Cited by 448Treatment of Major DepressionElectroconvulsive Therapy StudiesTranscranial Magnetic Stimulation Studies

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Management of Treatment-Resistant Depression: Challenges and Strategies

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Voineskos, Daphne, Daskalakis, Zafiris J, Blumberger, Daniel M.·2020·Neuropsychiatric Disease and Treatment

DOI 10.2147/ndt.s198774PMC PMC6982454

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Abstract

Treatment-resistant depression (TRD) is a subset of Major Depressive Disorder which does not respond to traditional and first-line therapeutic options. There are several definitions and staging models of TRD and a consensus for each has not yet been established. However, in common for each model is the inadequate response to at least 2 trials of antidepressant pharmacotherapy. In this review, a comprehensive analysis of existing literature regarding the challenges and management of TRD has been compiled. A PubMed search was performed to assemble meta-analyses, trials and reviews on the topic of TRD. First, we address the confounds in the definitions and staging models of TRD, and subsequently the difficulties inherent in assessing the illness. Pharmacological augmentation strategies including lithium, triiodothyronine and second-generation antipsychotics are reviewed, as is switching of antidepressant class. Somatic therapies, including several modalities of brain stimulation (electroconvulsive therapy, repetitive transcranial magnetic stimulation, magnetic seizure therapy and deep brain stimulation) are detailed, psychotherapeutic strategies and subsequently novel therapeutics including ketamine, psilocybin, anti-inflammatories and new directions are reviewed in this manuscript. Our review of the evidence suggests that further large-scale work is necessary to understand the appropriate treatment pathways for TRD and to prescribe effective therapeutic options for patients suffering from TRD.

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TL;DR

This review synthesizes definitions, assessment challenges, and treatment options for treatment-resistant depression (TRD), noting no consensus definition but a common criterion of inadequate response to at least two antidepressant trials. It reviews pharmacological, psychotherapeutic, brain stimulation, and novel therapies, concluding that large-scale work is still needed to establish treatment pathways and maintain remission.

Key findings

TRD affects approximately 30% of people with MDD; in STAR*D, cumulative remission after 4 antidepressant trials was 67%, and 10%–20% of MDD patients remained significantly symptomatic for 2 years or longer.
ECT remains the best-established option: bitemporal standard pulse ECT has a response rate up to 75%; the CORE report found 65% remission by the tenth treatment and 75% by the end of the course, yet only 0.25% of almost 1 million patients with a mood disorder in US insurance data received ECT.
rTMS showed a 29.3% response rate in 1371 TRD patients, almost double the 16.8% response rate seen with antidepressant medications beyond the third sequential trial; rTMS was 5 times more likely to help TRD patients achieve remission than sham, with a 4.5% adverse-effect discontinuation rate versus 25.1% for antidepressant medication.
Novel therapeutics include ketamine, whose effects last approximately 5–7 days and which has an FDA-approved intranasal esketamine form; psilocybin produced 58% response up to 3 months in 12 TRD patients; and SAGE-217 produced 79% response versus 41% for placebo on day 15 in 89 patients with MDD.

Methods

A PubMed search was performed to assemble meta-analyses, trials, and reviews on TRD; recent meta-analyses and original studies were collated, and the review was limited to studies.
The review covers definitions and staging models, assessment challenges, pharmacological augmentation and switching, psychotherapy, brain stimulation modalities (ECT, rTMS, MST, DBS, VNS), and novel therapeutics including ketamine, psilocybin, anti-inflammatories, and other rapid-acting antidepressants.
No primary data collection or formal meta-analysis is reported.

Limitations

Stated: there is no consensus definition or staging model for TRD; further large-scale work is necessary to understand appropriate treatment pathways and prescribe effective options.
Stated: little is known about maintaining remission from TRD aside from continuation strategies with ECT; many brain stimulation trials are small and few report continuation treatment or relapse prevention.
Evident from the text: as a review/meta-review, it does not report a systematic search strategy, inclusion/exclusion criteria, or risk-of-bias assessment, and conclusions rely on heterogeneous studies and definitions.

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Registry

Crossref · 10.2147/ndt.s198774

Cites

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In the paper
“In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, the cumulative remission rate after 4 trials of antidepressant treatment (within 14 months) was 67%.125”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Introduction
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
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None of the sources cited for this claim have been checked yet.
In the paper
“Even after sequential treatments, 10% to 20% of the MDD patients remained significantly symptomatic for 2 years or longer.69,70”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Introduction
What the sources say
- Not checked yetcites [69] Keitner GI, Ryan CE, Solomon DA. Realistic expectations and a disease management model for depressed patients with persistent symptoms. J Clin Psychiatry. 2006; 67(9): 1412– 1421. doi: 10.4088/JCP.v67n0912 17017828
- Not checked yetcites [70] Keller MB, Shapiro RW, Lavori PW, Wolfe N. Recovery in major depressive disorder: analysis with the life table and regression models. Arch Gen Psychiatry. 1982; 39(8): 905– 910. doi: 10.1001/archpsyc.1982.04290080025004 7103679
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In the paper
“MDD is, therefore, a very heterogeneous disorder, and approximately 30% of people with this illness are resistant to conventional treatments.96”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Introduction
What the sources say
- Not checked yetcites [96] McLachlan G. Treatment resistant depression: what are the options? BMJ. 2018; 363: k5354. doi: 10.1136/bmj.k5354 30563939
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In the paper
“In the meta-analysis referenced here, the augmentation of TCA with T3 had a number needed to treat of 4.3.5”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Therapeutic Options for TRD > Traditional Pharmacological Approaches
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
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In the paper
“Importantly, there is little concrete evidence that switching to medication from the same antidepressant class is an effective strategy for MDD.112”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Therapeutic Options for TRD > Traditional Pharmacological Approaches
What the sources say
- Not checked yetcites [112] Papakostas GI, Fava M, Thase ME. Treatment of SSRI-resistant depression: a meta-analysis comparing within- versus across-class switches. Biol Psychiatry. 2008; 63(7): 699– 704. doi: 10.1016/j.biopsych.2007.08.010 17919460
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In the paper
“In general, it is accepted that although antidepressant medications can be effective in treating MDD, they fail to achieve remission in approximately 1 out of 3 patients.73”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Introduction
What the sources say
- Not checked yetcites [73] Kennedy SH, Giacobbe P. Treatment resistant depression–advances in somatic therapies. Ann Clin Psychiatry. 2007; 19(4): 279– 287. doi: 10.1080/10401230701675222 18058285
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In the paper
“Below, we have focused on the three main augmentation strategies with strong evidence vs placebo augmentation in detail: lithium, T3 and second-generation antipsychotics.148”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Therapeutic Options for TRD > Traditional Pharmacological Approaches
What the sources say
- Not checked yetcites [148] Zhou X, Ravindran AV, Qin B, et al. Comparative efficacy, acceptability, and tolerability of augmentation agents in treatment-resistant depression: systematic review and network meta-analysis. J Clin Psychiatry. 2015; 76(4): e487– e498. doi: 10.4088/JCP.14r09204 25919841
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In the paper
“Olanzapine was examined specifically in combination with fluoxetine, with the combination demonstrating 60% response in a sample of 28 patients with TRD.132”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Therapeutic Options for TRD > Traditional Pharmacological Approaches
What the sources say
- Not checked yetcites [132] Shelton RC, Tollefson GD, Tohen M, et al. A novel augmentation strategy for treating resistant major depression. Am J Psychiatry. 2001; 158(1): 131– 134. doi: 10.1176/appi.ajp.158.1.131 11136647
Strength:boosted· not yet calibratedCausal:direct· not yet calibratedn = 28
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
None of the sources cited for this claim have been checked yet.
In the paper
“In the augmentation of SSRIs, open-label studies have shown some promise.2,63,72”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Therapeutic Options for TRD > Traditional Pharmacological Approaches
What the sources say
- Not checked yetcites [2] Abraham G, Milev R, Stuart Lawson J. T3 augmentation of SSRI resistant depression. J Affect Disord. 2006; 91(2–3): 211– 215. doi: 10.1016/j.jad.2006.01.013 16483669
- Not checked yetcites [63] Iosifescu DV, Nierenberg AA, Mischoulon D, et al. An open study of triiodothyronine augmentation of selective serotonin reuptake inhibitors in treatment-resistant major depressive disorder. J Clin Psychiatry. 2005; 66(8): 1038– 1042. doi: 10.4088/JCP.v66n0812 16086620
- Not checked yetcites [72] Kelly TF, Lieberman DZ. Long term augmentation with T3 in refractory major depression. J Affect Disord. 2009; 115(1–2): 230– 233. doi: 10.1016/j.jad.2008.09.022 19108898
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In the paper
“The best evidence for augmenting antidepressant pharmacotherapy with lithium comes from studies involving tricyclic antidepressants (TCAs).24”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Therapeutic Options for TRD > Traditional Pharmacological Approaches
What the sources say
- Not checked yetcites [24] Crossley NA, Bauer M. Acceleration and augmentation of antidepressants with lithium for depressive disorders: two meta-analyses of randomized, placebo-controlled trials. J Clin Psychiatry. 2007; 68(6): 935– 940. doi: 10.4088/JCP.v68n0617 17592920
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In the paper
“A study by Baumann et al9 demonstrated benefit to augmenting citalopram with lithium, resulting in a 60% response rate in 24 patients, compared to a 14% response rate in the placebo arm.”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Therapeutic Options for TRD > Traditional Pharmacological Approaches
What the sources say
- Not checked yetcites [9] Baumann P, Nil R, Souche A, et al. A double-blind, placebo-controlled study of citalopram with and without lithium in the treatment of therapy-resistant depressive patients: a clinical, pharmacokinetic, and pharmacogenetic investigation. J Clin Psychopharmacol. 1996; 16(4): 307– 314. doi: 10.1097/00004714-199608000-00006 8835706
Strength:boosted· not yet calibratedCausal:direct· not yet calibratedn = 24
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None of the sources cited for this claim have been checked yet.
In the paper
“Specifically, quetiapine,8,31 aripiprazole,12,13,88 olanzapine132 and risperidone68,86 have good evidence in the augmentation of ADs for TRD.”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Therapeutic Options for TRD > Traditional Pharmacological Approaches
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
- Not checked yetcites [12] Berman RM, Marcus RN, Swanink R, et al. The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: a multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2007; 68(6): 843– 853. doi: 10.4088/JCP.v68n0604 17592907
Load-bearingStrength:plain· not yet calibratedCausal:correlational· not yet calibratedn = 28
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
In the paper
“The STAR*D trial reported a 16% remission in the group of patients taking citalopram augmented by lithium.”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Therapeutic Options for TRD > Traditional Pharmacological Approaches
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
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None of the sources cited for this claim have been checked yet.
In the paper
“Despite this evidence, and the anti-suicidal nature of lithium,22,47 it continues to be under-utilized and under-prescribed.118”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Therapeutic Options for TRD > Traditional Pharmacological Approaches
What the sources say
- Not checked yetcites [22] Cipriani A, Hawton K, Stockton S, Geddes JR. Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis. BMJ. 2013; 346: f3646. doi: 10.1136/bmj.f3646 23814104
- Not checked yetcites [47] Guzzetta F, Tondo L, Centorrino F, Baldessarini RJ. Lithium treatment reduces suicide risk in recurrent major depressive disorder. J Clin Psychiatry. 2007; 68(3): 380– 383. doi: 10.4088/JCP.v68n0304 17388706
- Not checked yetcites [118] Post RM. The new news about lithium: an underutilized treatment in the United States. Neuropsychopharmacology. 2018; 43(5): 1174– 1179. doi: 10.1038/npp.2017.238 28976944 PMC5854802
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In the paper
“In fact, a meta-analysis more recently compiled compelling data that lithium is just as effective as the more common second-generation antipsychotics prescribed for augmentation.104”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Therapeutic Options for TRD > Traditional Pharmacological Approaches
What the sources say
- Not checked yetcites [104] Nelson JC, Baumann P, Delucchi K, Joffe R, Katona C. A systematic review and meta-analysis of lithium augmentation of tricyclic and second generation antidepressants in major depression. J Affect Disord. 2014; 168: 269– 275. doi: 10.1016/j.jad.2014.05.053 25069082
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In the paper
“A recent Cochrane review examined 6 studies of psychological interventions for TRD,59 including dialectical behavioural therapy, cognitive behavioural therapy, interpersonal therapy and intensive short-term dynamic psychotherapy.”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Therapeutic Options for TRD > Traditional Pharmacological Approaches
What the sources say
- Not checked yetcites [59] Ijaz S, Davies P, Williams CJ, Kessler D, Lewis G, Wiles N. Psychological therapies for treatment-resistant depression in adults.”. Cochrane Database Syst Rev. 2018; 5: CD010558. 29761488 PMC6494651
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None of the sources cited for this claim have been checked yet.
In the paper
“Meta-analyses have shown that ECT is superior to sham ECT, placebo or antidepressant medications.45,111”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Electroconvulsive Therapy
What the sources say
- 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
- Not checked yetcites [111] Pagnin D, de Queiroz V, Pini S, Cassano GB. Efficacy of ECT in depression: a meta-analytic review. J ECT. 2004; 20(1): 13– 20. doi: 10.1097/00124509-200403000-00004 15087991
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In the paper
“A report by the CORE Group57 found that 65% of patients who underwent bilateral ECT 3 times per week achieved remission by the tenth treatment.”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Electroconvulsive Therapy
What the sources say
- Not checked yetcites [57] Husain MM, Rush AJ, Fink M, et al. Speed of response and remission in major depressive disorder with acute electroconvulsive therapy (ECT): a Consortium for Research in ECT (CORE) report. J Clin Psychiatry. 2004; 65(4): 485– 491. doi: 10.4088/JCP.v65n0406 15119910
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In the paper
“In this study of 212 patients with MDD, the remission rate with deep TMS was 32.6%, compared to 14.6% with sham rTMS.”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Repetitive Transcranial Magnetic Stimulation
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
Load-bearingStrength:plain· not yet calibratedn = 212
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
None of the sources cited for this claim have been checked yet.
In the paper
“rTMS was initially tested in healthy volunteers, who demonstrated moderate mood improvements44,115 after application over the left DLPFC.”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Repetitive Transcranial Magnetic Stimulation
What the sources say
- Not checked yetcites [44] George MS, Wassermann EM, Williams WA, et al. Changes in mood and hormone levels after rapid-rate transcranial magnetic stimulation (rTMS) of the prefrontal cortex. J Neuropsychiatry Clin Neurosci. 1996; 8(2): 172– 180. 9081553
- Not checked yetcites [115] Pascual-Leone A, Catala MD, Pascual-Leone A. Lateralized effect of rapid-rate transcranial magnetic stimulation of the prefrontal cortex on mood. Neurology. 1996; 46(2): 499– 502. doi: 10.1212/WNL.46.2.499 8614521
Strength:boosted· not yet calibratedCausal:direct· not yet calibrated
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In the paper
“Deep TMS has been shown to be relatively well tolerated, especially in late-life populations.65”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Repetitive Transcranial Magnetic Stimulation
What the sources say
- Not checked yetcites [65] Kaster TS, Daskalakis ZJ, Noda Y, et al. Efficacy, tolerability, and cognitive effects of deep transcranial magnetic stimulation for late-life depression: a prospective randomized controlled trial. Neuropsychopharmacology. 2018; 43(11): 2231– 2238. doi: 10.1038/s41386-018-0121-x 29946106 PMC6135812
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In the paper
“Using focal, high-frequency TMS, George and colleagues found strikingly beneficial effects of rTMS to the left prefrontal cortex in four of six patients with TRD;43”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Repetitive Transcranial Magnetic Stimulation
What the sources say
- Not checked yetcites [43] George MS, Wassermann EM, Williams WA, et al. Daily repetitive transcranial magnetic stimulation (rTMS) improves mood in depression. Neuroreport. 1995; 6(14): 1853– 1856. doi: 10.1097/00001756-199510020-00008 8547583
Strength:boosted· not yet calibratedCausal:direct· not yet calibratedn = 4
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In the paper
“Other studies have reported that over 50% of patients who have failed to respond to one or more adequate antidepressant medication trials respond to ECT.120”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Electroconvulsive Therapy
What the sources say
- Not checked yetcites [120] Prudic J, Haskett RF, Mulsant B, et al. Resistance to antidepressant medications and short-term clinical response to ECT. Am J Psychiatry. 1996; 153(8): 985– 992. 8678194
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In the paper
“A systematic review and meta-analysis published in the Journal of Clinical Psychiatry relatively recently, reported that rTMS was 5 times more likely to help TRD patients achieve remission than placebo (“sham”) TMS.40”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Repetitive Transcranial Magnetic Stimulation
What the sources say
- Not checked yetcites [40] Gaynes BN, Lloyd SW, Lux L, et al. Repetitive transcranial magnetic stimulation for treatment-resistant depression: a systematic review and meta-analysis.”. J Clin Psychiatry. 2014; 75(5): 477– 489. doi: 10.4088/JCP.13r08815 24922485
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In the paper
“Interestingly, cognitive behavioural therapy appeared to have good effects in the “medium” and “long term” ranges (12 and 46 months, respectively) after the acute treatment phase in terms of lower depression scores.”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Therapeutic Options for TRD > Traditional Pharmacological Approaches
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
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In the paper
“Early research into these alternate coil designs and configurations determined that by increasing the strength and depth of the stimulus in the cortex, there was a reciprocal relationship with focality of the stimulus.28”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Repetitive Transcranial Magnetic Stimulation
What the sources say
- Not checked yetcites [28] Deng ZD, Lisanby SH, Peterchev AV. Electric field depth-focality tradeoff in transcranial magnetic stimulation: simulation comparison of 50 coil designs. Brain Stimul. 2013; 6(1): 1– 13. doi: 10.1016/j.brs.2012.02.005 22483681 PMC3568257
Strength:plain· not yet calibratedCausal:correlational· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
In the paper
“ECT was initially thought to be the most effective in what was previously termed “melancholic depression”, but evidence has demonstrated that a depressive episode with catatonic or psychotic symptoms has a greater likelihood of responding to a course of ECT.113”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Electroconvulsive Therapy
What the sources say
- Not checked yetcites [113] Parker G, Roy K, Hadzi-Pavlovic D, Pedic F. Psychotic (delusional) depression: a meta-analysis of physical treatments. J Affect Disord. 1992; 24(1): 17– 24. doi: 10.1016/0165-0327(92)90056-C 1347545
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None of the sources cited for this claim have been checked yet.
In the paper
“Several small trials initially indicated that iTBS had the potential to be effective in TRD.19,53,78”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Repetitive Transcranial Magnetic Stimulation
What the sources say
- Not checked yetcites [19] Chistyakov AV, Rubicsek O, Kaplan B, Zaaroor M, Klein E. Safety, tolerability and preliminary evidence for antidepressant efficacy of theta-burst transcranial magnetic stimulation in patients with major depression. Int J Neuropsychopharmacol. 2010; 13(3): 387– 393. doi: 10.1017/S1461145710000027 20128955
- Not checked yetcites [53] Holzer M, Padberg F. Intermittent theta burst stimulation (iTBS) ameliorates therapy-resistant depression: a case series. Brain Stimul. 2010; 3(3): 181– 183. doi: 10.1016/j.brs.2009.10.004 20633448
- Not checked yetcites [78] Li CT, Chen MH, Juan CH, et al. Efficacy of prefrontal theta-burst stimulation in refractory depression: a randomized sham-controlled study. Brain. 2014; 137(Pt 7): 2088– 2098. doi: 10.1093/brain/awu109 24817188
Load-bearingStrength:hedged· not yet calibratedCausal:conditional· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
In the paper
“In the entire sample, 75% of patients achieved remission by the end of the course, reinforcing the impressive efficacy rate of ECT.”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Electroconvulsive Therapy
What the sources say
- Not checked yetcites [57] Husain MM, Rush AJ, Fink M, et al. Speed of response and remission in major depressive disorder with acute electroconvulsive therapy (ECT): a Consortium for Research in ECT (CORE) report. J Clin Psychiatry. 2004; 65(4): 485– 491. doi: 10.4088/JCP.v65n0406 15119910
Strength:plain· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
In the paper
“in one of these patients, the beneficial effects of rTMS were associated with normalisation of prefrontal hypometabolism, as shown by positron emission tomography.”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Repetitive Transcranial Magnetic Stimulation
What the sources say
- Not checked yetcites [43] George MS, Wassermann EM, Williams WA, et al. Daily repetitive transcranial magnetic stimulation (rTMS) improves mood in depression. Neuroreport. 1995; 6(14): 1853– 1856. doi: 10.1097/00001756-199510020-00008 8547583
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedSingle case
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
In the paper
“In fact, a recent investigation of American health insurance databases identified that only 0.25% of almost 1 million patients with a mood disorder received ECT.142”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Electroconvulsive Therapy
What the sources say
- Not checked yetcites [142] Wilkinson ST, Agbese E, Leslie DL, Rosenheck RA. Identifying recipients of electroconvulsive therapy: data from privately insured Americans. Psychiatr Serv. 2018; 69(5): 542– 548. doi: 10.1176/appi.ps.201700364 29385954 PMC6248332
Strength:plain· not yet calibratedSingle case
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
In the paper
“A report from the Consortium for Research in ECT (CORE)57 revealed that over half of the subjects showed an improvement within the first week.”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Electroconvulsive Therapy
What the sources say
- Not checked yetcites [57] Husain MM, Rush AJ, Fink M, et al. Speed of response and remission in major depressive disorder with acute electroconvulsive therapy (ECT): a Consortium for Research in ECT (CORE) report. J Clin Psychiatry. 2004; 65(4): 485– 491. doi: 10.4088/JCP.v65n0406 15119910
Strength:plain· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
In the paper
“The remission rate was likely low as patients had fewer stimulus trains and fewer days of treatment.”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Repetitive Transcranial Magnetic Stimulation
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
Strength:hedged· not yet calibratedCausal:conditional· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
In the paper
“Theta-burst stimulation (TBS) is a recently developed form of rTMS that appears to more closely target and induce cortical plasticity than conventional rTMS by approximating the endogenous theta frequency emitted by the brain.136”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Repetitive Transcranial Magnetic Stimulation
What the sources say
- Not checked yetcites [136] Suppa A, Huang YZ, Funke K, et al. Ten years of theta burst stimulation in humans: established knowledge, unknowns and prospects. Brain Stimul. 2016; 9(3): 323– 335. doi: 10.1016/j.brs.2016.01.006 26947241
Strength:hedged· not yet calibratedCausal:conditional· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
None of the sources cited for this claim have been checked yet.
In the paper
“these studies utilized lower powered MST devices”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Magnetic Seizure Therapy
What the sources say
- Not checked yetcites [67] Kayser S, Bewernick BH, Matusch A, Hurlemann R, Soehle M, Schlaepfer TE. Magnetic seizure therapy in treatment-resistant depression: clinical, neuropsychological and metabolic effects. Psychol Med. 2015; 45(5): 1073– 1092. doi: 10.1017/S0033291714002244 25420474
- Not checked yetcites [37] Fitzgerald PB, Hoy KE, Herring SE, Clinton AM, Downey G, Daskalakis ZJ. Pilot study of the clinical and cognitive effects of high-frequency magnetic seizure therapy in major depressive disorder. Depress Anxiety. 2013; 30(2): 129– 136. doi: 10.1002/da.22005 23080404
Strength:plain· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
In the paper
“It is focally discharged over the prefrontal cortex and evidence shows significantly fewer cognitive side effects with MST.”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Magnetic Seizure Therapy
What the sources say
- Not checked yetcites [56] Hoy KE, Fitzgerald PB. Magnetic seizure therapy for treatment-resistant depression. Expert Rev Med Devices. 2011; 8(6): 723– 732. doi: 10.1586/erd.11.55 22029469
Load-bearingStrength:boosted· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
None of the sources cited for this claim have been checked yet.
In the paper
“Earlier studies of DBS applied to the SCC report variable response rates over several months that appear to improve over time, ranging from 29% to 75%.74,82,90”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Deep Brain Stimulation
What the sources say
- Not checked yetcites [74] Kennedy SH, Giacobbe P, Rizvi SJ, et al. Deep brain stimulation for treatment-resistant depression: follow-up after 3 to 6 years. Am J Psychiatry. 2011; 168(5): 502– 510. doi: 10.1176/appi.ajp.2010.10081187 21285143
- Not checked yetcites [82] Lozano AM, Giacobbe P, Hamani C, et al. A multicenter pilot study of subcallosal cingulate area deep brain stimulation for treatment-resistant depression. J Neurosurg. 2012; 116(2): 315– 322. doi: 10.3171/2011.10.JNS102122 22098195
- Not checked yetcites [90] Mayberg HS, Lozano AM, Voon V, et al. Deep brain stimulation for treatment-resistant depression. Neuron. 2005; 45(5): 651– 660. doi: 10.1016/j.neuron.2005.02.014 15748841
Strength:hedged· not yet calibratedCausal:correlational· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
In the paper
“the single high dose study targeting the SCC reported a 92% response rate at 2 years post-implantation in a TRD sample.52”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Deep Brain Stimulation
What the sources say
- Not checked yetcites [52] Holtzheimer PE, Kelley ME, Gross RE, et al. Subcallosal cingulate deep brain stimulation for treatment-resistant unipolar and bipolar depression. Arch Gen Psychiatry. 2012; 69(2): 150– 158. doi: 10.1001/archgenpsychiatry.2011.1456 22213770 PMC4423545
Strength:plain· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
In the paper
“The FDA approved VNS as an adjunctive long-term therapy for TRD, specifically in patients who have not responded to 4 or more different medications.17”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Vagus Nerve Stimulation
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
Strength:plain· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
In the paper
“A large meta-analysis of non-surgical brain stimulation in TRD reported on studies of different electrode placements in ECT, several types of rTMS and transcranial direct current stimulation (tDCS).100”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Vagus Nerve 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
Strength:plain· not yet calibratedn = 6,000
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
In the paper
“The analysis suffered from small sample sizes of several investigatory trials and called for new, large-scale, high quality randomized controlled trials to further categorize rTMS paradigms by efficacy.”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Repetitive Transcranial Magnetic Stimulation
What the sources say
- Not checked yetcites Brunoni et al15
Load-bearingStrength:plain· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
In the paper
“This larger scale trial analysed outcomes for 86 patients with moderately resistant TRD, as assessed by the ATHF.”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Magnetic Seizure Therapy
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
Load-bearingStrength:plain· not yet calibratedn = 86
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
In the paper
“with 84% of individuals who have remitted with ECT relapsing within 6 months if no further treatment (ECT or pharmacotherapy) ensued.129”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Vagus Nerve Stimulation
What the sources say
- Not checked yetcites [129] Sackeim HA, Haskett RF, Mulsant BH, et al. Continuation pharmacotherapy in the prevention of relapse following electroconvulsive therapy: a randomized controlled trial. JAMA. 2001; 285(10): 1299– 1307. doi: 10.1001/jama.285.10.1299 11255384
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
In the paper
“Neurophysiological evidence supporting these proposals demonstrates higher levels of neuroplasticity and cortical excitability with multiple rTMS sessions in one day.85”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Repetitive Transcranial Magnetic Stimulation
What the sources say
- Not checked yetcites [85] Maeda F, Keenan JP, Tormos JM, Topka H, Pascual-Leone A. Modulation of corticospinal excitability by repetitive transcranial magnetic stimulation. Clin Neurophysiol. 2000; 111(5): 800– 805. doi: 10.1016/S1388-2457(99)00323-5 10802449
Strength:boosted· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
In the paper
“Comparably, an earlier pilot study of 13 patients37 reported a response rate of 38% and remission rate of 15%.”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Magnetic Seizure Therapy
What the sources say
- Not checked yetcites [37] Fitzgerald PB, Hoy KE, Herring SE, Clinton AM, Downey G, Daskalakis ZJ. Pilot study of the clinical and cognitive effects of high-frequency magnetic seizure therapy in major depressive disorder. Depress Anxiety. 2013; 30(2): 129– 136. doi: 10.1002/da.22005 23080404
Strength:plain· not yet calibratedn = 13
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
In the paper
“More recent evidence purports that ketamine’s antidepressant effects are at least in part due to action on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors downstream from the initial NMDAR effects.147”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Novel Therapeutics > Ketamine
What the sources say
- Not checked yetcites [147] Zanos P, Gould TD. Mechanisms of ketamine action as an antidepressant. Mol Psychiatry. 2018; 23(4): 801– 811. doi: 10.1038/mp.2017.255 29532791 PMC5999402
Strength:hedged· not yet calibratedCausal:conditional· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
In the paper
“Novel compounds targeting the delta opioid receptor have shown promise in small initial drug development trials.122”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Novel Therapeutics > Novel Therapeutic Compounds and Rapid Acting Antidepressants
What the sources say
- Not checked yetcites [122] Richards EM, Mathews DC, Luckenbaugh DA, et al. A randomized, placebo-controlled pilot trial of the delta opioid receptor agonist AZD2327 in anxious depression. Psychopharmacology (Berl). 2016; 233(6): 1119– 1130. doi: 10.1007/s00213-015-4195-4 26728893 PMC5103283
Strength:plain· not yet calibratedCausal:conditional· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
In the paper
“Evidence of hypercholinergic states in MDD39 has also guided research towards the development and examination of anticholinergic compounds, such as the repurposing of scopolamine, an antimuscarinic medication.”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Novel Therapeutics > Novel Therapeutic Compounds and Rapid Acting Antidepressants
What the sources say
- Not checked yetcites [39] Furey ML, Drevets WC. Antidepressant efficacy of the antimuscarinic drug scopolamine: a randomized, placebo-controlled clinical trial. Arch Gen Psychiatry. 2006; 63(10): 1121– 1129. doi: 10.1001/archpsyc.63.10.1121 17015814 PMC3250308
Strength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
In the paper
“In a sample of patients with MDD, an initial intravenous infusion of scopolamine resulted in significantly reduced depression and anxiety symptoms within a few days, when compared to placebo.30”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Novel Therapeutics > Novel Therapeutic Compounds and Rapid Acting Antidepressants
What the sources say
- Not checked yetcites [30] Drevets WC, Furey ML. Replication of scopolamine’s antidepressant efficacy in major depressive disorder: a randomized, placebo-controlled clinical trial. Biol Psychiatry. 2010; 67(5): 432– 438. doi: 10.1016/j.biopsych.2009.11.021 20074703 PMC3264395
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
In the paper
“More recently, a tumour necrosis factor (TNF) antagonist, infliximab, has been investigated specifically in TRD patients with elevated plasma CRP levels, compared to TRD patients without elevated peripheral inflammatory markers.121”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Novel Therapeutics > Anti-Inflammatories
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
Load-bearingStrength:plain· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
None of the sources cited for this claim have been checked yet.
In the paper
“with a preferential treatment effect in individuals with comorbid anxiety or an “anxious depression”.60,61”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Novel Therapeutics > Ketamine
What the sources say
- Not checked yetcites [60] Ionescu DF, Luckenbaugh DA, Niciu MJ, et al. Effect of baseline anxious depression on initial and sustained antidepressant response to ketamine. J Clin Psychiatry. 2014; 75(9): e932– e938. doi: 10.4088/JCP.14m09049 25295436
- Not checked yetcites [61] Ionescu DF, Luckenbaugh DA, Niciu MJ, Richards EM, Zarate CA Jr. A single infusion of ketamine improves depression scores in patients with anxious bipolar depression. Bipolar Disord. 2015; 17(4): 438– 443. doi: 10.1111/bdi.2015.17.issue-4 25400146 PMC4431955
Strength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
In the paper
“A recently developed positive allosteric GABAA receptor modulator, SAGE-217, was investigated in a multi-site trial of 89 patients with MDD for its potentially acute antidepressant effects.46”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Novel Therapeutics > Novel Therapeutic Compounds and Rapid Acting Antidepressants
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
Load-bearingStrength:plain· not yet calibratedn = 89
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes

Probably not a substantial claim. 30
It may state two separate claims as one. 69

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).”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Abstract
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
Load-bearingStrength:plain· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
Probably not a substantial claim.
In the paper
“The Maudsley Staging Method (MSM) assesses treatment resistance in depression in a “multi-dimensional” manner.34”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Defining Treatment-Resistant Depression
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
Strength:plain· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it.
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.”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Challenges in Assessing TRD
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
Strength:hedged· not yet calibratedCausal:conditional· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
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.”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Therapeutic Options for TRD > Traditional Pharmacological Approaches
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
Load-bearingStrength:plain· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
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.”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Defining Treatment-Resistant Depression
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
Strength:plain· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
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.”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Therapeutic Options for TRD > Traditional Pharmacological Approaches
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
Strength:boosted· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
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”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Therapeutic Options for TRD > Traditional Pharmacological Approaches
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
Strength:boosted· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
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”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Defining Treatment-Resistant Depression
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
Strength:plain· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“TRD can also be associated with prolonged, costly periods of inpatient treatment.140”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Introduction
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
Strength:plain· not yet calibratedCausal:correlational· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“As with lithium, the initial T3 studies were performed in augmentation of TCA pharmacotherapy.5,119”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Therapeutic Options for TRD > Traditional Pharmacological Approaches
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
Strength:plain· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it.
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”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Therapeutic Options for TRD > Traditional Pharmacological Approaches
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
Strength:hedged· not yet calibratedCausal:conditional· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
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).”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Defining Treatment-Resistant Depression
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.
Strength:plain· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it.
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%.”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Therapeutic Options for TRD > Traditional Pharmacological Approaches
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
Strength:plain· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
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.”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Challenges in Assessing TRD
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
Strength:plain· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
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”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Challenges in Assessing TRD
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
Strength:hedged· not yet calibratedCausal:conditional· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
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.”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Therapeutic Options for TRD > Traditional Pharmacological Approaches
Load-bearingStrength:hedged· not yet calibratedCausal:conditional· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes? Based: unclear
It may state two separate claims as one.
- Rests on an assumption: Second-generation antipsychotics have some effect on serotonin receptors.
None of the sources cited for this claim have been checked yet.
In the paper
“Chronically depressed patients have a lower chance of recovery,98 and often suffer from TRD.25,87”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Defining Treatment-Resistant Depression
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
Strength:plain· not yet calibratedCausal:correlational· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
In the paper
“Triiodothyronine (T3) is usually the form of thyroid hormone prescribed in augmentation of AD pharmacotherapy.5”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Therapeutic Options for TRD > Traditional Pharmacological Approaches
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
Strength:plain· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Rests on an assumption: Thyroid hormone levels have a significant effect on mood.
- Rests on an assumption: T3 is the hormone form that may have central nervous system activity.
None of the sources cited for this claim have been checked yet.
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”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Electroconvulsive Therapy
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
Strength:boosted· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
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”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Therapeutic Options for TRD > Traditional Pharmacological Approaches
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
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
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”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Electroconvulsive Therapy
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
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
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”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Repetitive Transcranial Magnetic Stimulation
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
Load-bearingStrength:plain· not yet calibratedCausal:correlational· not yet calibratedn = 1,371
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The first large clinical trials for rTMS in MDD were published in 2007110 and subsequently in 2010.42”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Repetitive Transcranial Magnetic Stimulation
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
Strength:plain· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Bitemporal Standard pulse ECT is the most commonly used form,76 with a response rate of up to 75%.”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Electroconvulsive Therapy
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
Strength:plain· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“These are inhibitors of MAO-A and B enzymes and are very effective antidepressants.”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Therapeutic Options for TRD > Traditional Pharmacological Approaches
Strength:plain· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Rests on an assumption: MAOIs are very effective antidepressants.
None of the sources cited for this claim have been checked yet.
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%.”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Therapeutic Options for TRD > Traditional Pharmacological Approaches
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
Strength:boosted· not yet calibratedCausal:correlational· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
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.”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Repetitive Transcranial Magnetic Stimulation
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
Strength:plain· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
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”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Repetitive Transcranial Magnetic Stimulation
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
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedn = 2
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
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”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Therapeutic Options for TRD > Traditional Pharmacological Approaches
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
Strength:plain· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
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”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Therapeutic Options for TRD > Traditional Pharmacological Approaches
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
Load-bearingStrength:hedged· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
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.”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Repetitive Transcranial Magnetic Stimulation
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
Strength:plain· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
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”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Repetitive Transcranial Magnetic Stimulation
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
Strength:plain· not yet calibratedCausal:direct· not yet calibratedn = 212
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
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”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Repetitive Transcranial Magnetic Stimulation
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
Strength:plain· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
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.”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Repetitive Transcranial Magnetic Stimulation
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
Strength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Cognitive scores remained unaffected, aside from autobiographical memory scores, which would be expected to decrease over time.92”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Magnetic Seizure Therapy
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.
Load-bearingStrength:hedged· not yet calibratedn = 86
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
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”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Vagus Nerve Stimulation
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
Strength:plain· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“All rTMS interventions were well tolerated, in a similar manner to sham.”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Repetitive Transcranial Magnetic Stimulation
What the sources say
- Not checked yetcites Brunoni et al15
Load-bearingStrength:plain· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
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.”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Repetitive Transcranial Magnetic Stimulation
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
Strength:plain· not yet calibratedn = 115
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
In the paper
“Over 6000 patients underwent one of these brain stimulation treatments, despite many trials being of small sample size.”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Vagus Nerve 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
Strength:plain· not yet calibratedn = 6,000
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
In the paper
“This trial, the largest brain stimulation trial to date, prompted the FDA to approve iTBS as a novel treatment for TRD.”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Repetitive Transcranial Magnetic Stimulation
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
Strength:plain· not yet calibratedCausal:direct· not yet calibratedn = 414
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
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.”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Magnetic Seizure Therapy
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
Load-bearingStrength:hedged· not yet calibratedCausal:correlational· not yet calibratedn = 86
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
In the paper
“A study by Kayser et al67 reported a 69% response rate in 26 patients with TRD, comparable to ECT response rates.”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Magnetic Seizure Therapy
What the sources say
- Not checked yetcites Kayser et al67
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedn = 26
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
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.”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Vagus Nerve 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
Load-bearingStrength:plain· not yet calibratedn = 6,000
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
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.”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Repetitive Transcranial Magnetic Stimulation
What the sources say
- Not checked yetcites Brunoni et al15
Load-bearingStrength:plain· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
In the paper
“Importantly, tolerability was high in both arms and pain/discomfort scores were similar in each treatment arm.”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Repetitive Transcranial Magnetic Stimulation
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
Strength:plain· not yet calibratedn = 414
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
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”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Repetitive Transcranial Magnetic Stimulation
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
Strength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
- Rests on an assumption: Daily rTMS is quite well tolerated but requires several days to weeks of treatment to induce symptom response.
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%).”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Magnetic Seizure Therapy
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
Load-bearingStrength:plain· not yet calibratedCausal:correlational· not yet calibratedn = 86
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
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.”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Magnetic Seizure Therapy
What the sources say
- Not checked yetcites Daskalakis et al27
Load-bearingStrength:plain· not yet calibratedn = 86
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
In the paper
“High frequency, low frequency, bilateral rTMS and TBS were all found to be superior to sham stimulation in terms of response.”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Repetitive Transcranial Magnetic Stimulation
What the sources say
- Not checked yetcites Brunoni et al15
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
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.”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Magnetic Seizure Therapy
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
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
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.”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Repetitive Transcranial Magnetic Stimulation
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
Strength:plain· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it.
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.”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Repetitive Transcranial Magnetic Stimulation
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
Load-bearingStrength:plain· not yet calibratedn = 414
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
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”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Vagus Nerve Stimulation
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
Strength:hedged· not yet calibratedCausal:correlational· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
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.”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Vagus Nerve 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
Load-bearingStrength:plain· not yet calibratedCausal:correlational· not yet calibratedn = 6,000
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
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.”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Brain Stimulation > Vagus Nerve Stimulation
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
Strength:plain· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
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”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Novel Therapeutics > Ketamine
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
Strength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
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”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Novel Therapeutics > Anti-Inflammatories
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
Load-bearingStrength:hedged· not yet calibratedCausal:correlational· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
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.”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Novel Therapeutics > Ketamine
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
Strength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
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.”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Novel Therapeutics > Novel Therapeutic Compounds and Rapid Acting Antidepressants
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
Load-bearingStrength:plain· not yet calibratedn = 45
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
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.”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Novel Therapeutics > Novel Therapeutic Compounds and Rapid Acting Antidepressants
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
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
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”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Novel Therapeutics > Anti-Inflammatories
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
Strength:hedged· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
In the paper
“In a recent editorial in JAMA Psychiatry, Dr. M. Freeman addresses this specific topic, with recommendations to individualize maintenance interventions.38”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Conclusions
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
Strength:plain· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
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”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Novel Therapeutics > Ketamine
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
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
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”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Novel Therapeutics > Psilocybin
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
Strength:boosted· not yet calibratedCausal:direct· not yet calibratedn = 12
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
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.”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Novel Therapeutics > Anti-Inflammatories
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
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
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”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Novel Therapeutics > Novel Therapeutic Compounds and Rapid Acting Antidepressants
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
Strength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
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”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Novel Therapeutics > Novel Therapeutic Compounds and Rapid Acting Antidepressants
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
Strength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
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”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Novel Therapeutics > Anti-Inflammatories
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
Strength:plain· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
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”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Novel Therapeutics > Anti-Inflammatories
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
Strength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“In this study the substance was relatively well tolerated, although transient anxiety was frequently experienced, as was mild tachycardia.”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Novel Therapeutics > Psilocybin
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
Strength:plain· not yet calibratedn = 12
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“By allosterically enhancing GABAA receptor function, the antidepressant activity of allopregnanolone is attributed to an increase in GABAergic inhibition.97,102”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Novel Therapeutics > Anti-Inflammatories
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
Strength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“the effects of ketamine appear to come on rapidly and last approximately 5–7 days145”
§ Management of Treatment-Resistant Depression: Challenges and Strategies > Novel Therapeutics > Ketamine
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
Strength:hedged· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.

88 of 88

The paper relies on this without support.
Thyroid hormone levels have a significant effect on mood.
“Thyroid hormone levels are known to have a significant effect on mood.”
The paper relies on this without support.
T3 is the hormone form that may have central nervous system activity.
“This is in contrast to the treatment of hypothyroidism, as T3 is the hormone form which may have CNS activity.”
The paper relies on this without support.
T3 is generally better tolerated than lithium and requires significantly less clinical monitoring.
“Importantly, however, T3 is generally better tolerated than lithium and requires significantly less clinical monitoring.”
The paper relies on this without support.
Second-generation antipsychotics have some effect on serotonin receptors.
“SGAs are known to have some effect on serotonin receptors and therefore may be effective in combination with SSRI/SNRIs in treating TRD.”
The paper relies on this without support.
MAOIs are very effective antidepressants.
“These are inhibitors of MAO-A and B enzymes and are very effective antidepressants.”
The paper relies on this without support.
Daily rTMS is quite well tolerated but requires several days to weeks of treatment to induce symptom response.
“As daily rTMS is quite well tolerated but requires several days to weeks of treatment to induce symptom response, newer protocols of multiple treatment sessions per day have been proposed, especially in TRD patients who require urgent response, such as those with acute and severe suicidal ideation.”
The paper relies on this without support.
A relatively large proportion of patients with MDD may be classified as having TRD.
“There are several challenges which accompany the treatment of TRD, not the least of which is the relatively large proportion of patients with MDD who may be classified as having TRD.”
The paper relies on this without support.
Specific guidelines for TRD have not been widely accepted.
“specific guidelines for TRD have not been widely accepted to our knowledge”

8 of 8

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Yaşlı Kadınlarda Üreme Sağlığı
Kokanalı, D., & Engin Üstün, Y. (n.d.) · DergiPark (Istanbul University) · Cited by 170,090
A rating scale for depression
Hamilton, M. (1960) · Journal of Neurology, Neurosurgery & Psychiatry · doi:10.1136/jnnp.23.1.56 · Cited by 32,817 · cited 2×
“…a signi ﬁ cant layer of dif ﬁ culty in diagnosing TRD. Prospectively using objective clinical scales such as the Hamilton Depression Rating Scale 48 and the Inventory of Depressive Symptomatology 124 and retrospectively using treatment history forms such as the Antidepressant Treatment History…”
Correspondence - Tranexamic acid for traumatic brain injury
(2005) · London School of Economics and Political Science Theses Online (London School of Economics and Political Science) · doi:10.1016/s0140-6736 · Cited by 11,894
Molecular Mechanisms of Depression: Perspectives on New Treatment Strategies
Lang, U. E., & Borgwardt, S. (2013) · Cellular Physiology and Biochemistry · doi:10.1159/000350094 · Cited by 8,526
Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report
Rush, A. J., Trivedi, M. H., Wisniewski, S. R., Nierenberg, A. A., Stewart, J. W., Warden, D., Niederehe, G., Thase, M. E., Lavori, P. W., Lebowitz, B. D., et al. (2006) · American Journal of Psychiatry · doi:10.1176/ajp.2006.163.11.1905 · Cited by 5,643
Deep Brain Stimulation for Treatment-Resistant Depression
Mayberg, H. S., Lozano, A. M., Voon, V., McNeely, H. E., Seminowicz, D., Hamani, C., Schwalb, J. M., & Kennedy, S. H. (2005) · Neuron · doi:10.1016/j.neuron.2005.02.014 · Cited by 4,059
Antidepressant effects of ketamine in depressed patients
Berman, R. M., Cappiello, A., Anand, A., Oren, D. A., Heninger, G. R., Charney, D. S., & Krystal, J. H. (2000) · Biological Psychiatry · doi:10.1016/s0006-3223(99)00230-9 · Cited by 3,856
Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans: Psychotomimetic, Perceptual, Cognitive, and Neuroendocrine Responses
Krystal, J. H. (1994) · Archives of General Psychiatry · doi:10.1001/archpsyc.1994.03950030035004 · Cited by 3,330 · cited 1×
“147 Although initially investigated as a psychomime tic substance, 75 the antidepressant effect of ketamine was quickly recognized after a low dose intravenous infusion.”
Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis.
Howren, M. B., Lamkin, D. M., & Suls, J. (2009) · Psychosomatic Medicine · doi:10.1097/psy.0b013e3181907c1b · Cited by 2,766
The Inventory of Depressive Symptomatology (IDS): Psychometric properties
Rush, A. J., Gullion, C. M., Basco, M. R., Jarrett, R. B., & Trivedi, M. H. (1996) · Psychological Medicine · doi:10.1017/s0033291700035558 · Cited by 2,177

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Depression
McCarron, R. M., Shapiro, B. B., Rawles, J., & Luo, J. S. (2021) · Annals of Internal Medicine · doi:10.7326/aitc202105180 · Cited by 511
Psychedelics, mystical experience, and therapeutic efficacy: a systematic review
Ko, K., Knight, G., Rucker, J. J., & Cleare, A. J. (2022) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2022.917199 · Cited by 306
Mobile cognition: imaging the human brain in the ‘real world’
Stangl, M., Maoz, S. L., & Suthana, N. (2023) · Nature reviews. Neuroscience · doi:10.1038/s41583-023-00692-y · Cited by 206
Single-dose psilocybin for a treatment-resistant episode of major depression: Impact on patient-reported depression severity, anxiety, function, and quality of life
Goodwin, G. M., Aaronson, S. T., Alvarez, O., Atli, M., Bennett, J. C., Croal, M., DeBattista, C., Dunlop, B. W., Feifel, D., Hellerstein, D. J., et al. (2023) · Journal of Affective Disorders · doi:10.1016/j.jad.2023.01.108 · Cited by 191
Psychedelic therapy for depressive symptoms: A systematic review and meta-analysis
Ko, K., Kopra, E. I., Cleare, A. J., & Rucker, J. J. (2023) · Journal of Affective Disorders · doi:10.1016/j.jad.2022.09.168 · Cited by 150

See all 448

Authors: Voineskos, D., Daskalakis, Z. J., & Blumberger, D. M.
Affiliations: Centre for Addiction and Mental Health (CA)
Corresponding author: Blumberger, Daniel M.
ORCID: Voineskos, Daphne
Daskalakis, Zafiris J
Blumberger, Daniel M.
Venue: Neuropsychiatric Disease and Treatment
Publisher: Informa UK Limited
Published: 2020-01
Volume: Volume 16
Pages: 221-234
ISSN: 1176-6328 (ISSN-L)
1178-2021
DOI: 10.2147/ndt.s198774
PMC: PMC6982454
OpenAlex: W3000386776
Cited by: 446
References: 161
Citations by year: 2026: 58 · 2025: 95 · 2024: 105 · 2023: 76 · 2022: 61 · 2021: 39 · 2020: 11
FWCI: 6.13
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by-nc
creativecommons.org/licenses/by-nc/3.0/ (unspecified)
Locations: Neuropsychiatric Disease and Treatment (publishedVersion, cc-by-nc)
PubMed Central (publishedVersion, cc-by-nc)
PubMed (publishedVersion)
Dove Medical Press (Taylor and Francis Group) (submittedVersion, cc-by-nc)
Topics: Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
Life Sciences › Neuroscience › Neurology › Transcranial Magnetic Stimulation Studies
Keywords: treatment-resistant depression, major depressive disorder, antidepressant non-response, drug augmentation, lithium, triiodothyronine, atypical antipsychotics, antidepressant switching, electroconvulsive therapy, repetitive transcranial magnetic stimulation, magnetic seizure therapy, deep brain stimulation, ketamine, psilocybin, anti-inflammatory therapy, psychotherapy

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Management of Treatment-Resistant Depression: Challenges and Strategies

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