Designing scalable psychedelic therapies for treatment‑resistant depression
Kevin Craig, Chief Medical Officer of AtaiBeckley, discusses the current therapeutic landscape for major depressive disorder and therapeutic advances for this hard-to-treat disease.
Major depressive disorder (MDD), or depression, remains one of the most urgent and complex challenges in mental health. More than 300 million people1 worldwide live with the condition, but a substantial proportion of these people – commonly estimated at 30-502– do not respond to first-line treatments like selective serotonin reuptake inhibitors (SSRIs). A subset of these patients go on to develop something called treatment-resistant depression (TRD), a chronic, relapsing condition typically defined as an insufficient response to at least two mechanistically distinct antidepressant interventions.
For decades, pharmacologic innovation in TRD has been defined by incrementalism, with reformulations of existing antidepressants often failing to meaningfully improve efficacy or durability. But the field is progressing, with innovation from psychedelic-based compounds, such as psilocybin-based therapy, which is now approaching regulatory approval, signaling a watershed moment. As these compounds advance toward regulatory review, the central challenge is no longer one of scientific plausibility but the practical question of how to deliver them at scale within real-world clinical systems.
Psychedelics as a mechanistic shift in psychiatry
Classic psychedelics, such as psilocybin, LSD, DMT, and 5-MeO-DMT, work primarily by activating the 5-HT2A receptor, a serotonin receptor in the brain which has an important role in cognitive function and flexibility, mood, perception, and neural plasticity – the brain’s ability to reorganise itself and form new connections. These compounds seem to briefly increase the brain’s neuroplasticity, creating a window during which cognitive and emotional patterns can be reshaped for lasting change.
Furthermore, unlike conventional antidepressants, which can require weeks to produce noticeable therapeutic effects, clinical studies across the psychedelic compounds have demonstrated rapid symptom improvements, sometimes in a matter of days. These mechanistic insights have led to a surge of academic, investor and biotech interest in what many have called a ‘psychedelic renaissance’.
The psychedelic renaissance: innovation meets regulation
Regulators have signalled cautious openness to psychedelics in recent years. The US Food and Drug Administration (FDA), for example, has granted Breakthrough Therapy Designation to several psychedelic-based programmes in TRD and post-traumatic stress disorder, including BPL-003, a rapid-acting intranasal formulation of 5-MeO-DMT being developed for TRD by AtaiBeckley. Such designations acknowledge the potential of these compounds to deliver substantial improvement over existing therapies, especially in areas of high unmet need. But regulatory progress is only one dimension of translational success. Another is translating promises into practice – conducting rigorous trials, with consistent dosing, and building treatment models that can feasibly scale in the real world.
A new treatment landscape taking shape
While mechanistically distinct from classic psychedelics, the approval of Spravato (esketamine), developed by J&J, in 2019, established a precedent for rapid-acting, clinical-administered psychiatric treatments. Delivered intranasally under medical supervision with a two-hour in-clinic monitoring window, it created a practical framework for rapid-acting interventional psychiatry treatments in real-world settings. Yet for all that Spravato established, durability remains a persistent challenge. The treatment requires frequent, ongoing clinic visits, typically twice weekly for the first month, then weekly or biweekly on an ongoing basis, to sustain its antidepressant effects. For patients with a chronic, relapsing condition like TRD, a model dependent on frequent, repeat dosing poses challenges to burden of care and the ability to treat geographically diverse patients.
Psilocybin-based therapies have provided a compelling answer to this challenge. In clinical trials, they have demonstrated not just rapid effects, but durability – with patients experiencing sustained benefits long after treatment. That could be a game-changer for a chronic relapsing condition like TRD. But psilocybin sessions typically require six to eight hours of in-clinic monitoring and significant clinic resources. It works and it’s a significant step forward for the field, but those operational demands raise serious questions about scalability: the sheer time-per-patient make it difficult to see how psilocybin, or any longer-duration approach, reaches the millions of patients with TRD who need it. The next question is whether a shorter-duration compound can deliver the same degree of efficacy and durable benefit without the same operational ceiling.
Potential next-generation compounds like BPL-003 (an intranasal formulation of 5-MeO-DMT) are designed to address exactly this. With psychoactive effects lasting 30-60 minutes, BPL-003 aims to preserve the durable therapeutic benefits of psilocybin while dramatically reducing the operational footprint burden. Phase IIb data reported last year demonstrated significant, sustained improvements for patients with TRD, with the majority of patients deemed ready for discharge within two hours of dosing, uniquely fitting within Spravato’s proven in-clinic window.
Each of these approaches marks a step forward. Spravato proved the model. Psilocybin-based therapies offer dramatically approved durability. The next generation is now asking whether both can be delivered at scale.
What does success look like in psychedelic drug development?
As psychedelic therapeutics advance into late-stage development, several criteria are emerging as central to long-term success. Innovation must translate into clinically meaningful and durable efficacy in well-controlled studies. TRD is a chronic and often relapsing condition, so understanding the durability of response after single or intermittent dosing will be essential for defining long-term treatment paradigms and health-economic value. Operational scalability will also matter. Treatments that require extensive infrastructure, prolonged monitoring, or highly-specialised personnel may struggle to achieve widespread adoption, regardless of efficacy. Clinical performance alone will not determine reach. The compounds that scale commercially will be those whose treatment model can meet the volume and economics the market requires; a bar that current longer-duration approaches may struggle to clear. Finally, integration into clinical practice will require careful planning of training, reimbursement, and access to determine whether these therapies remain limited to specialised centres or become broadly accessible.
If developers can align efficacy and durability with operational feasibility, psychedelic-based medicines may not only expand treatment options for TRD but represent an entirely new class of treatments that could redefine the mental health sector for good.
References
1: https://www.who.int/news-room/fact-sheets/detail/depression
About the author
Kevin Craig MD became Chief Medical Officer of AtaiBeckley in 2025, previously serving as Senior Vice President and Vice President of Clinical Development at atai Life Sciences. He is responsible for developing and driving the execution of clinical development, regulatory affairs, drug safety, biostatistics, global clinical operations and early commercial planning.
The views and opinions expressed in this article are those of the author and do not necessarily reflect the official policy or position of AtaiBeckley or its affiliates.