Depression

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:

Psychomotor retardation
Flattening or loss of reactivity in the patient's affect (ie, emotional expression)
Psychomotor agitation or restlessness

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]:

Depressed mood: For children and adolescents, this can also be an irritable mood
Diminished interest or loss of pleasure in almost all activities (anhedonia)
Significant weight change or appetite disturbance: For children, this can be failure to achieve expected weight gain
Sleep disturbance (insomnia or hypersomnia)
Psychomotor agitation or retardation
Fatigue or loss of energy
Feelings of worthlessness
Diminished ability to think or concentrate; indecisiveness
Recurrent thoughts of death, recurrent suicidal ideation without a specific plan, or a suicide attempt or specific plan for committing suicide

See Clinical Presentation for more detail.

Diagnosis

Screening instruments

Self-report screening instruments for depression include the following:

Patient Health Questionnaire-9 (PHQ-9): A 9-item depression scale; each item is scored from 0-3, providing a 0-27 severity score.
Beck Depression Inventory (BDI) or the Beck Depression Inventory-II (BDI-II): 21-question symptom-rating scales providing a 0-63 severity score.
BDI for primary care: A 7-question scale adapted from the BDI.
Zung Self-Rating Depression Scale: A 20-item survey.
Center for Epidemiologic Studies-Depression Scale (CES-D): A 20-item instrument that allows patients to evaluate their feelings, behavior, and outlook from the previous week.

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:

Selective serotonin reuptake inhibitors (SSRIs)
Serotonin/norepinephrine reuptake inhibitors (SNRIs)
Atypical antidepressants
Tricyclic antidepressants (TCAs)
Monoamine oxidase inhibitors (MAOIs)
N-methyl-D-aspartate (NMDA) receptor antagonists
St. John's wort (Hypericum perforatum)

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]}

Behavior Therapy/Behavioral Activation
Cognitive Therapy
Cognitive Behavioral Analysis System of Psychotherapy
Interpersonal psychotherapy (IPT)
Problem-solving therapy (PST)
Self-Management/Self-Control Therapy

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

Interpersonal psychotherapy (IPT)
Cognitive-behavioral therapy (CBT)
Behavior therapy (BT)

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:

Need for a rapid antidepressant response
Failure of drug therapies
History of good response to ECT
Patient preference
High risk of suicide
High risk of medical morbidity and mortality

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.

References

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]:

Impaired social supports
Caregiver burden
Loneliness
Bereavement
Negative life events

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]:

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

References

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]}:

Diagnosis of major depression
Previous history of suicide attempts
Depressive symptoms with agitation or distress
Burden of medical disease and the presence of a current serious medical condition (although this risk may be mediated by a diagnosis of depression)
Recent stressful life events, especially family discord
Lack of social support
Being widowed or divorced
The presence of a gun in the home
Unexplained weight loss
High levels of anxiety
Lack of a reason not to commit suicide
Presence of a specific plan that can be carried out
Rehearsal of the plan

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.

References

Pharmacologic Therapy for Depression

Drugs used for treatment of depression include the following:

Selective serotonin reuptake inhibitors (SSRIs)
Serotonin/norepinephrine reuptake inhibitors (SNRIs)
Atypical antidepressants
Serotonin-Dopamine Activity Modulators (SDAMs)
Tricyclic antidepressants (TCAs)
Monoamine oxidase inhibitors (MAOIs)
N-methyl-D-aspartate (NMDA) receptor antagonists
St. John's wort

Selective serotonin reuptake inhibitors

SSRIs include the following:

Citalopram (Celexa)
Escitalopram (Lexapro)
Fluoxetine (Prozac)
Fluvoxamine (Luvox)
Paroxetine (Paxil)
Sertraline (Zoloft)
Vilazodone (Viibryd)
Vortioxetine (Brintellix)

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:

Amitriptyline (Elavil)
Clomipramine (Anafranil)
Desipramine (Norpramin)
Doxepin (Sinequan)
Imipramine (Tofranil)
Nortriptyline (Pamelor)
Protriptyline (Vivactil)
Trimipramine (Surmontil)

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]:

Bupropion
Citalopram
Duloxetine
Escitalopram
Fluoxetine
Fluvoxamine
Mirtazapine
Paroxetine
Sertraline
Trazodone
Venlafaxine

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]

References

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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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.

References

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:

Accuracy of diagnosis and possible comorbid medical conditions
Adequacy of medication dose and duration of treatment, as well as adherence to treatment regimen
Possible comorbid psychiatric conditions (eg, substance abuse, anxiety disorders, personality disorders)

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]:

Increasing the medication dose to the maximum tolerated
Augmenting the current medication with another antidepressant
Changing to a different antidepressant
Adding psychotherapy or more intensive care if not already completed
Considering the use of ECT

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:

Bright-light therapy plus any antidepressant
Buspirone (BuSpar) plus a TCA or SSRI
Lithium (Eskalith, Lithane, Lithobid) plus any antidepressant
Methylphenidate (Ritalin) or dextroamphetamine (Dexedrine) plus any antidepressant other than an MAOI
TCA plus an SSRI
Triiodothyronine (Cytomel) plus any antidepressant

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.

References

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:

For mild depression, CBT or interpersonal psychotherapy (IPT) is recommended first
For pharmacologic therapy, SSRIs are the first-line choice
If there is no response to the SSRI, switch to a second SSRI

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

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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:

A black-box warning label should be placed on all antidepressants, indicating that they increase the risk of suicidal thinking and behavior (suicidality)
A patient information sheet (“Medication Guide”) should be provided to the patient and the patient’s caregiver with every prescription
The results of controlled pediatric trials of depression should be included in the labeling for antidepressant drugs

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.

References

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]

References

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]:

Female gender
Smoking
Low body weight
Tumors
Respiratory or CNS illnesses
Previous episodes of hyponatremia
Concomitant use of other medications (particularly diuretics)
Antidepressant-induced hyponatremia occurs through the syndrome

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:

Sedation
Confusion
Dry mouth
Orthostasis
Constipation
Urinary retention
Sexual dysfunction
Weight gain

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]

References

Are there effective treatments for major depressive disorder (clinical depression)?What is the presentation of major depressive disorder (clinical depression)?Which symptoms must be present to meet the diagnostic criteria for a major depressive disorder (clinical depression)?Which screening instruments may be used in the diagnosis of major depressive disorder (clinical depression)?Are lab studies used in the diagnosis of major depressive disorder (clinical depression)?What drugs are used for the treatment of major depressive disorder (clinical depression)?Which psychotherapeutic treatments are available for adults with major depressive disorder (clinical depression)?What psychotherapeutic treatments are available for children and adolescents with major depressive disorder (clinical depression)?Which psychosocial interventions for the treatment of mild depression are supported by APA guidelines?When is electroconvulsive therapy (ECT) indicated in the treatment of major depressive disorder (clinical depression)?Which stimulation techniques for the treatment of major depressive disorder (clinical depression) have been approved by the FDA?What are the barriers to diagnosis and treatment of major depressive disorder (clinical depression)?What is the likely presentation of major depressive disorder (clinical depression) in a primary care setting?How does the DSM-5 classify depressive disorders?Which disorders should be included in the differential diagnoses of major depressive disorder (clinical depression)?Which tests are used for to screen for depression and bipolar disorder?Which treatments are effective for the management of major depressive disorder (clinical depression)?How should medications be selected for the treatment of major depressive disorder (clinical depression)?What is the underlying pathophysiology of major depressive disorder (clinical depression)?Does central nervous system serotonin (5-HT) activity have a role in the pathophysiology of major depressive disorder (clinical depression)?What is the pathogenesis of seasonal affective disorder (SAD)?What is the role of vascular lesions in the pathogenesis of major depressive disorder (clinical depression)?What do functional neuroimaging findings reveal about the pathogenesis of major depressive disorder (clinical depression)?What changes in brain structures have been reported in major depressive disorder (clinical depression)?In which areas of the brain is activity diminished in unipolar depression and bipolar depression?Which abnormalities were found in brain regions during a major depressive episode?What may lead to disruptions in the functional circuitry of emotion regulation in major depressive disorder (clinical depression)?Which endocrine changes increase the risk for developing major depressive disorder (clinical depression)?What are the causes of major depressive disorder (clinical depression)?What is the role of genetics in the development of major depressive disorder (clinical depression)?Which susceptibility loci have been identified for major depressive disorder (clinical depression)?Which genes are likely to influence the susceptibility to major depressive disorder (clinical depression)?What are the genetic implications of serotonin utilization and production in the etiology of major depressive disorder (clinical depression)?What is the role of the gene FKBP5 in the etiology of major depressive disorder (clinical depression)?Does a family history of affective disorder, panic disorder, or alcohol dependence also predispose to depression?What common genetic variants in children and adolescents have been found to influence their susceptibility for major depressive disorder (clinical depression)?Is late-onset major depressive disorder (clinical depression) etiologically different from early-onset major depressive disorder (clinical depression)?What is the role of genetics in the response to pharmacologic treatment of major depressive disorder (clinical depression)?Why do patients treated with an SSRI for major depressive disorder (clinical depression) discontinue treatment or switch medications?Which genetic marker reduces the risk of nonresponse to antidepressant therapy in major depressive disorder (clinical depression)?Which factors increase the risk of major depressive disorder (clinical depression)?Which psychosocial factors increase the risk for developing major depressive disorder (clinical depression) late in life?What is the cognitive-behavioral model of depression?Which drugs and substances of abuse increase the risk of developing major depressive disorder (clinical depression)?What is the role of genetic vulnerability, environmental stressors, and brain structural abnormalities in the development of major depressive disorder (clinical depression)?What is the role of the neurotransmitter system in the development of major depressive disorder (clinical depression)?Which neurodegenerative diseases increase the risk for major depressive disorder (clinical depression) in the elderly?What is the parent-child relation model of depression?How are children affected by a maternal diagnosis of major depressive disorder (clinical depression)?What is the vascular depression hypothesis?What is the prevalence of major depressive disorder (clinical depression) in the US?What is the global prevalence of major depressive disorder (clinical depression)?What is the global risk for affective disorders?Are there gender and age differences in the global prevalence of major depressive disorder (clinical depression)?What is the incidence of depression in children and adolescents?What is the incidence of major depressive disorder (clinical depression) in adolescents in the US?Is major depressive disorder (clinical depression) more common in boys or girls?Which demographic groups are at higher risk for major depressive disorder (clinical depression)?What are age differences in the incidence of clinically significant depressive symptoms?What is the prognosis of major depressive disorder (clinical depression)?What are the risk factors for recurrent episodes and treatment resistance in major depressive disorder (clinical depression)?What is the prognosis after an initial episode of psychotic depression?Which factors increase the risk for the recurrence of major depressive disorder (clinical depression)?What is the prognosis of late-onset major depressive disorder (clinical depression)?What is the effect of comorbidities on the prognosis of older patients with major depressive disorder (clinical depression)?What is the "rule of thirds" concerning the prognosis of late-onset major depressive disorder (clinical depression)?Which medical conditions are risk factors for the development of late-onset major depressive disorder (clinical depression)?What is the suicide rate among persons with depressive disorder (clinical depression)?What are the risk factors for suicide?Does the use of antidepressants to treat major depressive disorder (clinical depression) increase the risk of suicide?Which demographic groups are at increased risk for suicide attempts?How does access to health care affect suicide rates?What is the global suicide death rate?What education should patients be given about major depressive disorder (clinical depression)?What online resources are available for patient and family education for major depressive disorder (clinical depression)?What online resources are available for late-onset major depressive disorder (clinical depression)?How does the initial presentation of major depressive disorder (clinical depression) vary in adults, children, and elderly persons?Why should family history be a focus in suspected major depressive disorder (clinical depression)?What are common expressions of dysphoric moods in major depressive disorder (clinical depression)?How is psychosis evaluated in major depressive disorder (clinical depression)?Which disorders should be included in the differential diagnoses of suspected major depressive disorder (clinical depression) and symptoms of psychosis?What is the basis for diagnosis of major depressive disorder (clinical depression)?How might appearance and affect change in patients with major depressive disorder (clinical depression)?How might speech change among persons with major depressive disorder (clinical depression)?What are the DSM-5 criteria for diagnosis of major depressive disorder (clinical depression)?How are depressive disorders (clinical depression) rated in the DSM-5?Does bereavement induce major depressive disorder (clinical depression)?How is depression with anxious distress defined in the DSM-5?How is depression with melancholic features defined in the DSM-5?According to the DSM-5, when is depression with melancholic features applicable?What are the DSM-5 criteria for the diagnosis the depressive episodes with catatonia?What are the DSM-5 criteria for the diagnosis of atypical depression?How common is depression in the postpartum period?Are postpartum psychiatric illnesses diagnostically distinct?What are the risk factors for postpartum mood disorder with psychotic features?What are the signs and symptoms of postpartum blues?When should women with postpartum blues be screened for postpartum depression?What are the signs and symptoms of postpartum depression?How many infants are born to mothers who are depressed?How does untreated maternal postpartum depression affect the child?What are the DSM-5 criteria for the diagnosis of seasonal affective disorder (SAD)?How is seasonal affective disorder (SAD) diagnosed in children?Which psychotic features may be present with major depressive disorder (clinical depression)?According to the DSM-5, which disorders have features of depression but do not meet the criteria for a specific depressive disorder?What is the role of metabolic syndrome in major depressive disorder (clinical depression)?What is the role of cultural influences in the diagnosis of major depressive disorder (clinical depression)?When is assessment for suicidal ideation indicated in major depressive disorder (clinical depression)?Which disorders should be included in the differential diagnoses of major depressive disorder (clinical depression)?How is major depressive disorder (clinical depression) differentiated from persistent depressive disorder (dysthymia)?How is major depressive disorder (clinical depression) differentiated from bipolar disorder (manic depression)?Are anxiety disorders a risk factor for developing major depressive disorder (clinical depression)?How is major depressive disorder (clinical depression) differentiated from personality disorders?Are eating disorders a risk factor for developing major depressive disorder (clinical depression)?Does major depressive disorder (clinical depression) cause focal neurologic signs?What is pseudodementia in patients with major depressive disorder (clinical depression)?Which endocrinologic disorders are likely to produce changes in mood?Which medications produce changes in mood?What is the role of antihypertensive agents in major depressive disorder (clinical depression)?Do calcium channel blockers (CCD) impair the effectiveness of antidepressants in the treatment of major depressive disorder (clinical depression)?What is the role of substance use in major depressive disorder (clinical depression)?Which infectious processes can cause mood and behavior changes?Which sleep disorder can cause psychiatric symptoms?What are the differential diagnoses for Depression?What is the role of depression screening in the diagnosis of major depressive disorder (clinical depression)?What are the USPSTF recommendations for depression screening?What are simple screening tests for depression and what are their efficacy?Which depression self-report screening instruments are available for clinical use?What is the Hamilton Depression Rating Scale (HDRS)?What is the Geriatric Depression Scale (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'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?What are the treatment guidelines for omega-3 polyunsaturated fatty acids (PUFAs) as adjunctive therapy for major 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?

References

level of support	Therapy
Efficacious and specific	Interpersonal psychotherapy (IPT)
	Cognitive behavior therapy (CBT)
	Problem-solving therapy (PST)
	Behavioral activation (BA)/contingency management
Possibly efficacious	Dynamic psychotherapy
	Cognitive behavioral analysis system for psychotherapy (CBASP)
	Emotion-focused therapy (EFT)

level of support	Therapy
Efficacious and specific	Prior CBT to prevent relapse
Efficacious	Mindfulness-based cognitive therapy (MBCT) to prevent relapse/recurrence
Possibly efficacious	Prior 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
Fluoxetine	62	69	81
Cognitive-behavioral therapy (CBT)	48	65	81
Fluoxetine plus CBT	73	85	86

Depression

Practice Essentials

Signs and symptoms

Diagnosis

Management

Background

Pathophysiology

Brain structures

Aging

Etiology

Genetics

Stressors

Risk-factor interactions

Neuroendocrine abnormalities and neurodegenerative diseases

Parent-child relations

Vascular depression

Epidemiology

United States statistics

International statistics

Children and adolescents

Elderly persons

Prognosis

Recurrence of early depression

Late-onset depression

Suicide

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....

Patient Education

History

Familial, social, and environmental factors

Dysphoric mood

Psychosis

Physical Examination

Appearance and affect

Speech

Major Depressive Disorder

Depression with Anxious Distress

Depression With Melancholic Features

Depression With Catatonia

Atypical Depression

Postpartum Depression

Seasonal Affective Disorder

Major Depressive Disorder with Psychotic Features

Other Specificed Depressive Disorders

Metabolic Depression

Cultural Influences on Expression of Depression

Suicidal Ideation

Approach Considerations

Screening Tests

Geriatric Depression Scale.

Geriatric Depression Scale-Short.

Cornell Scale for Depression in Dementia.

Laboratory Studies to Rule Out Organic Causes

Neuroimaging

Approach Considerations

Medications

Psychotherapy

Pharmacologic Therapy for Depression

Selective serotonin reuptake inhibitors

Serotonin/norepinephrine reuptake inhibitors

Atypical antidepressants

Serotonin-Dopamine Activity Modulators

Tricyclic antidepressants

Monoamine oxidase inhibitors

N-methyl-D-aspartate antagonists

St. John's wort

Psilocybin

Comparative effectiveness of antidepressants

Antidepressant effectiveness and depression severity

Psychotherapy

See Table

See Table

Behavioral activation (BA)

Cognitive-behavioral therapy (CBT)

Interpersonal therapy (IPT)

Mindfulness based cognitive therapy (MBCT)

Problem-solving therapy (PST)

Electroconvulsive Therapy

Bright-Light Therapy

Additional Therapies for Depression

Treatment-Resistant Depression