Treatment-resistant depression explained

Treatment-resistant depression
Synonyms:Treatment-refractory depression
Field:Psychiatry
Symptoms:Depressive mood, anhedonia, low energy
Complications:Self-harm, suicide

Treatment-resistant depression (TRD) is major depressive disorder in which an affected person does not respond adequately to at least two different antidepressant medications at an adequate dose and for an adequate duration.[1] Inadequate response has most commonly been defined as less than 25% reduction in depressive symptoms following treatment with an antidepressant.[2] Many clinicians and researchers question the construct validity and clinical utility of treatment-resistant depression as currently conceptualized.[3] [4]

Other factors that may contribute to inadequate treatment are: a history of repeated or severe adverse childhood experiences, early discontinuation of treatment, failure to consider psychotherapy and other psychosocial interventions, patient noncompliance, misdiagnosis, cognitive impairment, low income and other social determinants, and concurrent medical conditions, including comorbid psychiatric disorders. Cases of treatment-resistant depression may also be referred to by which medications people are resistant to (e.g.: SSRI-resistant).[5] Adding further treatments such as aripiprazole or quetiapine is weakly supported as of 2022.[6]

Risk factors

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 major depressive disorder 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 attention deficit hyperactivity disorder,[7] personality disorders, obsessive compulsive disorder, and eating disorders.[8]

Comorbid medical disorders

Some people 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.[8]

Features of depression

People with depression who also display 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.[5] Finally, people with more severe depression and those who are suicidal are more likely to be nonresponsive to antidepressant treatment.

Treatment

See also: Management of depression.

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.[9]

Medication

Antidepressants

Dose increase

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 person reports intolerable side effects, symptoms are eliminated, or the dose is increased to the limit of what is considered safe.[10]

Switching antidepressants

Studies have shown a wide variability in the effectiveness of switching antidepressants, with anywhere from 25 to 70% of people responding to a different antidepressant.[11] There is support for the effectiveness of switching people to a different SSRI; 50% of people that were non-responsive after taking one SSRI were responsive after taking a second type. Switching people with treatment-resistant depression to a different class of antidepressants may also be effective. People who are non-responsive after taking an SSRI may respond to moclobemide or tricyclic antidepressants, bupropion or an MAOI.[10]

Some off label antidepressants are low dose ketamine and highly serotonergic catecholamines (including very controlled use of MDMA in the treatment of PTSD and crippling depression/anxiety). For lethargic syndromes, dysthymia, or caffeine-resistant amotivation, a dopaminergic stimulant such as methylphenidate, or even dextroamphetamine or methamphetamine can be helpful.

Primarily dopaminergic or norepinephrine releasing stimulants, in low doses, have been used especially in the past, or in conjunction with a multidisciplinary therapy approach, although more targeted and "mild" agents, including modafinil and atomoxetine are considered first line for both childhood and adult lethargy and inattention disorders, due to their virtually nonexistent abuse potential (limited to one or two cases per 10 000), and higher selectivity, safety, and thus slightly broader therapeutic index. When depression is related or co-morbid to an inattention disorder, often ADHD, then both can be carefully managed with the same first line stimulant medication, typically both methylphenidate and lisdexamfetamine.[12]

Other medications

Medications that have been shown to be effective in people with treatment-resistant depression include lithium, liothyronine, benzodiazepines, atypical antipsychotics, and stimulants. Adding lithium may be effective for people taking some types of antidepressants; it does not appear to be effective in patients taking SSRIs. Liothyronine (synthetic 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.[13]

Since the entry of olanzapine into psychopharmacology, many psychiatrists have been adding low dose olanzapine to antidepressants and other atypical antipsychotics such as aripiprazole and quetiapine. Eli Lilly, the company that sells both olanzapine and fluoxetine individually, has also released a combination formulation which contains olanzapine and fluoxetine in a single capsule. Some low to moderate quality evidence points to success in the short term (8–12 weeks) using mianserin (or antipsychotics cariprazine, olanzapine, quetiapine or ziprasidone) to augment antidepressant medications.[14] These have shown promise in treating refractory depression but come with serious side effects.[15] Stimulants such as amphetamines and methylphenidate have also been tested with positive results but have potential for abuse. However, stimulants have been shown to be effective for the unyielding depressed combined lacking addictive personality traits or heart problems.[16] [17] [18]

Ketamine has been tested as a rapid-acting antidepressant[19] for treatment-resistant depression in bipolar disorder, and major depressive disorder.[20] Spravato, a nasal spray form of esketamine, was approved by the FDA in 2019 for use in treatment-resistant depression when combined with an oral antidepressant.[21] [22]

Research

A 2016 placebo randomized controlled trial evaluated the rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression with positive outcome.[23] [24]

In 2018, the United States Food and Drug Administration (FDA) granted breakthrough therapy designation for psilocybin-assisted therapy for treatment-resistant depression.[25] [26] A systematic review published in 2021 found that the use of psilocybin as a pharmaceutical substance was associated with reduced intensity of depression symptoms.[27]

Physical psychiatric treatments

Electroconvulsive therapy

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.[28] It is associated with an increase in glial cell line derived neurotrophic factor.[29]

rTMS

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[30] confirming the efficacy of rTMS in treatment-resistant major depression, as well as naturalistic studies showing its effectiveness in "real world" clinical settings.[31] [32]

dTMS

dTMS (deep transcranial magnetic stimulation) is a continuation of the same idea as rTMS, but with the hope that deeper stimulation of subcortical areas of the brain leads to increased effect. A 2015 systematic review and health technology assessment found lacking evidence in order to recommend the method over either ECT or rTMS because so few studies had been published.[33]

Vagus Nerve Stimulation

Vagus nerve stimulation has also been used for treatment-resistant depression.[34]

Deep Brain Stimulation

Deep brain stimulation has been used in a small number of clinical trials to treat people with severe treatment-resistant depression.[35]

Magnetic seizure therapy

Magnetic seizure therapy is currently being investigated for treating refractory depression.

Transcranial direct-current stimulation

Transcranial direct-current stimulation is a form of neuromodulation that uses constant, low direct current delivered via electrodes on the head.

Psychotherapy

There is sparse evidence on the effectiveness of psychotherapy in cases of treatment-resistant depression.[36] However, a review of the literature suggests that it may be an effective treatment option.[37] Psychotherapy may be effective in people with treatment-resistant depression because it can help relieve stress that may contribute to depressive symptoms.[38]

A Cochrane systematic review has shown that psychological therapies (including cognitive behavioural therapy, dialectical behavior therapy, interpersonal therapy and intensive short-term dynamic psychotherapy) added to usual care (with antidepressants) can be beneficial for depressive symptoms and for response and remission rates over the short term (up to six months) for patients with treatment-resistant depression. Medium‐ (7–12 months) and long‐term (longer than 12 months) effects seem similarly beneficial. Psychological therapies added to usual care (antidepressants) seem as acceptable as usual care alone.[39]

Outcomes

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 people with treatment-resistant depression 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.[40]

Another study saw just 8 of 124 patients in remission after two years of standard depression treatment.[41]

Notes and References

  1. Wijeratne C, Sachdev P . Treatment-resistant depression: critique of current approaches . The Australian and New Zealand Journal of Psychiatry . 42 . 9 . 751–762 . September 2008 . 18696279 . 10.1080/00048670802277206 . 2848646 .
  2. Sforzini L, Worrell C, Kose M, Anderson IM, Aouizerate B, Arolt V, Bauer M, Baune BT, Blier P, Cleare AJ, Cowen PJ, Dinan TG, Fagiolini A, Ferrier IN, Hegerl U, Krystal AD, Leboyer M, McAllister-Williams RH, McIntyre RS, Meyer-Lindenberg A, Miller AH, Nemeroff CB, Normann C, Nutt D, Pallanti S, Pani L, Penninx BW, Schatzberg AF, Shelton RC, Yatham LN, Young AH, Zahn R, Aislaitner G, Butlen-Ducuing F, Fletcher C, Haberkamp M, Laughren T, Mäntylä FL, Schruers K, Thomson A, Arteaga-Henríquez G, Benedetti F, Cash-Gibson L, Chae WR, De Smedt H, Gold SM, Hoogendijk WJ, Mondragón VJ, Maron E, Martynowicz J, Melloni E, Otte C, Perez-Fuentes G, Poletti S, Schmidt ME, van de Ketterij E, Woo K, Flossbach Y, Ramos-Quiroga JA, Savitz AJ, Pariante CM . 6 . A Delphi-method-based consensus guideline for definition of treatment-resistant depression for clinical trials . Molecular Psychiatry . 27 . 3 . 1286–1299 . March 2022 . 34907394 . 9095475 . 10.1038/s41380-021-01381-x .
  3. Malhi . Gin S. . Das . Pritha . Mannie . Zola . Irwin . Lauren . 2019 . Treatment-resistant depression: problematic illness or a problem in our approach? . British Journal of Psychiatry . en . 214 . 1 . 1–3 . 10.1192/bjp.2018.246 . 0007-1250 . failure to respond is often the result of administering inappropriate treatment, which occurs principally because of paradigm failure.
  4. Rost . Felicitas . Booker . Thomas . Gonsard . Aneliya . de Felice . Giulio . Asseburg . Lorena . Malda-Castillo . Javier . Koutoufa . Iakovina . Ridsdale . Hannah . Johnson . Rebecca . Taylor . David . Fonagy . Peter . 2024 . The complexity of treatment-resistant depression: A data-driven approach . Journal of Affective Disorders . en . 358 . 292–301 . 10.1016/j.jad.2024.04.093 . Our findings reveal a complex and multifaceted condition and call for an urgent reconceptualization of TRD, which encompasses many interdependent variables and experiences..
  5. Berman RM, Narasimhan M, Charney DS . Treatment-refractory depression: definitions and characteristics . Depression and Anxiety . 5 . 4 . 154–164 . 1997 . 9338108 . 10.1002/(sici)1520-6394(1997)5:4<154::aid-da2>3.0.co;2-d . 33974050 .
  6. Nuñez . Nicolas A . Joseph . Boney . Pahwa . Mehak . Kumar . Rakesh . Resendez . Manuel Gardea . Prokop . Larry J . Veldic . Marin . Seshadri . Ashok . Biernacka . Joanna M . Frye . Mark A . Wang . Zhen . Singh . Balwinder . January 2022 . Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis . Journal of Affective Disorders . en . 302 . 385–400 . 10.1016/j.jad.2021.12.134 . 9328668 . 34986373.
  7. Sternat T, Katzman MA . Neurobiology of hedonic tone: the relationship between treatment-resistant depression, attention-deficit hyperactivity disorder, and substance abuse . Neuropsychiatric Disease and Treatment . 12 . 2149–2164 . 2016-08-25 . 27601909 . 5003599 . 10.2147/NDT.S111818 . free .
  8. Kornstein SG, Schneider RK . Clinical features of treatment-resistant depression . The Journal of Clinical Psychiatry . 62 . Suppl 16 . 18–25 . 2001 . 11480880 .
  9. Book: Andrews LW . 2010 . Encyclopedia of depression. . Santa Barbara, Calif . Greenwood Press.
  10. Shelton RC, Osuntokun O, Heinloth AN, Corya SA . Therapeutic options for treatment-resistant depression . CNS Drugs . 24 . 2 . 131–161 . February 2010 . 20088620 . 10.2165/11530280-000000000-00000 . 32936223 .
  11. Book: Managing depression in clinical practice. . Friedman ES, Anderson IM . 2011 . Springer . London. page 81
  12. Ruhé HG, Huyser J, Swinkels JA, Schene AH . Switching antidepressants after a first selective serotonin reuptake inhibitor in major depressive disorder: a systematic review . The Journal of Clinical Psychiatry . 67 . 12 . 1836–1855 . December 2006 . 17194261 . 10.4088/JCP.v67n1203 . 9758110 .
  13. Carvalho AF, Cavalcante JL, Castelo MS, Lima MC . Augmentation strategies for treatment-resistant depression: a literature review . Journal of Clinical Pharmacy and Therapeutics . 32 . 5 . 415–428 . October 2007 . 17875106 . 10.1111/j.1365-2710.2007.00846.x . free .
  14. Davies P, Ijaz S, Williams CJ, Kessler D, Lewis G, Wiles N . Pharmacological interventions for treatment-resistant depression in adults . The Cochrane Database of Systematic Reviews . 12 . 12 . CD010557 . December 2019 . 31846068 . 6916711 . 10.1002/14651858.CD010557.pub2 .
  15. Book: Stead LG, Stead SM, Kaufman MS, Melin GJ . First aid for the psychiatry clerkship: a student-to-student guide . McGraw-Hill . New York . 2005 . 978-0-07-144872-7 . 140.
  16. Parker G, Brotchie H . Do the old psychostimulant drugs have a role in managing treatment-resistant depression? . Acta Psychiatrica Scandinavica . 121 . 4 . 308–314 . April 2010 . 19594481 . 10.1111/j.1600-0447.2009.01434.x . 11417490 .
  17. Satel SL, Nelson JC . Stimulants in the treatment of depression: a critical overview . The Journal of Clinical Psychiatry . 50 . 7 . 241–249 . July 1989 . 2567730 .
  18. Warneke L . Psychostimulants in psychiatry . Canadian Journal of Psychiatry . 35 . 1 . 3–10 . February 1990 . 2180548 . 10.1177/070674379003500102 . 35020426 .
  19. Abdallah CG, Sanacora G, Duman RS, Krystal JH . Ketamine and rapid-acting antidepressants: a window into a new neurobiology for mood disorder therapeutics . Annual Review of Medicine . 66 . 509–523 . 2015 . 25341010 . 4428310 . 10.1146/annurev-med-053013-062946 . Gerard Sanacora .
  20. Serafini G, Howland RH, Rovedi F, Girardi P, Amore M . The role of ketamine in treatment-resistant depression: a systematic review . Current Neuropharmacology . 12 . 5 . 444–461 . September 2014 . 25426012 . 4243034 . 10.2174/1570159X12666140619204251 .
  21. McIntyre RS, Rosenblat JD, Nemeroff CB, Sanacora G, Murrough JW, Berk M, Brietzke E, Dodd S, Gorwood P, Ho R, Iosifescu DV, Lopez Jaramillo C, Kasper S, Kratiuk K, Lee JG, Lee Y, Lui LM, Mansur RB, Papakostas GI, Subramaniapillai M, Thase M, Vieta E, Young AH, Zarate CA, Stahl S . 6 . Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation . The American Journal of Psychiatry . 178 . 5 . 383–399 . May 2021 . 33726522 . 10.1176/appi.ajp.2020.20081251 . American Psychiatric Association Publishing . 9635017 .
  22. Bahr R, Lopez A, Rey JA . Intranasal Esketamine (Spravato) for Use in Treatment-Resistant Depression In Conjunction With an Oral Antidepressant . P & T . 44 . 6 . 340–375 . June 2019 . 31160868 . 6534172 .
  23. Palhano-Fontes F, Barreto D, Onias H, Andrade KC, Novaes MM, Pessoa JA, Mota-Rolim SA, Osório FL, Sanches R, Dos Santos RG, Tófoli LF, de Oliveira Silveira G, Yonamine M, Riba J, Santos FR, Silva-Junior AA, Alchieri JC, Galvão-Coelho NL, Lobão-Soares B, Hallak JE, Arcoverde E, Maia-de-Oliveira JP, Araújo DB . 6 . Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial . Psychological Medicine . 49 . 4 . 655–663 . March 2019 . 29903051 . 6378413 . 10.1017/S0033291718001356 .
  24. Antidepressant Effects of Ayahuasca: a Randomized Placebo Controlled Trial in Treatment Resistant Depression - Full Text View - ClinicalTrials.gov . clinicaltrials.gov . 15 February 2017 . en. Barros de Araujo D .
  25. Web site: COMPASS Pathways Receives FDA Breakthrough Therapy Designation for Psilocybin Therapy for Treatment-resistant Depression . live . https://web.archive.org/web/20181204005741/https://compasspathways.com/compass-pathways-receives-fda-breakthrough-therapy-designation-for-psilocybin-therapy-for-treatment-resistant-depression/ . December 4, 2018 . 2018-12-03 . Compass Pathways.
  26. Web site: Richard Staines . 2 December 2019 . FDA tags psilocybin drug as clinical depression Breakthrough Therapy . live . https://web.archive.org/web/20210907170203/https://pharmaphorum.com/news/fda-tags-psilocybin-drug-as-clinical-depression-breakthrough-therapy/ . September 7, 2021 . 7 September 2021 . Pharmaphorum.
  27. Więckiewicz G, Stokłosa I, Piegza M, Gorczyca P, Pudlo R . August 2021 . Lysergic Acid Diethylamide, Psilocybin and Dimethyltryptamine in Depression Treatment: A Systematic Review . Pharmaceuticals . 14 . 8 . 793 . 10.3390/ph14080793 . 8399008 . 34451890 . free.
  28. Book: Fink M . 2009 . Electroconvulsive therapy: A guide for professionals and their patients. . Oxford . Oxford University Press.
  29. Zhang X, Zhang Z, Sha W, Xie C, Xi G, Zhou H, Zhang Y . Electroconvulsive therapy increases glial cell-line derived neurotrophic factor (GDNF) serum levels in patients with drug-resistant depression . Psychiatry Research . 170 . 2–3 . 273–275 . December 2009 . 19896212 . 10.1016/j.psychres.2009.01.011 . 3392108 .
  30. Hovington CL, McGirr A, Lepage M, Berlim MT . Repetitive transcranial magnetic stimulation (rTMS) for treating major depression and schizophrenia: a systematic review of recent meta-analyses . Annals of Medicine . 45 . 4 . 308–321 . June 2013 . 23687987 . 10.3109/07853890.2013.783993 . 46443378 . free .
  31. Carpenter LL, Janicak PG, Aaronson ST, Boyadjis T, Brock DG, Cook IA, Dunner DL, Lanocha K, Solvason HB, Demitrack MA . 6 . Transcranial magnetic stimulation (TMS) for major depression: a multisite, naturalistic, observational study of acute treatment outcomes in clinical practice . Depression and Anxiety . 29 . 7 . 587–596 . July 2012 . 22689344 . 10.1002/da.21969 . 22968810 .
  32. 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 . 10.2217/fnl.15.8.
  33. Web site: Effekter av djup transkraniell magnetstimulering med H-spole . Statens beredning för medicinsk och social utvärdering (SBU) . Swedish Agency for Health Technology Assessment and Assessment of Social Services . sv. 2017-06-02. October 2015.
  34. Carreno FR, Frazer A . July 2017 . Vagal Nerve Stimulation for Treatment-Resistant Depression . Neurotherapeutics . 14 . 3 . 716–727 . 10.1007/s13311-017-0537-8 . 5509631 . 28585221.
  35. Anderson RJ, Frye MA, Abulseoud OA, Lee KH, McGillivray JA, Berk M, Tye SJ. Deep brain stimulation for treatment-resistant depression: efficacy, safety and mechanisms of action. Neuroscience and Biobehavioral Reviews. 36. 8. 1920–1933. September 2012. 22721950. 10.1016/j.neubiorev.2012.06.001. 207089716.
  36. Book: Thase ME, Kasper S, Montgomery S. Treatment-resistant Depression - The Role of Psychotherapy in the Management of Treatment-resistant Depression . 2013. 10.1002/9781118556719. 183–208. 9781118556719 .
  37. Trivedi RB, Nieuwsma JA, Williams JW . Examination of the utility of psychotherapy for patients with treatment resistant depression: a systematic review . Journal of General Internal Medicine . 26 . 6 . 643–650 . June 2011 . 21184287 . 3101965 . 10.1007/s11606-010-1608-2 .
  38. Book: Greden J, Riba M, McInnis M . 2011 . Treatment resistant depression: A roadmap for effective care. . Arlington, VA . American Psychiatric Publishing.
  39. Ijaz S, Davies P, Williams CJ, Kessler D, Lewis G, Wiles N . Psychological therapies for treatment-resistant depression in adults . The Cochrane Database of Systematic Reviews . 5 . 5 . CD010558 . May 2018 . 29761488 . 6494651 . 10.1002/14651858.CD010558.pub2 .
  40. Fekadu A, Wooderson SC, Markopoulo K, Donaldson C, Papadopoulos A, Cleare AJ . 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 . July 2009 . 19007996 . 10.1016/j.jad.2008.10.014 .
  41. Web site: APA PsycNet.

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Treatment-resistant depression".

Except where otherwise indicated, Everything.Explained.Today is © Copyright 2009-2024, A B Cryer, All Rights Reserved. Cookie policy.