Refractory Depression Management

Aka: Refractory Depression Management, Depression Unresponsive to Medication, Treatment-Resistant Depression

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II. Definitions

  1. Treatment-Resistant Depression
    1. Persistence of Major Depression using validated scoring tools AND
    2. Two or more Antidepressant medications trialed at adequate dose, duration and adherance
  2. Partial Treatment Response
    1. Major Depression rating scores improve <50% with treatment

III. Epidemiology

  1. Treatment-Resistant Depression occurs in nearly one third of Major Depression patients

IV. Risk Factors: Treatment-Resistant Depression

  1. Multiple comorbid conditions (e.g. cardiovascular disease)
  2. Major Depression onset at an early age
  3. Childhood Trauma
  4. Comorbid mental health disorder
    1. Substance Use Disorder
    2. Anxiety Disorder
    3. Personality Disorder

V. Management: Step 1

  1. Evaluate for Suicidality and other conditions requiring emergency care
  2. Assess Major Depression Differential Diagnosis
    1. Consider Bipolar Disorder (present in in up to 25% of Mood Disorder patients in primary care)
  3. Maximize non-medication therapies (e.g. Exercise, psychotherapy)
    1. See Depression Management
    2. Structured Exercise program (aerobic and Resistance Training)
    3. Psychotherapy
  4. Assess Adequacy of Antidepressant trial
    1. Minimum Duration: 6-8 weeks
    2. Minimum Dose: one dose increase at 2-4 weeks
  5. Assess for comorbid confounding factors
    1. Anxiety Disorder
    2. Increased Psychosocial Stressors
    3. Alcohol or Drug Abuse
    4. Excessive Caffeine intake
    5. Chronic medical illness
    6. Medications Predisposing to Depression
  6. Assess Compliance
    1. Medication nonadherance occurs in almost half of patients with Major Depression
    2. Has patient abruptly discontinued Antidepressant
    3. Has patient missed or skipped Antidepressant doses
    4. Has Antidepressant been temporarily interrupted
      1. Missed medication refill
      2. Travel or lifestyle interfering with dosing

VI. Management: Step 2

  1. Overall Approach
    1. Medication management is in combination with non-medication interventions (including psychotherapy)
    2. Trial each medication for at least 8 to 12 weeks
    3. Reassess initially every 1 to 2 weeks while titrating medication doses
    4. Later, reassess every 4 to 8 weeks
  2. Factors impacting medication selection
    1. Medication Cost
    2. Adverse Effects
    3. Major Depression Severity
    4. Management Urgency
    5. Pharmacogenetics
      1. Variable efficacy in improving Major Depression outcomes
      2. Wang (2023) BMC Psychiatry 23(1): 334 [PubMed]
  3. Consider alternative Antidepressant
    1. Indications
      1. Little or no response to Antidepressant at 8 to 12 weeks of optimal dosing
      2. Adverse effects limit continued use, adequate dosing or compliance
      3. Single medication therapy is preferred by patient to reduce cost and risk of adverse effects
    2. Consider switching from one SSRI to another
    3. Consider switching from an SSRI to a unique Antidepressant class
      1. Mirtazapine (Remeron)
      2. SNRI: Venlafaxine (Effexor), Duloxetine
    4. Protocol for cross-tapering to a new SSRI
      1. First 5-7 days
        1. Cut dose of agent 1 to 50%
        2. Start low dose of agent 2
          1. Delay start of new agent when switching from Fluoxetine (Prozac) due to very long half life
      2. Next
        1. Stop agent 1
        2. Increase dose of agent 2
      3. Example: Celexa to Lexapro over 5 days
        1. Decrease Celexa 40 to 20 and then stop
        2. Start Lexapro 5 mg, then increase to 10 mg
      4. Example: Paxil to Zoloft over at least 7 days
        1. Decrease Paxil 20 to 10 and then stop
        2. Start Zoloft 25 mg, then increase to 50 mg
        3. Paroxetine taper often needs longer duration
  4. Consider Augmenting current Antidepressant regimen
    1. Indications
      1. Partial response to first Antidepressant (intended to be continued)
      2. Desire for faster response rate with augmentation (in contrast to delays with a new single agent)
    2. Augment Selective Serotonin Reuptake Inhibitor (SSRI)
      1. Add Bupropion (Wellbutrin)
        1. Consider in comorbid Fatigue or Antidepressant Induced Sexual Dysfunction
      2. Add SNRI (Venlafaxine, Duloxetine)
        1. Risk of Serotonin Syndrome
        2. Consider in comorbid anxiety
      3. Add Miratazapine (Remeron)
        1. Consider in comorbid Insomnia or Nausea
      4. Add Buspirone (Buspar)
        1. Dosing 15 to 30 mg orally daily
        2. Consider in comorbid anxiety
        3. Variable evidence, with some studies demonstrating no benefit
      5. Add Tricyclic Antidepressant (e.g. Amitriptyline, Desipramine, Nortriptyline)
        1. Use at low dose (25 to 50 mg at bedtime)
        2. Consider in comorbid Insomnia, Headaches or neuropathic pain
        3. Tricyclic Antidepressant Overdose risk
      6. Add Trazodone
        1. Consider in comorbid Insomnia
    3. Atypical Antipsychotics at low dose (however associated with other adverse effects)
      1. See Atypical Antipsychotics for adverse effects
      2. Aripiprazole (Abilify) 2 to 15 mg/day
        1. Preferred of the Atypical Antipsychotics for augmentation due to cost, tolerability
      3. Brexpiprazole (Rexulti) 0.5 to 3 mg daily
      4. Cariprazine (Vraylar) 0.5 to 4.5 mg daily
      5. Olanzapine (Zyprexa) 2.5 to 10 mg daily
        1. Limited evidence for use
      6. Quetiapine (Seroquel) 150 to 300 mg daily
      7. Risperidone (Risperdal) 0.25 to 3 mg daily
      8. Ziprasidone 20 to 80 mg twice daily
    4. Agents used by Psychiatrists to augment therapy (response to these agents is often rapid within 10 days)
      1. Lithium
        1. Dosing 300 to 600 mg daily in divided doses (blood levels 0.4 to 0.8 mEq/L)
        2. Consider if associated Suicidality
        3. Requires close monitoring including levels
      2. Liothyronine (Cytomel, T3)
        1. Dosing 25-50 mcg daily
        2. Similar efficacy to Lithium in refractory depression
        3. May increase nervousness and anxiety
      3. Methylphenidate (Ritalin)
        1. Dosing 10 to 15 mg daily
        2. Consider in comorbid apathy and Fatigue
      4. Pindolol (Visken)
        1. Dosing 2.5 to 7.5 mg daily
      5. Esketamine (Spravato)
        1. Administered 56 to 84 mg intranasally twice weekly for 4 weeks, then every 1-2 weeks
        2. Monitor for 2 hours after each dose (for Hypertension, dissociation, sedation)
        3. Must be given at hospital or clinic within designated REMS program
      6. Ketamine
        1. Infused 0.5 mg/kg IV over 40 minutes for 2 to 3 times weekly
        2. Requires infusion facility and risk of emergence reaction (see Ketamine)
        3. May decrease Suicidal Ideation
    5. Psychedelics
      1. Various Psychedelics have been recommended for treatment refractory depression but evidence is limited
      2. One study found high dose Psilocybin to be slightly better than Placebo
        1. Same study found no benefit with MDMA, LSD or ayahuasca
        2. Hsu (2024) BMJ 386: e078607 [PubMed]

VII. Management: Step 3

  1. Consider Electroconvulsive Therapy

VIII. References

  1. (2023) Presc Lett 30(9): 51-2
  2. Ables (2003) Am Fam Physician 67(3):547-4 [PubMed]
  3. Bridges (1995) Br J Hosp Med 54:501-6 [PubMed]
  4. Cadieux (1998) Am Fam Physician 58(9):2059-62 [PubMed]
  5. Davies (2019) Cochrane Database Syst Rev 12(12):CD010557 +PMID: 31846068 [PubMed]
  6. Gaddey (2024) Am Fam Physician 109(5): 410-6 [PubMed]
  7. Little (2009) Am Fam Physician 80(2):167-72 [PubMed]
  8. Preston (2013) Curr Psychiatry Rep15(7):370 [PubMed]
  9. Ruhe (2006) J Clin Psychiatry 67:1836-1855 [PubMed]

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