A cortisol-targeting antidepressant has produced statistically significant improvements in depression that peaked four weeks after patients stopped taking it, according to a new peer-reviewed study in the British Journal of Psychiatry. The findings transform the results from a corporate announcement to independently scrutinized science.
The Drug and Its Mechanism
Xanamem (emestedastat), developed by Australian biotech Actinogen Medical, does not work on serotonin or dopamine. It blocks the production of cortisol inside brain cells, a mechanism that operates on a timeframe of weeks, not hours. The drug selectively inhibits an enzyme called 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which converts inactive cortisone to active cortisol inside cells.
The brain—specifically the hippocampus and frontal cortex—contains high concentrations of this enzyme. By blocking it locally, Xanamem reduces intraneuronal cortisol without touching the adrenal glands, which produce the body’s systemic cortisol. This distinction is clinically critical because systemic cortisol regulates immune function, blood pressure, and metabolism. Suppressing it entirely would cause serious harm, so the drug is designed to lower the brain’s cortisol environment while leaving the body’s stress response intact.
The XanaCIDD Trial Results
The XanaCIDD trial was a Phase 2a, randomized, double-blind, placebo-controlled study conducted in 165 participants with moderate major depressive disorder and measurable cognitive impairment. Approximately 80% were receiving background antidepressant therapy, and the mean number of prior depressive episodes per participant was ten. This population had not responded to repeated treatment attempts.
Participants received either 10 mg of Xanamem once daily or placebo for six weeks, followed by four weeks of blinded observation with no active drug. The primary endpoint was a composite of cognitive attention and working memory tests. Xanamem did not meet that primary cognitive endpoint, likely due to an unexpectedly large placebo response that compressed the margin needed to detect a drug effect.
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The depression story was different. Measured by the Montgomery-Åsberg Depression Rating Scale (MADRS), Xanamem showed statistically significant superiority over placebo, with an effect that grew after treatment stopped. The remission advantage amounts to a 50% higher remission rate for patients on Xanamem compared with those on placebo, measured four weeks after dosing ended.
A Dissociation Between Mood and Cognition
One of the British Journal of Psychiatry paper’s key conclusions challenges a long-held clinical assumption: that when depression lifts, cognitive symptoms improve along with it. This did not happen in XanaCIDD. Improvements in depression and cognition were not correlated, according to the published findings. Patients whose mood improved did not consistently show parallel cognitive gains, and vice versa.
This dissociation has implications beyond Actinogen’s drug development program. It suggests that cognitive impairment in depression may not be a secondary symptom that resolves when mood resolves, but an independently driven biological process that requires separate targeting. If that finding is robust, it has potential consequences for how clinical trials in this population are designed and how physicians treat patients who recover from depression but remain cognitively impaired.
Prof. Michael Berk AO, an academic psychiatrist and co-author of the BJP paper, framed the finding in terms of the drug’s broader significance. “There remains a significant unmet medical need for therapies such as Xanamem that have a novel mechanism of action and can be safely combined with existing depression treatments,” he said in the company’s announcement.
Effect Duration
The durability of Xanamem’s antidepressant effect—growing stronger in the weeks after the drug was stopped—is mechanistically predictable. Cortisol-related biological effects do not resolve the moment cortisol levels drop. When patients begin or stop chronic corticosteroid therapy such as prednisone, physicians expect the downstream biological effects to take weeks to normalize. Xanamem’s time course matches exactly that pattern: the drug gradually lowers intraneuronal cortisol during the six-week treatment, the affected biological pathways continue normalizing through the four-week follow-up, and the maximum antidepressant effect appears at the trough of that normalization.
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The drug’s delayed peak suggests that the biological pathways damaged by chronic high cortisol require weeks to repair, even after the drug is gone. This aligns with how the body responds to corticosteroids, where the removal of the medication doesn’t immediately reverse the physiological changes it caused. While this is promising for sustained symptom relief, it also means that patients might not feel better immediately after stopping the medication, requiring careful management of expectations.
Actinogen has another trial underway, the XanaMIA trial, which has enrolled 247 patients with mild to moderate, biomarker-confirmed Alzheimer’s disease across sites in Australia and the United States. The primary endpoint is the Clinical Dementia Rating Scale – Sum of Boxes (CDR-SB). An independent Data Monitoring Committee conducted a scheduled safety review on June 17, 2026, and recommended the trial continue without amendment. Final topline results from the 36-week randomized phase are expected in November 2026.
Should the XanaMIA results be positive, Actinogen has received scientific advice from both the U.S. Food and Drug Administration and the European Medicines Agency on potential accelerated approval pathways. The FDA has signaled openness to reviewing applications supported by a single key trial with adequate supporting evidence. The company outlined these regulatory discussions in its April 2026 business update, which also highlighted the potential for data collectives to play a role in managing patient information.
Xanamem (emestedastat) is not approved for any indication by the FDA or any global regulatory authority. It is an investigational product available only within clinical trials. The XanaMIA-DUR open-label extension allows participants who completed the XanaMIA randomized phase to continue receiving active Xanamem for up to 25 months. Members of the public cannot obtain Xanamem outside of a clinical trial setting.