Aticaprant

Aticaprant was made by Eli Lilly as LY2456302 and has since been known as CERC-501 and JNJ-67953964 [5]. It blocks the kappa-opioid receptor, the receptor for the stress-released peptide dynorphin, with about 30-fold selectivity over the mu receptor [6]. Older kappa blockers such as nor-BNI and JDTic act for weeks after one dose; a dose of aticaprant no longer blocked the receptor a week later in rats, which made it practical to test as a daily medicine [1][7].

Anhedonia. The NIMH-funded FAST-MAS trial gave 89 adults with anhedonia (a SHAPS score of 20 or more) and depression, bipolar depression or an anxiety disorder 10 mg a day or placebo for 8 weeks. The primary outcome was a brain measure: ventral striatal activation while anticipating a monetary reward rose more on aticaprant (effect size 0.58). Anhedonia scores on the SHAPS fell more than on placebo (Hedges' g 0.44), but the planned analysis of reward learning on the Probabilistic Reward Task was negative, and depression and anxiety ratings did not change [3]. Trial-level modeling of the reward task found faster learning from reward on aticaprant, with reward sensitivity unchanged [8].

Depression. In Janssen's phase 2 trial, 169 adults still moderately to severely depressed on an SSRI or SNRI took 10 mg or placebo on top of it for 6 weeks. In the prespecified primary population (people who had not improved during a placebo lead-in), MADRS scores fell 2.1 points more on aticaprant (effect size 0.23); across everyone randomized the difference was 3.1 points (0.36). The study set its significance level at a one-sided 0.20 and did not adjust for multiple comparisons. Among people with above-median anhedonia the difference was 5.1 points, against 1.9 points below the median. Self-rated anhedonia on the SHAPS did not improve more than placebo, and remission rates (31% against 22%) were not significantly different [2]. A review judged the 2.1-point difference perhaps not clinically significant [9]. Phase 3 trials (VENTURA) followed; in March 2025 Johnson & Johnson ended the program for insufficient efficacy, saying full results would be presented later [4].

Addiction. In a laboratory trial, 8 days of 15 mg did not delay smoking after 18 hours of abstinence (16.5 against 17.7 minutes), change the number of cigarettes smoked, or ease craving, withdrawal or mood [10]. Four days of 10 mg in people in early abstinence from cocaine changed neither cocaine craving nor depression scores, in a deliberately low-stress inpatient setting [7]. Animal work was more positive: it reduced escalated alcohol drinking and stress-triggered relapse in rats [11], and eased nicotine withdrawal in mice [12].

Chronic stress raises dynorphin, and dynorphin acting on kappa receptors suppresses dopamine release from the ventral tegmental area during reward processing and serotonin release from the dorsal raphe; this is thought to contribute to anhedonia and low mood. Blocking the receptor is meant to let that release return to normal. Because reuptake-inhibiting antidepressants only act on transmitter that has been released, the developers proposed that the two mechanisms complement each other [2].

Aticaprant binds the human kappa receptor with a Ki of 0.81 nM, against 24 nM at mu and 155 nM at delta [6]. In a broad receptor screen it had no appreciable affinity for monoamine, muscarinic or adrenergic receptors, ion channels, transporters or the benzodiazepine site. In rats, oral doses occupied central kappa receptors with an ED50 of 0.33 mg/kg, over 90% at 10 mg/kg, with no mu or delta occupancy up to 30 mg/kg; kappa occupancy fell below 50% within 48 hours, and a dose no longer blocked a kappa agonist one week later, while nor-BNI still did [1]. In people, PET showed 94% kappa occupancy 2.5 hours after 10 mg and 72% at 24 hours [13]. Mu blockade, measured as reversal of fentanyl's pupil constriction, appeared only at 25 and 60 mg [6].

In animals. In the mouse forced swim test, 10 mg/kg by mouth cut immobility about as much as 15 mg/kg of imipramine, while naltrexone had no effect. A 3 mg/kg dose that did nothing alone, combined with an inactive dose of imipramine or citalopram, produced a strong effect, more than the sum of the two [1]. In alcohol-preferring rats, 3 mg/kg cut free-access drinking as much as 10 mg/kg of naltrexone, mainly by trimming large drinking bouts, and 10 mg/kg kept working over 4 days of dosing while naltrexone lost its effect after the first day [1]. In male mice given 4 weeks of chronic mild stress, 11 daily doses reversed the loss of sucrose preference and nest building and the changes in the forced swim and hot plate tests, effects that lasted through a recovery period; it did not reverse stress effects in the light-dark and social interaction tests [5]. In rats it reversed alcohol-withdrawal anxiety, suppressed escalated but not basal alcohol self-administration, and blocked stress-induced but not cue-induced relapse to alcohol seeking [11]. In mice it reduced relapse-like drinking, and a dose below the effective one did so when combined with a low dose of naltrexone [14].

In people. Besides the ventral striatal fMRI effect [3], an individualized brain-mapping analysis of FAST-MAS found changes in the size of frontoparietal and orbitofrontal-limbic network regions after 8 weeks [15]. An exploratory analysis split FAST-MAS participants into two anhedonia subgroups; the less severe one tended to respond more on brain and behavioral measures, and the more severe one on self-report [16].

In the phase 2 depression trial, 47% on aticaprant and 36% on placebo had an adverse event, nearly all mild or moderate. Headache (12% against 7%), diarrhea (8% against 2%), nasopharyngitis (6% against 2%) and pruritus (6% against 0%) were the most common. One person in each group stopped because of an adverse event, suicidal ideation was similar in the two groups (5% and 4%), and adverse events suggestive of abuse potential occurred in 2.4% of each group. Weight, laboratory tests, vital signs and ECGs did not change meaningfully [2].

In the 8-week anhedonia trial there were no serious adverse events. More-than-mild pruritus (11% against 2%), worsening depression (7% against 0%) and rash (7% against 0%) were more common than on placebo [3]. In the cocaine study, about 60% had a mild side effect over 4 days; itching, usually of the hands and feet, lasted under 30 minutes, and one healthy volunteer left the study with an itchy rash that resolved with hydrocortisone and an antihistamine [7]. In smokers, adverse events were as frequent on aticaprant as on placebo (52% and 54%) [10].

In phase 1, single doses up to 60 mg and 14 days of up to 35 mg caused no serious adverse events. Side effects of repeated dosing were all mild; dyspepsia (5 events in 4 people), headache and itching were the most common, and the itching was generalized and confined to 3 of 9 people on 35 mg. One volunteer had an asymptomatic 5-beat run of ventricular tachycardia about 8 hours after a single 25 mg dose, picked up on telemetry and judged drug-related; 24 hours of further monitoring were clear, and there were no other meaningful ECG changes, including no QTc prolongation. Dosing was capped to keep plasma levels 30-fold below the no-effect level for convulsions in a rabbit toxicology study, and no convulsions occurred in people [17]. An earlier kappa antagonist, JDTic, had its phase 1 trial suspended over runs of ventricular tachycardia [7].

In rats it did not impair balance on the rotarod at 10 or 30 mg/kg, did not change dopamine levels in the nucleus accumbens at 3–30 mg/kg (one index of abuse potential), and did not disrupt prepulse inhibition on its own [1]. In stopping the phase 3 program, Johnson & Johnson said the data showed no new safety signals [4].

In the phase 2 trial it was taken on top of SSRIs and SNRIs for 6 weeks without a safety signal [2]. In phase 1, a social dose of alcohol (0.6–0.7 g/kg) taken at steady state on 10 mg did not change aticaprant levels; alcohol exposure rose slightly (22% by one AUC measure), which the authors did not consider clinically significant. Aticaprant neither impaired reaction time, vigilance, tracking or balance on its own nor worsened alcohol's effect on them [17]. In rats it did not change alcohol's lowering of body temperature [1]. At 25 and 60 mg it partly blocked fentanyl's effect on pupil size, while 4–10 mg had little or no effect [6].