Psychedelics and Patient Selection Tools Propelling Precision Psychiatry

By Deborah Borfitz 

December 2, 2025 | How depression gets treated in the next decade is poised for significant change thanks to encouraging developments in the use of psychedelics and dissociative compounds like ketamine to alleviate symptoms of the mood disorder. “We’re in the second golden era of neuropsychopharmacology,” according to Hans Eriksson, M.D., Ph.D., chief medical officer (CMO) for precision psychiatry company HMNC Brain Health. 

The traditional treatment order for depression often begins with serotonergic drugs like selective serotonin reuptake inhibitors (SSRIs), sometimes followed by tricyclic antidepressants and monoamine oxidase (MAO) inhibitors, classes of antidepressants developed in the 1950s, says Eriksson, a clinical psychiatrist with over 20 years of experience in the clinical development of therapeutics for psychiatric indications. Compass Pathways, where Eriksson was previously CMO, hopes the Food and Drug Administration (FDA) will approve its COMP360 psilocybin treatment for treatment-resistant depression in late 2026 or early 2027. 

Scientific interest in psychedelic-based therapies has skyrocketed in recent years, driven by promising clinical trial outcomes, a flood of financial investment, and the urgent need for new treatments to counter a growing mental health crisis, he says. The tide turned on psychedelics as a potential treatment depression in the early 2000s, before which they were regarded as “interesting stuff that peculiar people wanted to use.” 

Many patients don’t respond to conventional psychiatric medications, which also come with a range of unwanted side effects such as nausea, sleep disturbances, and weight gain. But psychedelics, a category that in Eriksson’s view broadly includes ketamine as well as psilocybin and LSD, have their own set of complications. 

The core experience can cause feelings of disconnection from oneself or one's environment, which is often managed within a therapeutic setting, says Eriksson. Since they primarily act on serotonergic receptors, they can also lead to cardiovascular changes that are generally but not always transient. 

This is where the KET01 oral ketamine formulation of HMNC Brain Health comes in, offering good therapeutic benefits without the unwanted dissociative experiences, Eriksson reports. In a phase 2 study in treatment-resistant depression, researchers saw an emerging antidepressant signal within seven hours of the first dose with a separation from placebo with a less-than-5% chance of being caused by random chance observed by day four. Significance was lost at three weeks because of a temporary improvement in the placebo arm, he adds. 

Separately, HMNC Brain Health also has a program where novel antidepressants are being used in combination with genetic patient selection tools, adds Eriksson. KET01 does not have its own diagnostic for patient selection, at least not yet.  

Role of Metabolites 

The phase 2 trial of KET01 involved twenty-nine research sites in Germany, Poland, and the Czech Republic. “We gave this medication at home without any supervision ... and we had no issues,” says Eriksson. “Only the first dose was supervised ... [when] we monitored the patients very closely to ensure there was no sign of disassociation or cardiovascular effects.” 

Perhaps the biggest surprise was that KET01 produced an improvement of depressive symptoms “of a similar magnitude to what has been shown with the prescription nasal spray from Janssen,” the FDA-approved Spravato (esketamine), and without causing dissociation or negative cardiovascular effects, says Eriksson. Spravato commonly causes a temporary increase in blood pressure and heart rate. 

Eriksson believes the reason KET01 had no such issues is because it’s formulated to be released from the gut slowly, not reaching peak concentration in the blood until after seven hours. During “first-pass metabolism” of the medicine in the liver, hepatic enzymes efficiently convert ketamine to metabolites. “Ketamine is the culprit when it comes to these dissociative and cardiovascular effects,” he points out.  

“We never obtain so high of concentrations in the blood that these effects are seen,” he continues. “On the other hand, we see quite a lot of the metabolites and our hypothesis is that it is the metabolites that carry the antidepressant properties of ketamine.” 

For many years, scientists have instead been looking at the NMDA (glutamate) receptor where ketamine interacts as the key to the antidepressant effect, says Eriksson. “We cannot exclude that it contributes, but it seems as if other effects may be more important, and our hypothesis is that AMPA receptors [a molecular basis for learning and memory] are involved.”  

Personalizing Treatment 

Eriksson says he was working as a clinician during the 1990s and used the traditional antidepressant treatments—tricyclics, MAO inhibitors, and new-on-the-scene SSRIs and SNRIs like fluoxetine (Prozac) and venlafaxine (Effexor) that were considered safer with fewer side effects. He also witnessed the development of antipsychotic medications for treating schizophrenia that were “making headway into the depression space.” 

Shortly after the turn of the millennium, Eriksson began working with escitalopram (Lexapro) and later, while at AstraZeneca, he led the development program for depression with quetiapine (Seroquel). “I saw that we made progress, but we were knocking on the same mechanisms all the time; it was all about modulating serotonin, noradrenalin, and dopamine,” he says. 

“Psychedelics are also serotonin drugs, but they work in a different way,” Eriksson points out. The emergence of this drug class, which had its first heyday in the 1960s, and later successes of ketamine in addressing treatment-resistant depression and suicidal ideation, sparked his interest in pursuing this entirely new direction in medicines development. 

Eriksson joined Compass Pathways, the largest company in the psychedelic medicine industry, in 2019. His tenure with the company was a relatively short 18 months, but during that time he was involved in building the clinical trial for COMP360 in healthy volunteers. His 2021 pivot to HMNC Brain Health was more about the pandemic than any doubts he had about the compound’s therapeutic potential, he notes.  

But the approach of the two companies is different in that Compass Pathways focuses on psilocybin-based therapy in conjunction with psychological support while HMNC Brain Health concentrates on personalized therapies using predictive patient selection tools and various compounds, including ketamine, says Eriksson. The company formed in 2010 by Florian Holsboer, who for many years was head of the Max Plank Institute of Psychiatry in Munich, and German entrepreneur Carsten Maschmeyer.  

The emphasis on precision psychiatry means “ensuring that the right medication ends up with the right patient where it can have the best benefit for that individual,” Eriksson says. That has long been the passion of Franz Humer, Ph.D., the former chairman of HMNC Holding GmbH and former chairman and CEO of Roche Holding Ltd. He and Eriksson were part of the company’s leadership team that was newly assembled in 2021. 

Scaling Up 

In developing therapeutics for depression, Eriksson says, one of the big lessons has been that psychedelic compounds “all come with different degrees of psychological experiences ... quickly after taking the drug and often coincide with peak concentration of the active component and have resulted in a need to provide a safe treatment environment for the patients.” 

Some companies, including Compass Pathways, are dealing with the issue by offering a treatment combining psychological support with the supervised therapeutic use of psychedelic drugs. In this context, the role of therapists is primarily to provide a safe environment for patients to go through the psychedelic experience, Eriksson says. 

The same holds true for individuals getting off-label treatment with intravenous ketamine, he adds. Even with Spravato, administration needs to be directly overseen by skilled healthcare staff. “That’s a challenge because we’re not used to treating depressed patients that way,” other than with electroconvulsive therapy (ECT). “All the oral treatments have otherwise been administered as pills, medications you take at home without any supervision.” 

When supervision is required, the question becomes what constitutes an appropriate degree of oversight in terms of the skill and training of people around the patient, he continues. “It might be tempting to have very sophisticated oversight [e.g., Ph.D. level psychologist or psychiatrist] ... but if you conduct your clinical trials that way, that’s the way regulators will request treatment to be administered in real life after approval.” 

Eriksson admits he has personally struggled with the question of how to scale up in a way that makes the interventions available to a broader group of patients. An argument could also be made for supportive “wrap-arounds” for oversight-intensive treatments, including some psychedelics as well as ECT and transcranial magnetic stimulation, perhaps at sites that specialize in administering multiple modalities. The added advantage would be that clinicians could more easily select between different interventions. 

Positive Signals 

HMNC Brain Health currently has two projects that combine patient selection tools, supported by artificial intelligence, with novel treatments correcting disturbances in the stress resilience system, reports Eriksson. Such disturbances, notably hypothalamic-pituitary-adrenal (HPA) axis dysregulation, are key mechanistic causes and risk factors for a large proportion of depressed individuals. 

Everyone has a specific stress resilience system whereby the brain regulates the release of the stress hormone cortisol from the adrenals, tiny glands located close to the kidneys, he explains. “The brain orchestrates this by releasing peptide hormones from the hypothalamus, the two main ones being vasopressin and CRH [corticotropin-releasing hormone], and we are now developing inhibitors to each of these two hormones because there seems to be hyperactivity in these systems in roughly 30% to 50% of depressed individuals.” 

Two decades ago, there was intense interest in developing inhibitors to these hormones to overcome depression, but none of the compounds in development ever made it to patients, says Eriksson. Despite the failures, there were positive signals and, on this basis, HMNC Brain Health decided to in-license the vasopressin blocker nelivaptan from Sanofi. It terminated an earlier collaboration with Eisai on the development of a CRH inhibitor but has another drug in the same class in a phase 2 clinical trial in the UK together with California-based Spruce Biosciences, he adds.  

In August this year, a readout from the 338-patient phase 2 trial of nelivaptan showed good efficacy when paired with the company’s genetic selection tool identifying individuals who would have a more profound response to the intervention, he continues. “We see it as a correction of a hyperactive HPA axis.” 

Better Patient Selection

Currently, the problem in distinguishing the subset of people with overactivity in the HPA axis is that the decades-old process is so burdensome and impractical that it is rarely incorporated into the armamentarium of treating physicians, says Eriksson. The process requires that patients undergo a physiological challenge test, which generally means a two-day stay in the hospital for hormone injections followed by blood draws several times the following day.  

The Max Planck Institute of Psychiatry consequently decided to conduct a trial in several hundred depressed individuals who underwent this gold-standard test but also gave biomarker samples to find the genetic signature that maps to the test result. They thereby created a “shortcut” method of identifying candidates for treatment with nelivaptan based on a genetic analysis of their blood.  

Turnaround time on the lab test in the clinical trials was about a week, Eriksson adds, but the research team is working on shortening that period so clinicians can know earlier if patients would be good candidates for the treatment or perhaps benefit more from some other intervention. “Our intention is to pair the drug with the diagnostic ... [but] we saw a good benefit across the board,” he emphasizes. 

Sanofi originally ran 19 clinical trials of nelivaptan, and one of the two large major depressive disorder studies likewise showed efficacy for the entire study population even without a patient selection tool, he notes. “We’re quite confident the compound we’re working with is an antidepressant in its own right, [but] what we’re now trying to increase the value of [it]” with the addition of the patient selection tool telling clinicians if a patient is more or less likely to respond to the intervention. 

“We now have biomarkers for most of these patients, and also outcome data,” says Eriksson. Work is underway to further refine the test, since the prototype version used in the trials produced three different outcomes related to degree of improvement, and the goal is a yes-or-no type test preferred by clinicians.  

The plan currently is to conduct a phase 2b trial deploying the refined test, he adds. The data examined and simulations done thus far suggest that it will be an even stronger selection tool than the one used in the last study.