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• Lu AF11167 is a selective, high affinity inhibitor of PDE10A. • Treatment with Lu AF11167 did not reduce negative symptoms in schizophrenia. • Lu AF11167 was safe and generally well tolerated. • Placebo-controlled monotherapy studies for prominent negative symptoms are safe. 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. [ABSTRACT FROM AUTHOR]

Finding novel biological targets in psychiatry has been difficult, partly because current diagnostic categories are not defined by pathophysiology and difficult to model in animals. The study of species-conserved systems-level mechanisms implicated in psychiatric disease could be a promising strategy to address some of these difficulties. Altered hippocampal–prefrontal (HC-PFC) connectivity during working memory (WM) processing is a candidate for such a translational phenotype as it has been repeatedly associated with impaired cognition in schizophrenia patients and animal models for psychiatric risk factors. Specifically, persistent hippocampus-dorsolateral prefrontal cortex (HC-DLPFC) coupling during WM is an intermediate phenotype for schizophrenia that has been observed in patients, healthy relatives and carriers of two different risk polymorphisms identified in genome-wide association studies. Rodent studies report reduced coherence between HC and PFC during anesthesia, sleep and task performance in both genetic, environmental and neurodevelopmental models for schizophrenia. We discuss several challenges for translation including differences in anatomy, recording modalities and WM paradigms and suggest that a better understanding of HC-PFC coupling across species can be achieved if translational neuroimaging is used to control for task differences. The evidence for potential neurobiological substrates underlying HC-PFC dysconnectivity is evaluated and research strategies are proposed that aim to bridge the gap between findings from large-scale association studies and disease mechanisms. [ABSTRACT FROM AUTHOR]

• PANSS G#7 and TMT-B have a surrogate value for psychomotor slowing in SZ. • Primary motor cortex thinning contribute to psychomotor slowing in SZ. • Cortical rather than subcortical regions contribute to psychomotor slowing in SZ. Psychomotor slowing (PS) is characterized by slowed movements and lower activity levels. PS is frequently observed in schizophrenia (SZ) and distressing because it impairs performance of everyday tasks and social activities. Studying brain topography contributing to PS in SZ can help to understand the underlying neurobiological mechanisms as well as help to develop more effective treatments that specifically target affected brain areas. Here, we conducted structural magnetic resonance imaging (sMRI) of three independent cohorts of right-handed SZ patients (SZ#1: n = 72, SZ#2: n = 37, SZ#3: n = 25) and age, gender and education matched healthy controls (HC) (HC#1: n = 40, HC#2: n = 37, HC#3: n = 38). PS severity in the three SZ cohorts was determined using the Positive and Negative Syndrome Scale (PANSS) item #G7 (motor retardation) and Trail-Making-Test B (TMT-B). FreeSurfer v7.2 was used for automated parcellation and segmentation of cortical and subcortical regions. SZ#1 patients showed reduced cortical thickness in right precentral gyrus (M1; p = 0.04; Benjamini-Hochberg [BH] corr.). In SZ#1, cortical thinning in right M1 was associated with PANSS item #G7 (p = 0.04; BH corr.) and TMT-B performance (p = 0.002; BH corr.). In SZ#1, we found a significant correlation between PANSS item #G7 and TMT-B (p = 0.005, ρ =0.326). In conclusion, PANSS G#7 and TMT-B might have a surrogate value for predicting PS in SZ. Cortical thinning of M1 rather than alterations of subcortical structures may point towards cortical pathomechanism underlying PS in SZ. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic strongly impacted people's daily lives. However, it remains unknown how the pandemic situation affects daily-life experiences of individuals with preexisting severe mental illnesses (SMI). In this real-life longitudinal study, the acute onset of the COVID-19 pandemic in Germany did not cause the already low everyday well-being of patients with schizophrenia (SZ) or major depression (MDD) to decrease further. On the contrary, healthy participants' well-being, anxiety, social isolation, and mobility worsened, especially in healthy individuals at risk for mental disorder, but remained above the levels seen in patients. Despite being stressful for healthy individuals at risk for mental disorder, the COVID-19 pandemic had little additional influence on daily-life well-being in psychiatric patients with SMI. This highlights the need for preventive action and targeted support of this vulnerable population. [ABSTRACT FROM AUTHOR]

Pharmacotherapy is effective in helping many patients suffering from psychiatric and neurological disorders, and both psychotherapeutic and stimulation-based techniques likewise have important roles to play in their treatment. However, therapeutic progress has recently been slow. Future success for improving the control and prevention of brain disorders will depend upon deeper insights into their causes and pathophysiological substrates. It will also necessitate new and more rigorous methods for identifying, validating, developing and clinically deploying new treatments. A field of Research and Development (R and D) that remains critical to this endeavour is Neuropsychopharmacology which transformed the lives of patients by introducing pharmacological treatments for psychiatric disorder some 60 years ago. For about half of this time, the European College of Neuropsychopharmacology (ECNP) has fostered efforts to enhance our understanding of the brain, and to improve the management of psychiatric disorders. Further, together with partners in academia and industry, and in discussions with regulators and patients, the ECNP is implicated in new initiatives to achieve this goal. This is then an opportune moment to survey the field, to analyse what we have learned from the achievements and failures of the past, and to identify major challenges for the future. It is also important to highlight strategies that are being put in place in the quest for more effective treatment of brain disorders: from experimental research and drug discovery to clinical development and collaborative ventures for reinforcing “R and D”. The present article sets the scene, then introduces and interlinks the eight articles that comprise this Special Volume of European Neuropsychopharmacology. A broad-based suite of themes is covered embracing: the past, present and future of “R and D” for psychiatric disorders; complementary contributions of genetics and epigenetics; efforts to improve the treatment of depression, neurodevelopmental and neurodegenerative disorders; and advances in the analysis and neuroimaging of cellular and cerebral circuits. [ABSTRACT FROM AUTHOR]

Modern neuropsychopharmacology commenced in the 1950s with the serendipitous discovery of first-generation antipsychotics and antidepressants which were therapeutically effective yet had marked adverse effects. Today, a broader palette of safer and better-tolerated agents is available for helping people that suffer from schizophrenia, depression and other psychiatric disorders, while complementary approaches like psychotherapy also have important roles to play in their treatment, both alone and in association with medication. Nonetheless, despite considerable efforts, current management is still only partially effective, and highly-prevalent psychiatric disorders of the brain continue to represent a huge personal and socio-economic burden. The lack of success in discovering more effective pharmacotherapy has contributed, together with many other factors, to a relative disengagement by pharmaceutical firms from neuropsychiatry. Nonetheless, interest remains high, and partnerships are proliferating with academic centres which are increasingly integrating drug discovery and translational research into their traditional activities. This is, then, a time of transition and an opportune moment to thoroughly survey the field. Accordingly, the present paper, first , chronicles the discovery and development of psychotropic agents, focusing in particular on their mechanisms of action and therapeutic utility, and how problems faced were eventually overcome. Second , it discusses the lessons learned from past successes and failures, and how they are being applied to promote future progress. Third , it comprehensively surveys emerging strategies that are (1), improving our understanding of the diagnosis and classification of psychiatric disorders; (2), deepening knowledge of their underlying risk factors and pathophysiological substrates; (3), refining cellular and animal models for discovery and validation of novel therapeutic agents; (4), improving the design and outcome of clinical trials; (5), moving towards reliable biomarkers of patient subpopulations and medication efficacy and (6), promoting collaborative approaches to innovation by uniting key partners from the regulators, industry and academia to patients. Notwithstanding the challenges ahead, the many changes and ideas articulated herein provide new hope and something of a framework for progress towards the improved prevention and relief of psychiatric and other CNS disorders, an urgent mission for our Century. [ABSTRACT FROM AUTHOR]

The 15q13.3 microdeletion copy number variation is strongly associated with schizophrenia and epilepsy. The CHRNA 7 gene, encoding nicotinic acetylcholine alpha 7 receptors (nAChA7Rs), is hypothesized to be one of the main genes in this deletion causing the neuropsychiatric phenotype. Here we used a recently developed 15q13.3 microdeletion mouse model to explore whether an established schizophrenia-associated connectivity phenotype is replicated in a murine model, and whether positive modulation of nAChA7 receptor might pharmacologically normalize the connectivity patterns. Resting-state fMRI data were acquired from male mice carrying a hemizygous 15q13.3 microdeletion ( N =9) and from wild-type mice ( N =9). To study the connectivity profile of 15q13.3 mice and test the effect of nAChA7 positive allosteric modulation, the 15q13.3 mice underwent two imaging sessions, one week apart, receiving a single intraperitoneal injection of either 15 mg/kg Lu AF58801 or saline. The control group comprised wild-type mice treated with saline. We performed seed-based functional connectivity analysis to delineate aberrant connectivity patterns associated with the deletion (15q13.3 mice (saline treatment) versus wild-type mice (saline treatment)) and their modulation by Lu AF58801 (15q13.3 mice (Lu AF58801 treatment) versus 15q13.3 mice (saline treatment)). Compared to wild-type mice, 15q13.3 mice evidenced a predominant hyperconnectivity pattern. The main effect of Lu AF58801 was a normalization of elevated functional connectivity between prefrontal and frontal, hippocampal, striatal, thalamic and auditory regions. The strongest effects were observed in brain regions expressing nAChA7Rs, namely hippocampus, cerebral cortex and thalamus. These effects may underlie the antiepileptic, pro-cognitive and auditory gating deficit-reversal effects of nAChA7R stimulation. [ABSTRACT FROM AUTHOR]

Abstract: Dopamine D2 receptor antagonists effectively reduce positive symptoms in schizophrenia, implicating abnormal dopaminergic neurotransmission as an underlying mechanism of psychosis. Despite the well-established, albeit incomplete, clinical efficacies of D2 antagonists, no studies have examined their effects on functional interaction between brain regions. We hypothesized that haloperidol, a widely used antipsychotic and D2 antagonist, would modulate functional connectivity in dopaminergic circuits. Ten male Sprague-Dawley rats received either haloperidol (1mg/kg, s.c.) or the same volume of saline a week apart. Resting-state functional magnetic resonance imaging data were acquired 20min after injection. Connectivity analyses were performed using two complementary approaches: correlation analysis between 44 atlas-derived regions of interest, and seed-based connectivity mapping. In the presence of haloperidol, reduced correlation was observed between the substantia nigra and several brain regions, notably the cingulate and prefrontal cortices, posterodorsal hippocampus, ventral pallidum, and motor cortex. Haloperidol induced focal changes in functional connectivity were found to be the most strongly associated with ascending dopamine projections. These included reduced connectivity between the midbrain and the medial prefrontal cortex and hippocampus, possibly relating to its therapeutic action, and decreased coupling between substantia nigra and motor areas, which may reflect dyskinetic effects. These data may help in further characterizing the functional circuits modulated by antipsychotics that could be targeted by innovative drug treatments. [Copyright &y& Elsevier]

B Background: b Sleep spindles are a key characteristic of NREM stage 2 sleep and show a strong heritability. B Discussion: b The present results replicate earlier results that describe an association of polygenic SCZ risk with sleep spindle density, but do not replicate CACNA1I specific associations. [Extracted from the article]

Background The prevalence of schizophrenia is higher in urban areas than in rural areas. The association between urbanization and schizophrenia has been reported before in relation to place of birth, place of upbringing and place of residence. Two major hypotheses have been proposed to explain this phenomenon: (1) the causation hypothesis, where the stress of city life and undefined factors in the urban environment would increase the risk of this disease, and (2) the selection hypothesis, where individuals with genetic liability for schizophrenia would move into urban areas. On the other hand, genetic factors have been shown to have a higher impact on the country v.s city living as people grow older (>40y), while the impact of family background decreases. Heritability estimates reported for full ACE models were 12.7%, 22% and 41.2% for those under 20, 20-40 and over 40, respectively. Our aim was to test the alternative hypothesis that adults with higher genetic risk for schizophrenia are more likely to move to and live in urbanized and populated areas than those with lower risk. Methods Our sample was comprised of 15,253 participants in 7,007 families (63.4% women) over 40 years old (M = 54.43, SD = 10.86) living in Australia. The participants reported their postcode as part of the protocols of several studies on health and wellbeing conducted from QIMR. Participants were genotyped genome-wide and imputed to 1000G v.3. We used three measures of urbanicity; (i) subjects’ zip code were categorized into urban, suburban or rural zones; we also computed (ii) distance to the closest city centre and (iii) the population density of the postcode district. Polygenic risk scores (PRS) for schizophrenia based on summary statistics from the Psychiatric Genomics Consortium (PGC-2) were computed with PLINK 1.90 (version 3) for eight different P-value thresholds. We used linear mixed models to predict the three urbanicity measures from the schizophrenia PRS, controlling for age, sex, genetic principal components, GWAS chip and genetic relationship matrix. Predictions were calculated using GCTA (Genome-wide Complex Trait Analysis, version 1.22). Results Genetic risk for schizophrenia was associated with the place where the participants lived in the expected direction, with increased effects as the risk scores included more SNPs. P-values for PRS at thresholds <0.05 were 7.02*10-5 , 4.75*10-2 and 9.78*10-6, for zone, city distance and population density respectively while for threshold P<1 they were correspondingly 4.75*10-7 , 1.2*10-3 and 1.19*10-6. Discussion Our results suggest that people with a higher genetic risk for schizophrenia may prefer to live in more urban and populated areas. Importantly, this study does not use a case-control sample but a non-selected sample where the genetic risk for schizophrenia was estimated. This study proposes that greater genetic predisposition to schizophrenia is at least one mechanism explaining why this illness is more prevalent in city environments. Future research should test if this effect is replicated in other countries. Financial Support: NHMRC Grant 1103603 [ABSTRACT FROM AUTHOR]