Research on Major Depression

Abstract

DEPRESSION IS AN ILLNESS THAT FREQUENTLY STARTS early in life, tends to run a chronic course, and produces substantial disability. According to the World Health Organization, depression is the leading global cause of years of life lived with disability and the fourth leading cause of disability-adjusted life-years, a measure that takes premature mortality into account. Depression is not only widespread and common, it may be fatal; an estimated 90% of suicides are associated with mental illness, most commonly depression. There were nearly 30000 suicides in the United States in 1999, almost twice the number of homicides. Suicide has become the third leading cause of death in individuals aged 15 to 24 years. Despite the high morbidity and mortality associated with depression, the etiology and pathophysiology of depression have not been precisely defined. Depression as currently diagnosed likely represents a heterogeneous set of disorders, usually characterized by sad mood and anhedonia (inability to experience pleasure), but often including profound abnormalities in cognition and neurovegetative, or physiological, function. Recent progress has occurred in identifying the neural circuits and neurochemicals involved in the vulnerability toward depressive illness. Neuroimaging studies have revealed abnormalities in several regions of the prefrontal cortex, amygdala, and hippocampus. Abnormalities in the regulation of neurotransmitters, including serotonin, norepinephrine, dopamine, glutamate, and -aminobutyric acid, and hormones and neuropeptides, such as cortisol, corticotrophin-releasing hormone, neuropeptide Y, and substance P, have been reported, any or all of which potentially suggest novel drug targets. However, none of these findings has resulted in a specific biomarker or diagnostic test for depression. In addition, vulnerability genes for depression have not been identified, although recently several genes associated with risk for other neuropsychiatric disorders have been reported. Depression is now recognized as a multisystem disorder affecting brain and body. It has been associated with alterations in endocrine, cardiovascular, and immune systems as well as changes in bone metabolism. These effects appear to have important medical consequences. For example, after a myocardial infarction, patients with depression have a 3.5-fold increase in cardiovascular mortality relative to patients without depression after a myocardial infarction. The impact of depression on post–myocardial infarction survival has been found to be at least equivalent to that of left ventricular dysfunction and history of previous myocardial infarction. Patients with depression also appear to be more likely to develop stroke, diabetes, and osteoporosis. Although the presence of depression has negative consequences on the prognosis of these illnesses, recent evidence suggests that treating depression may alter the course of comorbid medical illnesses. For instance, in patients with depression and diabetes, both antidepressants and cognitive behavior therapy decreased glycosylated hemoglobin levels. What is perhaps most remarkable about depression is there has been far more success in treating this illness than in understanding it. Antidepressants are generally effective, in that most studies demonstrate at least a 50% decrease in symptoms for about 70% of patients. Although all currently used antidepressants block uptake of 1 or more of the monoamines (serotonin, norepinephrine, or dopamine), the relationship of these neurochemical effects, which occur within hours, to the therapeutic effect, which requires several weeks, remains unclear. In addition to the medications used as antidepressants, specific structured psychotherapies have been shown to treat depression, particularly in less severe, nonpsychotic patients. What are the priorities and future directions for studies of depression? Last year the National Institute of Mental Health published a Strategic Plan for Mood Disorders that addressed this issue. The priority areas can be summarized as follows: Identify the vulnerability genes for depression. Several forms of depression have been identified based on clinical presentation. Some, such as bipolar disorder, are clearly heritable and undoubtedly polygenic. The discovery of the genes that confer vulnerability to bipolar disorder and other forms of depression may provide biomarkers, pathophysiological mechanisms, and new therapeutic targets.