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Gaynes BN, Asher G, Gartlehner G, et al. Definition of Treatment-Resistant Depression in the Medicare Population [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2018 Feb 9.

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Definition of Treatment-Resistant Depression in the Medicare Population [Internet].

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Table 6Definitions Of Treatment-Resistant Depression And Level Of Consensus By Number Of Treatment Failures: Guidelines And Consensus Statements As Source

Number of Treatment Failures as a ConsensusFocus of Guideline or Consensus Statement, Author, DateDefinition of Treatment-Resistant DepressionDefine FailureCurrent Episode?Define Adequate Dose?Define Adequate Duration?Consensus?Specifically Stated or Most Frequently Used Definition?
1 or moreInternational Workshop on “Present and Future of TMS: Safety and Ethical Guideline” Rossi et al., 200968Patients with medication-refractory unipolar depression who failed one good (but not more than one) pharmacological trialNot foundNot foundNot foundNot foundYesReport is from a consensus conference for TRD about when rTMS should be offered
2 or moreWorld Federation of Societies of Biological Psychiatry Guidelines for Unipolar Depression Bauer et al., 200967Patients who remain depressed and do not achieve adequate relief and a satisfactory level of functioning even after two or more adequate courses of treatment. Having failed to improve after two adequately performed trials of AD drug; these no-responders are considered “treatment resistant.”Patient is not showing any improvement after 4 weeks of treatment with an AD drug at an appropriate doseNot foundNot foundAt least 6 weeks, and 8 to 10 weeksNoReports the most commonly used definition. Notes that there is no clear consensus which strategy should be favored for the non-responding patient since to date no rigorous trial with a randomized, double-blind design has been conducted to answer this question.
Unipolar Depression Guideline Harter et al., 201070In therapy-resistant depression (where pharmacotherapy has been administered adequately, with at least two drugs, one after the other, at a sufficiently high dosage and given for a long enough time interval), patients should be offered appropriate psychotherapyNot foundNot foundNot foundNot foundYesProposed a definition for when psychotherapy should be offered
Institute for Clinical and Economic Review ICER) Coverage Policy Analysis, 201238Notes that definitions of so-called “treatment-resistant” depression vary; this generally refers to patients with persistent depression after attempted management with two or more medicationsFailure to evoke a clinically significant and lasting responseNot foundNot foundNot foundNoReports the most commonly used definition
Report from European Medicines Agency consensus meeting in 2009—Improving outcomes in TRD Schlaepfer et al., 201269CHMP has stated that a patient is considered to be therapy resistant when consecutive treatment with two antidepressants of different classes (different mechanism of action), used for a sufficient length of time and at an adequate dose, fail to induce an acceptable effect. CHMP also notes that the definition of TRD itself is not always consistent between studies or treatment guidelines, and a clear definition would go some way to refining treatment options.Not foundNot foundNot defined and consensus from the wider psychiatric community is still requiredNot defined and consensus from the wider psychiatric community is still requiredYesCites the CHMP (EMA) definition. Some staging models have been used to define TRD, but further clinical validation is needed. In addition, true pharmacological resistance needs to be distinguished from resistance attributable to ongoing somatic or psychosocial problems
British Association for Psycho-pharmacology Guidelines for all depressive orders, revision based on 2012 consensus meeting Cleare et al., 201579Most describe it as a failure to respond to two or more adequate AD treatment trialsLack of improvement (defined as at least a 20% to 30% reduction in HAM-D in different studies) at 4 and 6 weeks; only 20% and 10%, respectively, will go on to eventual response (≥50% improvement) at 8 weeksImportant to consider the current episode in the context of the overall history of depression and the nature of previous episodes when considering treatment optionsAdequate treatment, defined as “recommend ed therapeutic dose”4–8 weeksNoReports the most commonly used definition. Notes that problems arise in defining what comprises an adequate treatment trial, which drugs are to be included and in taking account of psychological treatments.
VA/DoD Clinical Practice Guidelines for Management of MDD, 201623Lack of full response despite at least two adequate treatment trialsLack of full response to an adequate treatment trialNot foundNot foundNot foundYesGuideline says there is consensus
CANMAT Guidelines, 2016 Kennedy et al., 201674 Pharmacological treatments Psychological treatments Parikh et al., 201675 Neuro-stimulation treatments Milevet al., 201676 CAM treatments Ravindran et al., 201677 Special populations: youth, women, and the elderly MacQueen et al., 201678Notes that the most commonly employed definition is inadequate response to 2 or more AD drugsInadequate response (e.g., 25%-49% reduction in symptom scores) or no response (e.g., <25% reduction)Not foundNot foundNot foundNoReports the most commonly used definition
Notes that the commonly applied definition does not take into account adjunctive strategies and does not differentiate between patients who have had partial response versus those who have had no response
2 or more (MDD: ≥2; Bipolar I: ≥2 [specific treatments specified], Bipolar II: ≥2 [specific treatments specified])Australian and New Zealand clinical practice guidelines for mood disorders Malhiet al., 201542MDD: Lack of improvement following adequate trials of two or more ADs

Bipolar I depression: Failure to reach remission with adequately dosed lithium or to other adequate ongoing mood-stabilizing treatment, plus lamotrigine or with full-dose quetiapine as monotherapy

Bipolar II depression: Failure to reach remission with adequately dosed lithium or other adequate ongoing mood-stabilizing treatment, plus lamotrigine or with full-dose quetiapine as monotherapy
Failure to reach remission with adequate doseNot foundNot found6 weeks of treatmentYeProvides several definitions depending on the underlying mood disorder
3 or more, 3 different classesICSI, Guidelines for adult depression in primary care Trangle et al., 201621Defines true treatment resistance Failure to as failure to achieve remission achieve with an adequate trial of therapy remission and three different classes of AD drugs at adequate duration and dosageFailure to achieve remissionNot foundNot foundNot foundNoIdentifies a definition for primary care clinicians

“True treatment resistance is seen as occurring on a continuum, from failure to reach remission after an adequate trial of a single [AD drug] to failure to achieve remission despite several trials of [AD drugs] augmentation strategies, ECT and psychotherapy.”
Did not specifically addressAmerican Psychiatric Association guideline for the treatment of MDD Gelenberg et al., 201019Frequently uses the term “treatment-resistant” but never defines it; refers to “next steps” in treatmentNot foundFor rTMS, FDA says individuals with MDD who have not had a satisfactory response to at least one AD trial in the current episode of illnessNot foundNot addressed for TRD; generally, adequate treatment with an AD medication for at least 4–6 weeks

For psychotherapy, a few months
NoNot found
NICE Depression Guidance, 200971 NICE VNS Guidance, 200973 NICE rTMS Guidance 201571

Various guidelines concerning depression, use of vagal nerve stimulation, and use of rTMS
Did not define

Earlier NICE guidelines had referred to TRD defined as depression that had not responded adequately to two courses of AD drugs (of adequate dose and length)

The current guideline groups preferred to approach the problem of inadequate response by considering sequenced treatment options rather than by a category of patient
Does not clearly define; refers to Inadequate response, which could reflect both lack of response and lack of remission, and considers both patient and clinician perspectivesNot foundNot foundNot foundNo. NICE eschews use of the term “treatment-resistant depression”Previous versions of the guidelines stated that the most commonly used definition was nonresponse to two or more adequate trials of ADs. Due to this definition not including psychotherapeutic treatment, non-antidepressant augmenting agents and psychosocial factors, the new guidelines use a sequence of treatment options rather than number of failures.
Unipolar depression Ontario Health Association, 201664Considers stages of treatment resistance (e.g., Stage 1 indicates failure to achieve response after one course of adequate treatment; Stage 2 indicates failure to achieve response after two courses of adequate treatment)Cannot achieve remissionCites FDA definition for rTMS: Treatment of adult patients with unipolar depression whose current episode did not respond to one adequate dose of AD medicationNot foundLong enough to take effect, at least 2 weeks or 10 sessionsNoDoes not identify the most commonly used definition

Notes that definition of adequate response ranges from failure to achieve response to failure to achieve full symptom remission and that most experts agree that inadequate response is the failure to achieve full symptom remission

AD = antidepressant; CAM = complementary and alternative medicine; CANMAT = Canadian Network for Mood and Anxiety Treatments; CHMP = Committee for Medicinal Products for Human Use; ECT = electroconvulsive therapy; EMA = European Medicines Agency; FDA = Food and Drug Administration; HAM-D = Hamilton Depression Rating Scale; ICER = Institute for Clinical and Economic Review; ICSI = Institute for Clinical Systems Improvement; MDD = major depressive disorder; NICE = National Institute for Health and Clinical Excellence; rTMS = repetitive transcranial magnetic stimulation; TMS = transcranial magnetic stimulation; TRD = treatment-resistant depression; VA/DoD = Department of Veterans Affairs and Department of Defense; VNS = vagus nerve stimulation.

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