Background: Onfasprodil (MIJ821) is a highly potent and novel selective NR2B subunit negative allosteric modulator. This phase 2, randomized, placebo-controlled, proof-of-concept study evaluated efficacy and safety of onfasprodil in patients with treatment-resistant major depression (TRD). Methods: Adults with TRD who did not respond to ≥2 antidepressants were randomized (3:3:3:3:6:4) to receive a 40-minute intravenous infusion of onfasprodil 0.16 mg/kg weekly (n = 11), onfasprodil 0.16 mg/kg biweekly (n = 10), onfasprodil 0.32 mg/kg weekly (n = 10), onfasprodil 0.32 mg/kg biweekly (n = 9), placebo weekly (n=20), or ketamine 0.5 mg/kg weekly (n= 10) for 6 weeks. Primary end point was change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) score at 24 hours. Secondary end points were change in MADRS score at 48 hours and at final follow-up at 6 weeks. Safety and tolerability were assessed during the study. Results: Of 70 randomized patients, 53 (75.7%) completed the study. At 24 hours, adjusted mean differences versus placebo for pooled onfasprodil 0.16 mg/kg, 0.32 mg/kg, and ketamine groups were -8.25 (P = .001), -5.71 (P = .019), and -5.67 (P = .046), and at 48 hours, -7.06 (P = .013), -7.37 (P = .013), and -11.02 (P = .019), respectively. At Week 6, adjusted arithmetic mean MADRS difference between ketamine and placebo was -5.24 (80% CI, -10.42 to -0.06; P= .0974). At Week 6, the difference versus placebo on MADRS was -5.78 (P= .0427) for pooled 0.16 mg/kg and -4.24 (P= .1133) for pooled 0.32 mg/kg groups. The commonest treatment-emergent adverse events in the onfasprodil groups were dizziness (14.3%), transient amnesia (14.3%), and somnolence (11.4%). It had overall a good safety profile and was well tolerated. Conclusion: Onfasprodil appeared to be effective and well-tolerated across all dosing regimens in patients with TRD and demonstrated rapid onset of action (24 hours) with evidence of antidepressant effects to be maintained at Week 6, particularly for the lower-dose group. Trial Registration: ClinicalTrials.gov identifier: NCT03756129.

Background: Onfasprodil (MIJ821) is a highly potent and novel selective NR2B subunit negative allosteric modulator. This phase 2, randomized, placebo-controlled, proof-of-concept study evaluated efficacy and safety of onfasprodil in patients with treatment-resistant major depression (TRD). Methods: Adults with TRD who did not respond to ≥2 antidepressants were randomized (3:3:3:3:6:4) to receive a 40-minute intravenous infusion of onfasprodil 0.16 mg/kg weekly (n = 11), onfasprodil 0.16 mg/kg biweekly (n = 10), onfasprodil 0.32 mg/kg weekly (n = 10), onfasprodil 0.32 mg/kg biweekly (n = 9), placebo weekly (n=20), or ketamine 0.5 mg/kg weekly (n= 10) for 6 weeks. Primary end point was change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) score at 24 hours. Secondary end points were change in MADRS score at 48 hours and at final follow-up at 6 weeks. Safety and tolerability were assessed during the study. Results: Of 70 randomized patients, 53 (75.7%) completed the study. At 24 hours, adjusted mean differences versus placebo for pooled onfasprodil 0.16 mg/kg, 0.32 mg/kg, and ketamine groups were -8.25 (P = .001), -5.71 (P = .019), and -5.67 (P = .046), and at 48 hours, -7.06 (P = .013), -7.37 (P = .013), and -11.02 (P = .019), respectively. At Week 6, adjusted arithmetic mean MADRS difference between ketamine and placebo was -5.24 (80% CI, -10.42 to -0.06; P= .0974). At Week 6, the difference versus placebo on MADRS was -5.78 (P= .0427) for pooled 0.16 mg/kg and -4.24 (P= .1133) for pooled 0.32 mg/kg groups. The commonest treatment-emergent adverse events in the onfasprodil groups were dizziness (14.3%), transient amnesia (14.3%), and somnolence (11.4%). It had overall a good safety profile and was well tolerated. Conclusion: Onfasprodil appeared to be effective and well-tolerated across all dosing regimens in patients with TRD and demonstrated rapid onset of action (24 hours) with evidence of antidepressant effects to be maintained at Week 6, particularly for the lower-dose group. Trial Registration: ClinicalTrials.gov identifier: NCT03756129.

Objective:This study aimed to examine the impact of the COVID-19 pandemic on patients with serious mental illness (SMI), specifically relating to psychiatric morbidity, pandemic-induced stress, and ability to cope with pandemic-related precautionary measures, restrictions, and disruptions to daily life.Design:A cross-sectional survey study of 277 clinical trial patients was conducted. This sample included nonpsychiatric controls (n=139) and patients with a diagnosis of bipolar disorder, major depressive disorder (MDD), or schizophrenia (n=138) located at five clinical trial sites across the United States. A univariate analysis was performed to obtain general frequencies of the sample. Unpaired t-tests were used in comparing the groups on numerical variables, and analysis of variance (ANOVA) was performed to identify differences when comparing three or more categories.Results:Patients with SMI were more likely to report wearing face masks, avoiding large gatherings, and endorsing the use of precautionary measures, despite receiving a COVID-19 vaccine (p<0.001). A total of 70.3 percent (n=97) of all patients with SMI reported experiencing at least one episode of symptom worsening, 48 percent reported experiencing suicidal ideation, and 66 percent reported a need for increased mental healthcare due to COVID-19-related distress. Patients with SMI reported higher levels of stress, compared to controls, with patients with MDD having the highest levels of stress (p<0.001).Conclusion:These findings demonstrate an increased vulnerability to symptom worsening in patients with SMI during a pandemic and suggest the need to account for pandemic-induced psychological stress in clinical trial design, subject selection, and symptoms ratings.

Risperidone extended-release injectable suspension (R-ERIS; marketed as RYKINDO) is a novel immediate-release version of risperidone formulated as extended-release microspheres for biweekly intramuscular injection to treat schizophrenia in adults. The pharmacokinetics (PK) and safety of R-ERIS were evaluated in a multicenter, randomized, open-label, multiple-dose study in patients with stable schizophrenia or schizoaffective disorder. Eligible patients (N = 108) 18 to 65 years old were randomized (1:1) to receive IM injections of R-ERIS 25 mg or the comparator, a biweekly risperidone long-acting injectable (BW-RLAI; marketed as RISPERDAL CONSTA) 25 mg for a total of 5 injections. The primary objective was to evaluate the relative bioavailability of active moiety (risperidone plus 9-hydroxyrisperidone) at steady state. Blood samples were analyzed for risperidone and 9-hydroxyrisperidone using a validated, specific, and sensitive liquid chromatography with tandem mass spectrometry method. Plasma concentration-time data were analyzed using non-compartmental methods. Pharmacokinetic parameters were calculated based on individual patient PK profiles. Safety was assessed using standard measures. At steady state, mean plasma concentrations of the active moiety were similar for R-ERIS and BW-RLAI. R-ERIS rapidly released risperidone after the injection without apparent lag time. Plasma active moiety levels reached steady state after the second injection of R-ERIS. The elimination of the drug was completed approximately 2 weeks earlier for R-ERIS as compared to that for BW-RLAI. R-ERIS was safe and well tolerated. Overall, R-ERIS exhibited a faster onset and offset than BW-RLAI and statistical analysis of exposure parameters demonstrated bioequivalence at steady state.

Objective:To analyze the effect of Risperidone ISM on social functioning and health-related quality of life (HR-QoL) in both short- and long-term treatment of patients with schizophrenia.Patients and Methods:This analysis was based on data from both phases of the PRISMA-3 study, including 433 relapsed patients from the double-blind (DB) phase of the PRISMA-3 trial who were treated for 12-weeks with once-monthly (every 28 days) intramuscular Risperidone ISM 75 mg or 100 mg (n = 288), or placebo (n = 145), as well as 174 patients transitioning from the DB to an open-label 52-week extension (OLE) phase, plus 41 de novo patients treated on a stable maintenance dose of oral risperidone. The clinician-administered Personal and Social Performance (PSP) scale and the patient-reported 20-item Subjective Well-being under Neuroleptics scale (SWN-20) were used to measure social functioning and HR-QoL outcomes, respectively.Results:Risperidone ISM significantly improved PSP total score from baseline to endpoint (Day 85) versus placebo in the DB phase with mean change total score (95% CI) of 10.7 (9; 12) compared to 4.8 (3; 7) for placebo (p < 0.0001). The statistically significant improvement was present from the first measurement time point (Day 29). SWN-20-measured HR-QoL increased on average in patients treated with Risperidone ISM in the DB phase. A significant improvement was also observed for PSP and SWN-20 scores from the OLE baseline to week 52 for patients transitioning from the DB phase. Stable de novo patients maintained similar PSP and SWN-20 scores during the whole OLE phase.Conclusion:Risperidone ISM provided a rapid and sustained improvement in personal and social functioning, and HR-QOL without need of oral risperidone supplementation or loading doses. These findings, along with a fast onset of efficacy, could contribute to reinforcing the therapeutic alliance and possibly an earlier discharge. Moreover, patient functioning continued improving or was maintained with long-term treatment.

Several attempts have been made to enhance N-methyl-D-aspartate (NMDA) receptor function in schizophrenia, but they have yielded mixed results. Luvadaxistat, a D-amino acid oxidase (DAAO) inhibitor that increases the glutamate co-agonist D-serine levels, is being developed for the treatment of cognitive impairment associated with schizophrenia. We conducted a biomarker study in patients, assessing several endpoints related to physiological outcomes of NMDA receptor modulation to determine whether luvadaxistat affects neural circuitry biomarkers relevant to NMDA receptor function and schizophrenia. This was a randomized, placebo-controlled, double-blind, two-period crossover phase 2a study assessing luvadaxistat 50 mg and 500 mg for 8 days in 31 patients with schizophrenia. There were no treatment effects of luvadaxistat at either dose in eyeblink conditioning, a cerebellar-dependent learning measure, compared with placebo. We observed a nominally significant improvement in mismatch negativity (MMN) and a statistical trend to improvement for auditory steady-state response at 40 Hz, in both cases with 50 mg, but not with 500 mg, compared with placebo. Although the data should be interpreted cautiously owing to the small sample size, they suggest that luvadaxistat can improve an illness-related circuitry biomarker at doses associated with partial DAAO inhibition. These results are consistent with 50 mg, but not higher doses, showing a signal of efficacy in cognitive endpoints in a larger phase 2, 12-week study conducted in parallel. Thus, MMN responses after a short treatment period may predict cognitive function improvement. MMN and ASSR should be considered as biomarkers in early trials addressing NMDA receptor hypofunction.

Introduction:Recent research on the COVID-19 pandemic suggests that individuals who suffer from serious mental illness (SMI) are at heightened risk of infection and have increased mortality due to their illness and/or lack of access to healthcare. Consequently, progress in developing new treatments for SMIs has been disrupted, with many interruptions to clinical trials in psychiatry due to concerns regarding the pandemic and its risks to patients with SMI.Objective:This study aimed to examine the impact of the COVID-19 pandemic on patients with SMI, specifically relating to psychiatric morbidity, pandemic-induced stress, and ability to cope with pandemic-related precautionary measures, restrictions, and disruptions to daily life.Design:A cross-sectional survey study of 94 clinical trial patients diagnosed with bipolar disorder, major depressive disorder (MDD), or schizophrenia was conducted in three geographically distinct clinical trial sites between June and September 2020. Prevalence rates were calculated for sample characteristics and demographics, and low versus high stress groups were compared on survey variables using Pearson's Chi-squared test of independence.Results:The results from the surveys indicated that COVID-19 knowledge, awareness, and the use of precautionary safety measures (e.g., handwashing, personal protective equipment [PPE], and social distancing) were robust and mirrored the general population. While the majority of patients reported experiencing moderate or extreme levels of distress (61.5%, n=56), high levels of stress were correlated with positive coping skills.Conclusion:These findings suggest that clinical trial patients with SMI can safely participate in clinical trials despite the increase safety risks posed by the COVID-19 pandemic.

Objective: The goal was to review the impact of the COVID-19 pandemic on psychiatric drug development and clinical trials. Main Points of Discussion: Disruption of pharmaceutical industry- sponsored clinical trials for psychiatric disorders by the COVID-19 pandemic, prompted by concerns regarding the safety of trial participants and the feasibility of trial conduct, has adversely impacted psychiatric drug development. In response, psychiatry trial sites have modified clinical trials and adapted trial conduct, through the use of social distancing, personal protective equipment, laboratory testing, and remote assessments, to reduce the risks of COVID-19. We review the implications of these modifications for participant safety, safe trial conduct, and data integrity. Conclusion: Given these implications, ongoing communication and consultation are needed between trials sites, sponsors, and all other stakeholders to ensure continued progress in psychiatric drug development during the pandemic.

Introduction MIJ821 is a novel N-methyl-D-aspartate (NMDA) receptor antagonist, with a potentially low rate of the psychotomimetic side effects that limit the therapeutic utility of ketamine in treatment-refractory depression (TRD). Objectives To assess efficacy and safety of MIJ821. Methods Adults with TRD (>2 prior treatment failures; Montgomery-Asberg Depression Rating Scale [MADRS], >24) were eligible and were randomized (n=70) to low versus high doses of MIJ821, with two dosing regimens of weekly or biweekly, versus ketamine versus placebo. The primary outcome was change in MADRS total score at 24 hours and final follow up was at 6 weeks. Results At 24 hours, adjusted mean differences (ΔAM) versus placebo were –8.25 (p=0.001), –5.71 (p=0.019) and –5.67 (p=0.046) and at 48 h were –7.06 (p=0.013), –7.37 (p=0.013), –11.02 (p=0.019) in the pooled MIJ821 low dose, high dose, and ketamine groups, respectively. At 6 weeks, ΔAM (80% CI) versus placebo on MADRS were –6.46 (–11.8, –1.15); p=0.059 for low dose MIJ821, –5.42 (–10.8, –0.02); p=0.099) for high dose MIJ821, and –5.24 (–10.4, –0.06); p=0.097 for ketamine. Further details on dosing, efficacy, and safety outcomes will be provided. Conclusions In this proof-of-concept study, MIJ821 was effective and tolerable in TRD. This study was funded by Novartis. Clinical trial.gov: NCT03756129 Conflict of interest Employee of Novartis.

Recent research on the COVID-19 pandemic suggests that individuals who suffer with serious mental illness (SMI) is at heightened risk of infection and have increased mortality, due to their illness or lack of access to healthcare. As a consequence, progress in developing new treatments for the SMI have been disrupted, with many interruptions and holds places on clinical trials in psychiatry due to concerns regarding the pandemic and its risks to SMI patients. To investigate this further, we conducted, a multi-site cross-sectional survey of 94 clinical trial patients diagnosed with bipolar disorder (n=23), major depressive disorder (n=27), or schizophrenia (n=44) in three geographically distinct clinical trial sites (Maryland, Georgia and Florida) between June and September 2020. The survey collected data on COVID health service utilization, COVID knowledge and concerns, risk perceptions, use of precautionary measures, and psychological distress. Prevalence rates were calculated for sample characteristics and demographics, and low vs high stress groups were compared on survey variables using the Pearson's Chi Squared Test of Independence. The results from the surveys indicate that COVID19 knowledge, awareness, and the use of precautionary safety measures (i.e. handwashing, personal protective equipment, and social distancing) were robust and mirrored the general population. While the majority of patients reported experiencing moderate or extreme levels of distress (61.5%, n=56), high levels of stress were correlated with positive coping skills. These findings suggest that clinical trial patients with SMI can participate safely in clinical trials despite the increase safety risks posed by the COVID-19 pandemic.

OBJECTIVE:To evaluate long-term efficacy, safety and tolerability of Risperidone ISM® in patients with schizophrenia, a multicenter, open-label extension of the PRISMA-3 study was conducted.METHODS:Eligible placebo (unstable) and Risperidone ISM® (stabilized) rollover patients from a previous 12-week double-blind phase and de novo stable patients received once-monthly intramuscular injections of Risperidone ISM® 75 or 100 mg for 12 months. The long term-efficacy assessment included the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression-Severity (CGI-S) and Clinical Global Impression-Improvement (CGI-I) scales. Safety evaluation included treatment-emergent adverse events (TEAEs), injection site reactions (ISR), laboratory tests and several safety scales.RESULTS:Altogether, 215 patients entered the study (55 unstable, 119 stabilized and 41 stable patients). Most patients (74.9%) completed, and discontinuation rates were broadly similar across the study subgroups, mainly due to withdrawal of consent (12.1%). PANSS total and subscales scores decreased from baseline to endpoint in all groups, with the largest decrease for unstable patients. Improvement from baseline to 12 months was also shown for CGI-S and CGI-I scores for both unstable and stabilized patients; the CGI-S and CGI-I scores remained almost unchanged for the stable group. At least one treatment-related TEAE was reported in 39.1% of patients; the most common were headache (12.1%), hyperprolactinemia (9.8%) and asthenia (5.1%). ISR were reported in 8 (0.3%) patients; injection site pain score was low across the 2355 doses assessed.CONCLUSION:Risperidone ISM® is an effective, safe, and well-tolerated long-term treatment of schizophrenia in adults, regardless of the initial disease severity or whether patients were previously treated with Risperidone ISM® during an acute exacerbation or switched from stable doses of oral risperidone.

To evaluate the efficacy and safety of Risperidone ISM ® against placebo in patients with acute exacerbation of schizophrenia. A multicenter, randomized, double-blind, placebo-controlled study was conducted between June 2017 and December 2018 (NCT03160521). Eligible patients received once-monthly intramuscular injections of Risperidone ISM ® (75 or 100 mg) or placebo for 12 weeks. The primary efficacy outcome was change in Positive and Negative Syndrome Scale (PANSS) total score from baseline to week 12. The key secondary efficacy outcome was change from baseline in Clinical Global Impressions-Severity of Illness scale (CGI-S) score. Altogether, 438 patients were randomized (1:1:1) and 390 included in the modified ITT efficacy set. The PANSS total score (mean difference, 95% CI) improved significantly from baseline to day 85 with Risperidone ISM ® 75 and 100 mg, with placebo-adjusted differences of −13.0 (95% CI, −17.3 to −8.8); ( p < 0.0001), and −13.3 (−17.6 to −8.9); ( p < 0.0001), respectively. Significantly improved mean changes were also obtained for CGI-S score from baseline to day 85 for both doses of Risperidone ISM ® compared with placebo −0.7 (−1.0 to −0.5); p < 0.0001, for both doses. The statistically significant improvement for both efficacy outcomes were observed as early as 8 days after first injection. The most frequently reported treatment-emergent adverse events were increased blood prolactin (7.8%), headache (7.3%), hyperprolactinemia (5%), and weight increase (4.8%). Neither new nor unexpected relevant safety information was recorded. Risperidone ISM ® provided rapid and progressive reduction of symptoms in patients with acutely exacerbated schizophrenia without need of oral risperidone supplementation or loading doses. Both doses were safe and well tolerated.

Background: Several studies have implicated herpes simplex virus-type 1 (HSV-1) in the pathophysiology of schizophrenia. A recent trial demonstrated that the anti-viral medication valacylovir, which prevents replication of activated HSV-1, improved selected cognitive deficits in people with schizophrenia. In this study, we examined demographic and illness related differences between HSV-1 positive versus HSV-1 negative subjects with early phase schizophrenia and attempted to replicate the previous valacyclovir treatment results in this population. Methods: 170 subjects with schizophrenia (HSV-1 positive N = 70: HSV-1 negative N = 96) from 12 US sites participated in the HSV-1 positive versus negative comparisons, and were randomized 1:1 to valacyclovir (15 g BID) or placebo for a 16-week, double-blind efficacy trial. The primary endpoints were working and verbal memory. Results: The HSV-1 positive group, as compared to the HSV-1 negative group, were older (p < 0.001) with fewer males (p = 0.003). and had a longer duration of illness (p = 0.008), more positive symptoms (p = 0.013), poorer quality of life (p = 0.034) and more impairment on the letter-number sequencing test, which is a measure of working memory (p = 0.045). Valacyclovir failed to significantly improve any of the cognitive indices, symptom or functioning measures. Conclusions: HSV-1 sero-positivity appears to be a marker of a subgroup with a more severe form of schizophrenia. Valacyclovir was not efficacious in the study, perhaps because the herpes virus was in the dormant, non-activated state and therefore non-responsive to valacyclovir effects. (C) 2018 Published by Elsevier B.V.

Dopamine D2 receptor occupancy (D2RO) is a key feature of all currently approved antipsychotic medications. However, antipsychotic efficacy associated with high D2RO is often limited by side effects such as motor disturbances and hyperprolactinemia. Lumateperone (ITI-007) is a first-in-class selective and simultaneous modulator of serotonin, dopamine and glutamate in development for the treatment of schizophrenia and other disorders. The primary objective of the present study was to determine D2RO at plasma steady state of 60 mg ITI-007, a dose that previously demonstrated antipsychotic efficacy in a controlled trial, administered orally open-label once daily in the morning for two weeks in patients with schizophrenia (N = 10) and after at least a two-week washout period from standard of care antipsychotics. D2RO was determined using positron emission tomography with 11C-raclopride as the radiotracer. Mean peak dorsal striatal D2RO was 39% at 60 mg ITI-007 occurring 1 h post-dose. Lumateperone was well-tolerated with a favorable safety profile in this study. There were no clinically significant changes in vital signs, ECGs, or clinical chemistry laboratory values, including prolactin levels. There were no adverse event reports of akathisia or other extrapyramidal motor side effects; mean scores on motor function scales indicated no motor disturbances with lumateperone treatment. This level of occupancy is lower than most other antipsychotic drugs at their efficacious doses and likely contributes to the favorable safety and tolerability profile of lumateperone with reduced risk for movement disorders and hyperprolactinemia. If approved, lumateperone may provide a new and safe treatment option for individuals living with schizophrenia.

This study characterized the pharmacokinetics, safety, and tolerability of Risperidone ISM, a new long-acting intramuscular formulation, for monthly administration without oral supplementation. Patients with schizophrenia received multiple intramuscular injections of 75 mg in the gluteal or deltoid muscle at 28-day intervals. Of the 70 randomized patients, 67 received at least one dose of study medication. The mean Cmax of the active moiety was achieved 24–48 h (tmax) after each administration, regardless of injection site. They ranged over four consecutive doses from 39.6 to 53.2 and 54.1 to 61 ng/ml, when given in gluteal or deltoid muscle, respectively. Active moiety achieved therapeutic levels by 2 h after dose, and the levels were maintained throughout the 4-week dosing period. No significant changes across the study were observed on either Positive and Negative Syndrome Scale or Extrapyramidal Symptoms Scale. Overall, 63 (94%) patients experienced at least one treatment-emergent adverse event (TEAE). One serious TEAE (dystonia) was related to study treatment. The most frequently reported TEAEs were hyperprolactinaemia (57.7%) and injection site pain (32.8%). Risperidone ISM achieved therapeutic levels from the first hours after drug administration and provided a sustained release throughout the 4-week dosing period over multiple intramuscular injections and was found to be safe and well tolerated.

Global rating scale measures are useful for assessing the clinical relevance of patient change. Cariprazine, a dopamine D3 and D2 receptor partial agonist, is FDA‐approved for the adult treatment of acute manic/mixed episodes of bipolar I disorder and schizophrenia. Post hoc evaluations of Clinical Global Impressions‐Severity (CGI‐S) scores from the cariprazine pivotal trials in both indications were conducted.