Dr. Alison McInnes sat before Kaiser Permanente's unconventional use committee in 2014, preparing to propose something that seemed unthinkable: using ketamine, best known as an anesthetic and party drug, to treat severe depression at a major health maintenance organization. In the room, skepticism mingled with curiosity. Traditional antidepressants were failing a third of depression patients, and pharmaceutical companies had largely abandoned psychiatric drug development. The field desperately needed innovation.

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"It was wonderful to give a presentation to that committee," she recalls, "and well-suited to me." Her confidence came from observing research at Mount Sinai, where early ketamine studies had revealed something extraordinary: "Depression symptoms would start to melt away in hours," she explains. "You have to understand how incredible this was. We had spent years waiting four to six weeks for antidepressants to take effect."

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The committee's approval launched one of the first ketamine programs at a major healthcare institution. It also marked the beginning of a decade that would transform psychiatric medicine. By 2024, the data would tell a remarkable story: tracking thousands of patients, researchers found ketamine therapy reduced the percentage of severely depressed patients from 75% to 21%. More surprisingly, a study she lead showed that 80% maintained their improvement at one month, 60% at two months - all without maintenance treatments.

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But as McInnes would discover over the next ten years, rapid symptom relief was just the beginning. The real revolution lay in how ketamine would challenge fundamental assumptions about depression, plasticity, and the very nature of psychiatric treatment.

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Follow this decade-long journey below, or watch Dr. McInnes' complete presentation to discover how ketamine therapy evolved from experimental treatment to mainstream medicine.
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From Serotonin to Synapses: The Science of Rapid Relief

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‍For half a century, psychiatry viewed depression through a single lens: monoamine neurotransmitters like serotonin. Ketamine shattered this paradigm. It worked through an entirely different system - glutamate - triggering neural changes that would transform our understanding of how the brain heals.

"We were seeing a whole host of growth factors here," McInnes explains, pointing to the cascade of molecular events in the neural pathway diagram. "Strengthening of synapses and an increase in the number of synapses. This is really great for the brain." More than just relieving symptoms, ketamine appeared to be rewiring neural circuits themselves.

This rewiring had deeper implications. At Hopkins, Gul Dölen's lab discovered that ketamine could reopen "critical periods" - windows of heightened brain plasticity typically closed in adulthood. While brief - just 48 hours compared to weeks for other psychedelics - this window offered crucial therapeutic potential. "Gul Dölen had the insight," McInnes notes, "that this may be why you need to overlap the ketamine infusions, space them more closely together to get a sustained effect. Maybe you're getting a sustained period of critical reopening when infusions are clustered together."

Sam Wilkinson's team demonstrated how to capitalize on these windows. By combining ketamine with cognitive behavioral therapy, they achieved significantly greater sustained improvement. "We need to create behavioral change that lasts," McInnes emphasizes, "because otherwise we're not getting at the underlying problem."

This new understanding of rapid-acting antidepressants reignited pharmaceutical interest. "One of the great gifts of ketamine and esketamine," McInnes reflects, "is getting pharma back and excited about new drug targets in psychiatry. All these different cascades represent opportunities for new drug targets." After decades of stagnation, companies began exploring novel compounds targeting various points along ketamine's pathway.

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From Lab to Clinic: The Power of Real-World Evidence

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By 2020, ketamine had proven itself in controlled trials. But a crucial question remained: Would these results hold up in the messy reality of clinical practice? Traditional studies excluded patients with multiple comorbid conditions - but as McInnes notes, "Real-world patients have complicated health conditions."

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Through Osmind's structured data collection, researchers began tracking treatment outcomes across thousands of patients. The results surpassed expectations. Among patients with severe depression, the number dropped from 75% to 21% after treatment. Notably, a study she led showed that 80% of patients receiving 6 infusions maintained their improvement at one month and 60% at two months, all without maintenance treatments.

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"And we managed to replicate additional outcomes data in two independent patient cohorts," McInnes adds with satisfaction. "That is, you know, that is an achievement in psychiatry these days." These two studies yielded compelling effect sizes for both depression (Cohen's d = 1.56) and anxiety (1.17).

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When comparing over 7,000 ketamine infusion patients with those receiving esketamine, clear patterns emerged. "It took 12 days for the response to kick in for ketamine whereas it was over 27 days for esketamine," McInnes explains, "with ketamine showing a much steeper slope" in symptom improvement.

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Her research expanded to examine ketamine's effects on PTSD with comorbid major depression. In a study of 1,300 patients - 66% female, 94% Caucasian, with a mean age of 42 - response rates increased from 27% after the first infusion to 65% after the fourth infusion, reaching 73% at the sixth treatment (response defined as a >/= 30% reduction in the PCL-5. The mean drop in scores after the 4th infusion was 19.  AND the PHQ-9 decreased by ~50% after the 4th infusion.  The mean dose at the final infusion during the induction phase was 1.13 mg/kg, significantly higher than in earlier controlled studies.

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The hope is that these real-world findings will shift the conversation with insurance companies. As McInnes observes, "Real world evidence is used to leverage payers." Clinical experience was finally being validated by large-scale data.

From FDA Approval to Expanding Access

The FDA's approval of esketamine in 2019 signaled a new phase. Ketamine therapy was entering mainstream medicine - bringing both opportunities and challenges. During the pandemic, telemedicine platforms emerged, offering at-home treatments. "From the advent of DTC ketamine during the pandemic," McInnes observes, "we start to see the DEA investigating compounding pharmacies, manufacturers screening providers more carefully."

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The field moved to regulate itself. The American Society of Ketamine Physicians (ASKP3) convened expert panels to establish treatment guidelines. "The Pledge includes nine basics of administration," McInnes explains. "Recipients must be screened by a mental health professional and must be treated for a psychiatric disorder." This push against "wellness" use aimed to prevent misuse and ensure patient safety.

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Yet economics remain the central barrier. While ketamine could save insurers $9,500 per patient annually by preventing progression to treatment-resistant depression, most clinics operate at just 60% capacity. With treatments costing $400-$1,200 per session out of pocket, many of the 2.9 million adults with treatment-resistant depression in the U.S. cannot access care.

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Meanwhile, pharmaceutical development continues. Companies are now exploring the use of different types of NMDA-R modulators seeking ketamine's benefits with the hope of fewer side-effects and reduced abuse potential. For example, some explore abuse-deterrent formulations of ketamine/esketamine derivatives for home use, while others investigate compounds like rapamycin to extend treatment effects and still others look at allosteric modulation of NMDA-R subunits.

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"Access is still a major problem and drives the direct-to-consumer industry," McInnes notes, pointing to persistent "racial and ethnic inequality and economic inequality." Ten years after that first Kaiser committee meeting, the challenge isn't proving ketamine works - it's ensuring those who need it can access it safely and affordably.

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A Decade of Discovery: What's Next

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After ten years on ketamine's frontlines, McInnes's key insight challenges our assumptions about psychiatric treatment. Studies reveal significantly higher placebo responses in depression (effect size 2.0) compared to conditions like schizophrenia (0.59) - suggesting that for mood disorders, the therapeutic context matters as much as the medication. "The thing that I learned the most," she reflects, "is that psychotherapy and behavior modification is crucially important to altering the course of future illness."

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The path forward requires solving complex puzzles: establishing safe dosing protocols, expanding insurance coverage, and addressing racial and economic disparities in access. But ketamine has already achieved something remarkable: it has shown psychiatry that rapid relief is possible, that the brain's capacity for change extends far beyond what we imagined,  and that innovation in mental health treatment remains very much alive.