Iliyan D. Iliev, PhD is a professor of immunology in medicine and co-director of the microbiome core laboratory at the Jill Roberts Institute for Research in Inflammatory Bowel Disease at Weill Cornell Medicine

Gut fungal dysbiosis has been implicated in

, yet strategies for targeting the intestinal mycobiota remain unexplored.¹ Iliyan D. Iliev, PhD, is professor of immunology in medicine and co-director of the microbiome core laboratory at the Jill Roberts Institute for Research in Inflammatory Bowel Disease at Weill Cornell Medicine. He led a new prospective observational study testing whether clearing intestinal Candida could reshape the gut microbiome and disease activity in patients with IBD and oral thrush.

His laboratory has previously shown some Candida albicans strains produce candidalysin, a toxin damaging epithelial and immune cells, linked to impaired intestinal healing and response to therapy in mouse models and patient association studies.²

Investigators compared a topical nystatin rinse (n = 18) with systemic fluconazole (n = 35) in 53 patients with mild-to-moderate ulcerative colitis or Crohn disease and oral thrush treated as part of routine care.¹ Fluconazole, but not nystatin, reduced intestinal Candida burden, increased bacterial diversity, and expanded short-chain fatty acid-producing taxa in the gut.¹ Fluconazole was also associated with improved disease activity indices, measured by the partial Mayo score and Harvey-Bradshaw Index, and a decreased risk of disease progression over 8 weeks.¹

"These results highlight the potential of microbiome-based approaches to restore a balanced microbial community in the gut," said Iliev.³ The study was not randomized or placebo-controlled, and a placebo-controlled trial with longer follow-up and endoscopic data is needed to confirm the findings. In the following interview, Iliyan D. Iliev, PhD, discusses the mechanism linking Candida to intestinal inflammation, the disease activity findings, and the trial needed to confirm antifungal cotherapy in IBD.

Q&A: Fluconazole, Candida, and the Gut Microbiome in IBD

HCPLive: What were you and your co-investigators trying to understand about the gut microbiome in patients with IBD?

Iliyan Iliev, PhD: I'm Iliyan Iliev, and I'm a professor of immunology at Weill Cornell Medical College. We are very interested in the mucosal immune response in the intestines, and we have been working for many years on an interesting part of the intestinal microbiota, the mycobiome, or the fungal communities. 

This became very relevant in the context of inflammatory bowel disease because we observed in our patients an expansion of specific fungal species, particularly Candida albicans. Other groups have also shown other members of the mycobiome expanding in the intestines of these patients. We started asking what those species are doing there, and whether there is anything causative happening in the intestine. We studied the immune response and different mediators, and what turned out, in a nutshell, is that those species of Candida albicans are transferred. They are very common in our community, they live in our intestines, and they expand in those patients. 

Some of those strains have the ability to produce a toxin called candidalysin, and it drills holes in the epithelial cells and in other inflammatory immune cell populations. What that leads to, we found, is that those cells start producing inflammatory mediators, thinking an infection is happening, and they try to fight the microbe, which leads to increased inflammation. We found this in different mouse models, and we also did association studies in patients showing it actually influences intestinal healing and sometimes even the response to therapy. That study took a long time because the design was very important. We had enough evidence to look at how the treatment would affect the patient population, but not enough to design a placebo-controlled clinical trial. So we explored more what was happening in those patients, and we saw that some of them developed mild candidiasis in their mouth, called oral thrush. We started looking into it more deeply, and it became something very interesting. We started tracking those strains. We have technologies in the lab that can isolate strains from the gut and from the oral mucosa and see if they are the same, and it turned out they are. This brought the idea that some of those strains are transferring from the oral mucosa to the gut, and we know they produce that toxin. So what will happen if we target them? 

We designed this study to target Candida in both situations. The patients receive antifungals to control the thrush, and it happens that they are IBD patients. Some of them are treated with nystatin, so they wash their mouth and clear the Candida with nystatin twice a day for two weeks. They clear Candida in their mouth. But what we found is they don't clear it in the gut. Once it seeds the gut, it stays there. The other patients are prescribed fluconazole, which also has a systemic effect. It clears Candida in the oral cavity, and we found it also clears Candida in the gut. So we had two groups of patients we could follow. We followed them for 8 weeks, and in the fluconazole group, where Candida was cleared in both sites, we started seeing a recovery of the microbiome in the gut. In IBD, the diversity of the healthy gut community drops, but after fluconazole treatment, the community started recovering its diversity. Species associated with a healthy gut also started repopulating the gut. 

Most importantly, they started producing metabolites known to be important for intestinal healing, such as butyrate. We also looked at some bile acids. We started seeing this recovery after we cleaned the intestinal Candida, but not when we cleaned only the oral Candida with nystatin. This brought us to the conclusion that removing the Candida species that are expanding can lead to some recovery. We cannot tell if it is indirect, meaning you clean the Candida, inflammation subsides, and that is why you have the bacterial recovery. Since this was a short study, only 8 weeks, there is no standard of care that would perform colonoscopy twice in that period, before and after. So we did not have that data, but we had the clinical scores. 

We had patients with ulcerative colitis, using the Mayo score, and patients with Crohn disease, using the Harvey-Bradshaw Index, and in both situations we saw clinical improvement. This brought us to the hypothesis that removing the Candida species producing the toxin may lead to a better situation, where you slightly recover from the inflammatory effect of the strains.

HCPLive: What do the disease activity improvements show, and what are the clinical implications?

Iliyan Iliev, PhD: The disease activity is an interesting angle. Again, we didn't have colonoscopy or biopsies that could be taken in such a short time, so the disease activity was probably the best direction we could go. What we saw in both ulcerative colitis and Crohn disease patients is they reported improvement, so improved disease activity, when they were treated with fluconazole, which removes Candida in the oral cavity and in the gut. 

This brought the hypothesis that this type of treatment is the one that leads to some benefits. Of course, to have something conclusive, it has to be a placebo-controlled study, and we probably need other angles that will assess, in the long term, whether the patients can be evaluated again in six months or so, and collect colonoscopy data as well. Then we will have a good idea if this is a long-term effect and if it's clinically meaningful. But for that, it has to be a placebo-controlled study. However, in a situation where you start something new, this is the first step, and it's very important to have that first step. It's 53 patients that we could assess here.

HCPLive: What would need to happen before targeted antifungal therapy could become part of how clinicians manage IBD?

Iliyan Iliev, PhD: I feel the next step is, of course, a placebo-controlled clinical trial. Antifungal drugs, if you use them very long term, can lead to liver toxicity and so on. They can lead to resistance. So it's not something we would recommend using, or even test that way, to use it for a very long term.

 But in those windows where you have this Candida expansion, that's where we will be targeting. It will be short-term treatment, where we show here it's actually effective, and we do it in a setting where we have the answer of whether this could be a standard of care one day for this subpopulation of patients that experience overgrowth.

HCPLive: Was there anything else you wanted to highlight or add about the study?

Iliyan Iliev, PhD: It's something we have been working on for many years. Mechanistically, it's very interesting because we're learning more and more that fungal species living on our body can do a lot to our normal physiology, but there is a very fine line. People call it dysbiosis. I would call it expansion of those populations. 

They find an environment where they will actually grow uncontrollably, and then the immune system reacts to that. It sees there is this growth, and it tries to compensate, and that's where we have these more pathological situations. But as commensals, it's very interesting to study how fungal species and also some bacterial species have an important role in immune system development and in our health overall.

Editor's Note: This transcript has been edited for grammar and clarity using artificial intelligence tools.

Pan X, Conroy A, Ngima TS, et al. Antifungal therapy improves microbiome dynamics in inflammatory bowel disease. Nat Med. 2026;32(9):3385-3395. doi:10.1038/s41591-026-04616-y

Li XV, Leonardi I, Putzel GG, et al. Immune regulation by fungal strain diversity in inflammatory bowel disease. Nature. 2022;603(7902):672-678. doi:10.1038/s41586-022-04502-w

Weill Cornell Medicine. Antifungal therapy shows potential for IBD patients with candida overgrowth. Published September 1, 2026. Accessed September 23, 2026. 

https://www.eurekalert.org/news-releases/1142314

Articles

Candida overgrowth in IBD may be mechanistically linked to inflammation via candidalysin-mediated epithelial injury and downstream immune activation, with evidence of oral-to-gut strain transfer. In a prospective observational cohort of 53 patients with mild-to-moderate UC or Crohn disease plus oral thrush, systemic fluconazole—unlike topical nystatin—reduced intestinal Candida burden, increased bacterial diversity, and enriched short-chain fatty acid–producing taxa. Fluconazole use correlated with improved partial Mayo and Harvey–Bradshaw scores and lower 8-week progression risk, warranting randomized, endoscopy-informed validation.

Iliyan D. Iliev, PhD, discusses how fluconazole targets gut Candida to improve disease activity in IBD.

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Targeting Gut Candida to Treat IBD, With Iliyan D. Iliev, PhD

Manish Wadhwa, MD, is a cardiologist and electrophysiologist with San Diego Arrhythmia Associates and the chief executive officer of SummaCor.

Charalambos Antoniades, MD, PhD, is the director of the Acute Multidisciplinary Imaging & Interventional Centre and BHF chair of cardiovascular medicine at the University of Oxford and founder and chief scientific officer at Caristo Diagnostics.

Sadiya Khan, MD, MSc, is the Magerstadt Professor of Cardiovascular Epidemiology, associate professor of medicine, preventive medicine, and medical social sciences, and the director of the Center for Population Science and Aging at Northwestern University Feinberg School of Medicine.

Artificial intelligence (AI) is a burgeoning industry, evolving in practically every direction as it continues to develop. AI-based algorithms are being implemented in countless fields, medicine not least among them. 

 in particular has seen a wide range of AI innovations in the past 5 years alone, from screening and analyzing patient characteristics to streamlining clinician workflows.

An Uncharted Path: How Clinicians are Implementing Artificial Intelligence Across Cardiology

In this feature article, the editorial team at 

 sat down with Manish Wadhwa, MD, a cardiologist and electrophysiologist with San Diego Arrhythmia Associates, Charalambos Antoniades, MD, PhD, director of the Acute Multidisciplinary Imaging & Interventional Centre and BHF chair of cardiovascular medicine at the University of Oxford, and Sadiya Khan, MD, MSc, the Magerstadt Professor of Cardiovascular Epidemiology at Northwestern University Feinberg, to discuss how AI is already implemented into cardiovascular care – as well as the debates over equity and access that naturally spring up around these devices.

Existing Integration and Future Directions

 from May 2026 highlighted the extent to which AI is already integrated into cardiovascular care, analyzing the impact these algorithms have had on real-world patient outcomes. Examining categories such as workflow efficiency, patient engagement, and clinical outcomes, the study found that the use of AI algorithms, more specifically machine learning and deep learning, substantially increased all 3 metrics.

Several clinical trials have also been published, and many more are ongoing, investigating the place AI may take in cardiovascular care. The ORFAN-MAESTRIA trial, for example, shone a spotlight on a particular algorithm’s efficacy in identifying indicators and measuring risk of cardioembolic 

. Using standard computed tomography (CT) scans, this program is capable of fully automated phenotyping of the peri-left atrial (LA) space, detecting LA myopathy before symptoms appear.

AI has also found a home in implantable devices, such as the ILR ECG Analyzer from Implicity, which received approval from the 

 in August 2026. This algorithm serves as a secondary filter for alerts generated by implantable cardiac monitors (ICMs), helping clinicians and patients alike by filtering out false positive alerts. Not only can this reduce the number of alerts flooding a given clinician’s inbox, but it also serves to help optimize the way clinicians spend their time, allowing them to aid more patients in need.

However, for all the benefits AI can provide to clinicians and patients, it remains a thorny issue among the public. Questions regarding data privacy and equitable access have sprung up across a variety of medical specialties, exacerbated by the fact that AI algorithms are in many ways subservient to the data on which they are trained. Any biases present in these data, including disparities in race or gender among patients, could remain as the algorithm is moved into day-to-day use.

Additionally, medical AI models often work with an immense amount of patient data, including imaging, genetic information, and patient history. This could make these data more vulnerable to breaches or unauthorized access. Many clinicians have discussed the need for stricter cybersecurity measures and guidelines before these programs are made capable of handling this sensitive information.

Despite these concerns, however, AI has already proven itself beneficial in myriad ways for cardiology clinics and clinicians. Be it through simplifying workflows, providing an extra layer of confirmation for alerts or indicators of disease, or simply categorizing patient data more efficiently, these algorithms have begun to integrate themselves in many aspects of practice. With the speed at which the technology is evolving, it is difficult to call AI integration into cardiology, and medicine writ large, anything but inevitable.

Editors’ Note: Antoniades reports disclosures with AstraZeneca, Caristo Diagnostics, Lexicon, Novo Nordisk, Sanofi, Silence Therapeutics, and others. Khan reports no relevant disclosures. Wadhwa reports his position as a clinical advisor for Implicity.

Lin YE, Yang SM, Huang CJ, et al. Impact of artificial intelligence on cardiovascular workflow, engagement, and outcomes: a systematic review. 

https://doi.org/10.1038/s41746-026-02690-7

Livingston R. ORFAN-MAESTRIA: AI Predicts Cardioembolic Stroke, Atrial Fibrillation from CT Scans. 

. September 6, 2026. Accessed September 23, 2026. 

https://www.hcplive.com/view/orfan-maestria-ai-predicts-cardioembolic-stroke-atrial-fibrillation-from-ct-scans

Livingston R. FDA-Cleared, AI-Assisted ECG Analyzer Algorithm Reduces False Positives in ICMs. 

. August 21, 2026. Accessed September 23, 2026. 

https://www.hcplive.com/view/fda-cleared-ai-assisted-ecg-analyzer-algorithm-reduces-false-positives-in-icms

Livingston R. Equitable and Ethical AI Use in Cardiology: Addressing Biases and Privacy Concerns. 

. September 11, 2026. Accessed September 23, 2026. 

https://www.hcplive.com/view/equitable-and-ethical-ai-use-in-cardiology-addressing-biases-and-privacy-concerns

Videos

As AI continues to evolve at a breakneck pace, catch up on some of the ways it’s already been implemented in cardiovascular care.

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Features

 should center on intentional, purposeful use and on tracking cumulative exposure across topical, inhaled, systemic, and injectable routes, according to Adam Friedman, MD, professor and chair of dermatology at George Washington University School of Medicine and Health Sciences. Friedman spoke with 

 at the National Corticosteroid Stewardship Summit in Washington, DC, on September 22, 2026. He discussed at-risk patients, practical monitoring tools, and the role of steroid-sparing therapies.

Corticosteroid Stewardship Is Not Steroid Avoidance, With Adam Friedman, MD

Corticosteroid Stewardship and Cumulative Exposure in Dermatology

Friedman framed toxicity as a function of concentration and exposure rather than of any single ingredient or therapeutic class. He stressed stewardship does not mean avoiding corticosteroids, which remain life-saving in many settings.

"Steroids will always be an essential part of our therapeutic armamentarium," he said.

The first step, according to Friedman, is following the labeled indication. Topical corticosteroids are intended for acute use, typically two to three weeks at a time depending on the label, followed by discontinuation.

Patients often receive corticosteroids from several clinicians, including inhaled, systemic, and injectable formulations prescribed outside dermatology. Friedman called for an easy way to track cumulative exposure across practitioners without adding administrative hassle. Awareness of existing corticosteroid use could prompt a dermatologist to select an alternative, though no established tracking system exists yet.

The concern extends across specialties. A 2026 review linked repeated short courses of systemic corticosteroids and long-term high-dose inhaled corticosteroids to adverse health effects, and it outlined prescriber-level and health system approaches to stewardship.¹

Patients with chronic inflammatory skin diseases face the greatest risk of unrecognized overexposure, Friedman said. These patients may receive large-quantity refills, such as a 1-lb jar, repeatedly over years without follow-up. Comorbid conditions such as connective tissue diseases may also require corticosteroids by other routes.

How to Monitor Corticosteroid Exposure During Routine Visits

Friedman identified thorough medication reconciliation as the first practical tool, noting clinical assistants can help keep the medication list current. An accurate medication record is also a component of meaningful use of an electronic medical record system, he said.

Clinicians should also look for, and ask about, signs of overuse. Cutaneous signs include skin lightening, thinning, fragility, and easy bruising, while signs of systemic absorption include plethora and central obesity.

Topical exposure alone can produce systemic toxicity. A 2025 case report described a patient with Hailey-Hailey disease who applied topical clobetasol or betamethasone for more than 10 years at doses up to 50 g/day.² She developed Cushingoid features, metabolic abnormalities, and hypothalamic-pituitary-adrenal axis suppression, followed by adrenal insufficiency after tapering.²

Friedman described several basic questions as potential early predictors of excess exposure, particularly with higher-dose systemic corticosteroids. These questions address sleep, hunger, mentation, and whether patients feel more easily angered or stressed.

Where Do Steroid-Sparing Therapies Fit in Corticosteroid Stewardship?

Friedman described steroid-sparing therapies as companions to corticosteroids rather than replacements. In his view, corticosteroids best serve acute and emergency use, while nonsteroidal agents are better suited as the maintenance workhorse in chronic inflammatory skin diseases.

Real-world data reflect this overlap. In a 2026 prospective study of 688 patients with inflammatory diseases receiving biologic or targeted synthetic disease-modifying antirheumatic drugs, 17.4% reported active glucocorticoid use, with a mean therapy duration of 112 days.³

Integrating these options into practice is not simple, however. Friedman said access "is probably our greatest hurdle. It is the most toxic thing in healthcare today." He added access is even more limited in certain patient populations and demographics, and new options should not obscure the continued need for corticosteroids when used correctly.

As one change dermatologists can make this month, Friedman recommended written handouts on best-use practices. Patients may retain about 10% of what clinicians tell them, he said. A handout can reinforce consistent use for a set duration, including once- or twice-weekly maintenance when alternatives are inaccessible.

Friedman recalled patients reporting daily use of topical triamcinolone as a moisturizer, which he attributed to poor retention rather than a lack of counseling.

Written materials have supported stewardship in other settings. At 2 urgent care centers, a program combining clinician education, patient pamphlets, and peer comparison feedback reduced glucocorticoid prescribing for acute respiratory infections from 20.4 to 8.8 per 100 eligible visits (

Gallub V, Rogers L, Kim B. Corticosteroid stewardship in asthma: from individual prescribers to system-level change. Curr Opin Pulm Med. 2026;32(3):203-209. doi:10.1097/MCP.0000000000001254

Iwamoto Y, Komi M, Fushimi Y, et al. A case of Hailey-Hailey disease accompanied by Cushing's syndrome and adrenal insufficiency due to long-term usage of topical steroids with review of literature. Endocr J. 2025;72(12):1369-1376. doi:10.1507/endocrj.EJ25-0164

Lopez V, Ritenour A, Harmon K. Pharmacist-led steroid stewardship in inflammatory diseases: evaluating glucocorticoid use and patient outcomes. Am J Health Syst Pharm. Published online September 10, 2026. doi:10.1093/ajhp/zxag276

Patel D, Dubois T, Weston V, et al. Urgent care stewardship for glucocorticoid overuse in acute respiratory infections. JAMA Netw Open. 2026;9(4):e269261. doi:10.1001/jamanetworkopen.2026.9261

Friedman outlines how dermatologists can track cumulative corticosteroid exposure, identify at-risk patients, and improve patient adherence with handouts.

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The HCPLive dermatology page is a resource for medical news and expert insights on skin disease. This page features expert-led coverage, articles, videos and research on the therapies and development of treatments for dermatologic conditions, and more.

Corticosteroid Stewardship in Dermatology is Not Steroid Avoidance, With Adam Friedman, MD

Chelsie Derman is an associate editor for 

who covers allergy and  psychiatry. She joined MJH Life Sciences in September 2023 after graduating from The College of New Jersey with a bachelor’s degree in journalism and professional writing. In her free time, she enjoys creative writing and reading.

Helus Pharma's phase 3 PARADIGM program is evaluating 8 mg and 16 mg doses of HLP003, a deuterated psilocin analog, as an adjunctive treatment for 

 in adults with inadequate response to antidepressants, according to trial design data presented at Psych Congress 2026 in New Orleans, Louisiana from September 15 to 19.¹

Approximately 50% of patients with MDD do not respond adequately to first-line treatment, and adjunctive agents are often added to an antidepressant to pursue remission.¹ HLP003, previously known as CYB003, is a serotonergic agonist with activity at multiple 5-hydroxytryptamine (5-HT) receptors, including 5-HT2A, and has received US Food and Drug Administration (FDA) Breakthrough Therapy Designation for adjunctive use in MDD.¹,² Investigators positioned the program as a potential source of data for patients seeking an alternative to atypical antipsychotics.¹

“The early completion of enrollment in APPROACH brings us closer to determining whether HLP003 can provide a durable clinical benefit within a practical adjunctive treatment model for people with MDD,” said Amir Inamdar, MBBS, chief medical officer of Helus Pharma, in a July statement announcing completed APPROACH enrollment.² Inamdar was the presenting author of the Psych Congress poster.¹

HLP003 Phase 3 PARADIGM Trial Design and Eligibility Criteria

PARADIGM comprises 2 randomized, double-blind, placebo-controlled, multicenter phase 3 trials, each 12 weeks long, plus a long-term extension.¹ APPROACH randomized 223 participants 1:1 to HLP003 16 mg or placebo.¹,² EMBRACE is randomizing approximately 330 participants 1:1:1 to HLP003 16 mg, HLP003 8 mg, or placebo.¹

In both trials, participants receive a first dose on day 1 and a second dose on day 22.¹ The primary endpoint is change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score at day 42, and the key secondary endpoint is the same measure at day 84.¹

Eligible adults are aged 18 to 85 years with a first MDD episode before age 60 years.¹ Participants must have a MADRS score of ≥ 24, a Clinical Global Impressions-Severity (CGI-S) score of ≥ 4, and < 50% improvement on a stable antidepressant dose.¹ Exclusions include treatment-resistant MDD (failure of ≥ 2 antidepressants), psychotic or bipolar disorders, and significant lifetime suicide risk on the Columbia-Suicide Severity Rating Scale (C-SSRS).¹

Psychedelic exposure within 12 months or 10 or more times in a lifetime, and ketamine or esketamine use within 6 months, are also exclusionary.¹ Among 202 APPROACH participants with reported baseline data, median age was 44.0 years in the HLP003 arm and 50.0 years in the placebo arm.¹ Each arm was 64.4% female, and mean baseline MADRS scores were 33.1 and 33.3, respectively.¹

EXTEND Re-Treatment Design and Phase 1/2a HLP003 Efficacy Data


HLP003, formerly CYB003, is an investigational oral deuterated psilocin analog in phase 3 development as an adjunctive treatment for MDD. It holds FDA Breakthrough Therapy Designation.


APPROACH and EMBRACE compare 2 doses of HLP003 given 21 days apart with placebo in adults on a stable antidepressant, with MADRS change at Day 42 as the primary endpoint. EXTEND evaluates durability and re-treatment through 43 weeks.


Helus Pharma expects APPROACH topline data in the fourth quarter of 2026, with EMBRACE and EXTEND estimated to finish in 2027 and 2028.

EXTEND is a 43-week extension open to participants completing APPROACH or EMBRACE who continue the same antidepressant.¹ Responders who relapse may receive 2 additional HLP003 doses 21 days apart, and nonresponders receive 2 HLP003 doses on entry.¹ The primary endpoint is the probability of stable response, defined as a ≥ 50% MADRS reduction from baseline at day 84 without relapse, at week 43.¹

Key secondary endpoints include time to first relapse among participants with initial stable response and the percentage requiring 2 or 3 additional treatment sessions.¹ Safety assessments across the program include treatment-emergent adverse events, electrocardiograms, C-SSRS items 4 and 5, potential abuse-related adverse events, and sedation.¹

The program builds on a randomized, double-blind, placebo-controlled phase 1/2a trial, which found a single 16 mg dose produced a 12.99-point greater MADRS improvement versus placebo at day 21 (95% CI, −22.3 to −3.7; 

 =.008; effect size, 2.54).¹ After a second dose on day 22, the mean MADRS change from baseline reached −22.6 at day 364 (n = 7), with nearly all participants remaining in remission.¹

Helus Pharma expects APPROACH topline data in the fourth quarter of 2026, and EMBRACE and EXTEND are estimated to finish in 2027 and 2028, respectively.¹,² The company has stated it is targeting a potential New Drug Application (NDA) in 2028.²

Inamdar A, Kulikova A, Massa A, et al. A phase 3 clinical program evaluating the efficacy and safety of the deuterated psilocin analog HLP003 as an adjunctive treatment for major depressive disorder (PARADIGM). Presented at: Psych Congress; September 15-19, 2026; New Orleans, LA. Poster 121.

Helus Pharma. Helus Pharma completes enrollment in phase 3 APPROACH study of HLP003 in adjunctive treatment of major depressive disorder ahead of schedule. Published July 21, 2026. Accessed September 23, 2026. 

https://ir.helus.com/news-releases/news-release-details/helus-pharma-completes-enrollment-phase-3-approach-study-hlp003

Helus Pharma’s PARADIGM phase 3 program is testing adjunctive HLP003, a deuterated psilocin analog with FDA Breakthrough Therapy Designation, in adults with MDD inadequately responsive to antidepressants. Two 12-week, randomized, double-blind trials (APPROACH and EMBRACE) evaluate 16 mg and 8 mg dosing given on days 1 and 22, with MADRS change at day 42 as primary endpoint and durability assessed at day 84. A 43-week extension (EXTEND) examines re-treatment after relapse and longer-term stable response.

Two 12-week phase 3 trials and a 43-week extension will test 8 mg and 16 mg HLP003 added to antidepressants, with APPROACH enrollment now complete.

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Phase 3 PARADIGM: HLP003 (Psilocibin-d10) for Adjunctive MDD Use 

Andrew J. Cutler, MD, clinical professor of psychiatry at SUNY Upstate Medical University.

Interim data from the real-world ProACt study suggest clinicians may not need to wait weeks to know whether adjunctive cariprazine is working, with PHQ-9 and Functioning Assessment Short Test scores continuing to improve through week 6 in patients with 

, alongside earlier gains in anhedonia and motivation.

Meta-analyses show augmentation with atypical antipsychotics produces greater response rates than antidepressant monotherapy alone, and evidence suggests early response within the first 2 weeks of augmentation can predict eventual improvement.

About 30% to 50% of patients with MDD show inadequate response to antidepressant therapy, yet augmentation strategies are often delayed in routine practice.

 Atypical antipsychotics carry the strongest evidence among augmentation options and are FDA-approved for this indication, but many clinicians reach for them only after multiple antidepressant trials. Consensus reviews find augmentation more effective than switching or combining antidepressants for many patients with partial response.

Despite mixed feelings among prescribers about metabolic and movement-related risks, evidence-based augmentation strategies remain underused relative to their potential benefit.¹ In the following Q&A, Cutler discusses how quickly clinicians should expect to see movement with augmentation and how real-world data like ProACt can inform decisions for a skeptical colleague.

Q&A: Why Clinicians Should Not Wait to Augment Inadequate Response in MDD

What does this data suggest about how long clinicians should wait before judging whether augmentation is working?

 Unfortunately, people are not feeling urgency to treat depression all the way. My good friend Dr. Rakesh Jain and I surveyed a large database of what prescribers are actually doing for MDD, and we found they start an SSRI and then do nothing for 7 months. That’s unacceptable that you allow somebody to have inadequate treatment that long.

In the real world, they'll then switch from [an] SSRI to another SSRI or an SNRI. The next thing they do is [add] another antidepressant called bupropion, which is not evidence-based or FDA approved [for this use]. Eventually, [at] fourth or fifth line, people are adding an atypical antipsychotic. The 5 atypical antipsychotics are FDA approved [and] have the best evidence. We should be using them earlier.

There's now evidence you don't have to wait weeks. If you're not seeing somebody getting…at least 20% to 25% better in the first 2 weeks, you should do something. That something can be raise the dose, switch, or augment.

Part of the problem is we adjust our expectations to what our medicines can do, and because traditional antidepressants get people better but not all the way, we sort of say, “Oh, you’re better. That’s good.”

I understand the reluctance to use atypical antipsychotics. There are risks: weight gain and metabolic issues, drug-induced movement disorders, and so on.

You have to consider what's the risk of inadequately treating the illness. The fact is, it causes [a] big impact [on] people's lives, and there's even a risk of suicide. So, we should be more aggressive.

Now, the same thing applies when you add an atypical antipsychotic. You should see movement in the first 2 weeks. You don't have to wait 6 or 8 weeks. What's interesting about the newer atypical antipsychotics is it appears that they move the needle within 1 week.

How does real-world data like this change the conversation with a skeptical colleague?

 I think a lot of clinicians have become skeptical because they realize [the pivotal trial population] is small… [and] hand-selected…not representative of [their] own patients.

They [may not] understand the rating scales as well, [or] what they mean, [and some have] been burned when they see this data that looks so good and the [medicine doesn’t] get as good results. Real-world data is extremely helpful [for informing] clinical practice and [giving] reassurance it's worth trying 1 of these medicines.

What are you hoping the completed ProACt dataset will clarify?

 I'm hoping it helps overcome the reluctance to use an evidence-based, FDA-approved atypical antipsychotic like cariprazine. The newest agents, cariprazine, lumateperone, and brexpiprazole, are extremely effective, safe, well tolerated, and can work fast.

Any patient subgroups you're especially watching as more data comes in?

 Clinical trials don't [always] get good representation across ethnic groups, races, and even genders, although MDD tends to have a female preponderance [of] two-thirds women [to] one-third men. I'm also really interested in the older population, [which] tends to be underrepresented; you're more careful with older people [so] they might have more medical problems, more medications.

The other population that we don't allow into studies are people with [a history of or current] substance abuse. There is some evidence if you effectively treat depression, you can make a dent in the substance abuse because sometimes people are self-medicating.

There's [also] a high association of obesity, cardiovascular disease, and diabetes with depression. Sometimes, those patients…may not be allowed in the clinical trials. We know that successfully treating depression can lead to decreases in these issues. People take better care of themselves; they follow lifestyle changes or the medication regimen. It's been shown that treatment of depression not only can decrease suicide but can decrease cardiovascular and metabolic risk.

Read part 1 of our interview with Cutler here: 

ProACt Data Show Early Functional Gains with Adjunctive Cariprazine In MDD

AbbVie highlights new real-world data supporting the effectiveness of VRAYLAR (cariprazine) at Psych Congress 2026. AbbVie. Published September 18, 2026. Accessed September 22, 2026. 

Rafeyan R, Papakostas GI, Jackson WC, Trivedi MH. Inadequate response to treatment in major depressive disorder: augmentation and adjunctive strategies. 

Interim ProACt data show adjunctive cariprazine may work within 2 weeks, easing reluctance to augment antidepressant therapy in MDD, Andrew Cutler, MD, says.

Why Clinicians Should Not Wait to Augment Inadequate Response in MDD

Tim Smith joined the MJH Life Sciences team in 2022 and is currently an associate editor for 

. He is also the executive producer of two podcasts: 

. Previously, he was the producer of the Lungcast podcast. He graduated from UC Berkeley and worked in multimedia journalism as a staff writer prior to joining MJH. You can contact him at tsmith@mjhlifesciences.com.

This preview of EADV 2026 provides a teaser of new data and interviews being highlighted at this Vienna dermatology conference.

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Conference Preview: 2026 EADV Congress in Vienna

Alex Hillenbrand is an assistant editor for 

. She earned her BA in English from Lafayette College in 2023 and went on to write for pop culture, entertainment, and sports media outlets before joining MJH Life Sciences in 2025. In her free time, Alex enjoys cooking, going on walks, and meeting new people. Contact her at mjhlifesciences.com.

Phase 2b AMPLIFIED data show a 42.7% UACR drop in AMKD with modest proteinuria; AMPLITUDE interim data are due early 2027.

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The HCPLive nephrology page is a resource for medical news and expert insights on kidney disease. This page features expert-led coverage, articles, videos and research on the therapies and development of treatments in nephrology, and more.

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Jennifer Soung, MD, and Mona Shahriari, MD, discuss diagnosing psoriasis in diverse skin tones and why severity scores overlook dyspigmentation.

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Professor of Medicine at the University of Barcelona

Agusti, chair of the GOLD Board of Directors, discusses which COPD diagnostic bottleneck AI is closest to solving and more.

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Using AI for COPD Diagnosis, Equity, Guideline Gaps: Alvar Agusti, MD, PhD

George Vasquez-Rios, MD, MSCR, FASN, is a nephrologist and glomerular disease specialist and director of the Glomerular & Genetic Diseases Center.

George Vasquez-Rios, MD, explains how the ASN's GD-C Compendium curates glomerular disease guidance for general clinicians and specialists alike.

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How the ASN's GD-C Compendium Aims to Unify Glomerular Disease Care

Diana Isaacs, PharmD, is an endocrine clinical pharmacist, director of Education and Training in Diabetes Technology, and codirector of Endocrine Disorders in Pregnancy at the Cleveland Clinic.

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