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    Major Depressive Disorder

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    Dec.02.2022

    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 tools,r1 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 r8

    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 r9

    Classification

    • DSM-5-TR diagnostic criteria for major depressive disorder r10
      • At least 5 of the following symptoms are present nearly every day during the same 2-week period:
        • Depressed mood most of the day
        • Markedly reduced interest or pleasure in all or nearly all activities
        • Change in appetite or weight (increase or decrease)
        • Sleep disturbance (insomnia or hypersomnia)
        • Psychomotor agitation or retardation (observable by others)
        • Fatigue or lack of energy
        • Reduced ability to think or concentrate; indecisiveness
        • Feelings of worthlessness or excessive, inappropriate guilt
        • Recurrent thoughts of death or suicidal ideation or attempt
      • Symptoms represent a change from usual functioning
      • At least 1 of the symptoms is depressed mood or loss of interest or pleasure
      • Symptoms cause clinically significant distress or impairment in social, work, or other areas of functioning
      • Episode is not attributable to the physiologic effects of substance use or other medical disorder

    Diagnosis

    Clinical Presentation

    History

    • Patients do not always present with a straightforward complaint of feeling depressed r11
    • 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 r11
      • 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 r9
      • 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 r9
      • Depressed or flat affect c30c31
      • Appears withdrawn, with poor eye contact c32c33
      • Psychomotor agitation or retardation c34c35
      • Crying c36
      • Anxious behavior c37
      • Irritability c38
      • Evidence of self-neglect with poor personal hygiene c39c40
    • Dermatologic findings r11
      • Evidence of self-harm (eg, healed lacerations, scars on body or extremities) c41c42c43
    • Weight loss, weight gain, or evidence of poor nutrition r11c44

    Causes and Risk Factors

    Causes

    Risk factors and/or associations

    Age r12
    • Median age of onset is 32 years c46
    • Overall prevalence is low until early adolescence c47
    Sex r12
    • Female individuals are twice as likely as male individuals to experience major depressive disorder, regardless of racial background, ethnic background, or socioeconomic status c48c49
      • Times of hormonal fluctuation convey the greatest risk
    Genetics r11
    • Major depressive disorder is a multifactorial disorder with genetic susceptibility c50
      • Greatest risk for major depressive disorder is observed in families with early age at onset r11c51
    Ethnicity/race r12
    • Higher incidence in Black and Hispanic populations compared with White populations c52c53c54
    Other risk factors/associations r12
    • History of childhood maltreatment in any form c55
    • Early parental loss (for female individuals) c56c57

    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 r1r2r4r11
    • History and physical examination provide definitive diagnosis c58
    • 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 r13c59c60

    Other diagnostic tools

    • Standardized depression inventory tests c61
      • 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 r2c62
        • 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 r2c63
        • Observer-rated scale designed to be administered by the health care professional
      • Major Depression Inventory r3c64
        • Self-rated questionnaire
        • Incorporates both the ICD‐10 symptoms of depression and the DSM-IV symptoms of major depression
      • Patient Health Questionnaire-9 r4r14c65
        • Self-rated questionnaire with 9 items

    Differential Diagnosis

    Most common r15

    • Persistent depressive disorder (dysthymia) c66
      • 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 r16c67d1
      • 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 r17
        • 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 r18c68
      • 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 r19c69
      • 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 r20c70d2
      • 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 c71d3
      • Disorder that affects thoughts, feelings, and perceptions; primary symptom is psychosis with auditory hallucinations and delusions
      • Persons with schizophrenia may develop secondary major depression r16
      • Distinguished from major depressive disorder by the following:
        • Severe personality deterioration
        • Thought disorder, including loose associations
        • Grandiose delusions
        • Hallucinations, which are typically auditory
        • Bizarre behavior
      • Differentiated based on history and physical examination
    • Schizoaffective disorder c72
      • Milder psychotic symptoms than schizophrenia with presence of mood disorder r16
    • Hypothyroidism r21c73d4
      • 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 c74c75
      • 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 r14c90
      • Drug classes that are known to produce symptoms similar to depression include:
        • Benzodiazepines c91
        • Steroids c92
        • Levodopa c93
        • Oral contraceptives c94
        • Interferon c95
      • Differentiated based on history and physical examination

    Treatment

    Goals

    • Assess patient for suicidality and take steps to protect patient as needed r22
    • Reduce signs and symptoms, including residual symptoms r11r23r24
    • Relieve any complications (eg, malnutrition, substance use disorder) r14
    • Restore prior level of psychosocial and occupational function r14
    • Prevent relapse and recurrence r14

    Disposition

    Admission criteria r24

    • 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 r13r25
        • 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
      • 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 N-methyl-D-aspartate receptor antagonist to receive FDA approval for major depression—can be used as an adjunct to an oral antidepressant for major depression with acute suicidal ideation or behavior or treatment-resistant depression r28r29

    Drug therapy

    • Selective serotonin reuptake inhibitors c96
      • Citalopram c97
        • Citalopram Hydrobromide Oral solution; Children and Adolescents 7 to 17 years: 10 to 20 mg PO once daily, initially. May increase the dose by 10 mg/day every 4 weeks if inadequate response and depending on tolerability; some studies increased the dose as often as every week. Usual dose: 20 mg/day. Max: 40 mg/day or 20 mg/day for CYP2C19 poor metabolizers. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
        • Citalopram Hydrobromide Oral tablet; Adults 18 to 60 years: 20 mg PO once daily, initially. May increase the dose at intervals of at least 1 week if inadequate response and depending on tolerability. Max: 40 mg/day or 20 mg/day for CYP2C19 poor metabolizers. 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. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
      • Escitalopram c98
        • Escitalopram Oral solution; Children and Adolescents 12 to 17 years: 10 mg PO once daily, initially. May increase the dose to 20 mg/day after at least 3 weeks if inadequate response and depending on tolerability. Usual dose: 10 mg/day. Max: 20 mg/day.
        • Escitalopram Oral tablet; Adults: 10 mg PO once daily, initially. May increase the dose to 20 mg/day after at least 1 week if inadequate response and depending on tolerability. Usual dose: 10 mg/day. Max: 20 mg/day.
        • Escitalopram Oral tablet; Older Adults: 10 mg PO once daily.
      • Fluoxetine c99
        • Fluoxetine Hydrochloride Oral solution [Depression/Mood Disorders]; Children and Adolescents 8 to 17 years: 10 or 20 mg PO once daily, initially. Increase dose to 20 mg/day after 1 week and may increase dose after several weeks if inadequate response and depending on tolerability. May divide doses of 20 mg/day or more in 2 doses. Usual dose: 10 to 20 mg/day. Max: 60 mg/day.
        • Fluoxetine Hydrochloride Oral capsule [Depression/Mood Disorders]; Adults: 20 mg PO once daily, initially. May increase dose after several weeks if inadequate response and depending on tolerability. May divide doses of 20 mg/day or more in 2 doses. Max: 80 mg/day.
      • Paroxetine c100
        • Immediate-release
          • Paroxetine Hydrochloride Oral tablet; Adults: 20 mg PO once daily, initially. Increase dose by 10 mg/day at intervals of at least 1 week if inadequate response and depending on tolerability. Max: 50 mg/day.
          • Paroxetine Hydrochloride Oral tablet; Older Adults: 10 mg PO once daily, initially. Increase dose by 10 mg/day at intervals of at least 1 week if inadequate response and depending on tolerability. Max: 40 mg/day.
        • Extended-release
          • Paroxetine Hydrochloride Oral tablet, extended-release; Adults: 25 mg PO once daily, initially. Increase dose by 12.5 mg/day at intervals of at least 1 week if inadequate response and depending on tolerability. Max: 62.5 mg/day.
          • Paroxetine Hydrochloride Oral tablet, extended-release; Older Adults: 12.5 mg PO once daily, initially. Increase dose by 12.5 mg/day at intervals of at least 1 week if inadequate response and depending on tolerability. Max: 50 mg/day.
      • Sertraline c101c102
        • Evidence recommends that physicians use caution when prescribing sertraline in pediatric patients (if at all). r30
        • Sertraline Hydrochloride Oral solution; Children 6 to 11 years†: 12.5 to 25 mg PO once daily, initially. May increase dose by 12.5 to 25 mg/day every 4 weeks if inadequate response and depending on tolerability; some studies report titration by 25 to 50 mg/day every 1 to 2 weeks. Max: 200 mg/day.
        • Sertraline Hydrochloride Oral solution; Children and Adolescents 12 to 17 years†: 25 to 50 mg PO once daily, initially. May increase dose by 12.5 to 25 mg/day every 4 weeks if inadequate response and depending on tolerability; some studies report titration by 25 to 50 mg/day every 1 to 2 weeks. Max: 200 mg/day.
        • Sertraline Hydrochloride Oral tablet; Adults: 50 mg PO once daily, initially. May increase dose by 25 to 50 mg/day at intervals of at least 1 week if inadequate response and depending on tolerability. Usual dose: 50 to 200 mg/day. Max: 200 mg/day.
      • Vilazodone
        • Has not received enough study to judge safety in older patients or in those with, or at high risk for, cardiovascular disease. r31
        • Vilazodone hydrochloride Oral tablet; Adults: 10 mg PO once daily for 7 days, then 20 mg PO once daily. May increase dose by 10 mg/day after at least 7 days if inadequate response and depending on tolerability. Usual dose: 20 to 40 mg/day. Max: 40 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
      • Vortioxetine
        • Vortioxetine Oral tablet; Adults: 10 mg PO once daily, initially, then increase dose to 20 mg PO once daily depending on tolerability. May reduce dose to 5 mg/day for persons who do not tolerate higher doses. Max: 20 mg/day or 10 mg/day for CYP2D6 poor metabolizers. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
    • Serotonin-norepinephrine reuptake inhibitors c103
      • Desvenlafaxine
        • Desvenlafaxine Succinate Oral tablet, extended-release; Adults: 50 mg PO once daily, initially. Usual dose: 50 mg/day. Max: 400 mg/day, although no additional benefit was demonstrated at doses more than 50 mg/day and adverse reactions and discontinuations were more frequent at higher doses. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
      • Duloxetine c104
        • Duloxetine Oral capsule, gastro-resistant pellets; Adults: 20 or 30 mg PO twice daily or 60 mg PO once daily, initially. May consider 30 mg PO once daily initially, then 60 mg PO once daily. Max: 120 mg/day, although there is no evidence that doses more than 60 mg/day confer any additional benefits.
      • Levomilnacipran
        • Has not received enough study to judge safety in older patients or in those with, or at high risk for, cardiovascular disease. r31
        • Levomilnacipran Oral capsule, extended-release; Adults: 20 mg PO once daily for 2 days, then 40 mg PO once daily, initially. May increase dose by 40 mg/day at intervals of at least 2 days if inadequate response and depending on tolerability. Usual dose: 40 to 120 mg/day. Max: 120 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
      • Venlafaxine c105
        • Immediate-release
          • Venlafaxine Hydrochloride Oral tablet; Adults: 75 mg/day PO divided in 2 or 3 doses, initially. May increase dose by 75 mg/day at intervals of at least every 4 days as needed. Usual Max: 225 mg/day. Max: 375 mg/day in 3 divided doses.
        • Extended-release
          • Venlafaxine Hydrochloride Oral tablet, extended-release; Adults: 75 mg PO once daily, or alternatively, 37.5 mg PO once daily for 4 to 7 days, then 75 mg PO once daily, initially. May increase dose by 75 mg/day at intervals of at least every 4 days as needed. Usual Max: 225 mg/day. Max: 375 mg/day.
    • Noradrenergic and specific serotonin antidepressants c106
      • Mirtazapine c107
        • Mirtazapine Oral tablet; Adults: 15 mg PO once daily at bedtime, initially. May increase dose up to 45 mg/day at intervals of at least 1 to 2 weeks if inadequate response. Max: 45 mg/day.
    • Noradrenergic and dopaminergic antidepressants c108
      • Bupropion c109
        • Immediate-release
          • Bupropion Hydrochloride Oral tablet [Depression/Mood Disorders]; Children† and Adolescents† 6 to 17 years: Dosage not established. Suggested dosage ranges from 1.4 to 6 mg/kg/day PO, titrated upward slowly and administered in divided doses. Average effective dose: 3 mg/kg/day. Max: 250 to 300 mg/day.
          • Bupropion Hydrochloride Oral tablet [Depression/Mood Disorders]; Adults: 100 mg PO twice daily, initially. May increase dose to 100 mg PO 3 times daily after 3 days, then may increase dose up to 450 mg/day after several weeks if inadequate response. Max: 450 mg/day and 150 mg/dose.
        • Extended-release (12-hour)
          • Bupropion Hydrochloride Oral tablet, extended release 12 hour [Depression/Mood Disorders]; Adolescents†: Limited data are available. 2 mg/kg/dose (Max: 100 mg/dose) PO once daily in the morning, initially. May increase dose gradually to 3 mg/kg/dose PO every morning and 2 mg/kg/dose every evening, and then may increase dose to 3 mg/kg/dose PO twice daily if inadequate response. Max: 6 mg/kg/day and 150 mg/dose. Alternatively, 150 mg PO once daily in the morning, initially. May increase dose up to 150 mg PO twice daily after at least 4 days, and then may increase dose to 200 mg PO twice daily after several weeks if inadequate response.
          • Bupropion Hydrochloride Oral tablet, extended release 12 hour [Depression/Mood Disorders]; Adults: 150 mg PO once daily in the morning, initially. May increase dose to 150 mg PO twice daily after 3 days, and then may increase dose to 200 mg PO twice daily after several weeks if inadequate response. Max: 400 mg/day.
        • Extended-release (24-hour)
          • Bupropion Hydrochloride Oral tablet, extended release 24 hour [Depression/Mood Disorders]; Adults: 150 mg PO once daily in the morning, initially. May increase dose to 300 mg PO once daily after at least 4 days if inadequate response. Max: 450 mg/day.
    • Tricyclic antidepressants c110
      • Amitriptyline c111
        • Amitriptyline Hydrochloride Oral tablet; Adolescents: 10 mg PO 3 times daily with 20 mg PO once daily at bedtime. Reduce dose to the lowest dose that will maintain remission after satisfactory improvement has occurred.
        • Amitriptyline Hydrochloride Oral tablet; Outpatient Adults: 75 mg/day PO in divided doses, or alternately, 50 to 100 mg PO once daily at bedtime, initially. May increase dose by 25 to 50 mg/day at bedtime as needed and tolerated. Usual dose: 40 to 100 mg/day. Max: 150 mg/day. Reduce dose to the lowest dose that will maintain remission after satisfactory improvement has occurred.
        • Amitriptyline Hydrochloride Oral tablet; Older Adults: 10 mg PO 3 times daily with 20 mg PO once daily at bedtime. Reduce dose to the lowest dose that will maintain remission after satisfactory improvement has occurred.
      • Desipramine c112
        • Desipramine Hydrochloride Oral tablet; Adolescents: 25 to 100 mg/day PO once daily or in divided doses; start at lower dose and increase dose gradually as needed and tolerated. Max: 150 mg/day. Reduce dose to the lowest dose that will maintain remission after satisfactory improvement has occurred.
        • Desipramine Hydrochloride Oral tablet; Adults: 100 to 200 mg/day PO once daily or in divided doses; start at lower dose and increase dose gradually as needed and tolerated. Max: 300 mg/day. Reduce dose to the lowest dose that will maintain remission after satisfactory improvement has occurred.
        • Desipramine Hydrochloride Oral tablet; Older Adults: 25 to 100 mg/day PO once daily or in divided doses; start at lower dose and increase dose gradually as needed and tolerated. Max: 150 mg/day. Reduce dose to the lowest dose that will maintain remission after satisfactory improvement has occurred.
      • Imipramine c113
        • Imipramine Hydrochloride Oral tablet; Adolescents: 30 to 40 mg PO once daily, initially. May increase dose gradually as needed and tolerated. Usual Max: 100 mg/day. Reduce dose to the lowest dose that will maintain remission after satisfactory improvement has occurred.
        • Imipramine Hydrochloride Oral tablet; Outpatient Adults: 75 mg PO once daily, initially. May increase dose to 150 mg/day gradually as needed and tolerated. Usual dose: 50 to 150 mg/day. Max: 200 mg/day. Reduce dose to the lowest dose that will maintain remission after satisfactory improvement has occurred.
        • Imipramine Hydrochloride Oral tablet; Hospitalized Adults: 100 mg/day PO in divided doses. May increase dose to 200 mg/day gradually as needed and tolerated; further increase dose to 250 to 300 mg/day if no response after 2 weeks. Reduce dose to the lowest dose that will maintain remission after satisfactory improvement has occurred.
        • Imipramine Hydrochloride Oral tablet; Older Adults: 30 to 40 mg PO once daily, initially. May increase dose gradually as needed and tolerated. Usual Max: 100 mg/day. Reduce dose to the lowest dose that will maintain remission after satisfactory improvement has occurred.
      • Nortriptyline c114
        • Nortriptyline Hydrochloride Oral solution; Adolescents: 30 to 50 mg PO once daily or in divided doses. Reduce dose to the lowest dose that will maintain remission after satisfactory improvement has occurred.
        • Nortriptyline Hydrochloride Oral capsule; Adults: 25 mg PO 3 or 4 times daily, or alternately, 75 to 100 mg PO once daily, initially; start at lower dose and increase dose gradually as needed and tolerated. Max: 150 mg/day. Reduce dose to the lowest dose that will maintain remission after satisfactory improvement has occurred.
        • Nortriptyline Hydrochloride Oral capsule; Older Adults: 30 to 50 mg PO once daily or in divided doses. Reduce dose to the lowest dose that will maintain remission after satisfactory improvement has occurred.
    • MAOIs c115
      • 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. r32
      • Do not use concomitantly with other serotonergic drugs r32r33
      • Isocarboxazid c116
        • Isocarboxazid Oral tablet; Adolescents 16 to 17 years: 10 mg PO twice daily, initially. May increase dose by 10 mg/day every 2 to 4 days up to 40 mg/day by the end of the first week, then may increase dose by 20 mg/week as needed and tolerated. Max: 60 mg/day in 2 to 4 divided doses. Reduce dose to the lowest dose that will maintain remission after satisfactory improvement has occurred.
        • Isocarboxazid Oral tablet; Adults: 10 mg PO twice daily, initially. May increase dose by 10 mg/day every 2 to 4 days up to 40 mg/day by the end of the first week, then may increase dose by 20 mg/week as needed and tolerated. Max: 60 mg/day in 2 to 4 divided doses. Reduce dose to the lowest dose that will maintain remission after satisfactory improvement has occurred.
      • Phenelzine c117
        • Phenelzine Sulfate Oral tablet; Adults: 15 mg PO 3 times daily, initially. Increase the dose up to 60 mg/day at a fairly rapid pace as tolerated; it may be necessary to increase the dose up to 90 mg/day. Reduce dose to the lowest dose that will maintain remission after satisfactory improvement has occurred. Usual maintenance dose: 15 mg PO once daily or every other day
      • Selegiline c118
        • Selegiline Hydrochloride Transdermal patch - 24 hour; Adults: 6 mg/24 hours transdermally once daily, initially. May increase dose by 3 mg/24 hours at intervals of 2 weeks or more. Usual dose: 6 to 12 mg/24 hours. Max: 12 mg/24 hours.
      • Tranylcypromine
        • Tranylcypromine Sulfate Oral tablet; Adolescents 16 to 17 years: 15 mg PO twice daily, initially. May increase dose by 10 mg/day at intervals of 1 to 3 weeks if inadequate response. Max: 60 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
        • Tranylcypromine Sulfate Oral tablet; Adults: 15 mg PO twice daily, initially. May increase dose by 10 mg/day at intervals of 1 to 3 weeks if inadequate response. Max: 60 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
    • N-methyl-D-aspartate receptor antagonists c119
      • Esketamine nasal spray r28r29c120
        • First N-methyl-D-aspartate antagonist to receive FDA approval for major depression
        • Used as an adjunct to oral antidepressant
        • 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 is clinically stable and safe to leave the health care setting r28
        • For major depression with acute suicidal ideation or behavior
          • Esketamine Nasal spray, solution; Adults: 84 mg intranasally twice weekly for 4 weeks, initially. May reduce dose to 56 mg intranasally twice weekly as tolerated. Evaluate evidence of therapeutic benefit after 4 weeks to determine need for continued therapy.
        • For treatment-resistant depression
          • Esketamine Nasal spray, solution; Adults: 56 mg intranasally on day 1, then 56 or 84 mg intranasally twice weekly for weeks 1 through 4, then 56 or 84 mg intranasally once weekly for weeks 5 through 8, and then 56 or 84 mg intranasally once weekly or every 2 weeks.

    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 r34c121

    Acupuncture r35c122

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

    Exercise r36c123

    • Exercise has been shown to have significant effect in reducing depressive symptoms in patients with major depressive disorder,r37 especially regular, moderate-level, aerobic exercise
    Procedures
    Psychotherapy c124c125c126
    General explanation
    • Includes cognitive behavioral therapy, behavioral activation therapy, interpersonal psychotherapy, problem-solving therapy, nondirective counseling, and psychodynamic therapy r14
    • First line recommendations for acute major depressive disorder include cognitive behavioral therapy, interpersonal psychotherapy, and behavioral activation therapy r38
    • All types are known to be effective options r14r39
    • 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 r14
    • Cognitive behavioral therapy administered concurrently with medication may increase the rate of patient response r38r40
    • Cognitive behavioral therapy administered after medication is withdrawn may impart a protective effect against relapse r41
    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 r42c127c128c129c130c131
    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 r25r43
    • 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 r44c132
    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: r5r45
        • 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 r46
      • Typical session lasts 30 to 60 minutes and does not require anesthesia r45
    Indication
    • First line treatment for patients with major depression who have not responded to antidepressant drug therapy r7r43
    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 r47
    • Headache
    • Scalp discomfort
    • Seizures

    Comorbidities

    • Anxiety disorder c133
      • Approximately one-half of patients with anxiety disorders have other mood disorders (typically dysthymia or depression) r48
    • Obsessive-compulsive disorder c134
      • Often produces additional depression symptoms
    • Substance use disorder (eg, alcohol, opioids, amphetamine, cocaine, cannabis) c135
      • Associated with depression and suicide attempts
      • Impulsivity is heightened when under the influence of substances r49
    • Coronary artery disease c136
      • 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 r50
      • Depression has been shown to be an independent risk factor for mortality in cardiovascular disease, especially in patients with a heart failure diagnosis r51
    • Diabetes mellitus c137
      • Patients with diabetes and depression experience worse glycemic control and an increased risk of diabetic complications r50
    • Obesity c138
      • Depression-associated low motivation, poor adherence, negative thinking, fatigue, and sleep problems reduce the success of early-treatment weight loss programs r52
    • Hypertension c139
      • People who carry a diagnosis of depression have a higher incidence of hypertension than in the general population r53
      • Antidepressants can affect blood pressure and the individual effect can be highly variable with greater increases noted in the elderly, those with higher baseline blood pressure, and those using antihypertensive therapy or with kidney disease r54
      • Selective serotonin reuptake inhibitors have a lower impact on blood pressure than other antidepressants r53
      • Monoamine oxidase inhibitors, tricyclic antidepressants, and serotonin-norepinephrine reuptake inhibitors have a higher chance of increasing blood pressure r53r55

    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 patients r1r7
    • Older adults
      • Antidepressants pose greater risk for adverse events because of multiple medical comorbidities and drug-drug interactions in case of polypharmacy r56
    • Patients diagnosed with dementia
      • High-quality evidence does not support the use of pharmacologic treatment of depression in patients with dementia r56

    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 c140
      • The relationship between suicidal ideation and lifetime suicide attempts is strongest at low, as opposed to high, levels of depression r22
    • Substance use disorder c141

    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
      • The burden of side effects that are present as early as 4 days post-treatment predicts poorer treatment outcome and should be monitored closely r57
    • 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 r1c142c143c144c145
    • US Preventive Services Task Force recommends screening adolescents aged 12 to 18 years for major depressive disorder r58
    • American Academy of Pediatrics guidelines recommends screening adolescent patients aged 12 years and older annually for depression with a formal self-report screening tool r59
    • US Department of Veterans Affairs recommends screening for major depression annually r14c146c147c148c149
    • 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 r60

    Screening tests

    • Standardized depression inventory tests include Beck Depression Inventory, Major Depression Inventory, Hamilton Depression Rating Scale, and Patient Health Questionnaire-9 r1r2r3r14c150c151c152c153

    Prevention c154

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