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Introduction: Treatment resistance constitutes the highest burden of disease within schizophrenia. We hypothesized that the synergistic activity of Lu AF35700 at dopamine D 1 and D 2 receptors might provide superior antipsychotic effects versus first-line antipsychotic therapy in patients with treatment resistant schizophrenia (TRS), with a benign tolerability profile., Methods: This was a randomized, double-blind, active-controlled clinical trial (NCT02717195) followed by a one year open-label safety extension (NCT02892422). Following prospective confirmation of treatment resistance, patients were randomized (1:1:1) to 10 weeks double-blind treatment with Lu AF35700 10 mg or 20 mg, or active comparator (risperidone or olanzapine)., Results: 1628 patients were screened for TRS, of which 1092 entered the prospective confirmation period. Of these, 697 were randomized (Lu AF35700 10 mg n = 235, 20 mg n = 232, comparator n = 230) and 395 discontinued before randomization, including 264 (24 %) who responded to treatment. 586 patients completed the double-blind phase, of which 524 entered the open-label extension and 318 completed 1-year of open-label treatment. At the end of the double-blind phase, the mean ± SE change in positive and negative syndrome scale (PANSS) total score was -10.1 ± 0.96 for Lu AF35700 10 mg, -8.22 ± 0.98 for Lu AF35700 20 mg, and - 9.90 ± 0.97 for the comparator group. Treatment differences [95 % CI] versus comparator treatment were non-significant (-0.12 [-2.37; 2.13] and 1.67 [-0.59; 3.94], respectively). The most common adverse events with Lu AF35700 were increased weight and headache. Prolactin values decreased by ≥50 % in both sexes treated with Lu AF35700., Conclusions: Despite evidence of antipsychotic efficacy, treatment with Lu AF35700 failed to differentiate from conventional antipsychotic treatment for patients with TRS., Competing Interests: Declaration of competing interest John Kane reports personal fees for consultancy from Lundbeck and was an investigator in the DayBreak and Debut studies. Pedro Such, Aurélia Mittoux and Ole M. Lemming are employed by H. Lundbeck A/S as was Peter Hertel at the time of study. Bruce Kinon and Carlos Forray were employed by Lundbeck Pharmaceuticals LLC at the time of study. Oliver Howes is a part-time employee of H. Lundbeck A/S and was an advisor on the DayBreak and Debut studies. Author disclosures: Dr Kane has received consulting fees from Alkermes, Allergan, Dainippon Sumitomo, H. Lundbeck, Intra-Cellular Therapies, Janssen Pharmaceuticals, LB Pharmaceuticals, Merck, Minerva, Neurocrine Biosciences, Otsuka, Reviva, Roche, Saladex, Sunovion, Takeda, and Teva; has ownership interest in LB Pharmaceuticals, Vanguard Research Group, and North Shore Therapeutics; has received royalties from Up to Date; has received honoraria for lectures from Dainippon Sumitomo, H. Lundbeck, Janssen Pharmaceuticals, Otsuka, Saladex and Teva. He has received grant support from Janssen, H. Lundbeck, Otsuka and Sunovion. Pedro Such, Aurélia Mittoux and Ole M Lemming are employed by Lundbeck. Bruce Kinon is employed by Cyclerion Therapeutics and was employed by Lundbeck Pharmaceuticals LLC at the time of study. Carlos Forray was employed by Lundbeck Pharmaceuticals LLC at the time of study. Peter Hertel is employed by Genmab and was employed by H. Lundbeck A/S at the time of study. Oliver Howes is a part-time employee of H. Lundbeck A/S and has received investigator-initiated research funding from and/or participated in advisory/speaker meetings organized by Angellini, Autifony, Biogen, Boehringer-Ingelheim, Eli Lilly, Heptares, Global Medical Education, Invicro, Janssen, Lundbeck, Neurocrine, Otsuka, Sunovion, Recordati, Roche and Viatris/Mylan. Neither Dr Howes nor his family have holdings/a financial stake in any pharmaceutical company. Dr Howes has a patent for the use of dopaminergic imaging., (Copyright © 2022. Published by Elsevier B.V.)

Lu AF11167 is a selective, high-affinity inhibitor of PDE10A that modulates dopamine D1 and D2 receptor-mediated intraneuronal signalling without binding to these receptors. This randomized, double-blind, parallel-group, placebo-controlled study (NCT03793712) with open-label extension (NCT03929497) evaluated the efficacy of two fixed-flexible doses (1-2mg/day and 3-4mg/day) of Lu AF11167 in stable, non-acute patients with schizophrenia and persistent prominent negative symptoms. The studies were discontinued following a futility analysis of the double-blind study, and we report data collected up to study termination. Of the 210 patients screened, 162 were randomized, 111 completed the double-blind study and 96 entered the open-label study before early termination. The withdrawal rate due to impending relapse was low and comparable across treatment groups (n = 2-4 per group in the double-blind study and n = 1 in the open-label extension). Double-blind treatment with Lu AF11167 3-4mg was not superior to placebo in the reduction of Brief Negative Symptom Scale (BNSS) total scores from Baseline to Week 12 (primary endpoint); adjusted mean changes were -6.8 with placebo, -5.7 with Lu AF11167 1-2 mg group and -6.0 with Lu AF11167 3-4mg. Treatment with Lu AF11167 1-2mg also failed to separate from placebo on the primary endpoint. Neither dose group showed significant improvements versus placebo on any of the secondary efficacy measures exploring effect of treatment on overall symptomology, negative symptoms, positive symptoms, or functioning. Administration of Lu AF11167 was safe and well tolerated and adverse events were not a major reason for withdrawal from the study., Competing Interests: Conflict of interest AML has received consultant fees from Agence Nationale de la Recherche, Catania International Summer School of Neuroscience (CISSN), Daimler und Benz Stiftung, EPFL Brain Mind Institute, Fondation FondaMental, Hector Stiftung II, Invisio, Janssen-Cilag GmbH, Lundbeck A/S, Lundbeckfonden, Lundbeck Int. Neuroscience Foundation, MedinCell, Sage Therapeutics, SERVIER, Techspert.io, The LOOP Zürich, University Medical Center Utrecht, University of Washington, von Behring Röntgen Stiftung. He has received speaker fees from Ärztekammer Nordrhein, BAG Psychiatrie Oberbayern, Biotest AG, Forum Werkstatt Karlsruhe, International Society of Psychiatric Genetics, Brentwood, Klinik für Psychiatrie und Psychotherapie Ingolstadt, Lundbeck SAS France, med Update GmbH, Merz-Stiftung, Siemens Healthineers, Society of Biological Psychiatry, Universität Prag, Vitos-Klinik Rheingau. He has received editorial fees from American Association for the Advancement of Science, Elsevier, ECNP, Thieme Verlag and author fees from Thieme Verlag. JN, PS, OML, and CvdG are employed by H. Lundbeck A/S as were JZ and RB at the time of study., (Copyright © 2022. Published by Elsevier B.V.)

Aims: Two post-authorisation studies assessed the safety and persistence of patients' use of nalmefene., Methods: The START study (EUPAS5678) was a non-interventional, multi-country, prospective, 18-month (8 follow-up visits) cohort study including outpatients initiating nalmefene for the first time. The multi-database retrospective cohort study (MDRC, EUPAS14083) included baseline and follow-up data from German, Swedish and UK healthcare databases. Both studies permitted 'all comers' without explicit exclusion criteria; predefined subgroups of interest included the elderly (≥65 years) as well as patients with significant psychiatric and/or somatic comorbidities., Results: START study: Overall, the mean duration of nalmefene treatment was 10.3 ± 7.3 months (N = 1348), with 49.0% of patients treated for ≥1 year; frequent reasons for treatment discontinuation were 'goal reached' and 'drug cost'. The most frequently reported adverse drug reactions (ADRs) were nausea (4.7%), dizziness (3.2%) and insomnia (2.0%). ADR rates appeared higher in the elderly subpopulation (18.6% reported ≥1 ADR vs. 12.0% in the total population) but were not higher in the other predefined subgroups.MDRC study: The database follow-up analysis followed 2892 patients over 18 months for whom the duration of nalmefene treatment was between 2 and 3 months and <5% of patients used nalmefene for ≥1 year., Conclusions: Despite the inclusion of a wider patient population (e.g. elderly patients and those with relevant co-morbidities), the safety and tolerability profile of nalmefene given in routine practice was consistent with previous clinical studies. The differing rates of persistence beyond 1 year likely reflect the different methodologies and highlight the relevance of psychosocial support at follow-up visits., (© The Author(s) 2021. Medical Council on Alcohol and Oxford University Press.)

Objectives: In this 6-month open-label extension (OLE) of NCT01491035 (a 14-day, open-label, pharmacokinetic/safety lead-in study), the long-term safety and tolerability of vortioxetine (5-20 mg/day) were investigated in children and adolescents with a DSM-IV-TR™ diagnosis of depressive or anxiety disorder in the United States or Germany. The study also was designed to provide data to inform dose selection and titration in future pediatric studies with vortioxetine., Methods: Safety evaluations included spontaneously reported adverse events (AEs), the Columbia Suicide Severity Rating Scale (C-SSRS), and the Pediatric Adverse Events Rating Scale (PAERS; clinician administered). Clinical effectiveness was determined by Clinical Global Impressions. Comorbid attention-deficit/hyperactivity disorder was permitted, including concomitant use of stimulant medication (US sites only)., Results: Of the 47 patients who completed the lead-in period, 41 continued into the OLE. Most patients (n = 39 [95%]) continued their previous dose regimen. Twenty-one patients (51%) withdrew during the OLE; the most common primary reasons were administrative [n = 8], AEs [n = 4], and lack of efficacy [n = 3]. Thirty-five patients (85%) had ≥1 AE, 86% of which were mild or moderate in severity. Five patients (12%) reported a severe AE, none of which was considered related to study medication. The most common AEs (≥10%) were headache (27%), nausea (20%), dysmenorrhea (females; 19%), and vomiting (15%), with no relationship between AE intensity and age or dose. Five patients reported instances of suicidal ideation during the OLE, one of whom also reported this during the lead-in period. Two patients had nonsuicidal self-injurious behavior; one had a nonfatal suicide attempt. Throughout the study, there was a decrease over time in the incidence and intensity of AEs collected using the PAERS. Effectiveness assessment indicated a trend toward improvement based on numeric results., Conclusion: This OLE confirms the findings from the lead-in study, which concluded that a dosing strategy of 5-20 mg/day is safe, well tolerated, and suitable for future clinical studies of vortioxetine in pediatric patients.

Objective: The primary objectives of this study were to evaluate the pharmacokinetics (PK) and tolerability of single and multiple doses of vortioxetine in children and adolescents with a depressive or anxiety disorder and to provide supportive information for appropriate dosing regimens for pediatric clinical trials., Methods: This prospective, open-label, multinational, multisite, multiple-dose trial enrolled 48 patients (children and adolescents; 1:1 ratio) divided into 8 cohorts (4 adolescent and 4 child), with each cohort including 6 patients. The cohorts in each age group were assigned to receive one of four dosing regimens: vortioxetine 5, 10, 15, or 20 mg q.d. for 14 days. The total treatment period lasted 14-20 days with patients in the higher dose cohorts uptitrated over 2-6 days. Plasma samples for PK analysis were obtained on the first and last days of dosing., Results: Among children and adolescents, respectively, 62% and 92% had depression and 58% and 33% had anxiety disorder. Comorbid attention-deficit/hyperactivity disorder (ADHD) was present in 50% of children and 38% of adolescents. After 14 days q.d. at the target dose, the PK of vortioxetine concentrations was generally proportional to the dose in both age groups. Exposure, as assessed by maximum plasma concentrations and area under the plasma concentration-time curve from time 0 to 24 hours, was 30%-40% lower in adolescents than in children. There was no significant relationship between sex, height, or ADHD diagnosis and PK parameters. Most adverse events were mild in severity and consistent with those seen in adults., Conclusion: The results suggest that the dosages of vortioxetine evaluated (5-20 mg q.d.; approved for treatment in adults) and the uptitration schedule used are appropriate for pediatric efficacy and safety trials.

Our objective was to validate the different versions of the Hamilton Depression Scale (HAM-D) both psychometrically (scalability) and clinically in discriminating antidepressants from placebo in terms of remission rates in an 8-week clinical trial in the acute treatment of major depression. The traditional HAM-D17 version was compared with the shorter HAM-D6 and the longer HAM-D21 or HAM-D24 in a fixed-dose placebo-controlled vortioxetine study. Clinical Global Impression of Severity scores were used to establish standardized cutoff scores for remission across each scale. Using these cutoff scores, we compared the ability of each scale to separate drug-placebo remission rates, evaluated by the number needed to treat for clinical evidence. The HAM-D6 was superior to HAM-D17 in separating drug-placebo remission rates at the end point, defined as number needed to treat of less than 10. More items in the longer HAM-D versions indicated smaller discriminating validity over placebo. The HAM-D6 indicated a dose effect on remission for vortioxetine in both moderate and severe major depression. The brief HAM-D6 was thus found superior to HAM-D17, HAM-D21, and HAM-D24 both in terms of scalability and in discriminating antidepressants from placebo.

Objective: The 30-item Positive and Negative Syndrome Scale (PANSS-30) is the most widely used rating scale in schizophrenia, but too long for clinical use. Shorter PANSS versions have been proposed, including the PANSS-14 and PANSS-8. However, none of these PANSS versions has been validated using the parametric Rasch rating scale model, which evaluates 'scalability'. Scalability means that each item in a rating scale provides unique information regarding syndrome severity and is a statistical prerequisite for using the total score as a measure of overall severity., Method: Based on data from two randomized placebo-controlled trials in schizophrenia, we tested the scalability of PANSS-30, PANSS-14 and PANSS-8 by means of the parametric Rasch rating scale model. Furthermore, we tested whether a scalable PANSS version could separate efficacy of haloperidol and sertindole from placebo., Results: Neither PANSS-30, PANSS-14 nor PANSS-8 was scalable. However, PANSS-6, consisting of the items: P1-Delusions, P2-Conceptual disorganization, P3-Hallucinations, N1-Blunted Affect, N4-Social withdrawal, N6-Lack of spontaneity and flow of conversation, was scalable. Furthermore, PANSS-6 captured superior symptom reduction and higher remission rates during treatment with haloperidol and sertindole vs. placebo., Conclusion: PANSS-6 is a short schizophrenia severity rating scale that adequately separates antipsychotic efficacy from that of placebo., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)