European Neuropsychopharmacology (v.25, #5)

Contents (OBC).

60 years of advances in neuropsychopharmacology for improving brain health, renewed hope for progress by Mark J. Millan; Guy M. Goodwin; M. Hamon; Andreas Meyer-Lindenberg; Sven Ove Ögren (591-598).
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.
Keywords: fMRI; DSM; Translational; Personalised medicine; Animal models; Schizophrenia; Depression; Bipolar disorder; ADHD; Antipsychotic; Anxiolytic; Network; Circuit; Paediatric;

Learning from the past and looking to the future: Emerging perspectives for improving the treatment of psychiatric disorders by Mark J. Millan; Guy M. Goodwin; Andreas Meyer-Lindenberg; Sven Ove Ögren (599-656).
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.
Keywords: Genomics; Genetics; Epigenetics; Prevention; DSM; Translational; Biomarker; Discovery; Clinical trial; Schizophrenia; Depression; OCD; Anxiety; ADHD; Bipolar; Personalised; iPSC;

Major depression is a severe psychiatric syndrome with very high prevalence and socio-economic impact. Its pathophysiology is poorly known, yet several neurotransmitter systems and brain areas have been implicated. Selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors (SSRI) and serotonin and norepinephrine reuptake inhibitors (SNRI) are most used antidepressant treatments. However, these drugs show slow onset of action and limited efficacy, making necessary the use of drug augmentation strategies or more aggressive interventions. Two important observations have emerged in recent years indicating that more rapid and effective antidepressant treatments are possible. Hence, the deep brain stimulation (DBS) of ventral anterior (subgenual) cingulate cortex (Cg25) evokes rapid mood improvements in subgroups of treatment-resistant depressive patients, likely mediated by a functional remodelling of cortico-limbic circuits. On the other hand, the non-competitive NDMA receptor antagonist ketamine can also evoke rapid (e.g., 2 h) and persistent (up to 1 wk) improvements in some treatment-resistant patients. Moreover, recent preclinical observations indicate the antidepressant capacity of mGluR agents. Overall, this supports the usefulness of glutamatergic transmission as a new area in antidepressant drug development. On the monoamine side, new preclinical and clinical research should clarify the different roles played by 5-HT receptors in depression as well as the brain areas and circuits responsible for therapeutic improvement. This will lead to the synthesis of new agents blocking the serotonin (and possibly norepinephrine) transporter which will also activate or block 5-HT receptors playing respectively positive (e.g., postsynaptic 5-HT1A, 5-HT4) or negative (e.g., presynaptic 5-HT1A,/1B, 5-HT2A, 5-HT2C,5-HT3, etc.) roles in antidepressant effects.
Keywords: 5-hydroxytryptamine (serotonin) receptors; Antidepressant drugs; Glutamatergic neurotransmission; Major depression; Norepinephrine; Reuptake inhibition;

One justification for the major scientific and financial investments in genetic and genomic studies in medicine is their therapeutic potential, both for revealing novel targets for drugs which treat the disease process, as well as allowing for more effective and safe use of existing medications. This review considers the extent to which this promise has yet been realised within psychopharmacology, how things are likely to develop in the foreseeable future, and the key issues involved. It draws primarily on examples from schizophrenia and its treatments. One observation is that there is evidence for a range of genetic influences on different aspects of psychopharmacology in terms of discovery science, but far less evidence that meets the standards required before such discoveries impact upon clinical practice. One reason is that results reveal complex genetic influences that are hard to replicate and usually of very small effect. Similarly, the slow progress being made in revealing the genes that underlie the major psychiatric syndromes hampers attempts to apply the findings to identify novel drug targets. Nevertheless, there are some intriguing positive findings of various kinds, and clear potential for genetics and genomics to play an increasing and major role in psychiatric drug discovery.
Keywords: Antipsychotic; Drug response; Neuroleptic; Pharmacogenetics; Pharmacogenomics; Schizophrenia; Tolcapone;

Aberrant changes in gene function are believed to be involved in a wide spectrum of human disease including behavioral, cognitive and neurodegenerative pathologies. Most of the attention in last few decades have focused on changes in gene sequence as a cause of gene dysfunction leading to disease and mental health disorders. Germ line mutations or other alterations in the sequence of DNA that associate with different behavioral and neurological pathologies have been identified. However, sequence alterations explain only a small fraction of the cases. In addition there is evidence for “gene–environment” interactions in the brain suggesting mechanisms that alter gene function and the phenotype through environmental exposure. Genes are programmed by “epigenetic” mechanisms such as chromatin structure, chromatin modification and DNA methylation. These mechanisms confer on similar sequences different identities during cellular differentiation. Epigenetic differences are proposed to be involved in differentiating gene function in response to different environmental contexts and could result in alterations in functional gene networks that lead to brain disease. Epigenetic markers could serve important biomarkers in brain and behavioral diseases. Moreover, epigenetic processes are potentially reversible pointing to epigenetic therapeutics in psychotherapy.
Keywords: DNA methylation; Epigenetics; Histone deacetylase (HDAC) inhibitors; Early life adversity; Alzheimer disease; Schizophrenia; Epilepsy; Valproic acid; S-adenosylmethionine (SAM); Epigenetic therapy;

The field of child and adolescent psychiatry has always lagged behind adult psychiatry. With recent evidence that the vast majority of mental disorders, even when they emerge in adulthood, cause abnormal neurodevelopment and resultant emphasis on prevention and early intervention, there is a need to put child psychiatry at the top of the agenda in mental health research. This should also be the case for developmental neuropsychopharmacology. The target of drug discovery should shift toward a population younger than the one that is typically included in clinical trials. This is not only a matter of trying to replicate what has been found in individuals with mature brains; it is about searching for new strategies that address developing brains while the therapeutic window for their effect is still open. At present, major concerns in developmental psychopharmacology are over-prescription rates and use of psychotropic medications for conditions with a particularly underdeveloped evidence base, as well as adverse effects, especially potentially life-shortening cardiometabolic effects and suicidal ideation. The future of research in this area should focus on the use of drugs for primary and secondary prevention that would modify abnormal brain development.

The current review covers proteinopathies an umbrella term for neurodegenerative disorders that are characterized by the accumulation of specific proteins within neurons or in the brain parenchyma. Most prevalent examples for typical proteinopathies are Alzheimer's disease and Parkinson's disease. In healthy brain, these proteins are unstructured as a monomer, serving most likely as the physiological form. In a disease condition, the unstructured proteins experience a conformational change leading to small oligomers that eventually will aggregate into higher order structures. Prion disease is an exception within the family of proteinopathies as the aggregated prion protein is highly infectious and can self-aggregate and propagate. Recent reports might implicate a prion-like spread of misfolded proteins in Alzheimer's and Parkinson's disease; however there are evident differences in comparison to prion diseases. As proteinopathies are caused by the aggregation of disease-typical proteins with an ordered structure, active and passive immunization protocols have been used to expose model systems to therapeutic antibodies that bind to the aggregates thereby inhibiting the prolongation into higher ordered fibrils or dissolving the existing fibrillar structure. While most of the immunization treatments have been only carried out in preclinical model systems overexpressing the disease-relevant aggregating protein, other approaches are already in clinical testing. Taking the core concept of proteinopathies with conformationally altered protein aggregates into account, immunization appears to be a very promising therapeutic option for neurodegenerative disorders.
Keywords: Amyloid; Proteinopathy; Immunization; Clinical trial;

Early diagnosis and treatment of patients with psychosis are associated with improved outcome in terms of future functioning, symptoms and treatment response. Identifying neuroimaging biomarkers for illness onset and treatment response would lead to immediate clinical benefits. In this review we discuss if neuroimaging may be utilised to diagnose patients with psychosis, predict those who will develop the illness in those at high risk, and stratify patients. State-of-the-art developments in the field are critically examined including multicentre studies, longitudinal designs, multimodal imaging and machine learning as well as some of the challenges in utilising future neuroimaging biomarkers in clinical trials. As many of these developments are already being applied in neuroimaging studies of Alzheimer׳s disease, we discuss what lessons have been learned from this field and how they may be applied to research in psychosis.
Keywords: Early diagnosis; Psychosis; Biomarkers;

Connectomics: A new paradigm for understanding brain disease by Alex Fornito; Edward T. Bullmore (733-748).
In recent years, pathophysiological models of brain disorders have shifted from an emphasis on understanding pathology in specific brain regions to characterizing disturbances of interconnected neural systems. This shift has paralleled rapid advances in connectomics, a field concerned with comprehensively mapping the neural elements and inter-connections that constitute the brain. Magnetic resonance imaging (MRI) has played a central role in these efforts, as it allows relatively cost-effective in vivo assessment of the macro-scale architecture of brain network connectivity. In this paper, we provide a brief introduction to some of the basic concepts in the field and review how recent developments in imaging connectomics are yielding new insights into brain disease, with a particular focus on Alzheimer’s disease and schizophrenia. Specifically, we consider how research into circuit-level, connectome-wide and topological changes is stimulating the development of new aetiopathological theories and biomarkers with potential for clinical translation. The findings highlight the advantage of conceptualizing brain disease as a result of disturbances in an interconnected complex system, rather than discrete pathology in isolated sub-sets of brain regions.
Keywords: Graph analysis; Complex network; Psychosis; Dementia; fMRI; DTI;