A primer on the use of machine learning to distil knowledge from data in biological psychiatry.

Applications of machine learning in the biomedical sciences are growing rapidly. This growth has been spurred by diverse cross-institutional and interdisciplinary collaborations, public availability of large datasets, an increase in the accessibility of analytic routines, and the availability of powerful computing resources. With this increased access and exposure to machine learning comes a responsibility for education and a deeper understanding of its bases and bounds, borne equally by data scientists seeking to ply their analytic wares in medical research and by biomedical scientists seeking to harness such methods to glean knowledge from data. This article provides an accessible and critical review of machine learning for a biomedically informed audience, as well as its applications in psychiatry. The review covers definitions and expositions of commonly used machine learning methods, and historical trends of their use in psychiatry. We also provide a set of standards, namely Guidelines for REporting Machine Learning Investigations in Neuropsychiatry (GREMLIN), for designing and reporting studies that use machine learning as a primary data-analysis approach. Lastly, we propose the establishment of the Machine Learning in Psychiatry (MLPsych) Consortium, enumerate its objectives, and identify areas of opportunity for future applications of machine learning in biological psychiatry. This review serves as a cautiously optimistic primer on machine learning for those on the precipice as they prepare to dive into the field, either as methodological practitioners or well-informed consumers.

How evolutionary psychiatry can advance psychopharmacology
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The prevailing paradigm for psychopharmacology focuses on understanding brain mechanisms as the key to finding new medications and improving clinical outcomes, but frustration with slow progress has inspired many pleas for new approaches. Evolutionary psychiatry brings in an additional basic science that poses new questions about why natural selection left us vulnerable to so many mental disorders, and new insights about how drugs work. The integration of neuroscience with evolutionary psychiatry is synergistic, going beyond reductionism to provide a model like the one used by the rest of medicine. It recognizes negative emotions as symptoms, that are, like pain and cough, useful defenses whose presence should initiate a search for causes. An integrative evolutionary approach explains why agents that block useful aversive responses are usually safe, and how to anticipate when they may cause harm. More generally, an evolutionary framework suggests novel practical strategies for finding and testing new drugs.
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El paradigma común para la psicofarmacología se centra en entender los mecanismos cerebrales como la clave para encontrar nuevos medicamentos y mejorar los resultados clínicos, pero la frustración con el lento progreso ha inspirado muchos motivos para nuevas aproximaciones. La psiquiatría evolutiva conlleva una ciencia básica adicional que plantea nuevas preguntas sobre el por qué la selección natural nos dejó vulnerables a tantos trastornos mentales y aporta nuevas perspectivas sobre cómo funcionan los fármacos. La integración de las neurociencias con la psiquiatría evolutiva es sinérgica, y va más allá del reduccionismo para proporcionar un modelo como el que utiliza el resto de la medicina. Reconoce las emociones negativas como síntomas, que son, como el dolor y la tos, defensas útiles cuya presencia debe iniciar una búsqueda de causas. Un enfoque evolutivo integrador explica por qué los agentes que bloquean las respuestas aversivas útiles suelen ser seguros y cómo anticipar cuándo pueden causar daño. De manera más general, un marco evolutivo sugiere nuevas estrategias prácticas para encontrar y probar nuevos medicamentos.

Le modèle prévalent de la psychopharmacologie se concentre sur la compréhension des mécanismes du cerveau comme la clé pour découvrir de nouveaux médicaments et améliorer les résultats cliniques, mais la frustration ressentie devant les lents progrès de cette méthode a inspiré de nombreux plaidoyers pour d'autres approches. La psychiatrie évolutionniste apporte une connaissance scientifique fondamentale supplémentaire qui pose de nouvelles questions sur la raison pour laquelle la sélection naturelle nous a laissé si vulnérables à tant de troubles mentaux, et des idées nouvelles sur la façon dont fonctionnent les médicaments. L'intégration de la psychiatrie évolutionniste aux neurosciences est source de synergies, allant bien au-delà du réductionnisme en fournissant un modèle semblable à celui utilisé par le reste de la médecine. Il reconnaît les émotions négatives comme des symptômes, exactement comme le sont la douleur et la toux, défenses habituelles qui doivent initier une recherche des causes. Une approche évolutionniste intégrative explique pourquoi des agents qui bloquent des réactions pertinentes d'aversion sont généralement sans danger, et comment anticiper lorsqu'ils pourraient causer un préjudice. Plus généralement, un modèle évolutionniste propose de nouvelles stratégies pratiques pour trouver et tester de nouveaux médicaments.

Clinical guidelines for the management of treatment-resistant depression: French recommendations from experts, the French Association for Biological Psychiatry and Neuropsychopharmacology and the fondation FondaMental.

BACKGROUND: Clear guidance for successive antidepressant pharmacological treatments for non-responders in major depression is not well established. METHOD: Based on the RAND/UCLA Appropriateness Method, the French Association for Biological Psychiatry and Neuropsychopharmacology and the fondation FondaMental developed expert consensus guidelines for the management of treatment-resistant depression. The expert guidelines combine scientific evidence and expert clinicians' opinions to produce recommendations for treatment-resistant depression. A written survey comprising 118 questions related to highly-detailed clinical presentations was completed on a risk-benefit scale ranging from 0 to 9 by 36 psychiatrist experts in the field of major depression and its treatments. Key-recommendations are provided by the scientific committee after data analysis and interpretation of the results of the survey. RESULTS: The scope of these guidelines encompasses the assessment of pharmacological resistance and situations at risk of resistance, as well as the pharmacological and psychological strategies in major depression. CONCLUSION: The expert consensus guidelines will contribute to facilitate treatment decisions for clinicians involved in the daily assessment and management of treatment-resistant depression across a number of common and complex clinical situations.

Fear Extinction Retention: Is It What We Think It Is?

There has been an explosion of research on fear extinction in humans in the past 2 decades. This has not only generated major insights, but also brought a new goal into focus: how to maintain extinction memory over time (i.e., extinction retention). We argue that there are still important conceptual and procedural challenges in human fear extinction research that hamper advancement in the field. We use extinction retention and the extinction retention index to exemplarily illustrate these challenges. Our systematic literature search identified 16 different operationalizations of the extinction retention index. Correlation coefficients among these different operationalizations as well as among measures of fear/anxiety show a wide range of variability in four independent datasets, with similar findings across datasets. Our results suggest that there is an urgent need for standardization in the field. We discuss the conceptual and empirical implications of these results and provide specific recommendations for future work.

Guidelines for the standardized collection of blood-based biomarkers in psychiatry: Steps for laboratory validity - a consensus of the Biomarkers Task Force from the WFSBP.

Recently, there has been a major shift in the field of psychiatry towards the exploration of complex relationships between blood-based biomarkers and the pathophysiology of psychiatric and neuropsychiatric disorders. However, issues with study reproducibility, validity and reliability have hindered progress towards the identification of clinically relevant biomarkers for psychiatry. The achievement of laboratory validity is a crucial first step for the posterior development of clinical validity. There is evidence that the variability observed in blood-based research studies may be minimised with the implementation of standardised pre-analytical methods and uniform clinical protocols (i.e., pre-venipuncture). It has been documented that errors made in the pre-analytical phase account for 46-68.2% of laboratory testing errors. Thus, standardising clinical assessment, ethical procedures and pre-analytical phase of clinical research is essential for the reproducibility, validity and reliability of blood marker assessment, and reducing the risk of invalid test results. Various other areas of research have already moved towards guidelines for the standardised collection of blood-based biomarkers. Here we aim to provide a set of guidelines that we believe would improve biomarker research: (1) pre-venipuncture information and documentation, (2) ethics of participant consent and (3) pre-analytical methods. Ultimately, we hope this will assist study planning and will improve data comparison across studies allowing for the discovery of biomarkers in psychiatry with both laboratorial and clinical validity.

Clinical guidelines for the management of depression with specific comorbid psychiatric conditions French recommendations from experts (the French Association for Biological Psychiatry and Neuropsychopharmacology and the fondation FondaMental).

BACKGROUND: Recommendations for pharmacological treatments of major depression with specific comorbid psychiatric conditions are lacking. METHOD: The French Association for Biological Psychiatry and Neuropsychopharmacology and the fondation FondaMental developed expert consensus guidelines for the management of depression based on the RAND/UCLA Appropriatneness Method. Recommendations for lines of treatment are provided by the scientific committee after data analysis and interpretation of the results of a survey of 36 psychiatrist experts in the field of major depression and its treatments. RESULTS: The expert guidelines combine scientific evidence and expert clinician's opinion to produce recommendations for major depression with comorbid anxiety disorders, personality disorders or substance use disorders and in geriatric depression. CONCLUSION: These guidelines provide direction addressing common clinical dilemmas that arise in the pharmacologic treatment of major depression with comorbid psychiatric conditions.

Brain space and time in mental disorders: Paradigm shift in biological psychiatry.

Contemporary psychiatry faces serious challenges because it has failed to incorporate accumulated knowledge from basic neuroscience, neurophilosophy, and brain-mind relation studies. As a consequence, it has limited explanatory power, and effective treatment options are hard to come by. A new conceptual framework for understanding mental health based on underlying neurobiological spatial-temporal mechanisms of mental disorders (already gained by the experimental studies) is beginning to emerge.

Toward Neuroproteomics in Biological Psychiatry: A Systems Approach Unravels Okadaic Acid-Induced Alterations in the Neuronal Phosphoproteome.

Neuroproteomics is an evolving field of postgenomic medicine, highlighting the convergence of psychiatry/neurology and proteomics, yet compared with neurogenetics, it has received little attention. This study in rat primary neuronal cultures provides an example of a neuroproteomic approach relevant to the study of psychiatric disease pathophysiology, focusing on Alzheimer's disease. In this context, okadaic acid (OA) is routinely used in experimental designs to investigate phosphorylation-mediated events. It is a potent protein phosphatase (PP) inhibitor, particularly of PP1 and PP2A. Typically, a single protein and its phosphorylation level are monitored upon OA exposure. Although useful, this can be misleading as protein phosphorylation-mediated events involve complex signaling cascades and an array of kinases, phosphatases, and substrates. Bearing in mind the involvement of multiple pathways and cascade cross talk, this study employed a systems approach to analyze OA-induced molecular responses through PP inhibition. We showed that upon OA exposure, the recovery rate of 245 phosphoproteins significantly increased, while that of 75 significantly decreased. The prominent biological processes affected included anatomical structural development, transport, cell differentiation, and signal transduction. The associated phosphointeraction networks identified nodes representing OA-responsive phosphoproteins. Many of these are key players of signaling cascades relevant to a range of pathologies. In summary, the data presented results from a neuroproteomic preclinical study offering an array of phosphoproteins as potential targets for future diagnostic and therapeutic strategies in biological psychiatry. We note, however, the nonspecificity of targeting PPs themselves and emphasize the need for future neuroproteomic approaches toward systems psychiatry.

Nutritional psychiatry: the present state of the evidence.

Mental illness, including depression, anxiety and bipolar disorder, accounts for a significant proportion of global disability and poses a substantial social, economic and heath burden. Treatment is presently dominated by pharmacotherapy, such as antidepressants, and psychotherapy, such as cognitive behavioural therapy; however, such treatments avert less than half of the disease burden, suggesting that additional strategies are needed to prevent and treat mental disorders. There are now consistent mechanistic, observational and interventional data to suggest diet quality may be a modifiable risk factor for mental illness. This review provides an overview of the nutritional psychiatry field. It includes a discussion of the neurobiological mechanisms likely modulated by diet, the use of dietary and nutraceutical interventions in mental disorders, and recommendations for further research. Potential biological pathways related to mental disorders include inflammation, oxidative stress, the gut microbiome, epigenetic modifications and neuroplasticity. Consistent epidemiological evidence, particularly for depression, suggests an association between measures of diet quality and mental health, across multiple populations and age groups; these do not appear to be explained by other demographic, lifestyle factors or reverse causality. Our recently published intervention trial provides preliminary clinical evidence that dietary interventions in clinically diagnosed populations are feasible and can provide significant clinical benefit. Furthermore, nutraceuticals including n-3 fatty acids, folate, S-adenosylmethionine, N-acetyl cysteine and probiotics, among others, are promising avenues for future research. Continued research is now required to investigate the efficacy of intervention studies in large cohorts and within clinically relevant populations, particularly in patients with schizophrenia, bipolar and anxiety disorders.

How to: Measuring blood cytokines in biological psychiatry using commercially available multiplex immunoassays.

Cytokines produced by both immune and non-immune cells are likely to play roles in the development and/or progression of psychiatric disorders. Indeed, many investigators have compared the blood cytokine levels in psychiatric patients with those of healthy controls or monitored their levels in patients during disease progression to identify biomarkers. Nevertheless, very few studies have confirmed that such cytokines remain stable in healthy individuals through periods of weeks and months. This is an important issue to consider before using blood cytokine levels as biomarkers of disease traits, disease state, or treatment response. Although multiplex assay technology represents an advance in identifying biomarkers because it allows simultaneous examination of large panels of analytes from a small volume of sample, it is necessary to verify whether these assays yield enough sensitivity and reproducibility when applied to the blood from neuropsychiatric patients. Therefore, we compared two multiplex immunoassays, the bead-based Luminex® (Bio-Rad) and the electro-chemiluminescence-based V-plex® (MesoScaleDiscovery), for the detection and quantification of 31 cytokines, chemokines and growth factors in both the sera and plasma of patients with major depressive episodes (MDE) and age- and sex-matched healthy control subjects during a 30-week period. Although both platforms exhibited low coefficients of variability (CV) between the duplicates in the calibration curves, the linearity was better in general for the V-PLEX® platform. However, neither platform was able to detect the absolute values for all of the tested analytes. Among the 16 analytes that were detected by both assays, the intra-assay reproducibility was in general better with the V-PLEX® platform. Although it is not a general rule that the results from sera and plasma will be correlated, consistent results were more frequent with the V-PLEX® platform. Furthermore, the V-PLEX® results were more consistent with the gold standard ELISA simplex assay for IL-6 in both sera and plasma. The intra-individual variability of the measurements, among the sera and plasma for the 4 samples harvested from each healthy individual, was low for Eotaxin, G-CSF, IL-4, IL-7, IL-9, IL-12p40, IL-12p70, IL-15, MIP-1ß, PDGF-BB, TNF, TNF-ß and VEGF, but intermediate or high for IFN-γ, IL-6, IL-8, IL-10, and IP10. Together, these data suggest that extreme caution is needed in translating the results of multiplex cytokine profiling into biomarker discovery in psychiatry.

Psychiatric gene discoveries shape evidence on ADHD's biology.

A strong motivation for undertaking psychiatric gene discovery studies is to provide novel insights into unknown biology. Although attention-deficit hyperactivity disorder (ADHD) is highly heritable, and large, rare copy number variants (CNVs) contribute to risk, little is known about its pathogenesis and it remains commonly misunderstood. We assembled and pooled five ADHD and control CNV data sets from the United Kingdom, Ireland, United States of America, Northern Europe and Canada. Our aim was to test for enrichment of neurodevelopmental gene sets, implicated by recent exome-sequencing studies of (a) schizophrenia and (b) autism as a means of testing the hypothesis that common pathogenic mechanisms underlie ADHD and these other neurodevelopmental disorders. We also undertook hypothesis-free testing of all biological pathways. We observed significant enrichment of individual genes previously found to harbour schizophrenia de novo non-synonymous single-nucleotide variants (SNVs; P=5.4 × 10(-4)) and targets of the Fragile X mental retardation protein (P=0.0018). No enrichment was observed for activity-regulated cytoskeleton-associated protein (P=0.23) or N-methyl-D-aspartate receptor (P=0.74) post-synaptic signalling gene sets previously implicated in schizophrenia. Enrichment of ADHD CNV hits for genes impacted by autism de novo SNVs (P=0.019 for non-synonymous SNV genes) did not survive Bonferroni correction. Hypothesis-free testing yielded several highly significantly enriched biological pathways, including ion channel pathways. Enrichment findings were robust to multiple testing corrections and to sensitivity analyses that excluded the most significant sample. The findings reveal that CNVs in ADHD converge on biologically meaningful gene clusters, including ones now established as conferring risk of other neurodevelopmental disorders.

[Practice relevant research in biological psychiatry]. / Praxisrelevante Forschung in der biologischen Psychiatrie.

The practice of psychiatry would be unthinkable without modern psychopharmacology. Drug treatment, especially of severe psychiatric disorders, is often a precondition of community participation, societal reintegration and recovery. Seen in this context it is understandable that biological psychiatry has long been primarily defined by its close interconnection with psychopharmacology and has been perceived this way by practicing physicians. In recent years, however, the concept of what is "biological" has markedly expanded and so has the outreach of this approach into the practice of psychiatry. This article discusses examples showing that biological research methods provide new impulses for individualized medicine, psychotherapy and understanding environmental risks and therefore provide the basis for a preemptive and preventive approach that will be the key to master the challenges posed by the severe burden of mental illness.

World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Schizophrenia. Part 3: Update 2015 Management of special circumstances: Depression, Suicidality, substance use disorders and pregnancy and lactation.

These updated guidelines are based on the first edition of the World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of schizophrenia published in the years 2005 and 2006. For this 2015 revision, all available publications pertaining to the biological treatment of schizophrenia were reviewed systematically to allow for an evidence-based update. These guidelines provide evidence-based practice recommendations which are clinically and scientifically relevant. They are intended to be used by all physicians diagnosing and treating patients with schizophrenia. Based on the first version of these guidelines a systematic review, as well as a data extraction from national guidelines have been performed for this update. The identified literature was evaluated with respect to the strength of evidence for its efficacy and subsequently categorised into six levels of evidence (A-F) and five levels of recommendation (1-5). This third part of the updated guidelines covers the management of the following specific treatment circumstances: comorbid depression, suicidality, various comorbid substance use disorders (legal and illegal drugs), and pregnancy and lactation. These guidelines are primarily concerned with the biological treatment (including antipsychotic medication and other pharmacological treatment options) of patients with schizophrenia.

From psychiatric disorders to animal models: a bidirectional and dimensional approach.

Psychiatric genetics research is bidirectional in nature, with human and animal studies becoming more closely integrated as techniques for genetic manipulations allow for more subtle exploration of disease phenotypes. This synergy highlights the importance of considering the way in which we approach the genotype-phenotype relationship. In particular, the nosologic divide of psychiatric illness, although clinically relevant, is not directly translatable in animal models. For instance, mice will never fully recapitulate the broad criteria for many psychiatric disorders; additionally, mice will never have guilty ruminations, suicidal thoughts, or rapid speech. Instead, animal models have been and continue to provide a means to explore dimensions of psychiatric disorders to identify neural circuits and mechanisms underlying disease-relevant phenotypes. The genetic investigation of psychiatric illness can yield the greatest insights if efforts continue to identify and use biologically valid phenotypes across species. This review discusses the progress to date and the future efforts that will enhance translation between human and animal studies, including the identification of intermediate phenotypes that can be studied across species and the importance of refined modeling of human disease-associated genetic variation in mice and other animal models.

Convergence of advances in genomics, team science, and repositories as drivers of progress in psychiatric genomics.

After many years of unfilled promise, psychiatric genetics has seen an unprecedented number of successes in recent years. We hypothesize that the field has reached an inflection point through a confluence of four key developments: advances in genomics; the orientation of the scientific community around large collaborative team science projects; the development of sample and data repositories; and a policy framework for sharing and accessing these resources. We discuss these domains and their effect on scientific progress and provide a perspective on why we think this is only the beginning of a new era in scientific discovery.

World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of schizophrenia, part 2: update 2012 on the long-term treatment of schizophrenia and management of antipsychotic-induced side effects.

Abstract These updated guidelines are based on a first edition of the World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of schizophrenia published in 2006. For this 2012 revision, all available publications pertaining to the biological treatment of schizophrenia were reviewed systematically to allow for an evidence-based update. These guidelines provide evidence-based practice recommendations that are clinically and scientifically meaningful. They are intended to be used by all physicians diagnosing and treating people suffering from schizophrenia. Based on the first version of these guidelines, a systematic review of the MEDLINE/PUBMED database and the Cochrane Library, in addition to data extraction from national treatment guidelines, has been performed for this update. The identified literature was evaluated with respect to the strength of evidence for its efficacy and then categorised into six levels of evidence (A-F) and five levels of recommendation (1-5) ( Bandelow et al. 2008a ,b, World J Biol Psychiatry 9:242, see Table 1 ). This second part of the updated guidelines covers long-term treatment as well as the management of relevant side effects. These guidelines are primarily concerned with the biological treatment (including antipsychotic medication and other pharmacological treatment options) of adults suffering from schizophrenia.