Depression 

As many as two thirds of people with depression do not realize that they have a treatable illness and therefore do not seek treatment. In addition, persistent ignorance and misperceptions of the disease by the public, including many health providers, as a personal weakness or failing that can be willed or wished away leads to painful stigmatization and avoidance of the diagnosis by many of those affected.

Depression classifications include major depressive disorder (MDD), depression with melancholic or catatonic features, atypical depression, and seasonal affective disorder (SAD).

In the primary care setting, where many of these patients first seek treatment, the presenting complaints often can be somatic, such as fatigue, headache, abdominal distress, or change in weight. (See Clinical Presentation.)

The differential diagnosis for depression includes other psychiatric disorders, CNS diseases, endocrine disorders, drug-related conditions, infectious and inflammatory diseases, and sleep-related disorders. (See Differentials.)

Depression screening tests can be used to screen for depression and bipolar disorder. The most widely used is the Hamilton Depression Rating Scale (HDRS). It is important to understand that the results obtained from the use of any depression rating scales are imperfect in any population, especially the geriatric population. (See Workup.)

Many effective treatments are available for major depressive disorder, including brief psychotherapy (eg, cognitive-behavioral therapy, interpersonal therapy), used either alone or in combination with medication. However, the combined approach generally provides the patient with the quickest and most sustained response. (See Treatment Strategies and Management.)

All antidepressants are potentially effective, with 2-6 weeks at a therapeutic dose level needed to achieve clinical response. The choice of medication should be guided by anticipated safety and tolerability, physician familiarity, and history of previous treatments. (See Medications.)

The underlying pathophysiology of major depressive disorder has not been clearly defined. Clinical and preclinical trials suggest a disturbance in central nervous system (CNS) serotonin (5-HT) activity as an important factor. Other neurotransmitters implicated include norepinephrine (NE) and dopamine (DA).^[1]

The role of CNS 5-HT activity in the pathophysiology of major depressive disorder is suggested by the efficacy of selective serotonin reuptake inhibitors (SSRIs) in the treatment of major depressive disorder. Furthermore, studies have shown that an acute, transient relapse of depressive symptoms can be produced in research subjects in remission using tryptophan depletion, which causes a temporary reduction in CNS 5-HT levels. Serotonergic neurons implicated in affective disorders are found in the dorsal raphe nucleus, the limbic system, and the left prefrontal cortex.

Seasonal affective disorder is a form of major depressive disorder that arises during the winter and resolves during the spring and summer. Studies suggest that seasonal affective disorder is also mediated by alterations in CNS levels of 5-HT and appears to be triggered by alterations in circadian rhythm and sunlight exposure.

Vascular lesions may contribute to depression by disrupting the neural networks involved in emotion regulation—in particular, frontostriatal pathways that link dorsolateral prefrontal cortex, orbitofrontal cortex, anterior cingulate, and dorsal cingulate.^[2] Other components of limbic circuitry, in particular the hippocampus and amygdala, have been implicated in depression.

Functional neuroimaging studies support the hypothesis that the depressed state is associated with decreased metabolic activity in neocortical structures and increased metabolic activity in limbic structures.^[3] In recent years, an abnormality in an area of the brain that helps to control emotional reactions has been found and contributes to a new understanding of why persons develop depression and other affective disturbances.

By using positron emission tomographic (PET) images, researchers found an area of the prefrontal cortex with an abnormally diminished activity in patients with unipolar depression and bipolar depression. This region is related to emotional response and has widespread connections with other areas of the brain. These other areas are responsible for the regulation of DA, noradrenaline, and 5-HT, which have important roles in the regulation of mood.

An integrative model of late-onset depression posits that age-related brain changes and disease-related changes (eg, cerebrovascular disease), coupled with physiologic vulnerabilities (eg, genetic risk factors, personal history of depression) and psychosocial adversity, lead to disruptions in the functional circuitry of emotion regulation (namely, hypometabolism of cortical structures and hypermetabolism of limbic structures), resulting in the clinical manifestations of depression.^[2]

Endocrine changes in depression are evident across the life span, but some are unique to aging. Women with a previous history of depression are at higher risk of developing depression during menopause, suggesting a role for estrogen in mood regulation; low testosterone levels have been associated with depression in older men.

The specific cause of major depressive disorder is not known. As with most psychiatric disorders, major depressive disorder appears to be multifactorial in its origin.

According to the American Academy of Child and Adolescent Psychiatry (AACAP) practice parameters for depressive disorders in childhood and adolescence, a history of a previous depressive episode, subsyndromal symptoms of depression, dysthymia, and anxiety disorders increase the risk for future depression.^[4]

Symptoms of major depression in adolescence strongly predicted adult episodes of major depression in a study of an epidemiologic sample of 776 adolescents by Pine and associates.^[5]

Genetics

Genetic susceptibility plays a role in the development of major depressive disorder. Individuals with a family history of affective disorders (7%), panic disorder, and alcohol dependence (8%) carry a higher risk for major depressive disorder. Studies such as those reported by Akiskal and Weller^[6] and Weissman et al^[7] suggest a genetic component in the etiology of depressive disorders.

Nobile et al found that human platelet 5-HT uptake is differentially influenced in children with and without depression by a common genetic variant of the promoter region of 5-HT.^[8] Birmaher et al found that, before onset of affective illness, children who were at high risk had the same pattern of neuroendocrine response to 5-hydroxy-L-tryptophan (L-5-HTP) challenge as did children with major depression.^[9] These findings could constitute the identification of a trait marker for depression in children.

Some evidence suggests that late-onset depression (after age 60 y) is an etiologically and clinically distinct syndrome^[10] and that genetic factors likely play less of a role in late-onset than early-onset depression. A family history of depression is less common among older adults with depression than younger adults. However, certain genetic markers have been, although inconsistently, associated with late-onset depression, including polymorphisms of the apolipoprotein E, BDNF, and 5-HT transporter genes. Interestingly, these markers have also been associated with cognitive impairment, hippocampal volume, and antidepressant response, respectively.

Stressors

Although major depressive disorder can arise without any precipitating stressors, stress and interpersonal losses certainly increase risk. Psychodynamic formulations find that significant losses in early life predispose to major depressive disorder over the lifespan of the individual, as does trauma, either transient or chronic. Cognitive-behavioral models of depression posit that depression is a behavioral response to repeated stressors and that cognitive distortions (ie, negative thoughts) contribute to and perpetuate depressed mood.^[10]

Chronic pain, medical illness, and psychosocial stress can also play a role in both the initiation and maintenance of major depressive disorder. Older adults may perceive medical illness as psychologically distressing, and these illnesses may lead to increased disability, decreased independence, and disruption of social networks.^[11] Other psychosocial risk factors for depression in late life include the following^[12] :

• Impaired social supports
• Caregiver burden
• Loneliness
• Bereavement
• Negative life events

In addition, neurochemical hypotheses point to the deleterious effects of cortisol and other stress-related substances on the neuronal substrate of mood in the CNS.

Exposure to certain pharmacologic agents also increases the risk of depression; medications such as reserpine or beta-blockers, as well as abused substances such as cocaine, amphetamine, narcotics, and alcohol, are associated with higher rates of major depressive disorder.

A meta-analysis that included all relevant studies exploring the interaction between a serotonin transporter promoter polymorphism (5-HTTLPR) and stress in the development of depression suggests that 5-HTTLPR moderates the relationship between stress and depression.^[13]

Neuroendocrine abnormalities and neurodegenerative diseases

Prepubertal children who were depressed had lower cortisol secretion during the first 4 hours of sleep than did children in the control group, according to De Bellis et al, who studied neuroendocrine changes in depressed prepubertal children.^[14] The investigators examined nocturnal secretion of adrenocorticotropin (ACTH), cortisol, growth hormone (GH), and prolactin (PL) in the groups with depression and control groups, respectively. ACTH, GH, and PL secretion did not differ between the 2 groups.

Possible abnormalities of the neurotransmitter systems remain under investigation.

Neurodegenerative diseases (especially Alzheimer disease and Parkinson disease, stroke, multiple sclerosis, seizure disorders, cancer, macular degeneration, and chronic pain have been associated with higher rates of depression.^[15]

Parent-child relations

The parent-child relation model conceptualizes depression as the result of poor parent-child interaction. Adults with depression report low paternal involvement and high maternal overprotection during early childhood. Troubled relationships with parents, siblings, and peers are common in children and adolescents with affective illness. A child who is affectively ill often has a parent who is affectively ill.

It is not uncommon for children to report abuse and/or neglect by parents who are affectively ill. Childhood abuse and neglect, as well as a cumulative load of stressors over a lifetime, have both been associated with late-onset depression. Hammen et al reported a significant temporal association between mother and child.^[16] They found that children with substantial stress exposure who also had symptomatic mothers were significantly more depressed than children who were exposed to comparable levels of stress only.

Vascular depression

The vascular depression hypothesis posits that cerebrovascular disease may cause or contribute to late-life depression. Various lines of evidence support this hypothesis, including the following:^[17]

• Higher incidence of depression following a stroke
• Higher prevalence of ischemic white-matter changes in older adults with depression than those without
• Bidirectional association between depression and coronary artery disease (CAD)
• Higher rates of depression among patients with vascular dementia than those with Alzheimer disease

The lifetime incidence of major depressive disorder in the United States is 20% in women and 12% in men. The prevalence is as high as 10% in patients observed in a medical setting. Klerman^[18] and Gershon et al^[19] reported a progressive increase in the lifetime cases of major depression over the last 70 years, with high rates of affective disorders among relatives and a younger age of onset in successive cohorts. In 2010, the Centers for Disease Control and Prevention (CDC) released a report estimating the prevalence of current depression among adults from 2006-2008. Among 235,067 adults, 9% met the criteria for current depression, including 3.4% who met the criteria for major depression.^[20]

Internationally reported adult prevalence rates of depression generally mirror those of the United States, and estimates of prevalence of depression among community-dwelling elderly are surprisingly consistent (eg, England, 2.9%; The Netherlands, 2.0%; Sweden, 5.6%; Nigeria, 1.6%). However, sparse data are available on the international incidence of major depression in children and adolescents.

Helgason examined the entire Icelandic birth cohort of 1895-97 with periodic follow-up until cohort individuals reached age 74-76 years. The lifetime estimates of risk for any affective disorder were 14.8% for females and 9.8% for males.^[21] The World Health Organization (WHO) collaborative study on the assessment of depressive disorders found considerable similarity in depressive symptomatology across cultures in Canada, Iran, Japan, and Switzerland.^[22]

The Stirling County Study, which began shortly after World War II, offered a 40-year perspective of the prevalence and incidence of psychiatric disorders among an adult population in Atlantic Canada, in which the overall prevalence of depression remained stable at 5% across 3 separate samples in 1952, 1970, and 1992. In the 2000 sample, however, the prevalence had shifted from older to younger persons, and the female-to-male ratio had increased.^[23]

Copeland et al found widely ranging prevalences for depression in elderly persons in 9 European populations. The prevalence for females was higher than that for males, and there was no constant association between prevalence and age. Meta-analysis revealed an overall prevalence of 12.3% and sex frequencies of 14.1% for females and 8.6% for males.^[24]

Children and adolescents

In prepubertal children, boys and girls are affected equally. Hankin et al found that the most critical time for sex differences in depression to emerge is from age 15-18 years.^[25] During this period, the increase of the overall rates of depression and onset of new cases of depression peak.

The incidence of depression was 0.9% in preschool-aged children, 1.9% in school-aged children, and 4.7% in adolescents in a study by Kashani and Sherman.^[26]

More than 22% of female high school students and more than 11% of male high school students reported 1 current or lifetime episode of unipolar depression in one study. In this same study, the percentage of male students with 2 or more episodes of unipolar depression was 4.9%; it was 1.6% in female students.^[27]

Hispanic youths in Los Angeles county (aged 12-17 y) reported more symptoms of depression, independent of socioeconomic status, when compared with white, black, or Asian American adolescents, using the Children's Depression Inventory (CDI), according to an epidemiologic study by Siegel et al.^[28] This study also found significant effects of social class on depression. As income decreased, the average level of depression increased.

The 1-year incidence of major depression was 3.3% in adolescents aged 11-16 years in the southeastern US, according to Garrison et al.^[29]

Elderly persons

Although rates of depression in women and men are highest in those aged 25-44 years, the incidence of clinically significant depressive symptoms increases with advancing age, especially when associated with medical illness or institutionalization. However, the depression might not meet criteria for major depression (see Clinical Presentation, Major Depressive Disorder) because of somewhat atypical features of depression in elderly persons.

Minor depression and major depression

The prevalence of minor depression or subsyndromal depression is likely higher than that of major depressive disorder; levels of functional impairment, medical burden, and quality of life are lower than in major depressive disorder but higher than in older adults without any depression.^[30]

Major depressive disorder is a disorder with significant potential morbidity and mortality, contributing as it does to suicide, medical illness, disruption in interpersonal relationships, substance abuse, and lost work time.

With appropriate treatment, 70-80% of individuals with major depressive disorder can achieve a significant reduction in symptoms, although as many as 50% of patients may not respond to the initial treatment trial. Forty percent of individuals with major depressive disorder untreated at 1 year will continue to meet criteria for the diagnosis, whereas an additional 20% will have a partial remission. Pretreatment of irritability and psychoticlike symptoms may be associated with poorer outcomes. Partial remission and/or a history of chronic major depressive disorders are risk factors for recurrent episodes and treatment resistance.

Late-onset depression

The prognosis of late-onset depression is felt to be poorer in the elderly than in younger patients, and it appears to be dependent on physical handicap or illness and lack of social support. Of particular importance is the increasing risk of death by suicide, particularly among elderly men.

In older patients, depression is frequently comorbid with chronic medical conditions and can lead to worsening medical outcomes, including mortality; patients with depression have higher usage of medical services.^[10] For example, coronary artery disease is a risk factor for the development of depression, and depression is an independent risk factor for the development of coronary disease. Patients with both conditions are more likely to die than those with coronary artery disease alone. Both behavioral and physiologic explanations are likely for these associations.^[31]

Millard suggested the "rule of thirds" concerning the prognosis of late-onset depression, which states that regardless of treatment, approximately one third of patients will manifest remission, another one third will remain symptomatic in the same condition, and the remaining one third will worsen.^[32] In fact, research has shown that approximately 60% of patients with late-onset depression will have at least 1 recurrence, and up to 40% of these patients will have chronic or continuously recurrent depression.^[33]

Late-onset depression has been reported to double the risk of developing mild cognitive impairment^[34] and the likelihood that the mild cognitive impairment will develop into dementia.^[35] Compared with participants without depression history, those with late-life depression reportedly have increased all-cause dementia risk; however, early life depression had no association with dementia risk.^[36] Treating depression has been suggested to possibly stunt progression to mild cognitive impairment and from there to dementia, although there has been little evaluation of this hypothesis to date.

Suicide

Depression plays a role in more than one half of all suicide attempts, whereas the death rate from suicide among those with affective disorders can exceed 15%. According to Centers for Disease Control and Prevention (CDC) data, suicide was the eleventh leading cause of death in the US in 2006, accounting for 33,300 deaths^[37] , and it continues to rank as the second leading cause of death in adolescents and the third leading cause of death in people aged 15-24 years.

However, despite these data and the fact that depression is more often diagnosed in women, the highest suicide rate is in men older than 75 years (see the following graph); more men than women die from suicide by a factor of 4.5:1. White men complete more than 78% of all suicides, and 56% of suicide deaths in males involve firearms. Poisoning is the predominant method among females.

In addition to older age and male sex, risk factors for suicide include the following:^{[38, 39]}

• Diagnosis of major depression
• Previous history of suicide attempts
• Burden of medical disease and presence of current serious medical condition (although this risk may be mediated by a diagnosis of depression)
• Recent stressful life events, especially family discord
• Lack of social supports
• Being widowed or divorced
• The presence of a gun in the home
• Unexplained weight loss

The use of antidepressants may in fact be a protective factor.^[40]

Studies also show that major depressive disorder contributes to higher mortality and morbidity in the context of other medical illnesses, such as myocardial infarction, and that successful treatment of the depressive episode improves medical and surgical outcomes.

Suicide rates among American Indian and Alaskan natives between ages 15 and 34 years are almost twice the national average for this age range. Hispanic females make significantly more suicide attempts than their male or non-Hispanic counterparts.

In 2005, 1.4% of all deaths worldwide were attributed to suicide. The real number is unknown, as underreporting is predictably significant. Suicide is estimated to be the eighth leading cause of death in all age ranges. In Eastern Europe, 10 countries report more than 27 suicides per 100,000 persons. Latin America and Muslim countries report the lowest rates, with fewer than 6.5 cases per 100,000.

Education plays an important role in the successful treatment of major depressive disorder. Over the long term, patients may also become aware of signs of relapse and may seek treatment early. Patients should be aware of the rationale behind the choice of treatment, potential adverse effects, and expected results. The involvement of the patient in the treatment plan can enhance medication compliance and referral to counseling.

Family members also need education themselves about the nature of depression and may benefit from supportive interactions. Engaging family can be a critical component of a treatment plan, especially for pediatric and late-onset depression. Family members are helpful informants, can ensure medication compliance, and can encourage patients to change behaviors that perpetuate depression (eg, inactivity).

For excellent patient education resources, visit eMedicine's Depression Center. Also, see eMedicine's patient education article Depression.

The following Web sites are valuable resources for patient and family education:

• National Institute of Mental Health: Depression
• MedlinePlus: Depression
• FamilyDoctor.org: Depression
• Depression and Bipolar Support Alliance (DBSA)
• Families for Depression Awareness

Helpful Websites specifically for late-onset depression include the following:

• MedlinePlus: Depression - elderly
• WebMD: Depression in the Elderly
• National Institute of Mental Health: Older Adults: Depression and Suicide Facts
• University of Maryland Medical Center: Depression - elderly