Treatment-resistant depression

TRD is a narrower and sicker population than major depressive disorder, and that is not a detail, it is the reason two headline numbers cannot be compared. Effect sizes in TRD run structurally smaller, so a large result in MDD and a modest result in TRD may be the same drug performing identically against different odds. Our view is that any comparison of psychedelic readouts that does not first state the population is not an analysis, it is a press release with arithmetic. The second thing TRD carries is commercial: a treatment-resistant patient is, by the definition itself, already on antidepressants, which is why a protocol's stance on existing medication decides how many real patients a therapy can reach. And the threshold is not settled. What counts as resistant differs between regulators and between individual trial protocols, so a trial's own eligibility criteria are worth reading before its result. In our opinion that disagreement is informative rather than pedantic, because a looser threshold enrols a less refractory population and a less refractory population tends to produce a larger number.

The European regulator states the threshold precisely. Its guideline on clinical investigation of medicinal products in the treatment of depression says: "Treatment resistance in major depression is defined as lack of clinically meaningful improvement despite the use of adequate doses of at least two antidepressant agents, derived from the group(s) of commonly used first line treatment, prescribed for adequate duration with adequate affirmation of treatment adherence. At least one treatment failure should be shown prospectively." (EMA/CHMP/185423/2010 Rev 2, guideline PDF.)

The same guideline is candid that the criteria are not settled, noting that "the conceptual elaboration and definition of clear criteria for incomplete response and TRD is still limited". Individual protocols set their own bar, so two trials can both enrol treatment-resistant patients and not mean the same thing by it.

We have never printed that threshold in an issue. What we have printed is what it does to a number. In Issue 4, reading Definium's Emerge result against Compass's: "the populations differ: Emerge enrolled MDD, a broader and less refractory group than Compass's treatment-resistant depression, where effect sizes run structurally smaller. You cannot net the two numbers across populations, and we won't."

In Issue 5 we drew out the commercial consequence: "Real-world treatment-resistant patients are, almost by definition, on antidepressants." That single fact is why the washout question splits the field.

And in Issue 2 we named why every programme crowds into it: "Start with treatment-resistant depression (TRD), the indication every commercial programme is chasing." Issue 3 called it "psychedelics' flagship indication".