|Classification and external resources|
Treatment-resistant depression (TRD) or treatment-refractory depression is a term used in clinical psychiatry to describe cases of major depressive disorder (MDD) that do not respond adequately to appropriate courses of at least two antidepressants. The term was first coined with the development of the concept in 1974. Inadequate response has traditionally been defined as no response whatsoever. However, many clinicians consider a response inadequate if the patient does not achieve full remission of symptoms. Cases of treatment-resistant depression in which the course of treatment was not adequate are sometimes referred to as pseudoresistant. Some factors that contribute to inadequate treatment are: early discontinuation of treatment, insufficient dosage of medication, patient noncompliance, misdiagnosis, and concurrent psychiatric disorders. Cases of treatment-resistant depression may also be referred to by which medications they are resistant to (i.e.: SSRI-resistant).
- 1 Prevalence
- 2 Predictors
- 3 Drug treatment
- 4 Other treatment options
- 5 Outcomes
- 6 References
Treatment-resistance is relatively common in cases of MDD. Rates of total remission following antidepressant treatment are only 50.4%. In cases of depression treated by a primary-care physician, 32% of patients partially responded to treatment and 45% did not respond at all.
Comorbid psychiatric disorders
Comorbid psychiatric disorders commonly go undetected in the treatment of depression. If left untreated, the symptoms of these disorders can interfere with both evaluation and treatment. Anxiety disorders are one of the most common disorder types associated with treatment-resistant depression. The two disorders commonly co-exist, and have some similar symptoms. Some studies have shown that patients with both MDD and panic disorder are the most likely to be nonresponsive to treatment. Substance abuse may also be a predictor of treatment-resistant depression. It may cause depressed patients to be noncompliant in their treatment, and the effects of certain substances can worsen the effects of depression. Other psychiatric disorders that may predict treatment-resistant depression include personality disorders, obsessive compulsive disorder, and eating disorders.
Comorbid medical disorders
Some patients who are diagnosed with treatment-resistant depression may have an underlying undiagnosed health condition that is causing or contributing to their depression. Endocrine disorders like hypothyroidism, Cushing's disease, and Addison's disease are among the most commonly identified as contributing to depression. Others include diabetes, coronary artery disease, cancer, HIV, and Parkinson's disease. Another factor is that medications used to treat comorbid medical disorders may lessen the effectiveness of antidepressants or cause depression symptoms.
Features of depression
Cases of depression in which the patient also displays psychotic symptoms such as delusions or hallucinations are more likely to be treatment resistant. Another depressive feature that has been associated with poor response to treatment is longer duration of depressive episodes. Finally, patients with more severe depression and those who are suicidal are more likely to be nonresponsive to antidepressant treatment.
There are three basic categories of drug treatment that can be used when a medication course is found to be ineffective. One option is to switch the patient to a different medication. Another option is to add a medication to the patient’s current treatment. This can include combination therapy: the combination of two different types of antidepressants, or augmentation therapy: the addition of a non-antidepressant medication that may increase the effectiveness of the antidepressant.
Increasing the dosage of an antidepressant is a common strategy to treat depression that does not respond after adequate treatment duration. Practitioners who use this strategy will usually increase the dose until the patient reports intolerable side effects, symptoms are eliminated, or the dose is increased to the limit of what is considered safe.
Studies have shown a wide variability in the effectiveness of switching antidepressants, with anywhere from 25-70% of patients responding to a different antidepressant. There is support for the effectiveness of switching patients to a different SSRI; 50% of patients that were nonresponsive after taking one SSRI were responsive after taking a second type. Switching patients to a different class of antidepressants may also be effective. Patients who are nonresponsive after taking an SSRI may respond to bupropion or a MAOI.
Medications that have been shown to be effective in cases of treatment-resistant depression include lithium, triiodothyronine, benzodiazepines, atypical antipsychotics, and stimulants. Adding lithium may be effective for patients taking some types of antidepressants, but it does not appear to be effective in patients taking SSRI’s. Triiodothyroxine (T3) is a type of thyroid hormone and has been associated with improvement in mood and depression symptoms. Benzodiazepines may improve treatment-resistant depression by decreasing the adverse side effects caused by some antidepressants and therefore increasing patient compliance. Since the entry of olanzapine into psychopharmacology, many[quantify] psychiatrists have been adding low dose olanzapine to antidepressants and other atypical antipsychotics such as aripiprazole and quetiapine. Particularly, the combination of olanzapine and fluoxetine seems to be effective.
These have shown promise in treating refractory depression but come with serious side effects. 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 unyielding depressed combined lacking addictive personality traits or heart problems.
Other treatment options
Electroconvulsive therapy is generally only considered as a treatment option in severe cases of treatment-resistant depression. It is used when medication has repeatedly failed to improve symptoms, and usually when the patient’s symptoms are so severe that they have been hospitalized. Electroconvulsive therapy has been found to reduce thoughts of suicide and relieve depressive symptoms. It is associated with an increase in glial cell line derived neurotrophic factor.
Vagus nerve stimulation
Vagus nerve stimulation is a more invasive procedure than electroconvulsive therapy, but it has been shown to be well tolerated. During the procedure a stimulating electrode is surgically attached to the vagus nerve; this allows for continuous stimulation after implantation. Like electroconvulsive therapy, it is usually only used in severe cases of treatment-resistant depression that have been non-responsive to medication.
There is sparse evidence on the effectiveness of psychotherapy in cases of treatment-resistant depression. However, a review of the literature suggests that it may be an effective treatment option. Psychotherapy may be effective in these cases because it can help relieve stress that may contribute to depressive symptoms.
rTMS (Repetitive Transcranial Magnetic Stimulation) is gradually becoming recognised as a valuable therapeutic option in treatment-resistant depression. A number of randomised placebo-controlled trials have compared real versus sham rTMS. These trials have consistently demonstrated the efficacy of this treatment against major depression. There have also been a number of meta-analyses of RCTs  confirming the efficacy of rTMS in treatment-resistant major depression, as well as naturalistic studies showing its effectiveness in "real world" clinical settings 
Treatment-resistant depression is associated with more instances of relapse than depression that is responsive to treatment. One study showed that as many as 80% of patients who needed more than one course of treatment relapsed within a year. Treatment-resistant depression has also been associated with lower long term quality of life.
- 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.
- Papakostas, G. I., & Fava, M. (2010). Pharmacotherapy for depression and treatment-resistant depression. Hackensack, NJ: World Scientific.
- Souery D., Papakostas G., Trivedi M. (2006). "Treatment-resistant depression". Journal of Clinical Psychiatry 67: 16–22.
- Berman R., Narasimhan M., Charney D. (1997). "Treatment-refractory depression: definitions and characteristics". Depression and Anxiety 5: 154–164. doi:10.1002/(sici)1520-6394(1997)5:4<154::aid-da2>3.0.co;2-d.
- Kornstein S., Schneider R. K. (2001). "Clinical features of treatment-resistant depression". Journal of Clinical Psychiatry 62: 18–25.
- Kasper, S., & Montgomery, S. A. (2013). Treatment-resistant depression. Somerset, NJ: Wiley.
- Andrews, L. W. (2010). Encyclopedia of depression. Santa Barbara, Calif: Greenwood Press.
- Shelton R., Osuntokun O., Heinloth A., Corya S. (2010). "Therapeutic options for treatment-resistant depression". CNS Drugs 24 (2): 131–161. doi:10.2165/11530280-000000000-00000.
- Friedman, E. S., & Anderson, I. M. (2011). Managing depression in clinical practice. London: Springer.
- Carvalho A. F., Cavalcante J. L., Castelo M. S., Lima M. C. (2007). "Augmentation strategies for treatment-resistant depression: A literature review". Journal of Clinical Pharmacy and Therapeutics 32 (5): 415–428. doi:10.1111/j.1365-2710.2007.00846.x.
- Thase, ME; Corya, SA; Osuntokun, O; Case, M; Henley, DB; Sanger, TM; Watson, SB; Dubé, S (Feb 2007). "A randomized, double-blind comparison of olanzapine/fluoxetine combination, olanzapine, and fluoxetine in treatment-resistant major depressive disorder.". The Journal of Clinical Psychiatry 68 (2): 224–36. doi:10.4088/jcp.v68n0207. PMID 17335320.
- 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.
- 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.
- 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.
- Warneke L (February 1990). "Psychostimulants in psychiatry". Can J Psychiatry 35: 3–10. PMID 2180548.
- Fink, M. (2009). Electroconvulsive therapy: A guide for professionals and their patients. Oxford: Oxford University Press.
- Zhang, X; Zhang, Z; Sha, W; Xie, C; Xi, G; Zhou, H; Zhang, Y (Dec 30, 2009). "Electroconvulsive therapy increases glial cell-line derived neurotrophic factor (GDNF) serum levels in patients with drug-resistant depression.". Psychiatry Research 170 (2-3): 273–5. doi:10.1016/j.psychres.2009.01.011. PMID 19896212.
- Rogers, M. H., & Anderson, P. B. (2009). Deep brain stimulation: Applications, complications and side effects. New York: Nova Biomedical Books.
- Trivedi R. B., Nieuwsma J. A., Williams J. W. (2011). "Examination of the Utility of Psychotherapy for Patients with Treatment Resistant Depression: A Systematic Review". Journal of General Internal Medicine 26 (6): 643–650. doi:10.1007/s11606-010-1608-2.
- Greden, J., Riba, M., & McInnis, M. (2011). Treatment resistant depression: A roadmap for effective care. Arlington, VA: American Psychiatric Publishing.
- Hovington CL, McGirr A, Lepage M; et al. (2013). "Repetitive transcranial magnetic stimulation (rTMS) for treating major depression and schizophrenia: a systematic review of recent meta-analyses". Ann Med. 45 (4): 308–21. doi:10.3109/07853890.2013.783993.
- Carpenter LL, Janicak PG, Aaronson ST; et al. (2012). "Transcranial magnetic stimulation (TMS) for major depression: a multisite, naturalistic, observational study of acute treatment outcomes in clinical practice". Depress Anxiety 29 (7): 587–596. doi:10.1002/da.21969.
- Euba R., Panihhidina I, Zamar A. (2015). "Treatment-resistant depression: the experience of the first rTMS Clinic in the UK". Future Neurology 10 (3): 211–215. doi:10.2217/fnl.15.8.
- Fekadu A., Wooderson S. C., Markopoulo K., Donaldson C., Papadopoulos A., Cleare A. J. (2009). "What happens to patients with treatment-resistant depression? A systematic review of medium to long term outcome studies". Journal of Affective Disorders 116 (1-2): 4–11. doi:10.1016/j.jad.2008.10.014.