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    Major Depressive Disorder

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    Feb.20.2025

    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) for at least 2 weeks
    • Diagnosis relies on history and physical examination as well as validated depression inventory tools, including Beck Depression Inventory,r1Hamilton Depression Rating Scale,r1 Major Depression Inventory,r2 and Patient Health Questionnaire-9r3
    • Rule out underlying physical illnesses that may mimic major depressive disorder (eg, hypothyroidism, dementia)
    • Diagnosis established using DSM-5-TR diagnostic criteria for major depressive disorder
    • Structured psychological treatment is foundational in the treatment of all depressive presentations and is the recommended initial treatment for patients with mild major depressive disorder r4r5r6
    • For patients with moderate to severe major depressive disorder, evidence-based psychotherapy, pharmacotherapy, or combination therapy (psychotherapy and an antidepressant) is recommended for initial treatment r4r5
    • Selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors are commonly used as first line pharmacotherapy options due to efficacy, acceptability, and familiarity/experience
    • Treatment strategies for patients with inadequate response to an adequate trial of initial pharmacotherapeutic management include switching to another antidepressant, adding another agent to augment treatment, switching to psychotherapy, adding psychotherapy to augment treatment, adding a second-generation antipsychotic to augment treatment, repetitive transcranial magnetic stimulation, and electroconvulsive therapy
    • Electroconvulsive therapy may be necessary if patient has a high risk of suicide or if welfare is threatened (eg, lack of nutrition or fluid intake)
    • In patients who achieve remission with antidepressant medication, ongoing close monitoring and support and slow tapering of medication is necessary to prevent relapse
    • 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 r7

    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 those 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-TR diagnostic criteria for major depressive disorder r8
      • 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 r9
    • 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 r9
      • 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
      • 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 r9
      • Evidence of self harm (eg, healed lacerations, scars on body or extremities) c41c42c43
    • Weight loss, weight gain, or evidence of poor nutrition r9c44c45c46

    Causes and Risk Factors

    Causes

    • Unknown

    Risk factors and/or associations

    Age
    • Prevalence of major depressive disorder is greatest among younger adults r11c47
    Sex
    • Major depressive disorder is more prevalent among women r11c48c49
    Genetics r9
    • 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 r9c51
    Ethnicity/race
    • In the US, prevalence of major depressive disorder in adults is greater among White and Native American individuals than among African American and Asian American individuals r11c52c53c54
    Other risk factors/associations r11
    • Exposure to adversity in childhood or adulthood
    • Low income
    • Other psychiatric disorders

    Diagnostic Procedures

    Primary diagnostic tools

    • Depression screening tools (eg, Beck Depression Inventory, Patient Health Questionnaire-2, Patient Health Questionnaire-9) can be used initially to identify patients requiring full diagnostic interviews using standard diagnostic criteria r1r3r9r12c55
    • History and physical examination provide definitive diagnosis c56
    • 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 r13c57c58

    Other diagnostic tools

    • Standardized depression inventory tools c59
      • 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" r12
      • Beck Depression Inventory r1c60
        • 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 r1c61
        • Observer-rated scale designed to be administered by the health care professional
      • Major Depression Inventory r2c62
        • Self-rated questionnaire
        • Incorporates both the ICD‐10 symptoms of depression and the DSM-IV symptoms of major depression
      • Patient Health Questionnaire-9 r3r14c63
        • Self-rated questionnaire with 9 items
      • Patient Health Questionnaire-2 r3r15
        • Abbreviated version of Patient Health Questionnaire-9 consisting of the first 2 items from the longer questionnaire; assesses the degree to which an individual has experienced depressed mood or anhedonia in the past 2 weeks
        • Designed specifically for screening
        • Widely used in primary care due to convenience and brevity
        • Patients who screen positive should be assessed further with the Patient Health Questionnaire-9, another standardized depression inventory test, or full diagnostic interview using standardized criteria

    Differential Diagnosis

    Most common r16

    • Persistent depressive disorder (dysthymia) c64
      • Characteristics
        • 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-TR 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 r17c65d1
      • 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 r18
        • 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 r19c66
      • 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 r20c67
      • Especially in older patients, may be mistaken for major depressive disorder during early stages of the illness
      • Features 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 r21c68d2
      • Progressive disorder of the central nervous system that often coexists with depression
      • Associated with symptoms of major depressive disorder, in addition to the following:
        • 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 c69d3
      • Disorder that affects thoughts, feelings, and perceptions; primary symptom is psychosis with auditory hallucinations and delusions
      • Persons with schizophrenia may develop secondary major depression r17
      • 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 c70
      • Milder psychotic symptoms than schizophrenia with presence of mood disorder r17
    • Hypothyroidism r22c71d4
      • 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 c72c73
      • May cause symptoms of depression with chronic use or from withdrawal
      • Causative substances include:
      • Differentiated from major depressive disorder by the following:
        • 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 r14c88
      • Drug classes that are known to produce symptoms similar to depression include:
        • Benzodiazepines c89
        • Steroids c90
        • Levodopa c91
        • Oral contraceptives c92
        • Interferon c93
      • Differentiated based on history and physical examination

    Treatment

    Goals

    • Assess patient for suicidality and take steps to protect patient as needed r23
    • Reduce signs and symptoms, including residual symptoms r9r24r25
    • 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

    Recommended initial treatment options for patients with moderate to severe major depressive disorder r4

    • Evidence-based psychotherapy (eg, cognitive behavioral therapy)
    • Pharmacotherapy
    • Combination therapy with psychotherapy and pharmacotherapy

    Recommended initial treatment for patients with mild major depressive disorder is cognitive behavioral therapy r4

    • Pharmacotherapy may be chosen for initial treatment based on considerations such as access to or cost of psychotherapy, history of moderate or severe major depression, or patient preference r4
    • Consider combination therapy (psychotherapy and pharmacotherapy) when the response to a single therapy is inadequate

    Initial treatment with a combination of pharmacotherapy and psychotherapy is recommended for patients with any of the following: r5r13r26r27

    • Severe major depressive disorder (eg, Patient Health Questionnaire-9 score greater than 20)
    • Persistent major depressive disorder (duration longer than 2 years)
    • Recurrent major depressive disorder (2 or more previous episodes)

    These agents and drug classes are first line options for pharmacotherapy: start treatment at low dose and gradually increase to approved maximum dose r4r5r27r28

    • Bupropion
    • Mirtazapine
    • Serotonin-norepinephrine reuptake inhibitors
    • Selective serotonin reuptake inhibitors r29
    • Serotonin modulators (includes trazodone and newer agents such as vilazodone and vortioxetine)
      • Vilazodone has not received enough study to judge safety in older patients or in those with, or at high risk for, cardiovascular disease r30

    Choice of initial pharmacotherapy should be individualized, accounting for factors such as efficacy, side effect profile, tolerability, cost, insurance coverage, and patient or clinician preference. Guidelines vary in terms of specific recommendations, but selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors are frequently preferred over newer agents due to efficacy, acceptability, and familiarity/experience r5r28r31

    Gepirone (approved in 2023) and combination dextromethorphan-bupropion (approved in 2022) are the most recently approved therapies for major depressive disorder; clinical experience is relatively limited, and US guidelines have yet to clearly define role of these new agents in treatment, inclusive of whether they are appropriate for use as first line agents r32r33

    For patients with an inadequate response to an adequate trial of initial pharmacotherapy (ie, 1 of the above agents at maximum dose for at least 4 to 6 weeks), options include: r5r27r31

    • Switching to another antidepressant
      • A different first line antidepressant agent or drug class r4
      • A second line agent (eg, tricyclic antidepressants, monoamine oxidase inhibitors [MAOIs], nefazodone) r5
        • When using MAOIs, 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
        • Do not use MAOIs concomitantly with other serotonergic drugs
      • Esketamine nasal spray as monotherapy may be considered for treatment-resistant depression (ie, inadequate response to adequate trials of 2 or more oral antidepressants) r34
        • Esketamine is 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
    • Adding another agent (eg, mirtazapine, bupropion, or buspirone) to augment treatment r4
      • Ketamine or esketamine nasal sprayr34 may be considered as an adjunct to an oral antidepressant in patients with treatment-resistant depression or with acute suicidal ideation r27
    • Switching to psychotherapy
    • Adding psychotherapy to augment treatment
      • 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 r5
    • Adding a second-generation antipsychotic (eg, aripiprazole) to augment treatment

    Offer repetitive transcranial magnetic stimulation to patients with inadequate response to 2 or more adequate trials of medication r5

    Consider electroconvulsive therapy for patients with any of the following: r5

    • Catatonia r6
    • Psychotic depression r6
    • Severe suicidality
    • Previous good response to electroconvulsive therapy
    • Need for rapid, definitive treatment for medical or psychiatric reasons (eg, lack of nutrition or fluid intaker6)
    • Risks associated with other treatments are greater than the risks of electroconvulsive therapy for the specific patient
    • Previous poor response or intolerable side effects to multiple antidepressants

    Relapse prevention r26

    • In patients who achieve remission with antidepressant medication, continue antidepressants at the therapeutic dose for at least 4 to 9 months to decrease risk of relapse r4r5
    • For patients at high risk for relapse or recurrence (eg, 2 or more prior episodes, unstable remission status) offer a course of cognitive behavioral therapy, interpersonal therapy, or mindfulness-based cognitive therapy after remission is achieved on medication
    • Slowly taper antidepressant medication to minimize withdrawal symptoms; abrupt discontinuation can cause antidepressant discontinuation syndrome r4r26
      • Flulike symptoms (eg, nausea, vomiting, diarrhea, headaches)
      • Sensory/movement disturbances (eg, vertigo, dizziness)
      • Cognitive symptoms (eg, hyperarousal, confusion)
    • 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

    Drug therapy

    • Selective serotonin reuptake inhibitors c94
      • Citalopram c95
        • 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. Usual dose: 20 mg/day. Max: 40 mg/day. 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. 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 c96
        • 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 c97
        • 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 the 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 the 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 c98
        • Immediate release
          • Paroxetine Hydrochloride Oral tablet; Adults: 20 mg PO once daily, initially. May increase the 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. May increase the 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. May increase the 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. May increase the 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 c99c100
        • Sertraline Hydrochloride Oral solution; Children† 6 to 11 years: 12.5 to 25 mg PO once daily, initially. May increase the dose by 12.5 to 50 mg/day at intervals of 1 to 4 weeks if inadequate response and depending on tolerability. 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 the dose by 12.5 to 50 mg/day at intervals of 1 to 4 weeks if inadequate response and depending on tolerability. Max: 200 mg/day.
        • Sertraline Hydrochloride Oral tablet; Adults: 50 mg PO once daily, initially. May increase the 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.
    • Serotonin-norepinephrine reuptake inhibitors c101
      • Desvenlafaxine c102
        • 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 c103
        • Duloxetine Oral capsule, gastro-resistant pellets; Adults: 20 or 30 mg PO twice daily or 60 mg PO once daily, initially. Alternatively, 30 mg PO once daily for 1 week, then 60 mg PO once daily. Usual Max: 60 mg/day. Max: 120 mg/day.
      • Levomilnacipran c104
        • Levomilnacipran Oral capsule, extended-release; Adults: 20 mg PO once daily for 2 days, then 40 mg PO once daily, initially. May increase the 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 the dose by 75 mg/day at intervals of at least every 4 days if inadequate response and depending on tolerability. 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 the dose by 75 mg/day at intervals of at least every 4 days if inadequate response and depending on tolerability. Max: 225 mg/day.
    • Noradrenergic and specific serotonin antidepressants c106
      • Mirtazapine c107
        • Mirtazapine Oral tablet; Adults: 15 mg PO once daily at bedtime, initially. May increase the dose up to 45 mg/day at intervals of at least 1 to 2 weeks if inadequate response. Max: 45 mg/day.
    • Norepinephrine and dopamine reuptake inhibitors c108
      • Bupropion c109
        • Immediate release
          • Bupropion Hydrochloride Oral tablet [Depression/Mood Disorders]; Children† and Adolescents† 6 to 17 years: 1.4 to 6 mg/kg/day PO, titrated upward slowly and administered in divided doses. Usual 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 the dose to 100 mg PO 3 times daily after 3 days, and then 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†: 2 mg/kg/dose (Max: 100 mg/dose) PO once daily for 2 to 3 weeks, initially. May increase the dose to 3 mg/kg/dose (Max:150 mg/dose) PO once daily for 2 to 3 weeks, then 3 mg/kg/dose (Max: 150 mg/dose) PO every morning and 2 mg/kg/dose (Max: 150 mg/dose) PO every evening for 2 to 3 weeks, and then 3 mg/kg/dose (Max: 150 mg/dose) PO twice daily if inadequate response. Alternately, 100 mg PO once daily for 1 week, initially. May increase the dose to 150 mg PO once daily for 2 weeks, then 150 mg PO twice daily for 1 to 3 weeks, and then 200 mg PO twice daily if inadequate response.
          • Bupropion Hydrochloride Oral tablet, extended release 12 hour [Depression/Mood Disorders]; Adults: 150 mg PO once daily, initially. May increase the dose to 150 mg PO twice daily after 3 days, and then 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, initially. May increase the dose to 300 mg PO once daily after at least 4 days if inadequate response. Max: 450 mg/day.
    • Serotonin modulators r5
      • Gepirone
        • Gepirone Oral tablet, extended release; Adults: 18.2 mg PO once daily, initially. May increase the dose to 36.3 mg/day on Day 4, 54.5 mg/day after Day 7, and 72.6 mg/day after an additional week based on clinical response and tolerability. Max: 72.6 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
        • Gepirone Oral tablet, extended release; Older Adults: 18.2 mg PO once daily, initially. May increase the dose to 36.3 mg/day after Day 7 based on clinical response and tolerability. Max: 36.3 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
      • Trazodone
        • Trazodone Hydrochloride Oral tablet; Children† 6 to 12 years: 1.5 to 2 mg/kg/day PO in divided doses, initially. May increase the dose every 3 to 4 days if inadequate response and based on tolerability. Max: 6 mg/kg/day in divided doses.
        • Trazodone Hydrochloride Oral tablet; Adolescents†: 25 mg PO once daily at bedtime, or alternatively 1.5 to 2 mg/kg/day PO in divided doses, initially. May increase the dose every 3 to 4 days if inadequate response and based on tolerability. Max: 100 to 150 mg/day or 6 mg/kg/day in divided doses.
        • Trazodone Hydrochloride Oral tablet; Adults: 150 mg/day PO in divided doses, initially. May increase the dose by 50 mg/day every 3 to 4 days if inadequate response and based on tolerability. Usual Max: 400 mg/day. Max: 600 mg/day.
      • Vilazodone c110
        • Vilazodone hydrochloride Oral tablet; Adults: 10 mg PO once daily for 7 days, then 20 mg PO once daily. May increase the 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 c111
        • Vortioxetine Oral tablet; Adults: 10 mg PO once daily, initially, then increase the 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. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
    • Tricyclic antidepressants c112
      • Amitriptyline c113
        • 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 the 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; Hospitalized Adults: 75 to 100 mg/day PO in divided doses, initially. May increase the dose to 200 mg/day gradually as needed and tolerated. Max: 300 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 c114
        • 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 c115
        • Imipramine Hydrochloride Oral tablet; Adolescents: 30 to 40 mg PO once daily, initially. May increase the 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 the 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 the 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 the 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 c116
        • 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 c117
      • Isocarboxazid c118
        • Isocarboxazid Oral tablet; Adolescents 16 to 17 years: 10 mg PO twice daily, initially. May increase the 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 the dose by 20 mg/week if inadequate response and depending on tolerability. 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 the 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 the dose by 20 mg/week if inadequate response and depending on tolerability. 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 c119
        • 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 c120
        • Selegiline Hydrochloride Transdermal patch - 24 hour; Adults: 6 mg/24 hours transdermally once daily, initially. May increase the 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 c121
        • Tranylcypromine Sulfate Oral tablet; Adolescents 16 to 17 years: 15 mg PO twice daily, initially. May increase the 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 the 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 c122
      • Esketamine r34r35c123
        • 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 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.
      • Ketamine
        • Ketamine Hydrochloride Solution for injection; Adults 18 to 64 years: 0.5 mg/kg/dose IV as a single dose or 1 to 3 times weekly for up to 6 doses.
    • N-methyl D-aspartate receptor antagonist/sigma-1 receptor agonist and norepinephrine and dopamine reuptake inhibitor combination
      • Dextromethorphan and bupropion combination
        • Dextromethorphan Hydrobromide, Bupropion Hydrochloride Oral tablet, extended-release; Adults: 45 mg dextromethorphan; 105 mg bupropion PO once daily for 3 days, then increase the dose to 45 mg dextromethorphan; 105 mg bupropion PO twice daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    Nondrug and supportive care

    Psychotherapy

    • 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
    • Recommended approaches include cognitive behavioral therapy, behavioral activation therapy, interpersonal psychotherapy, problem-solving therapy, nondirective counseling, psychodynamic therapy, acceptance and commitment therapy, mindfulness-based cognitive therapy, and short-term psychodynamic psychotherapy r5r14r28
    • US Department of Veterans Affairs/Department of Defense, American Psychological Association, and National Institute for Health and Care Excellence guidelines recommend a range of psychotherapies for treatment of depression; however, American College of Physicians guidelines only recommend cognitive behavioral therapy, citing insufficient evidence for other forms r5r9r14r27r36r37
    • May be offered in individual or group format according to patient preference r27
    • 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 r38
    • Cognitive behavioral therapy administered after medication is withdrawn may impart a protective effect against relapse r39

    Digital health technologies

    • Various digital interventions have been developed as adjuncts to pharmacotherapy and/or traditional psychotherapy for major depressive disorder r40
    • Several self-management applications have been shown to reduce depressive symptoms, as supported by randomized controlled trial data r40
    • Rejoyn (approved in 2024) is the first prescription digital therapeutic approved by the FDA for the treatment of major depressive disorder, as an adjunct to clinician-managed outpatient care for adults aged 22 years or older who are receiving pharmacotherapy r41r42r43
      • Provides 6 weeks of treatment through a combination of cognitive behavioral therapy–based lessons, cognitive-emotional exercises, and personalized reminders and messaging; lessons can be revisited after the initial 6 weeks of treatment
      • In a multicenter, double-blinded, randomized controlled trial of adult participants with major depressive disorder who were receiving antidepressant therapy, participants in the intervention group had significant reduction in depressive symptoms compared with those who received sham treatment, as assessed by patient and clinician-rated symptom scales

    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 r44c124

    Acupuncture r45c125

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

    Exercise r46c126

    • Exercise has been shown to have significant effect in reducing depressive symptoms in patients with major depressive disorder,r47 especially regular, moderate-level, aerobic exercise
    Procedures
    Electroconvulsive therapy r48c127c128c129c130c131
    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 r5r28
    • May be used as first line therapy for patients who have the following:
      • 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 r49c132
    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: r50
        • 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 r51
      • Typical session lasts 30 to 60 minutes and does not require anesthesia r50
    Indication
    • Treatment option for patients with major depression who have not responded to antidepressant drug therapy r5r28
    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 r52
    • Headache
    • Scalp discomfort
    • Seizures

    Comorbidities

    • Anxiety disorder c133
      • Approximately one-half of patients with anxiety disorders have other mood disorders (typically dysthymia or depression) r53
    • 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 r54
    • Coronary artery disease c136
      • Risk of future cardiac events is 2 to 3 times higher in patients with coronary artery disease and depression compared with patients without depression r55
      • Depression has been shown to be an independent risk factor for mortality in cardiovascular disease, especially in patients with a heart failure diagnosis r56
    • Diabetes mellitus c137
      • Patients with diabetes and depression experience worse glycemic control and an increased risk of diabetic complications r55
    • Obesity c138
      • Depression-associated low motivation, poor adherence, negative thinking, fatigue, and sleep problems reduce the success of early-treatment weight loss programs r57
    • Hypertension c139
      • People with a diagnosis of depression have a higher incidence of hypertension than those in the general population r58
      • Antidepressants can affect blood pressure, and the individual effect can be highly variable with greater increases noted in older adults, those with higher baseline blood pressure, and those using antihypertensive therapy or with kidney disease r59
      • Selective serotonin reuptake inhibitors have a lower impact on blood pressure than other antidepressants r58
      • MAOIs, tricyclic antidepressants, and serotonin-norepinephrine reuptake inhibitors have a higher chance of increasing blood pressure r58r60

    Special populations

    • Pregnant patients d8
      • 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 r5
    • Postpartum patients d9
      • Postpartum depression is a major depressive episode with an onset of mood symptoms that occurs within 4 weeks of delivery
      • Individuals with histories of mood and anxiety disorders are particularly vulnerable to postpartum depression
      • Psychosocial therapies can benefit all patients. Drug therapy (generally with a selective serotonin reuptake inhibitor) is typically reserved for patients with severe depression, those who do not respond to nondrug therapy, or those desiring pharmacotherapy over psychotherapy
    • Children and adolescents r61
      • Depressive disorders are common in children and adolescents
      • Routine, regular screening with a validated screening instrument is recommended; Patient Health Questionnaire-2 or Patient Health Questionnaire-9 commonly used in primary care
      • Clinical interview (ie, when prompted by positive screening or other clinical suspicion) should inventory and assess depressive symptoms; diagnosis is based on DSM-5-TR diagnostic criteria
      • Based on symptom severity, clinicians can treat patients with antidepressants or refer to mental health specialists for ongoing treatment
      • Antidepressants increased the risk of suicidal thoughts and behavior during the first few months of treatment in children and adolescents with major depressive disorder in short-term studies; monitor closely for clinical worsening, suicidality, or unusual changes in behavior in children or adolescents started on antidepressant therapy
    • Older adults
      • Antidepressants pose greater risk for adverse events because of multiple medical comorbidities and drug-drug interactions in case of polypharmacy r62
      • Levomilnacipran and vilazodone have not received enough study to judge safety in older patients or in those with, or at high risk for, cardiovascular disease
    • Patients diagnosed with dementia
      • High-quality evidence does not support the use of pharmacologic treatment of depression in patients with dementia r62

    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 r29
    • 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
      • Relationship between suicidal ideation and lifetime suicide attempts is strongest at low, as opposed to high, levels of depression r23
    • 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 r26
      • 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
      • Burden of side effects that are present as early as 4 days post treatment predicts poorer treatment outcome and should be monitored closely r63
    • Untreated depression increases risk of self-inflicted injury or suicide

    Screening and Prevention

    Screening

    At-risk populations

    • US Preventive Services Task Force recommends screening for major depression in adults, including pregnant, postpartum, and older adults, and adolescents aged 12 to 18 years r12r64
    • American Academy of Pediatrics guidelines recommends annual screening for adolescent patients aged 12 years or older for depression with a formal self-report screening tool r65
    • US Department of Veterans Affairs recommends annual screening for major depression r14
    • 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 r66

    Screening tests

    • Depression inventory tools include the Patient Health Questionnaire-9, Center for Epidemiologic Studies Depression Scale, Beck Depression Inventory, Major Depression Inventory, Hamilton Depression Rating Scale, Geriatric Depression Scale, and the Edinburgh Postnatal Depression Scale. The Patient Health Questionnaire-2 is a widely used, abbreviated version of the Patient Health Questionnaire-9 developed specifically for screening r1r2r3r12r14c142c143c144c145c146
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