Major Depressive Disorder

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 ^[8]

Classification

• DSM-5-TR diagnostic criteria for major depressive disorder ^[8]

  • 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 ^[9]

• 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 ^[9]

  • Fatigue

  • Poor concentration

  • Memory impairment

  • Difficulty making day-to-day decisions

  • Decline in school or work performance

  • Decreased sexual interest

  • Sleep disturbance

  • Appetite changes

  • Weight changes (gain or loss)

  • Headache

  • Nausea

  • Pain

  • Change in bowel habits (constipation or diarrhea)

• Depressive symptoms ^[10]

  • Loss of interest or pleasure in previously enjoyable things

  • Disproportionate feelings of guilt or thoughts of worthlessness

  • Suicidal thoughts or thoughts about dying

  • Psychotic symptoms (particularly in older patients)

  • Anxiety and worry

  • Preoccupation with physical complaints

Physical examination

• Psychological findings

  • Depressed or flat affect

  • Appears withdrawn, with poor eye contact

  • Psychomotor agitation or retardation

  • Crying

  • Anxious behavior

  • Irritability

  • Evidence of self-neglect with poor personal hygiene

• Dermatologic findings ^[9]

  • Evidence of self harm (eg, healed lacerations, scars on body or extremities)

• Weight loss, weight gain, or evidence of poor nutrition ^[9]

Causes and Risk Factors

Causes

• Unknown

Risk factors and/or associations

Age

• Prevalence of major depressive disorder is greatest among younger adults ^[11]

Sex

• Major depressive disorder is more prevalent among women ^[11]

Genetics ^[9]

• Major depressive disorder is a multifactorial disorder with genetic susceptibility

  • Greatest risk for major depressive disorder is observed in families with early age at onset ^[9]

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 ^[11]

Other risk factors/associations ^[11]

• 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 ^{[1][3][9][12]}

• History and physical examination provide definitive diagnosis

• 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 ^[13]

Other diagnostic tools

• Standardized depression inventory tools

  • 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" ^[12]

  • Beck Depression Inventory ^[1]

    • 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 ^[1]

    • Observer-rated scale designed to be administered by the health care professional

  • Major Depression Inventory ^[2]

    • Self-rated questionnaire

    • Incorporates both the ICD‐10 symptoms of depression and the DSM-IV symptoms of major depression

  • Patient Health Questionnaire-9 ^[3][14]

    • Self-rated questionnaire with 9 items

  • Patient Health Questionnaire-2 ^[3][15]

    • 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 ^[16]

• Persistent depressive disorder (dysthymia)

  • 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 ^[17]

  • 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 ^[18]

    • 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 ^[19]

  • 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 ^[20]

  • 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 ^[21]

  • 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

  • Disorder that affects thoughts, feelings, and perceptions; primary symptom is psychosis with auditory hallucinations and delusions

  • Persons with schizophrenia may develop secondary major depression ^[17]

  • 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

  • Milder psychotic symptoms than schizophrenia with presence of mood disorder ^[17]

• Hypothyroidism ^[22]

  • 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

  • May cause symptoms of depression with chronic use or from withdrawal

  • Causative substances include:

    • Alcohol

    • Stimulants (eg, amphetamine, cocaine)

    • Cannabis (with chronic use)

    • Opiates

    • Anabolic steroids

  • 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 ^[14]

  • Drug classes that are known to produce symptoms similar to depression include:

    • Benzodiazepines

    • Steroids

    • Levodopa

    • Oral contraceptives

    • Interferon

  • Differentiated based on history and physical examination

Treatment

Goals

• Assess patient for suicidality and take steps to protect patient as needed ^[23]

• Reduce signs and symptoms, including residual symptoms ^[9][24][25]

• Relieve any complications (eg, malnutrition, substance use disorder) ^[14]

• Restore prior level of psychosocial and occupational function ^[14]

• Prevent relapse and recurrence ^[14]

Disposition

Admission criteria ^[25]

• 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 ^[5]

• 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 ^[5]

• 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 ^[5]

• 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: ^{[6][13][26][27]}

• 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 ^{[5][6][26][28]}

• Bupropion

• Mirtazapine

• Serotonin-norepinephrine reuptake inhibitors

• Selective serotonin reuptake inhibitors ^[29]

• 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 ^[30]

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 ^[6][28][31]

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 ^[32][33]

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: ^[6][26][31]

• Switching to another antidepressant

  • A different first line antidepressant agent or drug class ^[5]

  • A second line agent (eg, tricyclic antidepressants, monoamine oxidase inhibitors [MAOIs], nefazodone) ^[6]

    • 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) ^[34]

    • 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 ^[5]

  • Ketamine or esketamine nasal spray may be considered as an adjunct to an oral antidepressant in patients with treatment-resistant depression or with acute suicidal ideation ^[34][26]

• 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) ^[4]

  • For most patients, combination therapy (psychotherapy and medication) is more effective than either psychotherapy or antidepressant medication alone ^[6]

• 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 ^[6]

Consider electroconvulsive therapy for patients with any of the following: ^[6]

• Catatonia ^[4]

• Psychotic depression ^[4]

• Severe suicidality

• Previous good response to electroconvulsive therapy

• Need for rapid, definitive treatment for medical or psychiatric reasons (eg, lack of nutrition or fluid intake )^[4]

• 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 ^[27]

• 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 ^[5][6]

• 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 ^[5][27]

  • 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

  • Citalopram

    • 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

    • Escitalopram Oral solution; Children and Adolescents 12 to 17 years: 10 mg PO once daily, initially. May increase to 20 mg/day after at least 3 weeks, based on response and 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, based on response and tolerability. Usual dose: 10 mg/day. Max: 20 mg/day.

    • Escitalopram Oral tablet; Older Adults: 10 mg PO once daily.

  • Fluoxetine

    • 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

    • 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

    • 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

  • 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

    • 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

    • 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

    • 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

  • Mirtazapine

    • 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

  • Bupropion

    • 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 ^[6]

  • 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

    • 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

    • 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

  • Amitriptyline

    • 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

    • 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

    • 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

    • 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

  • Isocarboxazid

    • 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

    • 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

    • 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

    • 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

  • Esketamine ^[34][35]

    • 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 ^[4]

  • For all severities of depression, the most effective treatment is a combination of psychological interventions and pharmacotherapy ^[4]

• 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 ^[6][14][28]

• 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 ^{[6][9][14][26][36][37]}

• May be offered in individual or group format according to patient preference ^[26]

• 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 ^[14]

• Cognitive behavioral therapy administered concurrently with medication may increase the rate of patient response ^[38]

• Cognitive behavioral therapy administered after medication is withdrawn may impart a protective effect against relapse ^[39]

Digital health technologies

• Various digital interventions have been developed as adjuncts to pharmacotherapy and/or traditional psychotherapy for major depressive disorder ^[40]

• Several self-management applications have been shown to reduce depressive symptoms, as supported by randomized controlled trial data ^[40]

• 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 ^[41][42][43]

  • 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 ^[44]

Acupuncture ^[45]

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

Exercise ^[46]

• Exercise has been shown to have significant effect in reducing depressive symptoms in patients with major depressive disorder, especially regular, moderate-level, aerobic exercise^[47]

Procedures

Electroconvulsive therapy ^[48]

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 ^[6][28]

• 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 ^[49]

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: ^[50]

    • 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 ^[51]

  • Typical session lasts 30 to 60 minutes and does not require anesthesia ^[50]

Indication

• Treatment option for patients with major depression who have not responded to antidepressant drug therapy ^[6][28]

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 ^[52]

• Headache

• Scalp discomfort

• Seizures

Comorbidities

• Anxiety disorder

  • Approximately one-half of patients with anxiety disorders have other mood disorders (typically dysthymia or depression) ^[53]

• Obsessive-compulsive disorder

  • Often produces additional depression symptoms

• Substance use disorder (eg, alcohol, opioids, amphetamine, cocaine, cannabis)

  • Associated with depression and suicide attempts

  • Impulsivity is heightened when under the influence of substances ^[54]

• Coronary artery disease

  • Risk of future cardiac events is 2 to 3 times higher in patients with coronary artery disease and depression compared with patients without depression ^[55]

  • Depression has been shown to be an independent risk factor for mortality in cardiovascular disease, especially in patients with a heart failure diagnosis ^[56]

• Diabetes mellitus

  • Patients with diabetes and depression experience worse glycemic control and an increased risk of diabetic complications ^[55]

• Obesity

  • Depression-associated low motivation, poor adherence, negative thinking, fatigue, and sleep problems reduce the success of early-treatment weight loss programs ^[57]

• Hypertension

  • People with a diagnosis of depression have a higher incidence of hypertension than those in the general population ^[58]

  • 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 ^[59]

  • Selective serotonin reuptake inhibitors have a lower impact on blood pressure than other antidepressants ^[58]

  • MAOIs, tricyclic antidepressants, and serotonin-norepinephrine reuptake inhibitors have a higher chance of increasing blood pressure ^[58][60]

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 ^[6]

• Postpartum patients

  • 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 ^[61]

  • 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 ^[62]

  • 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 ^[62]

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 ^[29]

• 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

  • Relationship between suicidal ideation and lifetime suicide attempts is strongest at low, as opposed to high, levels of depression ^[23]

• Substance use disorder

Prognosis

• There is a high risk of relapse after a depressive episode, especially in the first 6 months; risk declines with time in remission ^[27]

  • 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 ^[63]

• 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 ^[12][64]

• 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 ^[65]

• US Department of Veterans Affairs recommends annual screening for major depression ^[14]

• 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 ^[66]

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 ^{[1][2][3][12][14]}