Completing the Regulatory Review of (2R,6R)-Hydroxynorketamine (HNK)

1The public health reality I am asking you to confront

I write as someone who has watched depression quietly reshape families, workplaces and communities across America. Ours is a continent of more than 375 million people — roughly 335 million in the United States and 41 million in Canada — and major depressive disorder now sits among the heaviest burdens either health system carries. What concerns me most is not depression in general, but its most stubborn form: the depression that does not yield to the treatments we already have.

I want to be precise about scale, because scale is what justifies urgency.

Annual prevalence of major depression

• United States: 7–8% of adults, or roughly 23 to 26 million people in a single year.
• Canada: 5–6% of the population, or roughly 2.0 to 2.4 million people in a single year.

Treatment-resistant depression (TRD)

Approximately 30% of patients fail to respond to two adequate courses of treatment. That single statistic converts a familiar illness into a medical emergency for millions:

• United States: an estimated 7 to 8 million people living with TRD.
• Canada: an estimated 500,000 to 700,000 people living with TRD.

These are not abstractions to me. Every one of those figures represents a person who has done what medicine asked of them, taken what was prescribed, waited the required weeks — and remained ill. That is the unmet medical need I am placing before you.

2What our current approach already costs us

I recognize that regulators are asked to weigh evidence, not budgets. But legislators are asked to weigh both, and so I offer the fiscal picture plainly. Treatment-resistant depression is among the most expensive conditions our health systems finance, and much of that spending purchases very little improvement.

3Why HNK deserves a complete and timely review

(2R,6R)-hydroxynorketamine is a metabolite of ketamine, and I raise it precisely because it is not simply another entry in an existing class. Its profile is distinctive in ways that matter both clinically and practically:

• Rapid effects on synaptic plasticity — acting on the biology of recovery within hours to days rather than weeks.
• No dissociative effects of the kind observed with ketamine in the available data — which speaks directly to tolerability and to the feasibility of care outside intensive monitoring settings.
• A novel mechanism of action aimed at restoring neural circuitry rather than adjusting monoamine levels alone.
• Therapeutic potential for patients who have already failed treatment — the exact population our current formulary serves least well.

Preclinical data and early clinical findings suggest HNK could represent a new class of rapid-acting antidepressants. I am not asking anyone to accept that conclusion on faith. I am asking that the evidence be examined thoroughly, on schedule, and with the seriousness that a candidate of this profile warrants.

4What responsible innovation could return to the public purse

Let me apply a deliberately conservative assumption. Suppose HNK improves outcomes for only 10–20% of TRD patients — a modest figure by the standards of any breakthrough claim. Even then, the effect on public spending is substantial.

United States

Canada

I do not present these savings as an argument for lowering any evidentiary standard. I present them because savings of this magnitude would let us reinvest in prevention, community-based care and the support services that are chronically underfunded on both sides of the border. That is the compounding return I would like legislators to keep in view.

5The human consequences behind every figure

Budgets are how we describe this problem to institutions. The following is how it is actually lived.

For patients

• Reduced suicide risk — the outcome that cannot be recovered once it is lost.
• A faster return to work, to study, to ordinary life.
• Fewer relapses and fewer months surrendered to illness.
• A meaningful improvement in quality of life, not merely in symptom scores.

For families

• Fewer acute crises to absorb, often without warning or support.
• Less sustained emotional distress carried by partners, parents and children.
• Greater household stability, financial and otherwise.

For our health systems

• Relief for psychiatric emergency departments operating beyond capacity.
• Fewer inpatient beds held by patients cycling through failed regimens.
• Fewer ineffective treatment courses funded from public money.
• Better use of the clinical workforce we already struggle to retain.

6What I am respectfully asking of you

Given the scale of treatment-resistant depression and its human and economic cost, I encourage Health Canada and the FDA — and the legislators who oversee them — to take the following steps.

1. Complete the regulatory review of HNK under established standards.Rigorously, transparently, and without avoidable delay. I am asking for timeliness, not for exemptions.
2. Weigh its potential against a documented and urgent unmet need.The relevant comparison is not against an ideal therapy, but against what these patients have available today.
3. Maintain open dialogue with researchers and clinicians.The people who treat TRD daily and those who study its biology should remain part of the conversation throughout.
4. Prioritize innovations capable of reducing the TRD burden.Where a candidate addresses a population our current tools consistently fail, that fact should inform how it is sequenced.