Management of Treatment-Resistant Depression: Challenges and Strategies

In the paper

“However, in common for each model is the inadequate response to at least 2 trials of antidepressant pharmacotherapy.”

• Also stated in: § Defining Treatment-Resistant Depression · hedged

  “Although many definitions for TRD have been proposed, the general consensus appears to be 2 unsuccessful trials of antidepressant pharmacotherapy (AD).”

What the sources say

• Not checked yetcites [125] 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. doi: 10.1176/ajp.2006.163.11.1905 17074942

In the paper

“The Maudsley Staging Method (MSM) assesses treatment resistance in depression in a “multi-dimensional” manner.34”

What the sources say

• Not checked yetcites [34] Fekadu A, Wooderson S, Donaldson C, et al. A multidimensional tool to quantify treatment resistance in depression: the Maudsley staging method. J Clin Psychiatry. 2009; 70(2): 177– 184. doi: 10.4088/JCP.08m04309 19192471

In the paper

“Pseudo-resistance may encompass the profile of patients who unfortunately were prescribed suboptimal doses of AD or had early discontinuation of a medication for any number of reasons, including intolerable side effects, patient non-adherence or under-dosing.”

What the sources say

• Not checked yetcites [107] Nierenberg AA, Amsterdam JD. Treatment-resistant depression: definition and treatment approaches. J Clin Psychiatry. 1990; 51(Suppl): 39– 47. 2112132

In the paper

“Thase et al139 and Peselow et al116 each examined switching from SSRI/SNRI medications to tricyclic antidepressants (TCAs), specifically imipramine, and reported response rates of 44–73% in total.”

What the sources say

• Not checked yetcites [139] Thase ME, Rush AJ, Howland RH, et al. Double-blind switch study of imipramine or sertraline treatment of antidepressant-resistant chronic depression. Arch Gen Psychiatry. 2002; 59(3): 233– 239. doi: 10.1001/archpsyc.59.3.233 11879161
• Not checked yetcites [116] Peselow ED, Filippi AM, Goodnick P, Barouche F, Fieve RR. The short- and long-term efficacy of paroxetine HCl: A. Data from a 6-week double-blind parallel design trial vs. imipramine and placebo. Psychopharmacol Bull. 1989; 25(2): 267– 271. 2532373

In the paper

“Further staging models have included the Massachusetts General Hospital Staging method117 which carefully documents the optimization of medication doses and number of failed medications.”

What the sources say

• Not checked yetcites [117] Petersen T, Papakostas GI, Posternak MA, et al. Empirical testing of two models for staging antidepressant treatment resistance. J Clin Psychopharmacol. 2005; 25(4): 336– 341. doi: 10.1097/01.jcp.0000169036.40755.16 16012276

In the paper

“Large-scale guidelines, including from the American Psychiatric Association (APA)3 and the World Federation of Societies of Biological Psychiatry7 strongly recommend lithium as an effective augmentation strategy in MDD.”

What the sources say

• Not checked yetcites [3] APA. Practice guideline for the treatment of patients with major depressive disorder. Available from: https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf. Accessed 1 8, 2020.
• Not checked yetcites [7] Bauer M, Pfennig A, Severus E, Whybrow PC, Angst J, Moller HJ, D. World Federation of Societies of Biological Psychiatry. Task Force on Unipolar Depressive. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders, part 1: update 2013 on the acute and continuation treatment of unipolar depressive disorders. World J Biol Psychiatry. 2013; 14(5): 334– 385. doi: 10.3109/15622975.2013.804195 23879318

In the paper

“Quetiapine at a dose of 300mg per day demonstrated up to 48% response and 24.5% remission in combination with SSRIs and has since been approved for adjunctive treatment of MDD by the FDA.8,31”

What the sources say

• Not checked yetcites [8] Bauer M, Pretorius HW, Constant EL, Earley WR, Szamosi J, Brecher M. Extended-release quetiapine as adjunct to an antidepressant in patients with major depressive disorder: results of a randomized, placebo-controlled, double-blind study. J Clin Psychiatry. 2009; 70(4): 540– 549. doi: 10.4088/JCP.08m04629 19358791
• Not checked yetcites [31] El-Khalili N, Joyce M, Atkinson S, et al. Extended-release quetiapine fumarate (quetiapine XR) as adjunctive therapy in major depressive disorder (MDD) in patients with an inadequate response to ongoing antidepressant treatment: a multicentre, randomized, double-blind, placebo-controlled study. Int J Neuropsychopharmacol. 2010; 13(7): 917– 932. doi: 10.1017/S1461145710000015 20175941

In the paper

“The Souery Operational Criteria for TRD provide a slightly different approach to staging TRD as an illness, by defining TRD as any single failure of an adequate (6–8 week) trial of an AD.133”

What the sources say

• Not checked yetcites [133] Souery D, Amsterdam J, de Montigny C, et al. Treatment resistant depression: methodological overview and operational criteria. Eur Neuropsychopharmacol. 1999; 9(1–2): 83– 91. doi: 10.1016/S0924-977X(98)00004-2 10082232

In the paper

“TRD can also be associated with prolonged, costly periods of inpatient treatment.140”

What the sources say

• Not checked yetcites [140] Ustun TB, Kessler RC. Global burden of depressive disorders: the issue of duration. Br J Psychiatry. 2002; 181: 181– 183. doi: 10.1192/bjp.181.3.181 12204918

In the paper

“As with lithium, the initial T3 studies were performed in augmentation of TCA pharmacotherapy.5,119”

What the sources say

• Not checked yetcites [5] Aronson R, Offman HJ, Joffe RT, Naylor CD. Triiodothyronine augmentation in the treatment of refractory depression. A meta-analysis. Arch Gen Psychiatry. 1996; 53(9): 842– 848. doi: 10.1001/archpsyc.1996.01830090090013 8792761
• Not checked yetcites [119] Prange AJ Jr, Wilson IC, Rabon AM, Lipton MA. Enhancement of imipramine antidepressant activity by thyroid hormone. Am J Psychiatry. 1969; 126(4): 457– 469. doi: 10.1176/ajp.126.4.457 4185164

In the paper

“However, in this large-scale study, lithium levels were kept quite low, which may have contributed to the low-response rate.108”

What the sources say

• Not checked yetcites [108] 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. doi: 10.1176/ajp.2006.163.9.1519 16946176

In the paper

“although even the term “adequate response” may be fraught with contention, as there is not consensus on what constitutes “adequate.””

In the paper

“The initial model proposed by Thase and Rush138 included treatment resistance levels ranging from one failed AD trial to a lack of response to electroconvulsive therapy (ECT).”

What the sources say

• Not checked yetcites [138] Thase ME, Rush AJ. Treatment resistant depression In: Bloom FE, Kupfer DJ, editors. Psychopharmacology: The Fourth Generation of Progress. New York: Raven Press Ltd.; 1995: 1081– 1097.

In the paper

“However, in the STAR*D trial, no statistically significant superiority over augmentation with lithium was discovered,108 with the T3 augmentation remission rate at 24.7%.”

What the sources say

• Not checked yetcites [108] 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. doi: 10.1176/ajp.2006.163.9.1519 16946176

In the paper

“Importantly, the ATHF-SF focuses on the current episode of depression, as opposed to life-time trials of pharmacological treatments, a more streamlined approach to assessing the level of resistance of the current illness episode.”

What the sources say

• Not checked yetcites [128] Sackeim HA, Aaronson ST, Bunker MT, et al. The assessment of resistance to antidepressant treatment: rationale for the Antidepressant Treatment History Form: Short Form (ATHF-SF). J Psychiatr Res. 2019; 113: 125– 136. doi: 10.1016/j.jpsychires.2019.03.021 30974339

In the paper

“Further, comorbidities such as anxiety disorders, personality disorders or substance-use disorders may complicate the clinical picture and can have deleterious effects on treatment response.114,127”

What the sources say

• Not checked yetcites [114] Parker GB, Malhi GS, Crawford JG, Thase ME. Identifying “paradigm failures” contributing to treatment-resistant depression. J Affect Disord. 2005; 87(2–3): 185– 191. doi: 10.1016/j.jad.2005.02.015 15979725
• Not checked yetcites [127] Sackeim HA. The definition and meaning of treatment-resistant depression. J Clin Psychiatry. 2001; 62(Suppl 16): 10– 17. 11480879

In the paper

“SGAs are known to have some effect on serotonin receptors and therefore may be effective in combination with SSRI/SNRIs in treating TRD.”

In the paper

“Chronically depressed patients have a lower chance of recovery,98 and often suffer from TRD.25,87”

What the sources say

• Not checked yetcites [98] Mueller TI, Leon AC. Recovery, chronicity, and levels of psychopathology in major depression. Psychiatr Clin North Am. 1996; 19(1): 85– 102. doi: 10.1016/S0193-953X(05)70275-6 8677222
• Not checked yetcites [25] Crown WH, Finkelstein S, Berndt ER, et al. The impact of treatment-resistant depression on health care utilization and costs. J Clin Psychiatry. 2002; 63(11): 963– 971. doi: 10.4088/JCP.v63n1102 12444808
• Not checked yetcites [87] Malhi GS, Parker GB, Crawford J, Wilhelm K, Mitchell PB. Treatment-resistant depression: resistant to definition? Acta Psychiatr Scand. 2005; 112(4): 302– 309. doi: 10.1111/acp.2005.112.issue-4 16156838

In the paper

“Triiodothyronine (T3) is usually the form of thyroid hormone prescribed in augmentation of AD pharmacotherapy.5”

What the sources say

• Not checked yetcites [5] Aronson R, Offman HJ, Joffe RT, Naylor CD. Triiodothyronine augmentation in the treatment of refractory depression. A meta-analysis. Arch Gen Psychiatry. 1996; 53(9): 842– 848. doi: 10.1001/archpsyc.1996.01830090090013 8792761

In the paper

“However, the argument may be made that lack of achieving remission may be classified as an inadequate response as residual depressive symptoms can significantly contribute to difficulty functioning.”

In the paper

“ECT is the established best therapeutic option for TRD, but its neurophysiological mechanism of action is yet to be elucidated.66,126”

What the sources say

• Not checked yetcites [66] Kato N. Neurophysiological mechanisms of electroconvulsive therapy for depression. Neurosci Res. 2009; 64(1): 3– 11. doi: 10.1016/j.neures.2009.01.014 19321135
• Not checked yetcites [126] Sackeim HA. Central issues regarding the mechanisms of action of electroconvulsive therapy: directions for future research. Psychopharmacol Bull. 1994; 30(3): 281– 308. 7878177

In the paper

“In combination with usual care, psychotherapy overall contributed to an improvement in depressive symptoms, especially when the psychotherapy employed was cognitive behavioural analysis system of psychotherapy (CBASP), cognitive behavioural therapy, interpersonal therapy or mindfulness-based cognitive therapy.141”

What the sources say

• Not checked yetcites [141] van Bronswijk S, Moopen N, Beijers L, Ruhe HG, Peeters F. Effectiveness of psychotherapy for treatment-resistant depression: a meta-analysis and meta-regression. Psychol Med. 2019; 49(3): 366– 379. doi: 10.1017/S003329171800199X 30139408

In the paper

“ECT remains the most effective option to treat TRD, especially in situations where a patient’s life may be at risk.149,45”

What the sources say

• Not checked yetcites [149] Berlim MT, van den Eynde F, Tovar-Perdomo S, Daskalakis ZJ. Response, remission and drop-out rates following high-frequency repetitive transcranial magnetic stimulation (rTMS) for treating major depression: a systematic review and meta-analysis of randomized, double-blind and sham-controlled trials. Psychol Med. 2014; 44(2): 225 –39. 23507264
• Not checked yetcites [45] Group UER. Efficacy and safety of electroconvulsive therapy in depressive disorders: a systematic review and meta-analysis. Lancet. 2003; 361(9360): 799– 808. 12642045

In the paper

“In 2014, Berlim et al reported response rates of 29.3% in 1371 TRD patients,149 almost double the 16.8% response rates seen with antidepressant medications beyond the third sequential trial.125”

What the sources say

• Not checked yetcites [149] Berlim MT, van den Eynde F, Tovar-Perdomo S, Daskalakis ZJ. Response, remission and drop-out rates following high-frequency repetitive transcranial magnetic stimulation (rTMS) for treating major depression: a systematic review and meta-analysis of randomized, double-blind and sham-controlled trials. Psychol Med. 2014; 44(2): 225 –39. 23507264
• Not checked yetcites [125] 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. doi: 10.1176/ajp.2006.163.11.1905 17074942

In the paper

“The first large clinical trials for rTMS in MDD were published in 2007110 and subsequently in 2010.42”

What the sources say

• Not checked yetcites [110] O’Reardon JP, Solvason HB, Janicak PG, et al. Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial. Biol Psychiatry. 2007; 62(11): 1208– 1216. doi: 10.1016/j.biopsych.2007.01.018 17573044
• Not checked yetcites [42] George MS, Lisanby SH, Avery D, et al. Daily left prefrontal transcranial magnetic stimulation therapy for major depressive disorder: a sham-controlled randomized trial. Arch Gen Psychiatry. 2010; 67(5): 507– 516. doi: 10.1001/archgenpsychiatry.2010.46 20439832

In the paper

“Bitemporal Standard pulse ECT is the most commonly used form,76 with a response rate of up to 75%.”

What the sources say

• Not checked yetcites [76] Leiknes KA, Jarosh-von Schweder L, Hoie B. Contemporary use and practice of electroconvulsive therapy worldwide. Brain Behav. 2012; 2(3): 283– 344. doi: 10.1002/brb3.37 22741102 PMC3381633

In the paper

“These are inhibitors of MAO-A and B enzymes and are very effective antidepressants.”

In the paper

“The majority of studies examining efficacy of switching to an MAOI were conducted by switch from a TCA,95,137 and demonstrated response rates of up to 60%.”

What the sources say

• Not checked yetcites [95] McGrath PJ, Stewart JW, Harrison W, Quitkin FM. Treatment of tricyclic refractory depression with a monoamine oxidase inhibitor antidepressant. Psychopharmacol Bull. 1987; 23(1): 169– 172. 3602314
• Not checked yetcites [137] Thase ME, Frank E, Mallinger AG, Hamer T, Kupfer DJ. Treatment of imipramine-resistant recurrent depression, III: efficacy of monoamine oxidase inhibitors. J Clin Psychiatry. 1992; 53(1): 5– 11. 1737741

In the paper

“Importantly, the retention rate was 88% overall in the randomized controlled trial (RCT) and minor adverse effects were no different in the active vs sham arms of the trial.”

What the sources say

• Not checked yetcites [42] George MS, Lisanby SH, Avery D, et al. Daily left prefrontal transcranial magnetic stimulation therapy for major depressive disorder: a sham-controlled randomized trial. Arch Gen Psychiatry. 2010; 67(5): 507– 516. doi: 10.1001/archgenpsychiatry.2010.46 20439832

In the paper

“rTMS has been approved as a treatment for TRD by Health Canada (2002), the US FDA (2008), and equivalent agencies in the European Union, Australia and Israel.”

In the paper

“In two patients with MDD, Hoflich et al only found small improvements to mood, although this was likely due to very low frequency of stimulation (0.3Hz) over the vertex and comparatively few number of stimuli.50”

What the sources say

• Not checked yetcites [50] Hoflich G, Kasper S, Hufnagel A, Ruhrmann S, Moller HJ. Application of transcranial magnetic stimulation in treatment of drug-resistant major depression: a report of two cases. Human Psychopharmacol. 1993; 8(5): 361– 365. doi: 10.1002/hup.470080510

In the paper

“Unfortunately, no significant difference was found in response between the two groups, with only 6.9% remission in the tranylcypromine group, which also suffered from poorer tolerance of the MAOI.94”

What the sources say

• Not checked yetcites [94] McGrath PJ, Stewart JW, Fava M, et al. Tranylcypromine versus venlafaxine plus mirtazapine following three failed antidepressant medication trials for depression: a STAR*D report. Am J Psychiatry. 2006; 163(9): 1531– 1541. doi: 10.1176/ajp.2006.163.9.1531 16946177

In the paper

“The efficacy of rTMS has been established in several dozen randomized controlled trials of thousands of patients over the past 20 years and affirmed in several large meta-analyses.”

In the paper

“There appears to be a significant comorbidity of personality disorders with MDD, which then leads to diminishing returns with respect to first line pharmacological treatments.105,106,134”

What the sources say

• Not checked yetcites [105] Newton-Howes G, Tyrer P, Johnson T. Personality disorder and the outcome of depression: meta-analysis of published studies. Br J Psychiatry. 2006; 188: 13– 20. doi: 10.1192/bjp.188.1.13 16388064
• Not checked yetcites [106] Newton-Howes G, Tyrer P, Johnson T, et al. Influence of personality on the outcome of treatment in depression: systematic review and meta-analysis. J Pers Disord. 2014; 28(4): 577– 593. doi: 10.1521/pedi_2013_27_070 24256103
• Not checked yetcites [134] Souery D, Oswald P, Massat I, et al., D. Group for the Study of Resistant. Clinical factors associated with treatment resistance in major depressive disorder: results from a European multicenter study. J Clin Psychiatry. 2007; 68(7): 1062– 1070. doi: 10.4088/JCP.v68n0713 17685743

In the paper

“This second study produced a 14.1% remission rate in the blinded study and approximately 30% remission rate in the follow-up open-label trial.”

What the sources say

• Not checked yetcites [42] George MS, Lisanby SH, Avery D, et al. Daily left prefrontal transcranial magnetic stimulation therapy for major depressive disorder: a sham-controlled randomized trial. Arch Gen Psychiatry. 2010; 67(5): 507– 516. doi: 10.1001/archgenpsychiatry.2010.46 20439832

In the paper

“Deep TMS devices were approved by the FDA beginning in 2013 (the H1-coil) in the treatment of depression, based largely on a study by Levkovitz et al.77”

What the sources say

• Not checked yetcites [77] Levkovitz Y, Isserles M, Padberg F, et al. Efficacy and safety of deep transcranial magnetic stimulation for major depression: a prospective multicenter randomized controlled trial. World Psychiatry. 2015; 14(1): 64– 73. doi: 10.1002/wps.20199 25655160 PMC4329899

In the paper

“Moreover, rTMS has an adverse effect discontinuation rate of only 4.5% in stark contrast to the 25.1% discontinuation rate for antidepressant medication.21,64”

What the sources say

• Not checked yetcites [21] Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet. 2009; 373(9665): 746– 758. doi: 10.1016/S0140-6736(09)60046-5 19185342
• Not checked yetcites [64] Janicak PG, O’Reardon JP, Sampson SM, et al. Transcranial magnetic stimulation in the treatment of major depressive disorder: a comprehensive summary of safety experience from acute exposure, extended exposure, and during reintroduction treatment. J Clin Psychiatry. 2008; 69(2): 222– 232. doi: 10.4088/JCP.v69n0208 18232722

In the paper

“There were, however, higher rates of treatment discomfort in the accelerated arm, and this contributed to slightly higher rates of treatment discontinuation in this arm.”

What the sources say

• Not checked yetcites [36] Fitzgerald PB, Hoy KE, Elliot D, Susan McQueen RN, Wambeek LE, Daskalakis ZJ. Accelerated repetitive transcranial magnetic stimulation in the treatment of depression. Neuropsychopharmacology. 2018; 43(7): 1565– 1572. doi: 10.1038/s41386-018-0009-9 29467437 PMC5983543

In the paper

“Cognitive scores remained unaffected, aside from autobiographical memory scores, which would be expected to decrease over time.92”

What the sources say

• Not checked yetcites [27] Daskalakis ZJ, Dimitrova J, McClintock SM, et al. Magnetic seizure therapy (MST) for major depressive disorder. Neuropsychopharmacology. 2019; 45(2): 276– 282. 31486777 PMC6901571
• Not checked yetcites [92] McElhiney MC. The Autobiographical Memory Interview-Short Form In: Psychiatry DoB. New York: New York State Psychiatric Institute; 2001.

In the paper

“All VNS systems have required surgical implantation until recently, with the development of transcutaneal systems, which are not yet FDA approved for TRD20,54”

What the sources say

• Not checked yetcites [20] Cimpianu CL, Strube W, Falkai P, Palm U, Hasan A. Vagus nerve stimulation in psychiatry: a systematic review of the available evidence. J Neural Transm (Vienna). 2017; 124(1): 145– 158. doi: 10.1007/s00702-016-1642-2 27848034
• Not checked yetcites [54] Howland RH. New developments with vagus nerve stimulation therapy. J Psychosoc Nurs Ment Health Serv. 2014; 52(3): 11– 14. 24745061

In the paper

“All rTMS interventions were well tolerated, in a similar manner to sham.”

What the sources say

• Not checked yetcites Brunoni et al15

In the paper

“More recently, Fitzgerald et al36 directly compared accelerated rTMS to standard rTMS in a randomized control trial of 115 patients and found no discernible difference in either response or remission rates between the two groups.”

What the sources say

• Not checked yetcites [36] Fitzgerald PB, Hoy KE, Elliot D, Susan McQueen RN, Wambeek LE, Daskalakis ZJ. Accelerated repetitive transcranial magnetic stimulation in the treatment of depression. Neuropsychopharmacology. 2018; 43(7): 1565– 1572. doi: 10.1038/s41386-018-0009-9 29467437 PMC5983543

In the paper

“The majority of these early studies of MST applied stimulation to the vertex of the skull.”

In the paper

“Over 6000 patients underwent one of these brain stimulation treatments, despite many trials being of small sample size.”

What the sources say

• Not checked yetcites [100] Mutz J, Vipulananthan V, Carter B, Hurlemann R, Fu CHY, Young AH. Comparative efficacy and acceptability of non-surgical brain stimulation for the acute treatment of major depressive episodes in adults: systematic review and network meta-analysis. BMJ. 2019; 364: l1079. doi: 10.1136/bmj.l1079 30917990 PMC6435996

In the paper

“This trial, the largest brain stimulation trial to date, prompted the FDA to approve iTBS as a novel treatment for TRD.”

What the sources say

• Not checked yetcites [14] Blumberger DM, Vila-Rodriguez F, Thorpe KE, et al. Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial. Lancet. 2018; 391(10131): 1683– 1692. doi: 10.1016/S0140-6736(18)30295-2 29726344

In the paper

“The results of this open-label trial27 appear promising and comparable to ECT, opening the door for further careful direct comparison with ECT and possibly a new favourable brain stimulation option for TRD.”

What the sources say

• Not checked yetcites [27] Daskalakis ZJ, Dimitrova J, McClintock SM, et al. Magnetic seizure therapy (MST) for major depressive disorder. Neuropsychopharmacology. 2019; 45(2): 276– 282. 31486777 PMC6901571

In the paper

“A study by Kayser et al67 reported a 69% response rate in 26 patients with TRD, comparable to ECT response rates.”

What the sources say

• Not checked yetcites Kayser et al67

In the paper

“As with the majority of studies in brain stimulation, the bulk of evidence supporting the efficacy of these treatments was assessed by depression scores at the end of the acute course of treatment, with few strategies reported to describe continuation treatment or prevention of relapse.”

What the sources say

• Not checked yetcites [100] Mutz J, Vipulananthan V, Carter B, Hurlemann R, Fu CHY, Young AH. Comparative efficacy and acceptability of non-surgical brain stimulation for the acute treatment of major depressive episodes in adults: systematic review and network meta-analysis. BMJ. 2019; 364: l1079. doi: 10.1136/bmj.l1079 30917990 PMC6435996

In the paper

“Brunoni et al15 examined data regarding the bulk of the existing rTMS therapies available with respect to efficacy and tolerability with the goal of establishing a treatment hierarchy. This novel analysis of 81 rTMS studies examined 8 different rTMS approaches and compared them with sham rTMS.”

What the sources say

• Not checked yetcites Brunoni et al15

In the paper

“Importantly, tolerability was high in both arms and pain/discomfort scores were similar in each treatment arm.”

What the sources say

• Not checked yetcites [14] Blumberger DM, Vila-Rodriguez F, Thorpe KE, et al. Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial. Lancet. 2018; 391(10131): 1683– 1692. doi: 10.1016/S0140-6736(18)30295-2 29726344

In the paper

“rTMS is an effective and well-tolerated therapeutic option for TRD”

In the paper

“more evidence is needed to create a clear hierarchy of rTMS approaches”

In the paper

“Several open-label trials of differing accelerated rTMS schedules have been conducted and all found improved remission and response rates, when compared to once daily rTMS6,51,93 including response rates of up to 56%.93”

What the sources say

• Not checked yetcites [6] Baeken C, Vanderhasselt MA, Remue J, et al. Intensive HF-rTMS treatment in refractory medication-resistant unipolar depressed patients. J Affect Disord. 2013; 151(2): 625– 631. doi: 10.1016/j.jad.2013.07.008 23896317
• Not checked yetcites [51] Holtzheimer PE 3rd, McDonald WM, Mufti M, et al. Accelerated repetitive transcranial magnetic stimulation for treatment-resistant depression. Depress Anxiety. 2010; 27(10): 960– 963. doi: 10.1002/da.v27:10 20734360 PMC3020591
• Not checked yetcites [93] McGirr A, Van den Eynde F, Tovar-Perdomo S, Fleck MP, Berlim MT. Effectiveness and acceptability of accelerated repetitive transcranial magnetic stimulation (rTMS) for treatment-resistant major depressive disorder: an open label trial. J Affect Disord. 2015; 173: 216– 220. doi: 10.1016/j.jad.2014.10.068 25462419

In the paper

“The high-frequency MST resulted in the highest remission rates in patients who underwent at least 8 treatments (33.3%), although this jumped significantly in patients who completed the full MST treatment protocol (to 60%).”

What the sources say

• Not checked yetcites [27] Daskalakis ZJ, Dimitrova J, McClintock SM, et al. Magnetic seizure therapy (MST) for major depressive disorder. Neuropsychopharmacology. 2019; 45(2): 276– 282. 31486777 PMC6901571

In the paper

“A recent paper by Daskalakis et al27 reported an open-label trial applying MST to the prefrontal cortex, with 3 different study arms – each arm applied a different MST frequency, ranging from 25–100Hz.”

What the sources say

• Not checked yetcites Daskalakis et al27

In the paper

“Few clinical trials have yet to be reported regarding the efficacy of MST when compared to other therapeutic options for TRD, but those published consistently demonstrate a clear antidepressant effect with fewer cognitive or memory side effects.”

In the paper

“High frequency, low frequency, bilateral rTMS and TBS were all found to be superior to sham stimulation in terms of response.”

What the sources say

• Not checked yetcites Brunoni et al15

In the paper

“It is believed that the stimulation of this cranial nerve alters various networks of the brain in order to treat psychiatric disease.”

In the paper

“As the magnetic field passes freely through the scalp and skull to discharge cortical neurons, there is no shunting of energy toward subcortical structures,80 thus sparing the memory centres of the brain.”

What the sources say

• Not checked yetcites [80] Lisanby SH. Update on magnetic seizure therapy: a novel form of convulsive therapy. J ECT. 2002; 18(4): 182– 188. doi: 10.1097/00124509-200212000-00003 12468992

In the paper

“Most recently, Williams et al143 examined the effects of multiple iTBS treatments per day in a small sample of patients who did not previously respond to a full course of rTMS and an acute course of ECT.”

What the sources say

• Not checked yetcites [143] Williams NR, Sudheimer KD, Bentzley BS, et al. High-dose spaced theta-burst TMS as a rapid-acting antidepressant in highly refractory depression. Brain. 2018; 141(3): e18. doi: 10.1093/brain/awx379 29415152 PMC5837258

In the paper

“In this trial, 414 patients were randomized to either 10Hz rTMS or iTBS and the efficacy of iTBS was found to be noninferior to conventional rTMS.”

What the sources say

• Not checked yetcites [14] Blumberger DM, Vila-Rodriguez F, Thorpe KE, et al. Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial. Lancet. 2018; 391(10131): 1683– 1692. doi: 10.1016/S0140-6736(18)30295-2 29726344

In the paper

“Vagus nerve stimulation (VNS) is proposed to modulate brain activity via stimulation of the tenth cranial nerve, the vagus nerve.”

In the paper

“Interestingly, there appears to be a bimodal distribution with respect to the timing of response. A portion of VNS patients respond “acutely,” whereas for others, the main effects appear to emerge after approximately 3 months of treatment.17”

What the sources say

• Not checked yetcites [17] Carreno FR, Frazer A. Vagal nerve stimulation for treatment-resistant depression. Neurotherapeutics. 2017; 14(3): 716– 727. doi: 10.1007/s13311-017-0537-8 28585221 PMC5509631

In the paper

“As expected, evidence lent itself to ECT, high frequency left and low-frequency right rTMS, with less evidence for the more recently developed forms of brain stimulation.”

What the sources say

• Not checked yetcites [100] Mutz J, Vipulananthan V, Carter B, Hurlemann R, Fu CHY, Young AH. Comparative efficacy and acceptability of non-surgical brain stimulation for the acute treatment of major depressive episodes in adults: systematic review and network meta-analysis. BMJ. 2019; 364: l1079. doi: 10.1136/bmj.l1079 30917990 PMC6435996

In the paper

“In the PRIDE Study,71 patients were randomized to a pharmacotherapeutic arm or a combination of continuation ECT with pharmacotherapy, with relapse rates of 20.3% and 13.1%, respectively at the 6-month mark.”

What the sources say

• Not checked yetcites [71] Kellner CH, Husain MM, Knapp RG, et al. A novel strategy for continuation ECT in geriatric depression: phase 2 of the PRIDE study. Am J Psychiatry. 2016; 173(11): 1110– 1118. doi: 10.1176/appi.ajp.2016.16010118 27418381 PMC7130448

In the paper

“These novel therapeutics all show promise in effectively treating TRD and warrant further investigation and comparison to existing efficacious TRD therapies.”

In the paper

“Psilocybin is the psychedelic compound isolated from hallucinogenic mushrooms. It is metabolized by the body into psilocin, which is a partial serotonin receptor agonist.”

In the paper

“Although initially investigated as a psychomimetic substance,75 the antidepressant effect of ketamine was quickly recognized after a low dose intravenous infusion.11”

What the sources say

• Not checked yetcites [11] Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000; 47(4): 351– 354. doi: 10.1016/S0006-3223(99)00230-9 10686270

In the paper

“Inflammation is increasingly thought to play a role in TRD, as elevated C-reactive protein and cytokines appear to be elevated in patients with MDD and specifically TRD.18,55,135”

What the sources say

• Not checked yetcites [18] Cattaneo A, Ferrari C, Uher R, et al. Absolute measurements of macrophage migration inhibitory factor and interleukin-1-beta mRNA levels accurately predict treatment response in depressed patients. Int J Neuropsychopharmacol. 2016; 19(10): pii: pyw045. PMC5091822 27207917
• Not checked yetcites [55] Howren MB, Lamkin DM, Suls J. Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom Med. 2009; 71(2): 171– 186. doi: 10.1097/PSY.0b013e3181907c1b 19188531
• Not checked yetcites [135] Strawbridge R, Arnone D, Danese A, Papadopoulos A, Herane Vives A, Cleare AJ. Inflammation and clinical response to treatment in depression: A meta-analysis. Eur Neuropsychopharmacol. 2015; 25(10): 1532– 1543. doi: 10.1016/j.euroneuro.2015.06.007 26169573

In the paper

“More recently, an intranasal form of esketamine (a ketamine enantiomer) has been developed, which has shown good effect with continued treatment in combination with an oral antidepressant26 and has now been approved by the FDA for restricted use in TRD.”

What the sources say

• Not checked yetcites [26] Daly EJ, Singh JB, Fedgchin M, et al. Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. 2018; 75(2): 139– 148. doi: 10.1001/jamapsychiatry.2017.3739 29282469 PMC5838571

In the paper

“Particular promise may be emerging with the newer acute treatments that have recently been approved by the FDA to specifically treat TRD (iTBS and intranasal esketamine).”

In the paper

“On the 15th day of medication administration, of the 45 patients in the active drug arm, 79% met response criteria (>50% reduction in Hamilton Rating Scale for Depression scores), whereas 41% met response criteria in the placebo arm.”

What the sources say

• Not checked yetcites [46] Gunduz-Bruce H, Silber C, Kaul I, et al. Trial of SAGE-217 in patients with major depressive disorder. N Engl J Med. 2019; 381(10): 903– 911. doi: 10.1056/NEJMoa1815981 31483961

In the paper

“Ketamine is a widely investigated N-methyl-D-aspartate (NDMA) antagonist as a potential therapeutic option for TRD and is considered a rapid acting antidepressant (RAADs).”

In the paper

“These novel combination compounds were deemed tolerable and did not result in opioid withdrawal or tolerance and induced a moderate antidepressant effect,33 showing most promise as an adjunctive therapy.”

What the sources say

• Not checked yetcites [33] Fava M, Memisoglu A, Thase ME, et al. Opioid modulation with buprenorphine/samidorphan as adjunctive treatment for inadequate response to antidepressants: a randomized double-blind placebo-controlled trial. Am J Psychiatry. 2016; 173(5): 499– 508. doi: 10.1176/appi.ajp.2015.15070921 26869247

In the paper

“COX-2 inhibitors are known to block prostaglandin production, which appears to be elevated in blood samples of some patients with TRD.79”

What the sources say

• Not checked yetcites [79] Lieb J, Karmali R, Horrobin D. Elevated levels of prostaglandin E2 and thromboxane B2 in depression. Prostaglandins Leukot Med. 1983; 10(4): 361– 367. doi: 10.1016/0262-1746(83)90048-3 6574523

In the paper

“Interestingly, the antidepressant effects were not thought to be due to intoxication but were noted around 3 hrs after the IV infusion had been discontinued and appeared to continue over several days.”

In the paper

“In a recent editorial in JAMA Psychiatry, Dr. M. Freeman addresses this specific topic, with recommendations to individualize maintenance interventions.38”

What the sources say

• Not checked yetcites [38] Freeman MP. Relapse prevention after recovery in patients with persistent major depressive disorder-an active pursuit. JAMA Psychiatry. 2019. doi: 10.1001/jamapsychiatry.2019.3637 31799999

In the paper

“This rapid response was reinforced by several randomized blinded and open-label studies and included a significant reduction in suicidal ideation in TRD patients.1,58,89,99”

What the sources say

• Not checked yetcites [1] Aan Het Rot M, Collins KA, Murrough JW, et al. Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression. Biol Psychiatry. 2010; 67(2): 139– 145. doi: 10.1016/j.biopsych.2009.08.038 19897179
• Not checked yetcites [58] Ibrahim L, Diazgranados N, Luckenbaugh DA, et al. Rapid decrease in depressive symptoms with an N-methyl-d-aspartate antagonist in ECT-resistant major depression. Prog Neuropsychopharmacol Biol Psychiatry. 2011; 35(4): 1155– 1159. doi: 10.1016/j.pnpbp.2011.03.019 21466832 PMC3100439
• Not checked yetcites [89] Mathew SJ, Murrough JW, Aan Het Rot M, Collins KA, Reich DL, Charney DS. Riluzole for relapse prevention following intravenous ketamine in treatment-resistant depression: a pilot randomized, placebo-controlled continuation trial.”. Int J Neuropsychopharmacol. 2010; 13(1): 71– 82. doi: 10.1017/S1461145709000169 19288975 PMC3883127

In the paper

“In a group of 12 patients with TRD, a feasibility study of high-dose psilocybin demonstrated response rates of 58% up to 3 months after 2 doses of psilocybin, an initial low dose to assess safety and a subsequent high dose (25mg) one week later, despite the psychedelic effects lasting approximately 6 hrs.16”

What the sources say

• Not checked yetcites [16] Carhart-Harris RL, Bolstridge M, Rucker J, et al. Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. Lancet Psychiatry. 2016; 3(7): 619– 627. doi: 10.1016/S2215-0366(16)30065-7 27210031

In the paper

“The depressive symptoms of patients with elevated CRP levels preferentially responded to infusions of infliximab and their CRP levels dropped post-treatment in a corresponding manner, whereas patients without elevated inflammatory markers did not seem to fall into the responder category.”

What the sources say

• Not checked yetcites [121] Raison CL, Rutherford RE, Woolwine BJ, et al. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry. 2013; 70(1): 31– 41. doi: 10.1001/2013.jamapsychiatry.4 22945416 PMC4015348

In the paper

“In recent years, attention has turned to the endogenous opioid system as one of interest in TRD, particularly when comorbid with anxiety symptoms, as happens relatively frequently, with a negative impact on treatment response.62”

What the sources say

• Not checked yetcites [62] Ionescu DF, Niciu MJ, Richards EM, Zarate CA Jr. Pharmacologic treatment of dimensional anxious depression: a review. Prim Care Companion CNS Disord. 2014; 16(3). PMC4195641 25317369

In the paper

“The GABA system has been of particular interest in the field of TRD research as it has downstream effects on the serotonergic and noradrenergic systems84 and there is evidence of reduced GABA levels in patients with MDD.49,131”

What the sources say

• Not checked yetcites [84] Luscher B, Shen Q, Sahir N. The GABAergic deficit hypothesis of major depressive disorder. Mol Psychiatry. 2011; 16(4): 383– 406. 21079608 PMC3412149
• Not checked yetcites [49] Hasler G, van der Veen JW, Tumonis T, Meyers N, Shen J, Drevets WC. Reduced prefrontal glutamate/glutamine and gamma-aminobutyric acid levels in major depression determined using proton magnetic resonance spectroscopy. Arch Gen Psychiatry. 2007; 64(2): 193– 200. doi: 10.1001/archpsyc.64.2.193 17283286
• Not checked yetcites [131] Sanacora G, Gueorguieva R, Epperson CN, et al. Subtype-specific alterations of gamma-aminobutyric acid and glutamate in patients with major depression. Arch Gen Psychiatry. 2004; 61(7): 705– 713. doi: 10.1001/archpsyc.61.7.705 15237082

In the paper

“Taken together, these results suggest that anti-inflammatory therapy may have a novel role in treating TRD patients, but largely only in those who demonstrate markers of inflammation.”

In the paper

“Cyclooxygenase-2 inhibitors (COX-2 inhibitors) were initially the focus of anti-inflammatory research in TRD and were investigated as augmentation options for traditional antidepressant pharmacotherapy.32,101”

What the sources say

• Not checked yetcites [32] Faridhosseini F, Sadeghi R, Farid L, Pourgholami M. Celecoxib: a new augmentation strategy for depressive mood episodes. A systematic review and meta-analysis of randomized placebo-controlled trials. Hum Psychopharmacol. 2014; 29(3): 216– 223. doi: 10.1002/hup.v29.3 24911574
• Not checked yetcites [101] Na KS, Lee KJ, Lee JS, Cho YS, Jung HY. Efficacy of adjunctive celecoxib treatment for patients with major depressive disorder: a meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry. 2014; 48: 79– 85. doi: 10.1016/j.pnpbp.2013.09.006 24056287

In the paper

“The neurosteroid brexanolone, an intravenous formation of allopregnanolone which acts by enhancing GABAergic inhibition, was FDA approved this year for the treatment of post-partum depression.144”

What the sources say

• Not checked yetcites [144] Wisner KL, Stika CS, Ciolino JD. The first food and drug administration-indicated drug for postpartum depression-brexanolone. JAMA Psychiatry. 2019; 76: 1001. doi: 10.1001/jamapsychiatry.2019.1546 31241747

In the paper

“In this study the substance was relatively well tolerated, although transient anxiety was frequently experienced, as was mild tachycardia.”

What the sources say

• Not checked yetcites [16] Carhart-Harris RL, Bolstridge M, Rucker J, et al. Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. Lancet Psychiatry. 2016; 3(7): 619– 627. doi: 10.1016/S2215-0366(16)30065-7 27210031

In the paper

“By allosterically enhancing GABAA receptor function, the antidepressant activity of allopregnanolone is attributed to an increase in GABAergic inhibition.97,102”

What the sources say

• Not checked yetcites [97] Meltzer-Brody S, Colquhoun H, Riesenberg R, et al. Brexanolone injection in post-partum depression: two multicentre, double-blind, randomised, placebo-controlled, Phase 3 trials. Lancet. 2018; 392(10152): 1058– 1070. doi: 10.1016/S0140-6736(18)31551-4 30177236
• Not checked yetcites [102] Naguy A. Brexanolone and postpartum depression: what does it have to do with GABA? Arch Womens Ment Health. 2019; 22(6): 833– 834. doi: 10.1007/s00737-019-00986-0 31302763

In the paper

“the effects of ketamine appear to come on rapidly and last approximately 5–7 days145”

What the sources say

• Not checked yetcites [145] Xu Y, Hackett M, Carter G, et al. Effects of low-dose and very low-dose ketamine among patients with major depression: a systematic review and meta-analysis. Int J Neuropsychopharmacol. 2016; 19(4). PMC4851268 26578082