Aticaprant is an investigational drug studied as an adjunctive treatment for psychiatric disorders, meaning it would be used alongside a primary antidepressant medication. The development of aticaprant has been led by companies like Janssen and was previously associated with Minerva Neurosciences. Its primary focus has been on addressing specific symptoms within Major Depressive Disorder (MDD) that are often not fully resolved by existing therapies.
How Aticaprant Works in the Brain
The human brain has a system that helps manage stress and mood, which involves a peptide called dynorphin and its corresponding kappa-opioid receptor (KOR). When the body undergoes stress, dynorphin is released and binds to these KORs. This binding can lead to feelings of dysphoria, or profound unease, and can dampen the brain’s reward system, making it difficult to experience pleasure. While this is a natural process, its overactivation is thought to contribute to the symptoms of depression.
Aticaprant is designed as a selective kappa-opioid receptor (KOR) antagonist. By occupying the receptor site, aticaprant stops the signal that dynorphin would normally send. This action is intended to interrupt the cycle of stress-induced negative feelings and the suppression of the brain’s reward pathways. The goal is to restore the normal regulation of mood and the capacity to feel pleasure.
The selectivity of aticaprant for the KOR is a specific feature of its design. It has a much lower affinity for other opioid receptors, such as the mu-opioid receptor, which is associated with the effects of traditional opioids. Positron emission tomography (PET) imaging studies have shown that a 10 mg dose of aticaprant can achieve nearly complete saturation of KORs in the brain.
Treating Major Depressive Disorder
Major Depressive Disorder (MDD) is a condition characterized by a persistent low mood and a range of emotional and physical problems. One of the most challenging symptoms of MDD to treat is anhedonia, which is the reduced ability to experience pleasure from activities that were once found enjoyable. Many individuals with MDD do not achieve full remission of their symptoms with standard antidepressant treatments, and persistent anhedonia is a common reason for this.
The therapeutic approach of aticaprant is considered novel because it directly targets the dynorphin/KOR system, which is believed to be overactive in people experiencing chronic stress and depression. This differs from more common antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs), which primarily work by increasing the levels of neurotransmitters like serotonin and norepinephrine. By blocking the KOR, aticaprant aims to directly counter the biological effects of stress and restore the function of the brain’s reward circuits.
Clinical Trial Efficacy and Safety
A Phase 2, randomized, double-blind, placebo-controlled study assessed aticaprant as an adjunctive therapy for adults with MDD who had not responded adequately to their current SSRI or SNRI treatment. The study involved 169 participants who received either 10 mg of aticaprant or a placebo once daily for six weeks.
The results of this Phase 2 study showed a statistically significant reduction in depressive symptoms for the aticaprant group compared to the placebo group. The primary measure of efficacy was the change in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score. The improvement was observed to be greater in participants who had higher levels of anhedonia at the start of the study, as measured by the Snaith-Hamilton Pleasure Scale (SHAPS).
In terms of safety, the Phase 2 trial found that aticaprant was generally well-tolerated. The most common treatment-emergent adverse events reported more frequently in the aticaprant group than the placebo group were:
- Headache (11.8% vs. 7.1%)
- Diarrhea (8.2% vs. 2.4%)
- Nasopharyngitis (5.9% vs. 2.4%)
- Pruritus (itching) (5.9% vs. 0%)
Following the promising results of the Phase 2 study, aticaprant advanced to a larger Phase 3 clinical trial program known as VENTURA. However, in early 2025, Johnson & Johnson announced the discontinuation of the VENTURA program. The decision was based on a determination of insufficient efficacy in the target population. While the drug continued to demonstrate a favorable safety profile, it did not meet the primary endpoints for effectiveness in these later-stage trials.
Current Development and Regulatory Status
Following the lack of sufficient efficacy in the Phase 3 VENTURA program, Johnson & Johnson halted the development of aticaprant as an adjunctive treatment for MDD in March 2025. This decision means that the company will not be moving forward with submitting a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for this indication.
The discontinuation of the Phase 3 trials effectively stops the regulatory process for aticaprant. An NDA is the formal step a drug sponsor takes to ask that the FDA consider approving a new drug for marketing in the United States. Without successful Phase 3 trials to provide substantial evidence of a drug’s effectiveness and safety, an NDA is unlikely to be submitted or approved.
While the journey of aticaprant for MDD has been halted, its developer has indicated that they may explore future development opportunities for the compound in other areas where there is a high unmet medical need. As a result, aticaprant is not an approved medication and is not available for prescription by the public.