Genomic Psychiatry Early Online Release

Introduction

Two articles in the current issue of Genomic Psychiatry present an interesting story spanning over a century of mental health research. Kendler and Justis carefully translate and analyze the 1897 monograph “La Mélancolie” by Roubinovitch and Toulouse (1). Meanwhile, Serretti et al. employ polygenic score analysis, showing that the genetic liability for C-reactive protein (CRP) associates with depression phenotypes and treatment outcomes (2). This gap in time, from 19^th-century phenomenology to 21^st-century genomics, illustrates the significant progress made in psychiatric science and the enduring relevance of specific clinical observations.

Inflammation has been implicated in the pathophysiology of major depressive disorder (MDD), with elevated serum C-reactive protein (CRP) and CRP polygenic scores (PGSs) previously associated with atypical symptoms and treatment outcomes. However, few studies have examined genetic CRP liability in relation to both depressive symptom profiles and pharmacological response within the same patient cohort. We investigated 1059 Caucasian patients with MDD from the European Group for the Study of Resistant Depression (GSRD) who received ≥ 4 weeks of antidepressant treatment. Depression severity was measured using Montgomery–Åsberg Depression Rating Scale (MADRS), with patients categorized as responders, nonresponders, or treatment-resistant cases. CRP-PGS were computed from individual-level genotypes using L1-penalized regression weights (snpnet) based on UK Biobank Genome‐wide association studies (GWAS) training data (n = 223,327), and scores were standardized. Associations were tested through univariable and multivariable models controlling for population stratification and established prognostic variables. Higher CRP-PGS correlated with greater body mass index, lower employment status, and less weight and appetite loss following treatment. Notably, CRP-PGS demonstrated significant differences between treatment outcome groups (F = 3.52, p = 0.03), with highest values observed in treatment-resistant patients yet also elevated among responders compared to nonresponders, indicating a nonlinear relationship. When controlling for age, episode frequency, suicidal ideation, anxiety comorbidity, employment status, functional disability scores, antipsychotic comedication, illness duration, and previous antidepressant trials, CRP-PGS retained an independent and stronger association with treatment outcome (F = 7.69, p < 0.001), with CRP-PGS accounting for an additional 1.9% of outcome variance. CRP-related genetic liability may delineate an immunometabolic subtype of MDD characterized by metabolic dysregulation, which may modestly influence therapeutic efficacy. CRP-PGS captures independent prognostic information beyond conventional staging approaches and may facilitate inflammation-guided treatment selection.

Cognitive function and longevity are phenotypically and genetically correlated. Whereas molecular genetic data have been used to show that adult cognitive function is genetically correlated with longevity, no such analysis has examined the association between childhood cognitive function and longevity. Using genome-wide association study data on childhood cognitive function (n = 12,441) and on parental longevity (n = 389,166) we found a positive genetic correlation of r_g = 0.35 (SE = 0.14, P = 0.01) between childhood cognitive function and parental longevity. These results add to the weight of evidence that the phenotypic link between childhood cognitive function and longevity is partly accounted for by shared genetic etiology.

Bruce M. Cohen, MD, PhD, stands as one of psychiatry's most innovative research leaders, transforming our understanding of neuropsychiatric disorders through groundbreaking multidisciplinary approaches at McLean Hospital and Harvard Medical School. As Robertson-Steele Professor of Psychiatry at Harvard and Director of the Program for Neuropsychiatric Research at McLean Hospital, Dr. Cohen has pioneered revolutionary techniques combining brain imaging, genomics, and induced pluripotent stem cell models to unlock the complex biological mechanisms underlying schizophrenia, bipolar disorder, and Alzheimer's disease. With over 400 peer-reviewed publications and five awarded patents spanning nearly five decades at McLean, his discoveries in mitochondrial dysfunction and energy metabolism abnormalities have opened unprecedented therapeutic pathways. His laboratory's cutting-edge ability to grow brain cells from patient samples represents what he describes as technology "giving us leads we did not have forty years ago." Named Psychiatrist of the Year twice by the National Alliance on Mental Illness of Massachusetts, Dr. Cohen's impact extends beyond research to institutional transformation. As McLean's President from 1997 to 2005, he reversed the hospital's financial decline, establishing over 30 new programs while achieving record levels of patient care, research funding, and educational training. His current work challenges century-old psychiatric diagnostic models with evidence-based dimensional approaches that better capture the complexity of mental illness. In this comprehensive Genomic Press Interview, Dr. Cohen shares insights from his remarkable journey from molecular genetics at MIT and Case Western to becoming a leading voice advocating for the replacement of stigmatizing terms like "schizophrenia" with scientifically accurate alternatives, while revealing the personal experiences and intellectual curiosity that have driven his dedication to understanding and treating the most challenging neuropsychiatric conditions.

Exercise mitigates the effects of a cafeteria diet on antidepressant-like behavior associated with plasma and microbial metabolites in adult male rats

Minke H.C. Nota,

Sarah Nicolas,

Sebastian Dohm-Hansen,

Erin P. Harris,

Tara Foley,

Olivia F. O'Leary, and

Yvonne M. Nolan

From melancholia to molecular mechanisms: Bridging centuries of understanding depression

Introduction

Polygenic liability to C-reactive protein defines immunometabolic depression phenotypes and influences antidepressant therapeutic outcomes

Shared genetic etiology between childhood cognitive function and longevity

Bruce M. Cohen: An eclectic life and a multidisciplinary approach to the complex determinants and diverse presentations of psychiatric disorders

Najaf Amin: Rare coding genetic variation and downstream omics hold the key to understanding the pathogenesis of depression

Martin Alda: Deciphering heterogeneity: The key to personalized psychiatry

Gerhard Andersson: Innovating psychotherapy research by using the internet

Oliver Pain: Bringing together functional and statistical genomics to enhance personalised medicine for neuropsychiatric disorders

Miguel E. Rentería: At the intersection of genomics, neuroscience, and big data

Alexander W. Charney: Leveraging genomics to advance the treatment of mental illness

Mateus Vidigal de Castro: Cellular and genetic determinants of healthy aging and disease resilience

Mirko Manchia: Exploring the biological landscape of psychiatric disorders to innovate clinical management with precision medicine approaches

Eric Sun: Understanding brain aging at spatial and single-cell resolution with machine learning

Barbara Franke: Understanding the biological pathways from genes to altered behaviour in neurodevelopmental conditions like ADHD – paving the way for improved understanding and care in psychiatry

Prader-Willi syndrome: Genetics, clinical symptoms, and model systems

The salience network is functionally twice as large in depression: The first depression biomarker?

Yehezkel Ben-Ari: The Neuroarcheology concept: From brain development to predicting, understanding, and treating brain disorders

Michael Meaney: What is the biology that underlies the gene x environment interdependence that shapes brain health?

Peter Falkai: In order to understand the neurobiological origins of psychoses we need to understand the genetic underpinnings of brain plasticity and its modulation due to environmental risk factors

The descriptive psychopathology of melancholia in Roubinovitch and Toulouse's 1897 monograph “La Mélancolie”

Exercise mitigates the effects of a cafeteria diet on antidepressant-like behavior associated with plasma and microbial metabolites in adult male rats

From melancholia to molecular mechanisms: Bridging centuries of understanding depression

Shared genetic etiology between childhood cognitive function and longevity

Polygenic liability to C-reactive protein defines immunometabolic depression phenotypes and influences antidepressant therapeutic outcomes

Psychedelics and time: Exploring altered temporal perception and its implications for consciousness, neuroscience, and therapy

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Table of Contents

Yogesh Dwivedi: Pre-clinical and translational research focusing on gene regulation through epigenetic and epitranscriptomic mechanisms and their implications in mood disorders and suicidal behavior

Real-world implications of the prospects for prevention of clinical Alzheimer's dementia

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