A New Paradigm for Psychiatry? Definium’s Data in MDD

Having worked on several neuroscience brands for nearly three decades, the news related to Definium Therapeutics’ EMERGE trial lit up a signal in my own brain synapses that we could be witnessing a significant paradigm shift in how we think about mental disorders and how we treat them.

Backing up for a minute, from my vantage point over the past three decades, psychiatric treatments have advanced through incremental improvements rather than big paradigm shifts. And when I speak of paradigm shifts, I am talking about things that drastically change the way we think about a disease and/or treat the disease. One example of this would be the introduction of Prozac (fluoxetine) in 1987. This molecule offered such a safe profile compared to tricyclics that doctors redefined their diagnoses and treatment of depression to include less severe patients.

Prozac then paved the path to the introduction of a whole family of serotonin-based treatments. The next wave of agents leaned on refinements of familiar mechanisms, such as Lexapro (escitalopram) which launched in 2002. And for nearly 20 years these agents have remained at the forefront of treatment. Only in the past few years have we seen unique approaches emerge; first with the launch of Spravato (esketamine) in 2019, followed by Auvelity and Exxual launches. And while Spravato started poking at a potential paradigm shift and the concept of neuroplasticity, the other two agents did not drastically change the treatment paradigm that we know today.

In schizophrenia, newer second‑generation antipsychotics such as Risperdal (risperidone) and Zyprexa (olanzapine) launched in the early 90’s represented meaningful safety improvements over first‑generation agents. And then we saw refinements in formulation to create depot long-acting injections to address compliance. Only recently has there been a new MOA introduced, with the launch of Cobenify (xanomeline-trospium) in 2024. This new MOA bypasses the dopamine pathway, eliminating the weight gain and movement disorder effects known with the atypical agents. However, its efficacy appears to be on par with the atypicals.

In both of these categories and others such as ADHD, side‑effect profiles and dosing optimization have often been the key areas of improvement over the past several decades, with some incremental gains in efficacy. Yet the unfortunate reality is that many patients still do not respond adequately to current therapies (in MDD, studies suggest that up to one-third of patients do not adequately respond to SSRIs). Adding to this, several psychiatric conditions, such as PTSD and addiction still rely heavily on only psychotherapy‑based approaches with limited pharmacologic innovation.

However, on the heels of Spravato’s launch, a rapid movement was seen in the exploration of psychedelics as a novel treatment approach for psychiatric disorders. And in late June, the first real proof-point of this psychedelic movement came to fruition with the release of Definium Therapeutic’s DT120 Phase 3 data in MDD. And I think it is NOTEWORTHY, despite some of the stigma around psychedelics.

DT120, an orally disintegrating, LSD‑based psychedelic, met both primary and secondary endpoints, demonstrating a reduction in depression symptoms not seen with other medications. In addition, the onset of this robust response was seen within one week and the effect was durable throughout twelve weeks. Treatment was generally well tolerated, and no major safety concerns were identified. Also noteworthy, no signs of increased suicidal ideation were observed. And finally, all of this was delivered in one dose. While we clearly need to wait for further data from the 40-week open label arm, this data suggests we may be seeing a truly different approach to the treatment of severe depression.  

Definium is not the only player investigating the potential of psychedelic treatments across mental health conditions. There are now dozens of active clinical trials from multiple manufacturers exploring psychedelics as treatments for a range of psychiatric disorders, with some programs reporting impressively rapid onset and meaningful symptom reductions. That is why Definium’s data feels BIG to me: it is not just a single readout, but part of a broader signal that psychiatry may finally be seeing a truly novel therapeutic approach emerge for patients who have not been well served by existing options or had not options.

At the same time, I’m not looking at this through rose‑colored glasses, nor am I downplaying important advances from non‑psychedelic therapies. Psychedelics still face considerable hurdles — including regulatory uncertainty, safety and monitoring requirements, reimbursement and cost, and persistent societal stigma, to name just a few. The delivery and administration model is also fundamentally different from how most psychiatrists practice today. These physicians are used to writing a prescription for an oral medication and sending patients home to take pills. But with psychedelics, it is very different where a patient needs to schedule an outpatient session for treatment like you do with an infusion treatment.  We are already seeing this play out with Spravato (esketamine), where certain practices have invested in new space, staffing, and protocols to deliver treatment safely. For me, that’s where the excitement and the caution meet: there is real potential for something meaningfully different, but it only becomes truly impactful if we keep a clear‑eyed view of the limitations, the unanswered questions, and the day‑to‑day realities of how today’s psychiatrists are ready — or not yet ready — to think, prescribe, and refer differently.

In my next post, I’ll shift from the molecules to the clinicians and explore how everyday psychiatrists may ultimately determine whether this emerging class of therapies moves from promise to practice.