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The modern era of drug development for Alzheimer's disease began with the proposal of the cholinergic hypothesis of memory impairment and the 1984 research criteria for Alzheimer's disease. Since then, despite the evaluation of numerous potential treatments in clinical trials, only four cholinesterase inhibitors and memantine have shown sufficient safety and efficacy to allow marketing approval at an international level. Although this is probably because the other drugs tested were ineffective, inadequate clinical development methods have also been blamed for the failures. Here, we review the development of treatments for Alzheimer's disease during the past 30 years, considering the drugs, potential targets, late-stage clinical trials, development methods, emerging use of biomarkers and evolution of regulatory considerations in order to summarize advances and anticipate future developments. We have considered late-stage Alzheimer's disease drug development from 1984 to 2013, including individual clinical trials, systematic and qualitative reviews, meta-analyses, methods, commentaries, position papers and guidelines. We then review the evolution of drugs in late clinical development, methods, biomarkers and regulatory issues. Although a range of small molecules and biological products against many targets have been investigated in clinical trials, the predominant drug targets have been the cholinergic system and the amyloid cascade. Trial methods have evolved incrementally: inclusion criteria have largely remained focused on mild-to-moderate Alzheimer's disease criteria, recently extending to early or prodromal Alzheimer disease or 'mild cognitive impairment due to Alzheimer's disease', for drugs considered to be disease modifying. The duration of trials has remained at 6-12 months for drugs intended to improve symptoms; 18- to 24-month trials have been established for drugs expected to attenuate clinical course. Cognitive performance, activities of daily living, global change and severity ratings have persisted as the primary clinically relevant outcomes. Regulatory guidance and oversight have evolved to allow for enrichment of early-stage Alzheimer's disease trial samples using biomarkers and phase-specific outcomes. In conclusion, validated drug targets for Alzheimer's disease remain to be developed. Only drugs that affect an aspect of cholinergic function have shown consistent, but modest, clinical effects in late-phase trials. There is opportunity for substantial improvements in drug discovery and clinical development methods.

This article describes the rationale, aims, and methodology of the Accelerating Medicines Partnership® Schizophrenia (AMP® SCZ). This is the largest international collaboration to date that will develop algorithms to predict trajectories and outcomes of individuals at clinical high risk (CHR) for psychosis and to advance the development and use of novel pharmacological interventions for CHR individuals. We present a description of the participating research networks and the data processing analysis and coordination center, their processes for data harmonization across 43 sites from 13 participating countries (recruitment across North America, Australia, Europe, Asia, and South America), data flow and quality assessment processes, data analyses, and the transfer of data to the National Institute of Mental Health (NIMH) Data Archive (NDA) for use by the research community. In an expected sample of approximately 2000 CHR individuals and 640 matched healthy controls, AMP SCZ will collect clinical, environmental, and cognitive data along with multimodal biomarkers, including neuroimaging, electrophysiology, fluid biospecimens, speech and facial expression samples, novel measures derived from digital health technologies including smartphone-based daily surveys, and passive sensing as well as actigraphy. The study will investigate a range of clinical outcomes over a 2-year period, including transition to psychosis, remission or persistence of CHR status, attenuated positive symptoms, persistent negative symptoms, mood and anxiety symptoms, and psychosocial functioning. The global reach of AMP SCZ and its harmonized innovative methods promise to catalyze the development of new treatments to address critical unmet clinical and public health needs in CHR individuals., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

In 2017, facing lack of progress and failures encountered in targeted drug development for Autism Spectrum Disorder (ASD) and related neurodevelopmental disorders, the ISCTM with the ECNP created the ASD Working Group charged to identify barriers to progress and recommending research strategies for the field to gain traction. Working Group international academic, regulatory and industry representatives held multiple in-person meetings, teleconferences, and subgroup communications to gather a wide range of perspectives on lessons learned from extant studies, current challenges, and paths for fundamental advances in ASD therapeutics. This overview delineates the barriers identified, and outlines major goals for next generation biomedical intervention development in ASD. Current challenges for ASD research are many: heterogeneity, lack of validated biomarkers, need for improved endpoints, prioritizing molecular targets, comorbidities, and more. The Working Group emphasized cautious but unwavering optimism for therapeutic progress for ASD core features given advances in the basic neuroscience of ASD and related disorders. Leveraging genetic data, intermediate phenotypes, digital phenotyping, big database discovery, refined endpoints, and earlier intervention, the prospects for breakthrough treatments are substantial. Recommendations include new priorities for expanded research funding to overcome challenges in translational clinical ASD therapeutic research., Competing Interests: Disclosures Dr. Anagnostou reports research funding from CIHR, Ontario Brain Institute, Brain Canada, Genome Canada, Ontario Research Fund, Azrieli Foundation, and Autism Speaks. Dr. Arango 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. Dr. Dawson is on the Scientific Advisory Boards of Janssen Research and Development, Akili, Inc, LabCorp, Inc, Roche Pharmaceutical Company, and Tris Pharma, and is a consultant to Apple, Gerson Lehrman Group, Guidepoint, Inc, Axial Ventures, Teva Pharmaceutical, and is CEO of DASIO, LLC. Dr. Dawson has received book royalties from Guilford Press, Oxford University Press, Springer Nature Press. In addition, Dr. Dawson has the following patent applications: 1802952, 1802942, 15141391, and 16493754. Dr. Dawson has developed technology that has been licensed and Dawson and Duke University have benefited financially. Dr. McCracken reports consultant income from Roche, Octapharma, TRIS Pharmaceuticals, GW Biosciences, and research contracts with Octapharma and GW Biosciences. Dr. McPartland consults with Customer Value Partners and BlackThorn Therapeutics, has received research funding from Janssen Research and Development, and receives royalties from Guilford Press, Lambert, and Springer. Dr. Murphy has received honoraria and research funding from Roche. Dr. Pandina is a full-time employee of Janssen Research & Development, LLC, and a Johnson & Johnson stockholder. Dr. Veenstra-VanderWeele reports income from consulting or advisory boards from Roche, Novartis, SynapDx, and research funding from Roche, Novartis, SynapDx, and Wiley. The other authors report no disclosures., (Copyright © 2021. Published by Elsevier B.V.)

Competing Interests: Declaration of Competing Interest The Authors declare no conflict of interest.

Regulatory agencies have a key role in facilitating the development of new drugs for Alzheimer disease, particularly given the challenges associated with early intervention. Here, we highlight the strategies of the European Medicines Agency to help address such challenges.

Health-care stakeholders increasingly recognize that the scientific and economic challenges associated with Alzheimer's disease (AD) are simply too great for individual stakeholder groups to address solely from within their own silos. In the necessary spirit of collaboration, we present in this perspective a set of multicountry multistakeholder recommendations to improve the organization of existing AD and dementia care and the development of new treatments. In brief, the five recommendations are (1) health-care systems must make choices regarding the patient populations to be diagnosed and treated, (2) health-care systems should use an evidence-based standard of care, (3) increased collaboration between public and private institutions is needed to enhance research, (4) reimbursement end points need to be agreed on and validated, and (5) innovative business models should be used to spur the introduction of new medicines., (Copyright © 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Data on neurobiological mechanisms underlying mood disorders are elusive; the aetiology of such states is multifactorial, including genetic predisposition and environmental factors. Diagnosis is currently being made only on an interview-based methodology. Biological markers, which could improve the current classification, and in perspective, stratify patients on a biological basis into more homogeneous clinically distinct subgroups, are highly needed. We describe here a comparative proteomic analysis of peripheral lymphocytes from patients affected by acute psychotic bipolar disorder (PBD) (n = 15), major depressive episode (MDE) with no personal or family history of psychosis (n = 11), and a group of demographically matched healthy controls (HC) (n = 15). All patients were evaluated by means of Structured Clinical Interview for DSM-IV-Patient version (SCID-I-P), Positive and Negative Symptoms Scale (PANSS), Young Mania Rating Scale (YMRS), Hamilton Anxiety Rating Scale (HAM-A) and Hamilton Depression Rating Scale (HAM-D-17) questionnaires. Blood lymphocytes were obtained by gradient separation, and 2-DE was carried out on protein extracts. Significant differences in protein patterns among the three groups were observed. Thirty-six protein spots were found to be differentially expressed in patients compared to controls, which collapsed into 25 different proteins after mass spectrometry identification. Twenty-one of these proteins failed to discriminate between PBD and MDE, suggesting common signatures for these disorders. Nevertheless, after the western blot validation only two of the remaining proteins, namely LIM and SH3 domain protein1, and short-chain specific acyl-CoA dehydrogenase mitochondrial protein, resulted in being significantly upregulated in PBD samples suggesting additional mechanisms that could be associated with the psychotic features of bipolar disorder.

We present a case report of a woman hospitalized for a ventricular-peritoneal shunting replacement, who developed a manic episode with psychotic symptoms after hydrocephalus resolution. We have no knowledge of cases of manic episodes due to hydrocephalus resolution by ventricular-peritoneal shunt replacement, although previous case reports have suggested that hydrocephalus might induce rapid-onset affective episodes or mood cycles. The patient's history revealed the lifetime presence of signs and features belonging to the subthreshold bipolar spectrum, in absence of previous full-blown episodes of a bipolar disorder. Our hypothesis is that such lifetime sub-threshold bipolar features represented precursors of the subsequent full-blown manic episode, triggered by an upregulated binding of striatum D2 receptors after the ventricular-peritoneal shunt replacement.

Recent studies (Prabakaran et al. in Mol Psychiat 9:684-697, 2004; Hanson and Gottesman in BMC Med Genet 6:7, 2005; Harris et al. in PLoS ONE 3:e3964, 2008) have suggested that microvascular abnormalities occur in the brains of patients with schizophrenia. To assess the integrity of the microvasculature in subcortical brain regions in schizophrenia, we investigated the microvessel length density, total microvessel length, and microvessel length per neuron using design-based stereologic methods in the caudate nucleus, putamen, nucleus accumbens, mediodorsal nucleus of the thalamus, and lateral nucleus of the amygdala in both hemispheres of 13 postmortem brains from male patients with schizophrenia and 13 age-matched male controls. A general linear model multivariate analysis of variance with diagnosis and hemisphere as fixed factors and illness duration (patients with schizophrenia) or age (controls), postmortem interval and fixation time as covariates showed no statistically significant differences in the brains from the patients with schizophrenia compared to the controls. These data extend our earlier findings in prefrontal cortex area 9 and anterior cingulate cortex area 24 from the same brains (Kreczmanski et al. in Acta Neuropathol 109:510-518, 2005), that alterations in microvessel length density, total length, and particularly length per neuron cannot be considered characteristic features of schizophrenia. As such, compromised brain metabolism and occurrence of oxidative stress in the brains of patients with schizophrenia are likely caused by other mechanisms such as functional disruption in the coupling of cerebral blood flow to neuronal metabolic needs.

Several studies have pointed to alterations in mean volumes, neuron densities and total neuron numbers in the caudate nucleus (CN), putamen, nucleus accumbens (NA), mediodorsal nucleus of the thalamus (MDNT) and lateral nucleus of the amygdala (LNA) in schizophrenia. However, the results of these studies are conflicting and no clear pattern of alterations has yet been established in these subcortical regions, possibly due to differences in quantitative histological methods used as well as differences in the investigated case series. The present study investigates these subcortical regions in both hemispheres of the same post-mortem brains for volume, neuron density and total neuron number with high-precision design-based stereology. The analysed case series consisted of 13 post-mortem brains from male schizophrenic patients [age range: 22-64 years; mean age 51.5 +/- 3.3 years (mean +/- SEM)] and 13 age-matched male controls (age range: 25-65 years; mean age 51.9 +/- 3.1 years). A general linear model multivariate analysis of variance with diagnosis and hemisphere as fixed factors and illness duration (schizophrenic patients) or age (controls), post-mortem interval and fixation time as covariates showed a number of statistically significant alterations in the brains from schizophrenic patients compared with the controls. There was a reduced mean volume of the putamen [-5.0% on the left side (l) and -4.1% on the right side (r)] and the LNA (l: -12.1%, r: -17.6%), and a reduced mean total neuron number in the CN (l: -10.4%, r: -10.2%), putamen (l: -8.1%, r: -11.6%) and the LNA (l: -15.9%, r: -16.2%). These data show a previously unreported, distinct pattern of alterations in mean total neuron numbers in identified subcortical brain regions in a carefully selected sample of brains from schizophrenic patients. The rigorous quantitative analysis of several regions in brains from schizophrenic patients and matched controls is crucial to provide reliable information on the neuropathology of schizophrenia as well as insights about its pathogenesis.