The phase 2 ERUDITE (NCT05182476) study evaluated the efficacy and safety of luvadaxistat, a selective ᴅ-amino acid oxidase inhibitor, for cognitive impairment associated with schizophrenia. ERUDITE was a randomized, double-blind, placebo-controlled, parallel-group study in adults with schizophrenia receiving background antipsychotic therapy. Following a 2-week placebo run-in, participants were randomized 2:1:1 to receive placebo, luvadaxistat 20 mg, or luvadaxistat 50 mg once daily for a 12-week treatment period. The primary endpoint was change from baseline to Day 98 in the Brief Assessment of Cognition in Schizophrenia (BACS) composite score. Safety outcomes included the incidence of treatment-emergent adverse events (TEAEs). Overall, 203 participants were randomized (placebo, n = 101; luvadaxistat 20 mg, n = 50; luvadaxistat 50 mg, n = 52), and 178 (87.7%) completed the treatment period. Luvadaxistat did not significantly improve performance (change from baseline) in BACS composite score versus placebo at Day 98 (least-squares mean difference [95% confidence interval]: 20 mg, -0.7 [-2.8, 1.4], p = 0.75; 50 mg, -0.5 [-2.7, 1.6], p = 0.69). TEAEs were reported in approximately one-third of participants across groups, with comparable rates observed between the luvadaxistat and placebo groups. TEAEs were mostly mild or moderate, and no safety concerns were identified. Luvadaxistat 20 mg or 50 mg did not show statistically significant changes in cognitive performance or functioning within the ERUDITE study. Trial registration: ClinicalTrials.gov identifier NCT05182476.

BACKGROUND:The Brief Assessment of Cognition in Schizophrenia (BACS) and Schizophrenia Cognition Rating Scale (SCoRS) tests help to assess cognition in schizophrenia; however, anchor-based determinations of meaningful change are needed. This analysis derived minimal clinically important difference (MCID) estimates using data from INTERACT, a phase 2 randomized study of luvadaxistat as treatment of negative symptoms of schizophrenia. METHODS:Blinded retrospective analysis of a subsample selected for cognitive impairment (baseline BACS composite score: 10-40). MCID ranges were estimated via anchor-based analyses using the SCoRS interviewer change rating (overall impression of global cognitive change) to group the subsample (n = 140) into observable interviewer-rated improvement (n = 81) and no observable interviewer-rated change (n = 59). Distribution analyses evaluated effect-size cutoffs. MCID thresholds were tested for treatment sensitivity across INTERACT arms. RESULTS:Baseline BACS composite score and SCoRS interviewer total score were comparable between subgroups. At end of treatment, the difference between subgroups in change from baseline in BACS composite score and SCoRS interviewer total score was 2.08 (P = 0.060) and 3.16 (P < 0.001), respectively, both directionally toward the improvement subgroup. Distribution analyses using a moderate effect-size cutoff (standard deviation: 0.5) indicated 3.98-point and 5.21-point subgroup differences for BACS and SCoRS, respectively, to be potentially significant. A 4-point MCID threshold was considered most sensitive to study treatment. CONCLUSION:Results suggest that a 2- to 4-point difference in BACS composite score and a 3- to 5-point difference in SCoRS interviewer total score may be clinically meaningful in cognitive impairment in schizophrenia.

BACKGROUND:Anhedonia is a core symptom of major depressive disorder (MDD) that may result from aberrant lateral habenula hyperactivity. Targeting G-protein coupled receptor 139 (GPR139) may improve anhedonia by modulating lateral habenula activity. NBI-1065846 is an investigational GPR139 agonist that improved anhedonia, anxiety, and depression in rodent models. METHODS:TERPSIS was a phase 2, proof-of-concept clinical study. Adults with MDD experiencing a major depressive episode with anhedonia were randomized 1:1 to NBI-1065846 or placebo for 8 weeks. The primary endpoint was the change in the Dimensional Anhedonia Rating Scale (DARS) score. Secondary endpoints were change in total Montgomery Åsberg Depression Rating Scale (MADRS) score in participants with a baseline 17-item Hamilton Depression Rating Scale (HAM-D17) score of ≥19 (moderate to severe) and change in Clinical Global Impression of Severity (CGI-S) score. All changes were from baseline to Day 57. RESULTS:In total, 93 participants received study treatment (NBI-1065846, n = 46; placebo, n = 47). Both groups showed notable improvements in DARS scores from baseline to day 57 (least-squares mean change: NBI-1065846, 13.5; placebo, 17.4), with no statistically significant difference (NBI-1065846 vs. placebo, P = 0.8663). Similarly, MADRS ( P = 0.7008) and CGI-S ( P = 0.9051) scores showed no significant difference between groups. All treatment-emergent adverse events in the NBI-1065846 group were mild or moderate in severity. CONCLUSIONS:The TERPSIS study did not meet its primary or secondary endpoints. NBI-1065846 was generally well tolerated. Addressing the lack of treatment options for anhedonia remains an important unmet clinical need.

Site-independent ratings derived from audio-digital recordings of site-based interviews are often used for quality assurance monitoring to affirm ratings reliability in CNS clinical trials. The present study of subjects with schizophrenia and persistent negative symptoms used video instead of audio recordings of site-based interviews and thereby facilitated visual observation of the subject by the remote rater. "Paired" site-independent scores of the Positive and Negative Syndrome Scale (PANSS) and Brief Negative Symptom Scale (BNSS) were obtained from video-recordings of site-based interviews. The intraclass correlation between site-based and paired site-independent ratings was r = 0.839 for the total PANSS scores (n = 1006) and r = 0.871 for the total BNSS scores (n = 892); <5 % of paired scores deviated outside the acceptable confidence intervals. Ratings "outliers" were identified and remediated. We examined the pattern of paired scoring deviations for the BNSS, total PANSS, PANSS symptom subscales, and the Marder negative symptom factor. Each metric revealed a bidirectional pattern of scoring deviations such that mean site-based ratings were higher than site-independent ratings when symptom severity was high but lower than site-independent ratings when symptom severity was low. The pattern of bidirectional paired scoring deviations observed in this analysis has previously been noted in paired ratings analyses of subjects experiencing an acute exacerbation of psychosis in schizophrenia and major depressive disorder as well. The bidirectional pattern may reflect inherent differences between live ratings and remotely scored recorded ratings. This analysis affirms the utility of video-recordings of site-based ratings for surveillance in trials with subjects with schizophrenia and persistent negative symptoms.

AbstractThis parallel‐arm, phase I study investigated the potential cytochrome P450 (CYP)3A induction effect of NBI‐1065845 (TAK‐653), an investigational α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor potentiator in phase II development for major depressive disorder. The midazolam treatment arm received the sensitive CYP3A substrate midazolam on Day 1, followed by NBI‐1065845 alone on Days 5–13; on Day 14, NBI‐1065845 was administered with midazolam, then NBI‐1065845 alone on Day 15. The oral contraceptive treatment arm received ethinyl estradiol–levonorgestrel on Day 1, then NBI‐1065845 alone on Days 5–13; on Day 14, NBI‐1065845 was administered with ethinyl estradiol–levonorgestrel, then NBI‐1065845 alone on Days 15–17. Blood samples were collected for pharmacokinetic analyses. The midazolam treatment arm comprised 14 men and 4 women, of whom 16 completed the study. Sixteen of the 17 healthy women completed the oral contraceptive treatment arm. After multiple daily doses of NBI‐1065845, the geometric mean ratios (GMRs) (90% confidence interval) for maximum observed concentration were: midazolam, 0.94 (0.79–1.13); ethinyl estradiol, 1.00 (0.87–1.15); and levonorgestrel, 0.99 (0.87–1.13). For area under the plasma concentration–time curve (AUC) from time 0 to infinity, the GMRs were as follows: midazolam, 0.88 (0.78–0.98); and ethinyl estradiol, 1.01 (0.88–1.15). For levonorgestrel, the GMR for AUC from time 0 to the last quantifiable concentration was 0.87 (0.78–0.96). These findings indicate that NBI‐1065845 is not a CYP3A inducer and support its administration with CYP3A substrates. NBI‐1065845 was generally well tolerated, with no new safety signals observed after coadministration of midazolam, ethinyl estradiol, or levonorgestrel.

Abstract Background While esketamine is effective in treatment-resistant depression (TRD), detailed information about the effect of esketamine on cognition is relatively scarce. This analysis assessed the effect of short-term (3 double-blind [DB] studies: DB1, DB2, and DB4) or long-term maintenance treatment (DB3) with esketamine nasal spray (ESK) compared with a placebo (PBO) combined with active-comparator, on cognition in patients with TRD. Methods Patients (DB1/DB2/DB3: [18–64 years, n = 747]; DB4: [65 years or older, n = 137]) with TRD received ESK (DB1/DB2/DB3: 56/84 mg; DB4: 28/56/84 mg) or PBO+newly initiated oral antidepressant (OAD) as per treatment schedules. Cognitive assessments—Cogstate battery and Hopkins Verbal Learning Test-Revised—were administered at baseline, Day 28/early withdrawal, and follow-up visits in DB1/DB2/DB4 and at 12-week intervals in the DB3 maintenance phase. Descriptive statistics were used to analyze ESK effects on cognition with effect sizes and 95% confidence intervals to express the nature and magnitude of treatment effects relative to active-comparator+PBO. Correlation between depression severity (Montgomery-Ǻsberg Depression Rating Scale scores [MADRS]) and cognition was assessed at baseline and endpoint(s). Results At baseline, mild-to-moderate impairment in psychomotor function, attention, and memory (working and episodic) were evident. For each DB1/DB2/DB4, group mean performance in Z-scores for ESK+OAD and OAD+PBO groups on all cognitive tests remained similar or slightly improved from baseline at endpoint (Day 28) and follow-up assessments. Similarly, in DB3 (maintenance phase), both groups generally showed improvement in cognitive performance at endpoint(s). Correlations between MADRS scores and performance on the cognitive test battery were small at baseline and endpoint(s). Conclusions This analysis did not identify evidence of negative effects on cognition following short-term or long-term maintenance treatment with ESK+OAD in patients with TRD.

Deficits in N-methyl-d-aspartate receptor (NMDAR) signaling are implicated in the pathogenesis of schizophrenia. Luvadaxistat (TAK-831/NBI-1065844) is an investigational d-amino acid oxidase (DAAO) inhibitor that increases d-serine levels at NMDAR coagonist sites. INTERACT is a phase 2 randomized, placebo-controlled study that evaluated the efficacy and safety of three doses of luvadaxistat, covering a range of DAAO occupancy and d-serine levels, in patients with schizophrenia with persistent negative symptoms. The study included a 14-day, single-blinded placebo run-in period and a 12-week, double-blinded treatment period. The primary efficacy endpoint was the 12-week change from baseline in Positive and Negative Syndrome Scale-Negative Symptom Factor Score (PANSS NSFS). Secondary efficacy endpoints included the 12-week changes from baseline in Brief Assessment of Cognition in Schizophrenia (BACS) score and Schizophrenia Cognition Rating Scale (SCoRS) score. Safety endpoints included adverse event assessments. The full analysis set included all randomized patients (N = 256 [placebo, n = 87; luvadaxistat 50 mg, n = 58; 125 mg, n = 56; 500 mg, n = 55]); 228 patients completed the study. No significant improvements in PANSS NSFS were observed at any dose versus placebo at week 12. Improvements were observed with luvadaxistat 50 mg versus placebo in cognitive endpoints: BACS composite score (nominal one-sided p = 0.031) and SCoRS interviewer total score (nominal one-sided p = 0.011). Luvadaxistat did not significantly improve negative symptoms of schizophrenia. However, luvadaxistat 50 mg met the prespecified secondary endpoints for cognitive performance (BACS) and function (SCoRS), warranting further investigation in patients with cognitive impairment associated with schizophrenia. Luvadaxistat was well-tolerated in INTERACT, with no new safety signals observed. ClinicalTrials.gov: NCT03382639.

This exploratory post hoc analysis of two pooled 4-week, phase 3, double-blind, placebo- and active-controlled studies that compared esketamine nasal spray plus a newly initiated oral antidepressant (ESK+AD; n = 310) with a newly initiated oral AD plus placebo nasal spray (AD+PBO; n = 208) in patients with treatment-resistant depression (TRD) examined baseline patient demographic and psychiatric characteristics as potential predictors of response (≥50% reduction from baseline in Montgomery-Åsberg Depression Rating Scale [MADRS] total score) and remission (MADRS total score ≤12) at day 28. Overall, younger age, any employment, fewer failed ADs in the current depressive episode, and reduction in Clinical Global Impression-Severity (CGI-S) score at day 8 were significant positive predictors of response and remission at day 28. Treatment assignment was an important predictor of both response and remission. Patients treated with ESK+AD had 68% and 55% increased odds of achieving response and remission, respectively, versus those treated with AD+PBO. In the ESK+AD group, attainment of response and remission was more likely in patients who were employed, without significant anxiety at baseline, and who experienced a reduction in CGI-S score at day 8. Identification of predictors of response and remission may facilitate identification of those patients with TRD most likely to benefit from ESK+AD. Trial Registration: ClinicalTrials.gov: NCT02417064 (clinicaltrials.gov/ct2/show/NCT02417064) and NCT02418585 (clinicaltrials.gov/ct2/show/NCT02418585).

Nasal esketamine is indicated for the treatment of adults with treatment-resistant depression and depressive symptoms in adults with major depressive disorder with acute suicidal ideation or behavior. Primary objectives of this study were to evaluate the effect of nasal decongestant pretreatment in patients with allergic rhinitis and the impact of daily nasal corticosteroid administration by healthy subjects on nasal esketamine pharmacokinetics. Patients with allergic rhinitis self-administered 56 mg of nasal esketamine after pretreatment with nasal oxymetazoline (0.05

Background Patients with treatment-resistant depression (TRD) report significant deficits in physical and mental health, as well as severely impaired health-related quality of life (HRQoL) and functioning. Esketamine effectively enhances the daily functioning in these patients while also improving their depressive symptoms. This study assessed HRQoL and health status of patients with TRD, who were treated with esketamine nasal spray and an oral antidepressant (ESK + AD) vs. placebo nasal spray and an AD (AD + PBO). Methods Data from TRANSFORM-2, a phase 3, randomized, double-blind, short-term flexibly dosed study, were analyzed. Patients (aged 18–64 years) with TRD were included. The outcome assessments included the European Quality of Life Group, Five Dimension, Five Level (EQ-5D-5L), EQ-Visual Analogue Scale (EQ-VAS), and Sheehan Disability Scale (SDS). The health status index (HSI) was calculated using EQ-5D-5L scores. Results The full analysis set included 223 patients (ESK + AD: 114; AD + PBO: 109; mean [SD] age: 45.7 [11.89]). At Day 28, a lower percentage of patients reported impairment in the ESK + AD vs. AD + PBO group in all five EQ-5D-5L dimensions: mobility (10.6% vs. 25.0%), self-care (13.5% vs. 32.0%), usual activities (51.9% vs. 72.0%), pain/discomfort (35.6% vs. 54.0%), and anxiety/depression (69.2% vs. 78.0%). The mean (SD) change from baseline in HSI at Day 28 was 0.310 (0.219) for ESK + AD and 0.235 (0.252) for AD + PBO, with a higher score reflecting better levels of health. The mean (SD) change from baseline in EQ-VAS score at Day 28 was greater in ESK + AD (31.1 [25.67]) vs. AD + PBO (22.1 [26.43]). The mean (SD) change in the SDS total score from baseline to Day 28 also favored ESK + AD (-13.6 [8.31]) vs. AD + PBO (-9.4 [8.43]). Conclusions Greater improvements in HRQoL and health status were observed among patients with TRD treated with ESK + AD vs. AD + PBO. Trial registration ClinicalTrials.gov Identifier: NCT02418585.

Abstract Background “Dissociation” comprises distinct phenomena, some of which are associated with esketamine treatment and some may overlap with positive symptoms of psychosis. Relationships between dissociation and psychotic symptoms assessed by clinician report vs conventional rating scales were investigated in a post hoc analysis of data from the initial treatment session in an open-label, long-term safety, phase 3 study of esketamine plus a newly initiated oral antidepressant in patients with treatment-resistant depression. Methods Adverse events of dissociation or psychosis were examined via investigator report and the Clinician Administered Dissociative States Scale (CADSS) and Brief Psychiatric Rating Scale-Plus, respectively, 40 minutes post first esketamine dose. The range of CADSS total scores associated with investigator-reported severity of dissociation was determined by equipercentile linking. Logistic regression models and receiver operating curve analysis explored the CADSS cutoff point for determining presence/absence of dissociation. Frequency of response to specific CADSS items was examined to investigate qualitative differences in the pattern of symptoms reported across investigator-reported levels of adverse event severity. Results Dissociation was reported as an adverse event in 14.3% (109/764) of patients. Severity of most CADSS items increased with the severity of investigator-reported dissociation. No CADSS cutoff point discriminated well between the presence and absence of dissociation events. Hallucinations were reported as adverse events in 5 patients; none reported delusions. Conclusions CADSS scores and severity of dissociation adverse events move generally in the same direction; however, there is substantial variability in this relationship. No signature profile of dissociative experiences was revealed, and psychotic symptoms were uncommon. Trial Registration Clinical Trials.gov identifier: NCT02497287

The objective of this study was to determine which symptoms measured by the Patient Health Questionnaire (PHQ-9) and Montgomery-Asberg Depression Rating Scale (MADRS) improve in those treated with esketamine nasal spray in combination with oral antidepressant (AD) compared with those treated with placebo plus AD for adult patients with treatment-resistant depression (TRD). These results complement the interpretation of PHQ-9 and MADRS total scores. The TRANSFORM 2 study evaluated the efficacy and safety of esketamine nasal spray in combination with AD. This post-hoc analysis used PHQ-9 and MADRS data to evaluate symptom changes. The total scores change and proportions of individual item change scores on the PHQ-9 and MADRS were evaluated at days 15 and 28; analysis of variance was used to test differences on total scores. Generalized estimation equations of logistic regression models were used to estimate the likelihood of improvement on instrument items. The mean total score reduction of the PHQ-9, indicating improvement, was greater in the esketamine plus AD arm compared with placebo plus AD at day 15 (− 1.8; p = 0.045) and day 28 (− 2.8; p = 0.006). Proportions of those who improved (≥ 1 point on a 4-point scale and ≥ 2 points on a 7-point scale for the PHQ-9 and MADRS, respectively) was greater in the esketamine plus AD group compared with the placebo plus AD group across all items. The odds of improving for those in the esketamine plus AD group compared with the placebo plus AD group were over two times greater on the PHQ-9 items: “Little interest/pleasure in things” (OR 2.252, 95% CI 1.165–4.355); “Feeling down, depressed, or hopeless” (OR 2.767, 95% CI 1.400–5.470); and “Feeling tired or having little energy” (OR 2.171, 95% CI 1.153–4.087). The mean reduction in total scores on the MADRS, indicating improvement, was numerically greater at day 15 (− 2.0; p = 0.189) and statistically significantly greater at day 28 (− 4.4; p = 0.017) in the esketamine plus AD arm compared with placebo plus AD. The odds of improving for those in the esketamine plus AD group compared with the placebo plus AD group were over two times greater on the MADRS items measuring “Apparent sadness” (OR 2.007, 95% CI 1.096–3.674); and “Inability to feel” (OR 2.099, 95% CI 1.180–3.735). Improvement in mean total scores in those treated with esketamine plus AD compared with placebo plus AD are important results to confirm efficacy. The odds of improving in those treated with esketamine plus AD was at least two times greater than with placebo plus AD on three patient- and two clinician-reported individual symptoms of TRD. These findings provide patient-relevant quantification of the esketamine plus AD treatment benefit, adding understanding as to which symptoms are most improved with treatment. ClinicalTrials.gov identifier: NCT02418585; first posted 16 April 2015.

Background: Intranasal esketamine demonstrates rapid improvement of depressive symptoms. However, transient adverse effects (dissociation, sedation and dizziness) may occur, which could impact driving performance. Aims: To evaluate the effects of 84 mg intranasal esketamine on driving performance in unipolar major depressive disorder (MDD) or persistent depressive disorder (PDD) patients. Methods: The study consisted of two parts. Part A was a single-blind, double-dummy, randomized three-period, cross-over study to compare effects of esketamine versus placebo on next morning driving, 18 ± 2 h post-treatment. Alcohol was administered to demonstrate assay sensitivity. In Part B, same-day driving, 6 ± 0.5 hours post-treatment, was assessed during twice weekly esketamine administration for 3 weeks. Twenty-seven patients with mild-to-moderate MDD or PDD without psychotic features completed a 100 km on-the-road driving test on a public highway in normal traffic. The primary outcome was standard deviation of lateral position (SDLP; cm; weaving of car). Results: In Part A, alcohol impaired driving performance compared to placebo: Least-square means (95% CI), p-value for delta SDLP (cm) compared with placebo: (ΔSDLP = + 1.83 (1.03; 2.62), p < 0.001), whereas esketamine did not: (ΔSDLP = −0.23 (−1.04; 0.58), p = 0.572). In Part B, weekly driving tests showed no differences between placebo baseline SDLP and after esketamine administration over 3 weeks: Day 11: (ΔSDLP = −0.96 (−3.72; 1.81), p = 0.493), Day 18: (ΔSDLP = −0.56 (−3.33; 2.20), p = 0.686) and Day 25: (ΔSDLP = −1.05 (−3.82; 1.71), p = 0.451). Conclusions: In this study, esketamine did not impair on-road driving performance the next morning following a single dose, or on same day after repeated administration.

BACKGROUND:In this post-hoc analysis, data from 2 positive, pivotal, phase 3 trials of esketamine nasal spray (ESK) in treatment-resistant depression (TRD)-short-term study (TRANSFORM-2) and maintenance study (SUSTAIN-1)-were analyzed to evaluate the relationship between dissociation and antidepressant effects of ESK.METHODS:Analysis by responder status, correlation analysis, and mediation analysis were performed to assess the relationships between peak Clinician Administered Dissociative States Scale (CADSS) scores after first (day 1) and last (day 25) ESK dose and change in Montgomery-Åsberg Depression Rating Scale (MADRS) total scores at the first (day 2) and last assessments (day 28) in TRANSFORM-2 and peak CADSS after first maintenance ESK dose and time to relapse in SUSTAIN-1 (only for mediation analysis).RESULTS:In TRANSFORM-2, the percentage of responders (>50% reduction in MADRS) at day 2 and day 28 did not significantly differ between patients who did vs did not manifest significant dissociation (peak CADSS scores >4 or ≤4, respectively) following the first ESK dose. Spearman correlation coefficients between dissociation and depression improvement were nonsignificant and close to zero. CADSS scores did not significantly mediate the reduction in MADRS at day 2 or 28 in TRANSFORM-2 or the time to depression relapse in SUSTAIN-1. The mean difference in MADRS between ESK and active-control arms persisted beyond day 2 without significant change across time, although the mean peak CADSS scores significantly decreased across consecutive doses and fewer patients experienced significant dissociation after the last ESK dose compared with the first.CONCLUSION:Within the dose range tested, the dissociative and antidepressant effects of ESK were not significantly correlated.TRIAL REGISTRATION:NCT02417064 (TRANSFORM-1); NCT02418585(TRANSFORM-2); NCT02493868 (SUSTAIN-1).