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Feb.18.2021View related content

Major depressive disorder

Synopsis

Key Points

  • Major depressive disorder is a chronic and relapsing disease, characterized by a pervasive sad mood and the loss of pleasure in most activities (anhedonia)
  • Rule out underlying physical illnesses that may mimic major depressive disorder (eg, hypothyroidism, dementia)
  • Diagnosis relies on history and physical examination, as well as validated depression inventory toolsr1 including Beck Depression Inventory,r2Hamilton Depression Rating Scale,r2 Major Depression Inventory,r3 and Patient Health Questionnaire-9r4
  • Psychotherapy is often adequate as initial therapy early in the course of the disease r5
  • Structured psychological treatment is foundational in the treatment of all depressive presentations r6
  • For all severities of depression, the most effective treatment is a combination of psychological interventions and pharmacotherapy (may not apply to the very severe presentations seen in tertiary care) r6
  • For most patients, combination therapy (psychotherapy and medication) is more effective than either psychotherapy or antidepressant medication alone r7
  • Consider combination therapy (psychotherapy and medication) when the response to a single therapy is inadequate
  • Use antidepressant medications for more severe or chronic disease
  • Electroconvulsive therapy will be necessary if patient has a high risk of suicide or if welfare is threatened (eg, lack of nutrition or fluid intake)
  • Untreated depression increases the risk of self-inflicted injury or suicide

Urgent Action

  • Suicidal ideation or suicide attempts require hospitalization and urgent evaluation by a psychiatrist

Pitfalls

  • Even if major depressive disorder is diagnosed correctly, bipolar disorder may be present; treatment varies by disorder, hence differentiation is required
  • Always consider substance use disorder as a potential contributor to major depressive disorder and a potential consequence of it
  • Discontinuing medications that influence serotonin levels (particularly with short half-lives) can suddenly cause antidepressant discontinuation syndrome:
    • Flulike symptoms (eg, nausea, vomiting, diarrhea, headaches)
    • Sensory/movement disturbances (eg, vertigo, dizziness)
    • Cognitive symptoms (eg, hyperarousal, confusion)

Terminology

Clinical Clarification

  • Major depressive disorder is a chronic and relapsing disease, characterized by a pervasive sad mood and the loss of pleasure in most activities (anhedonia) persisting for at least 2 weeks r8

Classification

  • DSM-5 diagnostic classification states that major depressive disorder presents with at least 5 of the following 9 symptoms: r9
    • Depressed mood or anhedonia (patient must have at least 1; present most of the day nearly every day for a minimum of 2 consecutive weeks)
    • Sleep disturbance
    • Change in appetite or weight
    • Psychomotor problems
    • Lack of energy
    • Poor concentration
    • Feelings of worthlessness or guilt
    • Suicidal ideation
  • Symptoms cause clinically significant distress or impairment in social, work, or other areas of functioning
  • Episode is not attributable to the physiologic effects of a substance use or other medical disorder

Diagnosis

Clinical Presentation

History

  • Patients do not always present with a straightforward complaint of feeling depressed r10
  • Vague somatic complaints or numerous complaints that do not fit any clear clinical pattern often occur, particularly in older patients and in patients for whom psychological symptoms are stigmatized r10
    • Fatigue c1
    • Poor concentration c2
    • Memory impairment c3
    • Difficulty making day-to-day decisions c4
    • Decline in school or work performance c5c6
    • Decreased sexual interest c7
    • Sleep disturbance c8
    • Appetite changes c9
    • Weight changes (gain or loss) c10c11c12
    • Headache c13
    • Nausea c14
    • Pain c15
    • Change in bowel habits (constipation or diarrhea) c16c17c18
  • Depressive symptoms r10
    • Loss of interest or pleasure in previously enjoyable things c19
    • Disproportionate feelings of guilt or thoughts of worthlessness c20c21c22
    • Suicidal thoughts or thoughts about dying c23c24
    • Psychotic symptoms (particularly in older patients) c25c26
    • Anxiety and worry c27c28
    • Preoccupation with physical complaints c29

Physical examination

  • Psychological findings r10
    • Depressed or flat affect c30c31
    • Appears withdrawn, with poor eye contact c32c33
    • Psychomotor agitation or retardation c34c35
    • Crying c36
    • Anxious behavior
    • Irritability c37
    • Evidence of self-neglect with poor personal hygiene c38c39
  • Dermatologic findings r10
    • Evidence of self-harm (eg, healed lacerations, scars on body or extremities) c40c41c42
  • Weight loss, weight gain, or evidence of poor nutrition r10

Causes and Risk Factors

Causes

Risk factors and/or associations

Age r8
  • Median age of onset is 32 years c44
  • Overall prevalence is low until early adolescence c45
Sex r8
  • Women are twice as likely as men to experience major depressive disorder, regardless of racial background, ethnic background, or socioeconomic status c46
    • Times of hormonal fluctuation convey the greatest risk
Genetics r8
  • Major depressive disorder is a multifactorial disorder with genetic susceptibility c47
    • Greatest risk for major depressive disorder is observed in families with early age at onset r11c48
Ethnicity/race r8
  • Higher incidence in Black and Hispanic populations compared with White populations c49c50
Other risk factors/associations r8
  • History of childhood maltreatment in any form c51
  • Early parental loss (for women) c52c53

Diagnostic Procedures

Primary diagnostic tools

  • Depression screening tools (eg, Beck Depression Inventory, Patient Health Questionnaire-9) can be used initially to identify patients requiring full diagnostic interviews using standard diagnostic criteria r1r2r3r4
  • History and physical examination provide definitive diagnosis c54
  • Laboratory analyses (eg, hypothyroidism testing [TSH], urine or serum drug screen) can be used to exclude medical disorders that produce or exacerbate mood symptoms or screen for substance-induced mood symptoms r12c55c56

Other diagnostic tools

  • Standardized depression inventory tests c57
    • US Preventive Services Task Force recommends the following: "All positive screening results should lead to additional assessment that considers severity of depression and comorbid psychological problems (eg, anxiety, panic attacks, or substance abuse), alternate diagnoses, and medical conditions" r1
    • Beck Depression Inventory r2c58
      • Self-rated questionnaire
      • Measures the intensity, severity, and depth of common depression symptoms
      • Standard test has 21 questions; a shorter 7-question version is optimized for screening use in the office setting
    • Hamilton Depression Rating Scale r2c59
      • Observer-rated scale designed to be administered by the health care professional
    • Major Depression Inventory r3c60
      • Self-rated questionnaire
      • Incorporates both the ICD‐10 symptoms of depression and the DSM-IV symptoms of major depression
    • Patient Health Questionnaire-9 r4r13c61
      • Self-rated questionnaire with 9 items

Differential Diagnosis

Most common r14

  • Persistent depressive disorder (dysthymia) c62
    • Characterized by:
      • Changes in eating
      • Altered sleeping pattern (eg, insomnia, hypersomnia)
      • Low energy
      • Low self-esteem
      • Inability to concentrate or make decisions
      • Feelings of hopelessness or pessimism
    • Fewer symptoms than major depressive disorder
    • Involves feeling depressed for periods of variable duration, but without meeting DSM-5 criteria for major depressive disorder
    • Such patients often have major depressive disorder interspersed throughout their lifetime
    • Differentiated based on history and physical examination
  • Bipolar disorder r15c63d1
    • Mood disorder characterized by episodes of mania or hypomania
    • Carefully screen patients with major depression for bipolar disorder
      • 15% of patients with major depression have bipolar disorder r16
      • Patients with bipolar disorder do not respond to antidepressants; therefore, differentiation is crucial
    • Presence of mania or hypomania is the cardinal feature that distinguishes bipolar disorder from major depressive disorder
      • Mania
        • A period of mood change (happy, excited, or irritable) that causes impairment and is distinct and noted by others
        • At least 4 of the following symptoms are present:
          • Inflated self-esteem or grandiosity
          • Little need for sleep (without development of fatigue)
          • Pressured or overly verbose speech
          • Racing thoughts
          • Distractibility
          • Irritability or agitation
          • Reckless or high-risk behavior
    • Differentiated based on history and physical examination
  • Adjustment disorder r17c64
    • Temporary, short-term, nonpsychotic response to an event or situation (eg, a divorce, a death in the family, a disappointment, a failure)
    • Symptoms can include sadness, anxiety, insomnia, poor concentration, poor performance in school
    • Symptoms persist for no longer than 6 months after termination of the stressor
    • Does not meet criteria for another mental disorder
    • Differentiated based on history and physical examination
  • Dementia r18c65
    • Especially in older patients, may be mistaken for major depressive disorder during early stages of the illness
    • The following features are more closely associated with dementia:
      • Impaired, inconsistent, and fluctuating orientation, mood, and behavior
      • Cognitive impairment that worsens over time
      • Neurologic deficits often present (eg, dysphasia, apraxia)
      • Disabilities concealed by the patient
      • Inability to remember recent events; often unaware of memory loss
      • Onset of memory loss occurs before mood change
      • Frequently uncooperative, confused, or disoriented
      • Demonstrated lack of concern about cognitive deficit
    • Differentiated based on history and physical examination
  • Parkinson disease r19c66d2
    • Progressive disorder of the central nervous system that often coexists with depression
    • Associated with symptoms of major depressive disorder, in addition to:
      • Increased muscle tone with cogwheel rigidity
      • Coarse resting tremor
      • Akinesia
      • Loss of facial expression
      • Shuffling gait
      • Flexed posture
    • Differentiated based on history and physical examination
  • Schizophrenia c67d3
    • Disorder that affects thoughts, feelings, and perceptions; primary symptom is psychosis with auditory hallucinations and delusions
    • Schizophrenic patients may develop secondary major depression r20
    • Distinguished from major depressive disorder by the following: r20
      • Severe personality deterioration
      • Thought disorder, including loose associations
      • Grandiose delusions
      • Hallucinations, which are typically auditory
      • Bizarre behavior
    • Differentiated based on history and physical examination
  • Hypothyroidism r21c68d4
    • Patients with hypothyroidism may have symptoms of major depressive disorder, in addition to signs and symptoms of slow metabolism (eg, dry skin, brittle hair, weight gain)
    • Differentiated by laboratory testing for hypothyroidism
  • Substance use disorders c69c70
    • May cause symptoms of depression with chronic use or from withdrawal
    • Causative substances include:
    • Differentiated from major depressive disorder by:
      • Positive result from urine or serum drug screen for the substance, if available
      • History of mood disorder that occurs temporally with substance use or withdrawal
  • Medication causes r13c85
    • Drug classes that are known to produce symptoms similar to depression include:
      • Benzodiazepines c86
      • Steroids c87
      • Levodopa c88
      • Oral contraceptives c89
      • Interferon c90
    • Differentiated based on history and physical examination

Treatment

Goals

  • Assess patient for suicidality and take steps to protect patient as needed r13
  • Reduce signs and symptoms, including residual symptoms r22r23r24
  • Relieve any complications (eg, malnutrition, substance use disorder) r13
  • Restore prior level of psychosocial and occupational function r13
  • Prevent relapse and recurrence r13

Disposition

Admission criteria r22

  • Patients unable to take care of themselves at home
  • Patients undergoing electroconvulsive therapy
  • Suicidal/homicidal ideation with intention or overt suicide/homicide attempts
  • Psychosis

Recommendations for specialist referral

  • Refer to psychiatrist if patient exhibits any of the following:
    • Suicidal or homicidal ideation or attempts
    • Severe confusion, raising the question of dementia or delirium
    • Delusions or hallucinations
    • Substance use or dependence
    • Suspected bipolar disorder
    • Depression that has not responded to appropriate drug therapy

Treatment Options

Mild to moderate disease

  • Psychotherapy is often adequate as initial therapy early in the disease course r5
  • Structured psychological treatment is foundational in the treatment of all depressive presentations r6
  • For all severities of depression, the most effective treatment is a combination of psychological interventions and pharmacotherapy  r6
  • Use antidepressant medications for more severe or chronic disease
    • Antidepressant medications are first line treatment for depression of any severity that has persisted for 2 years or more r25
      • Discontinuing medications that influence serotonin levels (particularly with short half-lives) can suddenly cause antidepressant discontinuation syndrome:
        • Flulike symptoms (eg, nausea, vomiting, diarrhea, headaches)
        • Sensory/movement disturbances (eg, vertigo, dizziness)
        • Cognitive symptoms (eg, hyperarousal, confusion)
    • First line options include: r5r7r26
      • Selective serotonin reuptake inhibitors r27
      • Serotonin-norepinephrine reuptake inhibitors
      • Noradrenergic and specific serotonin antidepressants
      • Noradrenergic and dopaminergic antidepressants
    • Second line options include: r25
      • Tricyclic antidepressants
      • MAOIs
  • Consider combination therapy (ie, psychotherapy and medication) when the response to a single therapy is inadequate
    • For most patients, combination therapy is more effective than either psychotherapy or antidepressant medication alone r7
    • Also consider for recurrent disease (with 3 or more episodes) r7

Severe disease

  • Structured psychological treatment is foundational in the treatment of all depressive presentations r6
  • For all severities of depression, the most effective treatment is a combination of psychological interventions and pharmacotherapy (may not apply to the very severe presentations seen in tertiary care) r6
    • For most patients, combination therapy (psychotherapy and medication) is more effective than either psychotherapy or antidepressant medication alone r7
  • Electroconvulsive therapy
    • Will be necessary if patient has a high risk of suicide or if welfare is threatened (eg, lack of nutrition or fluid intaker6)
    • May be used as first line therapy for patients who have psychotic depression or catatoniar6 and patients who have previously responded to this treatment method

Relapse prevention r25

  • Medication-responsive patients: continue medication at acute treatment dose after remission; use relapse risk to determine medication duration
    • Patients at lower risk of relapse (eg, experiencing first episode without other risk factors): continue medication at least 6 to 9 months after full remission r7r25
    • Other patients: tailor medication duration to individual relapse risk
      • Patients with any increased risk of relapse: continue medication at least 1 year after full remission r7
      • Higher risk patients (eg, having more than 5 lifetime episodes and/or 2 episodes in the past few years): continue medication for a minimum of 2 years; most will require long-term treatment
  • Patients with residual symptoms or at high risk of relapse: consider adding cognitive behavioral therapy to medication
  • Patients who respond well to acute-phase cognitive behavioral therapy: it is not routinely recommended to continue medication
  • Patients who are unstable or partial remitters (ie, patients in partial remission): continue cognitive behavioral therapy or antidepressants
  • Patients who respond to acute-phase electroconvulsive therapy: continue or initiate prophylactic medication; consider continuing electroconvulsive therapy in patients with frequent relapses who do not respond to prophylactic medication

Esketamine nasal spray—the first NMDA (N-methyl-D-aspartate) receptor antagonist to receive FDA approval for major depression—can be used as an adjunct to an oral antidepressant for treatment-resistant depression (those whose condition has failed to respond to 2 or more standard antidepressant treatments) r28r29

Drug therapy

  • Selective serotonin reuptake inhibitors r30c91
    • Citalopram c92
      • Citalopram Hydrobromide Oral solution; Children and Adolescents 7 to 17 years: 10 mg PO once daily initially. Some experts recommend initial doses of 20 mg/day PO in those 12 years and older. Clinical guidelines recommend to start with a low dose and titrate gradually, in 10 mg/day increments at 4-week intervals until clinical response is achieved. Some studies titrate as often as every week. A dose of 20 mg/day PO is considered effective. Max: 40 mg/day in the general population and 20 mg/day in poor metabolizers of CYP2C19 due to the potential for QT prolongation. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
      • Citalopram Hydrobromide Oral tablet; Adults 60 years and younger: Initially, 20 mg PO once daily; may increase to 40 mg PO once daily after 1 week if clinically indicated. Max: 40 mg/day in the general population and 20 mg/day in poor metabolizers of CYP2C19 due to the potential for QT prolongation. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
      • Citalopram Hydrobromide Oral tablet; Adults older than 60 years: 20 mg PO once daily is the recommended and maximum daily dosage. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
    • Escitalopram r31r32c93
      • Escitalopram Oral solution; Children and Adolescents 12 to 17 years: The initial and recommended dose is 10 mg PO once daily. If needed, may increase to 20 mg/day after a minimum of 3 weeks, but a trial in adults suggested no additional benefit. Max: 20 mg/day PO. Periodically reassess the need for continued treatment.
      • Escitalopram Oral tablet; Adults: 10 mg PO once daily is the initial and recommended dose. If needed, may increase to 20 mg once daily after a minimum of 1 week, but one trial suggested no additional benefit. Max: 20 mg/day PO. Periodically reassess the need for continued treatment.
      • Escitalopram Oral tablet; Geriatric Adults: 10 mg PO once daily is the initial and recommended dose. Periodically reassess the need for continued treatment.
    • Fluoxetine c94
      • Fluoxetine Hydrochloride Oral solution [Depression/Mood Disorders]; Children and Adolescents 8 to 17 years: 10 to 20 mg PO once daily. An initial dose of 10 mg/day may be appropriate in lower weight children; increase to 20 mg/day after 1 week. Usual effective dose: 10 to 20 mg/day. May increase by 10 to 20 mg increments if response not sufficient; full effect may take 4 weeks or longer. Max: 60 mg/day. May divide daily dose into 2 doses (e.g., morning and noon) if the dosage is 20 mg/day or more.
      • Fluoxetine Hydrochloride Oral tablet [Depression/Mood Disorders]; Adults: 20 mg/day PO initially. May increase after several weeks by 10 to 20 mg as needed and tolerated. Consider lower dosages for geriatric adults. Max: 80 mg/day PO. May divide daily dose into 2 doses (e.g., morning and noon) if the dosage is 20 mg/day or more.
    • Paroxetine c95
      • Paroxetine Hydrochloride Oral tablet; Adults: 20 mg PO once daily initially, usually in the morning. May increase by 10 mg at weekly intervals. Max: 50 mg/day PO. DEBILITATED or GERIATRIC ADULTS: 10 mg PO once daily initially, may increase by 10 mg at a minimum of weekly intervals; Max: 40 mg/day PO.
      • Paroxetine Hydrochloride Oral tablet, extended-release; Adults: 25 mg PO once daily initially, usually in the morning. May increase by 12.5 mg at weekly intervals. Max: 62.5 mg/day PO. DEBILITATED or GERIATRIC ADULTS: 12.5 mg/day PO initially, May increase by 12.5 mg at weekly intervals; Max: 50 mg/day PO.
    • Sertraline r33c96c97
      • Evidence recommends that physicians use caution when prescribing sertraline in pediatric patients (if at all)
      • Sertraline Hydrochloride Oral solution; Children 6 to 11 years†: 12.5 mg to 25 mg/day PO initially. Begin with a low dose and titrate gradually in 12.5 to 25 mg/day increments at 4-week intervals until clinical response is achieved; some studies report titration in 25 mg to 50 mg/day increments as often as every 1 to 2 weeks. A dose of 50 mg/day PO is considered effective in some patients. Max: 200 mg/day PO.
      • Sertraline Hydrochloride Oral tablet; Children and Adolescents 12 to 17 years†: 25 to 50 mg/day PO initially. Begin with a low dose and titrate gradually in 12.5 to 25 mg/day increments at 4-week intervals until clinical response is achieved; some studies report titration in 25 mg to 50 mg/day increments as often as every 1 to 2 weeks. A dose of 50 mg/day PO is considered effective in some patients. Max: 200 mg/day PO.
      • Sertraline Hydrochloride Oral tablet; Adults: 50 mg PO once daily. A lower initial dose (25 mg PO once daily) may be used to minimize adverse effects. If necessary, increase at intervals of not less than 1 week. Max: 200 mg/day PO. The length of treatment should be determined on an individual basis. Periodically reassess the need for continued treatment.
  • Serotonin-norepinephrine reuptake inhibitors c98
    • Duloxetine c99
      • Duloxetine Oral capsule, gastro-resistant pellets; Adults: Initially, give 20 mg PO twice daily or 60 mg/day PO as a single dose or in 2 divided doses (i.e., 30 mg PO twice daily). Alternatively, give 30 mg/day PO for 1 week, then increase to 60 mg/day. Target maintenance dose: 60 mg/day; dividing doses may increase tolerability. Max: 120 mg/day PO, but more than 60 mg/day has not been shown to have an additional benefit.
    • Milnacipran c100
      • Milnacipran Hydrochloride Oral tablet; Adults: Initially, 12.5 to 25 mg PO twice daily. Based on individual response, the dose may be titrated to 100 mg PO twice daily. Max: 200 mg/day. In one trial of adult patients with diabetes mellitus type 2 and co-morbid depression, 72.6% of treated patients fulfilled criteria for antidepressant response according to the Beck Depression Inventory scale.
    • Venlafaxine c101
      • Venlafaxine Hydrochloride Oral tablet; Adults: 75 mg/day PO, given in 2 or 3 divided doses, initially. If needed, may increase by 75 mg/day no less than every 4 days. Outpatient Max: 225 mg/day PO, given in divided doses. Institutional Max: 375 mg/day PO, given in 3 divided doses.
      • Venlafaxine Hydrochloride Oral tablet, extended-release; Adults: Initially, 75 mg PO once daily. Alternatively, 37.5 mg PO once daily can be given for 4 to 7 days to allow for tolerability before increasing to 75 mg PO once daily. If needed, may increase further by 75 mg/day at intervals of no less than every 4 days. Recommended Max: 225 mg/day PO.
  • Noradrenergic and specific serotonin antidepressants c102
    • Mirtazapine r31c103
      • Do not use concomitantly with MAOIs
      • Mirtazapine Oral tablet; Adults: 15 mg PO once daily at bedtime, initially. If needed, may titrate no sooner than every 1 to 2 weeks. Geriatric patients may need slower titration schedules. The effective dose range is 15 to 45 mg/day. Max: 45 mg/day PO.
  • Noradrenergic and dopaminergic antidepressants c104
    • Bupropion c105
      • Bupropion Hydrochloride Oral tablet [Depression/Mood Disorders]; Children† and Adolescents† 6 years and older: Dosage not established. Suggested dosage ranges from 1.4 to 6 mg/kg/day PO, titrated upward slowly and administered in divided doses. In trials, the average effective dose is roughly 3 mg/kg/day PO; the maximum dosage is generally 250 to 300 mg/day PO. Safety data are not extensive; most patients have also been diagnosed with ADHD.
      • Bupropion Hydrochloride Oral tablet [Depression/Mood Disorders]; Adults: Initially, 100 mg PO twice daily; titrate after 3 days to 100 mg PO 3 times per day if needed; no single dose should exceed 150 mg.
      • Bupropion Hydrochloride Oral tablet, extended release 12 hour [Depression/Mood Disorders]; Adolescents†: Limited data are available. Dosing may be weight based or may use a non-weight based titration similar to adults. One trial used initial doses up to 2 mg/kg (not to exceed 100 mg) PO once daily in the morning, followed by gradual titration to 3 mg/kg/dose every morning with 2 mg/kg/dose every evening at dinner. If needed, further titration to 3 mg/kg/dose PO twice daily occurred. Single doses of bupropion SR could not exceed 150 mg/dose. Max dose: 6 mg/kg/day PO, in divided doses. Alternatively, give no more than 150 mg PO once daily in the morning; titrate after no less than 4 days up to 150 mg PO twice daily if needed. After several weeks, titrate to 200 mg PO twice daily if needed with doses at least 8 hours apart.
      • Bupropion Hydrochloride Oral tablet, extended release 12 hour [Depression/Mood Disorders]; Adults: Initially, 150 mg PO each morning; titrate after 4 days to 150 mg PO twice daily if needed. After several weeks, titrate to 200 mg PO twice daily if needed; administer doses at least 8 hours apart.
      • Bupropion Hydrochloride Oral tablet, extended release 24 hour [Depression/Mood Disorders]; Adults: Initially, 150 mg PO once daily in the AM; titrate after 4 days to usual target dose of 300 mg PO once daily in the AM. Due to a dose-related risk of seizures, gradually titrate based on response and tolerance. Max: 450 mg PO once daily. When discontinuing treatment, doses of 300 mg/day or more should be tapered to 150 mg PO once daily prior to discontinuation.
  • Tricyclic antidepressants r30c106
    • Amitriptyline c107
      • Amitriptyline Hydrochloride Oral tablet; Adolescents: Begin at a low daily dosage, usually at bedtime, and titrate as needed and tolerated. Lower doses are used compared to young adults; 10 mg PO 3 times per day with 20 mg PO at bedtime may be satisfactory in adolescents who do not tolerate higher dosages. When satisfactory improvement has occurred, reduce to the lowest effective dose. Weight-based dosing has been used in clinical trials in adolescents for other indications. TCAs are not drugs of choice for pediatric patients with depression; there is lack of high-quality data to support efficacy and safety.
      • Amitriptyline Hydrochloride Oral tablet; Adults: Initially, 75 mg/day PO, given in divided doses, or, 50 mg to 100 mg PO once daily at bedtime. Hospitalized patients may require 100 mg/day PO initially. Titrate if needed, up to 150 mg/day PO, by increasing the daily dose 25 to 50 mg at weekly intervals, to response and tolerance. Max (hospitalized patients): 300 mg/day PO. Usual maintenance dose: 50 to 100 mg PO per day. In some patients, 40 mg/day PO is sufficient. For maintenance, give as a single dose, preferably at bedtime. Use lowest effective dose. It is appropriate to continue maintenance therapy 3 months or longer to lessen the possibility of relapse.
      • Amitriptyline Hydrochloride Oral tablet; Geriatric: 10 to 25 mg PO at bedtime initially. Titrate as needed and tolerated. Max: 150 mg/day PO, but such doses are not typically tolerated in the geriatric adult. Usual adult maintenance dosage: 50 to 100 mg per day. In some patients, 40 mg/day is sufficient. For maintenance therapy, give as a single dose, preferably at bedtime. Use lowest effective dose. It is appropriate to continue maintenance therapy 3 months or longer to lessen the possibility of relapse.
    • Desipramine c108
      • Desipramine Hydrochloride Oral tablet; Adolescents: 25 to 50 mg PO at bedtime initially. May titrate at weekly intervals by 25to 50 mg, depending on response and tolerance. Usual Max: 100 mg/day PO, in single or divided doses. Max (hospitalized patients): 150 mg/day PO. Once at a maintenance dosage, administering the total daily dose at bedtime may minimize daytime sedation and improve compliance. TCAs are not drugs of choice for pediatric patients with depression; there is lack of high-quality data to support efficacy and safety.
      • Desipramine Hydrochloride Oral tablet; Adults: 50 to 75 mg/day PO initially, in single or divided doses. Titrate by 25 to 50 mg at weekly intervals according to response and tolerance. The usual adult dose is 100 mg to 200 mg PO per day, in single or divided doses. Max: 300 mg/day PO. Patients requiring up to 300 mg/day should generally be hospitalized for therapy initiation. Once at a maintenance dosage, administering the total daily dose at bedtime may minimize daytime sedation and improve compliance.
      • Desipramine Hydrochloride Oral tablet; Geriatric: 25 mg PO at bedtime initially. May titrate at weekly intervals by 25 to 50 mg, depending on response and tolerance. Usual max: 100 mg/day PO, in single or divided doses. Max (hospitalized patients): 150 mg/day PO. Once at a maintenance dosage, administering the total daily dose at bedtime may minimize daytime sedation and improve compliance.
    • Imipramine c109
      • Imipramine Hydrochloride Oral tablet; Adolescents: Initially, 30 mg to 40 mg/day PO once daily at bedtime to help minimize daytime sedation. If necessary, titrate upward based on response and tolerability. Usual Max: 100 mg/day PO. Use the lowest effective dose that maintains remission. TCAs are not drugs of choice for pediatric patients with depression; there is lack of high-quality data to support efficacy and safety.
      • Imipramine Hydrochloride Oral tablet; Adults: OUTPATIENTS: Initially, 75 mg/day PO; bedtime dosing may reduce daytime sedation. The, titrate to 150 mg/day as a single dose or divided doses based on response and tolerability. Optimal response may take 1 to 3 weeks of treatment at a given dose. Maintenance: 50 to 150 mg/day. Outpatient Max: 200 mg/day PO. HOSPITALIZED ADULTS: Initially, 100 mg/day PO in divided doses, gradually increased to 200 mg/day PO in divided doses as required. If no response after 2 weeks, increase to 250 mg/day to 300 mg/day PO. Hospitalized patient Max: 300 mg/day PO. Use lowest effective dose that maintains remission.
      • Imipramine Hydrochloride Oral tablet; Geriatric Adults: Initially, 30 mg to 40 mg/day PO once daily at bedtime to help minimize daytime sedation. If necessary, titrate to response and tolerability. Usual Max: 100 mg/day. Use the lowest effective dose that maintains remission.
    • Nortriptyline c110
      • Nortriptyline Hydrochloride Oral capsule; Adolescents: Initially, 10 mg or 25 mg PO at bedtime.May increase as tolerated to 30 mg to 50 mg per day, given in divided doses or once daily at bedtime. TCAs are not drugs of choice for pediatric patients with depression; the quality of data to support efficacy and safety in adolescents is considered marginal.
      • Nortriptyline Hydrochloride Oral capsule; Adults: Initially, 25 mg to 50 mg PO per day, given in divided doses or at bedtime. May increase as needed and tolerated. Max: 150 mg/day PO.
      • Nortriptyline Hydrochloride Oral capsule; Geriatric Adults: Initially, 10 mg to 25 mg PO at bedtime. May increase as tolerated to 30 mg to 50 mg per day, in divided doses or at bedtime.
  • MAOIs r34c111
    • Avoid alcohol, tobacco, caffeine, and tyramine-containing foods (eg, aged cheeses, cured meats, fermented cabbage, soy sauce, fava beans) except when taking selegiline at the lowest dosage
    • Isocarboxazid c112
      • Isocarboxazid Oral tablet; Adolescents 16 years and older: In patients receiving contraindicated drugs known to interact with MAOIs, the interacting drug should be discontinued for at least 1 to 2 weeks before initiating isocarboxazid therapy. INITIAL DOSAGE: 10 mg PO twice daily. Carefully assess for drug efficacy and safety to individualize dosage. May increase by 10 mg/day PO every 2 to 4 days, up to 40 mg/day PO by end of first week. May increase further by up to 20 mg/week, if needed and tolerated. Max: 60 mg/day PO, given in 2 to 4 divided doses. Use caution if receiving more than 40 mg/day PO. MAINTENANCE DOSAGE: After maximum clinical response is achieved, reduce the dosage over several weeks to the lowest dosage that maintains effectiveness to limit cumulative MAOI effects and serious dose-related toxicity. Periodically re-evaluate for drug effectiveness and safety.
      • Isocarboxazid Oral tablet; Adults: In patients receiving contraindicated drugs known to interact with MAOIs, the interacting drug should be discontinued for at least 1 to 2 weeks before initiating isocarboxazid therapy. INITIAL DOSAGE: 10 mg PO twice daily. Carefully assess for drug efficacy and safety to individualize dosage. May increase by 10 mg/day PO every 2 to 4 days, up to 40 mg/day PO by end of first week. May increase further by up to 20 mg/week, if needed and tolerated. Max: 60 mg/day PO, given in 2 to 4 divided doses. Use caution if receiving more than 40 mg/day PO. MAINTENANCE DOSAGE: After maximum clinical response is achieved, reduce the dosage over several weeks to the lowest dosage that maintains effectiveness to limit cumulative MAOI effects and serious dose-related toxicity. Periodically re-evaluate for drug effectiveness and safety.
    • Phenelzine c113
      • Phenelzine Sulfate Oral tablet; Adults: 15 mg PO 3 times daily; may rapidly increase to 60 mg/day if tolerated. Individualize dosage based on careful observation. For some, an increase up to 90 mg/day may be necessary. Onset of maximum effect is 2 to 6 weeks. After the maximum benefit is achieved, reduce dosage slowly over several weeks to the lowest dose that maintains effectiveness. Maintenance dose may be as low as 15 mg/day PO or 15 mg PO every other day, continued as long as required. NOTE: In patients requiring a contraindicated drug known to interact with MAOIs, phenelzine should be discontinued for at least 2 weeks before initiating the interacting drug.
    • Selegiline c114
      • Selegiline Hydrochloride Transdermal patch - 24 hour; Adults: Initially, 6 mg/24 hours transdermally once daily. If clinically indicated, increase by 3 mg/24 hour at intervals of no less than 2 weeks. Effective dose range: 6 to 12 mg/24 hours. Max: 12 mg/24 hours. Inform patients to avoid tyramine-containing foods/beverages/dietary supplements beginning on the first day of selegiline 9 mg or 12 mg/24 hours treatment. Avoid tyramine for 2 weeks after dose reduction (to 6 mg/24 hours) or discontinuation of 9 mg/24 hours or 12 mg/24 hours.
  • NMDA (N-methyl-D-aspartate) receptor antagonists
    • Esketamine nasal spray r28r29
      • First NMDA antagonist to receive FDA approval for major depression
      • Used as an adjunct to an oral antidepressant for treatment-resistant depression (those who have failed 2 or more standard antidepressant treatments)
      • Only available through a restricted distribution system, under a Risk Evaluation and Mitigation Strategy, owing to risk of serious adverse outcomes resulting from sedation and dissociation, the potential for drug misuse, and suicidal thoughts and behaviors in young adults
      • Owing to sedation and dissociation risk, patients must be monitored for at least 2 hours after each treatment, followed by a repeat assessment to ensure patient clinically stable and safe to leave the healthcare setting r35
      • Esketamine Nasal spray, solution; Adults: INDUCTION PHASE: On day 1, administer 56 mg intranasally. Week 1 through 4: administer 56 mg or 84 mg twice per week. MAINTENANCE PHASE: Week 5 through 8: administer 56 mg or 84 mg once weekly. Week 9 and beyond: administer 56 mg or 84 mg once every 2 weeks or once weekly; use the least frequent dosing to maintain remission/response.

Nondrug and supportive care

Music therapy

  • Music therapy (provided by a music therapist) has been found to decrease depressive symptoms, improve anxiety associated with major depressive disorder, and improve functioning r36c115

Acupuncture r37c116

  • Small to moderate reduction in the severity of depressive symptoms has been reported

Exercise r38c117

  • Exercise has been shown to have significant effect in reducing depressive symptoms in patients with major depressive disorder,r39 especially regular, moderate-level, aerobic exercise
Procedures
Psychotherapy c118c119c120
General explanation
  • Includes cognitive behavioral therapy, behavioral activation therapy, interpersonal psychotherapy, problem-solving therapy, nondirective counseling, and psychodynamic therapy r13
  • First line recommendations for acute major depressive disorder include cognitive-behavioral therapy, interpersonal psychotherapy, and behavioral activation therapy r40
  • All types are known to be effective options r13r41
  • May be used as the initial treatment modality for patients with major depressive disorder, with or without concomitant medication therapy; often adequate as initial therapy, early in the course of the disease r13
  • Cognitive behavioral therapy administered concurrently with medication may increase the rate of patient response r40r42
  • Cognitive behavioral therapy administered after medication is withdrawn may impart a protective effect against relapse r42
Indication
  • Significant psychological stressors, intrapsychic conflict, or interpersonal difficulties
  • Mild to moderate depression r25
    • Patients are more likely to respond to psychotherapy than to medication
Electroconvulsive therapy r43c121c122c123c124c125
General explanation
  • Generalized seizures are intentionally induced using electrical impulses
  • Typically performed 2 to 3 times per week until clinical response is seen
  • Average course is 6 to 12 treatments, which are administered under anesthesia and with muscle relaxants
Indication r25r44
  • May be used as first line therapy for patients who have:
    • Psychotic depression
    • Catatonia
    • Previous response to this treatment method
    • Severe suicidality
    • Anorexia/rapidly deteriorating physical status
    • Treatment-resistant depression
    • Repeated medication intolerance
Contraindications
  • Relative contraindications
    • Age younger than 18 years
    • Space-occupying brain lesions
    • Elevated intracranial pressure
    • Recent myocardial infarction
    • History of retinal detachment
    • Pheochromocytoma
Complications
  • Associated with transient postictal confusion and a period of antegrade and retrograde memory loss
  • Can cause a transient rise in heart rate, in cardiac workload, and in blood pressure
Repetitive transcranial magnetic stimulation r45c126
General explanation
  • Magnetic fields stimulate nerve cells in the brain to improve symptoms of depression
    • Evaluate patients for seizure risk before repetitive transcranial magnetic stimulation, including: r5r46
      • Personal/family history of seizures or epilepsy
      • Previous head injury or stroke with neurologic sequelae
      • Current use of medications/substances that lower seizure threshold (eg, psychostimulants) or reduction in dose of medication with antiseizure properties (eg, benzodiazepine)
      • Presence of medical condition or neurologic disorder that may lower seizure threshold (eg, electrolyte imbalance, sleep deprivation, drug withdrawal)
  • Electromagnetic coil is held against the forehead and short electromagnetic pulses are administered through the coil
  • Left prefrontal repetitive transcranial magnetic stimulation repeated daily for 4 to 6 weeks is an effective and safe treatment in adult patients with unipolar major depressive disorder that has failed 1 or more antidepressant trials r47
    • Typical session lasts 30 to 60 minutes and does not require anesthesia r46
Indication
  • First line treatment for patients with major depression who have not responded to antidepressant drug therapy r7r44
Contraindications
  • Pregnancy
  • Aneurysm clips
  • Presence of other ferromagnetic material in the head, with the exception of the mouth
  • Deep brain stimulator use (unintended currents can result)
Complications r48
  • Headache
  • Scalp discomfort
  • Seizures

Comorbidities

  • Anxiety disorder c127
    • Approximately one-half of patients with anxiety disorders have other mood disorders (typically dysthymia or depression) r49
  • Obsessive-compulsive disorder c128
    • Often produces additional depression symptoms r50
  • Substance use disorder (eg, alcohol, opioids, amphetamine, cocaine, cannabis) c129
    • Associated with depression and suicide attempts
    • Impulsivity is heightened when under the influence of substances r51
  • Coronary artery disease c130
    • Risk of future cardiac events is 2 to 3 times higher in patients with coronary artery disease and depression when compared to patients without depression r52
  • Diabetes mellitus c131
    • Patients with diabetes and depression experience worse glycemic control and an increased risk of diabetic complications r53
  • Obesity c132
    • Depression-associated low motivation, poor adherence, negative thinking, fatigue, and sleep problems reduce the success of early-treatment weight loss programs r54

Special populations

  • Pregnant patients
    • Untreated major depressive disorder in pregnancy poses a risk to the mother and fetus (potential harm from malnutrition, poor prenatal care, substance use disorder, or suicide attempts)
    • Treatment can include psychotherapy and medications determined by the patient's obstetrician and psychiatrist
      • Given the potential harms to the fetus and neonate from certain pharmacologic agents, clinicians are encouraged to consider cognitive behavioral therapy or other evidence-based counseling interventions when managing depression in pregnant or breastfeeding women r1r7

Monitoring

  • During the initial phase of treatment, monitoring can vary from once per week to multiple times per week depending on severity
  • American Academy of Pediatrics guidelines recommend that adolescents are assessed in person within 1 week of treatment initiation r27
  • Frequency of monitoring can be based on severity, presence of suicidal ideation, patient adherence to treatment, social supports, and coexisting medical conditions

Complications and Prognosis

Complications

  • Suicide c133
    • Most patients who commit suicide have major depression
  • Substance use disorder c134

Prognosis

  • There is a high risk of relapse after a depressive episode, especially in the first 6 months; risk declines with time in remission r25
    • Risk factors for relapse include presence of residual symptoms, number of previous episodes, severity, duration, and degree of treatment resistance of the most recent episode
  • Untreated depression increases risk of self-inflicted injury or suicide
  • Prognosis of major depressive disorder in older patients is poor, as the majority of cases remain undetected r1

Screening and Prevention

Screening

At-risk populations

  • US Preventive Services Task Force recommends screening adults for major depression; the optimum interval for screening is unknown r1c135c136c137c138
  • US Preventive Services Task Force recommends screening adolescents aged 12 to 18 years for major depressive disorder r55
  • American Academy of Pediatrics guidelines recommends screening adolescent patients aged 12 years and older annually for depression with a formal self-report screening tool r56
  • US Department of Veterans Affairs recommends screening for major depression annually r13c139c140c141c142
  • American College of Obstetricians and Gynecologists recommends patients be screened for depression and anxiety symptoms at least once during the perinatal period, using a standardized, validated tool; screening for postpartum depression and anxiety is also recommended, using a validated instrument r57

Screening tests

  • Standardized depression inventory tests include Beck Depression Inventory, Major Depression Inventory, Hamilton Depression Rating Scale, and Patient Health Questionnaire-9 r1r2r3r13c143c144c145c146

Prevention c147

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