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

Management of Treatment-Resistant Depression: Challenges and Strategies

Open access
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.

AI snapshot

Written from the paper’s full text.

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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Integrity signals

Registry

Crossref · 10.2147/ndt.s198774

Cites

155 of 155 references verified0 citation errors · 0 not checkable

Statistics

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Claims the paper makes

0 of 164 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    In the STAR*D study, the cumulative remission rate after 4 trials of antidepressant treatment within 14 months was 67%.

    “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”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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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  • Premisecitation

    Even after sequential treatments, 10% to 20% of MDD patients remained significantly symptomatic for 2 years or longer.

    “Even after sequential treatments, 10% to 20% of the MDD patients remained significantly symptomatic for 2 years or longer.69,70”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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

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  • Premisecitation

    Approximately 30% of people with major depressive disorder are resistant to conventional treatments.

    “MDD is, therefore, a very heterogeneous disorder, and approximately 30% of people with this illness are resistant to conventional treatments.96”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [96] McLachlan G. Treatment resistant depression: what are the options? BMJ. 2018; 363: k5354. doi: 10.1136/bmj.k5354 30563939

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  • Premisenone given

    There is no established consensus on the definitions and staging models of treatment-resistant depression.

    “There are several definitions and staging models of TRD and a consensus for each has not yet been established.”
    Quote in the paperSubstantial claim
  • Premisecitation

    In meta-analysis, augmentation of tricyclic antidepressants with T3 had a number needed to treat of 4.3.

    “In the meta-analysis referenced here, the augmentation of TCA with T3 had a number needed to treat of 4.3.5”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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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  • Classified as probably not a substantial claim. 30
  • May combine two claims. 69

  • Classified as probably not a substantial claim.

    Premisecitation

    The general consensus and common feature of TRD definitions is inadequate response to at least 2 trials of antidepressant pharmacotherapy.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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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    Premisecitation

    The Maudsley Staging Method assesses treatment resistance in depression in a multi-dimensional manner.

    “The Maudsley Staging Method (MSM) assesses treatment resistance in depression in a “multi-dimensional” manner.34”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

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    Premisecitation

    Pseudo-resistance may encompass patients prescribed suboptimal doses of antidepressants or early discontinuation due to intolerable side effects, non-adherence or under-dosing.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [107] Nierenberg AA, Amsterdam JD. Treatment-resistant depression: definition and treatment approaches. J Clin Psychiatry. 1990; 51(Suppl): 39– 47. 2112132

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    Premisecitation

    Thase et al. and Peselow et al. examined switching from SSRI/SNRI medications to tricyclic antidepressants, specifically imipramine, and reported response rates of 44-73% in total.

    “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.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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

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    • cites [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

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    Premisecitation

    The Massachusetts General Hospital Staging method documents optimization of medication doses and number of failed medications.

    “Further staging models have included the Massachusetts General Hospital Staging method117 which carefully documents the optimization of medication doses and number of failed medications.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

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    Premisecitation

    APA and WFSBP guidelines strongly recommend lithium as an effective augmentation strategy in MDD.

    “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.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

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    Premisecitation

    Quetiapine at 300 mg per day demonstrated up to 48% response and 24.5% remission in combination with SSRIs and has been approved for adjunctive treatment of MDD by the FDA.

    “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”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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

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    • cites [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

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The Souery Operational Criteria define TRD as any single failure of an adequate 6-8 week trial of an antidepressant.

    “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”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    TRD can be associated with prolonged, costly periods of inpatient treatment.

    “TRD can also be associated with prolonged, costly periods of inpatient treatment.140”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

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    Premisecitation

    Initial T3 studies were performed in augmentation of tricyclic antidepressant pharmacotherapy.

    “As with lithium, the initial T3 studies were performed in augmentation of TCA pharmacotherapy.5,119”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

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    Interpretationcitation

    In STAR*D, lithium levels were kept quite low, which may have contributed to the low-response rate.

    “However, in this large-scale study, lithium levels were kept quite low, which may have contributed to the low-response rate.108”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    There is no consensus on what constitutes an adequate response in TRD.

    “although even the term “adequate response” may be fraught with contention, as there is not consensus on what constitutes “adequate.””
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The initial Thase and Rush staging model included treatment resistance levels ranging from one failed antidepressant trial to lack of response to electroconvulsive therapy.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In STAR*D, T3 augmentation had no statistically significant superiority over lithium, with a T3 augmentation remission rate of 24.7%.

    “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%.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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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    Premisecitation

    The ATHF-SF focuses on the current episode of depression rather than lifetime trials, providing a more streamlined approach to assessing the level of resistance of the current illness episode.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

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    Premisecitation

    Comorbidities such as anxiety disorders, personality disorders or substance-use disorders may complicate the clinical picture and have deleterious effects on treatment response.

    “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”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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

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    • cites [127] Sackeim HA. The definition and meaning of treatment-resistant depression. J Clin Psychiatry. 2001; 62(Suppl 16): 10– 17. 11480879

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  • May combine two claims.

    Interpretationreasoning

    SGAs have some effect on serotonin receptors and therefore may be effective in combination with SSRIs/SNRIs in treating TRD.

    “SGAs are known to have some effect on serotonin receptors and therefore may be effective in combination with SSRI/SNRIs in treating TRD.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Second-generation antipsychotics have some effect on serotonin receptors.

  • May combine two claims.

    Premisecitation

    Chronically depressed patients have a lower chance of recovery and often suffer from TRD.

    “Chronically depressed patients have a lower chance of recovery,98 and often suffer from TRD.25,87”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [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

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    • cites [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

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    • cites [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

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    Premisecitation

    Triiodothyronine (T3) is usually the form of thyroid hormone prescribed in augmentation of antidepressant pharmacotherapy.

    “Triiodothyronine (T3) is usually the form of thyroid hormone prescribed in augmentation of AD pharmacotherapy.5”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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 in the free run.

    • 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.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    Lack of achieving remission may be classified as an inadequate response because residual depressive symptoms can significantly contribute to difficulty functioning.

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

  • May combine two claims.

    Premisecitation

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

    “ECT is the established best therapeutic option for TRD, but its neurophysiological mechanism of action is yet to be elucidated.66,126”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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

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    • cites [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

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    Premisecitation

    In combination with usual care, psychotherapy overall contributed to an improvement in depressive symptoms, especially when the psychotherapy employed was CBASP, CBT, interpersonal therapy or mindfulness-based cognitive therapy.

    “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”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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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    Premisecitation

    ECT remains the most effective option to treat TRD, especially in situations where a patient's life may be at risk.

    “ECT remains the most effective option to treat TRD, especially in situations where a patient’s life may be at risk.149,45”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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

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    • cites [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

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    Premisecitation

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

    “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”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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

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    • cites [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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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The first large clinical trials for rTMS in MDD were published in 2007 and subsequently in 2010.

    “The first large clinical trials for rTMS in MDD were published in 2007110 and subsequently in 2010.42”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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

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    • cites [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

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    Premisecitation

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

    “Bitemporal Standard pulse ECT is the most commonly used form,76 with a response rate of up to 75%.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    MAOIs are inhibitors of MAO-A and B enzymes and are very effective antidepressants.

    “These are inhibitors of MAO-A and B enzymes and are very effective antidepressants.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: MAOIs are very effective antidepressants.

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    Premisecitation

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

    “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%.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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

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    • cites [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

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  • May combine two claims.

    Premisecitation

    In the 2010 rTMS randomized controlled trial, retention rate was 88% overall and minor adverse effects were no different in the active versus sham arms.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

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

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

  • May combine two claims.

    Premisecitation

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

    “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”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In one step of STAR*D, tranylcypromine compared to mirtazapine plus venlafaxine in patients who had not responded to three medication trials showed no significant difference in response, with only 6.9% remission in the tranylcypromine group, which also had poorer tolerance.

    “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”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

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

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

  • May combine two claims.

    Premisecitation

    There appears to be a significant comorbidity of personality disorders with MDD, which leads to diminishing returns with respect to first-line pharmacological treatments.

    “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”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The 2010 rTMS study produced a 14.1% remission rate in the blinded study and approximately 30% remission rate in the follow-up open-label trial.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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.

    “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”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    rTMS has an adverse effect discontinuation rate of only 4.5%, in contrast to the 25.1% discontinuation rate for antidepressant medication.

    “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”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In Fitzgerald et al.'s trial, there were higher rates of treatment discomfort in the accelerated arm, contributing to slightly higher rates of treatment discontinuation in this arm.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cognitive scores remained unaffected in the Daskalakis trial, aside from autobiographical memory scores, which would be expected to decrease over time.

    “Cognitive scores remained unaffected, aside from autobiographical memory scores, which would be expected to decrease over time.92”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [92] McElhiney MC. The Autobiographical Memory Interview-Short Form In: Psychiatry DoB. New York: New York State Psychiatric Institute; 2001.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    All VNS systems required surgical implantation until recently, with the development of transcutaneal systems, which are not yet FDA approved for TRD.

    “All VNS systems have required surgical implantation until recently, with the development of transcutaneal systems, which are not yet FDA approved for TRD20,54”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [54] Howland RH. New developments with vagus nerve stimulation therapy. J Psychosoc Nurs Ment Health Serv. 2014; 52(3): 11– 14. 24745061

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

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

    “All rTMS interventions were well tolerated, in a similar manner to sham.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Brunoni et al15

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Fitzgerald et al. 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.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

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

    “The majority of these early studies of MST applied stimulation to the vertex of the skull.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

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

    “Over 6000 patients underwent one of these brain stimulation treatments, despite many trials being of small sample size.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The iTBS non-inferiority trial was the largest brain stimulation trial to date and prompted the FDA to approve iTBS as a novel treatment for TRD.

    “This trial, the largest brain stimulation trial to date, prompted the FDA to approve iTBS as a novel treatment for TRD.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The results of the Daskalakis open-label trial 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.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    Kayser et al. reported a 69% response rate in 26 patients with TRD, comparable to ECT response rates.

    “A study by Kayser et al67 reported a 69% response rate in 26 patients with TRD, comparable to ECT response rates.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kayser et al67

      Not checked in the free run.

  • May combine two claims.

    Study design and conductcitation

    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.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Brunoni et al. conducted a network meta-analysis of 81 rTMS studies examining 8 different rTMS approaches and comparing them with sham rTMS.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Brunoni et al15

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the iTBS non-inferiority trial, tolerability was high in both arms and pain/discomfort scores were similar in each treatment arm.

    “Importantly, tolerability was high in both arms and pain/discomfort scores were similar in each treatment arm.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The evidence reinforces that rTMS is an effective and well-tolerated therapeutic option for TRD.

    “rTMS is an effective and well-tolerated therapeutic option for TRD”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationcitation

    More evidence is needed to create a clear hierarchy of rTMS approaches.

    “more evidence is needed to create a clear hierarchy of rTMS approaches”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Several open-label trials of differing accelerated rTMS schedules all found improved remission and response rates compared to once daily rTMS, including response rates of up to 56%.

    “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”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

    • Rests on an assumption: Daily rTMS is quite well tolerated but requires several days to weeks of treatment to induce symptom response.

  • May combine two claims.

    Premisecitation

    High-frequency MST resulted in the highest remission rates in patients who underwent at least 8 treatments (33.3%), and this jumped to 60% in patients who completed the full MST treatment protocol.

    “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%).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    Daskalakis et al. reported an open-label trial applying MST to the prefrontal cortex, with 3 different study arms each applying a different MST frequency ranging from 25-100Hz.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Daskalakis et al27

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Published clinical trials consistently demonstrate a clear antidepressant effect of MST with fewer cognitive or memory side effects.

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

  • May combine two claims.

    Premisecitation

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

    “High frequency, low frequency, bilateral rTMS and TBS were all found to be superior to sham stimulation in terms of response.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Brunoni et al15

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    It is believed that stimulation of the vagus nerve alters various networks of the brain in order to treat psychiatric disease.

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

  • May combine two claims.

    Interpretationcitation

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

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Williams et al. 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.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a large-scale non-inferiority RCT, 414 patients were randomized to either 10Hz rTMS or iTBS and the efficacy of iTBS was found to be noninferior to conventional rTMS.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    VNS is proposed to modulate brain activity via stimulation of the tenth cranial nerve, the vagus nerve.

    “Vagus nerve stimulation (VNS) is proposed to modulate brain activity via stimulation of the tenth cranial nerve, the vagus nerve.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    There appears to be a bimodal distribution in the timing of response to VNS: a portion of VNS patients respond acutely, whereas for others the main effects appear to emerge after approximately 3 months of treatment.

    “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”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the PRIDE Study, 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.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

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

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

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

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

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

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The antidepressant effect of ketamine was quickly recognized after a low dose intravenous infusion.

    “Although initially investigated as a psychomimetic substance,75 the antidepressant effect of ketamine was quickly recognized after a low dose intravenous infusion.11”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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.

    “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”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    An intranasal form of esketamine has been developed, which has shown good effect with continued treatment in combination with an oral antidepressant and has now been approved by the FDA for restricted use in TRD.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning

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

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

  • May combine two claims.

    Premisecitation

    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.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Ketamine is a widely investigated NMDA antagonist as a potential therapeutic option for TRD and is considered a rapid acting antidepressant.

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

  • May combine two claims.

    Premisecitation

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

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

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

    “COX-2 inhibitors are known to block prostaglandin production, which appears to be elevated in blood samples of some patients with TRD.79”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

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

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

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In a recent editorial in JAMA Psychiatry, Dr. M. Freeman addresses the topic of maintaining remission from TRD, with recommendations to individualize maintenance interventions.

    “In a recent editorial in JAMA Psychiatry, Dr. M. Freeman addresses this specific topic, with recommendations to individualize maintenance interventions.38”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The rapid response to ketamine was reinforced by several randomized blinded and open-label studies and included a significant reduction in suicidal ideation in TRD patients.

    “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”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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.

    “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”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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.

    “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”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

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

    “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”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

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

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

  • May combine two claims.

    Premisecitation

    COX-2 inhibitors were initially the focus of anti-inflammatory research in TRD and were investigated as augmentation options for traditional antidepressant pharmacotherapy.

    “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”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Brexanolone, an intravenous formation of allopregnanolone which acts by enhancing GABAergic inhibition, was FDA approved this year for the treatment of post-partum depression.

    “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”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

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

    “In this study the substance was relatively well tolerated, although transient anxiety was frequently experienced, as was mild tachycardia.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

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

    “By allosterically enhancing GABAA receptor function, the antidepressant activity of allopregnanolone is attributed to an increase in GABAergic inhibition.97,102”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    On average, the effects of ketamine appear to come on rapidly and last approximately 5-7 days.

    “the effects of ketamine appear to come on rapidly and last approximately 5–7 days145”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

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

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Authors
Voineskos, D., Daskalakis, Z. J., & Blumberger, D. M.
Affiliations
Centre for Addiction and Mental Health (CA)
Corresponding author
Blumberger, Daniel M.
ORCID
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 · 2012: 1
FWCI
6.13
Type
journal article
Language
en
Open access
Licence
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 › 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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Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

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