Husseini Manji on Developing Spravato

Developing Spravato: Dr. Husseini Manji’s Breakthrough with Esketamine

“I was delighted that S-ketamine, Spravato, was the first drug by the FDA ever designated with a breakthrough designation in neuroscience.”
_{— Dr. Husseini Manji}

Dr. Husseini Manji has spent his career at the intersection of neuroscience, psychiatry, and translational drug development. As former Global Head of Neuroscience at Johnson & Johnson and now a Professor of Psychiatry at Oxford, he’s best known for leading the work to bring Spravato (esketamine) to patients with treatment-resistant depression and those at risk of suicide.

Today, his focus has turned toward precision psychiatry, biomarkers, and reengineering care infrastructure to better serve the most complex patients.

From Lab Signals to Life-Saving Therapy

“We brought in patients with what's called treatment resistant depression. So the definition is that they failed the previous antidepressant trial. In fact, the population that came in had failed on average six antidepressants. They were given intravenous low dose IV ketamine, or placebo, and we saw remarkable rapid response. At 24 hours, 70% of this population would be classified as a responder.”

Before Spravato, Dr. Manji’s research at the NIH focused on the molecular mechanisms of depression—particularly brain plasticity. When early signals from Yale suggested ketamine’s antidepressant potential, his NIH team ran controlled trials in patients who had failed nearly every standard treatment.

The results were striking. But ketamine’s IV delivery model was difficult to scale. When he moved to J&J, Dr. Manji focused on turning ketamine’s mechanism into a viable medicine.

His team discovered that S-ketamine, the more potent enantiomer of the drug, could be delivered intranasally in low doses. That enabled a novel treatment approach—and eventually led to Spravato’s approval for both treatment-resistant depression and imminent suicide risk.

Scaling Access Through Infrastructure

“Psychiatrists often will think, this could be the best treatment for my patient, but they don't necessarily even have the nurse present who can give the information.”

One of the biggest barriers to delivering Spravato wasn’t the science—it was the infrastructure. Psychiatry traditionally lacks the procedural setup needed for treatments like Spravato or long-acting injectables.

To solve this, Dr. Manji helped develop Janssen Connect, a national network of clinics that could handle referrals, administration, and even transportation for patients.

This model helped normalize interventional psychiatry, a procedural approach to mental health care that is now gaining wider traction.

Diagnosing Differently: Biomarkers and Subtypes

“If you look at our current diagnostic classification for depression, it's basically a checklist. Depressed, food, antibiotics, eat too much, eat too little, eat too much,. And it's, I think it's naive to think that a single antidote can treat it all perfectly.”

Dr. Manji argues that psychiatry needs more biologically grounded diagnostics. The current system treats depression as a monolith, even though it likely comprises multiple subtypes with different biological drivers.

He sees a future shaped by biomarkers, genetics, and precision tools that allow clinicians to better match treatments to patients—whether that’s oral medications or interventional approaches. He also points to the work of researchers like Dr. Jordan Smoller, whose genetic studies are helping uncover shared pathways across psychiatric and physical conditions.

Mental Health as a Systemic Lever

“Recently insurance companies — about 20 percent of the population accounts for about 80 percent of the cost. And almost all of the 20 percent are people with comorbid physical and mental health conditions.”

One of Dr. Manji’s most powerful points is often overlooked: treating serious mental illness isn’t just compassionate—it reduces burden on our broader health care system. Patients with chronic physical and mental health conditions drive the majority of healthcare spending. By treating psychiatric conditions more effectively, we improve everything from diabetes control to cardiovascular health—and reduce systemic costs.

A Neuroscience Renaissance—If We Stay the Course

“This is still also a risk to try and develop new medication in this case. So I'm partially optimistic that might be a fairer thought for, trying to look at, for example, what we might call personalized approaches to treatment, not a one size fits all, using biomarkers etc. will increase the probability that you'll have, many novel mechanisms that will tell a different story. Many times we'll fail... But I remain optimistic that if we do it correctly, we'll be successful.”

Despite the setbacks, the failed trials, and the regulatory complexity, Dr. Manji remains hopeful. He believes we are living through a neuroscience renaissance, but that progress requires discipline—not hype. His journey—from early ketamine studies to global-scale infrastructure—has already reshaped the field. And with his next chapter at Oxford underway, he’s helping build what comes next.