aticaprant (JNJ-67953964) / J&J - LARVOL DELTA

Dissecting the contribution of mu and kappa opioid receptor signalling in effort and delay-related cost/benefit decision making. (PubMed, Psychopharmacology (Berl)) - "These results point to a selective contribution of mu opioid receptor signalling in modulating reward-related decisions involving effort, but not delay costs."

HEOR • Journal • Psychiatry

Xylazine reduces methamphetamine-induced hyperlocomotion in rats through κ-opioid and α2-adrenoceptor mechanisms. (PubMed, Neurosci Lett) - "Xylazine, a veterinary anesthetic, is an adulterant in fentanyl and heroin that worsens opioid-related adverse effects. In xylazine-naïve rats, neither LY2456302 (30 mg/kg) or yohimbine (1 mg/kg) affected METH-evoked hyperlocomotion or spontaneous locomotor activity. Our results show that METH-evoked hyperlocomotion is sensitive to κ-opioid and α2-adrenergic receptor activity and suggest both receptor systems contribute to xylazine's in vivo pharmacological profile."

Journal • Preclinical • Addiction (Opioid and Alcohol) • Anesthesia

KAPPTIVATE1001: A Study of the Feasibility, Safety and Tolerability of Aticaprant as Adjunctive Treatment in Participants With Schizophrenia (clinicaltrials.gov) - P1 | N=64 | Recruiting | Sponsor: Janssen Research & Development, LLC

New P1 trial • CNS Disorders • Psychiatry • Schizophrenia

VENTURA-LT: A Study of Aticaprant in Adult and Elderly Participants With Major Depressive Disorder (MDD) (clinicaltrials.gov) - P3 | N=871 | Terminated | Sponsor: Janssen Research & Development, LLC | Active, not recruiting ➔ Terminated; The study was Early Terminated as per Sponsor's decision (communicated to sites on 06Mar2025)

Trial termination • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Application of the research domain criteria in early-phase clinical development of transdiagnostic neurotherapeutics: A multidisciplinary perspective. (PubMed, Neurosci Appl) - "Through selected illustrative cases-most notably the aticaprant development program targeting anhedonia in mood and anxiety disorders-we demonstrate how early phase RDoC-aligned trial designs can be compromised at the pivotal stage by the absence of validated endpoints and regulatory constraints on labelling. On this basis, we propose pragmatic recommendations, including consensus-based definitions, registry tagging of RDoC-aligned trials, data-driven biomarker-based transdiagnostic enrichment strategies (i.e., biotyping), and early, iterative engagement with regulators and health technology assessment agencies. Systematic attention to these domains is required for enabling the development of neurobiologically RDoC informed treatments to be delivered to the right patients at the right time."

Journal • Review • CNS Disorders • Mood Disorders • Psychiatry

Mapping Kappa Opioid Receptor Binding in Titi Monkeys with [11C]GR103545 PET. (PubMed, Mol Imaging) - "CERC-501 pretreatment significantly reduced BPND (SRTM: 55.99%, LRTM: 59.68%) across several, but not all brain VOIs. This study establishes [11C]GR103545 PET as a viable tool for assessing KOR binding dynamics in titi monkeys, providing new opportunities to explore KOR modulation in social bonding and separation."

Journal • Mood Disorders • Psychiatry

Effect of morphine dependence and withdrawal on operant social interaction in male and female rats. (PubMed, Drug Alcohol Depend) - "Based on the literature, we also tested if a kappa opioid receptor (KOR) antagonist (LY2456302) and serotonin and dopamine reuptake inhibitors (fluoxetine and GBR12909), would independently reverse the effect of morphine exposure on social self-administration. Opioid dependence, but not withdrawal, decreased operant social interaction and food self-administration in male and female rats. This effect appears independent of KOR, serotonin, or dopamine signaling."

Journal • Preclinical • Addiction (Opioid and Alcohol) • CNS Disorders • Psychiatry

Effect of experimenter-induced morphine withdrawal on operant social behavior in rats (Neuroscience 2025) - "Based on the literature, we also tested whether kappa opioid receptor (KOR) antagonist (LY2456302), or serotonin and dopamine reuptake inhibitors (fluoxetine and GBR12909), could reverse opioid withdrawal-induced social deficits. Early, but not protracted, morphine withdrawal decreases operant social interaction. This effect appears independent of KOR, serotonin, or dopamine signaling."

Preclinical • Addiction (Opioid and Alcohol) • CNS Disorders • Psychiatry

Aticaprant in action: protecting mood and memory by blocking the κ-opioid receptor (ECNP 2025) - "Our findings are further supported by proteomic analysis of hippocampal synaptosomes showing that aticaprant reverses stress-induced changes in cytoskeletal organization and synaptic transmission (FDR=0.05, S0=0.1). These data provide evidence for the mechanism via which aticaprant exerts its therapeutic effects as a putative novel drug to alleviate stress-related symptoms."

CNS Disorders • Cognitive Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry • ATG7

Anhedonia as focus to reduce symptom heterogeneity of depression (ECNP 2025) - "Drugs such as vortioxetine, agomelatine, bupropion, ketamine, and brexpiprazole show promising anti-anhedonic effects, while traditional antidepressants such as SNRIs and, even more, SSRIs are less effective...Innovative treatments such as aticaprant and psilocybin showed promising results. Substantial evidence suggests that improving anhedonia leads to better psychosocial functioning, quality of life, and sustained remission. No conflict of interest"

Heterogeneity • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry • Schizophrenia

VENTURA-5: A Study of Aticaprant Plus an Antidepressant to Prevent Return of Depression Symptoms in Participants With Major Depressive Disorder Who Experience a Loss of Interest and Pleasure (clinicaltrials.gov) - P3 | N=48 | Terminated | Sponsor: Janssen Research & Development, LLC | N=660 ➔ 48 | Active, not recruiting ➔ Terminated; Sponsor decision

Enrollment change • Trial termination • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

VENTURA-7: A Study of Aticaprant 10 mg as Adjunctive Therapy in Adult Participants With Major Depressive Disorder (MDD) With Moderate-to-severe Anhedonia and Inadequate Response to Current Antidepressant Therapy and Long-term Extension Treatment With Aticaprant (clinicaltrials.gov) - P3 | N=101 | Terminated | Sponsor: Janssen Research & Development, LLC | Active, not recruiting ➔ Terminated; Sponsor decision

Trial termination • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

VENTURA-7: A Study of Aticaprant 10 mg as Adjunctive Therapy in Adult Participants With Major Depressive Disorder (MDD) With Moderate-to-severe Anhedonia and Inadequate Response to Current Antidepressant Therapy and Long-term Extension Treatment With Aticaprant (clinicaltrials.gov) - P3 | N=101 | Active, not recruiting | Sponsor: Janssen Research & Development, LLC | N=350 ➔ 101

Enrollment change • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Kappa Opioid Receptors Diminish Spontaneous Dopamine Signals in Awake Mice Through Multiple Mechanisms. (PubMed, Neuropharmacology) - "Next, mice were systemically administered the KOR agonist U50,488H in the presence or absence of the KOR antagonist aticaprant...The effects of KOR activation were stronger in males, while effects of KOR antagonism were stronger in females. Overall, KORs exerted significant inhibitory control over spontaneous DA signaling, acting through at least three mechanisms - inhibiting DA release, promoting DA transporter-mediated uptake, and reducing the frequency of signals."

Journal • Preclinical

Anhedonia: Current and future treatments. (PubMed, PCN Rep) - "Drugs such as vortioxetine, agomelatine, bupropion, ketamine, and brexpiprazole show promising anti-anhedonic effects, while traditional antidepressants, such as serotonin-norepinephrine reuptake inhibitors (SNRIs) and, even more so, selective serotonin reuptake inhibitors (SSRIs), are less effective...Innovative treatments, such as aticaprant and psilocybin, showed promising results...The reviewed evidence underscores the importance of routine assessment of anhedonia and the integration of symptom-specific strategies. Tailoring interventions to address individual patterns of reward disruption may optimize outcomes for patients with anhedonia."

Journal • Review • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

VENTURA-LT: A Study of Aticaprant in Adult and Elderly Participants With Major Depressive Disorder (MDD) (clinicaltrials.gov) - P3 | N=840 | Active, not recruiting | Sponsor: Janssen Research & Development, LLC | Trial completion date: Dec 2025 ➔ Apr 2025 | Trial primary completion date: Oct 2025 ➔ Apr 2025 | Recruiting ➔ Active, not recruiting

Enrollment closed • Trial completion date • Trial primary completion date • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

VENTURA-7: A Study of Aticaprant 10 mg as Adjunctive Therapy in Adult Participants With Major Depressive Disorder (MDD) With Moderate-to-severe Anhedonia and Inadequate Response to Current Antidepressant Therapy and Long-term Extension Treatment With Aticaprant (clinicaltrials.gov) - P3 | N=350 | Active, not recruiting | Sponsor: Janssen Research & Development, LLC | Recruiting ➔ Active, not recruiting | Trial completion date: Jul 2026 ➔ May 2025 | Trial primary completion date: Jun 2026 ➔ Apr 2025

Enrollment closed • Trial completion date • Trial primary completion date • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

VENTURA-2: A Study of Aticaprant 10 Milligrams (mg) as Adjunctive Therapy in Adult Participants With MDD With Moderate-to-severe Anhedonia and Inadequate Response to Current Antidepressant Therapy (clinicaltrials.gov) - P3 | N=444 | Completed | Sponsor: Janssen Research & Development, LLC | Recruiting ➔ Completed | Trial completion date: Jul 2025 ➔ Nov 2024 | Trial primary completion date: Jul 2025 ➔ Nov 2024

Trial completion • Trial completion date • Trial primary completion date • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

VENTURA-5: A Study of Aticaprant Plus an Antidepressant to Prevent Return of Depression Symptoms in Participants With Major Depressive Disorder Who Experience a Loss of Interest and Pleasure (clinicaltrials.gov) - P3 | N=660 | Active, not recruiting | Sponsor: Janssen Research & Development, LLC | Recruiting ➔ Active, not recruiting | Trial completion date: May 2027 ➔ May 2025 | Trial primary completion date: May 2027 ➔ Apr 2025

Enrollment closed • Trial completion date • Trial primary completion date • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

A Study to Explore the Efficacy of JNJ-67953964 in the Treatment of Depression (clinicaltrials.gov) - P2 | N=181 | Completed | Sponsor: Janssen Research & Development, LLC | Phase classification: P2a ➔ P2

Phase classification • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

VENTURA-1: A Study of Aticaprant as Adjunctive Therapy in Adult Participants With Major Depressive Disorder (MDD) With Moderate-to-severe Anhedonia and Inadequate Response to Current Antidepressant Therapy (clinicaltrials.gov) - P3 | N=513 | Completed | Sponsor: Janssen Research & Development, LLC | Recruiting ➔ Completed

Trial completion • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

VENTURA-2: A Study of Aticaprant 10 Milligrams (mg) as Adjunctive Therapy in Adult Participants With MDD With Moderate-to-severe Anhedonia and Inadequate Response to Current Antidepressant Therapy (clinicaltrials.gov) - P3 | N=710 | Recruiting | Sponsor: Janssen Research & Development, LLC | Completed ➔ Recruiting | N=444 ➔ 710 | Trial completion date: Nov 2024 ➔ Jul 2025 | Trial primary completion date: Nov 2024 ➔ Jul 2025

Enrollment change • Enrollment open • Trial completion date • Trial primary completion date • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

VENTURA-2: A Study of Aticaprant 10 Milligrams (mg) as Adjunctive Therapy in Adult Participants With MDD With Moderate-to-severe Anhedonia and Inadequate Response to Current Antidepressant Therapy (clinicaltrials.gov) - P3 | N=444 | Completed | Sponsor: Janssen Research & Development, LLC | Recruiting ➔ Completed | N=710 ➔ 444

Enrollment change • Trial completion • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

VENTURA-5: A Study of Aticaprant Plus an Antidepressant to Prevent Return of Depression Symptoms in Participants With Major Depressive Disorder Who Experience a Loss of Interest and Pleasure (clinicaltrials.gov) - P3 | N=660 | Recruiting | Sponsor: Janssen Research & Development, LLC

New P3 trial • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Adjunctive Aticaprant and Anhedonia in Major Depressive disorder (ECNP 2024) - "Tolerability and safety were reassuring. These promising Results of the co-administration of aticaprant to an SSRI/SNRI in depressed patients with prominent anhedonia support he further investigation of aticaprant in larger trials."

CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry