What Interventional Psychiatry Gets Wrong, with Lisa Harding, MD

Dr. Lisa Harding, former chief resident of interventional psychiatry at Yale and founder of the Mood Institute, joined Will Sauvé and Brittany Albright on Psychiatry Tomorrow to make one argument from several angles: the treatments work. What fails is how clinicians think about them, where they deliver them, how they dose them, and whether the math works.

• The cliché she would kill: "more is better" - more TMS pulses, more frequent ketamine, higher doses
• Why interventional treatments are wrongly reserved for the sickest patients
• How much set and setting move outcomes
• What the EQUIVALENCE trial is designed to settle about IV ketamine vs. esketamine
• Why mail-order sublingual ketamine worries her
• Why interventional practices fail

When Lisa Harding, MD was fifteen or sixteen, patients burned down the psychiatric hospital her father built in Guyana.

There are places named after her family there. The care that resumed afterward was the same care they had given before, delivered in tents.

That contrast has stayed with her: a beautiful building, and care that never quite reached the people it was built for. "Why this enormous spend on this thing?" she asked on a recent episode of Psychiatry Tomorrow podcast. "How do we meet in the middle? How do we go from tent to like the magneto suite?"

Will Sauvé, Osmind's Chief Medical Officer watched the well-funded version of the same failure. He described the center of excellence the military built at Bethesda for traumatic brain injury and PTSD: a glass and steel cathedral with a magnetoencephalography suite and some of the best clinicians in the country. By his estimate, a place like that treats ten patients in a month. "My goodness, we might help as many as 50 people a year," he said. "There's a ton of people out there, and how do we get it all to them?"

Harding trained in emergency medicine in the Caribbean before she trained in psychiatry, and she still describes herself as an ER physician. "If something's wrong with you, you need to be fixed now and then high five and get out of here. Like that's my brain in medicine."

What's the most damaging cliché in interventional psychiatry?

Sauvé asked which cliché in interventional psychiatry she would erase forever, and she did not hesitate. "More is better," she said. "For TMS as well. People do all of these, let's give them extra pulses, let's give ketamine, let's treat more frequently. That's what I want to go away in intervention, that more is better."

Sauvé, who came up in the military, admitted the reflex is hard to shake. "Anything worth doing is worth overdoing," he said, before conceding the data has not been kind to that instinct. Plenty of clinicians still believe five thousand TMS pulses beat three thousand. "We learned the hard way quite some time ago that that's not true," he said. Depending on protocol, more pulses may not even beat six hundred.

"None of these (interventional) treatments are better than the other" Sauvé said. "They're different treatments pointed at different targets." Harding finished the thought: "And there's no litmus test to tell which is your target."

Do patients have to be "sick enough" to get an intervention?

'Everyone talks about destigmatizing mental health,' Harding said; she would rather destigmatize the procedures. "I think the cumbersomeness of the procedures gives this idea that because it's not a pill, it's different." Clinicians carry a threshold in their heads — patients have to earn a higher level of care. "Like you can't be a regular depressed person walking around."

The running joke of the episode: Albright had texted them about a case where a colleague reached for carbamazepine before anyone considered an interventional option. Everyone recognized it. "There is a degree of illness perception in the mind of our colleagues," Harding said, "that they don't think of this as just the next thing to do."

When Sauvé suggested the field might be a victim of its own success, Harding stopped him. "I don't think we've been successful. Why do you think we've been successful?" Albright said she had been about to pick the same fight.

Harding's case for pessimism is a supply problem. "Our mindset still hasn't changed on illness perception, and the understanding of frameworks of delivery just get worse and worse. So I don't know how anyone's hopeful that any of these new treatments just won't meet the top two percent of our population. That's what I worry about."

She gives her predecessors some grace. The psychiatrists of twenty years ago had no other tools, so they could not afford to hand patients hopelessness in a pill. "The part I struggle with is we have these newer tools, and everybody's like, let me try one more. Still. And I don't know why."

How much does the treatment room matter?

The question Harding has been circling since childhood; how do you go from the tent to the magneto suite? And once you have the suite, does it matter?

She’s seen ketamine delivered in what patients described to her as a broom closet. Sauvé had a patient come to him for TMS after a first experience at a hospital that had installed its Brainsway device in* the basement*. "I think they spent extra money to install a special door that would creak just like on Frankenstein," he said. Flickering lights, scary music, a clinician who seemed unsure how to run the machine. The patient all but ran screaming and swore never to return. When the same patient tried the identical device in a calm office where everyone looked in control of the room and was utterly unconcerned about it, made the patient confident, which of course contributed to the outcome.

With psychedelics at least, set and setting matters: the patient's mindset going in and the physical and social environment surrounding the experience. Harding's former Yale supervisor David Ross gave her a less freighted version of the same idea: "the non-specific, non-pharmacological effects of treatment," precisely so he would not have to say placebo. She explains it to patients with a blunt analogy about orgasm: a full physiological event triggered with no drug introduced at all. There are fMRI studies, she notes, where prefrontal activity shows up as a patient reaches for an oral antidepressant, before the pill is swallowed.

Albright would use that effect rather than apologize for it. "Even if it is placebo, use it," she said. "That's in many ways our most powerful tool in psychiatry." Albright sees the same mechanism in TMS, where a warm technician greets the patient every single day.

Harding is careful with that power: she does not check in with patients before ketamine, on purpose, and she stays skeptical of bolting psychotherapy onto these drugs without randomized evidence. "People have models and they do things. I, Lisa Harding, am not that person." She thinks of the brain like a flower in bloom, and the setting as the climate it blooms into. "I do not want to be the Sahara Desert to a patient," she said, contrasting the desert with her home island of St. Lucia. "How do we know that forty years from now the people doing or having gotten ketamine-assisted psychotherapy will not have some other thing that we caused?"

What about IV ketamine vs intranasal (esketamine) aka Spravato?

For years, clinicians have held strong opinions about whether IV ketamine or intranasal esketamine works better, with almost no head-to-head data behind them. Harding is helping fix that. She is a site investigator on EQUIVALENCE, a randomized non-inferiority comparison of the two treatments funded by the Patient-Centered Outcomes Research Institute, with Yale's Samuel Wilkinson as contact principal investigator and Gerard Sanacora as co-principal investigator.

The clinical stakes are real: a retrospective chart review of 153 patients at McLean Hospital, published in the Journal of Clinical Psychiatry in September 2025, found IV ketamine produced earlier and greater symptom reduction than intranasal esketamine, a 49.22 percent drop on the QIDS-SR16 versus 39.55 percent by the final dose. The groups were uneven and the design couldn't settle the question — but a properly powered randomized trial can. If IV ketamine turns out to be non-inferior, the finding could push insurers to cover it and pull patients away from poorly regulated take-home ketamine.

Harding said yes to the trial for a reason that runs through her whole practice: "I do not assume safety in the absence of data." The EQUIVALENCE protocol caps ketamine at 60 mg per day and eight lifetime exposures — a condition of this trial, not a blanket FDA limit — and ketamine remains approved only as an anesthetic and is used off label in psychiatry. "They do not assume safety in the absence of data either," she said of the regulatory posture (at least in modern psychiatry…)

Being a trialist also made her question her own rituals, and then tighten them. She does not treat patients twice weekly beyond four weeks. A patient who has not reached more than a 50 percent symptom reduction is a non-responder; one who lands between 25 and 50 percent does not get a dose increase but a look at medication augmentation, or at whether they are now well enough to engage in psychotherapy.

The weighing ritual she is less sure about. Many clinics weigh patients before every IV ketamine session. "Do I think 61.5 milligrams of ketamine is different to like 60 milligrams?" she asked. "Why are we doing these arbitrary things?" Albright hears the mirror-image question from patients: why are there only two fixed doses of Spravato, yet ketamine dosing demands constant weighing?  Part of the answer is 30-50% biovalability with esketamine, and it’s hard to make an adjustable nasal spritz. Still, "none of us knows if what we're doing is nonsense," Harding said. "Or none of us also knows, is this the most brilliant thing we've done?"

What worries Harding about mail-order ketamine?

Some of Harding's sharpest worry is aimed at the subscribe-and-save model, sublingual ketamine shipped to a patient's door, flavored watermelon, used by someone who may or may not follow instructions. She pointed to work by her Yale colleague Sam Wilkinson on the proliferation of ketamine clinics, first around 2016 and again after pandemic-era telehealth rules loosened. Her description of that second wave: "the crazies came out and people did what they want, shrouding it in access to care."

The pharmacology compounds the problem. Oral ketamine's bioavailability for the parent drug runs roughly 16 to 24 percent, sublingual around 25 to 30, with heavy conversion to norketamine pushing effective exposure estimates higher still — and the dose-response follows an inverted U, where too much NMDA blockade can wipe out the effect you were going for. "How can you ever hit that bullseye," Sauvé asked, "with a means of administration that varies that wildly," shipped through a non-temperature-controlled environment.

Regulators have noticed. The FDA warned in October 2023 about compounded ketamine products for psychiatric use, including oral formulations, citing the absence of monitoring in at-home settings and an adverse event report of respiratory depression in a patient who took compounded oral ketamine at home.

The deeper problem is that the field has no warning sign for NMDA receptor overshoot. With antipsychotics, tardive dyskinesia tells clinicians when they've pushed a receptor too far. With ketamine and the newer psychedelics, no comparable signal exists. "We have no information about the quantity and quality of receptors per human being," Harding said. Sauvé framed it as the broader culture of more: the brain, he said, is not a volume knob. "It's a symphony. It's always going to be about the right amount of this and the right amount of that."

Why do interventional practices fail?

If a psychiatrist ten years into practice asked Harding for the single most useful piece of advice, she would start with the prescribing. Most of the people who come to her for consulting are burned out from watching sick patients not get better, still working from a toolkit that ends at one more medication. The first thing to undo is the assumption that carbamazepine is the next step.

After that, she would tell them the clinical part is the part they can already handle. "You think none of us couldn't sit for a patient and figure out how to treat them with a psychedelic? That's not the part that's gonna blow this up. How you're paying for it is gonna blow this up."

The real obstacle is the stack of masters a practice answers to once it adds interventions: the DEA, the FDA, the state board, and a REMS program you can fail. Spravato is available only through a restricted program that certifies the setting, requires self-administration under direct observation, and requires at least two hours of on-site monitoring with blood pressure checks before discharge. Certified settings agree to audits, and sustained non-compliance can cost a setting its certification. A lot of practices between 2019 and 2022 did not know the process would be this demanding, and some of them closed.

Then there is cash flow: TMS machines cost money, insurance reimburses slowly, and staff still need to be paid in the meantime. Harding calls the trait you need to survive that "belly," her Caribbean word for the stomach to carry financial risk while you wait to be paid.

She and Albright coach young clinicians to "practice to the top of your degree." When a psychiatrist offers to handle their own scheduling, Harding pushes back: that is a twenty-dollar-an-hour job. See patients, hire out the rest, keep the doors open. Albright solved the IV-nurse math her own way, switching to intramuscular ketamine and billing insurance rather than paying a nurse $150 an hour or passing a $1,200 infusion cost to the patient.

The clinicians who learned all of this the hard way have mostly gone quiet. Harding put it plainly: "Where are all these people that started Spravato and didn't do it anymore? You're not hearing from them." They lost money figuring out the launch, and their silence is why the field has so little honest accounting of what it takes.

Albright pointed to a beautiful rural clinic that accepts insurance without running thirty patients a day, and to Harding herself. "Rich or underserved, people want to use their insurance," Harding said. Good care, a decent-looking office, and insurance billing can coexist. They just require the belly.

Is Harding actually a pessimist?

Harding insists she is a pessimist, but Albright isn't buying it. "When I need a therapist, I call Lisa Harding," she said. The pessimism is a method: a standing refusal to assume safety, or success, before the data is in.

"Even though I am a pessimist, I am hopeful for science," she said. "I think we are in the only specialty where the horizon keeps moving. And that is a great place to be."

Takeaways

• Dr. Lisa Harding, former chief resident of interventional psychiatry at Yale and medical director of the Mood Institute in Connecticut, argues the treatments work fine. What fails is access, setting, dosing reflexes, and practice economics.
• The cliché she would kill: "more is better." More TMS pulses, more frequent ketamine, and higher doses are often not better and can be worse. Within a session, TMS pulse count follows an inverted U, and theta burst at 1,200 pulses turns inhibitory.
• Interventional care is wrongly reserved for the sickest patients. Depression is deadly, and these treatments are different tools pointed at different targets, not rungs on a severity ladder. Harding's worry is that new treatments only ever reach the top two percent.
• Set and setting move outcomes. Harding calls it "the non-specific, non-pharmacological effects of treatment." Albright's view: even if it is placebo, use it.
• Harding is a site investigator on EQUIVALENCE, the PCORI-funded randomized comparison of IV ketamine and esketamine: 400 patients with treatment-resistant depression, 200 per arm, eight treatments over four weeks, QIDS at four weeks as the primary endpoint. Results are not expected before 2028.
• Her own thresholds: no twice-weekly treatment beyond four weeks, non-response at anything under a 50 percent reduction, and no dose escalation for partial responders between 25 and 50 percent.
• Mail-order sublingual ketamine worries her. Bioavailability runs roughly 16 to 24 percent oral and 25 to 30 percent sublingual, the dose-response is non-linear, and the field has no warning sign for NMDA receptor overshoot.
• Practices fail on money, not medicine. Survive the REMS program, the slow reimbursement, and the cash-flow risk, and "practice to the top of your degree."

Clinical note

This article summarizes a clinical conversation for educational purposes and is not medical advice. Racemic ketamine is FDA-approved as an anesthetic and its use in psychiatry is off label. Dosing thresholds and protocols described here reflect the individual practice patterns of the clinicians speaking, not a standard of care. EQUIVALENCE is an ongoing trial with no published results. Approval status, REMS requirements, and prescribing information for the medications named can change. Clinicians should base treatment decisions on current prescribing information, individual patient assessment, and applicable regulatory guidance.

TL;DR

• Dr. Lisa Harding, former chief resident of interventional psychiatry at Yale and medical director of the Mood Institute in Connecticut, argues the treatments work fine. What fails is access, setting, dosing reflexes, and practice economics.
• The cliché she would kill: "more is better." More TMS pulses, more frequent ketamine, and higher doses are often not better and can be worse. Within a session, TMS pulse count follows an inverted U, and theta burst at 1,200 pulses turns inhibitory.
• Interventional care is wrongly reserved for the sickest patients. Depression is deadly, and these treatments are different tools pointed at different targets, not rungs on a severity ladder. Harding's worry is that new treatments only ever reach the top two percent.
• Set and setting move outcomes. Harding calls it "the non-specific, non-pharmacological effects of treatment." Albright's view: even if it is placebo, use it.
• Harding is a site investigator on EQUIVALENCE, the PCORI-funded randomized comparison of IV ketamine and esketamine: 400 patients with treatment-resistant depression, 200 per arm, eight treatments over four weeks, QIDS at four weeks as the primary endpoint. Results are not expected before 2028.
• Her own thresholds: no twice-weekly treatment beyond four weeks, non-response at anything under a 50 percent reduction, and no dose escalation for partial responders between 25 and 50 percent.
• Mail-order sublingual ketamine worries her. Bioavailability runs roughly 16 to 24 percent oral and 25 to 30 percent sublingual, the dose-response is non-linear, and the field has no warning sign for NMDA receptor overshoot.
• Practices fail on money, not medicine. Survive the REMS program, the slow reimbursement, and the cash-flow risk, and "practice to the top of your degree."

Timestamped show notes

Approximate.

• [00:00] Recording on Juneteenth, and why Harding calls herself a "freedom day baby"
• [03:02] Training as chief resident of interventional psychiatry at Yale, the field's one open spot
• [04:57] Two rejections from Yale, and a made-up specialty for people who wanted to do ER psych
• [05:48] From the ER to psychiatry: "I'll be the most empathetic physician you will ever meet"
• [07:59] Why she left academia: hospitals are a poor delivery mechanism
• [09:40] Sauvé on the Bethesda center of excellence that treats ten patients a month
• [10:30] The psychiatric hospital her father designed in Guyana, and the day patients burned it down
• [11:56] ECT in a bus, a detox bus, mobile TMS: bringing intervention into communities
• [13:47] The referral pipeline and the illness-perception threshold
• [15:52] "I don't think we've been successful." Harding pushes back
• [17:20] The worry: new treatments that only reach the top two percent
• [18:06] Set and setting: the broom closet and the sanitized ECT suite
• [19:11] Sauvé's Frankenstein-basement TMS story
• [21:02] The effect Harding refuses to call placebo
• [22:59] Why she does not check in with patients before ketamine
• [27:12] Building the Mood Institute: insurance-based TMS, Spravato, ketamine, yoga, four retreats a year
• [31:44] You can take insurance and not see thirty patients a day
• [32:40] EQUIVALENCE: IV ketamine vs. esketamine, and why she said yes
• [37:12] How strict the regulatory posture is on lifetime ketamine exposures
• [38:36] Subscribe-and-save ketamine, and a U-shaped response curve
• [41:04] Sublingual bioavailability and hitting a moving bullseye
• [42:16] "We don't have precision psychiatry. I tell patients that it is guesswork"
• [43:10] NMDA receptor homeostasis, overshoot, and the missing warning sign
• [46:02] Trial design: randomization, the switch option, and the observational arm
• [49:12] How becoming a trialist made her question the weighing ritual
• [50:20] Her thresholds: four weeks, 50 percent, and no dose escalation for partial response
• [52:28] The number one piece of advice for adding interventions
• [54:30] Why practices fail on economics, not medicine
• [58:42] REMS audits you can fail, and the "belly" to carry risk
• [59:40] The silent survivors of the Spravato launch
• [01:00:32] Lightning round: the cliché she'd kill ("more is better")
• [01:01:15] Why depression deserves more aggressive treatment
• [01:04:27] A pessimist who's still hopeful for science

References

1. Wilkinson ST, Prashad S, Dalthorp R, Harding L, Kitay B, Parikh SV, Dziura J, Clayton A, Fram G, Lepoutre V, Brown J, Ostroff RB, Sanacora G. Non-inferiority, comparative effectiveness study of intravenous ketamine v. intranasal esketamine for treatment-resistant depression: The EQUIVALENCE trial protocol. Contemporary Clinical Trials, 2026;164:108273. DOI: 10.1016/j.cct.2026.108273. ClinicalTrials.gov NCT06713616. PCORI contract BPS-2023C1-32153.
2. Meisner RC, Li S, Boyle B, et al. Comparative Effects of Repeated Ketamine Infusion Versus Intranasal Esketamine in Patients With Treatment-Resistant Depression: A Retrospective Chart Review. Journal of Clinical Psychiatry, 2025;86(4):25m15789. DOI: 10.4088/JCP.25m15789.
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9. U.S. Food and Drug Administration. FDA warns patients and health care providers about potential risks associated with compounded ketamine products, including oral formulations, for the treatment of psychiatric disorders. October 10, 2023.
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11. Pigott HE, Kim T, Xu C, Kirsch I, Amsterdam J. What are the treatment remission, response and extent of improvement rates after up to four trials of antidepressant therapies in real-world depressed patients? A reanalysis of the STAR*D study's patient-level data with fidelity to the original research protocol. BMJ Open, 2023;13(7):e063095.
12. Wajs E, Aluisio L, Holder R, et al. Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2). Journal of Clinical Psychiatry, 2020;81(3):19m12891.
13. U.S. Food and Drug Administration. Spravato (esketamine) nasal spray prescribing information and REMS program requirements. Approved March 5, 2019; REMS most recently modified October 9, 2025.