Research on Major Depression: Title and subTitle BreakStrategies and Priorities

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.¹ Depression is not only widespread and common, it may be fatal; an estimated 90% of suicides are associated with mental illness, most commonly depression.² There were nearly 30 000 suicides in the United States in 1999, almost twice the number of homicides.³ Suicide has become the third leading cause of death in individuals aged 15 to 24 years.⁴

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.⁵ Abnormalities in the regulation of neurotransmitters, including serotonin, norepinephrine, dopamine, glutamate, and γ-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.⁶ 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.⁷

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.^{8 - 10} 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.¹¹ 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.¹¹ Patients with depression also appear to be more likely to develop stroke, diabetes, and osteoporosis.¹² 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.¹³

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.⁶ 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.¹⁴

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.¹⁵ 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.¹⁶ 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.

Describe the neural basis for mood regulation and dysregulation. Although some key neural systems involved in depression are being identified, how the brain changes during the transition from mild to moderate-to-severe depression remains unknown. The neural plasticity that permits recovery, whether from medication or psychotherapy, is also an important and intriguing area for exploration.

Define the developmental risk factors for depression. Although genes confer vulnerability to depression, certain forms of experience (stress, loss, abuse) either in childhood or adulthood appear to increase the risk of depression, often with a prolonged latency. Neuroscience now has the tools to define how experience alters gene expression or neural function. Relating these effects to the risk of depression may yield an important strategy for prevention in high-risk individuals.

Develop new treatments. Virtually all of the pharmacological treatments for depression are variations on a theme established 40 years ago. Although selective serotonin reuptake inhibitors are generally safe and effective, they require prolonged use (at least 3-4 weeks) to reduce depressive symptoms and persistent (years in recurrent depression) administration to prevent relapses. New classes of medications with rapid and sustained effects are needed, as are nonpharmacological treatments that are effective for patients who cannot or will not take medications.

Reduce suicide. Although the risk of suicide is not limited to depression, suicide remains a serious risk for patients with depression, especially patients with a history of impulsive behavior. Effective strategies that specifically prevent suicide in patients with depression must be developed.

Decrease the impact of depression on comorbid illnesses. Depression is a multisystem disorder. Despite the importance of depression as a risk factor for the outcome of cardiovascular disease or diabetes, depression is underrecognized and undertreated in primary care settings.

Address the disturbing gap between what is known and what is applied in clinical practice. Most physicians should know how to treat depression, but only 25% of patients with depression receive appropriate psychopharmacological or psychosocial treatment.¹⁷ In 1 study, almost half of suicides younger than 25 years had previously attempted suicide, most of them within the previous year, yet less than 25% were receiving specialty mental health care.¹⁸ Many older adults, as much as 75%, who die by suicide, have visited a primary care physician within a month of their suicide.¹⁹

Patients with depression feel hopeless, helpless, and worthless. These symptoms of the disorder may preclude seeking treatment, because many patients with depression believe they are not worthy of feeling better. Many patients may feel the stigma of seeking treatment is greater than the stigma of living with the disorder.²⁰ A recent National Institute of Mental Health public awareness campaign has attempted to address some of these barriers to seeking care, especially in men with depression.²¹

Depression is a serious common medical disorder with high morbidity and mortality. Although much remains to be discovered about the etiology of this illness, safe and effective treatments are available. Sadly, too often these treatments are not used when they are needed or are given at a dose or for a duration that is ineffective. Research to decrease the burden of living with depression must not only discover the genes, cells, and circuits for this illness, but must also address the translation of new research findings into improved care for patients in real world settings.