Depression

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Practice Essentials

Major depressive disorder has significant potential morbidity and mortality, contributing to suicide, incidence and adverse outcomes of medical illness, disruption in interpersonal relationships, substance abuse, and lost work time. During 2009–2012, 7.6% of Americans aged 12 and over had depression (moderate or severe depressive symptoms in the past 2 weeks). Depression was more prevalent among females and persons aged 40–59.[1] With appropriate treatment, 70-80% of individuals with major depressive disorder can achieve a significant reduction in symptoms.

Signs and symptoms

Most patients with major depressive disorder present with a normal appearance. In patients with more severe symptoms, a decline in grooming and hygiene may be observed, as well as a change in weight. Patients may also show the following:

Major depressive disorder

Among the criteria for a major depressive disorder, at least 5 of the following symptoms have to have been present during the same 2-week period (and at least 1 of the symptoms must be diminished interest/pleasure or depressed mood)[2] :

See Clinical Presentation for more detail.

Diagnosis

Screening instruments

Self-report screening instruments for depression include the following:

In contrast to the above self-report scales, the Hamilton Depression Rating Scale (HDRS) is performed by a trained professional, not the patient. The HDRS has 17 or 21 items, scored from 0-2 or 0-4; a total score of 0-7 is considered normal, while scores of 20 or higher indicate moderately severe depression.

The Geriatric Depression Scale (GDS), although developed for older adults, has also been validated in younger adults. The GDS contains 30 items; a short-form GDS has 15 items.

Laboratory studies

No diagnostic laboratory tests are available to diagnose major depressive disorder, but focused laboratory studies may be useful to exclude potential medical illnesses that may present as major depressive disorder.

See Workup for more detail.

Management

In all patient populations, the combination of medication and psychotherapy generally provides the quickest and most sustained response.[3, 4]

Pharmacotherapy

Drugs used for treatment of depression include the following:

Psychotherapy

There are a number of evidence-based psychotherapeutic treatments for adults with major depressive disorder. The following have been deemed to have strong research support by Division 12 of the American Psychological Association:[5, 6]

Evidence-based psychotherapeutic treatments for children and adolescents with major depressive disorder include the following:[7]

Many of these treatments incorporate a parent/family component when working with children or adolescents.

In mild cases, psychosocial interventions are often recommended as first-line treatments. The American Psychiatric Association (APA) guideline supports this approach but notes that combining psychotherapy with antidepressant medication may be more appropriate for patients with moderate to severe major depressive disorder.[8]

Electroconvulsive therapy

Electroconvulsive therapy (ECT) is a highly effective treatment for depression. The indications for ECT include the following:

Stimulation techniques

Transcranial magnetic stimulation (TMS) is approved by the FDA for treatment-resistant major depression.

Vagus nerve stimulation (VNS) has been approved by the FDA for use in adult patients who have failed to respond to at least 4 adequate medication and/or ECT treatment regimens. The stimulation device requires surgical implantation.

See Treatment and Medication for more detail.

Background

As many as two thirds of people with depression do not realize that they have a treatable illness and therefore do not seek professional help. 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.

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 sleep problems. (See Presentation.)

The American Psychiatric Association’s Diagnostic Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)[2] classifies the depressive disorders as disruptive mood dysregulation disorder, major depressive disorder (including major depressive episode), persistent depressive disorder (dysthymia), premenstrual dysphoric disorder, and depressive disorder due to another medical condition. In addition, depressive disorders may be further categorized by specifiers that include peripartum onset, seasonal pattern, melancholic features, mood-congruent or mood-incongruent psychotic features, anxious distress, and catatonia. The common feature of the depressive disorders is the presence of sad, empty, or irritable mood, accompanied by somatic and cognitive changes that significantly affect the individual’s capacity to function. What differs among them are issues of duration, timing, or presumed etiology.[2]

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 DDx.)

Depression screening tests can be used to screen for depression and bipolar disorder. The most widely used is the Patient Health Questionnaire-9 (PHQ-9). 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 psychotherapy (e.g., cognitive-behavioral therapy, interpersonal psychotherapy, behavior therapy), used either alone or in combination with medication. However, the combined approach provides some patients with the quickest and most sustained response. Uncomplicated depression that is not severe typically responds equally well to psychotherapy or an antidepressant. (See Treatment.)

There is evidence to support the use of all antidepressants approved by the FDA for use in major depression, although predicting what an individual patient’s response to a particular agent will be is difficult. Assuming adherence to the treatment regimen and lack of drug or disease-state interactions, treatment for 2-12 weeks at a therapeutic-dose level is usually needed to achieve a clinical response. The choice of medication should be guided by anticipated safety and tolerability, physician familiarity, and personal and family history of previous treatments. (See Medications.)

This article focuses on major depressive disorder in adults. For information on depression in children and adolescents, see the Medscape Reference article Pediatric Depression. For information on depression in bipolar disorder, see Bipolar Affective Disorder.

Pathophysiology

The underlying pathophysiology of major depressive disorder has not been clearly defined. Current evidence points to a complex interaction between neurotransmitter availability and receptor regulation and sensitivity underlying the affective symptoms.

Clinical and preclinical trials suggest a disturbance in central nervous system serotonin (5-HT) activity as an important factor. Other neurotransmitters implicated include norepinephrine (NE), dopamine (DA), glutamate, and brain-derived neurotrophic factor (BDNF).[9] However, drugs that produce only an acute rise in neurotransmitter availability, such as cocaine or amphetamines, do not have the efficacy over time that antidepressants do.

The role of CNS 5-HT activity in the pathophysiology of major depressive disorder is suggested by the therapeutic efficacy of selective serotonin reuptake inhibitors (SSRIs). In addition, 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. However, the effect of SSRIs on 5HT reuptake is immediate, but the antidepressant effect requires exposure of several weeks' duration. Also, some antidepressants have no effect on 5HT (eg, desipramine), and the antidepressant tianeptine enhances 5HT uptake. All this, together with preclinical research findings, implies a role for neuronal receptor regulation, intracellular signaling, and gene expression over time, in addition to enhanced neurotransmitter availability.

Seasonal affective disorder is a form of major depressive disorder that typically arises during the fall and 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 the dorsolateral prefrontal cortex, orbitofrontal cortex, anterior cingulate, and dorsal cingulate.[10] Other components of limbic circuitry, in particular the hippocampus and amygdala, have been implicated in depression.

Brain structures

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.[11] Serotonergic neurons implicated in affective disorders are found in the dorsal raphe nucleus, the limbic system, and the left prefrontal cortex.

A meta-analysis comparing brain structures in patients with major depression, in healthy controls, and in patients with bipolar disorder demonstrated associations between depression and increased lateral ventricle size, larger cerebrospinal fluid volume, and smaller volumes of the basal ganglia, thalamus, hippocampus, frontal lobe, orbitofrontal cortex, and gyrus rectus. Patients experiencing a depressive episode had smaller hippocampal volume than those in remission.[12]

In one study, positron emission tomographic (PET) images showed abnormally diminished activity in an area of the prefrontal cortex 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, including the areas that appear to be responsible for the regulation of DA, noradrenaline (locus ceruleus), and 5-HT (raphe nuclei).[13]

Both functional and structural abnormalities were found in the same brain region during a major depressive episode. Sacher et al found increases in glucose metabolism in the right subgenual and pregenual anterior cingulate cortices and decreased gray matter volumes in the amygdala, dorsal frontomedian cortex, and right paracingulate cortex.[13]

Aging

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.[10]

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, although estrogen replacement does not relieve depression; low testosterone levels have been associated with depression in older men.

Etiology

The specific cause of major depressive disorder is not known. As with most psychiatric disorders, major depressive disorder appears to be a multifactorial and heterogeneous group of disorders involving both genetic and environmental factors.

Evidence from family and twin studies indicates that with depression that develops in early childhood, the transmission from parents to children appears to be related more to psychosocial influences than to genetics.[14] Adolescent-onset and adult-onset depression, while more heritable than prepubertal depression, likewise reflect an interaction between genes and environmental stressors.

Genetics

Genetic factors play an important role in the development of major depression. Evidence from twin studies suggests that major depression has a concordance of 40-50%. First-degree relatives of depressed individuals are about 3 times as likely to develop depression as the general population; however, depression can occur in people without family histories of depression, as well.[15]

Two susceptibility loci have been identified in which no specific gene of interest has been definitively identified. The MDD1 locus is located at 12q22-q23.2 and is most strongly linked to major depression in males.[16] The MDD2 locus is located at 15q25.2-q26.2 and has been associated with early onset or recurrent episodes of depression.[17]

Although multiple genes are likely to influence the susceptibility to depression, those involved in the serotonin system are a focus of investigation, especially because many antidepressant medications work by influencing serotonin.[18] The SLC6A4 gene, which is located at 17q11.2, encodes a serotonin transporter (also known as 5-hydroxytryptamine transporter) that is responsible for actively clearing serotonin from the synaptic space.

A polymorphism in the promoter region of the SLC6A4 gene consists of a 44bp insertion or deletion involving repeat elements. These polymorphisms are referred to as either a long allele or a short allele. Caspi et al found that persons who were homozygous or heterozygous for the short allele had more depressive symptoms and suicidality in association with stressful life events than those patients who were homozygous for the long allele.[19]

Other studies also suggest that genes controlling either the production or utilization of serotonin play an important role in the pathogenesis of depression. The TPH2 gene encodes tryptophan hydroxylase, which is the rate-limiting enzyme in the synthesis of serotonin. An in vitro study of a TPH2 polymorphism, R441H, found an approximately 80% loss in serotonin production.

The clinical significance of this polymorphism remains uncertain, however. Zhang et al found that the allele was more common in a cohort of patients with major depression than in a control population,[20] but a later study by Garriock et al did not find any patients with the R441H mutation in a cohort with major depression, a control group, or a group with bipolar disorder.[21]

The HTR3A and HTR3B regions, which encode serotonin receptors and are located at chromosome 11q23.2, are also known to be associated with major depression in both European and Japanese populations. Yamada e al surveyed 29 polymorphisms located within the HTR3A and HTR3B genes and found a single-nucleotide polymorphism that was associated with depression in females.[22]

A study of genes in the hypothalamic-pituitary-adrenal axis found that in patients with major depression, homozygosity for the T allele in the FKBP5 gene was associated with a quicker response to antidepressants than heterozygosity or homozygosity for the C allele in that location. However, homozygosity for the T allele was also associated with an increased recurrence of depressive episodes.[23]

Studies such as those reported by Akiskal and Weller[24] and Weissman et al[25] suggest a genetic component in the etiology of depressive disorders. Individuals with a family history of affective disorders, panic disorder, or alcohol dependence carry a higher risk for major depressive disorder.

Children and adolescents

Nobile et al found that human platelet 5-HT uptake is differentially influenced in children and adolescents with and without depression by a common genetic variant of the promoter region of the serotonin transporter gene (5-HTTLPR). Depressed persons had a lower rate of serotonin uptake and a lower serotonin dissociation constant[26]

Birmaher et al found that before the onset of affective illness, children who were at high risk for depression, on the basis of family history, had the same pattern of neuroendocrine response to infusion of a serotonergic precursor (5-hydroxy-L-tryptophan) challenge as did children with major depression. Compared with low-risk children, high-risk children and depressed children secreted significantly less cortisol and, in girls, more prolactin.[27] These findings could constitute the identification of a trait marker for depression in children.

Late-onset depression

Some evidence suggests that late-onset depression (after age 60 years) is an etiologically and clinically distinct syndrome[28] and that genetic factors likely play less of a role in late-onset depression than in early-onset depression. A family history of depression is less common among patients with late-onset depression than in younger adults with depression. However, although findings have been inconsistent, certain genetic markers have been found to be associated with late-onset depression. Such markers include polymorphisms of apolipoprotein E, BDNF, and 5-HT transporter genes. Interestingly, these markers have also been associated with cognitive impairment, hippocampal volume, and antidepressant response, respectively.

Genetic influences on antidepressant drug response

Genetics also play a significant part in the response to pharmacologic treatment of major depression. A study of the drug transporter gene ABCB1 (which encodes a transporter glycoprotein and functions as an active efflux pump for a number of drugs across the blood-brain barrier) found an association between 2 single-nucleotide polymorphisms and achievement of remission with citalopram, paroxetine, amitriptyline, and venlafaxine. Also, in a mouse model lacking the gene homologous to the human ABCB1 gene, the mice had significantly higher concentrations of citalopram, venlafaxine, or desvenlafaxine after 11 days of subcutaneous administration of the drugs, despite drug plasma concentrations that were identical to those in mice lacking this mutation.[29]

Approximately 40% of patients who are treated with a selective serotonin reuptake inhibitor (SSRI) will either discontinue treatment or switch medications because of an adverse effect of the medication. In one study, an increased risk for sexual dysfunction from SSRIs was found to be associated with alleles in the 5HT2A and GHB3 genes.[30]

A study of response to treatment with citalopram identified a significant association between treatment outcome and a marker in HTR2A, which is located at chromosome 13q14.2 and encodes the serotonin 2A receptor. The A allele (a single-nucleotide polymorphism in an intron of this gene) reduced the likelihood of nonresponse to citalopram in whites but not in the African-American population. An AA genotype resulted in a 16-18% reduction in absolute risk of being a nonresponder.[31]

Stressors

Although major depressive disorder can arise without any precipitating stressors, stress and interpersonal losses certainly increase risk. For example, loss of a parent before the age of 10 years increases the risk of later depression. Cognitive-behavioral models of depression posit that negative cognitions and underlying all-or-nothing schemata contribute to and perpetuate depressed mood.[28]

Chronic pain, medical illness, and psychosocial stress can also play a role in major depressive disorder. Older adults may find medical illness psychologically distressing, and these illnesses may lead to increased disability, decreased independence, and disruption of social networks.[32] Chronic aversive symptoms such as pain associated with chronic medical illness may disrupt sleep and other biorhythms leading to depression.

Other psychosocial risk factors for depression in late life include the following[33] :

Cognitive-behavioral models of depression suggest that the presence of negative life events in addition to one’s perception of or reaction to those events may impact the development and maintenance of depressive symptoms. Cognitive models of depression posit that negative cognitions and underlying all-or-nothing schemata contribute to and perpetuate depressed mood.[28] More specifically, cognitive vulnerability-stress models suggest that, in the face of negative life events, individuals who have a tendency to make negative attributions about the causes of those events, about themselves, and about future consequences (in line with the hopelessness theory of depression) may be more likely to develop depression.[34] This has been suggested as potentially contributing to gender differences in rates of depression following puberty (e.g., Hyde, Mezulis, and Abramson[35] ). Behavioral models suggest that depression may result from deficits in response-contingent positive reinforcement andinadequate social skills[36] or reliance upon escape and avoidance behaviors,[37] such that avoidance behaviors in response to negative life events and corresponding negative emotions may lead to worsened depression.[38]

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 increases the risk of depression, such as reserpine, beta-blockers, and steroids such as cortisol. Abused substances can also increase risk of major depressive disorder, such as cocaine, amphetamine, narcotics, and alcohol. With agents of abuse, however, it is unclear whether depression is a consequence or facilitator.

Risk-factor interactions

Researchers are currently investigating the relationship between genetic vulnerability, environmental stressors, and brain structural abnormalities in the development of depression. In an MRI genetic study, Frodl et al found that patients with major depression who carried the S allele of 5-HTTLPR and had a history of childhood emotional neglect had smaller hippocampal volumes than patients who had only one of those factors. They concluded that structural hippocampal brain changes resulting from stress may be part of the risk for developing depression and that these changes are more pronounced in individuals with the S-allele.[39]

Conflicting evidence exists regarding the interaction between the functional serotonin transporter promoter (5-HTTLPR) and stress in the development of depression. A 2011 meta-analysis suggested that 5-HTTLPR moderates the relationship between stress and depression.[40] Earlier, smaller meta-analyses had concluded that the evidence did not support the presence of the interaction.

Neuroendocrine abnormalities and neurodegenerative diseases

Possible abnormalities of the neurotransmitter systems remain under investigation. Compared with control subjects, depressed prepubertal children had lower cortisol secretion during the first 4 hours of sleep, according to De Bellis et al. Nocturnal secretion of adrenocorticotropin, growth hormone, and prolactin did not differ between the 2 groups.[41]

Potential biological risk factors have been identified for depression in the elderly. 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.[42]  Alternatively, a large, longitudinal study found that depression that starts early in life increases the risk for Alzheimer's disease (AD). Researchers used data from the Prospective Population Study of Women in Gothenburg Sweden, which began in 1968. The study sample included 800 women (mean age, 46 years), born between 1914 and 1930, who were followed up with in 1974, 1980, 1992, 2000, 2009, and 2012. Data show those women who experienced the onset of depression before age 20 years were three times more likely to develop AD (adjusted HR, 3.41; 95% CI, 1.78 - 6.54).[43]

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.

Affective illness in a parent may be a factor in child abuse and/or neglect that promotes affective illness in the child. Childhood abuse and neglect, as well as a cumulative load of stressors over a lifetime, have been associated with both early-adult and late-onset depression.

Hammen et al reported a significant temporal association between depression diagnoses in mother and child.[44] 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.

Mothers’ remission from depression, regardless of timing, has a consistently favorable influence on their children. In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Child study, all children whose mothers experienced remission from depression showed improvement in mood and behavior in the following year; children whose mothers recovered from depression within the first 3 months of treatment showed not only improved mood and behavior but significant improvement in functioning, as well.[45]

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[46] :

Epidemiology

United States statistics

During 2009–2012, 7.6% of Americans aged 12 and over had depression (defined as having moderate or severe depressive symptoms in the past 2 weeks). Depression was more prevalent among females than males and among adults aged 40–59 than those of other age groups. Rates of any depressive symptoms were lower among non-Hispanic white persons than among Hispanic and non-Hispanic black persons. Once poverty was taken into account, however, rates of depression did not differ significantly by race or Hispanic origin.[1]

In 2015, an estimated 16.1 million adults aged 18 or older in the United States had at least one major depressive episode in the past year. This number represented 6.7% of all U.S. adults.[47]

International statistics

Internationally reported adult prevalence rates of depression generally mirror those of the United States, and estimates of 1-month prevalence of depression in community-dwelling elderly are relatively 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.[48] 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.[49]

The Stirling County Study, which began shortly after World War II, offered a 40-year perspective of the prevalence and incidence of psychiatric disorders in 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.[50]

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 frequencies of 14.1% for females and 8.6% for males.[51]

Children and adolescents

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.[52] In another study, 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. The percentage of male students with 2 or more episodes of unipolar depression was 4.9%; it was 1.6% in female students.[53]

Garrison et al reported a 1-year incidence of major depression of 3.3% in adolescents aged 11-16 years.[54] Their epidemiologic study was conducted between 1987 and 1989 in a single school district in the southeastern United States.

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.[55] During this period, the increase in overall rates of depression and onset of new cases of depression peak.

Hispanic youths in Los Angeles county (aged 12-17 years) 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).[56] This study also found significant effects of social class on depression. As income decreased, the average prevalence of depression increased.

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 because of somewhat atypical features of depression in elderly persons. For instance, there is a higher prevalence of dysthymic disorder in aging and medically ill populations.

Prognosis

Major depressive disorder has significant potential morbidity and mortality, contributing as it does to suicide, incidence and adverse outcomes of 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.

Twenty percent of individuals with major depressive disorder untreated at 1 year will continue to meet criteria for the diagnosis, whereas an additional 40% will have a partial remission. Pretreatment irritability and psychotic symptoms may be associated with poorer outcomes. Partial remission and/or a history of prior chronic major depressive episodes are risk factors for recurrent episodes and treatment resistance.

A study of first-episode psychotic depression by Tohen et al found that most patients achieved syndromal remission (86%) and recovery (84%); however, only 35% recovered functionally. Earlier syndromal recovery was associated with subacute onset, lower initial depression scores, and lack of mood-incongruent psychotic features. Within 2 years, almost half the patients experienced new episodes. In 41% of patients, the diagnosis was changed, usually to bipolar or schizoaffective disorders.[57]

Recurrence of early depression

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.[58] In a study of an epidemiologic sample of 776 adolescents by Pine and associates, symptoms of majordepressioninadolescencestrongly predicted episodes of major depression in adulthood.[59]

Late-onset depression

The prognosis for patients with late-onset depression is felt to be poorer than that for younger patients, and it appears to be dependent on physical disability or illness and lack of social support. Of particular importance is the increasing risk of death by suicide, particularly among elderly men. The length of a depressive episode in the aging population is approximately 18 months, whereas in people 20–55 years of age, the length of an episode is 18 to 24 weeks.

In older patients, depression is frequently comorbid with chronic medical conditions and can lead to worsening medical outcomes, including mortality.[28] 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.[60]

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.[61] 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.[62]

Late-onset depression has been reported to double the risk of developing mild cognitive impairment[63] and the likelihood that the mild impairment will develop into dementia.[64] The Diabetes and Aging Study showed that when depression is comorbid with type 2 diabetes, it increases the risk of all-cause dementia by about 2-fold compared with diabetes alone.[65] A 40-month study of 2977 middle-aged and older adults with long-standing type 2 diabetes found depression at baseline to be associated with accelerated cognitive decline.[66, 67]

Compared with participants without a depression history, those with late-life depression reportedly have increased all-cause dementia risk; however, early-life depression had no association with dementia risk.[68] Treating depression has been suggested to possibly stunt progression to mild cognitive impairment and then 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 lifetime risk of suicide among patients with untreated depressive disorder is nearly 20%.[69] According to Centers for Disease Control and Prevention (CDC) data, suicide was the 10th leading cause of death in the United States in 2009, accounting for 36,909 deaths; it was the second leading cause of death in people 25-34 years of age, the third leading cause in people aged 10-24 years, and the fourth leading cause at ages 35-54.[70]

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 graph below); 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. Attempted suicide is more frequent in women.



View Image

From 1991-2006, the suicide rate was consistently higher among males. Suicide rates declined among both sexes from 1991-2000; the rate among males dec....

In addition to older age and male sex, risk factors for suicide include the following[71, 72] :

The relationship between use of antidepressants and risk of suicide varies with patient age. Treatment with antidepressants has been associated with increased suicidality in children, adolescents, and young adults 18 to 24 years of age. There is no evidence of increased risk for adults older than 24 years of age; for adults 65 years of age or older, the risk is actually decreased.[73]

Suicide rates among Native Americans 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 one study, there were strong correlations of suicide rates with indicators of access to health care in the United States.[74] Multivariate analysis of state-by-state statistics showed that the state rate of federal aid for mental health was the strongest indicator, followed by the rate of uninsured persons and population density of psychiatrists and physicians and by population density. These researchers concluded that the findings support the view that clinical intervention is a crucial element in the prevention of suicide.

In 2005, 1.4% of all deaths worldwide were attributed to suicide. The actual number is unknown, as underreporting is predictably significant in many regions of the world. 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 persons. Suicide rates increased from 1955-2009 in most countries but have decreased from 1990-2009.

Patient Education

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 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).

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

Helpful Web sites specifically for late-onset depression include the following:

History

Patients with major depressive disorder may not initially present with a complaint of low mood, anhedonia, or other typical symptoms. In the primary care setting, where many of these patients first seek treatment, the presenting complaints often can be somatic (e.g., fatigue, headache, abdominal distress, or change in weight). Patients may complain more of irritability or difficulty concentrating than of sadness or low mood.

Children with major depressive disorder may also present with initially misleading symptoms such as irritability, decline in school performance, or social withdrawal. Elderly persons may present with confusion or a general decline in functioning; they also experience more somatic complaints, cognitive symptoms, and fewer complaints of sad or dysphoric mood.

Familial, social, and environmental factors

Depression can be familial. Thus, a thorough family history is quite important. Familial, social, and environmental factors appear to play significant roles in the course of depressive illness in children and youths, even in preschool children.[75] René Spitz described anaclitic depression (marasmus) in infants being raised in an orphanage and in hospitalized children whose parents were not allowed to visit.[76]

Dysphoric mood

A dysphoric mood state may be expressed by patients as sadness, heaviness, numbness, or sometimes irritability and mood swings. They often report a loss of interest or pleasure in their usual activities, difficulty concentrating, or loss of energy and motivation. Their thinking is often negative, frequently with feelings of worthlessness, hopelessness, or helplessness.

Psychosis

Patients with major depressive disorder commonly show ruminative thinking. Nevertheless, it is important to evaluate each patient for evidence of psychotic symptoms, because this affects initial management.

Psychosis, when it occurs in the context of unipolar depression, is usually congruent in its content with the patient's mood state; for example, the patient may experience delusions of worthlessness or some progressive physical decline.

Symptoms of psychosis should prompt a careful history evaluation to rule out any of the following:

Physical Examination

No physical findings are specific to major depressive disorder; instead, the diagnosis is based on the history and the mental status examination. Nevertheless, a complete mental health evaluation should always include a medical evaluation to rule out organic conditions that might imitate a depressive disorder. Most of these fall into the following major general categories:

Appearance and affect

Most patients with major depressive disorder present with a normal appearance. In patients with more severe symptoms, a decline in grooming and hygiene can be observed, as well as a change in weight. Patients may show psychomotor retardation, which manifests as a slowing or loss of spontaneous movement and reactivity, as well as demonstrate a flattening or loss of reactivity in the patient's affect (i.e., emotional expression). Psychomotor agitation or restlessness can also be observed in some patients with major depressive disorder.

Speech

Speech may be normal, slow, monotonic, or lacking in spontaneity and content. Pressured speech should suggest anxiety or mania, whereas disorganized speech should prompt an evaluation for psychosis. Racing thoughts could also be an indication of anxiety, mania, or hypomania.

Major Depressive Disorder

The specific DSM-5 criteria for major depressive disorder are outlined below.

At least 5 of the following symptoms have to have been present during the same 2-week period (and at least 1 of the symptoms must be diminished interest/pleasure or depressed mood)[2] :

The symptoms cause significant distress or impairment in social, occupational or other important areas of functioning.

The symptoms are not attributable to the physiological effects of a substance (e.g., a drug of abuse, a medication) or another medical condition.

The disturbance is not better explained by a persistent schizoaffective disorder, schizophrenia, delusional disorder, or other specified or unspecified schizophrenia spectrum and other psychotic disorders

There has never been a manic episode or a hypomanic episode

Depressive disorders can be rated as mild, moderate, or severe. The disorder can also occur with psychotic symptoms, which can be mood congruent or incongruent. Depressive disorders can be determined to be in full or partial remission.

DSM-5 further notes the importance of distinguishing between normal sadness and grief from a major depressive disorder. While bereavement can induce great suffering, it does not typically induce a major depressive disorder. When the two exist concurrently, the symptoms and functional impairment is more severe and the prognosis is worse compared to bereavement alone. When major depressive disorder is most likely to be induced by bereavement in persons with other vulnerabilities to depressive disorders. A diagnosis of major depressive disorder following a significant loss requires clinical judgement based on the individuals history and the cultural context for expression of grief.

Depression with Anxious Distress

Anxious distress is defined as the presence of at least 2 of the following symptoms[2] :

Severity is further specified as:

High levels of anxiety are associated with higher suicide risk, longer duration of illness and greater likelihood of nonresponse to treatment.

Depression With Melancholic Features

In depression with melancholic features, either a loss of pleasure in almost all activities or a lack of reactivity to usually pleasurable stimuli is present. Additionally, at least 3 of the following are required:

According to DSM-5, this subtype is applied only when there is a near-complete absence of the capacity for pleasure, not merely a diminution. A depressed mood that is described as merely more severe, longer lasting or present without a reason is not considered a distinct quality. Melancholic features are more frequent in inpatients and are less likely to occur in milder major depressive episodes. They are also more likely to be comorbid with psychotic features.

Depression With Catatonia

The DSM-5 criteria for diagnosis of depressive episodes with catatonia requires the presence of 3 or more of 12 psychomotor features during most of the episode:[2]

Atypical Depression

An episode of depression may be identified as having atypical features. Characteristics of this subtype are mood reactivity and exclusion of melancholic and catatonic subtypes in addition to 2 or more of the following for a period of at least 2 weeks:

Postpartum Depression

Depression in the postpartum period is a common and potentially very serious problem; up to 85% of women can develop mood disturbances during this period. For most women, symptoms are transient and relatively mild (ie, “postpartum blues”); however, 10-15% of women experience a more disabling and persistent form ofdepression, with an onsetlaterthan the postpartum blues, and 0.1-0.2% of women experience postpartum psychosis.[33, 77, 78, 79]

Postpartum psychiatric illness was initially conceptualized as a group of disorders specifically linked to pregnancy and childbirth and thus was considered diagnostically distinct from other types of psychiatric illness. However, evidence within the past decade suggests that postpartum psychiatric illness is virtually indistinguishable from psychiatric disorders that occur at other times during a woman's life.[80, 81, 82] However, the likelihood of a bipolar outcome is substantially higher in postpartum psychosis.

Postpartum mood disorder (major depressive or manic) episodes with psychotic features appear to occur in from 1 in 500 to 1 in 1000 deliveries. The risk is particularly increased for women with prior postpartum mood episodes but is also elevated for those with a prior history of a depressive or bipolar disorder or a family history of bipolar disorder. Women who have had a postpartum episode with psychotic features have a risk of recurrence between 30-50% for subsequent deliveries.[2]

Rapidly fluctuating mood, tearfulness, irritability, and anxiety are common symptoms of postpartum blues.[83, 84, 85, 86] Symptoms peak on the fourth or fifth day after delivery and last for several days, but they are generally time-limited and spontaneously remit within the first 2 postpartum weeks.[83] Symptoms do not interfere with a mother's ability to function and to care for her child.

Women with more severe symptoms or symptoms persisting longer than 2 weeks should be screened for postpartum depression.[81, 82] According to DSM-5, 50% of “postpartum” major depressive episodes actually begin prior to delivery, and the specifier used collectively for these episodes is “with peripartum onset.”[2]

Signs and symptoms of postpartum depression are clinically indistinguishable from major depression that occurs in women at other times. These symptoms interfere with the mother’s ability to function, with risk of self-harm or harm to the infant.[87]

The American Academy of Pediatrics (AAP) states that more than 400,000 infants are born each year to mothers who are depressed. The AAP encourages pediatric practices to create a system to better identify postpartum depression to ensure a healthier parent-child relationship.[88]

Although effective nonpharmacologic and pharmacologic treatments are available, both patients and their caregivers frequently overlook postpartum depression.[81] Untreated postpartum affective illness places both the mother and infant at risk and is associated with significant long-term effects on child development and behavior[80, 82, 87] ; therefore, appropriate screening, prompt recognition, and treatment of depression are essential for both maternal and infant well-being and can improve outcomes.[89]

Seasonal Affective Disorder

About 70% of depressed people feel worse during the winter and better during the summer. To meet the DSM-5 diagnostic criteria[2] for major depressive disorder with seasonal pattern, depression should be present only at a specific time of year (e.g., in the fall or winter) and full remission occurs at a characteristic time of year (e.g., spring). An individual should demonstrate at least 2 episodes of depressive disturbance in the previous 2 years, and seasonal episodes should substantially outnumber nonseasonal episodes. Patients with seasonal affective disorder are more likely to report atypical symptoms, such as hypersomnia, increased appetite, and a craving for carbohydrates.

Cases where there is an obvious effect of seasonally related psychosocial stressors, (e.g., seasonal unemployment) do not meet the diagnostic criteria.

Diagnosing seasonal affective disorder in children is difficult because they experience the recurrent universal stressor of beginning school every autumn. Also, a young child might present with apparent seasonal affective disorder but not yet have had previous episodes.

Major Depressive Disorder with Psychotic Features

The presentation of severe major depressive disorder may include psychotic features. Psychotic features include delusions and hallucination and may be mood congruent or mood incongruent. Mood-congruent psychoses are often consistent with classic depressive themes, such as personal inadequacy, guilt, disease, or deserved punishment. Mood-incongruent psychoses are not consistent with these typical themes but may also occur in depression.

Major depressive disorder with psychotic features is considered a psychiatric emergency. Patients may require psychiatric hospitalization.

Other Specificed Depressive Disorders

The DSM-5 includes a category of disorders with features of depression that do not meet criteria for a specific depressive disorder. Examples include the following:[2]

Consult the DSM-5 for further details regarding the diagnostic criteria for other specified depressive disorders

Metabolic Depression

Several studies report an association between metabolic syndrome and depression. Vogelzangs et al suggest that later in life, waist circumference and not metabolic syndrome can predict onset of depression. Specifically, the larger the waistline, the higher the incidence of depression.[90] However, longitudinal studies have also shown that depression predicts subsequent obesity and centripetal obesity, likely because of poor diet, lack of exercise, and psychobiologic changes such as increased cortisol levels.

On the other hand, individuals with depression who have metabolic syndrome may simply be more likely to have persistent or recurrent depression. Thus, depression with metabolic abnormalities could be labeled metabolic depression, a possible chronic subtype of depression.[90]

Cultural Influences on Expression of Depression

Cultural influences on the presentation of depression can be significant. The practitioner should be aware of differences in the expression of psychological distress in patients from other countries or cultures.

Culturally distinctive experiences (e.g., fear of being hexed or bewitched; experience of visitations from the dead) should be distinguished from actual hallucinations or delusions that may be part of a major depressive episode with psychotic features.

Suicidal Ideation

Patients with depression should be assessed for suicidal ideation, especially if agitation is present. When a patient has contemplated or attempted suicide, the burden is on the health care provider to directly explore the situation with the patient in as much detail as possible to determine the current presence of suicidal ideation as well as accessible means and plans. Discussing these is the most important step clinicians can take in an attempt to prevent suicide in an at-risk patient. For more information, see the Medscape Reference article Suicide.

Approach Considerations

Depression screening tests can be valuable, with the most widely one used being the Patient Health Questionnaire-9 (PHQ-9). It is important to understand, however, that the results obtained from the use of any depression screening or rating scales do not diagnose depression and may be imperfect in any population, especially in elderly patients.

Screening Tests

The U.S. Preventive Services Task Force (USPSTF) recommends screening for depression in the general adult population, including older adults and pregnant and postpartum women.[95]  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.

The simplest screening test is a single question: Are you depressed? A pooled analysis found that single-question screening had a specificity of 97% but an overall sensitivity of 32% and, thus, would identify only 3 of every 10 patients with depression in primary care.[96]

The following 2-question test addresses depressed mood and anhedonia:

In a cross-sectional study, these 2 screening questions showed a sensitivity of 97% and a specificity of 67%.[97]

Longer self-report screening instruments for depression include the following:

In contrast to the above self-report scales, the Hamilton Depression Rating Scale (HDRS) is performed by a trained professional, not the patient. The HDRS has 17 or 21 items, scored from 0-2 or 0-4; a total score of 0-7 is considered normal, while scores of 20 or higher indicate moderately severe depression.

The Geriatric Depression Scale (GDS), although developed for older adults, has also been validated in younger adults. The GDS comprises 30 items; a short-form GDS has 15 items (see the images below).



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Geriatric Depression Scale.



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Geriatric Depression Scale-Short.

Given that the commonly atypical presentation of depression in the elderly population can challenge even the most experienced clinician, rating scales in the elderly should be used and interpreted only in the context of a more thorough examination for depression.

Patients with major depressive disorder often complain of poor memory or concentration. This may be due to the depression itself or to an underlying dementia.

In older patients with established dementia, the Cornell Scale for Depression in Dementia (see the image below) can be used to determine the category and severity of depression. The clinician completes the scale on the basis of prior observation and interviews with the patient and the patient’s caregiver.



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Cornell Scale for Depression in Dementia.

Laboratory Studies to Rule Out Organic Causes

Depression is a clinical diagnosis, based on the history and physical findings. No diagnostic laboratory tests are available to diagnose major depressive disorder, but focused laboratory studies may be useful to exclude potential medical illnesses that may present as major depressive disorder. These laboratory studies might include the following:

Neuroimaging

Neuroimaging can help clarify the nature of the neurologic illness that may produce psychiatric symptoms, but these studies are costly and may be of questionable value in patients without discrete neurologic deficits. Computed tomography (CT) scanning or magnetic resonance imaging (MRI) of the brain should be considered if organic brain syndrome or hypopituitarism is included in the differential diagnosis.

Positron emission tomography (PET) imaging provides the means for the study of receptor binding of certain ligands and the effect a compound may have on receptors. However, PET scanning is problematic for use with children and adolescents because it requires complex equipment and uses radiation.

Using single-photon emission computed tomography (SPECT) scanning, Tutus et al reported significant differences between the perfusion index values of untreated adolescents with depression and those of control patients. The researchers found that adolescents with major depressive disorder may have regional blood flow deficits in the left anterofrontal and left temporal cortical regions, with greater right-left perfusion asymmetry than healthy control patients.[98]

Approach Considerations

A wide range of effective treatments is available for major depressive disorder. Medication alone (see Medication) and brief psychotherapy (e.g., cognitive-behavioral therapy, interpersonal therapy) alone can relieve depressive symptoms. There is also empirical support for the ability of brief psychotherapy (CBT) to prevent relapse.

In children and adolescents, however, pharmacotherapy by itself is insufficient treatment. Moreover, in all patient populations, the combination of medication and psychotherapy generally provides the quickest and most sustained response. Combination therapy has also been associated with significantly higher rates of improvement in depressive symptoms; increased quality of life; and better treatment compliance, especially when treatment is needed for longer than 3 months.[3, 4]

Medications

Usually, 2–12 weeks at a therapeutic dose, with assumed adherence to the regimen, are needed for a clinical response to become evident. The choice of medication should be guided by anticipated safety and tolerability, which aid in compliance; physician familiarity, which aids in patient education and anticipation of adverse effects; and history of previous treatments. Often, treatment failures are caused by medication noncompliance, inadequate duration of therapy, or inadequate dosing.

According to the 2008 American College of Physicians (ACP) guideline (the most recent release of the guideline) on using second-generation antidepressants to treat depressive disorders, patient preferences should be given serious consideration when choosing the best course of pharmacotherapy for patients with depressive disorders. The patient may want to avoid use of a particular antidepressant if he or she had a previous negative experience with the drug.[99]

The 2008 ACP guideline advises that treatment for major depressive disorder should be altered if the patient does not have an adequate response to pharmacotherapy within 6–8 weeks. Once satisfactory response is achieved, treatment should be continued for 4–9 months in patients with a first episode of major depression that was not associated with significant suicidality or catastrophic outcomes. In those who have had 2 or more episodes of depression, a longer course of maintenance treatment may prove beneficial.[99]

In 2011, the American Psychiatric Association (APA) updated its Practice Guideline for the Treatment of Patients with Major Depressive Disorder.[8] The 2011 APA guideline emphasizes the need to customize a treatment plan for each patient based on a careful assessment of symptoms, including rating scale measurements administered by a clinician or the patient, as well as an analysis of therapeutic benefits and side effects.

Treatment should maximize patient function within specific and realistic goals. The initial modality should be chosen on the basis of the following[8] :

Psychotherapy

Psychotherapy is often conducted on an outpatient basis with weekly, 60-minute sessions. Although there is wide variation in practice, psychotherapy tends to be time-limited (e.g., 16 sessions).

In the 1990s, The American Psychological Association’s Division 12 Task Force on Promotion and Dissemination of Psychological Procedures[100, 101] developed criteria for evaluating the empirical support for psychological treatments. Chambless and Hollon[102] refined these guidelines such that a therapy is considered efficacious and specific if there is evidence from high-quality studies in two or more settings indicating that it is superior to a pill or psychological placebo or to another bonafide treatment. A treatment is considered efficacious if there is evidence from two or more settings that it is superior to no treatment. A therapy is considered to be possibly efficacious if there is research support from one or more studies in a single setting. It is recommended that individuals seeking psychotherapy for depression receive one with empirical support (see below).

Pharmacologic Therapy for Depression

Drugs used for treatment of depression include the following:

Selective serotonin reuptake inhibitors

SSRIs include the following:

SSRIs have the advantage of ease of dosing and low toxicity in overdose. SSRIs are greatly preferred over the other classes of antidepressants for the treatment of children and adolescents, and they are also the first-line medications for late-onset depression. This recommendation is supported by the 2011 APA guideline.[8]

The adverse-effect profile of SSRIs is less prominent than that of some other agents, which promotes better compliance. Common adverse effects include gastrointestinal upset, sexual dysfunction, and changes in energy level (ie, fatigue, restlessness).

The SSRIs are thought to be relatively unproblematic in patients with cardiac disease, as these agents do not appear to affect blood pressure, heart rate, cardiac conduction, or cardiac rhythm. However, dose-dependent QT prolongation has been reported with citalopram.

Consequently, the US Food and Drug Administration (FDA) has advised that citalopram is not recommended in patients with congenital long QT syndrome.[103] Use of citalopram may be appropriate for patients with this condition who lack viable alternatives; however, in such cases, the drug should be given at a low dose, and electrocardiographic and/or electrolyte monitoring should be performed. Citalopram should be discontinued in patients who are found to have a persistent corrected QT interval (QTc) greater than 500 ms.

The dose of citalopram should not exceed 40 mg/day, because of the risk of potentially fatal cardiac arrhythmias; furthermore, higher doses have not been shown to be more effective in treating depression. For patients older than 60 years, the maximum recommended dose of citalopram is 20 mg/day.[103, 104]

In September 2013, the FDA approved vortioxetine (Brintellix) for the treatment of major depressive disorder in adults. The drug’s mechanism of action involves enhancement of serotonergic activity through 5-HT reuptake inhibition. It also modulates serotonin receptor activity through 5-HT1A receptor agonism and 5-HT3 receptor antagonism, although the contribution of these activities to the antidepressant effect is not fully understood.

Approval was based on 5 short-term (6-8 week) studies,[105, 106, 107, 108, 109] including one that focused on elderly adults.[109] These studies demonstrated a statistically significant reduction in overall symptoms of depression with vortioxetine compared to placebo, with most consistent results obtained within a dosage range of 15-20 mg/day. Also, a long-term (24-64 week) maintenance study showed a significantly longer time to relapse with vortioxetine compared to placebo.[110, 111] Two studies using lower doses (2.5-5 mg/day) showed no significant difference in efficacy between the drug and placebo.[112, 113] The most common adverse effects were nausea, diarrhea, dry mouth, constipation, vomiting, dizziness, and sexual dysfunction.

Serotonin/norepinephrine reuptake inhibitors

SNRIs, which include venlafaxine (Effexor), desvenlafaxine (Pristiq), duloxetine (Cymbalta), and levomilnacipran (Fetzima) can be used as first-line agents, particularly in patients with significant fatigue or pain syndromes associated with the episode of depression. SNRIs also have an important role as second-line agents in patients who have not responded to SSRIs.

The concurrent use of SNRIs with other antidepressants may be more problematic. For example, the Combining Medications to Enhance Depression Outcomes (CO-MED) study found that the combination of extended-release venlafaxine plus mirtazapine may actually pose a greater risk of adverse events and does not outperform monotherapy.[114]

The safety, tolerability, and side-effect profiles of SNRIs include those of the SSRIs, as well as noradrenergic side effects, such as hypertension.

In July 2013, the FDA approved the newest SNRI levomilnacipram (Fetzima) which is available as a once-daily sustained-release formulation. It has greater potency for norepinephrine reuptake inhibition than for serotonin reuptake inhibition without directly affecting the uptake of dopamine or other neurotransmitters.

Atypical antidepressants

Atypical antidepressants include bupropion (Wellbutrin), mirtazapine (Remeron), nefazodone, and trazodone (Desyrel). They have all been found to be effective in monotherapy in major depressive disorder and may be used in combination therapy for more difficult to treat depression.

Nevertheless, this group also shows low toxicity in overdose. In addition, bupropion has the advantage over the SSRIs of causing less sexual dysfunction and less GI distress. Mirtazapine is associated with a high risk of weight gain, so patients who are treated with this agent should have careful monitoring of weight.

Serotonin-Dopamine Activity Modulators

SDAMs include brexpiprazole (Rexulti) and aripiprazole (Abilify). SDAMs act as a partial agonist at 5-HT1A and dopamine D2 receptors at similar potency, and as an antagonist at 5-HT2A and noradrenaline alpha1B/2C receptors. This mechanism of action is unique from other atypical antipsychotic drugs.

Brexpiprazole is indicated as adjunctive therapy for major depressive disorder (MDD). Aripiprazole is indicated for schizophrenia, acute treatment of manic and mixed episodes associated with bipolar I, as an adjunct to MDD, irritability associated with autistic disorder, and treatment of Tourette disorder. Also, aripiprazole prompt-acting injection is indicated for agitation associated with schizophrenia or bipolar mania.

In clinical trials, brexpiprazole was added to existing antidepressant therapy in patients who had failed multiple trials of antidepressant therapy. Patients enrolled met DSM-IV-TR criteria for MDD. Brexpiprazole (2 mg and 3 mg daily) plus antidepressant therapy was superior to placebo plus antidepressant therapy on the primary endpoint (ie, change in Montgomery-Åsberg Depression Rating Scale scores).[115]

Tricyclic antidepressants

TCAs include the following:

TCAs have a long record of efficacy in the treatment of depression. They are used less commonly because of their side-effect profile and their considerable toxicity in overdose (see Antidepressant Toxicity).

Monoamine oxidase inhibitors

MAOIs include isocarboxazid (Marplan), phenelzine (Nardil), selegiline (Emsam), and tranylcypromine (Parnate). These agents are widely effective in a broad range of affective and anxiety disorders. Because of the risk of hypertensive crisis, patients on these medications must follow a low-tyramine diet. Other adverse effects can include insomnia, anxiety, orthostasis, weight gain, and sexual dysfunction.

N-methyl-D-aspartate antagonists

The N-methyl-D-aspartate (NMDA) receptor antagonist esketamine intranasal (Spravato) has been shown to improve treatment-resistant depression in conjunction with an oral antidepressant. The precise mechanism by which esketamine elicits its antidepressant effect is not fully understood. NMDA is an ionotropic glutamate receptor. 

St. John's wort

St. John's wort (Hypericum perforatum) is an herbal remedy available over the counter. Although St. John's wort is considered a first-line antidepressant in many European countries, it has only recently gained popularity in the United States. Uses include treatment of mild to moderate depressive symptoms, but of note, it has not been shown to be effective in major depressive episodes and cannot be recommended as a first-line treatment in moderate depression.

St. John’s wort may act as an SSRI. The common dosage is 300 mg 3 times a day with meals to prevent GI upset. If no clinical response occurs after 3–6 months, encouraging the use of another medication is recommended.

In addressing the issue of alternative therapies for depression, the 2011 APA guideline noted that St. John's wort might be considered, but evidence for its effectiveness is modest, and more information is needed about its interaction with other drugs.[8]

Psilocybin

Psilocybin, a classic "psychedelic" drug, along with psychological support, is showing promise as a treatment for patients with treatment-resistant depression. A study of 19 patients measured cerebral blood flow (CBF) and blood oxygen-level dependent (BOLD) resting-state functional connectivity (RSFC) with functional magnetic resonance imaging (fMRI) before and after treatment with psilocybin. All 19 patients exhibited decreased depressive symptoms at 1 week post treatment and 47% met criteria for response at 5 weeks. Whole-brain analyses revealed post-treatment decreases in CBF in the temporal cortex, including the amygdala. Decreased amygdala CBF correlated with reduced depressive symptoms.[116]

Comparative effectiveness of antidepressants

The Agency for Healthcare Research and Quality (AHRQ) compared the effectiveness of the following 12 second-generation antidepressants[117] :

The AHRQ found that average effectiveness of those 12 antidepressants appeared similar, but the studies reviewed were not designed to test variation among patients’ responses to individual drugs. However, the AHRQ did find moderately strong evidence of differences among individual second-generation antidepressants with respect to onset of action and some measures (eg, sexual functioning) that could affect health-related quality of life.

The 2008 ACP guideline advises clinicians to choose second-generation antidepressants on the basis of adverse effects, cost, and patient preferences, since all these agents have comparable efficacy. Patient status, response to therapy, and adverse effects of antidepressants should be assessed within 1–2 weeks of starting therapy.[99]

Zisook et al found that among depressed patients with suicidal ideation at baseline, the combination of sustained-release bupropion and escitalopram was more effective at reducing suicidal ideation than sustained-release venlafaxine plus mirtazapine; the former was most effective at week 12 of treatment. In this study, of 665 outpatients with nonpsychotic chronic and/or recurrent major depressive disorder, 4 patients attempted suicide; all were receiving venlafaxine plus mirtazapine.[118]

Antidepressant effectiveness and depression severity

In a meta-analysis, Fournier et al found that medication superiority over placebo increased with increases in baseline depression severity, crossing the threshold for a clinically significant difference at a baseline Hamilton Depression Rating Scale (HDRS) score of 25.[119] In patients with mild or moderate depression, antidepressant medication had minimal or no benefit compared with placebo, but in patients with very severe depression, antidepressant drugs provided a substantial benefit compared with placebo.

More confirmation that antidepressants work for depression came from a large meta-analysis of 522 randomized controlled trials that compared 21 different antidepressants with placebo in more than 116,000 patients with major depressive disorder.[120] The 21 antidepressants included in the trials were agomelatine, amitriptyline, bupropion, citalopram, clomipramine, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, levomilnacipran, milnacipran, mirtazapine, nefazodone, paroxetine, reboxetine, sertraline, trazodone, venlafaxine, vilazodone, and vortioxetine. Results showed that each studied antidepressant was significantly more efficacious, defined as yielding a reduction of at least 50% in the total score of a standardized scale for depression, than placebo after 8 weeks. Patients who received agomelatine, escitalopram, and vortioxetine had both high response rates and low dropout rates.[120]

Psychotherapy

Hollon and Ponniah[5] reviewed the literature to identify treatments that met Chambless and Hollon’s[102] criteria for empirically supported treatments. Their findings for the treatment of acute major depressive disorder are presented below.

Table.



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See Table

Note: Adapted from Hollon & Ponniah [5] , p. 925.

Hollon and Ponniah[5] also identified empirically supported treatments for the prevention of relapse and recurrence.

Table.



View Table

See Table

Note: Adapted from Hollon & Ponniah [5] , p. 925.

A brief description of treatments listed as efficacious and specific or efficacious is presented below.

Behavioral activation (BA)

BA is based on early functional descriptions of depression by Lewinsohn[36] and Ferster[37] that emphasized the role of positive and negative reinforcement in depression,[121] suggesting that individuals with depression have deficient response-contingent positive reinforcement and engage in problematic avoidance behaviors. Modern BA treatments developed in response to a component analysis by Jacobson et al.[122] who found that the behavioral techniques in cognitive-behavioral therapy (CBT) were as effective as the full CBT package. While several different versions of BA exist, all emphasize the role of activity monitoring and activity scheduling in order to increase engagement in activities suggested to improve mood (see Kanter et al. for a review of specific tools used within different BA treatments[123] ). While early variants of BA emphasized activity scheduling that focused on increasing engagement in pleasant events (e.g., Lewinsohn[36] ), more recent versions haveemphasizedincorporating activities related to one’s values (e.g., Lejuez, Hopko, & Hopko,[124] ). Patients are typically given activity assignments to complete between sessions, with increasing difficulty over time. At times, activity assignments may be arranged along an activity hierarchy (e.g., Lejuez et al.[124] ). Mindfulness strategies may be incorporated to address rumination.[38]

BA is efficacious and specific for the treatment of acute depression.[5] There is also evidence suggesting that BA may be particularly well-suited for individuals with more severe depression. A placebo controlled trial compared BA, cognitive therapy (CT), and paroxetine and found that there were no differences between conditions for patients with lower depression severity, but for those with more severe depression, BA and paroxetine performed equivalently and each of those treatments led to greater improvement than the CT condition.[125] While the majority of research on BA has been conducted with adults, there are theoretical reasons to suggest that it may also be efficacious with adolescents[126] and a randomized clinical trial is being conducted to investigate this. In addition, there is some initial support for the use of BA with older adults in nursing home[127, 128] and community settings.[129]

Cognitive-behavioral therapy (CBT)

CBT is directed and time limited, usually involving between 10 and 20 treatments. Cognitive therapy (CT) is the most widely practiced version of CBT for depression. It is based on the premise that patients who are depressed exhibit the “cognitive triad” of depression, which includes a negative view of themselves, the world, and the future.[130] Related to the cognitive triad, depressed patients are believed to exhibit cognitive distortions that may maintain these negative beliefs.[131] Beck, Rush, Shaw, and Emery[131] postulated that negative automatic thoughts and distortions in thinking arise from problematic schemas, which are cognitive structures that influence how information is interpreted and recalled. CBT for depression typically includes behavioral strategies (i.e., activity scheduling), as well as cognitive restructuring for the purpose of changing negative automatic thoughts and addressing maladaptive schemas.

There is evidence supporting the use of CBT with individuals of all ages. For adults, CBT is considered to be efficacious and specific for the treatment of acute depression and prior CBT is considered to be efficacious and specific for the prevention of relapse.[5] It is particularly valuable for elderly patients, who may be more prone to problems or side effects with medications.[132, 133] In children and adolescents, 4 studies have shown group CBT to be better than no intervention in the reduction of depressive symptoms and improvement of self-esteem. In fact, in most pediatric clinical samples, CBT was found to be superior to other manualized treatments, including relaxation training and family and supportive therapy.

Interpersonal therapy (IPT)

Interpersonal therapy (IPT) is a time-limited (typically 16 sessions) treatment for major depressive disorder. While more structured than dynamic treatments, IPT has less structure than cognitive and behavioral approaches. IPT draws from attachment theory and emphasizes the role of interpersonal relationships,[134] focusing on current interpersonal difficulties. Specific areas of emphasis include grief, interpersonal disputes, role transitions, and interpersonal deficits.[135] The initial phase of treatment (sessions 1-4) focuses on building a working alliance as well as identifying an area of primary interpersonal focus based on the four areas previously mentioned, although other areas may be addressed as well. Patients are encouraged to assume the “sick role”, allowing them time to address their symptoms and have a brief respite from some responsibilities. During the middle phase of treatment (sessions 4-12), specific interventions are used to address the area of focus. Thisincludesproviding validation and support, improving communication skills, and working to solve interpersonal problems. The final phase of treatment (sessions 13-16) focuses on termination of therapy. This includes reviewing progress, developing relapse prevention strategies, and addressing emotions that come with ending the therapy relationship.[135]

IPT is an efficacious and specific treatment for major depressive disorder in adults.[5] Mufson and Fairbanks found that interpersonal therapy may be useful in the acute treatment of adolescents with major depressive disorder and that the rate of relapse is relatively low after acute IPT.[136] IPT may be modified for adolescents by flexibly determining session frequency and length, and use of telephone contact between sessions to support the development of the therapeutic alliance. In addition, a fifth area of focus on single-parent families has been added to IPT for adolescents (IPT-A) to address difficulties arising from a separation or divorce.[135] There is evidence to suggest that IPT may also be beneficial for depressed older adults.[137]

Mindfulness based cognitive therapy (MBCT)

Mindfulness based cognitive therapy (MBCT) was designed to reduce relapse among individuals who have been successfully treated for an episode of recurrent major depressive disorder. The primary treatment component is mindfulness training as developed by Jon Kabat-Zinn and his colleagues at the University of Massachusetts Medical Center.[138] MBCT specifically focuses on ruminative thought processes as being a risk factor for relapse, with the corresponding treatment strategy being to change one’s relationship with one’s thoughts through efforts to decenter and distance oneself from them.[139] Mindfulness presents a specific method for decentering and distancing oneself from one’s thoughts.

MBCT[140] integrates elements of CBT for depression[131] and mindfulness-based stress reduction (MBSR).[138] CBT elements include decentering strategies such as recognizing that thoughts are not facts and that “I am not my thoughts”.[139] Further, while MBSR may apply to a wide range of problems, MBCT was developed specifically for individuals in remission from recurrent major depressive disorder.

MBCT is a structured program that includes eight weekly, 2-hour group sessions. Patients are assigned homework on a daily basis. Homework consists of awareness exercises designed to help patients improve “…moment-by-moment nonjudgmental awareness of bodily sensations, thoughts, and feelings, together with exercises designed to integrate application of awareness skills into daily life.”[139] This includes awareness and acceptance of uncomfortable feelings and sensations rather than efforts to avoid contact with such experiences. Patients are encouraged to incorporate mindfulness into their daily activities as well as to practice specific mindfulness exercises.

Research indicated that MBCT reduced risk of relapse or recurrence among patients who completed treatment with medications for depression.[141, 142]  A meta-analysis found that MBCT was effective at reducing risk of relapse in patients with recurrent depression, especially in those with the most severe residual symptoms.[143]

Problem-solving therapy (PST)

Problem-solving therapy (PST) aims to improve individuals’ problem-solving attitudes and behaviors in order to decrease distress and improve quality of life.[141, 144] The use of PST for the treatment of major depressive disorder is based on a model characterizing social problem solving as a mediator (e.g., Nezu & Ronan[145] ) and moderator (e.g., Nezu, Nezu, Saraydarian, Kalmar, & Ronan[146] ) of the relationship between stress and depression. Social problem solving is defined as a cognitive-behavioral process that involves directing efforts to cope with a problem toward changing the nature of the situation, changing one’s reaction to the problem, or both. This includes the ability to identify and select a variety of coping responses to address the features of a specific stressful situation.[147]

According to social problem solving theory, one’s ability to successfully solve problems is based on both problem orientation and problem-solving style.[148, 149] Problem orientation includes an individual’s beliefs, attitudes, and emotional reactions to problems and their ability to cope with these problems. Problem orientation can either be positive (i.e., be optimistic that one can effectively solve problems, understand that negative emotions are an inevitable part of the process, understand that time and effort are required to solve problems) or negative (i.e., problems are viewed as threats, the individual feels pessimistic about their ability to solve problems, and they become especially upset in the face of problems and negative emotions). Problem-solving style refers to the activities someone engages in while trying to cope with a problem.[149, 148] This could be adaptive or maladaptive. An adaptive problem-solving style is referred to as rationalproblem-solving,whichincludes systematically applying skills to effectively solve a problem. These skills include: (a) defining a problem, (b) determining alternative solutions, (c) decision making regarding different solution strategies, and (d) implementing and evaluating a particular solution strategy. Maladaptive coping styles include the impulsivity-carelessness style and avoidance.[149] Treatment includes training in problem orientation, training in each of the steps of rational problem-solving, and practicing these skills.[150]

PST was found to be superior to nonspecific or wait list controls in two studies with adults[151, 152] and in one study with a geriatric sample.[153] PST was comparable to medications and superior to placebo in a study using a general practice sample.[154] Dowrick et al.[155] completed a large multi-center randomized trial across five European countries and found that PST was superior to an assessment only control in reducing depression severity.

Electroconvulsive Therapy

Electroconvulsive therapy (ECT) is a highly effective treatment for depression. Onset of action may be more rapid than that of drug treatments, with benefit often seen within 1 week of commencing treatment. A course of ECT (usually up to 12 sessions) is the treatment of choice for patients who do not respond to drug therapy, are psychotic, or are suicidal or dangerous to themselves.

Thus, the indications for the use of ECT include the following:

Although advances in brief anesthesia and neuromuscular paralysis have improved the safety and tolerability of ECT, this modality poses numerous risks, including those associated with general anesthesia, postictal confusion, and, more rarely, short-term memory difficulties. Especially in elderly patients, a preprocedure workup should be undertaken and should examine cardiac and vascular risk, because the procedure places a high cardiovascular demand on the patient.

Bright-Light Therapy

Bright-light therapy (BLT) for seasonal affective disorder is used at an intensity of 10,000 lux for 30-90 minutes daily, usually within 1 hour of arising in the morning. Like any effective antidepressant, BLT has the potential to precipitate a hypomanic or manic episode in susceptible individuals. Other common adverse effects include eye irritation, restlessness, and transient headaches. These lamps are not a significant source of ultraviolet (UV) light. Conventional antidepressants, with or without BLT, also can be used to treat seasonal affective disorder.

In addition to its established role in seasonal affective disorder, BLT may be effective in nonseasonal depression or as an augmenting agent with antidepressant medication. One study found that the combination of 30 minutes of bright light therapy a day plus 20 mg of fluoxetine significantly improves nonseasonal major depressive disorder. Data also show that light therapy alone is more effective than antidepressant monotherapy.[156]

Studies have demonstrated benefit of BLT for treatment of nonseasonal depression in pregnant patients and elderly patients.[157, 158]

Additional Therapies for Depression

Transcranial magnetic stimulation (TMS) has been approved by the FDA for the treatment of major depressive disorder when one class of antidepressant has failed. A double-blind, multicenter, controlled TMS trial found that 30.4% of patients in the trial’s active treatment group achieved remission from major depression after 5 weeks of TMS treatment.[159]

The study included 233 patients, all of whom suffered from major depression and had previously failed to respond to therapeutic treatments or could not tolerate antidepressant medication because of side effects. The TMS device used in the trial received FDA approval in 2013 for the treatment of depression.[159]  

In 2017, the FDA approved a next-generation TMS device for patients with treatment-resistant MDD.[160] At the time, this advanced system was the only FDA-cleared TMS treatment that can be delivered in less than 19 minutes, although treatment time may vary, depending on the physician's recommendation.

In 2018, the FDA approved a newer and faster treatment protocol for a TMS device first approved in 2015.[161] At that time, each treatment session with this device lasted up to 37 minutes, with 20 to 30 total sessions needed. With the new treatment protocol, which uses intermittent theta-burst stimulation (iTBS), a treatment session lasts only 3 minutes.[162]

Vagus nerve stimulation (VNS) has been approved by the FDA for use in adult patients who have failed to respond to at least 4 adequate medication and/or ECT treatment regimens. The device requires surgical implantation.

A meta-analysis of the therapeutic effect of physical exercise in depressed individuals revealed a short-term (≤16 wk) small positive effect on depression scores, but no long-term benefit was shown.[163] The authors felt that the evidence did not support the use of exercise for long-term benefits in clinically depressed individuals. The limited available evidence does not support using physical exercise as an “antidepressant.”

Deep brain stimulation (DBS) appears to be a safe and effective long-term treatment for treatment-resistant depression. Experience with this invasive technique is limited, however, and the method remains experimental.[164]

In a randomized, double-blind, controlled trial, Brunoni et al found that the efficacy of transcranial direct current stimulation (tDCS) was comparable to that of sertraline (50 mg/day) in the treatment of major depression and that the combination of tDCS with sertraline was superior to sertraline alone.[165] There was a significant difference in depression rating scale score between, on one hand, the combined treatment group and, on the other, the sertraline-only (mean difference, 8.5 points), tDCS only (5.9 points), and placebo groups (11.5 points).

In 2019, the FDA approved a cranial electrotherapy stimulator (CES) for treatment of anxiety, depression, and insomnia. The prescription device delivers micro pulses of electrical current across the brain, which in clinical trials led to a reduction in anxiety levels, insomnia, and depressed mood.[166] It is the first CES integrated into noise-cancelling, Bluetooth-enabled headphones and the first CES managed through an app.[167]

Treatment-Resistant Depression

In one third to two thirds of cases of depression, patients fail to remit with first-line therapy.[117, 168] No factors have been identified for reliably predicting whether an individual patient will respond.[168]

Assessment of patients with treatment-resistant depression should include consideration of the following:

Assuming that the assessment of the diagnosis is correct, there are no significant complicating diagnoses, and the current treatment has been at a therapeutic dose for a sufficient amount of time, possible interventions for persistent symptoms can include the following[8] :

The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial, the largest open-label trial to date, examined various strategies for treatment-resistant depression. The STAR*D trial showed that in patients who did not respond to an initial SSRI (citalopram), switching to another SSRI antidepressant, changing medication class, and switching to CBT were all equally effective treatments. Achieving remission, rather than partial response, was the best predictor of a better long-term prognosis.[168, 169]

The AHRQ found conflicting evidence regarding the differences between second-generation antidepressants for treatment-resistant depression. A good-quality study revealed no substantial differences in the effectiveness of sustained-release bupropion, sertraline, and sustained-release venlafaxine; however, fair-quality studies indicated a trend toward greater effectiveness with venlafaxine than with citalopram, fluoxetine, or paroxetine.[168]

Augmentation combinations can include the following:

The STAR*D trial found that augmentation of an SSRI with bupropion and augmentation with buspirone were equally effective after a lack of response to the SSRI.[168]

Aripiprazole (Abilify) is the first drug approved by the FDA for adjunctive treatment in major depressive disorder and the first drug to receive FDA approval for use in treatment-resistant depression.[170, 171, 172]

Esketamine nasal spray was approved by the FDA in March 2019 for treatment-resistant depression in conjunction with an oral antidepressant. It is administered in a physician’s office and the patient must be carefully monitored for at least 2 hours owing to risk of sedation, dissociation, and elevated blood pressure following the dose. 

Efficacy of esketamine was evaluated in 3 short-term (4-week) clinical trials and 1 longer-term maintenance-of-effect trial. In the short-term studies, patients were randomized to receive esketamine intranasal or a placebo nasal spray. Owing to the serious nature of treatment-resistant depression and the need for patients to receive some form of treatment, all patients started a new oral antidepressant at the time of randomization and the new antidepressant was continued throughout the trials. Primary efficacy was measured by the change from baseline on the Montgomery-Asberg Depression Rating Scale (MADRS) used to assess the severity of depressive symptoms. In one of the short-term studies, esketamine nasal spray demonstrated statistically significant effect compared with placebo on the severity of depression, and some effect was seen within 2 days. The 2 other short-term trials did not meet the pre-specified statistical tests for demonstrating effectiveness. In the longer-term maintenance-of-effect trial, patients in stable remission or with stable response who continued treatment with esketamine intranasal plus an oral antidepressant experienced a statistically significantly longer time to relapse of depressive symptoms than patients on placebo nasal spray plus an oral antidepressant.[173, 174]

Conway et al studied 13 patients with treatment-resistant major depression (TRMD) who received 12 months of treatment with vagus nerve stimulation (VNS).[175, 176] Positron emission tomography (PET) brain imaging was performed before the initiation of stimulation and again 3 and 12 months after stimulation had begun.

Of the 13 patients in the study, 9 experienced improvement in depression with the VNS treatment.[176] Among those who responded, the PET scans showed changes in brain metabolism after 3 months of stimulation, but this occurred several months before any improvements in their symptoms of depression were noted.

Transcranial magnetic stimulation (TMS) has also been studied in treatment-resistant patients. In one trial of 307 patients with a primary diagnosis of unipolar, nonpsychotic major depressive disorder who had failed to receive benefit from previous antidepressant therapy, acute treatment with TMS resulted in symptomatic improvement in 62% of patients and complete remission in 41%.[177]

Of the 257 patients who entered a 12-month follow-up phase of the study, 68% achieved symptomatic improvement at 12 months and 45% reported complete remission.[177] Long-term maintenance therapy consisted of continuation of antidepressant medication and access to TMS reintroduction for symptom recurrence.

Pediatric Depression Treatment

Increasingly, pediatric patients with depression have been treated with SSRIs or CBT. Fluoxetine is the only medication currently approved by the FDA for the treatment of depression in children. There are few studies on the use of medications for pediatric patients with major depressive disorder, and some of those that have been performed have methodologic problems. Additionally, very few pharmacokinetic studies have been performed in children, and most of those have focused on the effects of TCAs.[178] In adolescents, suicidality associated with antidepressants is an important issue.

The clinician needs to inform parents and patients about adverse effects, dose, timing of therapeutic effect, and danger of overdose, particularly with TCAs, before initiating pharmacologic treatment. Parents should take responsibility for medication storage and administration, especially with younger children and children at risk for suicide.

The Texas Children’s Medication Algorithm Project has created a consensus guideline for the treatment of major depression in pediatric patients that is based on evidence from scientific studies and the clinical expertise of the panel, which included child and adolescent psychiatry clinicians and research experts.[179] The guideline is as follows:

In the Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) study, patients who did not respond to an initial SSRI and were switched to combination therapy with CBT plus either another SSRI or venlafaxine had no better response than switching medications alone.[180] However, a switch to any second medication provided a good response, and each of the medications provided a similar response.

Selective serotonin reuptake inhibitors

The use of SSRIs as first-line medications in pediatric patients is supported by reports that these agents are effective in this population and have a relatively safe adverse-effect profile and very low lethality after overdose; in addition, SSRIs offer the convenience of once-daily administration. Several studies have reported a 70-90% response rate to SSRIs in adolescents with major depressive disorder.[181, 182, 183]

Children and adolescents with major depressive disorder responded significantly more frequently to fluoxetine (58%) than to placebo (32%), according to Emslie et al in an 8-week double-blind study.[184] However, only 31% of children achieved full remission. A possible explanation for the partial response in these young patients is that the effective treatment may involve variation in dose or length of treatment. Also, the ideal treatment likely involves a combination of pharmacologic and psychosocial interventions.

Except for lower initial doses, the administration of SSRIs in children and adolescents is similar to the treatment regimens used for adult patients. The clinician should treat patients with adequate and tolerable doses for at least 4 weeks. At 4 weeks, if the patient has not shown even minimal improvement, the clinician should consider increasing the dose. If, at this time, the patient shows improvement, the dose can be continued for at least 6 weeks. However, if no improvement is apparent at 6 weeks, other treatment strategies should be considered.

The clinician must cautiously apply the above recommendation; whether longer SSRI treatment increases the number of pediatric patients with late improvement is not clear. The Treatment of Adolescents with Depression Study (TADS) demonstrated significant increases in response to treatment over time (see Table 1, below).[185]

Table 1. Treatment Response Over Time in the Treatment of Adolescents with Depression Study



View Table

See Table

In TADS, suicidal ideation decreased less with fluoxetine therapy than with combination therapy or CBT. Suicidal events, but not actual suicides, occurred more often in patients receiving fluoxetine therapy (14.7%) than combination therapy (8.4%) or CBT (6.3%).

The SSRIs possess a relatively flat dose-response curve, suggesting that maximal clinical response may be achieved at minimum effective doses; therefore, adequate time must be allowed for clinical response, and frequent early-dose adjustments must be avoided. Blood levels are rarely indicated in clinical settings but may help clarify concerns about toxicity or compliance.

The adverse effects of all SSRIs in children are similar to those in adults; they are dose-dependent and may subside with time. SSRIs may induce mania, hypomania, and behavioral activation, in which patients become impulsive, silly, agitated, and daring. Other adverse effects include GI symptoms, restlessness, diaphoresis, headaches, akathisia, bruising, and changes in appetite, sleep, and sexual functioning. The long-term adverse effects of SSRIs are not yet known.

In December 2003, the UK Medicines and Healthcare Products Regulatory Agency (MHRA) issued an advisory that most SSRIs are not suitable for use by persons younger than 18 years for treatment of "depressive illness." After review, MHRA decided that the risks to pediatric patients outweigh the benefits of treatment with SSRIs, except for fluoxetine, which appears to have a positive risk-benefit ratio in the treatment of depressive illness in patients younger than 18 years.

A systematic review and meta-analysis by Tsapakis et al of randomized controlled trials of antidepressant therapy in young people with depression concluded that antidepressants of all types showed limited efficacy in juvenile depression. However, these researchers found that fluoxetine might be more effective, especially in adolescents.[183]

Antidepressants and suicidality in youths

In October 2003, the FDA issued a public health advisory regarding reports of suicidality in pediatric patients being treated with antidepressant medications for major depressive disorder. This advisory reported suicidality (both ideation and attempts) in clinical trials of various antidepressant drugs in pediatric patients. The FDA asked that additional studies be performed, because suicidality occurred in both treated and untreated patients with major depression and, thus, could not be definitively linked to drug treatment.

In September 2004, the results of an FDA analysis suggested that the risk of emergent suicidality in children and adolescents taking SSRIs was real. The FDA advisors (Columbia University) recommended the following:

The Psychopharmacologic Drugs and Pediatric Advisory Committees recommended that the products not be contraindicated, because access was important for those who could benefit from them. For more information, see the FDA Statement on Recommendations of the Psychopharmacologic Drugs and Pediatric Advisory Committees.

Given the possibility of increased suicidality, the FDA recommended that physicians who prescribe antidepressants to pediatric patients provide close monitoring in these cases. Close monitoring includes at least weekly face-to-face contact with patients or their family members or caregivers during the first 4 weeks of treatment; visits every other week for the next 4 weeks; visit at 12 weeks; and then visits as clinically indicated beyond 12 weeks. Additional contact by telephone may be appropriate between office visits.

Some studies have shown that the FDA warnings regarding suicide in children on antidepressants may have had the unintended result of a decrease in the rates of diagnosis and treatment of depression, as well as dosing adjustments by physicians and an increase in suicidality. It has also been noted that monitoring of these patients did not increase following the warnings.[186, 187]

Antidepressants were associated with a significant reduction in the risk of suicidal behavior in observational study by Leon et al, which followed 757 patients over a 27-year period. This study included participants with psychiatric and other medical comorbidity and those receiving acute or maintenance therapy, polypharmacy, or no psychopharmacologic treatment at all.[188] The results suggest, however, that clinicians must closely monitor patients when an antidepressant is initiated.

Other studies have argued that a decline in youth suicide rates coincided, to a striking extent, with significant increases in the prescription of antidepressants (mostly SSRIs) to adolescents.[189, 190, 191] The Treatment for Adolescents with Depression Study (TADS) lends support for fluoxetine's efficacy in adolescent depression, notably the combined use of fluoxetine and CBT.[192] Data from the TADS study also suggested a possible protective effect of CBT against suicidality when used in combination with fluoxetine.

Additionally, a study by the Group Health Cooperative in Seattle of more than 65,000 children and adults treated for depression found that suicide risk declines, not rises, with the use of antidepressants.[193] This is the largest study to date to address this issue. This study also showed that with psychotherapy and antidepressant drug therapy, the highest risk of suicide was in the month prior to seeking treatment. The month following initiation of treatment was also a period of high risk for both types of treatment, emphasizing the importance of close follow-up after treatment initiation.

Tricyclic antidepressants

TCAs are no longer considered the first-line treatment for pediatric patients with depressive disorders; however, individual cases may respond better to TCAs than to other medications. TCAs may also be useful for those with comorbid attention deficit hyperactivity disorder (ADHD), enuresis, and narcolepsy, as well as for augmentation strategies.

The TCAs require a baseline electrocardiogram (ECG), resting blood pressure, and pulse rate. Because of the potential of the TCAs to induce a fatal overdose, the clinician must carefully determine the exact amount of medication to be prescribed. Plasma levels should be monitored to measure compliance and to avoid toxicity. In addition, weight should be frequently documented.

No laboratory tests are currently indicated before or during the administration of the SSRIs. No other tests are indicated in a healthy child before starting antidepressants.

Depression During Pregnancy

Although avoiding the use of medication during pregnancy is preferable, the benefits of prompt medical treatment of major depressive disorder may often outweigh the risks of exposure of the fetus to an antidepressant. One meta-analysis found that the possible risks of untreated peripartum depression include increased risk of preterm birth, low birth weight, slower head growth, and intrauterine growth restriction.[194] There is no clear evidence that available antidepressants are teratogenic.

APA guidelines support psychotherapy as the first choice of therapy for pregnant women with mild depression.[8] In severe depression during pregnancy, especially in cases of psychosis, agitation, or severe retardation, electroconvulsive therapy may be the safest and quickest treatment option. One randomized, double-blind study found that bright-white-light therapy was significantly more effective than placebo for depression during pregnancy.[158]

Conflicting evidence exists regarding the use of SSRIs during pregnancy and an increased risk of persistent pulmonary hypertension of the newborn (PPHN). An initial Public Health Advisory in 2006 was based on a single retrospective study. Since then, studies have yielded conflicting findings, with 3 trials suggesting risk and 3 trials finding no risk of PPHN associated with antidepressants.[195, 196]

In a December 2011 review, the FDA concluded that, given the conflicting results from different studies, it is premature to reach any conclusion about a possible link between SSRI use in pregnancy and PPHN. The FDA advises health care professionals not to alter their current clinical practice of treating depression during pregnancy and to report any adverse events to the FDA MedWatch program.[197]

A further possible risk for infants born to women taking SSRIs is neonatal withdrawal symptoms, which includes high-pitched crying, tremors, and disturbed sleep. In one study, 30% of neonates exposed to SSRIs in utero developed withdrawal symptoms, typically peaking within 2 days of birth but sometimes as long as 4 days after birth.[198] These investigators recommended monitoring exposed neonates for as long as 48 hours after birth.

Postpartum Depression Treatment

Principles of treatment of postpartum major depressive disorder are the same as for depression during any other time of life. Earlier initiation of treatment is associated with better prognosis.[199]

A Cochrane review of 28 trials involving approximately 17,000 women concluded that psychosocial and psychological interventions can significantly reduce the number of women who develop postpartum depression. Women who received interventions including intensive, individualized postpartum home visits by nurses and midwives; peer-based telephone support; and interpersonal psychotherapy had an average risk ratio of 0.78, compared with women who received standard care.

Patients with postpartum depression should be assessed for danger to herself or to her children, as well as for other symptoms such as psychosis or substance abuse. Most antidepressants probably can be used safely during breast-feeding; however, this has not been studied thoroughly, and the same risk-benefit considerations should be applied as when treating depression during pregnancy.[200]

Postpartum blues are typically mild and resolve spontaneously; no specific treatment is required, other than support and reassurance. For first episodes of depression in postpartum women, 6-12 months of treatment is recommended. For women with recurrent major depression following pregnancy, long-term maintenance treatment with an antidepressant is indicated.[201]

Antidepressants and Breast-feeding

Most antidepressants probably can be used safely during breast-feeding; however, this has not been studied thoroughly, and the same risk-benefit considerations should be applied as when treating depression during pregnancy.[200]

Women who plan to breast-feed must be informed that antidepressants, like all psychotropic medications, are secreted into breast milk. Concentrations in breast milk vary widely.[202] Data on the use of TCAs, fluoxetine (Prozac), sertraline (Zoloft), and paroxetine (Paxil) during breast-feeding are encouraging, and serum antidepressant levels in the breast-fed infant are either low or undetectable. Reports of toxicity in breast-fed infants are rare, although the long-term effects of exposure to trace amounts of medication are not known.[87]

Antidepressants and the Elderly

Geriatric psychopharmacology follows the tenet of "start low, go slow, but go." This is based on the belief that elderly patients respond to such agents more slowly than younger patients and the fact that older patients tend to have a higher rate of side effects and adverse events from drug-drug or drug-disease interactions.

Most classes of medications have been associated with an increased risk of falls in elderly patients, especially the frail elderly. Furthermore, results from a study by Andreescu et al suggest that high levels of worry in elderly patients with depression were associated with slower response to pharmacotherapy and earlier recurrence.[203]

Start antidepressant medications at a lower dose (often, half the usual dose) in the elderly, and titrate more slowly than in younger adults. Furthermore, customary practice is to give the elderly patient a longer trial (12 wk vs customary 6-8 wk) before increasing the dose, changing the medication, or labeling it a failure. However, the need to wait 12 weeks remains a point of controversy and is undergoing more research.

In the elderly, drug-drug interactions are a concern with particular SSRIs because polypharmacy is common in this age group. Of the SSRIs, the likelihood of drug-drug interaction is highest with fluoxetine, paroxetine, and fluvoxamine. The specific interactions of these medications and medications commonly used in the elderly (eg, certain antibiotics, warfarin) are well established and available in many reference books.

SSRIs should be used in the elderly only with consideration by a physician familiar with these types of medications. The SSRIs that offer a lower likelihood of drug-drug interactions include escitalopram, citalopram, and sertraline. These medications should be used as first-line treatment in the elderly or in patients where drug-drug interaction is a concern.

Gastrointestinal side effects, including nausea, which can lead to weight loss, can be a problem in the elderly with use of SSRIs. Often, the nausea is short-lived, but when it is not, further options should be evaluated.

The value of pharmacologic treatment of refractory depression in geriatric patients remains uncertain. Cooper et al reviewed 14 studies of the management of depressive episodes that failed to respond to at least one course of treatment in patients aged 55 years and older. They found that half of the patients responded to further pharmacologic treatments; however, they noted that most of the studies had significant methodologic problems and that none were double-blind, randomized, placebo-controlled trials.[204]

Hospitalization

If suicidality is present, hospitalization with the patient's consent or via emergency commitment should be undertaken unless there are clear-cut means to ensure the patient's safety while outpatient treatment is begun. A child who is suicidal or has made an attempt at suicide should be admitted to a protected environment until all medical and social services can be employed.

In addition to suicidal or homicidal ideation, indications for psychiatric hospitalization include the following:

Diet and Activity

Diet plans

The low-sodium Dietary Approaches to Stop Hypertension (DASH) diet, previously shown to reduce hypertension and stroke risk, may also help ward off depression. Besides being low in sodium, the diet is rich in fruits, vegetables, whole grains, and low-fat dairy foods. A study found that participants who most closely adhered to the diet were 11% less likely to become depressed over time than those least adherent to the diet.[205]

The Mediterranean diet, which emphasizes fish, fruits, and vegetables, with olive oil as the main source of fat, protects cognition and can improve mental health in individuals with depression.[205, 206, 207]

The MIND diet is a combination of the Mediterranean and DASH diets and has also been shown to preserve brain health. It may be key in maintaining cognition and reducing dementia risk.[205, 208]

Dietary restrictions

Dietary restrictions are necessary only when prescribing monoamine oxidase inhibitors (MAOIs). Foods high in tyramine, which can produce a hypertensive crisis in the presence of MAOIs, should be avoided. These foods include the following:

Physical activity and exercise contribute to recovery from major depressive disorder. Patients should be counseled regarding stress reduction.

Complications of Treatment for Depression

SSRIs

Clinically significant hyponatremia may develop in elderly patients taking SSRIs. In addition to older age, risk factors include the following[209] :

of inappropriate secretion of antidiuretic hormone (SIADH), resulting in an euvolemic hyponatremia with low serum and high urine osmolalities. The hyponatremia generally starts within 1 month after starting the medication, and it reverses within a month after discontinuing the medication. Monitoring the sodium level in the elderly for at least 1 month after commencing an SSRI is suggested.

Although SSRIs do not have the same risk of cardiac arrhythmia as is present with TCAs, arrhythmia risk is especially pertinent in overdose. In addition, suicide risk must always be considered, especially when treating a child or adolescent with mood disorder.

Suicidality

A small number of case reports, such as those by King et al[210] and Teicher et al,[211] have described a putative association between SSRI administration and increased suicidality (perhaps linked to behavioral activation or akathisia). However, although such phenomena may have occurred in a small number of cases, several studies suggest that SSRIs, like other antidepressants, generally reduce the risk of suicide in adult patients who are depressed.

Stroke

A large-scale study that followed more than 80,000 women aged 54-79 found that women who suffer depression and use antidepressants face an increased risk of stroke. The hazard ratio for stroke was 1.29 for women with a history of depression.[212] A systematic review and meta-analysis of prospective studies found a hazard ratio of 1.45 for total stroke and 1.55 for fatal stroke.[213]

Withdrawal symptoms

Abrupt discontinuation of SSRIs that have shorter half-lives, such as paroxetine, may induce withdrawal symptoms, some of which may mimic a recurrence of a depressive episode (eg, tiredness, irritability, severe somatic symptoms). The withdrawal symptoms can appear after as few as 6-8 weeks of SSRI treatment. In addition to causing rebound depression, paroxetine discontinuation can also cause cholinergic rebound. Moreover, relapse may occur earlier after rapid withdrawal (< 15 days) than after more gradual withdrawal (≥ 15 days).[214]

Interactions with other drugs

Awareness of possible interactions with other medications is important. To varying degrees, but especially for fluvoxamine, the SSRIs inhibit the metabolism of several medications that are metabolized by the diverse clusters of hepatic cytochrome P-450 isoenzymes (eg, TCAs, neuroleptics, antiarrhythmics, benzodiazepines, carbamazepine, theophylline, warfarin, terfenadine [removed from United States market]). This inhibition results in higher plasma levels of those agents.

In addition, interactions of SSRIs with other serotonergic medications, particularly MAOIs, may induce the serotonergic syndrome, marked by agitation, confusion, and hyperthermia. SSRIs also have a high rate of protein binding, which can lead to increased therapeutic or toxic effects of other protein-bound medications. MAOIs should not be administered less than 5 weeks after discontinuation of fluoxetine and less than 2 weeks after discontinuation of other SSRIs. Also, the clinician should not prescribe SSRIs within 2 weeks after stopping the MAOIs.

Tricyclic antidepressants

The adverse effects of TCAs, which result largely from their anticholinergic and antihistaminic properties, include the following:

Caution should be used in patients with cardiac conduction abnormalities.

Bupropion is associated with a risk of seizure at doses above 450 mg a day, especially in patients with a history of seizure or epileptic disorders. This risk appears much lower in the sustained-release bupropion preparations.

Mirtazapine is a potent antagonist at 5-HT2, 5-HT3, alpha2-, and histamine (H1) receptors and, thus, can be very sedating and frequently causes weight gain. Adverse effects such as drowsiness may tend to improve over time and with higher doses. Trazodone is very sedating and usually is used as a sleep aid in small doses (ie, 25 to 50 mg) rather than as an antidepressant.

Nelson et al demonstrated that although adjunctive atypical antipsychotics (bupropion, mirtazapine, trazodone) were significantly more effective than placebo for augmenting therapy in major depressive disorder, discontinuance of therapy because of adverse events was higher for atypical antipsychotics than for placebo.[215]

Consultations

Consultation can be important at many stages of the treatment process. Certainly, treating physicians should seek consultation if they exhaust the options with which they feel comfortable.

A psychiatrist must be involved in the care of patients in whom more severe symptoms develop and for whom a more intensive level of care will be needed (eg, suicidal ideation, psychosis, mania, severe decline in physical health). Expertise in pharmacotherapy, other somatic therapies, and psychotherapy should be readily available.

Collaboration of psychiatrists and family practitioners/internists is of particular importance in patients with acute and chronic medical issues. A psychologist can be involved if psychological testing or more intensive specialized psychotherapy (eg, interpersonal therapy, cognitive-behavioral therapy) is needed.

Structured care in which nonmedical specialists augment primary care may offer an improved model. The use of an allied health professional supervised by a psychiatrist integrated into the primary care treatment of depression has been shown to double rates of adherence to antidepressants and significantly improve response to depression treatment.[216]

With the patient's consent, communication with the patient's therapist can be invaluable in guiding medical treatment of major depressive disorder. The therapist can provide information regarding clinical progress, symptoms, and adverse effects. This can facilitate timely and appropriate medical interventions.

Long-Term Monitoring

Observe patients at least monthly. Patient factors influencing the follow-up schedule include the following:

Medications should be reevaluated for drug-drug or drug-disease state interactions at every visit, as well as reevaluated for efficacy every 8-12 weeks. Nonresponse to treatment should raise the possibility of alternative diagnoses or alternative treatment.

Monitoring of mood and treatment response can be done during the clinical interview with use of the screening tools mentioned earlier (see Presentation) and, in pediatric or elderly patients, with collateral interviews with the family or caregiver. The 2011 APA guideline supports the use of rating-scale tools such as the PHQ-9 for evaluating the ongoing success of the treatment plan.[8]

The patient’s functional status and ability to perform activities of daily living should be evaluated at every visit. Suicidal ideation should be evaluated at each visit and between visits when indicated.

Psychotherapy can be used not only to consolidate the skills learned during the acute phase of treatment and help patients cope with the psychosocial sequelae of the depression but also to address the antecedents, contextual factors, environmental stressors, and intrapsychic conflicts that may contribute to a relapse. If the patient is taking antidepressants, psychotherapy can be used to foster medication compliance. In adolescents, one study suggested that monthly cognitive-behavioral therapy sessions may be effective to prevent relapses of depression.[217]

Guidelines Summary

French Association for Biological Psychiatry and Neuropsychopharmacology and the Fondation FondaMental

Clinical guidelines on the management of depression in patients with psychiatric comorbidities were published in January 2019 by the French Association for Biological Psychiatry and Neuropsychopharmacology and the Fondation FondaMental.[218]

Comorbid anxiety disorders

The following are recommended first-intention strategies during the first episode of major depressive disorder (MDD) with comorbid anxiety disorder:

First-intention medications and other treatment for MDD with comorbid obsessive-compulsive disorder, panic disorder, social anxiety, generalized anxiety disorder, or posttraumatic stress disorder include the following:

Comorbid substance use disorders

The following are recommended in first-intention treatment during the first episode of MDD with comorbid substance use disorder:

Also consider the following in first-intention treatment of patients with severe alcohol addiction:

First-intention medications and other treatments for MDD with comorbid substance use disorders include the following:

Comorbid personality disorders

The following are recommended during the first episode of MDD with comorbid personality disorder:

Geriatric depressive disorder

In adults over age 65 years, it is recommended, during an episode of MDD, that a physical examination and laboratory studies be performed to identify medical problems that could exacerbate or mimic depressive symptoms. Assessment includes the following:

First-intention treatments for geriatric depression include the following:

International Society for Nutritional Psychiatry Research

The International Society for Nutritional Psychiatry Research (ISNPR) recommends omega-3 polyunsaturated fatty acids (PUFAs) as adjunctive therapy for major depressive disorder.[219] The recommended therapeutic dosage of pure eicosapentaenoic acid (EPA) is 1–2 g/day (either from pure EPA or a combination of EPA and docosahexaenoic acid [DHA]) for at least 8 weeks as adjunctive treatment. The guideline also endorses n-3 PUFAs as a potential prophylactic treatment for high-risk populations, and indicates that they can be used in overweight patients and those individuals with elevated levels of inflammatory markers. 

Medication Summary

Drugs used for the treatment of depression include the following:

All antidepressants on the market are potentially effective.[120] Usually, 2–6 weeks at a therapeutic-dose level are needed to observe a clinical response. The choice of medication should be guided by anticipated safety and tolerability, which aid in compliance; physician familiarity, which aids in patient education and anticipation of adverse effects; and history of previous treatments. Often, treatment failures are caused not by clinical resistance but by medication noncompliance, inadequate duration of therapy, or inadequate dosing.

Antidepressants can have central and peripheral anticholinergic effects, as well as sedative effects, and can block the active reuptake of norepinephrine (NE), serotonin (5-HT), and dopamine. SSRIs are metabolized via the cytochrome P-450 system and may have drug interactions on that basis. The degree of enzyme inhibition varies among SSRIs. Effects on blood levels and bioavailability of coadministered drugs, as well as pharmacodynamic interactions, account for most clinically significant SSRI-drug interactions.

All available antidepressants appear to work via one or more of the following mechanisms[133] :

Citalopram (Celexa)

Clinical Context:  Citalopram enhances serotonin activity as a result of selective reuptake inhibition at the presynaptic neuronal membrane. It has minimal effects on norepinephrine and dopamine.

Although it has FDA approval only for depression, citalopram is commonly prescribed for other psychiatric disorders, including obsessive-compulsive disorder, generalized anxiety disorder, panic disorder, and premenstrual dysphoric disorder.

The FDA advises that the dose of citalopram not exceed 40 mg/day because of the risk of potentially fatal QT prolongation. Furthermore, higher doses have not been shown to be more effective in treating depression.[101]

Escitalopram (Lexapro)

Clinical Context:  Escitalopram is an SSRI and S-enantiomer of citalopram used for the treatment of depression. The mechanism of action is thought to be potentiation of serotonergic activity in the central nervous system resulting from inhibition of CNS neuronal reuptake of serotonin. Escitalopram has little or no effect on norepinephrine and dopamine reuptake.

Onset of depression relief may occur after 1-2 wk, but individual responses vary, and a full effect may not be seen until 8-12 weeks.

Fluoxetine (Prozac)

Clinical Context:  Fluoxetine is a commonly used SSRI and was the first of the SSRIs to become available in the United States. It selectively inhibits presynaptic serotonin reuptake with minimal or no effect on reuptake of norepinephrine or dopamine. It is commonly prescribed for many indications that are not FDA approved, including fibromyalgia, posttraumatic stress disorder, Raynaud phenomenon, social anxiety disorder, and selective mutism.

Fluvoxamine

Clinical Context:  Fluvoxamine enhances serotonin activity due to selective reuptake inhibition at the neuronal membrane. It does not significantly bind to alpha-adrenergic, histamine, or cholinergic receptors and thus has fewer side effects than tricyclic antidepressants. Fluvoxamine is a strong inhibitor of cytochrome P-450. Although fluvoxamine is FDA approved only for obsessive-compulsive disorder, it is commonly prescribed for other psychiatric disorders, including social anxiety disorder, posttraumatic stress disorder, pain disorder, and major depression.

Paroxetine (Paxil, Pexeva)

Clinical Context:  Paroxetine is a potent selective inhibitor of neuronal serotonin reuptake and also has a weak effect on norepinephrine and dopamine neuronal reuptake. It has slight anticholinergic effects and may cause more weight gain than other SSRIs. Paroxetine is sometimes prescribed for indications that are not FDA approved, such as eating disorders and the relief of vasomotor symptoms of menopause.

Sertraline (Zoloft)

Clinical Context:  Sertraline selectively inhibits presynaptic serotonin reuptake. It has very minimal effects on norepinephrine and dopamine neuronal uptake. Sertraline is sometimes prescribed for indications that are not FDA approved, such as eating disorders, generalized anxiety disorder, and panic disorder.

Vilazodone (Viibryd)

Clinical Context:  Vilazodone's mechanism of antidepressant effect is related to serotonergic activity in the CNS through selective inhibition of serotonin reuptake. This agent is also a partial agonist at serotonergic 5-HT1A receptors, although the contribution of this activity to the drug's antidepressant effect is unknown.

Vilazodone is indicated for major depressive disorder. The dose should be adjusted when this agent is given with moderate or strong CYP3A4 inhibitors.

Vortioxetine (Trintellix)

Clinical Context:  Vortioxetine enhances serotonergic activity through 5-HT reuptake inhibition. It also modulates serotonin receptor activity through 5-HT1A receptor agonism and 5-HT3 receptor antagonism, although the contribution of these activities to the antidepressant effect is not fully understood. It is approved to treat major depressive disorder in adults.

Class Summary

SSRIs are the initial antidepressants of choice for uncomplicated depression because of their minimal anticholinergic effects.

They have the advantage of ease of dosing and low toxicity in overdose. SSRIs are greatly preferred over the other classes of antidepressants for the treatment of children and adolescents, and these agents are also the first-line medications for late-onset depression, due to their superior tolerability and comparatively more benign safety profile.

The SSRIs are not thought to be as worrisome in patients with cardiac disease, as they do not appear to exert any effect on blood pressure, heart rate, cardiac conduction, or cardiac rhythm; however, dose-dependent QT prolongation has been reported with citalopram. Because of the risk for QT prolongation, citalopram is contraindicated in individuals with congenital long QT syndrome.[103, 104]

Because the adverse-effect profile of SSRIs is less prominent than other agents, improved compliance is promoted. Common adverse effects of SSRIs include gastrointestinal upset, sexual dysfunction, bleeding, emotional blunting, cognitive dysfunction, and changes in energy level (ie, fatigue, restlessness).

The US Food and Drug Administration issued a safety information update in December 2011 concluding that it is unclear whether the use of SSRIs during pregnancy causes persistent pulmonary hypertension in the newborn. The FDA currently recommends that health care professionals and patients weigh the small potential risk of persistent pulmonary hypertension against the substantial risks of untreated depression during pregnancy.[103]

Desvenlafaxine (Pristiq, Khedezla)

Clinical Context:  Desvenlafaxine is an SNRI that is indicated for the treatment of major depressive disorder.

Duloxetine (Cymbalta, Drizalma Sprinkle)

Clinical Context:  Duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine uptake, and antidepressant action is thought to be due to serotonergic and noradrenergic potentiation in the central nervous system.

Venlafaxine (Effexor XR)

Clinical Context:  Venlafaxine and its active metabolite inhibit neuronal serotonin and norepinephrine reuptake. They are weak inhibitors of dopamine reuptake. In addition, it causes beta-receptor down-regulation. Venlafaxine is sometimes prescribed for non–FDA-approved indications, such as obsessive-compulsive disorder, hot flashes, neuropathic pain, attention-deficit/hyperactivity disorder, and posttraumatic stress disorder.

Levomilnacipran (Fetzima)

Clinical Context:  Levomilnacipran is the active enantiomer milnacipran and should be administered once daily. It is a potent inhibitor of neuronal serotonin and norepinephrine reuptake, and inhibits norepinephrine uptake with approximately 3-fold higher potency in vitro than serotonin without directly affecting the uptake of dopamine or other neurotransmitters.

Class Summary

SNRIs can be used as first-line agents, particularly in patients with significant fatigue or pain syndromes associated with the episode of depression. The SNRIs also have an important role as second-line agents in patients who have not responded to SSRIs. Safety, tolerability, and side-effect profiles are similar to those of the SSRIs, with the exception that venlafaxine and desvenlafaxine have been associated (rarely) with a sustained rise in blood pressure. Venlafaxine has been particularly associated with hyponatremia.

Amitriptyline (Elavil)

Clinical Context:  Amitriptyline inhibits the reuptake of norepinephrine and, more potently, serotonin at the presynaptic neuronal membrane, which increases concentration in the CNS. It has a high affinity for histamine H1 and muscarinic M1 receptors. Amitriptyline can cause weight gain, sedation, and anticholinergic side effects. It is often used for non–FDA-approved indications, such as chronic pain management, diabetic neuropathy, migraine prophylaxis, and posttraumatic stress disorder.

Desipramine (Norpramin)

Clinical Context:  Desipramine inhibits the reuptake of serotonin and, more potently, norepinephrine at the presynaptic neuronal membrane. It is a commonly used TCA that is relatively less sedating and tends to have fewer anticholinergic and antihistaminic adverse effects than other TCAs. It is sometimes used for off-label indications such as peripheral neuropathy and attention-deficit/hyperactivity disorder.

Imipramine (Tofranil)

Clinical Context:  Imipramine is one of the oldest agents available for the treatment of depression. It is demethylated in the liver to desipramine. Imipramine inhibits the reuptake of norepinephrine and, more potently, serotonin at the presynaptic neuronal membrane. It has a strong affinity for alpha-adrenergic, H1, and M1 receptors. Common side effects include orthostasis, sedation, weight gain, and anticholinergic effects. It is also used off-label in the treatment of panic disorder, posttraumatic stress disorder, and attention deficit/hyperactivity disorder.

Clomipramine (Anafranil)

Clinical Context:  Clomipramine potently inhibits the reuptake of serotonin at the presynaptic neuronal membrane. It has strong affinities to both H1 and M1 receptors, which results in sedation, weight gain, and anticholinergic side effects. Although clomipramine is FDA approved only for obsessive-compulsive disorder, it has also been prescribed for depression, panic attacks, and chronic pain.

Nortriptyline (Pamelor)

Clinical Context:  Nortriptyline blocks the reuptake of serotonin and, more potently, norepinephrine at the presynaptic neuronal membrane. It has less affinity for H1 and M1 receptors and, thus, is better tolerated than other TCAs. Although nortriptyline is FDA approved only for depression, it has also been prescribed for chronic pain, myofascial pain, anxiety disorders, and attention-deficit/hyperactivity disorder. As with desipramine, there is a therapeutic window for nortriptyline

Protriptyline

Clinical Context:  Protriptyline increases the synaptic concentration of norepinephrine in the CNS by inhibiting reuptake at the presynaptic neuronal membrane. It has less affinity for H1 and M1 receptors and, thus, is better tolerated than tertiary amine TCAs.

Doxepin

Clinical Context:  Doxepin increases the concentration of serotonin and norepinephrine in the CNS by inhibiting their reuptake at the presynaptic neuronal membrane. These effects are associated with a decrease in the symptoms of depression. It has the highest affinity for H1 receptors of all TCAs and, thus, is very sedating and can cause weight gain.

Trimipramine (Surmontil)

Clinical Context:  Trimipramine inhibits reuptake of norepinephrine and serotonin at the presynaptic neuron and elicits strong anticholinergic effects. It has a high affinity for the H1 receptor and is thus very sedating, but it is useful for gastroesophageal reflux.

Amoxapine

Clinical Context:  Amoxapine inhibits reuptake of norepinephrine and, to a lesser extent, serotonin at the presynaptic neuron. It also blocks dopamine receptors, causing it to have antipsychotic activity, as well.

Class Summary

TCAs have a long record of efficacy in the treatment of depression and have the advantage of lower cost. They are used less commonly because of the need to titrate the dose to a therapeutic level and because of their considerable toxicity in overdose. TCAs are often prescribed for many other psychiatric disorders, such as generalized anxiety disorder and posttraumatic stress disorder. They are also used to treat chronic pain, such as neuropathy, and migraine headaches.

Selegiline transdermal patch (Emsam)

Clinical Context:  Selegiline inhibits MAOb at lower doses and both forms at higher doses. Because it does not inhibit MAOa, it does not require dietary restrictions at lower doses. Lower doses of oral selegiline (Eldepryl) appear to lack antidepressant properties and are usually prescribed to treat Parkinson disease. Higher doses are used to treat major depressive disorder, and the selegiline transdermal patch is FDA approved for this indication. Selegiline is sometimes used off-label to treat attention-deficit/hyperactivity disorder.

Dietary restrictions are not required for the 6 mg/24 hour patch because there is no risk of hypertensive crisis with this dose, given the lack of MAOa inhibition. Higher doses require dietary restrictions. The patch may be beneficial to those that cannot take oral medications. To avoid serotonin syndrome, initiating and stopping selegiline must be handled carefully.

Tranylcypromine (Parnate)

Clinical Context:  Tranylcypromine is used to treat major depression. It binds irreversibly to MAOa and to a lesser extent to MAOb, thereby reducing monoamine breakdown and enhancing synaptic availability. Clinical effects are not normally seen for 2-4 weeks. It has similar side effects as other MAOIs, but it is more likely to cause insomnia.

Phenelzine (Nardil)

Clinical Context:  Phenelzine is used to treat depression. It irreversibly inhibits both MOAa and MOAb. Side effects are similar to those of other MAOIs, but anticholinergic side effects are more common. Phenelzine causes less insomnia than tranylcypromine but is more likely to cause sedation, weight gain, and sexual dysfunction.

Isocarboxazid (Marplan)

Clinical Context:  Isocarboxazid is a nonselective hydrazine MAOI that is indicated for the treatment of depression. The mechanism by which MAOIs act as an antidepressant is not fully understood, but it is thought to be that these drugs increase the CNS concentrations of norepinephrine, dopamine, and serotonin.

Class Summary

Monoamine oxidase inhibitors were the first antidepressants discovered, in the early 1950s. They are widely effective in a broad range of affective and anxiety disorders. MAOIs irreversibly block monamine oxidase, which has 2 forms, including MOAa and MOAb. MAOa breaks down serotonin and norepinephrine. MOAb metabolizes phenylethylamine. Both forms break down dopamine.

MOAIs are not considered first-line treatment for depression because of the side effects, drug-drug interactions, and dietary restrictions. Common side effects include hypotension, dizziness, dry mouth, gastrointestinal upset, urinary hesitancy, headache and myoclonic jerks. Because of the risk of hypertensive crisis with drugs that specifically inhibit MAOa in the gastrointestinal tract, patients on these medications must follow a low-tyramine diet.

Lithium carbonate (Lithobid)

Clinical Context:  Lithium carbonate can be used as an effective augmenting agent in combination with an antidepressant in cases of treatment-resistant depression. It can also be used to treat or prevent episodes of depression. Lithium is contraindicated in patients with significant renal impairment.

It is important to note that lithium interacts with many drugs. Use of lithium often requires monitoring of lithium levels and renal and thyroid function tests.

Buspirone

Clinical Context:  Buspirone is marketed as an antianxiety medication; however, it may have antidepressant effects at doses above 45 mg/day. The antidepressant effects may increase when buspirone is used in combination with SSRIs and TCAs in patients with treatment-resistant depression. Buspirone is a partial 5-HT1A agonist with serotonergic and some dopaminergic effects in the CNS. It has anxiolytic effects but may take up to 2-3 weeks for full efficacy.

Class Summary

Augmentation is a common strategy for treatment-resistant depression. It consists of adding a medication with a different mechanism of action to the therapeutic regimen.

Brexpiprazole (Rexulti)

Clinical Context:  Serotonin-dopamine activity modulator (SDAM) indicated as an adjunct treatment for major depressive disorder. Dosage modifications are necessary with renal or hepatic impairment. Dosage modifications are also needed for individuals who are poor metabolizers of CYP2D6, or if coadministered drugs alter metabolism by CYP2D6 or CYP3A4.

Aripiprazole (Abilify, Abilify Discmelt)

Clinical Context:  Serotonin-dopamine activity modulator (SDAM) indicated as an adjunct treatment for major depressive disorder. Dosage modifications are also needed for individuals who are poor metabolizers of CYP2D6, or if coadministered drugs alter metabolism by CYP2D6 or CYP3A4. No dosage adjustment is required for renal or hepatic impairment.

Class Summary

Serotonin-dopamine activity modulators (SDAMs) act as a partial agonist at 5-HT1A and dopamine D2 receptors at similar potency, and as an antagonist at 5-HT2A and noradrenaline alpha1B/2C receptors. This mechanism of action is unique from other atypical antipsychotic drugs.

Bupropion (Wellbutrin, Aplenzin, Forfivo XL)

Clinical Context:  Bupropion inhibits neuronal dopamine reuptake and decreases the rate of norepinephrine activity. In addition to major depressive disorder, the indications for bupropion include smoking cessation. Off-label indications include attention-deficit/hyperactivity disorder and depression associated with bipolar disorder. Common side effects include headache and mild weight loss. Unlike other antidepressants, bupropion does not cause sexual dysfunction.

Mirtazapine (Remeron, Remeron SolTab)

Clinical Context:  Mirtazapine blocks both presynaptic and postsynaptic alpha-2 receptors but has low affinity for alpha-1 receptors. It also blocks serotonin receptors 5HT2 and 5HT3. Common side effects include sedation, weight gain, and dry mouth.

Trazodone (Oleptro)

Clinical Context:  Trazodone is effective in the treatment of major depression. It inhibits reuptake of serotonin and modulates serotonergic neurotransmission. It also significantly blocks histamine (H1) receptors. Its most common side effect is sedation, and thus, it has an off-label indication as a hypnotic. It can be very rarely associated with priapism, a medical emergency and a dangerous side effect of this drug in men. It is often used at a low dosage (25 to 50 mg) as an adjunct to SSRIs to treat insomnia.

Class Summary

Atypical antidepressants include bupropion (Wellbutrin, Wellbutrin SR), mirtazapine (Remeron), and trazodone (Desyrel). These agents are effective in treating major depression and may be effective in combination therapy in major depressive disorder. This group also shows low toxicity in overdose. Wellbutrin SR may have an advantage over the SSRIs by causing less sexual dysfunction and weight gain.

Dextroamphetamine (Dexedrine, ProCentra, Zenzedi)

Clinical Context:  This is an augmenting agent in resistant depression. It has been studied most for treating patients who are medically ill and depressed. It is available as a sustained-release preparation.

Methylphenidate (Ritalin, Aptensio XR, Concerta, Daytrana, Metadate ER, Quillivant ER)

Clinical Context:  Methylphenidate has been mostly studied for treating patients who are medically ill and depressed. It is available as a sustained-release preparation.

Class Summary

The CNS stimulants dextroamphetamine (Dexedrine) and methylphenidate (Ritalin) are sometimes used to augment antidepressants in patients with resistant depression.

Liothyronine (Cytomel, Triostat)

Clinical Context:  This synthetic salt of endogenous thyroid hormone may convert nonresponders (ie, nonresponders to antidepressants) to responders by increasing receptor sensitivity and enhancing the effects of TCAs.

Class Summary

Thyroid hormones liothyronine (T3, Cytomel) may modulate the effect of antidepressants.

Hypericum perforatum (St John's Wort)

Clinical Context:  St John's wort is believed to act as an antidepressant by increasing concentrations of CNS neurotransmitters, including serotonin. The common dosage is 300 mg 3 times a day with meals to prevent GI upset. If no clinical response occurs after 3-6 months, encouraging the use of another medication is essential.

Class Summary

Although St. John's wort is considered a first-line antidepressant in many European countries, it has only recently gained popularity in the United States. Uses include treatment of mild to moderate depressive symptoms, but efficacy has not been demonstrated for major depression.

Esketamine intranasal (Spravato)

Clinical Context:  Esketamine, the S-enantiomer of racemic ketamine, is a nonselective, noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist (NMDA is an ionotropic glutamate receptor). The mechanism by which esketamine exerts its antidepressant effect is unknown. It is indicated for treatment-resistant depression in conjunction with an oral antidepressant.

Ketamine (Ketalar)

Clinical Context:  A non-competitive NMDA antagonist that blocks glutamate and has been found to have antidepressant effects. Used off-label to treat treatment-resistant depression. By acting on the cortex and the limbic system, produces a cataleptic-like effect state, which in turn causes the patient to feel dissociated from the surrounding environment.

Class Summary

Studies have shown that the N-methyl-D-aspartate (NMDA) receptor may play a role in the pathophysiology of psychiatric disorders, including depression. The use of NMDA receptor antagonists have been shown to be effective in the treatment of major depressive disorder.

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(GDS)?How should rating scales for depression be interpreted in elderly persons?What is a common complaint of patients with major depressive disorder (clinical depression)?Which depression rating scale is used for older patients with dementia?Which lab tests are useful to exclude medical illnesses that may present as major depressive disorder (clinical depression)?What is the role of imaging studies in the diagnosis of major depressive disorder (clinical depression)?What is the role of PET imaging in the diagnosis of major depressive disorder (clinical depression)?What SPECT scanning findings might suggest major depressive disorder (clinical depression)?Are effective treatments available for major depressive disorder (clinical depression)?What factors should be considered in medication selection for the treatment of major depressive disorder (clinical depression)?What are the ACP guidelines for use of second-generation anti-depressants in the treatment of major depressive disorder (clinical depression)?What are the ACP guidelines for duration of pharmacotherapy in major depressive disorder (clinical depression)?What are the APA guidelines for treatment selection for major depressive disorder (clinical depression)?How often is psychotherapy conducted in the treatment of major depressive disorder (clinical depression)?According to the APA guidelines, when are psychological treatments considered efficacious?What drugs are used for the treatment of major depressive disorder (clinical depression)?Is St. John&#39;s wort effective in the treatment of major depressive disorder (clinical depression)?Which SSRIs are used in the treatment of major depressive disorder (clinical depression)?What are the advantages of SSRIs for the treatment of major depressive disorder (clinical depression)?What are the possible adverse effects of SSRIs in the treatment of major depressive disorder (clinical depression)?Are SSRIs contraindicated in patients with comorbid major depressive disorder (clinical depression) and cardiac disease?When is citalopram contraindicated in the treatment of major depressive disorder (clinical depression)?Is vortioxetine (Brintellix) effective in the treatment of major depressive disorder (clinical depression)?What is the role of SNRIs in the treatment of major depressive disorder (clinical depression)?Is concurrent use of SNRIs with other antidepressants safe and effective in the treatment of major depressive disorder (clinical depression)?Is levomilnacipran (Fetzima) effective in the treatment of major depressive disorder (clinical depression)?Which atypical antidepressants are effective in the treatment of major depressive disorder (clinical depression)?What is the role of SDAMs in the treatment of major depressive disorder (clinical depression)?Are SDAMs effective in the treatment of major depressive disorder (clinical depression)?Which tricyclic antidepressants (TCAs) are effective in the treatment of major depressive disorder (clinical depression)?Are MAOIs effective in the treatment of major depressive disorder (clinical depression)?Is psilocybin effective in the treatment of major depressive disorder (clinical depression)?What were the AHRQ findings regarding the effectiveness of second-generation antidepressants in the treatment of major depressive disorder (clinical depression)?What are the ACP guidelines for the selection of second-generation antidepressants in the treatment of major depressive disorder (clinical depression)?Which treatments have been found effective in major depressive disorder (clinical depression) with suicidal ideation?Does the effectiveness of antidepressant medications increase with depression severity?Which treatments are effective for acute major depressive disorder and for the prevention of relapse and recurrence?What is behavioral activation (BA) therapy for the treatment of major depressive disorder (clinical depression)?Is behavioral activation (BA) an effective treatment for major depressive disorder (clinical depression)?What is cognitive-behavioral therapy (CBT) for the treatment of major depressive disorder (clinical depression)?For which patient groups is cognitive-behavioral therapy (CBT) an effective treatment for major depressive disorder (clinical depression)?What is interpersonal therapy (IPT) for the treatment of major depressive disorder (clinical depression)?For which patient groups is interpersonal therapy (IPT) an effective treatment for major depressive disorder (clinical depression)?What is mindfulness based cognitive therapy (MBCT) for the treatment of major depressive disorder (clinical depression)?What is the basis of mindfulness based cognitive therapy (MBCT) for the treatment of major depressive disorder (clinical depression)?How is mindfulness-based cognitive therapy (MBCT) delivered in the treatment of major depressive disorder (clinical depression)?What is the efficacy of mindfulness based cognitive therapy (MBCT) in the treatment of major depressive disorder (clinical depression)?What is problem solving therapy (PST) in the treatment of major depressive disorder (clinical depression)?How is problem-solving therapy (PST) delivered in the treatment of major depressive disorder (clinical depression)?What is the efficacy of problem-solving therapy (PST) in the treatment of major depressive disorder (clinical depression)?What is the role of electroconvulsive therapy (ECT) in the treatment of major depressive disorder (clinical depression)?What are the indications for electroconvulsive therapy (ECT) in the treatment of major depressive disorder (clinical depression)?What are the possible adverse effects of electroconvulsive therapy (ECT) in the treatment of major depressive disorder (clinical depression)?What is the role of bright-light therapy (BLT) in the treatment of seasonal affective disorder (SAD)?What is the role of bright-light therapy (BLT) in the treatment of major depressive disorder (clinical depression)?What is the role of transcranial magnetic stimulation (TMS) in the treatment of major depressive disorder (clinical depression)?When is vagus nerve stimulation (VNS) indicated in the treatment of major depressive disorder (clinical depression)?What is the role of physical exercise in the treatment of major depressive disorder (clinical depression)?What is the role of deep brain stimulation (DBS) in the treatment of major depressive disorder (clinical depression)?Is transcranial direct current stimulation (tDCS) an effective treatment for major depressive disorder (clinical depression)?How common is failure to remit with first-line therapy in the treatment of major depressive disorder (clinical depression) and how is treatment resistance assessed?How is treatment-resistant major depression (TRMD) treated?Which second-generation antidepressants may be more effective therapy for treatment-resistant major depression (TRMD)?Which augmentation combination therapies may be considered for treatment-resistant major depression (TRMD)?Is vagus nerve stimulation (VNS) an effective treatment for treatment-resistant major depression (TRMD)?Is transcranial magnetic stimulation (TMS) an effective treatment for treatment-resistant major depression (TRMD)?What are the treatment options for children and adolescents with major depressive disorder (clinical depression)?What do parents and patients need to know before pharmacologic treatment is initiated for major depressive disorder (clinical depression)?What are the guidelines for the treatment of major depressive disorder (clinical depression) in children and adolescents?What are the treatment options for adolescents who do not respond to an initial SSRI for major depressive disorder (clinical depression)?Are SSRIs effective as a first-line medication in adolescents with major depressive disorder (clinical depression)?What is the recommended treatment regimen of SSRIs in children and adolescents with major depressive disorder (clinical depression)?Which form of therapy is associated with increased suicidal events in adolescents with major depressive disorder (clinical depression)?When is a maximal clinical response achieved for SSRIs in major depressive disorder (clinical depression)?What are the adverse effects of SSRIs in children and adolescents with major depressive disorder (clinical depression)?What is the efficacy of antidepressant treatment of major depressive disorder (clinical depression) in children and adolescents?Do antidepressants increase the risk of suicide in children and adolescents with major depressive disorder (clinical depression)?What are the 2004 FDA warnings and recommendations for children and adolescents taking SSRIs for major depressive disorder (clinical depression)?What were the effects of the FDA’s warnings regarding suicide in children taking antidepressants?Do antidepressants increase or decrease suicidal behavior in patients with major depressive disorder (clinical depression)?When are tricyclic antidepressants (TCAs) indicated in the treatment of children with major depressive disorder (clinical depression)?Which baseline and monitoring tests are required when tricyclic antidepressants are administered for treatment of major depressive disorder (clinical depression)?When is medical treatment for major depressive disorder (clinical depression) indicated during pregnancy?What are the guidelines for therapy in pregnant women with mild or severe depression?What are the possible adverse effects of SSRIs during pregnancy for the treatment of major depressive disorder (clinical depression)?What are the symptoms of neonatal withdrawal from in utero exposure to SSRIs?How is postpartum major depressive disorder treated?Which symptoms should be assessed in patients with suspected postpartum depression?What are the symptoms of postpartum blues and how are they treated?Is it safe for women to breastfeed when taking antidepressants?What are principles guiding geriatric psychopharmacology for major depressive disorder (clinical depression)?Do antidepressants increase the risk of falls in elderly patients with major depressive disorder (clinical depression)?What is the recommended administration of antidepressants in elderly patients with major depressive disorder (clinical depression)?Which drug-drug interactions may be present with the use of antidepressants in elderly patients with major depressive disorder (clinical depression)?What are possible adverse effects of SSRIs in elderly patients with major depressive disorder (clinical depression)?Are antidepressants effective in geriatric patients with major depressive disorder (clinical depression)?When is psychiatric hospitalization indicated in the treatment of major depressive disorder (clinical depression)?Which types of diets have been shown to improve mental health and possibly improve or prevent depression?What foods should be avoided when prescribing MAOIs and how can patients recover from major depressive disorder?What are the risk factors for hyponatremia in patients with major depressive disorder (clinical depression) taking SSRIs?Do SSRIs increase the risk of cardiac arrhythmia in patients with major depressive disorder (clinical depression)?Do SSRIs increase or decrease the risk of suicide in patients with major depressive disorder (clinical depression)Do antidepressants increase the risk of stroke in patients with major depressive disorder (clinical depression)?What are the possible withdrawal symptoms associated with the abrupt discontinuation of SSRIs?What possible interactions may occur when SSRIs are combined with other medications?What are the possible adverse effects of tricyclic antidepressants (TCAs)?At what dosage is bupropion associated with a risk of seizure?What are the effects of mirtazapine and trazodone?What is the role of atypical antidepressants in the treatment of major depressive disorder (clinical depression)?What is the role of the therapist in the medical treatment of major depressive disorder (clinical depression)?When is consultation with a psychiatrist indicated in the treatment of major depressive disorder (clinical depression)?What is the benefit of collaboration of psychiatrists and family practitioners/internists in the management of major depressive disorder (clinical depression)?What is structured care for the management of major depressive disorder (clinical depression)?Which factors could influence the follow-up schedule in patients with major depressive disorder (clinical depression)?How often should medications be reevaluated for treatment efficacy in patients with major depressive disorder (clinical depression)?How should mood and treatment response be monitored in patients with major depressive disorder (clinical depression)?Is psychotherapy beneficial in preventing relapse of major depressive disorder (clinical depression)?What are the treatment guidelines for depression in patients with comorbid anxiety disorders?What are the treatment guidelines for depression in patients with substance use disorders?What are the treatment guidelines for depression in patients with personality disorders?What are the treatment guidelines for depression in patients with geriatric depressive disorder?Which drugs are used for the treatment of depression?When is a clinical response seen after initiation of antidepressant therapy for major depressive disorder (clinical depression)?What are the effects of antidepressants for major depressive disorder (clinical depression)?What are the neuromechanisms of antidepressants for the treatment of major depressive disorder (clinical depression)?Which medications in the drug class Antidepressants, SSRIs are used in the treatment of Depression?Which medications in the drug class Antidepressants, SNRIs are used in the treatment of Depression?Which medications in the drug class Antidepressants, TCAs are used in the treatment of Depression?Which medications in the drug class Antidepressants, MAO Inhibitors are used in the treatment of Depression?Which medications in the drug class Augmenting Agents are used in the treatment of Depression?Which medications in the drug class Serotonin-Dopamine Activity Modulators are used in the treatment of Depression?Which medications in the drug class Antidepressants, Other are used in the treatment of Depression?Which medications in the drug class Stimulants are used in the treatment of Depression?Which medications in the drug class Thyroid Products are used in the treatment of Depression?Which medications in the drug class Neurology & Psychiatry, Herbals are used in the treatment of Depression?Which medications in the drug class NMDA Antagonists are used in the treatment of Depression?

Author

Jerry L Halverson, MD, Medical Director of Rogers Memorial Hospital at Oconomowoc; Voluntary Clinical Assistant Professor, Department of Psychiatry, University of Wisconsin School of Medicine and Public Health; Clinical Assistant Professor of Psychiatry, Department of Psychiatry and Behavioral Sciences, Medical College of Wisconsin

Disclosure: Nothing to disclose.

Coauthor(s)

Louise B Andrew, MD, JD, Medical-Legal, Risk Management and Trial Consultant, Litigation Stress Counselor

Disclosure: Nothing to disclose.

Pascale Moraille-Bhalla, MD, Medical Director, Outpatient Clinic of Hoboken University Medical Center; Staff Psychiatrist, Mental Health Clinic of Passaic

Disclosure: Nothing to disclose.

Rachel C Leonard, PhD, Clinical Director, Rogers Behavioral Health

Disclosure: Nothing to disclose.

Ravinder N Bhalla, MD, Assistant Clinical Professor of Child Psychiatry, Rutgers New Jersey Medical School; Medical Director, Mental Health Clinic of Passaic; Consulting Staff, Christian Health Care Center

Disclosure: Received income in an amount equal to or greater than $250 from: Allergen.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

David Bienenfeld, MD, Professor, Departments of Psychiatry and Geriatric Medicine, Wright State University, Boonshoft School of Medicine

Disclosure: Nothing to disclose.

Acknowledgements

Iqbal Ahmed, MBBS, FRCPsych (UK) Faculty, Department of Psychiatry, Tripler Army Medical Center; Clinical Professor of Psychiatry, Clinical Professor of Geriatric Medicine, University of Hawaii, John A Burns School of Medicine

Iqbal Ahmed, MBBS, FRCPsych (UK) is a member of the following medical societies: Academy of Psychosomatic Medicine, American Association for Geriatric Psychiatry, American Neuropsychiatric Association, American Psychiatric Association, American Society of Clinical Psychopharmacology, and Royal College of Psychiatrists

Disclosure: Nothing to disclose.

Sarah C Aronson, MD Associate Professor, Departments of Psychiatry and Medicine, Case Western Reserve School of Medicine/University Hospitals of Cleveland

Disclosure: Nothing to disclose.

Barry I Liskow, MD Professor of Psychiatry, Vice Chairman, Psychiatry Department, Director, Psychiatric Residency Program, University of Kansas School of Medicine; Director, Psychiatric Outpatient Clinic, The University of Kansas Medical Center

Disclosure: Nothing to disclose.

Mohammed A Memon, MD Chairman and Attending Geriatric Psychiatrist, Department of Psychiatry, Spartanburg Regional Medical Center

Mohammed A Memon, MD is a member of the following medical societies: American Association for Geriatric Psychiatry, American Medical Association, and American Psychiatric Association

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Art Walaszek, MD Associate Professor of Psychiatry, Residency Training Director, Department of Psychiatry, University of Wisconsin School of Medicine and Public Health; Consulting Staff, University of Wisconsin Hospital and Clinics, Meriter Hospital

Art Walaszek, MD is a member of the following medical societies: American Association for Geriatric Psychiatry, American Medical Association, American Psychiatric Association, and Association for Academic Psychiatry

Disclosure: Terra Nova Learning Systems, Inc. Consulting fee Consulting; Wisconsin Psychiatric Association Honoraria Speaking and teaching; Care Wisconsin, Inc. Honoraria Speaking and teaching

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From 1991-2006, the suicide rate was consistently higher among males. Suicide rates declined among both sexes from 1991-2000; the rate among males decreased from 24.64 to 20.67 suicides per 100,000 and 5.48 to 4.62 suicides per 100,000 among females. From 2000-2006, however, the suicide rates gradually increased among females. Note: All rates are age-adjusted to the standard 2000 population. Rates based on less than 20 deaths are statistically unreliable. Source: Centers for Disease Control and Prevention. National suicide statistics at a glance: Trends in suicide rates among persons ages 10 years and older, by sex, United States, 1991-2006. Available at: http://www.cdc.gov/violenceprevention/suicide/statistics/trends01.html. Accessed: May 5, 2010.

Geriatric Depression Scale.

Geriatric Depression Scale-Short.

Cornell Scale for Depression in Dementia.

From 1991-2006, the suicide rate was consistently higher among males. Suicide rates declined among both sexes from 1991-2000; the rate among males decreased from 24.64 to 20.67 suicides per 100,000 and 5.48 to 4.62 suicides per 100,000 among females. From 2000-2006, however, the suicide rates gradually increased among females. Note: All rates are age-adjusted to the standard 2000 population. Rates based on less than 20 deaths are statistically unreliable. Source: Centers for Disease Control and Prevention. National suicide statistics at a glance: Trends in suicide rates among persons ages 10 years and older, by sex, United States, 1991-2006. Available at: http://www.cdc.gov/violenceprevention/suicide/statistics/trends01.html. Accessed: May 5, 2010.

Geriatric Depression Scale.

Geriatric Depression Scale-Short.

Hamilton Depression Scale.

Center for Epidemiologic Studies Depression Scale.

Cornell Scale for Depression in Dementia.

Suicide rate by age and gender. 2004 data compiled from CDC. The mean suicide rate for the entire population was 12.8/100,000/year.

Depression in the US Household Population, 2009–2012. Courtesy of National Center for Health Statistics (NCHS), Centers for Disease Control and Prevention (CDC).

12-month Prevalence of Major Depressive Episode Among US Adults, 2015. Courtesy of National Center for Health Statistics (NCHS), Centers for Disease Control and Prevention (CDC).

level of support Therapy
Efficacious and specificInterpersonal psychotherapy (IPT)
Cognitive behavior therapy (CBT)
Problem-solving therapy (PST)
Behavioral activation (BA)/contingency management
Possibly efficaciousDynamic psychotherapy
Cognitive behavioral analysis system for psychotherapy (CBASP)
Emotion-focused therapy (EFT)
level of support Therapy
Efficacious and specificPrior CBT to prevent relapse
EfficaciousMindfulness-based cognitive therapy (MBCT) to prevent relapse/recurrence
Possibly efficaciousPrior dynamic psychotherapy to prevent recurrence
Maintenance IPT to prevent recurrence
Continuation cognitive therapy (CT) to prevent relapse/recurrence
Maintenance CBASP to prevent recurrence
EFT to prevent relapse
Treatment Response Rate (%)
  Week 12 Week 18 Week 36
Fluoxetine626981
Cognitive-behavioral therapy (CBT)486581
Fluoxetine plus CBT738586