In the early 2000s, psychiatrists faced a sobering reality: despite decades of development, at least a third of depressed patients weren't getting better with traditional medications. Pharmaceutical companies were retreating from neuroscience research. It was in this climate that Dr. Husseini Manji, M.D., F.R.C.P.C., and his team at the National Institutes of Health began exploring an innovative approach to treating depression.

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Five years after gaining FDA approval, their breakthrough – esketamine (SPRAVATO®) – has offered a new understanding of depression treatment and created a potential roadmap for future psychedelic medicines. Dr. Manji, Osmind Strategic Advisor and the pioneering scientist behind this breakthrough, shares the journey from lab to clinic and its implications for the future of psychiatry.

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In this deep dive, you'll discover:

• How targeting the NMDA receptor led to unprecedented response rates in treatment-resistant patients
• The development of a novel intranasal delivery system and dosing protocol
• Why the FDA granted its first-ever breakthrough designation in psychiatry
• The path toward potential first-line treatment and monotherapy approval
• Lessons for future psychedelic medicine development and approval
• The ongoing fight for mental health parity in insurance coverage

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The Science of Plasticity

Dr. Manji's journey began not with ketamine, but with fundamental questions about how the brain adapts and changes. His team focused on "plasticity pathways" – the mechanisms by which the brain strengthens or weakens connections between neurons.

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"A lot of basic science work started to look at certain receptors, particularly the NMDA and AMPA receptors," Dr. Manji explains. "Their movement into or out of synapses seemed to play a major role in regulating neuroplasticity." This insight led to a crucial hypothesis: these same molecules might be key players in both causing and treating depression.
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The Ketamine Breakthrough

A small study from Yale showing rapid antidepressant effects with low-dose ketamine caught Dr. Manji's attention. His team at the NIH designed a pivotal study targeting the most challenging cases in psychiatry – patients who had failed an average of six different antidepressant trials. These weren't simply treatment-resistant patients; they had been continuously depressed for three years, and some hadn't responded even to electroconvulsive therapy.

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The results were unprecedented. "Not only was there a remarkable response, but people started to respond within two hours. At 24 hours, 70 percent were classified as responders," Dr. Manji recalls. Even more remarkable was the durability – patients remained well for several days after the drug left their system.

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Tom Insel, then director of the NIMH, called it "the biggest breakthrough in psychiatry in about 50 years."

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Engineering a Solution

Moving to Johnson & Johnson, Dr. Manji faced a new challenge: how to make this treatment practical and accessible. The answer lay in esketamine – ketamine's more potent S-enantiomer, which could be delivered in smaller doses through a nasal spray.

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"We were able to show that ketamine comes in two versions, an R version and an S version. And the S version is four times more potent at the NMDA receptor, so you can get away with a very small amount of drug that could lend itself to intranasal delivery."

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But developing a novel psychiatric drug meant venturing into uncharted territory. "Almost everything was new," says Dr. Manji. "No one had ever developed a rapid-acting antidepressant, an intranasal drug, or a psychiatric medication administered just once every few weeks."

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Related reading: How to add SPRAVATO® to your practice

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Setting New Standards

The development program was unprecedented in its scope and rigor. Twenty-six studies examined everything from proper administration angles to the effects of nasal decongestants. A special disposable device was engineered to prevent misuse. The FDA required both acute and long-term data before approval – unusual for psychiatric medications.

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The treatment protocol that emerged was precise: patients receive treatment twice weekly for the first four weeks, then transition to less frequent administration – once every two to three weeks – based on individual response. Recent data shows patients maintaining response or remission for up to four and a half years with these maintenance doses.

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SPRAVATO® became the first psychiatric drug to receive FDA breakthrough designation and is now approved in 80 countries.
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Breaking New Ground

Perhaps most significantly, the SPRAVATO® trials challenged traditional psychiatric research boundaries by including suicidal patients – typically excluded from such studies.

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"We insisted on treating suicidal patients," Dr. Manji emphasizes, "implementing extra safety measures to do so responsibly." The drug showed rapid reduction in suicidal ideation, leading to a second FDA indication.

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The Fight for First-Line Treatment

A recent FDA submission for SPRAVATO® as monotherapy could expand treatment options beyond its current use in combination with oral antidepressants. But broader access faces a familiar obstacle in psychiatry: insurance coverage.

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The development challenges are substantial – about 90 percent of drug development attempts fail, often costing hundreds of millions even for successful medications. "In psychiatry, most of our medications are very low-priced compared to oncology and immunology," Dr. Manji notes. Insurance companies often require patients to try older, generic medications before approving newer treatments – a practice less common in other medical fields.

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The cost argument ignores larger economic impacts. "These are the chronic diseases of the young," Dr. Manji argues. "When you're continuously depressed, it affects your occupational functioning, your scholastic functioning, relationships break up, people die from suicide, people have much worse physical health."

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A New Chapter in Psychiatry

The SPRAVATO® story represents more than a new medication; it's a template for bringing innovative psychiatric treatments to patients. Its development challenged traditional assumptions about depression treatment, drug delivery, and clinical trial design.

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As other psychedelic medicines approach FDA consideration, the lessons learned from esketamine's journey from lab to clinic could help accelerate their path to patients. The challenge now lies not in proving these treatments work, but in ensuring they reach those who need them most.



Selected Timestamps from the podcast interview:‍

[00:00:00] Opening context about SPRAVATO's® approval in May 2019

[00:02:00] Dr. McInnes introducing Dr. Manji and the episode's focus

[00:03:00] Discussion of early 2000s psychiatry challenges and STAR-D findings

[00:04:00] Dr. Manji explaining plasticity pathways and synaptic connections

[00:05:00] Details of early animal studies on NMDA receptors

[00:06:00] Discussion of Yale group's initial ketamine findings

[00:07:00] Description of NIH trial with treatment-resistant patients

[00:08:00] Results showing 70% response rate within 24 hours

[00:09:00] Explanation of plasticity pathway effects

[00:10:00] Dr. Manji's transition to J&J and development strategy

[00:11:00] Development of intranasal delivery method

[00:13:00] Discussion of FDA approval process and monotherapy potential

[00:14:00] Details of rigorous development program (26 studies)

[00:15:00] Development of specific intranasal device and safety measures

[00:16:00] Treatment protocol details and dosing schedule

[00:17:00] Long-term efficacy data presentation

[00:18:00] REMS program development and DEA coordination

[00:19:00] Discussion of suicidal patient inclusion in trials

[00:20:00] Potential for first-line treatment consideration

[00:21:00] Discussion of development costs and insurance challenges

[00:22:00] Mental health parity issues and treatment access