Ketamine Therapy for Treatment-Resistant Depression

This article is the deep dive on ketamine for treatment-resistant depression (TRD). For a broader, less technical introduction, see Ketamine Therapy for Depression. Here, the goal is to give patients with documented TRD — and the family members and clinicians supporting them — an honest, evidence-anchored picture: how TRD is defined, what staging actually means, why "pseudoresistance" matters, what the head-to-head data versus electroconvulsive therapy says (ELEKT-D 2023), how Canadian programs structure acute and maintenance courses, what response and remission rates look like in real clinical practice, and what predicts response. The Canadian Network for Mood and Anxiety Treatments (CANMAT) places IV (intravenous) racemic ketamine as a third-line treatment for adults with TRD (Swainson et al., 2021). Spravato (intranasal esketamine) is Health Canada-approved for treatment-resistant MDD as of May 2020. Both deserve clear-eyed framing.

Key takeaways

• TRD definition typically requires failure of at least two adequate antidepressant trials from different classes at therapeutic dose for ≥6 weeks each (Maudsley staging, Thase & Rush 1997 staging, FDA Spravato operationalization). CANMAT 2023 reflects similar criteria.
• Pseudoresistance — inadequate dose, inadequate duration, poor adherence, or wrong diagnosis (often missed bipolarity) — accounts for a meaningful fraction of "TRD" referrals. ATMA CENA's intake call screens for this.
• Ketamine vs ECT — the ELEKT-D trial (Anand et al., NEJM 2023) found IV ketamine non-inferior to ECT for TRD without psychosis on the primary outcome. Both have a place; the right answer depends on patient profile.
• Acute response rates for IV ketamine in TRD are typically 50–70% at single-dose 24-hour assessment, with remission ~30%. Repeated dosing improves durability.
• Maintenance frameworks vary: Singh 2016 compared twice-weekly to thrice-weekly dosing; Phillips 2019 (Royal Ottawa) extended into maintenance phase. Most Canadian programs use 4–6 acute infusions over 2–3 weeks followed by individualized maintenance.
• The Edmonton public ketamine program (Misericordia/Grey Nuns) treats ultra-resistant TRD under AHCIP coverage; published outcomes describe meaningful response in this severely ill population.

How is treatment-resistant depression defined?

Several definitions are in use, and they differ in important ways.

Maudsley staging. TRD typically requires failure of at least two adequate antidepressant trials from different pharmacologic classes — for example, an SSRI followed by an SNRI, each at therapeutic dose for at least six weeks. "Failure" means meaningful symptom persistence, not absence of response. Maudsley extends with severity, chronicity, and treatment-history weighting.

Thase & Rush 1997 staging. A graded model where Stage 1 is failure of one antidepressant, Stage 2 is failure of antidepressants from two different classes, Stage 3 is Stage 2 plus failure of a tricyclic, Stage 4 is Stage 3 plus failure of an MAOI, and Stage 5 is Stage 4 plus failure of ECT. Most clinical practice and trials operationalize TRD as Stage 2 or higher.

FDA Spravato operationalization. For Spravato approval, TRD was operationalized as failure of two or more antidepressants of adequate dose and duration in the current depressive episode.

CANMAT 2016 and 2023 MDD guidelines. CANMAT criteria align with the two-failed-adequate-trials threshold and emphasize adequacy of dose, duration, and adherence.

The practical effect: if you are on antidepressant number three or four for the current episode, with documented adequacy and adherence, and your symptoms remain meaningful, you almost certainly meet a working TRD definition.

Pseudoresistance — the screening that matters first

Before TRD becomes the working diagnosis, a careful clinician asks four questions:

1. Was the dose adequate? Many "failed" antidepressant trials never reached therapeutic dose. Sertraline at 50 mg, escitalopram at 10 mg, or venlafaxine at 75 mg may all be sub-therapeutic for the patient. CANMAT-recommended therapeutic ranges should be reached and tolerated.
2. Was the duration adequate? Antidepressants typically require 4–6 weeks at therapeutic dose for the response window to play out. Switches at 2–3 weeks are common but premature.
3. Was adherence adequate? Side effects, cost, and stigma all undermine adherence. Patients may report a "trial" that included only intermittent dosing.
4. Is the diagnosis correct? Bipolar II depression, dysthymia, atypical depression, depression with anxious features, depression with mixed features, and substance-induced depression all change the treatment plan. Missed bipolarity is the most common surprise in TRD intakes.

The ATMA CENA information call screens for these four questions. If pseudoresistance is identified, the next step may be optimization rather than ketamine. This is honest care.

How ketamine works — and why it acts faster than SSRIs

Conventional antidepressants act on monoamine systems (serotonin, norepinephrine, dopamine) and require 4–6 weeks of receptor adaptation before clinical effects emerge. Ketamine acts on the brain's glutamate system through a different mechanism (Aleksandrova et al., 2017; Lullau et al., 2023):

1. NMDA receptor antagonism on cortical GABAergic interneurons disinhibits glutamatergic neurons.
2. The resulting glutamate surge activates AMPA receptors.
3. AMPA activation triggers BDNF release and mTOR-pathway signalling.
4. Synaptogenesis follows — new dendritic spines form within 24–72 hours, reversing the synaptic-density loss documented in chronic depression.

The result: clinical antidepressant effects in 2–72 hours from a single dose, rather than 4–6 weeks.

For the full mechanism breakdown, see What Is Ketamine Therapy?.

What the TRD-specific evidence actually shows

The TRD ketamine evidence base is large by interventional-psychiatry standards.

Foundational RCTs

Berman et al. 2000 — Biological Psychiatry — was the first IV ketamine RCT in depression (small N) showing rapid antidepressant effects from sub-anaesthetic IV dosing. Foundational proof of concept.

Zarate et al. 2006 — Archives of General Psychiatry — pivotal NIMH single-dose IV ketamine RCT in TRD. Single 0.5 mg/kg infusion produced significant antidepressant effects within 110 minutes, with response in ~71% at 24 hours. The trial that established the modern field (PubMed).

Murrough et al. 2013 — American Journal of Psychiatry — two-site randomized active-controlled trial confirming Zarate 2006 findings. Antidepressant response in 64% of ketamine versus 28% of midazolam at 24 hours (PubMed).

Repeated dosing and maintenance

aan het Rot et al. 2010 — Biological Psychiatry — first repeated-infusion open-label trial in TRD. Six infusions over 12 days produced sustained response in most patients (PubMed).

Singh et al. 2016 — American Journal of Psychiatry — RCT comparing twice-weekly versus thrice-weekly IV ketamine in TRD. Both schedules produced significant antidepressant effects with comparable efficacy; twice-weekly with somewhat better tolerability. Established that twice-weekly dosing is sufficient (PubMed).

Phillips et al. 2019 — American Journal of Psychiatry — Canadian (Royal Ottawa) study of single and repeated IV ketamine infusions in TRD with maintenance phase. Single-dose response ~28%; six-dose response ~60% with sustained remission rates approaching 50% at the end of the acute phase. The maintenance phase used individualized scheduling (PubMed).

Pooled meta-analytic evidence

Marcantoni et al. 2020 — Journal of Affective Disorders — meta-analysis of IV ketamine for TRD. Pooled response rates at 24 hours of ~50–70% depending on protocol; remission rates ~30–35%. Effect size large at 24 hours, attenuating over weeks without maintenance.

McIntyre et al. 2021 — CANMAT IV ketamine task force recommendations for TRD (sometimes cited alongside Swainson et al. 2021). Recommends IV racemic ketamine at 0.5 mg/kg over 40 minutes, twice weekly for the acute series of 4–8 infusions, with individualized maintenance.

Spravato (esketamine) RCTs

Daly et al. 2018 — JAMA Psychiatry — Spravato pivotal TRD RCT. Intranasal esketamine + oral antidepressant produced significant antidepressant effects versus placebo + oral antidepressant in TRD (PubMed).

Popova et al. 2019 — American Journal of Psychiatry — TRANSFORM-2 short-term efficacy of Spravato + oral antidepressant in TRD. Significant MADRS reduction at day 28 (PubMed).

Suicidality

Grunebaum et al. 2018 — American Journal of Psychiatry — RCT showing rapid reduction of suicidal ideation in MDD with single-dose IV ketamine versus midazolam. Important for emergency-presentation framing (PubMed).

The KAP add-on for durability

Wilkinson et al. 2017 — Psychotherapy and Psychosomatics — RCT showing that adding cognitive-behavioural therapy after the acute ketamine course extended antidepressant durability. Foundational evidence for the KAP (ketamine-assisted psychotherapy) integration model.

Ketamine versus ECT — the ELEKT-D answer

Until recently, the head-to-head question — ketamine versus ECT for TRD — had been answered mostly through indirect comparison.

Anand et al. 2023 — New England Journal of Medicine — the ELEKT-D trial randomized 403 patients with non-psychotic TRD to IV ketamine (0.5 mg/kg twice weekly) or ECT (three times weekly). The primary outcome (≥50% reduction on a 16-item self-report depression measure) was met in 55.4% of the ketamine arm versus 41.2% of the ECT arm — non-inferiority demonstrated (PubMed). ECT had more memory and musculoskeletal side effects; ketamine had more dissociation.

The honest interpretation: in TRD without psychosis, IV ketamine is non-inferior to ECT. Both have a place. ECT remains preferred for severe TRD with psychotic features or where rapid response in an inpatient setting is needed; ketamine is the better outpatient option for most non-psychotic TRD given side-effect profile and accessibility.

For Canadian patients, ECT is publicly funded but capacity-limited and stigma-affected. Ketamine outside Edmonton's Misericordia/Grey Nuns public program is private-pay or Spravato-via-private-insurance. Coverage drives the practical choice as much as efficacy.

Edmonton's public ketamine program — Canadian context

The Misericordia and Grey Nuns Hospital ketamine program in Edmonton — the only Canadian public ketamine program covered under provincial health insurance (AHCIP) — treats ultra-resistant TRD patients referred by psychiatry. Published outcomes describe meaningful response in this severely ill population (often Stage 4 or 5, with prior ECT non-response). Wait times reflect capacity constraints; psychiatrist referral is required.

For the Edmonton-specific access pathway, see Ketamine Therapy in Edmonton.

What does an acute course look like?

Most Canadian KAP programs structure the acute course as:

The specific protocol varies by clinic. ATMA CENA's pathways use this general structure; see ATMA CENA's published KAT pricing for program totals.

Predictors of response

Several variables associate with ketamine response in TRD, though prediction at the individual level remains imperfect:

• Anxious depression / anxious features — anxious-depression patients respond at similar or higher rates than non-anxious TRD in most analyses.
• Melancholic features — modestly favourable in some analyses, mixed in others.
• BMI — higher BMI has been associated with better response in some analyses.
• Family history of alcohol use disorder — repeatedly associated with better response (an unusual but reproducible finding).
• Dissociation during dosing — the controversial predictor: some early analyses associated dissociation with better antidepressant response, but more recent analyses have not replicated this. Dissociation is best treated as a manageable side effect rather than a therapeutic mediator.
• Concurrent benzodiazepines — associated with attenuated response in some analyses; our clinical team will discuss timing or tapering where appropriate.
• Suicidal ideation — ketamine produces rapid reductions in SI; this is a strong indication on its own (Grunebaum 2018).

Cost and insurance

ATMA CENA's published KAT pricing applies: KAT Psychedelic Pathway from CAD $1,585 + $795 per additional session; KAT Psycholytic Pathway from CAD $1,530 + $740 per additional session; customized programs CAD $2,325–$6,930. A non-refundable deposit of CAD $300 applies. For full pricing context, see Ketamine Therapy Cost in Canada.

Insurance reality:

• Spravato — most likely to be covered by private insurance with prior authorization for documented TRD.
• Generic IV/IM/SL ketamine — generally not covered by private insurance for psychiatric use.
• AHCIP (Alberta) — Edmonton's Misericordia/Grey Nuns public program is covered.
• VAC — covers ketamine drug forms for service-related TRD on a case-by-case basis.
• WSIB Ontario, WCB Alberta, ALBC PAT coverage — relevant subsets.
• Provincial drug plans (Pharmacare BC, ODB Ontario, RAMQ Quebec, etc.) generally do not list off-label ketamine; Spravato has Exceptional Access pathways in some provinces.

For full insurance navigation, see Insurance Coverage for Ketamine Therapy.

Frequently asked questions

How is TRD defined for ketamine eligibility? Failure of at least two adequate antidepressant trials from different classes at therapeutic dose for ≥6 weeks each in the current depressive episode. CANMAT 2023 reflects similar criteria. Spravato uses the same operationalization.

Is ketamine more effective than ECT? The ELEKT-D trial (Anand et al., NEJM 2023) found IV ketamine non-inferior to ECT for non-psychotic TRD on the primary outcome. ECT has more memory/musculoskeletal side effects; ketamine has more dissociation. For severe TRD with psychotic features, ECT remains preferred.

What response rate should I expect? Acute response (≥50% reduction on a depression measure) at 24 hours after a single dose is around 50–70% in published trials; remission ~30%. Repeated dosing improves both. ELEKT-D's 55.4% response after twice-weekly dosing is a useful real-world anchor.

How long does the response last? After a single dose, days to ~2 weeks. After 4–6 infusions, weeks to months in many responders, often with maintenance dosing (every 1–4 weeks). Wilkinson 2017 showed that integration psychotherapy after the acute course extends durability.

Should I do IV ketamine or Spravato? Spravato's evidence base is from the Daly 2018 / Popova 2019 trials in TRD with concurrent oral antidepressant. IV ketamine has a larger and longer evidence base and is non-inferior to ECT in ELEKT-D. The practical answer often turns on insurance coverage (Spravato is more often privately covered) and access (IV is more widely available off-label).

What if I've already had ECT and didn't respond? Stage 5 TRD (post-ECT non-response) is the population that Edmonton's Misericordia/Grey Nuns public program prioritizes. Published outcomes in this severely ill population describe meaningful response in a substantial subset.

Can I taper my SSRI / SNRI? Most ketamine protocols are compatible with continued SSRI/SNRI; some programs use ketamine as augmentation rather than replacement, similar to the Spravato + oral antidepressant model in the pivotal trials. Tapering is a clinical decision with your prescribing psychiatrist.

What about my benzodiazepines? Benzodiazepines may attenuate ketamine's antidepressant effect. Our clinical team will discuss timing or tapering with you and your prescriber where appropriate; this is rarely a hard exclusion but is a meaningful consideration.

How does maintenance work? Individualized. Common patterns: an initial acute series of 4–6 infusions over 2–3 weeks; then booster infusions every 1–2 weeks for 1–2 months; then every 3–4 weeks for several months; tapering as durability allows. Some patients transition off entirely; some maintain monthly indefinitely.

What if I'm suicidal? Ketamine produces rapid reductions in suicidal ideation (Grunebaum 2018). Active suicidality is not an exclusion — it is often an indication. The ATMA CENA intake call screens for safety planning and acute-care needs; in true emergency, please call 9-8-8 or go to your nearest emergency department.

How do I know if I have pseudoresistance instead of TRD? The four-question screen at intake: was your dose adequate, was your duration adequate, was your adherence adequate, was your diagnosis correct? Our clinical team will review this with you honestly. If pseudoresistance is the answer, the next step may be optimization rather than ketamine.

Where can I get ketamine therapy for TRD in Canada? See the city- and province-specific articles in this cluster: Calgary, Edmonton (public Misericordia/Grey Nuns option), Winnipeg, Toronto/GTA, Montreal (Montreal Model at Jewish General), Ottawa, Halifax, Mississauga, Hamilton, London ON, Vancouver, Victoria BC, Kelowna, Saskatoon.

Sources

1. ATMA CENA — Psychedelic-Assisted Therapy (pricing): https://psychedelic.healthcare/
2. Berman RM, et al. (2000). Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. https://pubmed.ncbi.nlm.nih.gov/10686270/
3. Zarate CA Jr, et al. (2006). Randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. https://pubmed.ncbi.nlm.nih.gov/16894061/
4. aan het Rot M, et al. (2010). Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression. Biol Psychiatry. https://pubmed.ncbi.nlm.nih.gov/20673878/
5. Murrough JW, et al. (2013). Antidepressant efficacy of ketamine in TRD: a two-site randomized controlled trial. Am J Psychiatry. https://pubmed.ncbi.nlm.nih.gov/23982301/
6. Singh JB, et al. (2016). A double-blind, randomized, placebo-controlled, dose-frequency study of intravenous ketamine in patients with treatment-resistant depression. Am J Psychiatry. https://pubmed.ncbi.nlm.nih.gov/27056608/
7. Wilkinson ST, et al. (2017). Cognitive behavior therapy for the prevention of relapse to ketamine. Psychother Psychosom. https://pmc.ncbi.nlm.nih.gov/articles/PMC5516265/
8. Daly EJ, et al. (2018). Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in TRD: pivotal RCT. JAMA Psychiatry. https://pubmed.ncbi.nlm.nih.gov/29282469/
9. Grunebaum MF, et al. (2018). Ketamine for rapid reduction of suicidal thoughts in MDD: a midazolam-controlled randomized clinical trial. Am J Psychiatry. https://pubmed.ncbi.nlm.nih.gov/29202575/
10. Phillips JL, et al. (2019). Single, repeated, and maintenance ketamine infusions for TRD. Am J Psychiatry. https://pubmed.ncbi.nlm.nih.gov/30764648/
11. Popova V, et al. (2019). Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in TRD: TRANSFORM-2. Am J Psychiatry. https://pubmed.ncbi.nlm.nih.gov/31109201/
12. Marcantoni WS, et al. (2020). Systematic review and meta-analysis of IV ketamine for TRD. J Affect Disord. https://pubmed.ncbi.nlm.nih.gov/32861973/
13. Swainson J, et al. (2021). CANMAT racemic ketamine task force recommendations. Can J Psychiatry. https://pubmed.ncbi.nlm.nih.gov/33174760/
14. Anand A, et al. (2023). Ketamine versus ECT for nonpsychotic TRD: ELEKT-D. N Engl J Med. https://pubmed.ncbi.nlm.nih.gov/37224135/
15. Aleksandrova LR, et al. (2017). Antidepressant mechanisms of ketamine. Can J Psychiatry. https://pubmed.ncbi.nlm.nih.gov/28234212/
16. Lullau APM, et al. (2023). Antidepressant mechanisms of ketamine. Front Neurosci. https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2023.1223145/full
17. Health Canada DPD — Spravato: https://health-products.canada.ca/dpd-bdpp/info?lang=eng&code=98903

Related articles in this cluster

• Ketamine Therapy in Canada
• What Is Ketamine Therapy?
• Ketamine Therapy for Depression — broader, less technical introduction
• Ketamine Therapy for Bipolar Depression
• Ketamine Therapy for Anxiety
• Ketamine Therapy for PTSD
• Ketamine Therapy Cost in Canada
• How to Qualify for Ketamine Therapy in Canada
• Insurance Coverage for Ketamine Therapy
• Ketamine Therapy in Edmonton — public AHCIP-covered program
• Ketamine Therapy in Montreal — Montreal Model

Last updated: 2026-05-06