> Table of Contents > Depression, Treatment Resistant
Depression, Treatment Resistant
Michelle Magid, MD
Roger L. McRoberts III, MD
image BASICS
  • Major depressive disorder (MDD) that has failed to respond to ≥2 adequate trials of antidepressant therapy in ≥2 different classes (1).
  • Antidepressant therapy must be given for 6 weeks at standard doses before being considered a failure.
  • Depression affects >18 million people in the United States and >340 million people worldwide.
  • 16% lifetime risk of MDD (2,3)
  • Approximately 1/3 of patients with MDD will develop treatment-resistant depression (3,4).
  • Unclear. Low levels of neurotransmitters (serotonin, norepinephrine, dopamine) have been indicated.
  • Serotonin has been linked to irritability, hostility, and suicidal ideation.
  • Norepinephrine has been linked to low energy.
  • Dopamine may play a role in low motivation and depression with psychotic features.
  • Environmental stressors such as abuse and neglect may affect neurotransmission.
  • Inflammation and oxidative stress in the brain can contribute to treatment-resistant depression (5).
A genetic abnormality in the serotonin transporter gene (5-HTTLPR) may increase risk for treatment-resistant depression.
  • Severity of disease
  • Mislabeling patients with depression who are bipolar
  • Comorbid medical disease (including chronic pain)
  • Comorbid personality disorder
  • Comorbid anxiety disorder
  • Comorbid substance abuse
  • Familial predisposition to poor response to antidepressants
  • Medication adherence in combination with psychotherapy
  • Maintenance electroconvulsive therapy (ECT) may prevent relapse.
  • Suicide
  • Bipolar disorder
  • Substance use disorders
  • Anxiety disorders
  • Dysthymia
  • Eating disorders
  • Somatic symptom disorders
Mental status exam may reveal poor hygiene, poor eye contact, blunted affect, tearfulness, weight loss or gain, psychomotor retardation, or agitation.
  • Bipolar disorder
  • Dysthymia
  • Dementia
  • Early-stage Parkinson disease
  • Personality disorder
  • Medical illness such as malignancy, thyroid disease, HIV
  • Substance use disorders
Initial Tests (lab, imaging)
  • Used to rule out medical factors that could be causing/contributing to treatment resistance
    • CBC
    • Complete metabolic profile, including liver tests, calcium, and glucose
    • Urine drug screen
    • Thyroid-stimulating hormone (TSH)
    • Vitamin D level (25-OH vitamin D)
    • Testosterone, if applicable
  • CT or MRI of the brain if neurologic disease, tumor, or dementia is suspected.
Follow-Up Tests & Special Considerations
Delirium and dementia may often look like depression.
Diagnostic Procedures/Other
  • Depression is a clinical diagnosis.
  • Validated depression rating scales to assist
    • Beck Depression Inventory
    • Hamilton Rating Scale for Depression
    • Patient Health Questionnaire 9 (PHQ-9)
First Line
  • Please see “Depression” topic. When those fail, augmentation and combination strategies are as follows:
    • Antidepressants in combination
      • Citalopram (Start 20 mg/day. Max dose 40 mg/day) + bupropion (start 100 mg BID; max dose 450 mg total) (4,6)[B]
      • Tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) may be used in combination. Proceed with caution due to risk of serotonin syndrome. Citalopram (start 20 mg/day; max dose 40 mg/day) + nortriptyline (start 50 mg at bedtime; max dose 150 mg at bedtime)
    • Antidepressants + antipsychotics
      • Citalopram (start 20 mg/day; max dose 40 mg/day) + aripiprazole (2 to 5 mg/day, different mechanism of action at higher doses) OR + risperidone (start 0.5 to 1 mg at bedtime; max dose 6 mg/day) OR + quetiapine (start 25 mg at bedtime; titrate to 100 to 300 mg at bedtime. Max dose 600 mg/day) (7,8)[A]
    • Antidepressant + lithium
      • TCA: nortriptyline (start 50 mg at bedtime; max dose 150 mg at bedtime) + lithium (start 300 mg at bedtime; max dose 900 mg BID) (1,7,9)[A]
      • SSRI: citalopram (start 20 mg/day; max dose 40 mg QD) + lithium (start 300 mg at bedtime; max dose 900 mg BID) (1,4,7)[B]
    • Antidepressant + thyroid supplementation
      • Citalopram (start 20 mg/day; max dose 40 mg/day) + triiodothyronine (T3) (12.5 to 50 &mgr;g/day) (4,10)[B]
  • In all above combinations, citalopram (Celexa) can be replaced with other SSRIs such as fluoxetine (Prozac) 20 to 80 mg/day, sertraline (Zoloft) 50 to 200 mg/day, and escitalopram (Lexapro) 10 to 20 mg/day or with serotonin-norepinephrine reuptake inhibitors (SNRIs) duloxetine (Cymbalta) 30 to 120 mg/day, venlafaxine XR (Effexor XR) 75 to 225 mg/day, or desvenlafaxine (Pristiq) 50 to 100 mg/day.
  • Maximum doses for medication in treatment-resistant cases may be higher than in treatment-responsive cases.
Second Line
Monamine oxidase inhibitor (MAOI)
  • Tranylcypromine (Parnate): start 10 mg BID, increase 10 mg/day every 1 to 3 weeks; max dose 60 mg/day
  • Selegiline transdermal (Emsam patch): Apply 6-mg patch daily, increase 3 mg/day; max dose 12 mg/day
  • P.279

  • Side-effect profile (e.g., hypertensive crisis), drug-drug interactions, and dietary restrictions make MAOIs less appealing. Patch version does not require dietary restrictions at lower doses.
  • High risk of serotonin syndrome, if combined with another antidepressant; 2-week washout period is advised.
Treatment-resistant depression should be managed in consultation with a psychiatrist.
  • First line
    • ECT: safe and effective treatment for treatment-resistant and life-threatening depression, with a 60-90% success rate (11,12)[A]:
      • Known to rapidly relieve suicidality, psychotic depression, and catatonia
      • Controversy due to cognitive side effects during the treatment
      • 3 types of lead placements
        • Bitemporal: rapid and effective. Usually need 6 to 10 treatments at 1.5× seizure threshold
        • Right unilateral: may be slightly less rapid but fewer cognitive side effects. Usually need 8 to 12 treatments at 6× seizure threshold
        • Bifrontal: newer technique that may offer similar speed to bitemporal, with slightly improved side-effect profile
  • Second line
    • Deep brain stimulation (DBS): Surgical implantation of intracranial electrodes, connected to an impulse generator implanted in the chest wall (13,14)[C]:
      • Reserved for those who have failed medications, psychotherapy, and ECT
      • Preliminary data are promising, showing 40-70% response rate and 35% remission rate, but further trials are warranted.
    • Transcranial magnetic stimulation (TCMS): Noninvasive brain stimulation technique that is generally safe. A few case reports on efficacy in treatment-resistant depression but thus far is only FDA approved for less severe forms of the illness (9,14)[C].
    • Vagus nerve stimulation (VNS): Surgical implantation of electrodes onto left vagus nerve. Its use in treatment-resistant depression has become limited in recent years (13)[C].
    • Ketamine—not FDA approved, but evidence of rapid improvement in mood and suicidal thinking, although the literature is limited. In addition, the effects of ketamine appear temporary, disappearing after days to weeks (9,15)[C].
Admission Criteria/Initial Stabilization
Inpatient care is indicated for severely depressed, psychotic, catatonic, or suicidal patients.
Discharge Criteria
Symptoms improving, no longer suicidal, psychosocial stressors addressed
  • Frequent visits (i.e., every month)
  • During follow-up, evaluate side effects, dosage, and effectiveness of medication as well as need for referral to ECT.
  • Patients who have responded to ECT may need maintenance treatments (q3-12wk) to prevent relapse.
  • Combination of lithium/nortriptyline after ECT appears to be as effective as maintenance ECT in reducing relapse.
Patients on MAOIs need dietary restriction.
Educate patients that depression is a medical illness, not a character defect.
  • Review signs and symptoms of worsening depression and when patient needs to come in for further evaluation.
  • Discuss safety plan to address suicidal thoughts.
With medication adherence, close follow-up, improved social support, and psychotherapy, prognosis improves.
1. Keller MB. Issues in treatment-resistant depression. J Clin Psychiatry. 2005;66(Suppl 8):5-12.
2. Kessler RC, Berglund P, Demler O, et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA. 2003;289(23):3095-3105.
3. Olchanski N, McInnis Myers M, Halseth M, et al. The economic burden of treatment-resistant depression. Clin Ther. 2013;35(4):512-522.
4. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006; 163(11):1905-1917.
5. Bakunina N, Pariante CM, Zunszain PA. Immune mechanisms linked to depression via oxidative stress and neuroprogression [published online ahead of print January 10, 2015]. Immunology. 2015;144;365-373. doi: 10.1111/imm.12443.
6. Trivedi MH, Fava M, Wisniewski SR, et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med. 2006;354(12):1243-1252.
7. Hicks P, Hicks XP, Meyer H, et al. How best to manage treatment-resistant depression? J Fam Pract. 2010;59(9);490-497.
8. Maglione M, Maher AR, Hu JH, et al. Off-Label Use of Atypical Antipsychotics: An Update. Rockville, MD: Agency for Healthcare Research and Quality; 2011. Report No. 11-EHC087-EF. AHRQ Comparative Effectiveness Reviews.
9. Holtzheimer PE. Advances in the management of treatment-resistant depression. Focus (Am Psychiatr Publ). 2010;8(4):488-500.
10. Nierenberg AA, Fava M, Trivedi MH, et al. A comparison of lithium and T(3) augmentation following two failed medication treatments for depression: a STAR*D report. Am J Psychiatry. 2006;163(9):1519-1530.
11. American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder, third edition. Am J Psychiatry. 2010;167(10):1-118. http://psychiatryonline.org/data/Books/prac/PG_Depression3rdEd.pdf
12. Weiner RD. The Practice of Electroconvulsive Therapy: Recommendations for Treatment, Training, and Privileging: A Task Force Report of the American Psychiatric Association. 2nd ed. Washington, DC: American Psychiatric Association; 2001:5-25.
13. Morishita T, Fayad SM, Higuchi MA, et al. Deep brain stimulation for treatment-resistant depression: systematic review of clinical outcomes. Neurotherapeutics. 2014;11(3):475-484.
14. Holtzheimer PE III, Mayberg HS. Deep brain stimulation for treatment-resistant depression. Am J Psychiatry. 2010;167(12):1437-1444.
15. Caddy C, Giaroli G, White TP, et al. Ketamine as the prototype glutamatergic antidepressant: pharmacodynamic actions, and a systematic review and meta-analysis of efficacy. Ther Adv Psychopharmacol. 2014;4(2):75-99.
  • F32.9 Major depressive disorder, single episode, unspecified
  • F33.9 Major depressive disorder, recurrent, unspecified
Clinical Pearls
  • Treatment-resistant depression is common, affecting 1/3 of those with MDD.
  • Combination and augmentation strategies with antidepressants, antipsychotics, and mood stabilizers can be helpful.
  • ECT should be considered in severe and life-threatening cases.