Good first pass. Now let me dig into the remaining angles: the earlier COMP360 phase 3 result, next-generation mechanisms (AMPA/KOR/psychoplastogens), and the "hedonic set point" science for the bliss half of the question.

Strong material. Let me open the two best pipeline sources for depth, and run a final batch on the resilience/prophylaxis and hedonic-baseline angles.

The evidence is in. The picture is clearer than I expected — two positive psilocybin phase 3s, a 5-MeO-DMT phase 2b in JAMA Psychiatry, prophylactic ketamine literature for the "resistance" half, and FAAH/set-point genetics for the "bliss" half. Per the research workflow, I'll now write this up as a report canvas.

Short answer: for depression-resistance, psilocybin and 5-MeO-DMT lead the clinic, with prophylactic ketamine the key preclinical tool; for lifelong bliss, no investigational agent exists — the nearest translational science is hedonic set-point genetics and DBS. I've written the full ranked analysis as the canvas "Depression-Resistance & Lifelong Bliss: The Investigational Frontier."

Top findings:

• COMP360 psilocybin is the strongest late-stage agent: both phase 3 trials in treatment-resistant depression hit their primary endpoints (−3.6 and −3.8 MADRS vs placebo, p<0.001) ( Compass Pathways), with 26-week durability after just two doses and an FDA filing targeted for Q4 2026 ( Compass Pathways). Months of resistance from episodic dosing is the nearest clinical approximation to your goal.
• GH001 inhaled 5-MeO-DMT showed rapid, significant reductions after single-day dosing in a randomized phase 2b published in JAMA Psychiatry ( Medscape).
• For literal prophylaxis — dosing before stressors to confer resilience — prophylactic ketamine has the deepest mechanistic literature, though human trials are still lacking ( Biological Psychiatry).
• The most promising scalable route is non-hallucinogenic neuroplastogens (zalsupindole, cleared for at-home phase 2 dosing) and the oral AMPA modulator osavampator (phase 3) ( Psychiatric Times).
• Candidly: nothing in trials targets lifelong bliss. The best feasibility evidence is the FAAH C385A "high-hedonic-tone" variant — naturally occurring, lower anxiety, blunted threat reactivity, demonstrated in mice and humans ( Nature Communications) — plus hedonic-circuit deep brain stimulation.

The canvas includes the full tiered pipeline, failed classes for calibration (KOR antagonists, GLP-1s), source table, and open questions — notably whether a raised hedonic baseline can avoid the motivation-flattening problem.