate recognition requires that the clinician have a high index of suspicion and know the diagnostic criteria for MDD. In this regard, it is important to distinguish a major depressive episode (MDE) from MDD.

An MDE typically represents a single or recurrent episode of MDD, but not necessarily. It could be a consequence of chronic substance abuse, a transient response to life-altering medical illness, or an episode of BPD. In each of these examples, the approach to comprehensive management of an MDE differs from the management of an MDE occurring in the context of MDD.

Like other medical illnesses, MDD has significant morbidity and mortality.1 It often complicates other conditions (e.g., diabetes mellitus, stroke, cancer, heart disease) and makes them more difficult to treat.2 It also accelerates mortality from these and other medical illnesses.3

Prevalence and Risk Factors

The National Comorbidity Survey Replication (NCS-R) is the most recent, broad-based assessment of MDD in the community.4 The NCS-R gathered data on prevalence rates, severity, disability, and rate and quality of treatment for MDD. The 12-month and lifetime prevalence of clinically significant MDD in the NCS-R were 6.6% and 16.2%, respectively. MDD tends not to occur in isolation; 75% to 80% of persons with either 1-year or lifetime MDD had a comorbid anxiety or substance-related disorder. Although 51.6% of patients received some treatment, only 21.7% of the total population of patients with MDD received adequate treatment during a 1-year period.

The first MDE usually occurs during adolescence or early adulthood. There is a bimodal curve of prevalence, with one peak in the late 20s and early 30s and a second peak around 65 to 70 years of age.

Women are affected by MDD two to three times more often than men. This may be explained by psychobiologic risk factors (e.g., menstrual cycle, pregnancy, or gender-related vulnerability to interpersonal conflict or loss) and women’s tendency to seek health care more than men do.

MDD occurs at higher rates in patients who seek general medical care. Nearly 70% of all antidepressant prescriptions are written by primary care physicians.5 Depressed patients are high users of medical care, and high users of medical care, in general, are more likely to have one or more psychiatric disorders. In one study, the 1-month prevalence of MDD in a group of high users was 40.3%.6

The risk of developing MDD is manifold and complex.7 Risk factors include:

Stress is a common, although not invariable, trigger of MDEs, and anyone can develop an MDE. Some, however—especially those with recurrent episodes and family histories of mood, anxiety, or substance abuse disorders—are more likely to develop an MDE even when stress levels are judged to be low. Certain medical disorders (e.g., stroke, neurodegenerative disorders, human immunodeficiency virus [HIV] infection, acquired immunodeficiency syndrome [AIDS], endocrine disorders) are associated with a higher than expected rate of MDD. Diabetes, for example, doubles the odds of comorbid MDD.8 A meta-analysis of studies that examined the prevalence of MDD in adults with diabetes showed that the prevalence of comorbidity was significantly higher in diabetic women (28%) than in diabetic men (18%), and in clinical (32%) rather than community (20%) samples.8

Pathophysiology and Natural History

Emerging data support the hypothesis that stress, genetic predisposition, and early-life experiences interact to increase the risk of MDD. Our understanding of the precise pathophysiologic mechanisms of MDD continues to evolve.

Family and twin studies suggest that genetic factors predispose to recurrent MDD.7 There is no one depression gene, nor is depression determined exclusively by genetic factors. Rather, it is more likely that multiple interacting genes code for factors that influence both vulnerability and resilience in the face of stress. One such factor appears to be a polymorphism in the promoter region of the serotonin transporter gene.9,10

The timing of stress is also important. Abnormal stress (e.g., neglect, abandonment, physical or sexual abuse) at critical developmental periods can have long-lasting effects on central nervous system development and function.11

A variety of studies suggest that brain regions involved in depression include the amygdala, hippocampus, hypothalamus, and prefrontal cortex.12 The presence of dense projections from the subgenual cingulate to the serotonin-rich brainstem dorsal raphe nucleus suggests that this cortical area plays some role in regulating serotoninergic activity, an activity that may be impaired in depression.12

Understanding of the biology of neurotransmission has progressed significantly beyond an appreciation of neurotransmitter synthesis, release, and activation of postsynaptic cell-surface receptors.13 Signal transduction pathways mediated by second and third messengers (e.g., cyclic adenosine monophosphate [cAMP], protein kinases, and neurotrophic factors) affect gene expression and protein production, with consequent re-regulation of neurotransmission and clinical improvement. The rate of gene expression corresponds more closely to the rate of antidepressant-associated clinical improvement (i.e., weeks) than the more-rapid changes in neurotransmission (i.e., hours to days). Moreover, studies of treatment response suggest a close correlation between antidepressant use and increased levels of proteins, such as brain-derived neurotrophic factor (BDNF).13 Central hypercortisolemia can mediate stress-induced effects on the brain that are reversed by antidepressant-induced BDNF production.11,13

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