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The failure rate of drugs being developed for neuropsychiatric indications remains high. Optimizing drug discovery and development requires not only a better neurobiological understanding of disease aetiology and development, but also the means by which we can measure relevant biological and clinical processes related to disease progression, drug target engagement, and sensitivity to treatment. Here we address the role and key considerations for the selection of biomarkers in clinical drug development for neuropsychiatric disorders. We do not provide an exhaustive list of biomarkers; rather we lay out a pragmatic, well-defined biomarker selection strategy that addresses the main goals for each of the phases in the drug development cycle. We discuss the key questions and issues that concern biomarker selection and implementation in each phase of development. For the better development of biomarkers, we emphasize the need to focus on discrete biological dysfunction and/or symptom domains rather than diagnoses. We also advocate the use of biomarker-based patient stratification in phase 2 and 3 to increase sensitivity and power and reduce costs. Our aim is to enhance precision and chances of success for these complex and heterogeneous brain disorders with a high unmet medical need., Competing Interests: Conflicts of interests DU is owner of xperimed LLC that provides consultation on all aspects of clinical drug development for neuropsychiatric indications, works on a contracting basis for Autifony Therapeutics and Gilgamesh pharmaceuticals and holds stocks of Roche, Novartis and Gilgamesh Pharmaceuticals. He has been consulting to Abbvie, Biogen, ERG, Forbion, Healthrhyhms, Kynexis, Psychogenic, Roche and Siesta. MJHK declares no conflicts of interest. GRD is owner of P1vital LTD that provides consultation on suitable biomarkers for inclusion in clinical clinicals and supplies biomarkers such as the Facial expression recognition task (FERT, described in the text to industry and academia., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Social dysfunction represents one of the most common signs of neuropsychiatric disorders, such as Schizophrenia (SZ) and Alzheimer's disease (AD). Perturbed socioaffective neural processing is crucially implicated in SZ/AD and generally linked to social dysfunction. Yet, transdiagnostic properties of social dysfunction and its neurobiological underpinnings remain unknown. As part of the European PRISM project, we examined whether social dysfunction maps onto shifts within socioaffective brain systems across SZ and AD patients. We probed coupling of social dysfunction with socioaffective neural processing, as indexed by an implicit facial emotional processing fMRI task, across SZ (N = 46), AD (N = 40) and two age-matched healthy control (HC) groups (N = 26 HC-younger and N = 27 HC-older). Behavioural (i.e., social withdrawal, interpersonal dysfunction, diminished prosocial or recreational activity) and subjective (i.e., feelings of loneliness) aspects of social dysfunction were assessed using the Social Functioning Scale and De Jong-Gierveld loneliness questionnaire, respectively. Across SZ/AD/HC participants, more severe behavioural social dysfunction related to hyperactivity within fronto-parieto-limbic brain systems in response to sad emotions (P = 0.0078), along with hypoactivity of these brain systems in response to happy emotions (P = 0.0418). Such relationships were not found for subjective experiences of social dysfunction. These effects were independent of diagnosis, and not confounded by clinical and sociodemographic factors. In conclusion, behavioural aspects of social dysfunction across SZ/AD/HC participants are associated with shifts within fronto-parieto-limbic brain systems. These findings pinpoint altered socioaffective neural processing as a putative marker for social dysfunction, and could aid personalized care initiatives grounded in social behaviour., Competing Interests: Declaration of competing interest Dr. Arango has been a consultant to or has received honoraria or grants from Acadia, Angelini, Biogen, Boehringer, Gedeon Richter, Janssen Cilag, Lundbeck, Medscape, Menarini, Minerva, Otsuka, Pfizer, Roche, Sage, Servier, Shire, Schering Plough, Sumitomo Dainippon Pharma, Sunovion and Takeda. AM and GRD are full-time employees of P1vital Ltd. GRD is an owner and shareholder of P1vital Ltd. and P1vital Products Ltd. ACB is an employee of P1vital Products Ltd. All other authors declare that they have nothing to disclose., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: A RCT of a novel intervention to detect antidepressant medication response (the PReDicT Test) took place in five European countries, accompanied by a nested study of its acceptability and implementation presented here. The RCT results indicated no effect of the intervention on depression at 8 weeks (primary outcome), although effects on anxiety at 8 weeks and functioning at 24 weeks were found., Methods: The nested study used mixed methods. The aim was to explore patient experiences of the Test including acceptability and implementation, to inform its use within care. A bespoke survey was completed by trial participants in five countries (n = 778) at week 8. Semi-structured interviews were carried out in two countries soon after week 8 (UK n = 22, Germany n = 20). Quantitative data was analysed descriptively; for qualitative data, thematic analysis was carried out using a framework approach. Results of the two datasets were interrogated together., Outcomes: Survey results showed the intervention was well received, with a majority of participants indicating they would use it again, and it gave them helpful extra information; a small minority indicated the Test made them feel worse. Qualitative data showed the Test had unexpected properties, including: instigating a process of reflection, giving participants feedback on progress and new understanding about their illness, and making participants feel supported and more engaged in treatment., Interpretation: The qualitative and quantitative results are generally consistent. The Test's unexpected properties may explain why the RCT showed little effect, as properties were experienced across both trial arms. Beyond the RCT, the qualitative data sheds light on measurement reactivity, i.e., how measurements of depression can impact patients., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Data from the UK suggests 13-55 % of depression patients experience some level of treatment resistance. However, little is known about how physicians manage inadequate response to antidepressants in primary care. This study aimed to explore the incidence of inadequate response to antidepressants in UK primary care. One-hundred-eighty-four medication-free patients with low mood initiated antidepressant treatment and monitored severity of depression symptoms, using the QIDS-SR16, for 48 weeks. Medication changes, visits to healthcare providers, and health-related quality of life were also recorded. Patients were classified into one of four response types based on their QIDS scores at three study timepoints: persistent inadequate responders (<50 % reduction in baseline QIDS at all timepoints), successful responders (≥50 % reduction in baseline QIDS at all timepoints), slow responders (≥50 % reduction in QIDS at week 48, despite earlier inadequate responses), and relapse (initial ≥50 % reduction in baseline QIDS, but inadequate response by week 48). Forty-eight weeks after initiating treatment 47 % of patients continued to experience symptoms of depression (QIDS >5), and 20 % of patients had a persistent inadequate response. Regardless of treatment response, 96 % (n = 176) of patients did not visit their primary care physician over the 40-week follow-up period. These results suggest that despite receiving treatment, a considerable proportion of patients with low mood remain unwell and fail to recover. Monitoring depression symptoms remotely can enable physicians to identify inadequate responders, allowing patients to be reassessed or referred to secondary services, likely improving patients' quality of life and reducing the socioeconomic impacts of chronic mental illness., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: GRD and JK own shares in the study sponsor (P1vital Products Ltd) which also owns the PReDicT predictive algorithm. ACB, RD, and JK are employees of P1vital Products Ltd. GRD owns shares in P1vital Ltd. ABA and GRD are employees of P1vital Ltd. HGR reports speakers’ bureau honoraria from Janssen, Lundbeck, and received research grants from ZonMW, HersenStichting, EU Horizon 2020, the Dutch Ministry of Health, and an unrestricted Educational grant from Janssen. AR has received honoraria for lectures and/or advisory boards from Janssen, Boehringer Ingelheim, COMPASS, SAGE/Biogen, LivaNova, Medice, Shire/Takeda and cyclerion. Also, he has received research grants from Medice and Janssen. GMG is Chief Medical Officer at Compass pathways, holds shares and options in Compass pathways and has served as consultant, advisor or CME speaker in the last 3 years for Beckley Psytech, Boehringer Ingelheim, Clerkenwell Health, Compass pathways, Evapharma, Janssen, Lundbeck, Medscape, Novartis, Ocean Neuroscience, P1Vital Ltd., Sage, Servier and Takeda. MB has acted as a consultant for Janssen Research, P1vital Ltd, Boehringer and CHDR, and was previously a paid employee of P1vital Ltd. RM has received payment from Novartis plc but have no other conflicts of interest to report. All other authors declare that they have no conflicts of interest. JS has received research grants from the ECNP, EU Horizon 2020, EU Horizon Europe, FWF, NIHR, WWTF, and academic advisor honoraria from the European Brain Council, (Copyright © 2024 Elsevier B.V. and ECNP. All rights reserved.)

The current neuropsychiatric nosological categories underlie pragmatic treatment choice, regulation and clinical research but does not encompass biological rationale. However, subgroups of patients suffering from schizophrenia or Alzheimer's disease have more in common than the neuropsychiatric nature of their condition, such as the expression of social dysfunction. The PRISM project presents here initial quantitative biological insights allowing the first steps toward a novel trans-diagnostic classification of psychiatric and neurological symptomatology intended to reinvigorate drug discovery in this area. In this study, we applied spectral clustering on digital behavioural endpoints derived from passive smartphone monitoring data in a subgroup of Schizophrenia and Alzheimer's disease patients, as well as age matched healthy controls, as part of the PRISM clinical study. This analysis provided an objective social functioning characterization with three differential clusters that transcended initial diagnostic classification and was shown to be linked to quantitative neurobiological parameters assessed. This emerging quantitative framework will both offer new ways to classify individuals in biologically homogenous clusters irrespective of their initial diagnosis, and also offer insights into the pathophysiological mechanisms underlying these clusters., Competing Interests: Conflict of interest MK has received (non-related) research funding from Novartis during the conduct of the study. MM is employee and CFB is director and shareholder of SBGneuro Ltd. CA has been a consultant to or has received honoraria or grants from Acadia, Angelini, Gedeon Richter, Janssen Cilag, Lundbeck, Minerva, Otsuka, Roche, Sage, Servier, Shire, Schering Plough, Sumitomo Dainippon Pharma, Sunovion and Takeda. BP has received (non-related) research funding from Jansen Research and Boehringer Ingelheim during the conduct of the study. ACB and GRD were fully employed by P1Vital during the conduct of the study. BS was fully employed by Boehringer Ingelheim during the conduct of the study. HM was fully employed by Eli Lilly and Company during the conduct of the study. All other authors declare no conflict of interests., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)