John H. Krystal’s research while affiliated with Yale University and other places

Deficits in working memory (WM) are a hallmark of neuropsychiatric disorders such as schizophrenia, yet their neurobiological basis remains poorly understood. Glutamate N-methyl-D-aspartate receptors (NMDARs) are critical for spatial WM (sWM), with NMDAR antagonist ketamine known to attenuate task-evoked activation and reduce sWM accuracy. Cortical microcircuit models hypothesize that NMDAR antagonism impairs sWM by broadening neural spatial tuning, but this mechanism has not been directly tested in humans. Using a pharmacological fMRI approach, we showed how ketamine broadened neural spatial tuning, attenuated activation across visual, parietal, and frontal areas, and worsened sWM performance in healthy humans. Ketamine-induced changes in tuning were more consistent across individuals and brain regions than changes in overall activation and correlated with individual differences in sWM performance. These findings provide empirical evidence linking NMDAR antagonism to disruptions in cortical microcircuit dynamics, the resulting neural tuning alterations, and sWM impairments, advancing frameworks for therapeutic development.

Objective: The authors critically examine the evidence base for psilocybin administered with psychological support/therapy (PST) in the treatment of psychiatric disorders and offer practical recommendations to guide future research endeavors. Methods: PubMed was searched for English-language articles from January 1998 to November 2023, using the search term "psilocybin." A total of 1,449 articles were identified and screened through titles and abstracts. Of these, 21 unique open-label or randomized controlled trials (RCTs) were identified that examine psilocybin for the treatment of obsessive-compulsive and related disorders (N=2), anxiety/depression associated with a cancer diagnosis (N=5), major depressive disorder (MDD; N=8), substance use disorders (N=4), anorexia (N=1), and demoralization (i.e., hopelessness, helplessness, and poor coping) in AIDS survivors (N=1). Results: The most developed evidence base is for the treatment of MDD (three double-blind RCTs with positive signals spanning a range of severities). However, the evidence is tempered by threats to internal and external validity, including unsuccessful blinding, small samples, large variability in dosing and PST procedures, limited sample diversity, and possibly large expectancy effects. Knowledge of mechanisms of action and predictors of response is currently limited. Conclusions: The evidence is currently insufficient to recommend psilocybin with PST as a psychiatric treatment. Additional rigorously designed clinical trials are needed to definitively establish efficacy in larger and more diverse samples, address dosing considerations, improve blinding, and provide information on mechanisms of action and moderators of clinical response. Head-to-head comparisons with other evidence-based treatments will better inform the potential future role of psilocybin with PST in the treatment of major psychiatric disorders.

These are exciting times for psychiatry and clinical neuroscience. Our knowledge of basic brain function continues to increase at an accelerating pace as the experimental tools available to basic and clinical scientists become ever more powerful and penetrating. After decades of frustration and relatively slow progress, this explosion of knowledge of the brain is at long last beginning to define the etiology and pathophysiology of complex neuropsychiatric disorders that have long defied biological explanations, which in turn is being translated into clinical advances in diagnosis and treatment of an increasing number of these illnesses. This new, sixth edition of Neurobiology of Mental Illness addresses these challenging, yet very promising, times and reflects the continuing reintegration of psychiatry into the mainstream of biomedical science and the increasing synthesis of psychiatry and neurology into a fully integrated clinical neuroscience.

These are exciting times for psychiatry and clinical neuroscience. Our knowledge of basic brain function continues to increase at an accelerating pace as the experimental tools available to basic and clinical scientists become ever more powerful and penetrating. After decades of frustration and relatively slow progress, this explosion of knowledge of the brain is at long last beginning to define the etiology and pathophysiology of complex neuropsychiatric disorders that have long defied biological explanations, which in turn is being translated into clinical advances in diagnosis and treatment of an increasing number of these illnesses. This new, sixth edition of Neurobiology of Mental Illness addresses these challenging, yet very promising, times and reflects the continuing reintegration of psychiatry into the mainstream of biomedical science and the increasing synthesis of psychiatry and neurology into a fully integrated clinical neuroscience.

This critical review summarizes the current state of omics‐based biomarkers in the alcohol research field. We first provide definitions and background information on alcohol and alcohol use disorder (AUD), biomarkers, and “omic” technologies. We next summarize using (1) genetic information as risk/prognostic biomarkers for the onset of alcohol‐related problems and the progression from regular drinking to problematic drinking (including AUD), (2) epigenetic information as diagnostic biomarkers for AUD and risk biomarkers for alcohol consumption, (3) transcriptomic information as diagnostic biomarkers for AUD, risk biomarkers for alcohol consumption, and (4) metabolomic information as diagnostic biomarkers for AUD, risk biomarkers for alcohol consumption, and predictive biomarkers for response to acamprosate in subjects with AUD. In the final section, the clinical implications of the findings are discussed, and recommendations are made for future research.

This cross-sectional study uses data from 1135 male, European-American US military veterans to assess whether risk and protective factors influenced associations between posttraumatic stress disorder and epigenetic age.