II. Indications

  1. Moderate to Severe Major Depression
  2. Consider in Mild Major Depression

III. Approach

  1. Combine Antidepressants with Psychotherapy for Depression
  2. Providers tend to under dose depression
    1. Refractory Depression may simply need higher levels
  3. Duration of therapy after remission of symptoms
    1. Young: 6 months minimum treatment
    2. Elderly: 2 years minimum use
    3. Rebound Depression off medication: Indefinite use
      1. Continued use reduces relapse risk by two thirds
      2. Geddes (2003) Lancet 361:653-61 [PubMed]
  4. Specific Population Approaches
    1. See Pediatric Depression
    2. See Antepartum Depression
    3. See Depression in Athletes
    4. See Depression in Older Adults
    5. See Postpartum Major Depression

IV. Efficacy

  1. Antidepressants offer Statistically SignificantMajor Depression improvement, but not all patients benefit
  2. Fewer than one third of patients achieve Major Depression remission with the first Antidepressant
  3. Number Needed to Treat (NNT) to result in clinical response or remission
    1. Tricyclic Antidepressants NNT 9
    2. Selective Serotonin Reuptake Inhibitors (SSRI) NNT 7
    3. Venlafaxine NNT 6
  4. References
    1. Arroll (2016) J Prim Health Care 8(4): 325-34 [PubMed]
    2. Cipriani (2016) Lancet 391(10128): 1357-66 [PubMed]

VI. Protocol

  1. Choosing an Antidepressant
    1. Consider Antidepressant Adverse Effects
    2. Consider Antidepressants that have been effective for close family members
    3. Consider Depression Types (see below)
      1. Anxious or agitated
      2. Inhibited or withdrawn
    4. Start with generic agents if possible
  2. Warn patients about expected side effects
    1. See Antidepressant Adverse Effects
    2. At least 60% of patients will have some adverse effects, and these effects precede the benefit by months
    3. Consider effect on sexual function (see below)
  3. Choosing a dosage
    1. Many patients are not on the optimal dose
      1. Write prescription to allow patient to increase
    2. Start at sub-therapeutic dose to reduce side effects
    3. Increase dose to minimum effective dose in 5-7 days
    4. Allow patient to increase dose again in 2-3 weeks
    5. Example: Celexa 20 mg (write for 60 with refills)
      1. Start at 1/2 tablet daily for 5-7 days
      2. Then increase to 1 pill daily for 2-3 weeks
      3. Then consider increase to 2 pills daily
  4. Titrating to effective dose
    1. Increase dose as tolerated to optimal dose over 6 to 12 weeks
    2. Reevaluate at 4 to 6 weeks of optimal dose
      1. Consider adding a second agent if inadequate effect
      2. Consider switching agents if no significant improvement
  5. Antidepressant Course
    1. Acute Phase (6 weeks to 3 months)
      1. Target remission of symptoms and improved function
    2. Continuation Phase (4 to 9 months)
      1. Reduce relapse rates and keep symptoms at bay
      2. Continuation for at least 6 months is recommended
    3. Maintenance Phase (10 months to >1 year)
      1. Reduce risk of symptom recurrence
      2. Continue reevaluation of Major Depression
      3. Consider discontinuation as risk of recurrence decreases
  6. Switching Antidepressants
    1. Balance the risk of Serotonin Syndrome with the risk of Antidepressant Withdrawal
      1. Risk of Serotonin Syndrome if multiple Serotonergic Medications are used at the same time
      2. Risk of Antidepressant Withdrawal during a gap between Antidepressants
    2. Cross Taper
      1. Slowly decrease one medication dose by 25% of maintenance dose every 4 weeks AND
      2. Simultaneously start and titrate the new medication dose by 25% of target dose every 4 weeks
    3. Direct switch
      1. Stop one medication (consider tapering dose by 25% every 4 weeks before stopping)
      2. Washout period or gap between medications
        1. Choose either no gap between medications, a short gap of 2-3 days or a longer gap of 7 days
        2. Consider longer washout periods (4-5 half-lives) with longer Half-Life medications
      3. Start the new medication and titrate dose slowly to target dose
  7. Antidepressant Discontinuation
    1. Antidepressant is recommended for at least 6 months before stopping
    2. Risk of Antidepressant Withdrawal on stopping medication
      1. See Antidepressant Discontinuation Syndrome
    3. Decrease dose by 25% every 4 weeks or 12.5% every 2 weeks (stopping medication over 3-4 months)
      1. Citalopram 40 mg for 4 weeks, then 30 mg for 4 weeks, then 20 mg for 4 weeks, then 10 mg for 4 weeks...
    4. Review risk of relapse after medication discontinuation with patient
      1. Consider scheduled follow-up at 6-12 months after stopping medication
      2. Major Depression relapse occurrs within 1 year in >50% of patients after stopping meds after initial resolution
        1. Lewis (2021) N Engl J Med 385(14): 1257-67 [PubMed]

VII. Management: General agents

  1. First choice
    1. Escitalopram (Lexapro) or Citalopram (Celexa)
    2. Sertraline (Zoloft)
    3. Buproprion (Wellbutrin)
      1. Activating (consider in Fatigue, use caution in anxiety)
  2. Second choice (due to side effects)
    1. Fluoxetine (Prozac): Activating
    2. Paroxetine (Paxil): Sedating and withdrawal risk
    3. Mirtazapine (Remeron): Sedating and weight gain
      1. Elderly may see side effects as helpful
      2. May be helpful in Insomnia
  3. References
    1. Goad (2007) Chronic Disease Lecture, MPLS

VIII. Management: Agitation or Insomnia

  1. Use Sedating Antidepressant
    1. Paroxetine (Paxil)
    2. Mirtazapine (Remeron)
      1. Also useful in stimulating appetite, but risk of increased weight gain
  2. Consider medication to assist sleep
    1. Trazodone (Desyrel) 25-50 mg PO qhs
  3. Consider Benzodiazepine for first 1-2 weeks (Exercise caution)
    1. Clonazepam

IX. Management: Anxiety

XI. Management: Psychotic Depression

XIII. Management: Sexual Dysfunction

  1. See Antidepressant Induced Sexual Dysfunction
  2. Man with Premature Ejaculation: Paxil
  3. Woman lacks orgasm: Buspar 30 minutes prior to sex
  4. Agents least likely to affect sexual function
    1. Nefazodone (Serzone)
    2. Bupropion (Wellbutrin)
    3. Mirtazapine (Remeron)
    4. Citalopram (Celexa)
    5. Fluvoxamine (Luvox)

XIV. Management: Perimenopausal Major Depression

XV. Management: Depression Refractory to Antidepressants

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Ontology: Major Depressive Disorder (C1269683)

Definition (MSH) Marked depression appearing in the involution period and characterized by hallucinations, delusions, paranoia, and agitation.
Definition (PSY) Affective disorder marked by dysphoric mood, inactivity, lack of interest, insomnia, feelings of worthlessness, diminished ability to think, and thoughts of suicide. Use DEPRESSION (EMOTION) for nonclinical depression.
Definition (CSP) one or more periods of depression in the absence of history of manic or hypomanic episodes; chronic type lasts 2 or more years; melancholic type is more severe, has vegetative signs, and responds well to somatic therapy.
Concepts Mental or Behavioral Dysfunction (T048)
MSH D003865
ICD10 F32.9
SnomedCT 370143000, 35489007
English Disorder, Major Depressive, Disorders, Major Depressive, Major Depressive Disorders, MDD, MAJOR DEPRESSIVE DISORDER, DEPRESSIVE DIS MAJOR, MAJOR DEPRESSIVE DIS, Major depressive disorder NOS, Major depressive illness, Major depression NOS, Depressive Disorder, Major [Disease/Finding], major depressive illness, major depressive disorder, major depression, Major depressive disorder (diagnosis), Major depression, Major depressive disorder (disorder), Major depressive disorder, Major depression, NOS, Major depressive disorder, NOS, Depressive Disorder, Major, Depressive Disorders, Major, Major Depressive Disorder, Major Depression
Dutch depressieve ziekte, depressieve stoornis NAO, major depression, Depressieve stoornis, ernstige, Ernstige depressieve stoornis, Involutiepsychose, Melancholie, involutionele, Parafrenie, involutionele, Psychose, involutionele, Involutiedepressie, Involutionele depressie
French Syndrome dépressif majeur SAI, Épisode dépressif majeur, Dépression grave, Grave dépression, Dépression majeure, Trouble dépressif majeur
German Major Depression NNB, schwere depressive Krankheit, Endogene Depression, Involutionsdepression, Melancholie, Involutions-, Paraphrenie, Involutions-, Psychose, Involutions-, Depressive Störung, majore, Majore depressive Störung
Italian Depressione maggiore NAS, Malattia depressiva maggiore, Depressione maggiore, Disturbo depressivo maggiore
Portuguese Doença depressiva major, Perturbação depressiva major NE, Depressão grave, Transtorno Depressivo Maior
Spanish Trastorno depresivo mayor NEOM, Enfermedad depresiva mayor, depresión mayor, trastorno depresivo mayor (trastorno), trastorno depresivo mayor, Depresión mayor, Trastorno Depresivo Mayor
Japanese 大うつ病NOS, オオウツビョウ, ダイウツビョウ, ダイウツビョウNOS, うつ病-退行期, 大うつ病性障害, 大鬱病, うつ病-更年期, 大うつ病, 初老期うつ病, 更年期うつ病, 更年期鬱病, 精神病-更年期, 退行期うつ病, 退行期パラフレニー, 退行期メランコリア, 退行期精神病, 鬱病-更年期, パラフレニー-退行期, 更年期うつ状態, 更年期メランコリー, 更年期精神病, 更年期鬱状態, 精神病-退行期, 退行期鬱病
Swedish Involutionsdepression
Czech psychóza involuční, deprese involuční, depresivní porucha unipolární, melancholie involuční, parafrenie involuční, Velké depresivní onemocnění, Velká deprese, Velká depresivní porucha NOS
Finnish Laaja-alainen masentuneisuushäiriö
Russian DEPRESSIVNOE RASSTROISTVO TIAZHELOE, DEPRESSIIA INVOLIUTSIONNAIA, MELANKHOLIIA INVOLIUTSIONNAIA, PSIKHOZ INVOLIUTSIONNYI, PARAFRENIIA INVOLIUTSIONNAIA, ДЕПРЕССИВНОЕ РАССТРОЙСТВО ТЯЖЕЛОЕ, ДЕПРЕССИЯ ИНВОЛЮЦИОННАЯ, МЕЛАНХОЛИЯ ИНВОЛЮЦИОННАЯ, ПАРАФРЕНИЯ ИНВОЛЮЦИОННАЯ, ПСИХОЗ ИНВОЛЮЦИОННЫЙ
Polish Wielkie zaburzenie depresyjne, Zaburzenie depresyjne wielkie, Ciężkie zaburzenie depresyjne, Depresja wielka, Parafrenia inwolucyjna, Depresja głęboka, Epizod depresji dużej, Depresja inwolucyjna
Hungarian Major depressiós betegség, Major depressio, Major depressiós zavar k.m.n.
Norwegian Depresjon, alvorlig, Markert depresjon, Depresjon, markert, Alvorlig depresjon, Markant depressiv forstyrrelse