Treatment-resistant depression (TRD) or Treatment-refractory depression is a term used in clinical psychiatry to describe cases of major depressive disorder that do not respond to adequate courses of at least two antidepressants.[1]

The term was first coined with the development of the concept in 1974. Treatment of refractory depression has traditionally most commonly involved electroconvulsive therapy and use of non-standard medications, but new technologies such as transcranial magnetic stimulation are being studied as a safer alternative. Treatment of refractory depression may also involve more invasive interventions, such as vagus nerve stimulation.

In treatment-resistant depression, some text books recommend addition of low dose lithium or low dose thyroxine, to antidepressants. Since the olanzapine entry into psychopharmacology, many psychiatrists have been adding low dose olanzapine to antidepressants, and other atypical antipsychotics, such as Abilify, have shown promise in treating refractory depression, but come with serious side effects. MAOIs are considered very effective for certain types of refractory depression.[2]

Stimulants, such as amphetamines and methylphenidate, have also been tested with positive results, but have a high potential for abuse. However, stimulants have been shown to be effective for the unyieldingly depressed lacking addictive personality traits, heart problems or gross moral deficits in melancholic or bipolar depression..[3][4]

Some psychiatrists have found that systematic search for coexistent mild or moderate systemic diseases, for example agitation or restlessness due to coexistent nasobronchial allergy, or which might have been missed in gone years of life of thousands of patients in developing countries or underdeveloped countries due to unsystematic approach to patient, or just because methcholine challenge test, due to its cost and its uncommon use in such countries or peak flow meter is measured rarely. This way, antidepressant-responsive depression might have been presumed to be treatment-resistant depression, and once the coexistent systemic disease's treatment also started, along with appropriate antidepressants in such patients, relief in depression was maximum.


  1. Wijeratne, Chanaka; Sachdev, Perminder (2008). "Treatment-resistant depression: critique of current approaches". The Australian and New Zealand journal of psychiatry 42 (9): 751–62. doi:10.1080/00048670802277206. PMID 18696279.
  2. Stead, Latha G.; Stead, S. Matthew; Kaufman, Matthew S.; Melin, Gabrielle J. (2005). First aid for the psychiatry clerkship: a student-to-student guide. New York: McGraw-Hill. p. 140. ISBN 978-0-07-144872-7.
  3. Parker, G; Brotchie, H (2010). "Do the old psychostimulant drugs have a role in managing treatment-resistant depression?". Acta psychiatrica Scandinavica 121 (4): 308–14. doi:10.1111/j.1600-0447.2009.01434.x. PMID 19594481.
  4. Satel, SL; Nelson, JC (1989). "Stimulants in the treatment of depression: a critical overview". The Journal of clinical psychiatry 50 (7): 241–9. PMID 2567730.


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