-
Suspected depression, awaiting dx
Acute safety risk, danger to self/others (eg, suicidal/homicidal) Assess acute safety risk @ initial assessment. Check PHQ-9, w/ special attention to last item: “thoughts that you would be better off dead or of hurting yourself in some way?” Assess homicidal ideation. Determine 1) whether pt has active plan & method/means (eg, weapons in home); 2) whom pt wishes to harm; 3) whether pt has ever lost control & acted violently; 4) seriousness/severity of violent hx Refer to emergent/inpt care for stabilization.1 Likelihood of lifetime suicide attempt ~5x greater for MDD pts;2 follow local, state, & federal regulations/mandates Perform diagnostic eval that incl:1 - Medical hx, incl relevant FHx, functional status, tx hx
- Physical exam. Focused exam as indicated by review of systems.3 R/O depression secondary to other causes (eg, hypothyroidism, vit B12 deficiency, syphilis, pain, chronic dz)1
- Labs. Test for secondary causes of MDD: Check TSH, CBC, chem profile, B12, pregnancy screen, tox panel as clinically indicated. Give ↑consideration to lab tests, esp if 1st major depressive episode occurs >40 yo, for older pts in general, if presence of sx that are rarely found in mood/anxiety disorders, or if depression doesn’t fully respond to routine tx3
- Measurement-based care (MBC). Incorporate MBC (eg, PHQ-9) in initial assessment
Eval per DSM-5 criteria; A, B, & C must be met for MDD dx:1,3 Criterion A: ≥5 present during same 2-wk period; ≥1 is either
depressed mood or loss of interest/pleasure:1
- Depressed mood most of day, nearly every day
- Diminished interest/pleasure in most activities, most of day, nearly every day
- Significant wt↓ (when not dieting) or wt↑
- Insomnia/hypersomnia nearly every day
- Psychomotor agitation/retardation nearly every day
- Fatigue/loss of energy every day
- Feelings of worthlessness or excessive inappropriate guilt
- Diminished ability to think, concentrate, or indecisiveness, nearly every day
- Recurrent thoughts of death, recurrent suicidal ideation w/o a specific plan, suicide attempt, or specific plan for committing suicide
Criterion B: Sx cause significant distress or functional impairment1 Criterion C: Episode not attributable to physiological effects of substance or another condition1 Consider alternative dx: - R/O persistent depressive disorder (aka dysthymia),2 subsyndromal depression, bipolar disorder (if misdiagnosed, antidepressants alone may destabilize pt),3 other specified depressive disorder, unspecified depressive disorder,3 anxiety/somatic conditions, etc3
- R/O secondary MDD causes:1,3 hypothyroidism,1,3 B12 deficiency, syphilis, pain,1 dementia, delirium, Parkinson dz, stroke, connective tissue dz,3 other chronic dz1,3
- Assess psychiatric comorbidities3 (substance use, anxiety, PTSD may ↑depression/complicate tx),1 ↓cognitive fxn, mania, hypomania
- Check drug use (esp sedatives, interferon alpha, varenicline),3 OTC, other psychoactive substances (eg, caffeine, nicotine)
If MDD dx confirmed, assess relapse/recurrence potential. Relapse=depressive sx return during same episode, ie, in acute (6-12wk) or continuation (4-9mo) phase. Recurrence=depressive sx return in new, distinct episode, ie, during maintenance phase (≥1y).4 Footnotes 1 VA 2022. VA/DoD Clinical Practice Guideline for the Management of Major Depressive Disorder. Last reviewed January 2021. Version 4.0. Department of Veterans Affairs. Department of Defense. February 2022. PDF
2 APA 2019. McQuaid JR, et al. Clinical Practice Guideline for the Treatment of Depression Across Three Age Cohorts. American Psychological Association. Feb 16, 2019. PDF
3 ICSI 2016. Trangle M, et al. Adult Depression in Primary Care. Health Care Guideline. Institute for Clinical Systems Improvement. Updated March 2016. PDF
4 ACP 2023. Qaseem A, et al. Nonpharmacologic and Pharmacologic Treatments of Adults in the Acute Phase of Major Depressive Disorder: A Living Clinical Guideline From the American College of Physicians. Ann Intern Med. 2023 Feb;176(2):239-252. Epub 2023 Jan 24. PubMed® abstract
Use PHQ-2 as initial depression screen or PHQ-9 (if MDD dx’d) to measure severity for initial tx planning/monitoring.1 If chronic medical illness (eg, hep C, chronic pain, post-MI), use PHQ-9 & maintain high index of suspicion.1 Dx MDD using DSM-5 criteria;1,2 assess recurrence/relapse potential.2 Depression prevalence 4x more common among US adults during COVID-19 pandemic vs 20193 If pt <65 yo not pregnant/postpartum: - Use routine screening: PHQ-2 score ≥3 suggests clinically significant depression & prompts PHQ-9 or clinical interview for MDD.1 Consider HADS + PHQ, per USPSTF;4 ICSI suggests considering additional tests: SCID-I, MINI, BDI, HAM-D, or QID-SR1
If pt pregnant/postpartum: - Screen @ 1st contact in antenatal & postnatal periods;2 screen pts at least once during perinatal period, per USPSTF.4 Repeat screen postpartum @ 4-6wk & 3-4mo after birth;2 @ infant’s 1-, 2-, & 4-mo visit4
- PHQ-2 score ≥3 suggests clinically significant depression & prompts completion of PHQ-9 (or Edinburgh Postnatal Depression Scale)1,4 or clinical interview to assess for MDD1
- Risk factors during pregnancy/postpartum incl poor self-esteem, child-care stress, prenatal anxiety, life stress, ↓social support, single/unpartnered relationship status, hx depression/postpartum depression, difficult infant temperament, lower socioeconomic status, unintended pregnancy;4 mood disorder hx, fragmented/poor sleep, substance use, past/current abuse, premorbid/gestational DM, difficulty breastfeeding 1st 2mo postpartum1
If pt ≥65 yo, identify depression independent of physical conditions2 for age: - PHQ-2 score ≥3 suggests clinically significant depression & prompts PHQ-9 or clinical interview to assess for MDD;1 or use PHQ-9; also consider Geriatric Depression Scale4
- If severe cognitive impairment: Use Cornell Scale for Depression in Dementia instead of PHQ-9, per ICSI1
- Risk factors in older adults incl disability, poor health status related to medical illness, complicated grief, chronic sleep disturbance, loneliness, depression hx4
Eval per DSM-5 criteria; A, B, & C must be met for MDD dx:1,2 Criterion A: ≥5 present during same 2-wk period; ≥1 is either depressed mood or loss of interest/pleasure:2 - Depressed mood most of day, nearly every day
- Diminished interest/pleasure in most activities, most of day, nearly every day
- Significant wt↓ (when not dieting) or wt↑
- Insomnia/hypersomnia nearly every day
- Psychomotor agitation/retardation nearly every day
- Fatigue/loss of energy every day
- Feelings of worthlessness or excessive inappropriate guilt
- Diminished ability to think, concentrate, or indecisiveness, nearly every day
- Recurrent thoughts of death, recurrent suicidal ideation w/o a specific plan, suicide attempt, or specific plan for committing suicide
Criterion B: Sx cause significant distress or functional impairment2 Criterion C: Episode not attributable to physiological effects of substance or another condition2 Consider alternative dx: - R/O persistent depressive disorder (aka dysthymia),5 subsyndromal depression, bipolar disorder (if misdiagnosed, antidepressants alone may destabilize pt),1 other specified depressive disorder, unspecified depressive disorder,1 anxiety/somatic conditions, etc1
- R/O secondary MDD causes:1,2 hypothyroidism,1,2 B12 deficiency, syphilis, pain,2 dementia, delirium, Parkinson dz, stroke, connective tissue dz,1 other chronic dz1,2
- Assess psychiatric comorbidities1 (substance use, anxiety, PTSD may ↑depression/complicate tx),2 ↓cognitive fxn, mania, hypomania
- Check drug use (esp sedatives, interferon alpha, varenicline),1 OTC, other psychoactive substances (eg, caffeine, nicotine)
If MDD dx confirmed, assess relapse/recurrence potential. Relapse=depressive sx return during same episode, ie, in acute (6-12wk) or continuation (4-9mo) phase. Recurrence=depressive sx return in new, distinct episode, ie, during maintenance phase (≥1y).6 Footnotes 1 ICSI 2016. Trangle M, et al. Adult Depression in Primary Care. Health Care Guideline. Institute for Clinical Systems Improvement. Updated March 2016. PDF
2 VA 2022. VA/DoD Clinical Practice Guideline for the Management of Major Depressive Disorder. Last reviewed January 2021. Version 4.0. Department of Veterans Affairs. Department of Defense. February 2022. PDF
3 CDC 2020. Mental Health, Substance Use, and Suicidal Ideation During the COVID-19 Pandemic – United States, June 24-30, 2020. 2020 Aug 14;69(32):1049-1057. MMWR Morb Mortal Wkly Rep. Accessed 10/7/20
4 USPSTF 2016. Siu AL, et al. Screening for Depression in Adults. US Preventive Services Task Force Recommendation Statement. JAMA. 2016. Jan 26;315(4):380-387. PDF
• Women, as well as young & middle-aged adults, have ↑rates of depression, as do undereducated, previously married, unemployed persons; Whites have ↓rates of depression compared w/ other racial/ethnic groups
• Pts w/ chronic illness, other mental health disorders, or FHx of psychiatric disorders are also at ↑risk
5 APA 2019. McQuaid JR, et al. Clinical Practice Guideline for the Treatment of Depression Across Three Age Cohorts. American Psychological Association. Feb 16, 2019. PDF
6 ACP 2023. Qaseem A, et al. Nonpharmacologic and Pharmacologic Treatments of Adults in the Acute Phase of Major Depressive Disorder: A Living Clinical Guideline From the American College of Physicians. Ann Intern Med. 2023 Feb;176(2):239-252. Epub 2023 Jan 24. PubMed® abstract
-
Mild/Moderate MDD (PHQ-9 ≤20) ≤2-yr duration, ≤2 episodes
Acute safety risk, danger to self/others (eg, suicidal/homicidal) Refer to emergent/inpt care for stabilization.1 Follow local, state, & federal regulations/mandates
Footnotes 1 VA 2022. VA/DoD Clinical Practice Guideline for the Management of Major Depressive Disorder. Last reviewed January 2021. Version 4.0. Department of Veterans Affairs. Department of Defense. February 2022. PDF
No acute safety risk: awaiting initial tx Age <65 yo, not pregnant/breastfeeding Offer either drug or psychotherapy as initial 1st-line tx for uncomplicated MDD—both equally efficacious.1-3 Psychotherapy preferred for subclinical sx.2 ICSI recommends psychotherapy + drug; if mono-tx used, psychotherapy preferred4 If neither drug nor psychotherapy acceptable, consider bright light tx, St. John’s wort,2,3 exercise,1,2 bibliotherapy, non-directive supportive tx, or psychodynamic tx3 If choosing drug as initial tx, offer 1st-line options: SSRI, SNRI;1-3 some groups incl bupropion, mirtazapine,1,3 nefazodone,1 trazodone, vilazodone, vortioxetine.1,3 VA/DoD does not recommend nefazodone as 1st-line tx because it’s assoc w/ ↑risk of hospitalizations resulting from liver toxicity vs other antidepressants.1 Evidence doesn’t favor one drug over another1-3 - Options. SSRIs: citalopram, escitalopram, fluoxetine, paroxetine, sertraline;1-3 but not fluvoxamine, per VA.3 SNRIs (start low dose):1-3 duloxetine, venlafaxine, desvenlafaxine, levomilnacipran. Atypical antidepressants: bupropion, mirtazapine,1,3 nefazodone,1 trazodone,1,3 vilazodone, vortioxetine1
- Consider factors: safety/side effect profile (eg, constipation, diarrhea, nausea, dizziness, insomnia, somnolence, sexual dysfxn), med list, drug interactions, cost, feasibility, pt-specific sx (insomnia, hypersomnia, fluctuation in appetite),1 anticholinergic effect, availability,2 prior tx response, chronicity, functional status, tolerability of prior tx,3 pt preference,1,3 dosing frequency. Consider impact on comorbid conditions1,3,4 (eg, certain drugs more favorable in CV dz;4 if smoking cessation desired, consider bupropion, but may worsen anxiety3)
- TCAs. Avoid tertiary amine TCAs d/t ↑orthostatic hypotension, sedation, cognitive problems, cardiac effects; but for moderate MDD, TCAs such as nortriptyline most effective4
- Counsel & advise. Caution pts to watch closely for worsening depression/unusual behavior, esp in 1st few wks of drug start or dose change; young adults <29 yo esp may have ↑suicidal thoughts/behavior on antidepressants5
- Monitor at least monthly after tx start/change until remission (ie, 2mo w/o sx).4 Once in remission, continue drug @ therapeutic dose ≥6mo to ↓relapse risk.3 ICSI recommends 4-9mo after remission achieved (ie, 6-12mo total). MDD relapses/recurrences occur in 50%-80% of pts on antidepressants long-term4
If choosing psychotherapy (CBT1 or non-CBT) as initial tx: Evidence doesn’t favor one type vs another.1-3 Pt preference guides use of CBT (as 1st-line or adjunctive tx)1 or individual vs group tx3 - 1st-line, evidence-based options: acceptance & commitment therapy, behavioral therapy/behavioral activation, cognitive behavioral therapy, cognitive therapy, interpersonal therapy, mindfulness-based cognitive therapy, problem-solving therapy, short-term psychodynamic psychotherapy
- If combining therapy w/ other tx: APA recommends CBT/interpersonal therapy + SGA2
- If COPD/DM: CBT valuable2
- If relationship distress: Offer couples-focused therapy;3 don’t use drug alone2
- Monitor at least monthly after tx start/change until remission (ie, 2mo w/o sx)4
Footnotes 1 ACP 2023. Qaseem A, et al. Nonpharmacologic and Pharmacologic Treatments of Adults in the Acute Phase of Major Depressive Disorder: A Living Clinical Guideline From the American College of Physicians. Ann Intern Med. 2023 Feb;176(2):239-252. Epub 2023 Jan 24. PubMed® abstract
• 2nd-gen antidepressants (SGAs): SSRIs, SNRIs, bupropion, mirtazapine, nefazodone, trazodone, vilazodone, vortioxetine.
• For mild MDD, ACP conditionally recommends mono-tx w/ CBT as initial tx in the acute phase (low-certainty evidence), but if CBT isn’t available/feasible, SGA mono-tx is a reasonable alternative approach. For mod to severe MDD, ACP strongly recommends mono-tx w/ either CBT or an SGA (mod-certainty evidence) & conditionally recommends combo tx w/ CBT + an SGA (low-certainty evidence).
Common Psychological Interventions to Treat Depression
• Cognitive behavioral therapy (CBT): aimed at identifying & modifying pt’s maladaptive thought processes & problematic behaviors through cognitive restructuring & behavioral techniques
• 3rd-wave CBT: focuses on mindfulness, emotions, acceptance, the therapist-pt relationship, values, goals, meta-cognition
• Psychodynamic therapies: focus on processes of change & development & place a premium on self-understanding & making meaning of what is unconscious
• Integrative therapy: selects theoretical models/techniques from various therapeutic schools to suit the pt’s particular problems
• Behavior therapy: applies the principles of learning & operant & classical conditioning to eliminate sx & modify ineffective/maladaptive behavior patterns
• Behavior modification: refers to the use of operant conditioning, biofeedback, modeling, aversion conditioning, reciprocal inhibition, or other techniques to change behavior; may be synonymous w/ behavior therapy
• Humanistic therapy: seeks to foster personal growth through direct experience & focuses on concrete personality change, responsibility for oneself, & trust in natural processes & spontaneous feeling
ACP 2024. Qaseem A, et al. Nonpharmacologic and Pharmacologic Treatments of Adults in the Acute Phase of Major Depressive Disorder: A Living Clinical Guideline From the American College of Physicians (Version 1, Update Alert 2). Ann Intern Med. 2024 Jul 16. Online ahead of print. Free, full-text article
2 APA 2019. McQuaid JR, et al. Clinical Practice Guideline for the Treatment of Depression Across Three Age Cohorts. American Psychological Association. Feb 16, 2019. PDF
3 VA 2022. VA/DoD Clinical Practice Guideline for the Management of Major Depressive Disorder. Last reviewed January 2021. Version 4.0. Department of Veterans Affairs. Department of Defense. February 2022. PDF
• Light therapy. Offer to pts w/ mild to mod MDD
• Bupropion. Consider for pts who desire smoking cessation. Contraindicated in pts w/ sz disorder, hx anorexia nervosa/bulimia, & can worsen anxiety
• Mirtazapine. Avoid if wt↑ or sedation is of concern
• Fluvoxamine not FDA approved for MDD
• St. John’s wort. Most commonly studied extracts were standardized to hypericin (0.1%-0.3%) or hyperforin (1%-6%); dosages ranged from 500 to 1,800 mg/day. But it’s commonly given tid, starting at 900 mg/day. Caution regarding herb-drug interactions; in combo with SSRIs or other serotonergic agents, ↑risk of serotonin syndrome
4 ICSI 2016. Trangle M, et al. Adult Depression in Primary Care. Health Care Guideline. Institute for Clinical Systems Improvement. Updated March 2016. PDF
• If cardiovascular or cerebrovascular dz: SSRIs, sertraline, & citalopram 1st line; may improve coronary heart dz prognosis & have more benign CV profile
5 USPSTF 2016. Siu AL, et al. Screening for Depression in Adults. US Preventive Services Task Force Recommendation Statement. JAMA. 2016. Jan 26;315(4):380-387. PDF
Refer for psychotherapy as 1st-line tx; evidence doesn’t favor one specific psychotherapy type vs another;1-3 however, Am Psychological Assn says to consider group Life-Review/CBT (alone or w/ usual care) or drug + interpersonal therapy combo in older pts.2 ICSI recommends psychotherapy + drug; if mono-tx used, psychotherapy preferred4 If neither psychotherapy nor drug acceptable, consider bright light tx, St. John’s wort,2,3 exercise,1,2 bibliotherapy,3 non-directive supportive tx, or psychodynamic tx3 If choosing psychotherapy, pt preference guides individual vs group model:3 - 1st-line, evidence-based options: acceptance & commitment therapy, behavioral therapy/behavioral activation, cognitive behavioral therapy, cognitive therapy, interpersonal therapy, mindfulness-based cognitive therapy, problem-solving therapy,1,3 short-term psychodynamic psychotherapy3
- If combining therapy w/ other tx: APA recommends interpersonal therapy + SGA in older adults vs interpersonal therapy alone; APA cautions against use of nortriptyline in older adults2
- If depression hx: Offer drug + either interpersonal therapy or supportive care2
- If cognitive impairment, psychotherapy limited:4 Offer (individual) problem-solving or related tx2
- If HIV: Consider group coping-improvement therapy, per APA2
- If COPD/DM: CBT valuable2
- If relationship distress: Offer couples-focused therapy;3 don’t use drug alone2
- Monitor at least monthly after tx start/change until remission (ie, 2mo w/o sx)4
If choosing drug as initial tx, offer 1st-line options: SSRI, SNRI;1-3 some groups incl bupropion, mirtazapine,1,3 nefazodone,1 trazodone, vilazodone, vortioxetine1,3. VA/DoD does not recommend nefazodone as 1st-line tx because it’s assoc w/ ↑risk of hospitalizations resulting from liver toxicity vs other antidepressants.3 Evidence doesn’t favor one drug over another1-3 - Options. SSRIs: citalopram, escitalopram, paroxetine, sertraline;1-3 but not fluvoxamine/fluoxetine, per VA.3 SNRIs (start low dose):1-3 duloxetine, venlafaxine, desvenlafaxine, levomilnacipran. Atypical antidepressants: bupropion, mirtazapine,1,3 nefazodone,1 trazodone,1,3 vilazodone, vortioxetine1
- Consider factors: safety/side effect profile (eg, constipation, diarrhea, nausea, dizziness, insomnia, somnolence, sexual dysfxn,1 ↑risk of upper GI bleeding, esp w/ SSRIs, in adults >70 yo, w/ risk ↑ w/ age5), med list, drug interactions, cost, feasibility, pt-specific sx (insomnia, hypersomnia, fluctuation in appetite),1 anticholinergic effect, availability,2 prior tx response, chronicity, functional status, tolerability of prior tx,3 pt preference,1,3 potential polypharmacy risk,4 dosing frequency. Consider impact on comorbid conditions1,3,4 (eg, any declining liver/kidney fxn; certain drugs more favorable in CV dz;4 if smoking cessation desired, consider bupropion, but may worsen anxiety3)
- TCAs. Avoid tertiary amine TCAs d/ to ↑incidence of orthostatic hypotension, sedation, cognitive problems, cardiac effects;4 APA specifically recommends avoiding nortriptyline in older adults2
- Counsel & advise. Caution pts to watch closely for worsening depression/unusual behavior, esp in 1st few wks of drug start or dose change
- Monitor at least monthly after tx start/change until remission (ie, 2mo w/o sx).4 Once in remission, continue drug @ therapeutic dose ≥6mo to ↓relapse risk.3 ICSI recommends 4-9mo after remission achieved (ie, 6-12mo total). MDD relapses/recurrences occur in 50%-80% of pts on antidepressants long-term4
Footnotes 1 ACP 2023. Qaseem A, et al. Nonpharmacologic and Pharmacologic Treatments of Adults in the Acute Phase of Major Depressive Disorder: A Living Clinical Guideline From the American College of Physicians. Ann Intern Med. 2023 Feb;176(2):239-252. Epub 2023 Jan 24. PubMed® abstract
• 2nd-gen antidepressants (SGAs): SSRIs, SNRIs, bupropion, mirtazapine, nefazodone, trazodone, vilazodone, vortioxetine.
• For mild MDD, ACP conditionally recommends mono-tx w/ CBT as initial tx in the acute phase (low-certainty evidence), but if CBT isn’t available/feasible, SGA mono-tx is a reasonable alternative approach. For mod to severe MDD, ACP strongly recommends mono-tx w/ either CBT or an SGA (mod-certainty evidence) & conditionally recommends combo tx w/ CBT + an SGA (low-certainty evidence).
Common Psychological Interventions to Treat Depression
• Cognitive behavioral therapy (CBT): aimed at identifying & modifying pt’s maladaptive thought processes & problematic behaviors through cognitive restructuring & behavioral techniques
• 3rd-wave CBT: focuses on mindfulness, emotions, acceptance, the therapist-pt relationship, values, goals, meta-cognition
• Psychodynamic therapies: focus on processes of change & development & place a premium on self-understanding & making meaning of what is unconscious
• Integrative therapy: selects theoretical models/techniques from various therapeutic schools to suit the pt’s particular problems
• Behavior therapy: applies the principles of learning & operant & classical conditioning to eliminate sx & modify ineffective/maladaptive behavior patterns
• Behavior modification: refers to the use of operant conditioning, biofeedback, modeling, aversion conditioning, reciprocal inhibition, or other techniques to change behavior; may be synonymous w/ behavior therapy
• Humanistic therapy: seeks to foster personal growth through direct experience & focuses on concrete personality change, responsibility for oneself, & trust in natural processes & spontaneous feeling
ACP 2024. Qaseem A, et al. Nonpharmacologic and Pharmacologic Treatments of Adults in the Acute Phase of Major Depressive Disorder: A Living Clinical Guideline From the American College of Physicians (Version 1, Update Alert 2). Ann Intern Med. 2024 Jul 16. Online ahead of print. Free, full-text article
2 APA 2019. McQuaid JR, et al. Clinical Practice Guideline for the Treatment of Depression Across Three Age Cohorts. American Psychological Association. Feb 16, 2019. PDF
3 VA 2022. VA/DoD Clinical Practice Guideline for the Management of Major Depressive Disorder. Last reviewed January 2021. Version 4.0. Department of Veterans Affairs. Department of Defense. February 2022. PDF
• Light therapy. Offer to pts w/ mild to mod MDD
• Bupropion. Consider for pts who desire smoking cessation. Contraindicated in pts w/ sz disorder, hx anorexia nervosa/bulimia, & can worsen anxiety
• Mirtazapine. Avoid if wt↑ or sedation is of concern
• Fluvoxamine not FDA approved for MDD
• Fluoxetine has a long half-life and may not be the best SSRI in older pts
• St. John’s wort. Most commonly studied extracts were standardized to hypericin (0.1%-0.3%) or hyperforin (1%-6%); dosages ranged from 500 to 1,800 mg/day. But it’s commonly given tid, starting at 900 mg/day. Caution regarding herb-drug interactions; in combo with SSRIs or other serotonergic agents, ↑risk of serotonin syndrome
4 ICSI 2016. Trangle M, et al. Adult Depression in Primary Care. Health Care Guideline. Institute for Clinical Systems Improvement. Updated March 2016. PDF
• If cardiovascular or cerebrovascular dz: SSRIs, sertraline, & citalopram 1st line; may improve coronary heart dz prognosis & have more benign CV profile
5 USPSTF 2016. Siu AL, et al. Screening for Depression in Adults. US Preventive Services Task Force Recommendation Statement. JAMA. 2016. Jan 26;315(4):380-387. PDF
If no MDD hx prior to pregnancy: Refer for psychotherapy as 1st-line tx; evidence doesn’t favor one specific psychotherapy type vs another.1-3 If pregnant pt had MDD hx prior to pregnancy, responded to antidepressant meds, & is stable on pharma-co tx: Weigh risk/benefit to both pt & fetus in continuing pharmaco-tx.3 ICSI recommends psychotherapy + drug; if mono-tx used, psychotherapy preferred4 If neither psychotherapy nor drug acceptable, consider bright light tx,2,3 St. John’s wort,2 exercise,1,2 bibliotherapy,3 non-directive supportive tx, or psychodynamic tx3 If choosing psychotherapy, pt preference guides individual vs group model:3 - 1st-line, evidence-based options: acceptance & commitment therapy, behavioral therapy/behavioral activation, cognitive behavioral therapy, cognitive therapy, interpersonal therapy, mindfulness-based cognitive therapy, problem-solving therapy,1,3 short-term psychodynamic psychotherapy3
- If combining therapy w/ other tx: APA recommends CBT/interpersonal therapy + SGA2
- If relationship distress: Offer couples-focused therapy;3 don’t use drug alone2
- If COPD/DM: CBT valuable2
- Monitor at least monthly after tx start/change until remission (ie, 2mo w/o sx)4
If choosing drug as initial tx, offer 1st-line options: SSRI, SNRI;1-3 some groups incl bupropion, mirtazapine,1,3 nefazodone,1 trazodone, vilazodone, vortioxetine.1,3 VA/DoD does not recommend nefazodone as 1st-line tx because it’s assoc w/ ↑risk of hospitalizations resulting from liver toxicity vs other antidepressants.3 Evidence doesn’t favor one drug over another1-3 - Options. SSRIs: citalopram, escitalopram, sertraline;1-3 but not fluvoxamine/fluoxetine, per VA.3 SNRIs (start low dose):1-3 duloxetine, venlafaxine, desvenlafaxine, levomilnacipran. Atypical antidepressants: bupropion,1 mirtazapine,1,3 nefazodone,1 trazodone,1,3 vilazodone, vortioxetine1
- Consider safety/side effect profile (eg, constipation, diarrhea, nausea, dizziness, insomnia, somnolence, sexual dysfxn1); SGA use during pregnancy may be assoc w/ small ↑risk of preeclampsia, postpartum hemorrhage, miscarriage, perinatal death, preterm birth, serotonin withdrawal syndrome, resp distress, pulm hypertension, major & cardiac malformations, & newborn small for gestational age (per observational evidence);5 fluoxetine has long half-life & may not be best in pregnancy, pts planning to breastfeed;3 paroxetine not recommended as 1st-line tx; assoc w/ ↑risk of major & cardiac malformations, unless pt already on paroxetine & has planned pregnancy. Weigh risks of paroxetine against d/c risks4
- Consider also med list, drug interactions, cost, feasibility, pt-specific sx (insomnia, hypersomnia, fluctuation in appetite),1 anticholinergic effect, availability,2 prior tx response, chronicity, functional status, tolerability of prior tx,3 pt preference,1,3 dosing frequency. Consider impact on comorbid conditions3,4 (certain drugs more favorable in CV dz;4 if smoking cessation desired, consider bupropion, but may worsen anxiety3)
- TCAs. Avoid tertiary amine TCAs d/t ↑incidence of orthostatic hypotension, sedation, cognitive problems, cardiac effects, but for moderate MDD, TCAs such as nortriptyline most effective4
- Counsel & advise. Caution pts to watch closely for worsening depression/unusual behavior, esp in 1st few wks of drug start or dose change
- Monitor at least monthly after tx start/change until remission (ie, 2mo w/o sx).4 Once in remission, continue drug @ therapeutic dose ≥6mo to ↓relapse risk.3 ICSI recommends 4-9mo once remission achieved (ie, 6-12mo total). MDD relapses/recurrences occur in 50%-80% of pts on antidepressants long-term4
Footnotes 1 ACP 2023. Qaseem A, et al. Nonpharmacologic and Pharmacologic Treatments of Adults in the Acute Phase of Major Depressive Disorder: A Living Clinical Guideline From the American College of Physicians. Ann Intern Med. 2023 Feb;176(2):239-252. Epub 2023 Jan 24. PubMed® abstract
• 2nd-gen antidepressants (SGAs): SSRIs, SNRIs, bupropion, mirtazapine, nefazodone, trazodone, vilazodone, vortioxetine.
• For mild MDD, ACP conditionally recommends mono-tx w/ CBT as initial tx in the acute phase (low-certainty evidence), but if CBT isn’t available/feasible, SGA mono-tx is a reasonable alternative approach. For mod to severe MDD, ACP strongly recommends mono-tx w/ either CBT or an SGA (mod-certainty evidence) & conditionally recommends combo tx w/ CBT + an SGA (low-certainty evidence).
Common Psychological Interventions to Treat Depression
• Cognitive behavioral therapy (CBT): aimed at identifying & modifying pt’s maladaptive thought processes & problematic behaviors through cognitive restructuring & behavioral techniques
• 3rd-wave CBT: focuses on mindfulness, emotions, acceptance, the therapist-pt relationship, values, goals, meta-cognition
• Psychodynamic therapies: focus on processes of change & development & place a premium on self-understanding & making meaning of what is unconscious
• Integrative therapy: selects theoretical models/techniques from various therapeutic schools to suit the pt’s particular problems
• Behavior therapy: applies the principles of learning & operant & classical conditioning to eliminate sx & modify ineffective/maladaptive behavior patterns
• Behavior modification: refers to the use of operant conditioning, biofeedback, modeling, aversion conditioning, reciprocal inhibition, or other techniques to change behavior; may be synonymous w/ behavior therapy
• Humanistic therapy: seeks to foster personal growth through direct experience & focuses on concrete personality change, responsibility for oneself, & trust in natural processes & spontaneous feeling
ACP 2024. Qaseem A, et al. Nonpharmacologic and Pharmacologic Treatments of Adults in the Acute Phase of Major Depressive Disorder: A Living Clinical Guideline From the American College of Physicians (Version 1, Update Alert 2). Ann Intern Med. 2024 Jul 16. Online ahead of print. Free, full-text article
2 APA 2019. McQuaid JR, et al. Clinical Practice Guideline for the Treatment of Depression Across Three Age Cohorts. American Psychological Association. Feb 16, 2019. PDF
3 VA 2022. VA/DoD Clinical Practice Guideline for the Management of Major Depressive Disorder. Last reviewed January 2021. Version 4.0. Department of Veterans Affairs. Department of Defense. February 2022. PDF
• Light therapy. Offer to pts w/ mild to mod MDD
• Bupropion. Consider for pts who desire smoking cessation. Contraindicated in pts w/ sz disorder, hx anorexia nervosa/bulimia, & can worsen anxiety
• Mirtazapine. Avoid if wt↑ or sedation is of concern
• Fluvoxamine not FDA approved for MDD
• Fluoxetine has long half-life & may not be best in pregnancy, pts planning to breastfeed
• St. John’s wort shouldn’t be used in pregnant/breastfeeding pts, d/t the lack of safety data in these populations
4 ICSI 2016. Trangle M, et al. Adult Depression in Primary Care. Health Care Guideline. Institute for Clinical Systems Improvement. Updated March 2016. PDF
• If cardiovascular or cerebrovascular dz: SSRIs, sertraline, & citalopram 1st line; may improve coronary heart dz prognosis & have more benign CV profile
5 USPSTF 2016. Siu AL, et al. Screening for Depression in Adults. US Preventive Services Task Force Recommendation Statement. JAMA. 2016. Jan 26;315(4):380-387. PDF
No acute safety risk: partial/non-response to initial tx If partial or no response to initial tx1 (after >4-6wk tx2), eval for specialty mental health care.2 If pt doesn't need specialty mental health care, either switch to a different single tx (either a drug or psychotherapy, regardless of initial tx)1,2 or augment w/ adjunctive psychotherapy or 2nd med.1-3 Combining 2 antidepressants is nonpreferred, given ↑potential for drug-drug interactions & adverse effects & lack of clinical benefit2 If changing or adding drug(s): - Prefer mono-tx w/ 1st-line antidepressants vs combo tx w/ 2 antidepressants2
- Bupropion contraindicated in pts w/ sz disorder, hx of anorexia nervosa, or bulimia. May ↑anxiety2
- Buspirone: Dose bid or tid, start @ 15 mg/day x1wk, increase to 30 mg/day x1-2wk, then 45 mg/day at wk 4. Max dose: 60 mg/day; 2-4wk for efficacy2
- Lithium: Monitor blood levels (therapeutic level 0.6-<1.0 mEq/L. Potentially toxic >1.5 mEq/L)2
- If hypothyroid, consider liothyronine (synthetic T3): 50 mcg/day, per VA;2 25-50 mcg/day, per ICSI.4 Caution in pts w/ CV dz, arrhythmias, DM, renal impairment, untreated adrenal insufficiency2
- Mirtazapine used in combo w/ SSRI may speed response4
- TCA: If used, monitor side effects & consider checking blood levels. SSRIs ↑TCA levels4
- If other strategies failed d/t significant side effects,4 consider atypical antipsychotics. Monitor glucose, CBC, hepatic panel, lipid panel, BMI, waist circumference, BP, involuntary movements/tardive dyskinesia;2 aripiprazole: Monitor for akathisia, wt↑, fatigue;2,4 quetiapine-XR: Monitor for wt↑ & sedation. Monitor w/ slit lamp exam; olanzapine/fluoxetine: olanzapine approved only for acute tx-resistant MDD when used in combo w/ fluoxetine. Monitor for wt↑ & sedation2
If psychotherapy & pharma-co tx options are ineffective/unacceptable, consider the following options for managing mild/mod MDD:1 - Exercise mono-tx.
- St. John’s wort (Hypericum perforatum) mono-tx. Avoid if pregnant/breastfeeding.2 Adverse effects: mild GI sx, skin reactions, dizziness, confusion, etc; consider herb-drug interactions, esp w/ antidepressants, warfarin, oral contraceptives, antiretroviral, anti-cancer, & anti-rejection drugs; ask pts what meds they are taking, incl OTC/supplements, to avoid these interactions4
Self-help/CAM to consider as adjuncts/alternatives: - Acupuncture. Consider adding acupuncture to antidepressant meds if psychotherapy, pharmaco-tx, exercise, St. John’s wort mono-tx aren’t acceptable/available, per APA;1 VA says insufficient evidence for acupuncture as adjunct;2 APA says insufficient evidence for acupuncture as mono-tx1
- Biofeedback. Insufficient evidence to recommend for or against as adjunct tx2
- Bright light tx. Offer for mild/mod MDD, w/ or w/o a seasonal pattern, as adjunct, or as alternative if 1st-line treatments aren’t acceptable/available;2,4 APA suggests considering bright light tx only if psychotherapy, pharmaco-tx, exercise, or St. John’s wort mono-tx aren’t acceptable/available1
- CBT-based bibliotherapy suggested as adjunct/alternative tx2
- Exercise (eg, yoga, tai chi, qigong, resistance, aerobics) suggested as adjunct2
- Meditation.3 Insufficient evidence to compare SGAs w/ meditation (or yoga, per ACP)3
- Omega-3 fatty acids. Insufficient evidence to recommend as mono-tx or combo tx (SGA + omega-3 fatty acids), per APA and ACP;1,3 VA recommends against use of omega-3 fatty acids for tx2
- Yoga. Consider if psychotherapy, pharmaco-tx, exercise, St. John’s wort not acceptable/available, per APA;1 effective adjunctive tx to ↓sx severity, per ICSI;4 insufficient evidence to compare SGAs w/ yoga (or meditation, per ACP)3
- Insufficient evidence to recommend for/against theta-burst stimulation,2 S-adenosyl-L-methionine (SAMe) mono-tx, tai chi1
- Not recommended: VNS/DBS; psilocybin, MDMA, cannabis, & other unapproved pharmacologic treatments; vitamin D supplements2
Footnotes 1 APA 2019. McQuaid JR, et al. Clinical Practice Guideline for the Treatment of Depression Across Three Age Cohorts. American Psychological Association. Feb 16, 2019. PDF
Psychotherapies to Treat Depression (w/ Comparable Effects)
• Behavioral therapy
• Cognitive, cognitive behavioral (CBT), & mindfulness-based cognitive behavioral therapy (MBCT)
• Interpersonal psychotherapy (IPT): focuses on relationships
• Psychodynamic therapies
• Supportive therapy
2 VA 2022. VA/DoD Clinical Practice Guideline for the Management of Major Depressive Disorder. Last reviewed January 2021. Version 4.0. Department of Veterans Affairs. Department of Defense. February 2022. PDF
• Light therapy. Offer to pts w/ mild to mod MDD
• Bupropion. Consider for pts who desire smoking cessation. Contraindicated in pts w/ sz disorder, hx anorexia nervosa/bulimia, & can worsen anxiety
• Mirtazapine. Avoid if wt↑ or sedation is of concern
• Fluvoxamine not FDA approved for MDD
• Fluoxetine has long half-life & may not be best in pregnancy, pts planning to breastfeed
• St. John’s wort. Most commonly studied extracts were standardized to hypericin (0.1%-0.3%) or hyperforin (1%-6%); dosages ranged from 500 to 1,800 mg/day. But it’s commonly given tid, starting at 900 mg/day. Caution regarding herb-drug interactions; in combo with SSRIs or other serotonergic agents, ↑risk of serotonin syndrome
3 ACP 2023. Qaseem A, et al. Nonpharmacologic and Pharmacologic Treatments of Adults in the Acute Phase of Major Depressive Disorder: A Living Clinical Guideline From the American College of Physicians. Ann Intern Med. 2023 Feb;176(2):239-252. Epub 2023 Jan 24. PubMed® abstract
• 2nd-gen antidepressants (SGAs): SSRIs, SNRIs, bupropion, mirtazapine, nefazodone, trazodone, vilazodone, vortioxetine.
• For mild MDD, ACP conditionally recommends mono-tx w/ CBT as initial tx in the acute phase (low-certainty evidence), but if CBT isn’t available/feasible, SGA mono-tx is a reasonable alternative approach. For mod to severe MDD, ACP strongly recommends mono-tx w/ either CBT or an SGA (mod-certainty evidence) & conditionally recommends combo tx w/ CBT + an SGA (low-certainty evidence).
Common Psychological Interventions to Treat Depression
• Cognitive behavioral therapy (CBT): aimed at identifying & modifying pt’s maladaptive thought processes & problematic behaviors through cognitive restructuring & behavioral techniques
• 3rd-wave CBT: focuses on mindfulness, emotions, acceptance, the therapist-pt relationship, values, goals, meta-cognition
• Psychodynamic therapies: focus on processes of change & development & place a premium on self-understanding & making meaning of what is unconscious
• Integrative therapy: selects theoretical models/techniques from various therapeutic schools to suit the pt’s particular problems
• Behavior therapy: applies the principles of learning & operant & classical conditioning to eliminate sx & modify ineffective/maladaptive behavior patterns
• Behavior modification: refers to the use of operant conditioning, biofeedback, modeling, aversion conditioning, reciprocal inhibition, or other techniques to change behavior; may be synonymous w/ behavior therapy
• Humanistic therapy: seeks to foster personal growth through direct experience & focuses on concrete personality change, responsibility for oneself, & trust in natural processes & spontaneous feeling
ACP 2024. Qaseem A, et al. Nonpharmacologic and Pharmacologic Treatments of Adults in the Acute Phase of Major Depressive Disorder: A Living Clinical Guideline From the American College of Physicians (Version 1, Update Alert 2). Ann Intern Med. 2024 Jul 16. Online ahead of print. Free, full-text article
4 ICSI 2016. Trangle M, et al. Adult Depression in Primary Care. Health Care Guideline. Institute for Clinical Systems Improvement. Updated March 2016. PDF
• If cardiovascular or cerebrovascular dz: SSRIs, sertraline, & citalopram 1st line; may improve coronary heart dz prognosis & have more benign CV profile
-
Severe/Complex MDD (PHQ-9 >20) or >2-yr duration or ≥2 episodes
Acute safety risk, danger to self/others (eg, suicidal/homicidal) Refer to emergent/inpt care for stabilization; offer ECT w/ or w/o psychotherapy if pt meets ECT criteria;1 follow local, state, & federal regulations/mandates Offer ECT w/ or w/o psychotherapy if pt meets any of the following:1 - Catatonia1,2
- Psychotic depression1,2
- Melancholic sx predominant2
- Depression in Parkinsonism2
- Severe suicidality1,2
- Hx of good response to ECT1,2
- Strong pt preference for ECT2
- Evinces need for rapid, definitive tx response on medical/psychiatric grounds1
- Risks from other tx outweigh risk from ECT. Although some co-occurring medical conditions may make ECT the safer option, these ↑ECT risks: recent MI, intracerebral hemorrhage, current MAOI use, retinal detachment1
- Hx of poor response or intolerable side effects to multiple antidepressants;1 hx ↑response/remission rates w/ ECT vs any other form of tx2
- Geriatric depression2
- Pregnancy: Strongly consider ECT in pregnant pts w/ severe sx of mental illness (psychosis, catatonia, or strong suicidal urges); risks of adverse events are low2
Footnotes 1 VA 2022. VA/DoD Clinical Practice Guideline for the Management of Major Depressive Disorder. Last reviewed January 2021. Version 4.0. Department of Veterans Affairs. Department of Defense. February 2022. PDF
Severe MDD Sx
• Active suicidal ideation w/ either intent or plan, or suicide attempt
• Active homicidal ideation
• Psychotic sx
• Severe anorexic sx (incl wt loss that poses health risk)
• Inability to maintain ADLs (eg, grooming, eating, catatonia)
2 ICSI 2016. Trangle M, et al. Adult Depression in Primary Care. Health Care Guideline. Institute for Clinical Systems Improvement. Updated March 2016. PDF
No acute safety risk, no danger to self/others Hx tx-resistant MDD (ie, after ≥2 adequate drug trials) Refer tx-resistant pts1 to mental health specialist. Offer ECT w/ or w/o psychotherapy if pt meets any of the following:1 - Catatonia1,2
- Psychotic depression1,2
- Melancholic sx predominant2
- Depression in Parkinsonism2
- Hx of good response to ECT1,2
- Strong pt preference for ECT2
- Evinces need for rapid, definitive tx response on medical/psychiatric grounds1
- Risks from other tx outweigh risk from ECT. Although some co-occurring medical conditions may make ECT the safer option, these ↑ECT risks: recent MI, intracerebral hemorrhage, retinal detachment1
- Hx of poor response or intolerable side effects to multiple antidepressants;1 hx ↑response/remission rates w/ ECT vs any other form of tx2
- Geriatric depression2
- Pregnancy: Strongly consider ECT in pregnant pts w/ severe sx of mental illness (psychosis, catatonia, or strong suicidal urges); risks of adverse events are low2
Footnotes 1 VA 2022. VA/DoD Clinical Practice Guideline for the Management of Major Depressive Disorder. Last reviewed January 2021. Version 4.0. Department of Veterans Affairs. Department of Defense. February 2022. PDF
Severe MDD Sx
• Active suicidal ideation w/ either intent or plan, or suicide attempt
• Active homicidal ideation
• Psychotic sx
• Severe anorexic sx (incl wt loss that poses health risk)
• Inability to maintain ADLs (eg, grooming, eating, catatonia)
Tx resistance = at least 2 adequate tx trials & lack of full response to each
2 ICSI 2016. Trangle M, et al. Adult Depression in Primary Care. Health Care Guideline. Institute for Clinical Systems Improvement. Updated March 2016. PDF
Refer tx-resistant1 pts to mental health specialist for other pharmaco-tx options, incl MAOIs/TCAs, or repetitive transcranial magnetic stimulation (rTMS), per VA;1 ICSI says to combine drugs w/ therapy, notes that MAOIs may be particularly effective for MDD pts w/ atypical features who don’t respond to other tx.2 Pregnant pts1,2 warrant special consideration. If MDD hx prior to pregnancy, response to antidepressant meds, & stable on pharma-co tx: Weigh risk/benefit to both pt & fetus in continuing to offer pharmaco-tx.1 If pt ≥65 yo: TCAs such as nortriptyline most effective;2 however, APA specifically recommends avoiding nortriptyline in older adults4 Modify tx as needed - Offer MAOI or TCA factoring safety considerations; provide pt ed on safety & side effects;1 per ICSI, use combined psychotherapy + pharmaco-tx as 1st line; if unable to combine these treatments, start w/ pharmaco-tx alone;2 avoid MAOIs in pregnancy/breastfeeding; weigh risk/benefit of TCAs during pregnancy; may use amitriptyline, clomipramine, desipramine, imipramine, nortriptyline while breastfeeding, but avoid doxepin & weigh risk/benefit for amoxapine, protriptyline, trimipramine
- Offer rTMS but not VNS/DBS, per VA;1 consider VNS/rTMS, MST, DBS, EMDR, per ICSI2
- Consider olanzapine, approved only for acute tx-resistant MDD when used in combo w/ fluoxetine1
- Ketamine/esketamine suggested as augmentation option in pts who haven’t responded to several adequate pharmacologic trials1,2
- Nefazodone: ↑risk of hepatotoxicity-related hospitalization vs other antidepressants1
Assess recurrence/relapse risk. Consider as potentially high risk if either of these:1 - ≥2 prior episodes
- Unstable remission status
After tx initiation/change, monitor at regular intervals; offer psychotherapy to ↓relapse risk1 - Once in remission, continue antidepressant drug @ therapeutic dose ≥6mo to ↓relapse risk; if high recurrence risk, offer maintenance pharmaco-tx for ≥12mo or indefinitely1
- After remission achieved, offer cognitive behavioral therapy, interpersonal therapy, or mindfulness-based cognitive therapy during continuation tx phase to ↓relapse/recurrence risk1,4
Self-help/CAM to consider as adjuncts/alternatives: - Acupuncture. Consider adding acupuncture to antidepressant meds if psychotherapy, pharmaco-tx, exercise, St. John’s wort mono-tx aren’t acceptable/available, per APA;4 VA says insufficient evidence for acupuncture as adjunct;1 APA says insufficient evidence for acupuncture as mono-tx4
- Biofeedback. Insufficient evidence to recommend for or against as adjunct tx1
- CBT-based bibliotherapy suggested as adjunct/alternative tx1
- Exercise (eg, yoga, tai chi, qigong, resistance, aerobics) suggested as adjunct1
- Meditation.5 Insufficient evidence to compare SGAs w/ meditation (or yoga, per ACP)5
- Omega-3 fatty acids. Insufficient evidence to recommend as mono-tx or combo tx (SGA + omega-3 fatty acids), per APA and ACP;4,5 VA recommends against use of omega-3 fatty acids for tx1
- Yoga. Consider if psychotherapy, pharmaco-tx, exercise, St. John’s wort not acceptable/available, per APA;4 effective adjunctive tx to ↓sx severity, per ICSI;2 insufficient evidence to compare SGAs w/ yoga (or meditation, per ACP)5
- Insufficient evidence to recommend for/against theta-burst stimulation,1 S-adenosyl-L-methionine (SAMe) mono-tx, tai chi4
- Not recommended: VNS/DBS; psilocybin, MDMA, cannabis, & other unapproved pharmacologic treatments; vitamin D supplements1
Footnotes 1 VA 2022. VA/DoD Clinical Practice Guideline for the Management of Major Depressive Disorder. Last reviewed January 2021. Version 4.0. Department of Veterans Affairs. Department of Defense. February 2022. PDF
Severe MDD Sx
• Active suicidal ideation w/ either intent or plan, or suicide attempt
• Active homicidal ideation
• Psychotic sx
• Severe anorexic sx (incl wt loss that poses health risk)
• Inability to maintain ADLs (eg, grooming, eating, catatonia)
Tx resistance = at least 2 adequate tx trials & lack of full response to each
MDMA = methylenedioxymethamphetamine
If pregnant pt had MDD hx prior to pregnancy, responded to antidepressant meds, & is stable on pharma-co tx:
• Fluoxetine has long half-life & may not be best in pregnancy, pts planning to breastfeed
If offering MAOIs:
• Require low-tyramine diet (except for selegiline 6 mg/24h transdermal patch); severe interactions leading to hypertensive crisis may occur w/ tyramine intake
• Avoid use w/ certain serotonergic meds d/t risk of serotonin syndrome
• Avoid use w/ certain sympathomimetic meds d/t potential for hypertensive crisis
• Requires adequate wash-out period when switching to/from another antidepressant class
If offering TCAs:
• Serious, potentially fatal risk of toxicity, incl CV, CNS, & anticholinergic toxicity; desipramine & nortriptyline more tolerable, although desipramine may also cause agitation
• Use w/ caution & dispense in limited quantities in pts at risk for suicide d/t low toxicity threshold (5 mg/kg)
• Monitor therapeutic plasma concentrations for desipramine, imipramine, & nortriptyline to limit risk of toxicity
2 ICSI 2016. Trangle M, et al. Adult Depression in Primary Care. Health Care Guideline. Institute for Clinical Systems Improvement. Updated March 2016. PDF
• Paroxetine not recommended as 1st-line tx in pregnant pts; assoc w/ increased risk of major & cardiac malformations, unless pt already on paroxetine & has planned pregnancy. Weigh risks/benefits to pt & fetus of continuing paroxetine.
3 USPSTF 2016. Siu AL, et al. Screening for Depression in Adults. US Preventive Services Task Force Recommendation Statement. JAMA. 2016. Jan 26;315(4):380-387. PDF
• SGA use during pregnancy may be assoc w/ small increase in risk of preeclampsia, postpartum hemorrhage, miscarriage, perinatal death, preterm birth, serotonin withdrawal syndrome, resp distress, pulm hypertension, major & cardiac malformations, & newborn small for gestational age (per observational evidence).
4 APA 2019. McQuaid JR, et al. Clinical Practice Guideline for the Treatment of Depression Across Three Age Cohorts. American Psychological Association. Feb 16, 2019. PDF
5 ACP 2023. Qaseem A, et al. Nonpharmacologic and Pharmacologic Treatments of Adults in the Acute Phase of Major Depressive Disorder: A Living Clinical Guideline From the American College of Physicians. Ann Intern Med. 2023 Feb;176(2):239-252. Epub 2023 Jan 24. PubMed® abstract
Refer to mental health specialist. Offer ECT w/ or w/o psychotherapy if pt meets any of the following:1 - Catatonia1,2
- Psychotic depression1,2
- Melancholic sx predominant2
- Depression in Parkinsonism2
- Hx of good response to ECT1,2
- Strong pt preference for ECT2
- Evinces need for rapid, definitive tx response on medical/psychiatric grounds1
- Risks from other tx outweigh risk from ECT. Although some co-occurring medical conditions may make ECT the safer option, these ↑ECT risks: recent MI, intracerebral hemorrhage, retinal detachment1
- Hx of poor response or intolerable side effects to multiple antidepressants;1 hx ↑response/remission rates w/ ECT vs any other form of tx2
- Geriatric depression2
- Pregnancy: Strongly consider ECT in pregnant pts w/ severe sx of mental illness (psychosis, catatonia, or strong suicidal urges); risks of adverse events are low2
Footnotes 1 VA 2022. VA/DoD Clinical Practice Guideline for the Management of Major Depressive Disorder. Last reviewed January 2021. Version 4.0. Department of Veterans Affairs. Department of Defense. February 2022. PDF
Severe MDD Sx
• Active suicidal ideation w/ either intent or plan, or suicide attempt
• Active homicidal ideation
• Psychotic sx
• Severe anorexic sx (incl wt loss that poses health risk)
• Inability to maintain ADLs (eg, grooming, eating, catatonia)
2 ICSI 2016. Trangle M, et al. Adult Depression in Primary Care. Health Care Guideline. Institute for Clinical Systems Improvement. Updated March 2016. PDF
Refer to mental health specialist; combine pharma-co tx + psychotherapy.1 Pregnant pts1,2 warrant special consideration. If MDD hx prior to pregnancy, response to antidepressant meds, & stable on pharma-co tx: Weigh risk/benefit to both pt & fetus in continuing to offer pharmaco-tx.1 Modify tx as needed - Pharmaco-tx options. SSRIs: citalopram, escitalopram, fluoxetine, paroxetine, sertraline;1,3,4 but not fluvoxamine, per VA.1 SNRIs (start low dose):1,3,4 duloxetine, venlafaxine, venlafaxine XR, desvenlafaxine, levomilnacipran. Atypical antidepressants: bupropion, mirtazapine,1,3 nefazodone,3 trazodone,1,3 vilazodone, vortioxetine.3 Nefazodone assoc w/ ↑risk of hepatotoxicity-related hospitalization vs other antidepressants1
- If pt ≥65 yo: TCAs such as nortriptyline most effective;2 however, APA specifically recommends avoiding nortriptyline in older adults4
Assess recurrence/relapse risk. Consider as potentially high risk if either of the these:1
- ≥2 prior episodes
- Unstable remission status
After tx initiation/change, monitor at regular intervals; offer psychotherapy to ↓relapse risk1 - Once in remission, continue antidepressant drug @ therapeutic dose ≥6mo to ↓relapse risk; if high recurrence risk, offer maintenance pharmaco-tx for ≥12mo or indefinitely1
- After remission achieved, offer cognitive behavioral therapy, interpersonal therapy, or mindfulness-based cognitive therapy during continuation tx phase to ↓relapse/recurrence risk1,4
Self-help/CAM to consider as adjuncts/alternatives: - Acupuncture. Consider adding acupuncture to antidepressant meds if psychotherapy, pharmaco-tx, exercise, St. John’s wort mono-tx aren’t acceptable/available, per APA;4 VA says insufficient evidence for acupuncture as adjunct;1 APA says insufficient evidence for acupuncture as mono-tx4
- Biofeedback. Insufficient evidence to recommend for or against as adjunct tx1
- CBT-based bibliotherapy suggested as adjunct/alternative tx1
- Exercise (eg, yoga, tai chi, qigong, resistance, aerobics) suggested as adjunct1
- Meditation.3 Insufficient evidence to compare SGAs w/ meditation (or yoga, per ACP)3
- Omega-3 fatty acids. Insufficient evidence to recommend as mono-tx or combo tx (SGA + omega-3 fatty acids), per APA and ACP;3,4 VA recommends against use of omega-3 fatty acids for tx1
- Yoga. Consider if psychotherapy, pharmaco-tx, exercise, St. John’s wort not acceptable/available, per APA;4 effective adjunctive tx to ↓sx severity, per ICSI;2 insufficient evidence to compare SGAs w/ yoga (or meditation, per ACP)3
- Insufficient evidence to recommend for/against theta-burst stimulation,1 S-adenosyl-L-methionine (SAMe) mono-tx, tai chi4
- Not recommended: VNS/DBS; psilocybin, MDMA, cannabis, & other unapproved pharmacologic treatments; vitamin D supplements1
Footnotes 1 VA 2022. VA/DoD Clinical Practice Guideline for the Management of Major Depressive Disorder. Last reviewed January 2021. Version 4.0. Department of Veterans Affairs. Department of Defense. February 2022. PDF
Severe MDD Sx
• Active suicidal ideation w/ either intent or plan, or suicide attempt
• Active homicidal ideation
• Psychotic sx
• Severe anorexic sx (incl wt loss that poses health risk)
• Inability to maintain ADLs (eg, grooming, eating, catatonia)
If pregnant pt had MDD hx prior to pregnancy, responded to antidepressant meds, & is stable on pharma-co tx:
• Fluvoxamine not FDA approved for MDD
• Fluoxetine has long half-life & may not be best in pregnancy, pts planning to breastfeed
2 ICSI 2016. Trangle M, et al. Adult Depression in Primary Care. Health Care Guideline. Institute for Clinical Systems Improvement. Updated March 2016. PDF
• Paroxetine not recommended as 1st-line tx in pregnant pts; assoc w/ increased risk of major & cardiac malformations, unless pt already on paroxetine & has planned pregnancy. Weigh risks/benefits to pt & fetus of continuing paroxetine.
3 ACP 2023. Qaseem A, et al. Nonpharmacologic and Pharmacologic Treatments of Adults in the Acute Phase of Major Depressive Disorder: A Living Clinical Guideline From the American College of Physicians. Ann Intern Med. 2023 Feb;176(2):239-252. Epub 2023 Jan 24. PubMed® abstract
4 APA 2019. McQuaid JR, et al. Clinical Practice Guideline for the Treatment of Depression Across Three Age Cohorts. American Psychological Association. Feb 16, 2019. PDF
5 USPSTF 2016. Siu AL, et al. Screening for Depression in Adults. US Preventive Services Task Force Recommendation Statement. JAMA. 2016. Jan 26;315(4):380-387. PDF
• SGA use during pregnancy may be assoc w/ small increase in risk of preeclampsia, postpartum hemorrhage, miscarriage, perinatal death, preterm birth, serotonin withdrawal syndrome, resp distress, pulm hypertension, major & cardiac malformations, & newborn small for gestational age (per observational evidence).
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