Treatment-Resistant Depression and Psychedelic-Assisted Therapy in Canada

Treatment-resistant depression (TRD) is the clinical situation where a patient with a major depressive disorder has failed to respond adequately to at least two trials of antidepressants from different pharmacological classes given at adequate dose and duration. Roughly 30% of patients with major depression meet TRD criteria after standard trials. This article is a Canadian evidence-and-pathway guide to psychedelic-assisted therapy options for TRD: esketamine (Spravato) — the only Health Canada-approved psychedelic-assisted therapy for TRD; off-label IV / IM / sublingual / oral ketamine — most established off-label pathway with substantial RCT base; psilocybin under Health Canada's Special Access Program — investigational in TRD with Goodwin et al. 2022 COMP001 New England Journal of Medicine as the pivotal phase 2 evidence and the MAGNUS phase 3 program ongoing. We also walk through what the evidence does — and does not — show, how decisions are made between options, and what insurance and clinical pathways exist in Canada.

Key takeaways

• TRD definition: failed response to ≥2 trials of antidepressants from different classes at adequate dose and duration. ~30% of MDD patients meet criteria.
• Spravato (esketamine) is the only Health Canada-approved psychedelic-assisted therapy for TRD — approved May 2020. Two-phase regimen (induction + maintenance); REMS-equivalent monitoring requirements.
• Off-label ketamine (IV, IM, SL, oral) is the most clinically established Canadian psychedelic-assisted therapy for TRD. Strong RCT evidence (Wajs 2020 SUSTAIN-2 for esketamine maintenance; Anand 2023 ELEKT-D ketamine non-inferior to ECT in TRD). Off-label legality is well-established under Canadian off-label prescribing principles.
• Psilocybin for TRD: investigational. Goodwin 2022 NEJM COMP001 phase 2 RCT is the pivotal evidence; MAGNUS phase 3 ongoing. Health Canada SAP is the only Canadian access pathway. Compass Pathways and Filament Health are the principal Canadian psilocybin supply chains.
• MDMA-AT is NOT TRD-indicated — MDMA-assisted therapy is investigated for PTSD, not depression. Patients should be cautious of providers conflating these.
• Insurance: Spravato has a structured prior auth pathway (PSHCP, Manulife, Sun Life, Green Shield); off-label ketamine generally NOT covered (private pay $400–$1,500/session); psilocybin not covered.
• Decision-making is highly individualized — past treatments, anesthesia tolerance, suicidal ideation context, cost, and clinic access all factor in.

Defining treatment-resistant depression

TRD (treatment-resistant depression) is a clinical situation, not a discrete diagnosis. The most-used research definition (Sackeim 2001 staging; Ruhé 2012; Health Canada Spravato label):

• Major depressive disorder (MDD) per DSM-5 criteria (or recurrent MDD)
• Failure of ≥2 prior antidepressant trials from different pharmacological classes
• Each trial at adequate dose and adequate duration (typically 6–8 weeks)
• Within the current depressive episode

About 30% of MDD patients meet TRD criteria after first- and second-line trials (Rush 2006 STAR*D). TRD is associated with greater functional impairment, higher healthcare utilization, more comorbid anxiety / substance-use / chronic pain, higher suicide risk.

The TRD evidence map for psychedelic-assisted therapy

Esketamine (Spravato) — Health Canada approved

• Approval: Health Canada Notice of Compliance May 2020 for TRD in adults
• Pivotal RCTs: Daly 2019, Popova 2019, Wajs 2020 (SUSTAIN-2 long-term maintenance, PMID 32316080)
• Mechanism: NMDA receptor antagonist, glutamatergic burst hypothesis
• Regimen: two-phase: Induction = twice weekly × 4 weeks; Maintenance = once weekly weeks 5–8, then every 1–2 weeks ongoing
• Monitoring: 2 hours post-dose; trained healthcare professional; REMS-equivalent
• Real-world evidence: STAR study (Reif 2023) confirmed efficacy in real-world TRD populations

Off-label ketamine (IV, IM, SL, oral) — clinically established

• IV ketamine for TRD: meta-analysis evidence base back to Berman 1999 first RCT, replicated extensively. Single-dose 0.5 mg/kg IV produces rapid antidepressant effect within 24 hours
• Anand 2023 ELEKT-D (PMID 37224135): RCT comparing ketamine IV with ECT for TRD; ketamine non-inferior to ECT
• Maintenance ketamine: emerging evidence base; KETOL multi-site Canadian RCT and ongoing observational cohorts
• Off-label legality: Health Canada DPD lists ketamine as approved anaesthetic; off-label psychiatric use within Canadian prescribing principles

Psilocybin — investigational under SAP

• Goodwin 2022 NEJM COMP001 (PMID 36322843): phase 2 RCT of single-dose psilocybin (1 mg, 10 mg, 25 mg) in TRD. 25 mg dose: 37% response, 29% remission at week 3
• Carhart-Harris 2021 NEJM (PMID 33852780): psilocybin vs escitalopram in MDD (not specifically TRD) — comparable response
• MAGNUS phase 3 program: Compass Pathways' two phase 3 trials (COMP005, COMP006) evaluating psilocybin in TRD; topline COMP005 results expected mid-2026
• Atira Pharmaceuticals MAGNUS-EU also relevant
• Canadian access: Health Canada SAP only — investigational, not approved

For more detail see Psilocybin for TRD, the Ketamine Therapy in Canada guide, and PSHCP/Canada Life Spravato Coverage.

Decision framework — comparing TRD options

Decisions between Spravato, off-label ketamine, and SAP-pathway psilocybin should be made between patient and prescribing physician. Common considerations:

Canadian access pathways

Spravato

Spravato is Health Canada-approved and provincially / privately reimbursable through varying pathways:

• PSHCP (federal public servants): Form M7520 prior auth; well-documented pathway
• Private insurance: Manulife, Sun Life, Green Shield typically cover with prior auth
• Provincial drug plans: most provinces non-benefit; ODB rare EAP via SADIE; BC PharmaCare non-benefit; Alberta ABC non-benefit; Quebec INESSS non-benefit
• Provider network: Janssen Journey-certified clinics

For more detail see PSHCP/Canada Life Spravato Coverage, Private Insurance Prior Authorization for Spravato, and Alberta Blue Cross PAT Coverage.

Off-label ketamine

• Out-of-pocket is the dominant pathway: typically $400–$1,500/session depending on route and clinic
• Workers' compensation: WSIB Ontario specialty formularies for compensable injuries
• VAC: established case-by-case for service-related conditions
• Public hospital exceptions: Edmonton Misericordia/Grey Nuns publicly funded outpatient psychiatric ketamine; Vancouver UBC Hospital VCH program

For more detail see Edmonton Misericordia/Grey Nuns Public Ketamine, Workers' Compensation for Psychedelic-Assisted Therapy, and VAC Coverage for Psychedelic-Assisted Therapy.

Psilocybin SAP

• Pathway: prescribing physician submits SAP application to Health Canada; approval typically 2–4 weeks for end-of-life and TRD-after-conventional-failure
• Supply: Filament Health (no-charge SAP psilocybin); other licensed suppliers
• Clinical capacity: TheraPsil-trained clinicians; concentrated in BC/Ontario; smaller capacity in Quebec, Atlantic, Prairies
• Quebec: RAMQ public-funding precedent (Farzin/Stephan December 2022) applies provincially for SAP-approved psilocybin patients; mostly used for end-of-life distress

For more detail see Quebec RAMQ Coverage for Psychedelic Therapy and Psilocybin Therapy in Canada.

What the evidence does NOT say

• No psychedelic-assisted therapy is curative for TRD. Maintenance ongoing is the realistic clinical pathway for Spravato and off-label ketamine. Psilocybin's durability of effect is still being established in MAGNUS phase 3.
• Response rates do not approach 100%. Goodwin 2022 COMP001 25 mg dose achieved 37% response, 29% remission at week 3. ELEKT-D ketamine showed similar non-inferiority to ECT at meaningful but partial response rates.
• Suicidal ideation effects: ketamine has demonstrated rapid reduction in suicidal ideation but does not prevent suicide attempts in all cases. Specific clinical pathways exist for acute suicidality.
• Safety considerations: Spravato sedation, dissociation, hypertension; ketamine equivalent; psilocybin requires comprehensive screening for psychotic-disorder personal/family history.
• Off-label ≠ unapproved. Off-label ketamine for TRD is within Canadian prescribing principles; the medication is Health Canada approved as an anaesthetic.

How ATMA CENA works with TRD patients

ATMA CENA's TRD pathway:

• Comprehensive intake: clinical history, prior treatments, anesthesia / cardiac considerations, safety screen
• Three-phase model: preparation + dosing + integration
• coordinated care: ATMA CENA can layer on top of an existing therapeutic relationship — your existing therapist, psychiatrist, or family physician stays primary
• Clinic network: Edmonton + Calgary corporate; Mississauga, Hamilton, London, Vaughan, Oakville, Saskatoon, Winnipeg member clinics; coordinated care available pan-Canadian

For more detail on ketamine options for TRD, see the Ketamine Therapy in Canada guide.

Frequently asked questions

What's TRD? Treatment-resistant depression — clinical situation where a major depressive disorder has failed to respond to ≥2 antidepressant trials at adequate dose and duration. ~30% of MDD patients meet criteria.

What's Health Canada-approved for TRD? Spravato (esketamine) is the only Health Canada-approved psychedelic-assisted therapy for TRD (approved May 2020). Spravato is given as a nasal spray under medical supervision.

Is off-label ketamine approved? No — but ketamine is Health Canada-approved as an anaesthetic, and off-label psychiatric use is within Canadian prescribing principles. Off-label ketamine for TRD has a substantial RCT evidence base (Anand 2023 ELEKT-D non-inferior to ECT).

What's the strongest psilocybin TRD evidence? Goodwin et al. 2022 New England Journal of Medicine COMP001 phase 2 RCT — 25 mg single dose achieved 37% response and 29% remission at week 3 in TRD patients. MAGNUS phase 3 (COMP005, COMP006) is ongoing.

Why is Spravato covered but off-label ketamine not? Insurers cover medications based on Health Canada label indications. Spravato is approved for TRD; off-label ketamine is not labelled for TRD even though the medication itself (ketamine) is Health Canada-approved as an anaesthetic.

What about MDMA for depression? MDMA-AT is investigated for PTSD, not depression. Patients should be cautious of providers conflating these. The FDA issued a Complete Response Letter on MDMA-AT for PTSD in August 2024. See MDMA-Assisted Therapy in Canada.

How do I know which option is right for me? This is a clinical decision made between you and a prescribing physician. Past treatments, anaesthesia / cardiac considerations, suicidal ideation context, cost, and clinic access all factor in. The ATMA CENA information call is one starting point.

What's the role of psychotherapy? For Spravato: optional; not required by label. For off-label ketamine: often optional but increasingly recommended. For psilocybin SAP: always required (preparation + integration).

What if my TRD is severe / suicidal? Severe / suicidal TRD requires comprehensive psychiatric assessment and may indicate ECT, inpatient care, or close-monitoring outpatient management. Ketamine has demonstrated rapid suicidal ideation reduction but does not replace acute psychiatric care for crisis.

What's the cost?

• Spravato: ~$250–$650/session out-of-pocket if uncovered; substantially less with insurance
• Off-label IV ketamine: ~$500–$1,500/session
• Off-label IM/SL ketamine: ~$400–$900/session
• Psilocybin SAP: variable; supply via Filament Health no-charge SAP option exists; clinical hours separate

Sources

1. Goodwin GM, Aaronson ST, Alvarez O, et al. (2022). Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. New England Journal of Medicine, 387(18):1637-1648. PMID: 36322843.
2. Wajs E, Aluisio L, Holder R, et al. (2020). Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2). J Clin Psychiatry, 81(3). PMID: 32316080.
3. Anand A, Mathew SJ, Sanacora G, et al. (2023). Ketamine versus ECT for Nonpsychotic Treatment-Resistant Major Depression. New England Journal of Medicine, 388(25):2315-2325. PMID: 37224135.
4. Carhart-Harris R, Giribaldi B, Watts R, et al. (2021). Trial of Psilocybin versus Escitalopram for Depression. New England Journal of Medicine, 384(15):1402-1411. PMID: 33852780.
5. Reif A, Bitter I, Buyze J, et al. (2023). Esketamine Nasal Spray versus Quetiapine for Treatment-Resistant Depression. New England Journal of Medicine, 389(14):1298-1309 (STAR study).
6. Berman RM, Cappiello A, Anand A, et al. (2000). Antidepressant effects of ketamine in depressed patients. Biol Psychiatry, 47(4):351-4. PMID: 10686270.
7. Health Canada — Spravato Notice of Compliance and Product Monograph: https://health-products.canada.ca/dpd-bdpp/info?lang=eng&code=98903
8. Health Canada — Special Access Program: https://www.canada.ca/en/health-canada/services/drugs-health-products/special-access.html
9. Health Canada — SAP psychedelic-assisted psychotherapy announcement: https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/announcements/requests-special-access-program-psychedelic-assisted-psychotherapy.html
10. Compass Pathways — MAGNUS phase 3 program: https://compasspathways.com/our-research/comp360-clinical-program/
11. Filament Health — no-charge SAP psilocybin program: https://filament.health/
12. Sackeim HA. (2001). The definition and meaning of treatment-resistant depression. J Clin Psychiatry, 62 Suppl 16:10-7. PMID: 11480879.
13. Rush AJ, Trivedi MH, Wisniewski SR, et al. (2006). Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry, 163(11):1905-17. PMID: 17074942.
14. McIntyre RS, Rosenblat JD, Nemeroff CB, et al. (2021). Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation. Am J Psychiatry, 178(5):383-399. PMID: 33726522.

Related articles

• Spravato Coverage — PSHCP and Canada Life
• Private Insurance Prior Authorization for Spravato
• Edmonton Misericordia/Grey Nuns Public Ketamine
• Quebec RAMQ Coverage for Psychedelic Therapy
• Psilocybin Therapy in Canada
• Ketamine Therapy in Canada
• Insurance Coverage for Psychedelic-Assisted Therapy in Canada
• PTSD and Psychedelic-Assisted Therapy
• End-of-Life Distress and Psychedelic-Assisted Therapy

Last updated: 2026-05-06