Major Depressive Disorder

History

• Patients do not always present with a straightforward complaint of feeling depressed ^r10
• Vague somatic complaints or numerous complaints that do not fit any clear clinical pattern often occur, particularly in older patients and in patients for whom psychological symptoms are stigmatized ^r10
  • Fatigue ^c1
  • Poor concentration ^c2
  • Memory impairment ^c3
  • Difficulty making day-to-day decisions ^c4
  • Decline in school or work performance ^c5c6
  • Decreased sexual interest ^c7
  • Sleep disturbance ^c8
  • Appetite changes ^c9
  • Weight changes (gain or loss) ^c10c11c12
  • Headache ^c13
  • Nausea ^c14
  • Pain ^c15
  • Change in bowel habits (constipation or diarrhea) ^c16c17c18
• Depressive symptoms ^r8
  • 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 ^r8
  • 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  • Appears withdrawn, with poor eye contact ^c32c33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 ^r10
  • Evidence of self harm (eg, healed lacerations, scars on body or extremities) ^c41c42c43
• Weight loss, weight gain, or evidence of poor nutrition ^r10c44c45c46

Causes

• Unknown ^c47

Risk factors and/or associations

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 ^{r1r3r10r12c56}
• History and physical examination provide definitive diagnosis ^c57
• 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 ^r13c58c59

Procedures

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" ^r12
  • Beck Depression Inventory ^r1c62
    • 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 ^r1c63
    • Observer-rated scale designed to be administered by the health care professional
  • Major Depression Inventory ^r2c64
    • Self-rated questionnaire
    • Incorporates both the ICD‐10 symptoms of depression and the DSM-IV symptoms of major depression
  • Patient Health Questionnaire-9 ^r3r14c65
    • Self-rated questionnaire with 9 items

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-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 ^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:
    • Alcohol ^c76c77d5
    • Stimulants (eg, amphetamine, cocaine) ^{c78c79c80c81c82c83d6}
    • Cannabis (with chronic use) ^c84c85
    • Opiates ^c86c87d7
    • Anabolic steroids ^c88c89
  • 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

Admission criteria ^r23

• 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

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. 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 ^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 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 ^c100
    • 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 ^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 the 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 the 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 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.
  • Vilazodone ^c103
    • 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 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 ^c104
    • 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.
• Serotonin-norepinephrine reuptake inhibitors ^c105
  • Desvenlafaxine ^c106
    • 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 ^c107
    • 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 ^c108
    • 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 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 ^c109
    • 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. Usual Max: 225 mg/day. Max: 375 mg/day.
• Noradrenergic and specific serotonin antidepressants ^c110
  • Mirtazapine ^c111
    • 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.
• Noradrenergic and dopaminergic antidepressants ^c112
  • Bupropion ^c113
    • 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.
• 5-HT2 receptor antagonists ^r5
  • 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 as needed based on clinical response. 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 as needed based on clinical response. 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 as needed based on clinical response. Gradually reduce dose once an adequate response has been achieved, with subsequent adjustment based on clinical response. Usual Max: 400 mg/day. Max: 600 mg/day.
• Tricyclic antidepressants ^c114
  • Amitriptyline ^c115
    • 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 ^c116
    • 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 ^c117
    • 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 ^c118
    • 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 ^c119
  • 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 ^c120
    • 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 ^c121
    • 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 ^c122
    • 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 ^c123
    • 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 ^c124
  • Esketamine ^r29r34c125
    • 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 ^r29
    • 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.
  • 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.

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 ^r14r25r35
• The 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 ^{r5r10r14r25r36r37}
• May be offered in individual or group format according to patient preference ^r25
• 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 ^r35r38
• Cognitive behavioral therapy administered after medication is withdrawn may impart a protective effect against relapse ^r39

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 ^r40c126

Acupuncture ^r41c127

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

Exercise ^r42c128

• Exercise has been shown to have significant effect in reducing depressive symptoms in patients with major depressive disorder,^r43 especially regular, moderate-level, aerobic exercise

Comorbidities

• Anxiety disorder ^c135
  • Approximately one-half of patients with anxiety disorders have other mood disorders (typically dysthymia or depression) ^r50
• Obsessive-compulsive disorder ^c136
  • Often produces additional depression symptoms
• Substance use disorder (eg, alcohol, opioids, amphetamine, cocaine, cannabis) ^c137
  • Associated with depression and suicide attempts
  • Impulsivity is heightened when under the influence of substances ^r51
• Coronary artery disease ^c138
  • Risk of future cardiac events is 2 to 3 times higher in patients with coronary artery disease and depression when compared to patients without depression ^r52
  • Depression has been shown to be an independent risk factor for mortality in cardiovascular disease, especially in patients with a heart failure diagnosis ^r53
• Diabetes mellitus ^c139
  • Patients with diabetes and depression experience worse glycemic control and an increased risk of diabetic complications ^r52
• Obesity ^c140
  • Depression-associated low motivation, poor adherence, negative thinking, fatigue, and sleep problems reduce the success of early-treatment weight loss programs ^r54
• Hypertension ^c141
  • People who carry a diagnosis of depression have a higher incidence of hypertension than those in the general population ^r55
  • 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 ^r56
  • Selective serotonin reuptake inhibitors have a lower impact on blood pressure than other antidepressants ^r55
  • Monoamine oxidase inhibitors, tricyclic antidepressants, and serotonin-norepinephrine reuptake inhibitors have a higher chance of increasing blood pressure ^r55r57

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
• Older adults
  • Antidepressants pose greater risk for adverse events because of multiple medical comorbidities and drug-drug interactions in case of polypharmacy ^r58
• Patients diagnosed with dementia
  • High-quality evidence does not support the use of pharmacologic treatment of depression in patients with dementia ^r58

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 ^r12r60
• American Academy of Pediatrics guidelines recommends screening adolescent patients aged 12 years and older annually for depression with a formal self-report screening tool ^r61
• US Department of Veterans Affairs recommends screening for major depression annually ^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 ^r62

Screening tests

• Depression screening inventory tests 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 ^{r1r2r12r14c144c145c146c147c148}