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Updated over 9 months ago

Most Recent Guidelines for Treatment-Resistant Depression (TRD) and Difficult-to-Treat Depression (DTD)

Treatment Resistant Depression (TRD) and Difficult-to-Treat Depression (DTD) do not have formal definition or diagnostic criteria, however for the sake of this document, both are defined as Major Depressive Disorder (MDD) that has not responded significantly to at least two antidepressant class medication treatment trials.

DTD is particularly meant to characterize an approach to treatment that includes augmenting care and adding treatment modalities with the goal of improving response to treatment/quality of life, rather than focusing on serial treatment trials.

Diagnostic Considerations

  • Reconfirm primary diagnosis and assess for comorbidities

  • Distinguish between TRD (≥2 failed adequate medication trials) and DTD (broader concept including psychosocial complexities)

  • Conduct comprehensive evaluation for medical conditions affecting treatment response

  • Screen for substance use disorders, personality disorders, and trauma history

First Line Approaches

  • Optimize current antidepressant therapy (dose and duration)

  • Switch to a different antidepressant class if no response

  • Add evidence-based psychotherapy (CBT, IPT, or behavioral activation)

  • Digital Therapeutic (recently FDA approved for MDD)

  • Implement measurement-based care using validated tools (PHQ-9, QIDS)

  • Esketamine nasal spray

Pharmacological Augmentation

  • Atypical antipsychotics (aripiprazole, brexpiprazole, quetiapine)

  • Lithium (particularly effective with suicidal ideation)

  • Thyroid hormone augmentation (T3)

  • Second antidepressant from a different class

  • L-methylfolate

Neuromodulation Therapies

  • Repetitive transcranial magnetic stimulation (rTMS) - non-invasive option

  • Vagus nerve stimulation (VNS) - for chronic, severe TRD

  • Electroconvulsive therapy (ECT) - highest efficacy for severe TRD

Key Citations

  1. Lam, R. W., Kennedy, S. H., Adams, C., Bahji, A., Beaulieu, S., Bhat, V., Blier, P., Blumberger, D. M., Brietzke, E., Chakrabarty, T., Do, A., Frey, B. N., Giacobbe, P., Gratzer, D., Grigoriadis, S., Habert, J., Ishrat Husain, M., Ismail, Z., McGirr, A., McIntyre, R. S., … Milev, R. V. (2024). Canadian Network for Mood and Anxiety Treatments (CANMAT) 2023 Update on Clinical Guidelines for Management of Major Depressive Disorder in Adults: Réseau canadien pour les traitements de l'humeur et de l'anxiété (CANMAT) 2023 : Mise à jour des lignes directrices cliniques pour la prise en charge du trouble dépressif majeur chez les adultes. Canadian journal of psychiatry. Revue canadienne de psychiatrie, 69(9), 641–687.

  2. McIntyre RS, Rosenblat JD, Nemeroff CB, Sanacora G, Murrough JW, Berk M, Brietzke E, Dodd S, Gorwood P, Ho R, Iosifescu DV, Lopez-Jaramillo C, Kasper S, Kratiuk K, Lee JG, Lee Y, Lui LMW, Mansur RB, Papakostas GI, Subramaniapillai M, Thase M, Vieta E, Young AH, Zarate CA Jr, Stahl S. "Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation." American Journal of Psychiatry. 2021;178(5):383-399.

  3. Veterans Affairs/Department of Defense (VA/DoD) Guidelines: VA/DoD Clinical Practice Guideline for the Management of Major Depressive Disorder. Version 4.0 (2022). The Management of Major Depressive Disorder Working Group. Washington, DC: Department of Veterans Affairs and Department of Defense.

  4. Rothman B, Slomkowski M, Speier A, Rush AJ, Trivedi MH, Lawson E, Fahmy M, Carpenter D, Chen D, Forbes A. Evaluating the Efficacy of a Digital Therapeutic (CT-152) as an Adjunct to Antidepressant Treatment in Adults With Major Depressive Disorder: Protocol for the MIRAI Remote Study. JMIR Res Protoc. 2024 Aug 20;13:e56960. doi: 10.2196/56960. PMID: 39163592; PMCID: PMC11372332.

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