当前期刊: American Journal of Psychiatry Go to current issue    加入关注   
显示样式:        排序: 导出
我的关注
我的收藏
您暂时未登录!
登录
  • Reproducible Genetic Risk Loci for Anxiety: Results From ∼200,000 Participants in the Million Veteran Program
    Am. J. Psychiatry (IF 13.655) Pub Date : 2020-01-07
    Daniel F. Levey; Joel Gelernter; Renato Polimanti; Hang Zhou; Zhongshan Cheng; Mihaela Aslan; Rachel Quaden; John Concato; Krishnan Radhakrishnan; Julien Bryois; Patrick F. Sullivan; the Million Veteran Program; Murray B. Stein

    Objective: Anxiety disorders are common and often disabling. The goal of this study was to examine the genetic architecture of anxiety disorders and anxiety symptoms, which are also frequently comorbid with other mental disorders, such as major depressive disorder. Methods: Using one of the world’s largest biobanks including genetic, environmental, and medical information, the Million Veteran Program, the authors performed a genome-wide association study (GWAS) of a continuous trait for anxiety (based on score on the Generalized Anxiety Disorder 2-item scale [GAD-2], N=199,611) as the primary analysis and self-report of physician diagnosis of anxiety disorder (N=224,330) as a secondary analysis. Results: The authors identified five genome-wide significant signals for European Americans and one for African Americans on GAD-2 score. The strongest were on chromosome 3 (rs4603973) near SATB1, a global regulator of gene expression, and on chromosome 6 (rs6557168) near ESR1, which encodes an estrogen receptor. The locus identified on chromosome 7 (rs56226325, MAF=0.17) near MAD1L1 was previously identified in GWASs of bipolar disorder and schizophrenia. The authors replicated these findings in the summary statistics of two major published GWASs for anxiety, and also found evidence of significant genetic correlation between the GAD-2 score results and previous GWASs for anxiety (rg=0.75), depression (rg=0.81), and neuroticism (rg=0.75). Conclusions: This is the largest GWAS of anxiety traits to date. The authors identified novel genome-wide significant associations near genes involved with global regulation of gene expression (SATB1) and the estrogen receptor alpha (ESR1). Additionally, the authors identified a locus (MAD1L1) that may have implications for genetic vulnerability across several psychiatric disorders. This work provides new insights into genetic risk mechanisms underpinning anxiety and related psychiatric disorders.

    更新日期:2020-01-07
  • A Population-Based Cohort Study Examining the Incidence and Impact of Psychotic Experiences From Childhood to Adulthood, and Prediction of Psychotic Disorder
    Am. J. Psychiatry (IF 13.655) Pub Date : 2020-01-07
    Sarah A. Sullivan; Daphne Kounali; Mary Cannon; Anthony S. David; Paul C. Fletcher; Peter Holmans; Hannah Jones; Peter B. Jones; David E.J. Linden; Glyn Lewis; Michael J. Owen; Michael O’Donovan; Alexandros Rammos; Andrew Thompson; Dieter Wolke; Jon Heron; Stanley Zammit

    Objective: The authors investigated the incidence, course, and outcome of psychotic experiences from childhood through early adulthood in the general population and examined prediction of psychotic disorder. Methods: This was a population-based cohort study using the semistructured Psychosis-Like Symptoms Interview at ages 12, 18, and 24 (N=7,900 with any data). Incidence rates were estimated using flexible parametric modeling, and positive predictive values (PPVs), sensitivity, specificity, and area under the curve were estimated for prediction. Results: The incidence rate of psychotic experiences increased between ages 13 and 24, peaking during late adolescence. Of 3,866 participants interviewed at age 24, 313 (8.1%, 95% CI=7.2, 9.0) had a definite psychotic experience since age 12. A total of 109 individuals (2.8%) met criteria for a psychotic disorder up to age 24, of whom 70% had sought professional help. Prediction of current psychotic disorder at age 24 (N=47, 1.2%), by both self-report and interviewer-rated measures of psychotic experiences at age 18 (PPVs, 2.9% and 10.0%, respectively), was improved by incorporating information on frequency and distress (PPVs, 13.3% and 20.0%, respectively), although sensitivities were low. The PPV of an at-risk mental state at age 18 predicting incident disorder at ages 18–24 was 21.1% (95% CI=6.1, 45.6) (sensitivity, 14.3%, 95% CI=4.0, 32.7). Conclusions: The study results show a peak in incidence of psychotic experiences during late adolescence as well as an unmet need for care in young people with psychotic disorders. Because of the low sensitivity, targeting individuals in non-help-seeking samples based only on more severe symptom cutoff thresholds will likely have little impact on population levels of first-episode psychosis.

    更新日期:2020-01-07
  • Efficacy of Deep Brain Stimulation of the Ventral Anterior Limb of the Internal Capsule for Refractory Obsessive-Compulsive Disorder: A Clinical Cohort of 70 Patients
    Am. J. Psychiatry (IF 13.655) Pub Date : 2020-01-07
    Damiaan Denys; Ilse Graat; Roel Mocking; Pelle de Koning; Nienke Vulink; Martijn Figee; Pieter Ooms; Mariska Mantione; Pepijn van den Munckhof; Rick Schuurman

    Objective: Deep brain stimulation (DBS) is an effective treatment option for patients with refractory obsessive-compulsive disorder (OCD). However, clinical experience with DBS for OCD remains limited. The authors examined the tolerability and effectiveness of DBS in an open study of patients with refractory OCD. Methods: Seventy consecutive patients, including 16 patients from a previous trial, received bilateral DBS of the ventral anterior limb of the internal capsule (vALIC) between April 2005 and October 2017 and were followed for 12 months. Primary effectiveness was assessed by the change in scores on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) from baseline until the 12-month follow-up. Response was defined by a ≥35% decrease in Y-BOCS score, partial response was defined by a 25%−34% decrease, and nonresponse was defined by a <25% decrease. Secondary effectiveness measures were the Hamilton Anxiety Rating Scale (HAM-A) and the Hamilton Depression Rating Scale (HAM-D). Results: Y-BOCS, HAM-A, and HAM-D scores all decreased significantly during the first 12 months of DBS. Twelve months of DBS resulted in a mean Y-BOCS score decrease of 13.5 points (SD=9.4) (40% reduction; effect size=1.5). HAM-A scores decreased by 13.4 points (SD=9.7) (55%; effect size=1.4), and HAM-D scores decreased by 11.2 points (SD=8.8) (54%; effect size=1.3). At the 12-month follow-up, 36 of the 70 patients were categorized as responders (52%), 12 patients as partial responders (17%), and 22 patients as nonresponders (31%). Adverse events included transient symptoms of hypomania, agitation, impulsivity, and sleeping disorders. Conclusions: These results confirm the effectiveness and safety of DBS of the vALIC for patients with treatment-refractory OCD in a regular clinical setting.

    更新日期:2020-01-07
  • The Devastating Clinical Consequences of Child Abuse and Neglect: Increased Disease Vulnerability and Poor Treatment Response in Mood Disorders
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-09-20
    Elizabeth T.C. Lippard; Charles B. Nemeroff

    A large body of evidence has demonstrated that exposure to childhood maltreatment at any stage of development can have long-lasting consequences. It is associated with a marked increase in risk for psychiatric and medical disorders. This review summarizes the literature investigating the effects of childhood maltreatment on disease vulnerability for mood disorders, specifically summarizing cross-sectional and more recent longitudinal studies demonstrating that childhood maltreatment is more prevalent and is associated with increased risk for first mood episode, episode recurrence, greater comorbidities, and increased risk for suicidal ideation and attempts in individuals with mood disorders. It summarizes the persistent alterations associated with childhood maltreatment, including alterations in the hypothalamic-pituitary-adrenal axis and inflammatory cytokines, which may contribute to disease vulnerability and a more pernicious disease course. The authors discuss several candidate genes and environmental factors (for example, substance use) that may alter disease vulnerability and illness course and neurobiological associations that may mediate these relationships following childhood maltreatment. Studies provide insight into modifiable mechanisms and provide direction to improve both treatment and prevention strategies.

    更新日期:2020-01-01
  • Association of Childhood Maltreatment With Interpersonal Distance and Social Touch Preferences in Adulthood
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-08-16
    Ayline Maier; Caroline Gieling; Luca Heinen-Ludwig; Vlad Stefan; Johannes Schultz; Onur Güntürkün; Benjamin Becker; René Hurlemann; Dirk Scheele

    Objective: Childhood maltreatment is a major risk factor for psychopathology associated with interpersonal problems in adulthood, but the etiological pathways involved are still unclear. The authors propose that childhood maltreatment confers risk for dysfunctional behavior in social interactions by altering interpersonal distance preference and the processing of social touch. Methods: Ninety-two medication-free adults (64 of them female) with low, medium, and high levels of childhood maltreatment were tested with an interpersonal distance paradigm and subsequently underwent a social touch functional MRI task during which they rated the perceived comfort of slow touch (C-tactile [CT] optimal speed; 5 cm/s) and fast touch (non-CT-optimal speed; 20 cm/s). Results: Participants with high childhood maltreatment levels preferred a larger interpersonal distance and experienced fast touch as less comforting compared with participants with no or moderate childhood maltreatment experiences. On the neural level, participants with severe childhood maltreatment exhibited exaggerated responses to fast touch in the right somatosensory and posterior insular cortex, which correlated with lower comfort ratings. Severe childhood maltreatment was associated with decreased activation in the right hippocampus in response to slow touch. This response pattern was not moderated or mediated by childhood maltreatment–associated region-specific reductions in gray matter volume. Conclusions: The study findings suggest that higher childhood maltreatment levels are associated with hypersensitivity characterized by a preference for larger interpersonal distance and discomfort of fast touch. These dysregulations were manifested in a sensory cortical hyperreactivity and limbic CT-related hypoactivation. These results may shed light on why individuals with severe childhood maltreatment exhibit an increased susceptibility to interpersonal dysfunctions and psychiatric disorders in adulthood.

    更新日期:2020-01-01
  • Adverse Childhood Experiences: Implications for Offspring Telomere Length and Psychopathology
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-09-06
    Kyle C. Esteves; Christopher W. Jones; Mark Wade; Keegan Callerame; Alicia K. Smith; Katherine P. Theall; Stacy S. Drury

    Objective: Adverse childhood experiences (ACEs) are associated with mental and physical health risks that, through biological and psychosocial pathways, likely span generations. Within an individual, telomere length (TL), an established marker of cellular stress and aging, is associated with both ACE exposure and psychopathology, providing the basis for an emerging literature suggesting that TL is a biomarker of the health risks linked to early-life adversity both within and across generations. The authors tested the effect of maternal ACEs on both the trajectory of infant TL and infant social-emotional problems at 18 months of age. Methods: Pregnant women were recruited, and maternal scores on the Adverse Childhood Experience questionnaire were obtained, along with demographic and prenatal stress measures. Postnatal visits with 155 mother-infant dyads occurred when infants were 4, 12, and 18 months of age. At each visit, infant buccal swabs were collected for TL measurement, and mothers completed measures of maternal depression. Mothers also completed the Child Behavior Checklist at the 18-month visit. Mixed-effects modeling was used to test how maternal ACEs influenced infant TL trajectory. Linear regression was used to test the association between maternal ACEs and infant internalizing and externalizing behaviors. Finally, the interaction between telomere attrition from 4 to 18 months and maternal ACEs was examined as a predictor of infant scores on the Child Behavior Checklist. Results: Higher maternal ACEs were associated with shorter infant TL across infancy and higher infant externalizing behavioral problems at 18 months. No associations were found with internalizing behavioral problems. Telomere attrition from 4 to 18 months interacted with maternal ACEs to predict externalizing behaviors. In infants whose mothers reported higher scores on the Adverse Childhood Experience questionnaire, greater telomere attrition predicted higher externalizing problems, even when accounting for maternal postnatal depression and prenatal stress. Conclusions: These data demonstrate an interactive pathway between maternal early-life adversity and infant TL that predicts emerging behavioral problems in the next generations.

    更新日期:2020-01-01
  • Association of Prospective Risk for Chronic PTSD Symptoms With Low TNFα and IFNγ Concentrations in the Immediate Aftermath of Trauma Exposure
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-07-29
    Vasiliki Michopoulos; Eleonore Beurel; Felicia Gould; Firdaus S. Dhabhar; Katharina Schultebraucks; Isaac Galatzer-Levy; Barbara O. Rothbaum; Kerry J. Ressler; Charles B. Nemeroff

    Objective: Although several reports have documented heightened systemic inflammation in posttraumatic stress disorder (PTSD), few studies have assessed whether inflammatory markers serve as prospective biomarkers for PTSD risk. The present study aimed to characterize whether peripheral immune factors measured in blood samples collected in an emergency department immediately after trauma exposure would predict later chronic development of PTSD. Methods: Participants (N=505) were recruited from a hospital emergency department and underwent a 1.5-hour assessment. Blood samples were drawn, on average, about 3 hours after trauma exposure. Follow-up assessments were conducted 1, 3, 6, and 12 months after trauma exposure. Latent growth mixture modeling was used to identify classes of PTSD symptom trajectories. Results: Three distinct classes of PTSD symptom trajectories were identified: chronic (N=28), resilient (N=160), and recovery (N=85). Multivariate analyses of covariance revealed a significant multivariate main effect of PTSD symptom trajectory class membership on proinflammatory cytokines. Univariate analyses showed a significant main effect of trajectory class membership on plasma concentrations of proinflammatory tumor necrosis factor α (TNFα) and interferon-γ (IFNγ). Concentrations of proinflammatory TNFα and IFNγ were significantly lower in individuals in the chronic PTSD class compared with those in the recovery and resilient classes. There were no significant differences in interleukin (IL) 1β and IL-6 concentrations by PTSD symptom trajectory class. Anti-inflammatory and other cytokines, as well as chemokines and growth factor concentrations, were not associated with development of chronic PTSD. Conclusions: Overall, the study findings suggest that assessing the proinflammatory immune response to trauma exposure immediately after trauma exposure, in the emergency department, may help identify individuals most at risk for developing chronic PTSD in the aftermath of trauma.

    更新日期:2020-01-01
  • Maternal Bacterial Infection During Pregnancy and Offspring Risk of Psychotic Disorders: Variation by Severity of Infection and Offspring Sex
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-10-04
    Younga H. Lee; Sara Cherkerzian; Larry J. Seidman; George D. Papandonatos; David A. Savitz; Ming T. Tsuang; Jill M. Goldstein; Stephen L. Buka

    Objective: Previous studies suggest that prenatal immune challenges may elevate the risk of schizophrenia and related psychoses in offspring, yet there has been limited research focused on maternal bacterial infection. The authors hypothesized that maternal bacterial infection during pregnancy increases offspring risk of psychotic disorders in adulthood, and that the magnitude of this association varies as a function of severity of infectious exposure and offspring sex. Methods: The authors analyzed prospectively collected data from 15,421 pregnancies among women enrolled between 1959 and 1966 at two study sites through the Collaborative Perinatal Project. The sample included 116 offspring with confirmed psychotic disorders. The authors estimated associations between maternal bacterial infection during pregnancy and psychosis risk over the subsequent 40 years, stratified by offspring sex and presence of reported parental mental illness, with adjustment for covariates. Results: Maternal bacterial infection during pregnancy was strongly associated with psychosis in offspring (adjusted odds ratio=1.8, 95% CI=1.2–2.7) and varied by severity of infection and offspring sex. The effect of multisystemic bacterial infection (adjusted odds ratio=2.9, 95% CI=1.3–5.9) was nearly twice that of less severe localized bacterial infection (adjusted odds ratio=1.6, 95% CI=1.1–2.3). Males were significantly more likely than females to develop psychosis after maternal exposure to any bacterial infection during pregnancy. Conclusions: The study findings suggest that maternal bacterial infection during pregnancy is associated with an elevated risk for psychotic disorders in offspring and that the association varies by infection severity and offspring sex. These findings call for additional investigation and, if the findings are replicated, public health and clinical efforts that focus on preventing and managing bacterial infection in pregnant women.

    更新日期:2020-01-01
  • Lithium Exposure During Pregnancy and the Postpartum Period: A Systematic Review and Meta-Analysis of Safety and Efficacy Outcomes
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-10-18
    Michele Fornaro; Elena Maritan; Roberta Ferranti; Leonardo Zaninotto; Alessandro Miola; Annalisa Anastasia; Andrea Murru; Eva Solé; Brendon Stubbs; André F. Carvalho; Alessandro Serretti; Eduard Vieta; Paolo Fusar-Poli; Philip McGuire; Allan H. Young; Paola Dazzan; Simone N. Vigod; Christoph U. Correll; Marco Solmi

    Objective: Uncertainty surrounds the risks of lithium use during pregnancy in women with bipolar disorder. The authors sought to provide a critical appraisal of the evidence related to the efficacy and safety of lithium treatment during the peripartum period, focusing on women with bipolar disorder and their offspring. Methods: The authors conducted a systematic review and random-effects meta-analysis assessing case-control, cohort, and interventional studies reporting on the safety (primary outcome, any congenital anomaly) or efficacy (primary outcome, mood relapse prevention) of lithium treatment during pregnancy and the postpartum period. The Newcastle-Ottawa Scale and the Cochrane risk of bias tools were used to assess the quality of available PubMed and Scopus records through October 2018. Results: Twenty-nine studies were included in the analyses (20 studies were of good quality, and six were of poor quality; one study had an unclear risk of bias, and two had a high risk of bias). Thirteen of the 29 studies could be included in the quantitative analysis. Lithium prescribed during pregnancy was associated with higher odds of any congenital anomaly (N=23,300, k=11; prevalence=4.1%, k=11; odds ratio=1.81, 95% CI=1.35–2.41; number needed to harm (NNH)=33, 95% CI=22–77) and of cardiac anomalies (N=1,348,475, k=12; prevalence=1.2%, k=9; odds ratio=1.86, 95% CI=1.16–2.96; NNH=71, 95% CI=48–167). Lithium exposure during the first trimester was associated with higher odds of spontaneous abortion (N=1,289, k=3, prevalence=8.1%; odds ratio=3.77, 95% CI=1.15–12.39; NNH=15, 95% CI=8–111). Comparing lithium-exposed with unexposed pregnancies, significance remained for any malformation (exposure during any pregnancy period or the first trimester) and cardiac malformations (exposure during the first trimester), but not for spontaneous abortion (exposure during the first trimester) and cardiac malformations (exposure during any pregnancy period). Lithium was more effective than no lithium in preventing postpartum relapse (N=48, k=2; odds ratio=0.16, 95% CI=0.03–0.89; number needed to treat=3, 95% CI=1–12). The qualitative synthesis showed that mothers with serum lithium levels <0.64 mEq/L and dosages <600 mg/day had more reactive newborns without an increased risk of cardiac malformations. Conclusions: The risk associated with lithium exposure at any time during pregnancy is low, and the risk is higher for first-trimester or higher-dosage exposure. Ideally, pregnancy should be planned during remission from bipolar disorder and lithium prescribed within the lowest therapeutic range throughout pregnancy, particularly during the first trimester and the days immediately preceding delivery, balancing the safety and efficacy profile for the individual patient.

    更新日期:2020-01-01
  • Dose-Response Meta-Analysis of Antipsychotic Drugs for Acute Schizophrenia
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-12-16
    Stefan Leucht; Alessio Crippa; Spyridon Siafis; Maxine X. Patel; Nicola Orsini; John M. Davis

    Objective: The dose-response relationships of antipsychotic drugs for schizophrenia are not well defined, but such information would be important for decision making by clinicians. The authors sought to fill this gap by conducting dose-response meta-analyses. Methods: A search of multiple electronic databases (through November 2018) was conducted for all placebo-controlled dose-finding studies for 20 second-generation antipsychotic drugs and haloperidol (oral and long-acting injectable, LAI) in people with acute schizophrenia symptoms. Dose-response curves were constructed with random-effects dose-response meta-analyses and a spline model. The outcome measure was total score reduction from baseline on the Positive and Negative Syndrome Scale or the Brief Psychiatric Rating Scale. The authors identified 95% effective doses, explored whether higher or lower doses than the currently licensed ones might be more appropriate, and derived dose equivalencies from the 95% effective doses. Results: Sixty-eight studies met the inclusion criteria. The 95% effective doses and the doses equivalent to 1 mg of oral risperidone, respectively, were as follows: amisulpride for patients with positive symptoms, 537 mg/day and 85.8 mg; aripiprazole, 11.5 mg/day and 1.8 mg; aripiprazole LAI (lauroxil), 463 mg every 4 weeks and 264 mg; asenapine, 15.0 mg/day and 2.4 mg; brexpiprazole, 3.36 mg/day and 0.54 mg; haloperidol, 6.3 mg/day and 1.01 mg; iloperidone, 20.13 mg/day and 3.2 mg; lurasidone, 147 mg/day and 23.5 mg; olanzapine, 15.2 mg/day and 2.4 mg; olanzapine LAI, 277 mg every 2 weeks and 3.2 mg; paliperidone, 13.4 mg/day and 2.1 mg; paliperidone LAI, 120 mg every 4 weeks and 1.53 mg; quetiapine, 482 mg/day and 77 mg; risperidone, 6.3 mg/day and 1 mg; risperidone LAI, 36.6 mg every 2 weeks and 0.42 mg; sertindole, 22.5 mg/day and 3.6 mg; and ziprasidone, 186 mg/day and 30 mg. For amisulpride and olanzapine, specific data for patients with predominant negative symptoms were available. The authors have made available on their web site a spreadsheet with this method and other updated methods that can be used to estimate dose equivalencies in practice. Conclusions: In chronic schizophrenia patients with acute exacerbations, doses higher than the identified 95% effective doses may on average not provide more efficacy. For some drugs, higher than currently licensed doses might be tested in further trials, because their dose-response curves did not plateau.

    更新日期:2019-12-17
  • Individual Patterns of Abnormality in Resting-State Functional Connectivity Reveal Two Data-Driven PTSD Subgroups
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-12-16
    Adi Maron-Katz; Yu Zhang; Manjari Narayan; Wei Wu; Russell T. Toll; Sharon Naparstek; Carlo De Los Angeles; Parker Longwell; Emmanuel Shpigel; Jennifer Newman; Duna Abu-Amara; Charles Marmar; Amit Etkin

    Objective: A major challenge in understanding and treating posttraumatic stress disorder (PTSD) is its clinical heterogeneity, which is likely determined by various neurobiological perturbations. This heterogeneity likely also reduces the effectiveness of standard group comparison approaches. The authors tested whether a statistical approach aimed at identifying individual-level neuroimaging abnormalities that are more prevalent in case subjects than in control subjects could reveal new clinically meaningful insights into the heterogeneity of PTSD. Methods: Resting-state functional MRI data were recorded from 87 unmedicated PTSD case subjects and 105 war zone–exposed healthy control subjects. Abnormalities were modeled using tolerance intervals, which referenced the distribution of healthy control subjects as the “normative population.” Out-of-norm functional connectivity values were examined for enrichment in cases and then used in a clustering analysis to identify biologically defined PTSD subgroups based on their abnormality profiles. Results: The authors identified two subgroups among PTSD cases, each with a distinct pattern of functional connectivity abnormalities with respect to healthy control subjects. Subgroups differed clinically on levels of reexperiencing symptoms and improved case-control discriminability and were detectable using independently recorded resting-state EEG data. Conclusions: The results provide proof of concept for the utility of abnormality-based approaches for studying heterogeneity within clinical populations. Such approaches, applied not only to neuroimaging data, may allow detection of subpopulations with distinct biological signatures so that further clinical and mechanistic investigations can be focused on more biologically homogeneous subgroups.

    更新日期:2019-12-17
  • Effect of CBT on Biased Semantic Network in Panic Disorder: A Multicenter fMRI Study Using Semantic Priming
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-12-16
    Yunbo Yang; Ulrike Lueken; Jan Richter; Alfons Hamm; André Wittmann; Carsten Konrad; Andreas Ströhle; Bettina Pfleiderer; Martin J. Herrmann; Thomas Lang; Martin Lotze; Jürgen Deckert; Volker Arolt; Hans-Ulrich Wittchen; Benjamin Straube; Tilo Kircher

    Objective: Cognitive-behavioral therapy (CBT) has been hypothesized to act by reducing the pathologically enhanced semantic, anxiety-related associations of patients with panic disorder. This study investigated the effects of CBT on the behavioral and neural correlates of the panic-related semantic network in patients with panic disorder. Methods: An automatic semantic priming paradigm specifically tailored for panic disorder, in which panic symptoms (e.g., “dizziness”) were primed by panic triggers (e.g., “elevator”) compared with neutral words (e.g., “bottle”), was performed during functional MRI scanning with 118 patients with panic disorder (compared with 150 healthy control subjects) before and 42 patients (compared with 52 healthy control subjects) after an exposure-based CBT. Neural correlates were investigated by comparing 103 pairs of matched patients and control subjects at the baseline (for patients) or T1 (for control subjects) assessment and 39 pairs at the posttreatment or T2 assessment. Results: At baseline or T1, patients rated panic-trigger/panic-symptom word pairs with higher relatedness and higher negative valence compared with healthy control subjects. Patients made faster lexical decisions to the panic-symptom words when they were preceded by panic-trigger words. This panic-priming effect in patients (compared with control subjects) was reflected in suppressed neural activation in the left and right temporal cortices and insulae and enhanced activation in the posterior and anterior cingulate cortices. After CBT, significant clinical improvements in the patient group were observed along with a reduction in relatedness and negative valence rating and attenuation of neural activation in the anterior cingulate cortex for processing of panic-trigger/panic-symptom word pairs. Conclusions: The findings support a biased semantic network in panic disorder, which is normalized after CBT. Attenuation of anterior cingulate cortex activation for processing of panic-related associations provides a potential mechanism for future therapeutic interventions.

    更新日期:2019-12-17
  • Distinct Polygenic Score Profiles in Schizophrenia Subgroups With Different Trajectories of Cognitive Development
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-12-16
    Dwight Dickinson; Sofia R. Zaidman; Evan J. Giangrande; Daniel P. Eisenberg; Michael D. Gregory; Karen F. Berman

    Objective: Different cognitive development histories in schizophrenia may reflect variation across dimensions of genetic influence. The authors derived and characterized cognitive development trajectory subgroups within a schizophrenia sample and profiled the subgroups across polygenic scores (PGSs) for schizophrenia, cognition, educational attainment, and attention deficit hyperactivity disorder (ADHD). Methods: Demographic, clinical, and genetic data were collected at the National Institute of Mental Health from 540 schizophrenia patients, 247 unaffected siblings, and 844 control subjects. Cognitive trajectory subgroups were derived through cluster analysis using estimates of premorbid and current IQ. PGSs were generated using standard methods. Associations were tested using general linear models and logistic regression. Results: Cluster analyses identified three cognitive trajectory subgroups in the schizophrenia group: preadolescent cognitive impairment (19%), adolescent disruption of cognitive development (44%), and cognitively stable adolescent development (37%). Together, the four PGSs significantly predicted 7.9% of the variance in subgroup membership. Subgroup characteristics converged with genetic patterns. Cognitively stable individuals had the best adult clinical outcomes and differed from control subjects only in schizophrenia PGSs. Those with adolescent disruption of cognitive development showed the most severe symptoms after diagnosis and were cognitively impaired. This subgroup had the highest schizophrenia PGSs and had disadvantageous cognitive PGSs relative to control subjects and cognitively stable individuals. Individuals showing preadolescent impairment in cognitive and academic performance and poor adult outcome exhibited a generalized PGS disadvantage relative to control subjects and were the only subgroup to differ significantly in education and ADHD PGSs. Conclusions: Subgroups derived from patterns of premorbid and current IQ showed different premorbid and clinical characteristics, which converged with broad genetic profiles. Simultaneous analysis of multiple PGSs may contribute to useful clinical stratification in schizophrenia.

    更新日期:2019-12-17
  • Acute Care, Prescription Opioid Use, and Overdose Following Discontinuation of Long-Term Buprenorphine Treatment for Opioid Use Disorder
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-12-02
    Arthur Robin Williams; Hillary Samples; Stephen Crystal; Mark Olfson

    Objective: Although buprenorphine treatment reduces risk of overdose and death in opioid use disorder, most patients discontinue treatment within a few weeks or months. Adverse health outcomes following buprenorphine discontinuation were compared among patients who were successfully retained beyond 6 months of continuous treatment, a minimum treatment duration recently endorsed by the National Quality Forum. Methods: A retrospective longitudinal cohort analysis was performed using the MarketScan multistate Medicaid claims database (2013–2017), covering 12 million beneficiaries annually. The sample included adults (18–64 years of age) who received buprenorphine continuously for ≥180 days by cohorts retained for 6–9 months, 9–12 months, 12–15 months, and 15–18 months. For outcome assessment in the postdiscontinuation period, patients had to be continuously enrolled in Medicaid for 6 months after buprenorphine discontinuation. Primary adverse outcomes included all-cause emergency department visits, all-cause inpatient hospitalizations, opioid prescriptions, and drug overdose (opioid or non-opioid). Results: Adverse events were common across all cohorts, and almost half of patients (42.1%−49.9%) were seen in the emergency department at least once. Compared with patients retained on buprenorphine for 6–9 months (N=4,126), those retained for 15–18 months (N=931) had significantly lower odds of emergency department visits (odds ratio=0.75, 95% CI=0.65–0.86), inpatient hospitalizations (odds ratio=0.79, 95% CI=0.64–0.99), and filling opioid prescriptions (odds ratio=0.67, 95% CI=0.56–0.80) in the 6 months following discontinuation. Approximately 5% of patients across all cohorts experienced one or more medically treated overdoses. Conclusions: Risk of acute care service use and overdose were high following buprenorphine discontinuation irrespective of treatment duration. Superior outcomes became significant with treatment duration beyond 15 months, although rates of the primary adverse outcomes remained high.

    更新日期:2019-12-02
  • A Single Ketamine Infusion Combined With Motivational Enhancement Therapy for Alcohol Use Disorder: A Randomized Midazolam-Controlled Pilot Trial
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-12-02
    Elias Dakwar; Frances Levin; Carl L. Hart; Cale Basaraba; Jean Choi; Martina Pavlicova; Edward V. Nunes

    Objective: Pharmacotherapy and behavioral treatments for alcohol use disorder are limited in their effectiveness, and new treatments with innovative mechanisms would be valuable. In this pilot study, the authors tested whether a single subanesthetic infusion of ketamine administered to adults with alcohol dependence and engaged in motivational enhancement therapy affects drinking outcomes. Methods: Participants were randomly assigned to a 52-minute intravenous administration of ketamine (0.71 mg/kg, N=17) or the active control midazolam (0.025 mg/kg, N=23), provided during the second week of a 5-week outpatient regimen of motivational enhancement therapy. Alcohol use following the infusion was assessed with timeline followback method, with abstinence confirmed by urine ethyl glucuronide testing. A longitudinal logistic mixed-effects model was used to model daily abstinence from alcohol over the 21 days after ketamine infusion. Results: Participants (N=40) were mostly middle-aged (mean age=53 years [SD=9.8]), predominantly white (70.3%), and largely employed (71.8%) and consumed an average of five drinks per day prior to entering the study. Ketamine significantly increased the likelihood of abstinence, delayed the time to relapse, and reduced the likelihood of heavy drinking days compared with midazolam. Infusions were well tolerated, with no participants removed from the study as a result of adverse events. Conclusions: A single ketamine infusion was found to improve measures of drinking in persons with alcohol dependence engaged in motivational enhancement therapy. These preliminary data suggest new directions in integrated pharmacotherapy-behavioral treatments for alcohol use disorder. Further research is needed to replicate these promising results in a larger sample.

    更新日期:2019-12-02
  • Cortico-Limbic Interactions Mediate Adaptive and Maladaptive Responses Relevant to Psychopathology
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-12-01
    Rothem Kovner; Jonathan A. Oler; Ned H. Kalin

    Cortico-limbic circuits provide a substrate for adaptive behavioral and emotional responses. However, dysfunction of these circuits can result in maladaptive responses that are associated with psychopathology. The prefrontal-limbic pathways are of particular interest because they facilitate interactions among emotion, cognition, and decision-making functions, all of which are affected in psychiatric disorders. Regulatory aspects of the prefrontal cortex (PFC) are especially relevant to human psychopathology, as the PFC, in addition to its functions, is more recent from an evolutionary perspective and is considerably more complex in human and nonhuman primates compared with other species. This review provides a neuroanatomical and functional perspective of selected regions of the limbic system, the medial temporal lobe structures—the hippocampus and amygdala as well as regions of the PFC. Beyond the specific brain regions, emphasis is placed on the structure and function of critical PFC-limbic circuits, linking alterations in the processing of information across these pathways to the pathophysiology and psychopathology of various psychiatric illnesses.

    更新日期:2019-12-02
  • Evidence for Dissociable Linkage of Dimensions of Psychopathology to Brain Structure in Youths
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-06-24
    Antonia N. Kaczkurkin; Sophia Seonyeong Park; Aristeidis Sotiras; Tyler M. Moore; Monica E. Calkins; Matthew Cieslak; Adon F.G. Rosen; Rastko Ciric; Cedric Huchuan Xia; Zaixu Cui; Anup Sharma; Daniel H. Wolf; Kosha Ruparel; Daniel S. Pine; Russell T. Shinohara; David R. Roalf; Ruben C. Gur; Christos Davatzikos; Raquel E. Gur; Theodore D. Satterthwaite

    Objective: High comorbidity among psychiatric disorders suggests that they may share underlying neurobiological deficits. Abnormalities in cortical thickness and volume have been demonstrated in clinical samples of adults, but less is known when these structural differences emerge in youths. The purpose of this study was to examine the association between dimensions of psychopathology and brain structure. Methods: The authors studied 1,394 youths who underwent brain imaging as part of the Philadelphia Neurodevelopmental Cohort. Dimensions of psychopathology were constructed using a bifactor model of symptoms. Cortical thickness and volume were quantified using high-resolution 3-T MRI. Structural covariance networks were derived using nonnegative matrix factorization and analyzed using generalized additive models with penalized splines to capture both linear and nonlinear age-related effects. Results: Fear symptoms were associated with reduced cortical thickness in most networks, and overall psychopathology was associated with globally reduced gray matter volume across all networks. Structural covariance networks predicted psychopathology symptoms above and beyond demographic characteristics and cognitive performance. Conclusions: The results suggest a dissociable relationship whereby fear is most strongly linked to reduced cortical thickness and overall psychopathology is most strongly linked to global reductions in gray matter volume. Such results have implications for understanding how abnormalities of brain development may be associated with divergent dimensions of psychopathology.

    更新日期:2019-12-02
  • Distinct Patterns of Neural Habituation and Generalization in Children and Adolescents With Autism With Low and High Sensory Overresponsivity
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-06-24
    Shulamite A. Green; Leanna Hernandez; Katherine E. Lawrence; Janelle Liu; Tawny Tsang; Jillian Yeargin; Kaitlin Cummings; Elizabeth Laugeson; Mirella Dapretto; Susan Y. Bookheimer

    Objective: Sensory overresponsivity (SOR), an atypical negative reaction to sensory stimuli, is highly prevalent in autism spectrum disorder (ASD). Previous work has related SOR to increased brain response in sensory-limbic regions. This study investigated where these atypical responses fall in three fundamental stages of sensory processing: arousal (i.e., initial response), habituation (i.e., change in response over time), and generalization of response to novel stimuli. Different areas of atypical response would require distinct intervention approaches. Methods: Functional MRI was used to examine these patterns of neural habituation to two sets of similar mildly aversive auditory and tactile stimuli in 42 high-functioning children and adolescents with ASD (21 with high levels of SOR and 21 with low levels of SOR) and 27 age-matched typically developing youths (ages 8–17). The relationship between SOR and change in amygdala-prefrontal functional connectivity across the sensory stimulation was also examined. Results: Across repeated sensory stimulation, high-SOR participants with ASD showed reduced ability to maintain habituation in the amygdala and relevant sensory cortices and to maintain inhibition of irrelevant sensory cortices. These results indicate that sensory habituation is a dynamic, time-varying process dependent on sustained regulation across time, which is a particular deficit in high-SOR participants with ASD. However, low-SOR participants with ASD also showed distinct, nontypical neural response patterns, including reduced responsiveness to novel but similar stimuli and increases in prefrontal-amygdala regulation across the sensory exposure. Conclusions: The results suggest that all children with autism have atypical brain responses to sensory stimuli, but whether they express atypical behavioral responses depends on top-down regulatory mechanisms. Results are discussed in terms of targeted intervention approaches.

    更新日期:2019-12-02
  • Limbic Hyperactivity in Response to Emotionally Neutral Stimuli in Schizophrenia: A Neuroimaging Meta-Analysis of the Hypervigilant Mind
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-09-06
    Jules R. Dugré; Nathalie Bitar; Alexandre Dumais; Stéphane Potvin

    Objective: It has long been assumed that paranoid ideation may stem from an aberrant limbic response to threatening stimuli. However, results from functional neuroimaging studies using negative emotional stimuli have failed to confirm this assumption. One of the potential reasons for the lack of effect is that study participants with psychosis may display aberrant brain responses to neutral material rather than to threatening stimuli. The authors conducted a functional neuroimaging meta-analysis to test this hypothesis. Methods: A literature search was performed with PubMed, Google Scholar, and Embase to identify functional neuroimaging studies examining brain responses to neutral material in patients with psychosis. A total of 23 studies involving schizophrenia patients were retrieved. Using t-maps of peak coordinates to calculate effect sizes, a random-effects model meta-analysis was performed with the anisotropic effect-size version of Seed-based d Mapping software. Results: In schizophrenia patients relative to healthy control subjects, increased activations were observed in the left and right amygdala and parahippocampus and the left putamen, hippocampus, and insula in response to neutral stimuli. Conclusions: Given that several limbic regions were found to be more activated in schizophrenia patients than in control subjects, the results of this meta-analysis strongly suggest that these patients confer aberrant emotional significance to nonthreatening stimuli. In theory, this abnormal brain reactivity may fuel delusional thoughts. Studies are needed in individuals at risk of psychosis to determine whether aberrant limbic reactivity to neutral stimuli is an early neurofunctional marker of psychosis vulnerability.

    更新日期:2019-12-02
  • Hyperactivity and Reduced Activation of Anterior Hippocampus in Early Psychosis
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-10-18
    Maureen McHugo; Pratik Talati; Kristan Armstrong; Simon N. Vandekar; Jennifer Urbano Blackford; Neil D. Woodward; Stephan Heckers

    Objective: In schizophrenia, the anterior hippocampus is hyperactive and shows reduced task-related recruitment, but the relationship between these two findings is unclear. The authors tested the hypothesis that hyperactivity impairs recruitment of the anterior hippocampus during scene processing. Methods: Functional MRI data from 45 early-psychosis patients and 35 demographically matched healthy control subjects were analyzed using a block-design 1-back scene-processing task. Hippocampal activation in response to scenes and faces compared with scrambled images was measured. In a subset of 20 early-psychosis patients and 31 healthy control subjects, baseline hippocampal activity using cerebral blood volume (CBV) mapping was measured. Correlation analyses were used to examine the association between baseline hippocampal activity and task-related hippocampal activation. Results: Activation of the anterior hippocampus was significantly reduced and CBV in the anterior hippocampus was significantly increased in the early stages of psychosis. Increased CBV in early-psychosis patients was inversely correlated with task-related activation during scene processing in the anterior hippocampus. Conclusions: Anterior hippocampal hyperactivity in early-psychosis patients appears to limit effective recruitment of this region during task performance. These findings provide novel support for the anterior hippocampus as a therapeutic target in the treatment of cognitive deficits in psychosis.

    更新日期:2019-12-02
  • No Alterations of Brain Structural Asymmetry in Major Depressive Disorder: An ENIGMA Consortium Analysis
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-07-29
    Carolien G.F. de Kovel; Lyubomir Aftanas; André Aleman; Aaron F. Alexander-Bloch; Bernhard T. Baune; Ivan Brack; Robin Bülow; Geraldo Busatto Filho; Angela Carballedo; Colm G. Connolly; Kathryn R. Cullen; Udo Dannlowski; Christopher G. Davey; Danai Dima; Katharina Dohm; Tracy Erwin-Grabner; Thomas Frodl; Cynthia H.Y. Fu; Geoffrey B. Hall; David C. Glahn; Beata Godlewska; Ian H. Gotlib; Roberto Goya-Maldonado; Hans Jörgen Grabe; Nynke A. Groenewold; Dominik Grotegerd; Oliver Gruber; Mathew A. Harris; Ben J. Harrison; Sean N. Hatton; Ian B. Hickie; Tiffany C. Ho; Neda Jahanshad; Tilo Kircher; Bernd Krämer; Axel Krug; Jim Lagopoulos; Elisabeth J. Leehr; Meng Li; Frank P. MacMaster; Glenda MacQueen; Andrew M. McIntosh; Quinn McLellan; Sarah E. Medland; Bryon A. Mueller; Igor Nenadic; Evgeny Osipov; Martina Papmeyer; Maria J. Portella; Liesbeth Reneman; Pedro G.P. Rosa; Matthew D. Sacchet; Knut Schnell; Anouk Schrantee; Kang Sim; Egle Simulionyte; Lisa Sindermann; Aditya Singh; Dan J. Stein; Benjamin N. Ubani; Nic J.A. Van der Wee; Steven J.A. Van der Werff; Ilya M. Veer; Yolanda Vives-Gilabert; Henry Völzke; Henrik Walter; Martin Walter; Melinda Westlund Schreiner; Heather Whalley; Nils Winter; Katharina Wittfeld; Tony T. Yang; Dilara Yüksel; Dario Zaremba; Paul M. Thompson; Dick J. Veltman; Lianne Schmaal; Clyde Francks

    Objective: Asymmetry is a subtle but pervasive aspect of the human brain, and it may be altered in several psychiatric conditions. MRI studies have shown subtle differences of brain anatomy between people with major depressive disorder and healthy control subjects, but few studies have specifically examined brain anatomical asymmetry in relation to this disorder, and results from those studies have remained inconclusive. At the functional level, some electroencephalography studies have indicated left fronto-cortical hypoactivity and right parietal hypoactivity in depressive disorders, so aspects of lateralized anatomy may also be affected. The authors used pooled individual-level data from data sets collected around the world to investigate differences in laterality in measures of cortical thickness, cortical surface area, and subcortical volume between individuals with major depression and healthy control subjects. Methods: The authors investigated differences in the laterality of thickness and surface area measures of 34 cerebral cortical regions in 2,256 individuals with major depression and 3,504 control subjects from 31 separate data sets, and they investigated volume asymmetries of eight subcortical structures in 2,540 individuals with major depression and 4,230 control subjects from 32 data sets. T1-weighted MRI data were processed with a single protocol using FreeSurfer and the Desikan-Killiany atlas. The large sample size provided 80% power to detect effects of the order of Cohen’s d=0.1. Results: The largest effect size (Cohen’s d) of major depression diagnosis was 0.085 for the thickness asymmetry of the superior temporal cortex, which was not significant after adjustment for multiple testing. Asymmetry measures were not significantly associated with medication use, acute compared with remitted status, first episode compared with recurrent status, or age at onset. Conclusions: Altered brain macro-anatomical asymmetry may be of little relevance to major depression etiology in most cases.

    更新日期:2019-12-02
  • Polygenic Risk Score Contribution to Psychosis Prediction in a Target Population of Persons at Clinical High Risk
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-11-12
    Diana O. Perkins; Loes Olde Loohuis; Jenna Barbee; John Ford; Clark D. Jeffries; Jean Addington; Carrie E. Bearden; Kristin S. Cadenhead; Tyrone D. Cannon; Barbara A. Cornblatt; Daniel H. Mathalon; Thomas H. McGlashan; Larry J. Seidman; Ming Tsuang; Elaine F. Walker; Scott W. Woods

    Objective: The 2-year risk of psychosis in persons who meet research criteria for a high-risk syndrome is about 15%−25%; improvements in risk prediction accuracy would benefit the development and implementation of preventive interventions. The authors sought to assess polygenic risk score (PRS) prediction of subsequent psychosis in persons at high risk and to determine the impact of adding the PRS to a previously validated psychosis risk calculator. Methods: Persons meeting research criteria for psychosis high risk (N=764) and unaffected individuals (N=279) were followed for up to 2 years. The PRS was based on the latest schizophrenia and bipolar genome-wide association studies. Variables in the psychosis risk calculator included stressful life events, trauma, disordered thought content, verbal learning, information processing speed, and family history of psychosis. Results: For Europeans, the PRS varied significantly by group and was higher in the psychosis converter group compared with both the nonconverter and unaffected groups, but was similar for the nonconverter group compared with the unaffected group. For non-Europeans, the PRS varied significantly by group; the difference between the converters and nonconverters was not significant, but the PRS was significantly higher in converters than in unaffected individuals, and it did not differ between nonconverters and unaffected individuals. The R2liability (R2 adjusted for the rate of disease risk in the population being studied, here assuming a 2-year psychosis risk between 10% and 30%) for Europeans varied between 9.2% and 12.3% and for non-Europeans between 3.5% and 4.8%. The amount of risk prediction information contributed by the addition of the PRS to the risk calculator was less than severity of disordered thoughts and similar to or greater than for other variables. For Europeans, the PRS was correlated with risk calculator variables of information processing speed and verbal memory. Conclusions: The PRS discriminates psychosis converters from nonconverters and modestly improves individualized psychosis risk prediction when added to a psychosis risk calculator. The schizophrenia PRS shows promise in enhancing risk prediction in persons at high risk for psychosis, although its potential utility is limited by poor performance in persons of non-European ancestry.

    更新日期:2019-11-13
  • Whither TMS: A One-Trick Pony or the Beginning of a Neuroscientific Revolution?
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-11-01
    Mark S. George

    Psychiatry has been at the forefront of advancing clinical transcranial magnetic stimulation (TMS) since the mid-1990s, shortly after the invention of modern TMS in 1985 by Barker. Clinical TMS for psychiatric applications is advancing rapidly, with novel methods and innovations for treating depression, as well as a new clinical indication in obsessive-compulsive disorder. This review summarizes the recent findings and peers into the near future of this fertile and rapidly changing field. It is possible that many, perhaps even most, psychiatrists will be incorporating some form of brain stimulation into their practice within the next decade. The author summarizes the reasons for this optimistic view.

    更新日期:2019-11-01
  • Cannabidiol for the Reduction of Cue-Induced Craving and Anxiety in Drug-Abstinent Individuals With Heroin Use Disorder: A Double-Blind Randomized Placebo-Controlled Trial
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-05-21
    Yasmin L. Hurd; Sharron Spriggs; Julia Alishayev; Gary Winkel; Kristina Gurgov; Chris Kudrich; Anna M. Oprescu; Edwin Salsitz

    Objective: Despite the staggering consequences of the opioid epidemic, limited nonopioid medication options have been developed to treat this medical and public health crisis. This study investigated the potential of cannabidiol (CBD), a nonintoxicating phytocannabinoid, to reduce cue-induced craving and anxiety, two critical features of addiction that often contribute to relapse and continued drug use, in drug-abstinent individuals with heroin use disorder. Methods: This exploratory double-blind randomized placebo-controlled trial assessed the acute (1 hour, 2 hours, and 24 hours), short-term (3 consecutive days), and protracted (7 days after the last of three consecutive daily administrations) effects of CBD administration (400 or 800 mg, once daily for 3 consecutive days) on drug cue–induced craving and anxiety in drug-abstinent individuals with heroin use disorder. Secondary measures assessed participants’ positive and negative affect, cognition, and physiological status. Results: Acute CBD administration, in contrast to placebo, significantly reduced both craving and anxiety induced by the presentation of salient drug cues compared with neutral cues. CBD also showed significant protracted effects on these measures 7 days after the final short-term (3-day) CBD exposure. In addition, CBD reduced the drug cue–induced physiological measures of heart rate and salivary cortisol levels. There were no significant effects on cognition, and there were no serious adverse effects. Conclusions: CBD’s potential to reduce cue-induced craving and anxiety provides a strong basis for further investigation of this phytocannabinoid as a treatment option for opioid use disorder.

    更新日期:2019-11-01
  • A Single Ketamine Infusion Combined With Mindfulness-Based Behavioral Modification to Treat Cocaine Dependence: A Randomized Clinical Trial
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-06-24
    Elias Dakwar; Edward V. Nunes; Carl L. Hart; Richard W. Foltin; Sanjay J. Mathew; Kenneth M. Carpenter; C.J. “Jean” Choi; Cale N. Basaraba; Martina Pavlicova; Frances R. Levin

    Objective: Research has suggested that subanesthetic doses of ketamine may work to improve cocaine-related vulnerabilities and facilitate efforts at behavioral modification. The purpose of this trial was to test whether a single ketamine infusion improved treatment outcomes in cocaine-dependent adults engaged in mindfulness-based relapse prevention. Methods: Fifty-five cocaine-dependent individuals were randomly assigned to receive a 40-minute intravenous infusion of ketamine (0.5 mg/kg) or midazolam (the control condition) during a 5-day inpatient stay, during which they also initiated a 5-week course of mindfulness-based relapse prevention. Cocaine use was assessed through self-report and urine toxicology. The primary outcomes were end-of-study abstinence and time to relapse (defined as first use or dropout). Results: Overall, 48.2% of individuals in the ketamine group maintained abstinence over the last 2 weeks of the trial, compared with 10.7% in the midazolam group (intent-to-treat analysis). The ketamine group was 53% less likely (hazard ratio=0.47; 95% CI=0.24, 0.92) to relapse (dropout or use cocaine) compared with the midazolam group, and craving scores were 58.1% lower in the ketamine group throughout the trial (95% CI=18.6, 78.6); both differences were statistically significant. Infusions were well tolerated, and no participants were removed from the study as a result of adverse events. Conclusions: A single ketamine infusion improved a range of important treatment outcomes in cocaine-dependent adults engaged in mindfulness-based behavioral modification, including promoting abstinence, diminishing craving, and reducing risk of relapse. Further research is needed to replicate these promising results in a larger sample.

    更新日期:2019-11-01
  • Efficacy and Safety of Deep Transcranial Magnetic Stimulation for Obsessive-Compulsive Disorder: A Prospective Multicenter Randomized Double-Blind Placebo-Controlled Trial
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-05-21
    Lior Carmi; Aron Tendler; Alexander Bystritsky; Eric Hollander; Daniel M. Blumberger; Jeff Daskalakis; Herbert Ward; Kyle Lapidus; Wayne Goodman; Leah Casuto; David Feifel; Noam Barnea-Ygael; Yiftach Roth; Abraham Zangen; Joseph Zohar

    Objective: Obsessive-compulsive disorder (OCD) is a chronic and disabling condition that often responds unsatisfactorily to pharmacological and psychological treatments. Converging evidence suggests a dysfunction of the cortical-striatal-thalamic-cortical circuit in OCD, and a previous feasibility study indicated beneficial effects of deep transcranial magnetic stimulation (dTMS) targeting the medial prefrontal cortex and the anterior cingulate cortex. The authors examined the therapeutic effect of dTMS in a multicenter double-blind sham-controlled study. Methods: At 11 centers, 99 OCD patients were randomly allocated to treatment with either high-frequency (20 Hz) or sham dTMS and received daily treatments following individualized symptom provocation, for 6 weeks. Clinical response to treatment was determined using the Yale-Brown Obsessive Compulsive Scale (YBOCS), and the primary efficacy endpoint was the change in score from baseline to posttreatment assessment. Additional measures were response rates (defined as a reduction of ≥30% in YBOCS score) at the posttreatment assessment and after another month of follow-up. Results: Eighty-nine percent of the active treatment group and 96% of the sham treatment group completed the study. The reduction in YBOCS score among patients who received active dTMS treatment was significantly greater than among patients who received sham treatment (reductions of 6.0 points and 3.3 points, respectively), with response rates of 38.1% and 11.1%, respectively. At the 1-month follow-up, the response rates were 45.2% in the active treatment group and 17.8% in the sham treatment group. Significant differences between the groups were maintained at follow-up. Conclusions: High-frequency dTMS over the medial prefrontal cortex and anterior cingulate cortex significantly improved OCD symptoms and may be considered as a potential intervention for patients who do not respond adequately to pharmacological and psychological interventions.

    更新日期:2019-11-01
  • Long-Term Outcomes of Subcallosal Cingulate Deep Brain Stimulation for Treatment-Resistant Depression
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-10-04
    Andrea L. Crowell; Patricio Riva-Posse; Paul E. Holtzheimer; Steven J. Garlow; Mary E. Kelley; Robert E. Gross; Lydia Denison; Sinead Quinn; Helen S. Mayberg

    Objective: Deep brain stimulation of the subcallosal cingulate (SCC DBS) has been studied as a potential treatment for severe and refractory major depressive disorder since 2005. The authors used an open-label, long-term follow-up design to examine participants enrolled in a clinical trial of SCC DBS for treatment-resistant depression. Methods: Long-term outcome data were collected for 28 patients (20 with major depressive disorder and seven with bipolar II disorder; one patient in the major depression subgroup was later reclassified as having bipolar II disorder) receiving SCC DBS for 4–8 years. Results: Response and remission rates were maintained at ≥50% and ≥30%, respectively, through years 2–8 of the follow-up period. Three-quarters of all participants met the treatment-response criterion for more than half of their duration of participation in the study, with 21% of all patients demonstrating continuous response to treatment from the first year onward. Of 28 participants, 14 completed ≥8 years of follow-up, 11 completed ≥4 years, and three dropped out before 8 years. The procedure itself was generally safe and well tolerated, and there were no side effects of acute or chronic stimulation. The rate of medical or surgical complications was consistent with the rate observed in studies of DBS for other indications. There were no suicides. Conclusions: In >8 years of observation, most participants experienced a robust and sustained antidepressant response to SCC DBS.

    更新日期:2019-11-01
  • Theta-Burst Transcranial Magnetic Stimulation for Posttraumatic Stress Disorder
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-06-24
    Noah S. Philip; Jennifer Barredo; Emily Aiken; Victoria Larson; Richard N. Jones; M. Tracie Shea; Benjamin D. Greenberg; Mascha van ’t Wout-Frank

    Objective: Posttraumatic stress disorder (PTSD) is a highly prevalent psychiatric disorder associated with disruption in social and occupational function. Transcranial magnetic stimulation (TMS) represents a novel approach to PTSD, and intermittent theta-burst stimulation (iTBS) is a new, more rapid administration protocol with data supporting efficacy in depression. The authors conducted a sham-controlled study of iTBS for PTSD. Methods: Fifty veterans with PTSD received 10 days of sham-controlled iTBS (1,800 pulses/day), followed by 10 unblinded sessions. Primary outcome measures included acceptability (retention rates), changes in PTSD symptoms (clinician- and self-rated), quality of life, social and occupational function, and depression, obtained at the end of 2 weeks; analysis of variance was used to compare active with sham stimulation. Secondary outcomes were evaluated 1 month after treatment, using mixed-model analyses. Resting-state functional MRI was acquired at pretreatment baseline on an eligible subset of participants (N=26) to identify response predictors. Results: Retention was high, side effects were consistent with standard TMS, and blinding was successful. At 2 weeks, active iTBS was significantly associated with improved social and occupational function (Cohen’s d=0.39); depression was improved with iTBS compared with the sham treatment (d=−0.45), but the difference fell short of significance, and moderate nonsignificant effect sizes were observed on self-reported PTSD symptoms (d=−0.34). One-month outcomes, which incorporated data from the unblinded phase of the study, indicated superiority of active iTBS on clinician- and self-rated PTSD symptoms (d=−0.74 and −0.63, respectively), depression (d=−0.47), and social and occupational function (d=0.93) (all significant). Neuroimaging indicated that clinical improvement was significantly predicted by stronger (greater positive) connectivity within the default mode network and by anticorrelated (greater negative) cross-network connectivity. Conclusions: iTBS appears to be a promising new treatment for PTSD. Most clinical improvements from stimulation occurred early, which suggests a need for further investigation of optimal iTBS time course and duration. Consistent with previous neuroimaging studies of TMS, default mode network connectivity played an important role in response prediction.

    更新日期:2019-11-01
  • Reducing Suicidal Ideation Through Insomnia Treatment (REST-IT): A Randomized Clinical Trial
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-09-20
    William V. McCall; Ruth M. Benca; Peter B. Rosenquist; Nagy A. Youssef; Laryssa McCloud; Jill C. Newman; Doug Case; Meredith E. Rumble; Steven T. Szabo; Marjorie Phillips; Andrew D. Krystal

    Objective: The authors sought to determine whether targeted treatment of insomnia with controlled-release zolpidem (zolpidem-CR) in suicidal adults with insomnia would provide a reduction in suicidal ideation superior to placebo. Methods: Reducing Suicidal Ideation Through Insomnia Treatment was an 8-week three-site double-blind placebo-controlled parallel-group randomized controlled trial of zolpidem-CR hypnotic therapy compared with placebo, in conjunction with an open-label selective serotonin reuptake inhibitor. Participants were medication-free 18- to 65-year-olds with major depressive disorder, insomnia, and suicidal ideation. Suicidal ideation was the main outcome, measured first by the Scale for Suicide Ideation and second by the Columbia–Suicide Severity Rating Scale (C-SSRS). Results: A total of 103 participants were randomly assigned to receive zolpidem-CR (N=51) or placebo (N=52) (64 women and 39 men; mean age=40.5 years). Zolpidem-CR had a robust anti-insomnia effect, especially in patients with the most severe insomnia symptoms. No significant treatment effect was observed on the Scale for Suicide Ideation (least squares mean estimate=−0.56, SE=0.83, 95% CI=−2.19, 1.08), but the reduction in scores was significantly positively related to improvement in insomnia after accounting for the effect of other depression symptoms. The C-SSRS indicated that zolpidem-CR had a significant treatment effect (least squares mean estimate=−0.26, SE=0.12, 95% CI=−0.50, −0.02). The advantage for zolpidem-CR in reducing suicidal ideation on the C-SSRS was greater in patients with more severe insomnia. No deaths or suicide attempts occurred. Conclusions: Although the results do not support the routine prescription of hypnotic medication for mitigating suicidal ideation in all depressed outpatients with insomnia, they suggest that coprescription of a hypnotic during initiation of an antidepressant may be beneficial in suicidal outpatients, especially in patients with severe insomnia.

    更新日期:2019-11-01
  • Reduction in Mental Health Treatment Utilization Among Transgender Individuals After Gender-Affirming Surgeries: A Total Population Study
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-10-04
    Richard Bränström; John E Pachankis

    Objective: Despite professional recommendations to consider gender-affirming hormone and surgical interventions for transgender individuals experiencing gender incongruence, the long-term effect of such interventions on mental health is largely unknown. The aim of this study was to ascertain the prevalence of mood and anxiety disorder health care visits and antidepressant and anxiolytic prescriptions in 2015 as a function of gender incongruence diagnosis and gender-affirming hormone and surgical treatment in the entire Swedish population. Methods: This study used the Swedish Total Population Register (N=9,747,324), linked to the National Patient Register and the Prescribed Drug Register. Among individuals who received a diagnosis of gender incongruence (i.e., transsexualism or gender identity disorder) between 2005 and 2015 (N=2,679), mental health treatment in 2015 was examined as a function of length of time since gender-affirming hormone and surgical treatment. Outcome measures were mood and anxiety disorder health care visits, antidepressant and anxiolytic prescriptions, and hospitalization after a suicide attempt. Results: Compared with the general population, individuals with a gender incongruence diagnosis were about six times as likely to have had a mood and anxiety disorder health care visit, more than three times as likely to have received prescriptions for antidepressants and anxiolytics, and more than six times as likely to have been hospitalized after a suicide attempt. Years since initiating hormone treatment was not significantly related to likelihood of mental health treatment (adjusted odds ratio=1.01, 95% CI=0.98, 1.03). However, increased time since last gender-affirming surgery was associated with reduced mental health treatment (adjusted odds ratio=0.92, 95% CI=0.87, 0.98). Conclusions: In this first total population study of transgender individuals with a gender incongruence diagnosis, the longitudinal association between gender-affirming surgery and reduced likelihood of mental health treatment lends support to the decision to provide gender-affirming surgeries to transgender individuals who seek them.

    更新日期:2019-10-04
  • Early Detection and Preventive Intervention in Schizophrenia: From Fantasy to Reality
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-10-01
    Jeffrey A. Lieberman; Scott A. Small; Ragy R. Girgis

    Scientific progress in understanding human disease can be measured by the effectiveness of its treatment. Antipsychotic drugs have been proven to alleviate acute psychotic symptoms and prevent their recurrence in schizophrenia, but the outcomes of most patients historically have been suboptimal. However, a series of findings in studies of first-episode schizophrenia patients transformed the psychiatric field’s thinking about the pathophysiology, course, and potential for disease-modifying effects of treatment. These include the relationship between the duration of untreated psychotic symptoms and outcome; the superior responses of first-episode patients to antipsychotics compared with patients with chronic illness, and the reduction in brain gray matter volume over the course of the illness. Studies of the effectiveness of early detection and intervention models of care have provided encouraging but inconclusive results in limiting the morbidity and modifying the course of illness. Nevertheless, first-episode psychosis studies have established an evidentiary basis for considering a team-based, coordinated specialty approach as the standard of care for treating early psychosis, which has led to their global proliferation. In contrast, while clinical high-risk research has developed an evidence-based care model for decreasing the burden of attenuated symptoms, no treatment has been shown to reduce risk or prevent the transition to syndromal psychosis. Moreover, the current diagnostic criteria for clinical high risk lack adequate specificity for clinical application. What limits our ability to realize the potential of early detection and intervention models of care are the lack of sensitive and specific diagnostic criteria for pre-syndromal schizophrenia, validated biomarkers, and proven therapeutic strategies. Future research requires methodologically rigorous studies in large patient samples, across multiple sites, that ideally are guided by scientifically credible pathophysiological theories for which there is compelling evidence. These caveats notwithstanding, we can reasonably expect future studies to build on the research of the past four decades to advance our knowledge and enable this game-changing model of care to become a reality.

    更新日期:2019-10-01
  • Cognitive Change in Schizophrenia and Other Psychoses in the Decade Following the First Episode
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-07-01
    Jolanta Zanelli; Josephine Mollon; Sven Sandin; Craig Morgan; Paola Dazzan; Izabela Pilecka; Tiago Reis Marques; Anthony S. David; Kevin Morgan; Paul Fearon; Gillian A. Doody; Peter B. Jones; Robin M. Murray; Abraham Reichenberg

    Objective: Schizophrenia is associated with a marked cognitive impairment that is widely believed to remain stable after illness onset. Yet, to date, 10-year prospective studies of cognitive functioning following the first episode with good methodology are rare. The authors examined whether schizophrenia patients experience cognitive decline after the first episode, whether this decline is generalized or confined to individual neuropsychological functions, and whether decline is specific to schizophrenia. Methods: Participants were from a population-based case-control study of patients with first-episode psychosis who were followed prospectively up to 10 years after first admission. A neuropsychological battery was administered at index presentation and at follow-up to patients with a diagnosis of schizophrenia (N=65) or other psychoses (N=41) as well as to healthy comparison subjects (N=103). Results: The schizophrenia group exhibited declines in IQ and in measures of verbal knowledge and of memory, but not processing speed or executive functions. Processing speed and executive function impairments were already present at the first episode and remained stable thereafter. The magnitude of declines ranged between 0.28 and 0.66 standard deviations. Decline in measures of memory was not specific to schizophrenia and was also apparent in the group of patients with other psychoses. Healthy individuals with low IQ showed no evidence of decline, suggesting that a decline is specific to psychosis. Conclusions: Patients with schizophrenia and other psychoses experience cognitive decline after illness onset, but the magnitude of decline varies across cognitive functions. Distinct mechanisms consequent to the illness and/or psychosocial factors may underlie impairments across different cognitive functions.

    更新日期:2019-10-01
  • Altered Cellular White Matter But Not Extracellular Free Water on Diffusion MRI in Individuals at Clinical High Risk for Psychosis
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-06-24
    Yingying Tang; Ofer Pasternak; Marek Kubicki; Yogesh Rathi; Tianhong Zhang; Junjie Wang; Huijun Li; Kristen A. Woodberry; Lihua Xu; Zhenying Qian; Anni Zhu; Susan Whitfield-Gabrieli; Matcheri S. Keshavan; Margaret Niznikiewicz; William S. Stone; Robert W. McCarley; Martha E. Shenton; Jijun Wang; Larry J. Seidman

    Objective: Detecting brain abnormalities in clinical high-risk populations before the onset of psychosis is important for tracking pathological pathways and for identifying possible intervention strategies that may impede or prevent the onset of psychotic disorders. Co-occurring cellular and extracellular white matter alterations have previously been implicated after a first psychotic episode. The authors investigated whether or not cellular and extracellular alterations are already present in a predominantly medication-naive cohort of clinical high-risk individuals experiencing attenuated psychotic symptoms. Methods: Fifty individuals at clinical high risk, of whom 40 were never medicated, were compared with 50 healthy control subjects, group-matched for age, gender, and parental socioeconomic status. 3-T multishell diffusion MRI data were obtained to estimate free-water imaging white matter measures, including fractional anisotropy of cellular tissue (FAT) and the volume fraction of extracellular free water (FW). Results: Significantly lower FAT was observed in the clinical high-risk group compared with the healthy control group, but no statistically significant FW alterations were observed between groups. Lower FAT in the clinical high-risk group was significantly associated with a decline in Global Assessment of Functioning Scale (GAF) score compared with highest GAF score in the previous 12 months. Conclusions: Cellular but not extracellular alterations characterized the clinical high-risk group, especially in those who experienced a decline in functioning. These cellular changes suggest an early deficit that possibly reflects a predisposition to develop attenuated psychotic symptoms. In contrast, extracellular alterations were not observed in this clinical high-risk sample, suggesting that previously reported extracellular abnormalities may reflect an acute response to psychosis, which plays a more prominent role closer to or at onset of psychosis.

    更新日期:2019-10-01
  • White Matter in Schizophrenia Treatment Resistance
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-07-29
    Peter Kochunov; Junchao Huang; Song Chen; Yanli Li; Shuping Tan; Fengmei Fan; Wei Feng; Yunhui Wang; Laura M. Rowland; Anya Savransky; Xiaoming Du; Joshua Chiappelli; Shuo Chen; Neda Jahanshad; Paul M. Thompson; Meghann C. Ryan; Bhim Adhikari; Hemalatha Sampath; Yimin Cui; Zhiren Wang; Fude Yang; Yunlong Tan; L. Elliot Hong

    Objective: Failure of antipsychotic medications to resolve symptoms in patients with schizophrenia creates a clinical challenge that is known as treatment resistance. The causes of treatment resistance are unknown, but it is associated with earlier age at onset and more severe cognitive deficits. The authors tested the hypothesis that white matter deficits that are involved in both neurodevelopment and severity of cognitive deficits in schizophrenia are associated with a higher risk of treatment resistance. Methods: The study sample (N=122; mean age, 38.2 years) included schizophrenia patients at treatment initiation (N=45), patients whose symptoms were treatment responsive (N=40), and patients whose symptoms were treatment resistant (N=37), as well as healthy control subjects (N=78; mean age, 39.2 years). White matter regional vulnerability index (RVI) was tested as a predictor of treatment resistance and cognitive deficits. Higher RVI is indicative of better agreement between diffusion tensor imaging fractional anisotropy across the brain in an individual and the pattern identified by the largest-to-date meta-analysis of white matter deficits in schizophrenia. Results: Patients with treatment-resistant symptoms showed the highest white matter RVI (mean=0.38 [SD=0.2]), which was significantly higher than the RVI among patients with treatment-responsive symptoms (mean=0.30 [SD=0.02]). At the onset of treatment, schizophrenia patients showed significantly higher RVI than healthy control subjects (mean=0.18 [SD=0.03] and mean=0.13 [SD=0.02], respectively). RVIs were significantly correlated with performance on processing speed and negative symptoms. Conclusions: Schizophrenia affects white matter microstructure in specific regional patterns. Susceptibility to white matter regional deficits is associated with an increased likelihood of treatment resistance. Developments to overcome schizophrenia treatment resistance should consider white matter as an important target.

    更新日期:2019-10-01
  • Baseline Frontoparietal Task-Related BOLD Activity as a Predictor of Improvement in Clinical Symptoms at 1-Year Follow-Up in Recent-Onset Psychosis
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-07-01
    Jason Smucny; Tyler A. Lesh; Cameron S. Carter

    Objective: The early course of illness in psychotic disorders is highly variable, and predictive biomarkers of treatment response have been lacking. Trial and error remains the basis for care in early psychosis, and poor outcomes are common. Early prediction of nonimprovement in response to treatment could help identify those who would benefit from alternative and/or supplemental interventions. The goal of this study was to evaluate the ability of functional MRI (fMRI) measures of cognitive control–related brain circuitry collected at baseline to predict symptomatic response in patients after 1 year. Methods: Patients with recent-onset (<2 years) psychotic disorders (N=82) in early psychosis specialty care were classified as improvers (>20% improvement in total score on the Brief Psychiatric Rating Scale [BPRS] at 1-year follow-up compared with baseline) or as nonimprovers. Behavioral (d′ context) and fMRI (proactive control–associated activation in a priori frontoparietal regions of interest) measures of cognitive control were then evaluated on their ability to predict BPRS improvement using linear and logistic regression. Results: Cognitive control–associated measures significantly predicted BPRS improvement and improver status, with 70% positive predictive value, 60% negative predictive value, and 66% accuracy. Only the fMRI-based measure (and not the behavioral measure) significantly predicted status. Conclusions: These results suggest that frontoparietal activation during cognitive control performance at baseline significantly predicts subsequent symptomatic improvement during early psychosis specialty care. Potential implications for fMRI-based personalized patient treatment are discussed.

    更新日期:2019-10-01
  • Penetrance and Pleiotropy of Polygenic Risk Scores for Schizophrenia in 106,160 Patients Across Four Health Care Systems
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-08-16
    Amanda B. Zheutlin; Jessica Dennis; Richard Karlsson Linnér; Arden Moscati; Nicole Restrepo; Peter Straub; Douglas Ruderfer; Victor M. Castro; Chia-Yen Chen; Tian Ge; Laura M. Huckins; Alexander Charney; H. Lester Kirchner; Eli A. Stahl; Christopher F. Chabris; Lea K. Davis; Jordan W. Smoller

    Objective: Individuals at high risk for schizophrenia may benefit from early intervention, but few validated risk predictors are available. Genetic profiling is one approach to risk stratification that has been extensively validated in research cohorts. The authors sought to test the utility of this approach in clinical settings and to evaluate the broader health consequences of high genetic risk for schizophrenia. Methods: The authors used electronic health records for 106,160 patients from four health care systems to evaluate the penetrance and pleiotropy of genetic risk for schizophrenia. Polygenic risk scores (PRSs) for schizophrenia were calculated from summary statistics and tested for association with 1,359 disease categories, including schizophrenia and psychosis, in phenome-wide association studies. Effects were combined through meta-analysis across sites. Results: PRSs were robustly associated with schizophrenia (odds ratio per standard deviation increase in PRS, 1.55; 95% CI=1.4, 1.7), and patients in the highest risk decile of the PRS distribution had up to 4.6-fold higher odds of schizophrenia compared with those in the bottom decile (95% CI=2.9, 7.3). PRSs were also positively associated with other phenotypes, including anxiety, mood, substance use, neurological, and personality disorders, as well as suicidal behavior, memory loss, and urinary syndromes; they were inversely related to obesity. Conclusions: The study demonstrates that an available measure of genetic risk for schizophrenia is robustly associated with schizophrenia in health care settings and has pleiotropic effects on related psychiatric disorders as well as other medical syndromes. The results provide an initial indication of the opportunities and limitations that may arise with the future application of PRS testing in health care systems.

    更新日期:2019-10-01
  • Effect of Intrinsic Patterns of Functional Brain Connectivity in Moderating Antidepressant Treatment Response in Major Depression
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-09-20
    Cherise R. Chin Fatt; Manish K. Jha; Crystal M. Cooper; Gregory Fonzo; Charles South; Bruce Grannemann; Thomas Carmody; Tracy L. Greer; Benji Kurian; Maurizio Fava; Patrick J. McGrath; Phillip Adams; Melvin McInnis; Ramin V. Parsey; Myrna Weissman; Mary L. Phillips; Amit Etkin; Madhukar H. Trivedi

    Objective: Major depressive disorder is associated with aberrant resting-state functional connectivity across multiple brain networks supporting emotion processing, executive function, and reward processing. The purpose of this study was to determine whether patterns of resting-state connectivity between brain regions predict differential outcome to antidepressant medication (sertraline) compared with placebo. Methods: Participants in the Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study underwent structural and resting-state functional MRI at baseline. Participants were then randomly assigned to receive either sertraline or placebo treatment for 8 weeks (N=279). A region of interest–based approach was utilized to compute functional connectivity between brain regions. Linear mixed-model intent-to-treat analyses were used to identify brain regions that moderated (i.e., differentially predicted) outcomes between the sertraline and placebo arms. Results: Prediction of response to sertraline involved several within- and between-network connectivity patterns. In general, higher connectivity within the default mode network predicted better outcomes specifically for sertraline, as did greater between-network connectivity of the default mode and executive control networks. In contrast, both placebo and sertraline outcomes were predicted (in opposite directions) by between-network hippocampal connectivity. Conclusions: This study identified specific functional network–based moderators of treatment outcome involving brain networks known to be affected by major depression. Specifically, functional connectivity patterns of brain regions between and within networks appear to play an important role in identifying a favorable response for a drug treatment for major depressive disorder.

    更新日期:2019-09-21
  • Characterizing Covariant Trajectories of Individuals at Clinical High Risk for Psychosis Across Symptomatic and Functional Domains
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-09-06
    Dana M. Allswede; Jean Addington; Carrie E. Bearden; Kristin S. Cadenhead; Barbara A. Cornblatt; Daniel H. Mathalon; Thomas McGlashan; Diana O. Perkins; Larry J. Seidman; Ming T. Tsuang; Elaine F. Walker; Scott W. Woods; Tyrone D. Cannon

    Objective: The authors sought to characterize differences in outcomes among help-seeking individuals at clinical high risk for psychosis by identifying covariant longitudinal patterns of symptoms and functioning. Methods: Group-based multitrajectory modeling was applied to longitudinal ratings of four symptom domains (positive, negative, disorganized, general) and general functioning among clinical high-risk individuals in an initial discovery sample (N=422). An independent sample (N=133) was used to test replicability. Results: Three trajectory groups were identified among clinical high-risk individuals in the discovery sample: group 1 (30%) exhibited substantial improvement across all domains, with half reaching positive outcomes for both functioning and positive symptoms; group 2 (49%) exhibited moderate impairments across domains, with approximately one-quarter meeting criteria for positive outcomes; the remaining participants (group 3; 22%) exhibited consistent levels of severe impairment across domains and did not experience positive outcomes. These trajectory groups and remission patterns were replicated in an independent sample. Conclusions: Replicable subgroups of help-seeking clinical high-risk cases can be ascertained based on distinctive profiles of change over time in symptoms and functioning. Within each of the three identified subgroups, similar patterns of change (i.e., rapid, moderate, or no improvement) were observed across the four symptom domains and functioning. This consistency of change over time across domains within each subgroup is a novel observation supporting the syndrome consistency of clinical high-risk symptoms and signs. The observed trajectory subgroups are suggestive of different degrees of need for clinical interventions, ranging from minimal or supportive for about one-third of cases to increasingly intensive among the remainder.

    更新日期:2019-09-06
  • Correlates of Future Violence in People Being Treated for Schizophrenia
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-04-24
    Alec Buchanan; Kyaw Sint; Jeffrey Swanson; Robert Rosenheck

    Objective: Violent behavior is infrequent among individuals with schizophrenia but is clinically important. The purpose of this study was to provide data on the correlates of violence, which may allow better risk assessment and care. Methods: A total of 1,435 individuals with schizophrenia who participated in the National Institute of Mental Health’s Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study and were followed for 18 months were examined. The dependent variables were self-reported injurious and noninjurious violence during follow-up. The independent variables, assessed at study entry, comprised participants' recent injurious and noninjurious violence, demographic and background variables, childhood risk factors, clinical condition, current circumstances, and recent contact with hospitals and prisons. Proportional hazards models of time to first injurious violence were used to generate bivariable and multivariable hazard ratios for all participants and, separately, for participants with no injurious violence at study entry. Results: Seventy-seven participants (5.4%) reported engaging in injurious violence during follow-up, and 119 (8.3%) reported engaging in exclusively noninjurious violence. In the multivariable analysis, baseline injurious violence (hazard ratio=4.02), recent violent victimization (hazard ratio=3.52), severity of drug use (hazard ratio=2.93), baseline noninjurious violence (hazard ratio=2.72), childhood sexual abuse (hazard ratio=1.85), and medication nonadherence (hazard ratio=1.39) were associated with future injurious violence. For participants with no history of injurious violence at study entry, baseline noninjurious violence was the strongest predictor (hazard ratio=3.02). Recent violent victimization was no longer a significant correlate. The remaining correlates and the strength of their association with future injurious violence were similar to those for all participants. Conclusions: This is the first longitudinal multivariable analysis of predictors of injurious violence in a large cohort of patients with schizophrenia followed over 18 months. The results revealed simultaneous strong effects of baseline injurious violence and recent violent victimization on future injurious violent behavior. Among clinical variables, poor medication adherence, but not baseline symptoms of psychosis or depression, significantly predicted injurious violence. Treatment strategies to reduce risk should emphasize medication adherence.

    更新日期:2019-09-03
  • Exposure to Maternal Depressive Symptoms in Fetal Life or Childhood and Offspring Brain Development: A Population-Based Imaging Study
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-05-06
    Runyu Zou; Henning Tiemeier; Jan van der Ende; Frank C. Verhulst; Ryan L. Muetzel; Tonya White; Manon Hillegers; Hanan El Marroun

    Objective: The authors examined associations of exposure to maternal depressive symptoms at different developmental stages from fetal life to preadolescence with child brain development, including volumetrics and white matter microstructure. Methods: This study was embedded in a longitudinal birth cohort in Rotterdam, the Netherlands. Participants were 3,469 mother-child pairs with data on maternal depressive symptoms and child neuroimaging at age 10. The authors also measured child emotional and behavioral problems at the time of neuroimaging. The association of maternal depressive symptoms with child brain development at each assessment was examined. Maternal depressive symptom trajectories were modeled across fetal life and childhood to determine the association of maternal depressive symptom patterns over time with child brain development. Results: The single-time-point analyses showed that maternal depressive symptoms at child age 2 months were associated with smaller total gray matter volume and lower global fractional anisotropy (FA), whereas maternal depressive symptoms assessed prenatally or in childhood were not. The trajectory analyses suggested in particular that children exposed to persistently high levels of maternal depressive symptoms across the perinatal period had smaller gray and white matter volumes as well as alterations (i.e., lower FA) in white matter microstructure compared with nonexposed children. Furthermore, the gray matter volume differences mediated the association between postnatal maternal depressive symptoms and child attention problems. Conclusions: Perinatal maternal depressive symptoms were consistently associated with child brain development assessed 10 years later. These results suggest that the postnatal period is a window of vulnerability for adversities such as maternal depressive symptoms.

    更新日期:2019-09-03
  • Prediction of Onset of Substance-Induced Psychotic Disorder and Its Progression to Schizophrenia in a Swedish National Sample
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-05-06
    Kenneth S. Kendler; Henrik Ohlsson; Jan Sundquist; Kristina Sundquist

    Objective: The objective of this study was to clarify the etiology of substance-induced psychotic disorder and its progression to schizophrenia in a Swedish national sample. Methods: Individuals with a registration of substance-induced psychotic disorder between 1997 and 2015 in national medical registries (N=7,606) were followed up for a mean of 84 months. Data from medical, criminal, and pharmacy registries on first-degree through third-degree relatives were used to calculate familial risk scores for nonaffective psychosis, drug abuse, and alcohol use disorder. Results: Individuals with substance-induced psychotic disorder had large elevations in standardized familial risk scores for drug abuse (+1.09, 95% CI=1.02, 1.15) and alcohol use disorder (+0.98, 95% CI=0.93, 1.03) and modest elevations for nonaffective psychosis (+0.35, 95% CI=0.30, 0.41). The cumulative risk for progression to schizophrenia was 11.3%; it was lowest for alcohol-induced and highest for cannabis-induced psychotic disorder, and it was predicted by early age at diagnosis of substance-induced psychotic disorder, male sex, and further registrations for episodes of drug abuse, alcohol use disorder, and substance-induced psychotic disorder. A risk prediction model found that 47% of individuals who converted to schizophrenia were in the upper 20% of risk. Familial risk scores for drug abuse and alcohol use disorder did not significantly discriminate those who converted to schizophrenia from those who did not, while familial risk score for nonaffective psychosis did (0.67, 95% CI=0.40, 0.95, versus 0.33, 95% CI=0.28, 0.39). Familial risk scores for nonaffective psychosis were indistinguishable between individuals with schizophrenia with and without prior substance-induced psychosis. Assignment of early retirement by the Swedish Social Insurance Agency strongly discriminated between individuals with substance-induced psychotic disorder with and without later schizophrenia. Conclusions: Substance-induced psychotic disorder appears to result from substantial drug exposure in individuals at high familial risk for substance abuse and moderately elevated familial risk for psychosis. Familial risk for psychosis, but not substance abuse, predicts progression from substance-induced psychosis to schizophrenia. Schizophrenia following substance-induced psychosis is likely a drug-precipitated disorder in highly vulnerable individuals, not a syndrome predominantly caused by drug exposure.

    更新日期:2019-09-03
  • The Emergent Course of Bipolar Disorder: Observations Over Two Decades From the Canadian High-Risk Offspring Cohort
    Am. J. Psychiatry (IF 13.655) Pub Date : 2018-12-11
    Anne Duffy; Sarah Goodday; Charles Keown-Stoneman; Paul Grof

    Objective: The authors sought to describe the emergent course of bipolar disorder in offspring of affected parents subgrouped by parental response to lithium prophylaxis. Methods: Parent bipolar disorder was confirmed by the best-estimate procedure and lithium response by research protocol. High-risk offspring (N=279) and control subjects (N=87) were blindly assessed, annually on average, with the Kiddie Schedule for Affective Disorders and Schizophrenia–Present and Lifetime version or the Schedule for Affective Disorders and Schizophrenia–Lifetime version. DSM-IV diagnoses were confirmed using the best-estimate procedure in blind consensus reviews. Cumulative incidence and median age at onset were determined for lifetime syndrome- and symptom-level data. Mixed models assessed the association between parent and offspring course. A multistate model was used to estimate the clinical trajectory into bipolar disorder. Results: The cumulative incidence of bipolar disorder was 24.5%, and the median age at onset was 20.7 years (range, 12.4 to 30.3). The clinical course of the affected parent was associated with that of the affected child. Depressive episodes predominated during the early bipolar course, especially among offspring of lithium responders. Childhood sleep and anxiety disorders significantly predicted 1.6-fold and 1.8-fold increases in risk of mood disorder, respectively, and depressive and manic symptoms predicted 2.7-fold and 2.3-fold increases in risk, respectively. The best-fit model of emerging bipolar disorder was a progressive sequence from nonspecific childhood antecedents to adolescent depression to index manic or hypomanic episode. Subthreshold sleep symptoms were significantly associated with transition from well to non-mood disorder, and psychotic symptoms in mood episodes were significantly associated with transition from unipolar to bipolar disorder. Conclusions: Bipolar disorder in individuals at familial risk typically unfolds in a progressive clinical sequence. Childhood sleep and anxiety disorders are important predictors, as are clinically significant mood symptoms and psychotic symptoms in depressive episodes.

    更新日期:2019-09-03
  • Increased Protein Insolubility in Brains From a Subset of Patients With Schizophrenia
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-05-06
    Leslie G. Nucifora; Matthew L. MacDonald; Brian J. Lee; Matthew E. Peters; Alexis L. Norris; Benjamin C. Orsburn; Kun Yang; Kelly Gleason; Russell L. Margolis; Jonathan Pevsner; Carol A. Tamminga; Robert A. Sweet; Christopher A. Ross; Akira Sawa; Frederick C. Nucifora, Jr.

    Objective: The mechanisms leading to schizophrenia are likely to be diverse. However, there may be common pathophysiological pathways for subtypes of the disease. The authors tested the hypothesis that increased protein insolubility and ubiquitination underlie the pathophysiology for a subtype of schizophrenia. Methods: Prefrontal cortex and superior temporal gyrus from postmortem brains of individuals with and without schizophrenia were subjected to cold sarkosyl fractionation, separating proteins into soluble and insoluble fractions. Protein insolubility and ubiquitin levels were quantified for each insoluble fraction, with normalization to total homogenate protein. Mass spectrometry analysis was then performed to identify the protein contents of the insoluble fractions. The potential biological relevance of the detected proteins was assessed using Gene Ontology enrichment analysis and Ingenuity Pathway Analysis. Results: A subset of the schizophrenia brains showed an increase in protein insolubility and ubiquitination in the insoluble fraction. Mass spectrometry of the insoluble fraction revealed that brains with increased insolubility and ubiquitination exhibited a similar peptide expression by principal component analysis. The proteins that were significantly altered in the insoluble fraction were enriched for pathways relating to axon target recognition as well as nervous system development and function. Conclusions: This study suggests a pathological process related to protein insolubility for a subset of patients with schizophrenia. Determining the molecular mechanism of this subtype of schizophrenia could lead to a better understanding of the pathways underlying the clinical phenotype in some patients with major mental illness as well as to improved nosology and identification of novel therapeutic targets.

    更新日期:2019-09-03
  • Neurofunctional Domains Derived From Deep Behavioral Phenotyping in Alcohol Use Disorder
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-01-04
    Laura E. Kwako; Melanie L. Schwandt; Vijay A. Ramchandani; Nancy Diazgranados; George F. Koob; Nora D. Volkow; Carlos Blanco; David Goldman

    Objective: The authors evaluated whether three neurofunctional domains proposed to be critical in the addiction cycle, namely, incentive salience, negative emotionality, and executive function, could be identified through factor analysis of a deeply phenotyped clinical sample. Methods: Clinical, behavioral, and self-report measures of addiction, personality, cognition, behavior, and exposure to early-life stress were collected as part of a screening and natural history study of alcohol use disorders in 454 individuals representing the spectrum of alcohol use and use disorders. The multiple indicators, multiple causes (MIMIC) approach was used to identify significant predictors of the latent factors identified by the analysis. Results: The results showed significant support for both three- and four-factor models to explain biobehavioral variation in this sample of participants with alcohol use disorder and control subjects, but the three-factor model had the best fit indices. With some nuances, including cross-correlation (lack of independence) between the three factors, the factors corresponded to incentive salience, negative emotionality, and executive function (executive control). The MIMIC model revealed that both exposure to early-life stress and sociodemographic variables predicted these factors. Conclusions: These findings suggest that three correlated neurofunctional domains are relevant for alcohol use disorder. More work is required to validate and standardize measures of neurofunctional domains in alcohol use disorder, to extend these findings to other addictive disorders, and to relate variations in them to predisposition, clinical course, treatment response, neuroimaging data, and other psychophysical indicators.

    更新日期:2019-09-03
  • Continued Benefits of Methylphenidate in ADHD After 2 Years in Clinical Practice: A Randomized Placebo-Controlled Discontinuation Study
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-05-21
    Anne-Flore M. Matthijssen; Andrea Dietrich; Margreet Bierens; Renee Kleine Deters; Gigi H.H. van de Loo-Neus; Barbara J. van den Hoofdakker; Jan K. Buitelaar; Pieter J. Hoekstra

    Objective: The benefits of long-term use of methylphenidate treatment in children and adolescents with attention deficit hyperactivity disorder (ADHD), as frequently prescribed in clinical practice, are unclear. The authors investigated whether methylphenidate remains beneficial after 2 years of use. Methods: Ninety-four children and adolescents (ages 8–18 years) who had been treated in regular care with methylphenidate for more than 2 years were randomly assigned to double-blind continuation of treatment for 7 weeks (36 or 54 mg/day of extended-release methylphenidate) or gradual withdrawal over 3 weeks, to 4 weeks of placebo. The primary outcome measure was the investigator-rated ADHD Rating Scale (ADHD-RS); secondary outcome measures were the investigator-rated Clinical Global Impressions improvement scale (CGI-I) and the Conners’ Teacher Rating Scale–Revised: Short Form (CTRS-R:S). Continuous ratings were analyzed with mixed model for repeated measures analyses, and the CGI-I with a chi-square test. Results: The mean ADHD-RS scores at baseline for the continuation and discontinuation groups, respectively, were 21.4 (SD=9.7) and 19.6 (SD=8.9); after 7 weeks, the mean scores were 21.9 (SD=10.8) and 24.7 (SD=11.4), with a significant between-group difference in change over time of −4.6 (95% CI=−8.7, −0.56) in favor of the group that continued methylphenidate treatment. The ADHD-RS inattention subscale and the CTRS-R:S ADHD index and hyperactivity subscale also deteriorated significantly more in the discontinuation group. The CGI-I indicated worsening in 40.4% of the discontinuation group, compared with 15.9% of the continuation group. Conclusions: Continued treatment with methylphenidate remains effective after long-term use. Some individual patients may, however, be withdrawn from methylphenidate without deterioration. This finding supports guideline recommendations that patients be assessed periodically to determine whether there is a continued need for methylphenidate treatment.

    更新日期:2019-09-03
  • Polygenic Risk: Predicting Depression Outcomes in Clinical and Epidemiological Cohorts of Youths
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-04-05
    Thorhildur Halldorsdottir; Charlotte Piechaczek; Ana Paula Soares de Matos; Darina Czamara; Verena Pehl; Petra Wagenbuechler; Lisa Feldmann; Peggy Quickenstedt-Reinhardt; Antje-Kathrin Allgaier; Franz Joseph Freisleder; Ellen Greimel; Tuomas Kvist; Jari Lahti; Katri Räikkönen; Monika Rex-Haffner; Eiríkur Örn Arnarson; W. Edward Craighead; Gerd Schulte-Körne; Elisabeth B. Binder

    Objective: Identifying risk factors for major depression and depressive symptoms in youths could have important implications for prevention efforts. This study examined the association of polygenic risk scores (PRSs) for a broad depression phenotype derived from a large-scale genome-wide association study (GWAS) in adults, and its interaction with childhood abuse, with clinically relevant depression outcomes in clinical and epidemiological youth cohorts. Methods: The clinical cohort comprised 279 youths with major depression (mean age=14.76 years [SD=2.00], 68% female) and 187 healthy control subjects (mean age=14.67 years [SD=2.45], 63% female). The first epidemiological cohort included 1,450 youths (mean age=13.99 years [SD=0.92], 63% female). Of those, 694 who were not clinically depressed at baseline underwent follow-ups at 6, 12, and 24 months. The replication epidemiological cohort comprised children assessed at ages 8 (N=184; 49.2% female) and 11 (N=317; 46.7% female) years. All cohorts were genome-wide genotyped and completed measures for major depression, depressive symptoms, and/or childhood abuse. Summary statistics from the largest GWAS to date on depression were used to calculate the depression PRS. Results: In the clinical cohort, the depression PRS predicted case-control status (odds ratio=1.560, 95% CI=1.230–1.980), depression severity (β=0.177, SE=0.069), and age at onset (β=−0.375, SE=0.160). In the first epidemiological cohort, the depression PRS predicted baseline depressive symptoms (β=0.557, SE=0.200) and prospectively predicted onset of moderate to severe depressive symptoms (hazard ratio=1.202, 95% CI=1.045–1.383). The associations with depressive symptoms were replicated in the second epidemiological cohort. Evidence was found for an additive, but not an interactive, effect of the depression PRS and childhood abuse on depression outcomes. Conclusions: Depression PRSs derived from adults generalize to depression outcomes in youths and may serve as an early indicator of clinically significant levels of depression.

    更新日期:2019-08-01
  • Neurobiology of Self-Regulation: Longitudinal Influence of FKBP5 and Intimate Partner Violence on Emotional and Cognitive Development in Childhood
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-04-05
    Thorhildur Halldorsdottir; Dunja Kurtoic; Bertram Müller-Myhsok; Elisabeth B. Binder; Clancy Blair

    Objective: Self-regulation includes the volitional and nonvolitional regulation of emotional, cognitive, and physiological responses to stimulation. It develops from infancy through individual characteristics and the environment, with the stress hormone system as a central player. Accordingly, the authors hypothesized that genes involved in regulating the stress system, such as FK506 binding protein 5 (FKBP5), interact with early-life stress exposure, such as exposure to intimate partner violence (IPV), to predict self-regulation indicators and associated outcomes, including behavioral and learning problems in school. Methods: Study participants were a longitudinal birth cohort of 910 children for whom FKBP5 genotypes were available and who were assessed for exposure to IPV during the first 2 years of life as well as multiple measures of self-regulation: stress-induced cortisol reactivity and fear-elicited emotional reactivity at 7, 15, and 24 months, executive function at 36, 48, and 60 months, and emotional and behavioral difficulties and reading and math achievement in school grades 1, 2, and 5. Data were analyzed using longitudinal clustering and ordinal logistic regression procedures followed by mixed linear modeling. Results: Children with two copies of a risk FKBP5 haplotype and IPV exposure were significantly more likely to have a developmental trajectory characterized by high, prolonged stress-induced cortisol reactivity and emotional reactivity in toddlerhood, followed by low executive function at school entry and high emotional and behavior problems and low reading ability in the primary school grades. Conclusions: The interaction of FKBP5 and IPV affects the physiological response to stress early in life, with consequences for emotional and cognitive self-regulation. Targeting self-regulation may present an early intervention strategy for children facing genetic and environmental risk.

    更新日期:2019-08-01
  • Identifying Novel Types of Irritability Using a Developmental Genetic Approach
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-07-01
    Lucy Riglin; Olga Eyre; Ajay K. Thapar; Argyris Stringaris; Ellen Leibenluft; Daniel S. Pine; Kate Tilling; George Davey Smith; Michael C. O’Donovan; Anita Thapar

    Objective: Irritability, which is strongly associated with impairment and negative outcomes, is a common reason for referral to mental health services but is a nosological and treatment challenge. A major issue is how irritability should be conceptualized. The authors used a developmental approach to test the hypothesis that there are several forms of irritability, including a “neurodevelopmental/ADHD-like” type, with onset in childhood, and a “depression/mood” type, with onset in adolescence. Methods: Data were analyzed from the Avon Longitudinal Study of Parents and Children, a prospective U.K. population-based cohort. Irritability trajectory classes were estimated for 7,924 individuals with data at multiple time points across childhood and adolescence (four possible time points from approximately ages 7 to 15). Psychiatric diagnoses were assessed at approximately ages 7 and 15. Psychiatric genetic risk was indexed by polygenic risk scores (PRSs) for attention deficit hyperactivity disorder (ADHD) and depression, derived using large genome-wide association study results. Results: Five irritability trajectory classes were identified: low (81.2%), decreasing (5.6%), increasing (5.5%), late-childhood limited (5.2%), and high-persistent (2.4%). The early-onset high-persistent trajectory was associated with male preponderance, childhood ADHD (odds ratio=108.64, 95% CI=57.45–204.41), and ADHD PRS (odds ratio=1.31, 95% CI=1.09–1.58). The adolescent-onset increasing trajectory was associated with female preponderance, adolescent depression (odds ratio=5.14, 95% CI=2.47–10.73), and depression PRS (odds ratio=1.20, 95% CI=1.05–1.38). Both the early-onset high-persistent and adolescent-onset increasing trajectory classes were associated with adolescent depression diagnosis and ADHD PRS. Conclusions: The developmental context of irritability may be important in its conceptualization: early-onset persistent irritability may be more neurodevelopmental/ADHD-like and later-onset irritability more depression/mood-like. These findings have implications for treatment as well as nosology.

    更新日期:2019-08-01
  • A Third Linear Association Between Olduvai (DUF1220) Copy Number and Severity of the Classic Symptoms of Inherited Autism
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-02-15
    Jonathan M. Davis; Ilea Heft; Stephen W. Scherer; James M. Sikela

    Objective: The authors previously reported that the copy number of sequences encoding an Olduvai protein domain subtype (CON1) shows a linear association with the severity of social deficits and communication impairment in individuals with autism. In this study, using an improved measurement method, the authors replicated this association in an independent population. Method: The authors obtained whole genome sequence (WGS) data and phenotype data on 215 individuals from the Autism Speaks MSSNG project. They derived copy number from WGS data using a modified sequence read-depth technique. A linear mixed-effects model was used to test the association between Olduvai CON1 copy number and symptom severity as measured by the Autism Diagnostic Interview–Revised. The authors then combined data from previous studies (N=524) for final analyses. Results: A significant linear association was observed between CON1 copy number and social diagnostic score (SDS) (β=0.24) and communicative diagnostic score (CDS) (β=0.23). Using the combined data, the authors present strong significant associations of CON1 dosage with SDS (β=0.18) and CDS (β=0.13). The authors also implicate Olduvai subtypes found in two genes, NBPF1 and NBPF14 (R2=6.2%). Associations were preferentially found in multiplex versus simplex families. Conclusions: The finding of a third dose-dependent association between Olduvai sequences and autism severity, preferentially in multiplex families, provides strong evidence that this highly duplicated and underexamined protein domain family plays an important role in inherited autism.

    更新日期:2019-08-01
  • GWAS of Suicide Attempt in Psychiatric Disorders and Association With Major Depression Polygenic Risk Scores
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-06-05
    Niamh Mullins; Tim B. Bigdeli; Anders D. Børglum; Jonathan R.I. Coleman; Ditte Demontis; Divya Mehta; Robert A. Power; Stephan Ripke; Eli A. Stahl; Anna Starnawska; Adebayo Anjorin; M.R.C.Psych; Aiden Corvin; Alan R. Sanders; Andreas J. Forstner; Andreas Reif; Anna C. Koller; Beata Świątkowska; Bernhard T. Baune; Bertram Müller-Myhsok; Brenda W.J.H. Penninx; Carlos Pato; Clement Zai; Dan Rujescu; David M. Hougaard; Digby Quested; Douglas F. Levinson; Elisabeth B. Binder; Enda M. Byrne; Esben Agerbo; Dr.Med.Sc; Fabian Streit; Fermin Mayoral; Frank Bellivier; Franziska Degenhardt; Gerome Breen; Gunnar Morken; Gustavo Turecki; Guy A. Rouleau; Hans J. Grabe; Henry Völzke; Ian Jones; Ina Giegling; Ingrid Agartz; Ingrid Melle; Jacob Lawrence; M.R.C.Psych; James T.R. Walters; Jana Strohmaier; Jianxin Shi; Joanna Hauser; Joanna M. Biernacka; John B. Vincent; John Kelsoe; John S. Strauss; Jolanta Lissowska; Jonathan Pimm; M.R.C.Psych; Jordan W. Smoller; José Guzman-Parra; Klaus Berger; Laura J. Scott; Lisa A. Jones; M. Helena Azevedo; Maciej Trzaskowski; Manolis Kogevinas; Marcella Rietschel; Marco Boks; Marcus Ising; Maria Grigoroiu-Serbanescu; Marian L. Hamshere; Marion Leboyer; Mark Frye; Markus M. Nöthen; Martin Alda; Martin Preisig; Merete Nordentoft; Michael Boehnke; Michael C. O’Donovan; Michael J. Owen; Michele T. Pato; Miguel E. Renteria; Monika Budde; Dipl.-Psych; Myrna M. Weissman; Naomi R. Wray; Nicholas Bass; M.R.C.Psych; Nicholas Craddock; Olav B. Smeland; Ole A. Andreassen; Ole Mors; Pablo V. Gejman; Pamela Sklar; Patrick McGrath; Per Hoffmann; Peter McGuffin; Phil H. Lee; Preben Bo Mortensen; René S. Kahn; Roel A. Ophoff; Rolf Adolfsson; Sandra Van der Auwera; Srdjan Djurovic; Stefan Kloiber; Stefanie Heilmann-Heimbach; Stéphane Jamain; Steven P. Hamilton; Susan L. McElroy; Susanne Lucae; Sven Cichon; Thomas G. Schulze; Thomas Hansen; Thomas Werge; Tracy M. Air; Vishwajit Nimgaonkar; Vivek Appadurai; Wiepke Cahn; Yuri Milaneschi; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium; Bipolar Disorder Working Group of the Psychiatric Genomics Consortium; Schizophrenia Working Group of the Psychiatric Genomics Consortium; Ayman H. Fanous; Kenneth S. Kendler; Andrew McQuillin; Cathryn M. Lewis

    Objective: More than 90% of people who attempt suicide have a psychiatric diagnosis; however, twin and family studies suggest that the genetic etiology of suicide attempt is partially distinct from that of the psychiatric disorders themselves. The authors present the largest genome-wide association study (GWAS) on suicide attempt, using cohorts of individuals with major depressive disorder, bipolar disorder, and schizophrenia from the Psychiatric Genomics Consortium. Methods: The samples comprised 1,622 suicide attempters and 8,786 nonattempters with major depressive disorder; 3,264 attempters and 5,500 nonattempters with bipolar disorder; and 1,683 attempters and 2,946 nonattempters with schizophrenia. A GWAS on suicide attempt was performed by comparing attempters to nonattempters with each disorder, followed by a meta-analysis across disorders. Polygenic risk scoring was used to investigate the genetic relationship between suicide attempt and the psychiatric disorders. Results: Three genome-wide significant loci for suicide attempt were found: one associated with suicide attempt in major depressive disorder, one associated with suicide attempt in bipolar disorder, and one in the meta-analysis of suicide attempt in mood disorders. These associations were not replicated in independent mood disorder cohorts from the UK Biobank and iPSYCH. No significant associations were found in the meta-analysis of all three disorders. Polygenic risk scores for major depression were significantly associated with suicide attempt in major depressive disorder (R2=0.25%), bipolar disorder (R2=0.24%), and schizophrenia (R2=0.40%). Conclusions: This study provides new information on genetic associations and demonstrates that genetic liability for major depression increases risk for suicide attempt across psychiatric disorders. Further collaborative efforts to increase sample size may help to robustly identify genetic associations and provide biological insights into the etiology of suicide attempt.

    更新日期:2019-08-01
  • The Relationship Between Common Variant Schizophrenia Liability and Number of Offspring in the UK Biobank
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-01-04
    Valentina Escott-Price; Antonio F. Pardiñas; Enrique Santiago; James Walters; George Kirov; Michael J. Owen; Michael C. O’Donovan

    Objective: Schizophrenia is associated with a marked reduction in reproductive success, yet alleles that are common contribute substantially to the liability of the disorder. Among several possible explanations for this, it has been postulated that individuals who carry risk alleles but are unaffected are at some reproductive advantage, offsetting the effects of negative selection among those who are affected. The authors sought to test this hypothesis, isolating the effects of risk alleles on fecundity from the effects that are contingent on expressing schizophrenia. Methods: The burden of schizophrenia risk alleles, as indexed by a polygenic risk score (PRS), carried by 139,679 participants in the UK Biobank study who did not have schizophrenia was compared with the number of offspring of these individuals. Results: Higher schizophrenia liability in study subjects without manifest disorder was weakly but significantly associated with having more children (B=0.006, 95% CI=0.002, 0.010). The relationship was dependent on sex, with a positive correlation between number of children and liability among females (B=0.011, 95% CI=0.006, 0.016), whereas among males, higher liability was associated with being childless (odds ratio=0.96, 95% CI=0.94, 0.98). The negative effect on number of children associated with schizophrenia itself was twofold to 15-fold greater than the positive effect associated with PRS in unaffected individuals. Conclusions: These findings suggest that a complex relationship between liability and fecundity is consistent with sexual selection. Although the overall pattern of a weak positive correlation with liability may contribute to the persistence of schizophrenia risk alleles, these results indicate that the negative selection acting on individuals affected by schizophrenia in the general population is larger than any advantage conferred by genetic loading in unaffected individuals.

    更新日期:2019-08-01
  • A Reckoning and Research Agenda for Neuroimaging in Psychiatry
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-07-01
    Amit Etkin

    Human neuroimaging has been a core component of both research in psychiatry and conceptual models of the brain circuit-level mechanisms underlying psychopathology. Despite landmark neuroimaging research over the past 25 years, we still lack the level of precision and insight needed for bringing neuroimaging tools into clinical care contexts. This brief review examines historical research trends in psychiatric neuroimaging, as well as the basic assumptions underlying current efforts, in order to understand factors that have limited the impact of neuroimaging efforts thus far. These factors include the pitfalls of case-control designs, confounders inherent in associational research approaches, and the challenges in embracing fully data-driven analyses. Several critical gaps emerge, the addressing of which could provide the critical new insights that have long been sought from neuroimaging. These include transitioning from group-to individual-level analyses (and through this to intervention studies carried out robustly at the level of individual patients), building “big data” from a longitudinal perspective and not only a cross-sectional one, a greater focus on identifying causal mechanisms, and the development of tools such as electroencephalography in addition to the dominant MRI methods to aid translation to real-world clinical care. Despite the still-unrealized potential of psychiatric neuroimaging, there is now much to be excited about as previous learnings are converted into fundamentally new directions. Indeed, we may now be at an inflection point for neuroimaging if the typical study designs are left in the past and the field systematically and thoughtfully embraces the challenges that the past 25 years of research have now made apparent.

    更新日期:2019-07-01
  • Cerebellar-Prefrontal Network Connectivity and Negative Symptoms in Schizophrenia
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-01-30
    Roscoe O. Brady, Jr.; Irene Gonsalvez; Ivy Lee; Dost Öngür; Larry J. Seidman; Jeremy D. Schmahmann; Shaun M. Eack; Matcheri S. Keshavan; Alvaro Pascual-Leone; Mark A. Halko

    Objective: The interpretability of results in psychiatric neuroimaging is significantly limited by an overreliance on correlational relationships. Purely correlational studies cannot alone determine whether behavior-imaging relationships are causal to illness, functionally compensatory processes, or purely epiphenomena. Negative symptoms (e.g., anhedonia, amotivation, and expressive deficits) are refractory to current medications and are among the foremost causes of disability in schizophrenia. The authors used a two-step approach in identifying and then empirically testing a brain network model of schizophrenia symptoms. Methods: In the first cohort (N=44), a data-driven resting-state functional connectivity analysis was used to identify a network with connectivity that corresponds to negative symptom severity. In the second cohort (N=11), this network connectivity was modulated with 5 days of twice-daily transcranial magnetic stimulation (TMS) to the cerebellar midline. Results: A breakdown of connectivity in a specific dorsolateral prefrontal cortex-to-cerebellum network directly corresponded to negative symptom severity. Restoration of network connectivity with TMS corresponded to amelioration of negative symptoms, showing a statistically significant strong relationship of negative symptom change in response to functional connectivity change. Conclusions: These results demonstrate that a connectivity breakdown between the cerebellum and the right dorsolateral prefrontal cortex is associated with negative symptom severity and that correction of this breakdown ameliorates negative symptom severity, supporting a novel network hypothesis for medication-refractory negative symptoms and suggesting that network manipulation may establish causal relationships between network markers and clinical phenomena.

    更新日期:2019-07-01
  • Separable and Replicable Neural Strategies During Social Brain Function in People With and Without Severe Mental Illness
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-01-04
    Colin Hawco; Robert W. Buchanan; Navona Calarco; Benoit H. Mulsant; Joseph D. Viviano; Erin W. Dickie; Miklos Argyelan; James M. Gold; Marco Iacoboni; Pamela DeRosse; George Foussias; Anil K. Malhotra; Aristotle N. Voineskos; for the SPINS Group

    Objective: Case-control study design and disease heterogeneity may impede biomarker discovery in brain disorders, including serious mental illnesses. To identify biologically and/or behaviorally driven as opposed to diagnostically driven subgroups of individuals, the authors used hierarchical clustering to identify individuals with similar patterns of brain activity during a facial imitate/observe functional MRI task. Methods: Participants in the Social Processes Initiative in Neurobiology of the Schizophrenia(s) study (N=179; 109 with a schizophrenia spectrum disorder and 70 healthy control participants) underwent MRI scanning at three sites. Hierarchical clustering was used to identify new data-driven groups of participants; differences on social and neurocognitive tests completed outside the scanner were compared among the new groups. Results: Three clusters with distinct patterns of neural activity were found. Cluster membership was not related to diagnosis or scan site. The largest cluster consisted of “typical activators,” with activity in the canonical “simulation” circuit. The other clusters represented a “hyperactivating” group and a “deactivating” group. Between-participants Euclidean distances were smaller within clusters than within site or diagnostics groups. The deactivating group had the highest social cognitive and neurocognitive test scores. The hierarchical clustering analysis was repeated on a replication sample (N=108; 32 schizophrenia spectrum disorder, 37 euthymic bipolar disorder, and 39 healthy control participants), which exhibited the same three cluster patterns. Conclusions: The study findings demonstrate replicable differing patterns of neural activity among individuals during a socio-emotional task, independent of DSM diagnosis or scan site. The findings may provide objective neuroimaging endpoints (biomarkers) for subgroups of individuals in target engagement research aimed at enhancing cognitive performance independent of diagnostic category.

    更新日期:2019-07-01
  • Brain Imaging of the Cortex in ADHD: A Coordinated Analysis of Large-Scale Clinical and Population-Based Samples
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-04-24
    Martine Hoogman; Ryan Muetzel; Joao P. Guimaraes; Elena Shumskaya; Maarten Mennes; Marcel P. Zwiers; Neda Jahanshad; Gustavo Sudre; Thomas Wolfers; Eric A. Earl; Juan Carlos Soliva Vila; Yolanda Vives-Gilabert; Sabin Khadka; Stephanie E. Novotny; Catharina A. Hartman; Dirk J. Heslenfeld; Lizanne J.S. Schweren; Sara Ambrosino; Bob Oranje; Patrick de Zeeuw; Tiffany M. Chaim-Avancini; Pedro G.P. Rosa; Marcus V. Zanetti; Charles B. Malpas; Gregor Kohls; Georg G. von Polier; Jochen Seitz; Joseph Biederman; Alysa E. Doyle; Anders M. Dale; Theo G.M. van Erp; Jeffery N. Epstein; Terry L. Jernigan; Ramona Baur-Streubel; Georg C. Ziegler; Kathrin C. Zierhut; Anouk Schrantee; Marie F. Høvik; Astri J. Lundervold; Clare Kelly; Hazel McCarthy; Norbert Skokauskas; Ruth L. O’Gorman Tuura; Anna Calvo; Sara Lera-Miguel; Rosa Nicolau; Kaylita C. Chantiluke; Anastasia Christakou; Alasdair Vance; Mara Cercignani; Matt C. Gabel; Philip Asherson; Sarah Baumeister; Daniel Brandeis; Sarah Hohmann; Ivanei E. Bramati; Fernanda Tovar-Moll; Andreas J. Fallgatter; Bernd Kardatzki; Lena Schwarz; Anatoly Anikin; Alexandr Baranov; Tinatin Gogberashvili; Dmitry Kapilushniy; Anastasia Solovieva; Hanan El Marroun; Tonya White; Georgii Karkashadze; Leyla Namazova-Baranova; Thomas Ethofer; Paulo Mattos; Tobias Banaschewski; David Coghill; Kerstin J. Plessen; Jonna Kuntsi; Mitul A. Mehta; Yannis Paloyelis; Neil A. Harrison; Mark A. Bellgrove; Tim J. Silk; Ana I. Cubillo; Katya Rubia; Luisa Lazaro; Silvia Brem; Susanne Walitza; Thomas Frodl; Mariam Zentis; Francisco X. Castellanos; Yuliya N. Yoncheva; Jan Haavik; Liesbeth Reneman; Annette Conzelmann; Klaus-Peter Lesch; Paul Pauli; Andreas Reif; Leanne Tamm; Kerstin Konrad; Eileen Oberwelland Weiss; Geraldo F. Busatto; Mario R. Louza; Sarah Durston; Pieter J. Hoekstra; Jaap Oosterlaan; Michael C. Stevens; J. Antoni Ramos-Quiroga; Oscar Vilarroya; Damien A. Fair; Joel T. Nigg; Paul M. Thompson; Jan K. Buitelaar; Stephen V. Faraone; Philip Shaw; Henning Tiemeier; Janita Bralten; Barbara Franke

    Objective: Neuroimaging studies show structural alterations of various brain regions in children and adults with attention deficit hyperactivity disorder (ADHD), although nonreplications are frequent. The authors sought to identify cortical characteristics related to ADHD using large-scale studies. Methods: Cortical thickness and surface area (based on the Desikan–Killiany atlas) were compared between case subjects with ADHD (N=2,246) and control subjects (N=1,934) for children, adolescents, and adults separately in ENIGMA-ADHD, a consortium of 36 centers. To assess familial effects on cortical measures, case subjects, unaffected siblings, and control subjects in the NeuroIMAGE study (N=506) were compared. Associations of the attention scale from the Child Behavior Checklist with cortical measures were determined in a pediatric population sample (Generation-R, N=2,707). Results: In the ENIGMA-ADHD sample, lower surface area values were found in children with ADHD, mainly in frontal, cingulate, and temporal regions; the largest significant effect was for total surface area (Cohen’s d=−0.21). Fusiform gyrus and temporal pole cortical thickness was also lower in children with ADHD. Neither surface area nor thickness differences were found in the adolescent or adult groups. Familial effects were seen for surface area in several regions. In an overlapping set of regions, surface area, but not thickness, was associated with attention problems in the Generation-R sample. Conclusions: Subtle differences in cortical surface area are widespread in children but not adolescents and adults with ADHD, confirming involvement of the frontal cortex and highlighting regions deserving further attention. Notably, the alterations behave like endophenotypes in families and are linked to ADHD symptoms in the population, extending evidence that ADHD behaves as a continuous trait in the population. Future longitudinal studies should clarify individual lifespan trajectories that lead to nonsignificant findings in adolescent and adult groups despite the presence of an ADHD diagnosis.

    更新日期:2019-07-01
  • Development and Validation of a Dementia Risk Prediction Model in the General Population: An Analysis of Three Longitudinal Studies
    Am. J. Psychiatry (IF 13.655) Pub Date : 2018-12-11
    Silvan Licher; Maarten J.G. Leening; Pinar Yilmaz; Frank J. Wolters; Jan Heeringa; Patrick J.E. Bindels; Alzheimer’s Disease Neuroimaging Initiative; Meike W. Vernooij; Blossom C.M. Stephan; Ewout W. Steyerberg; M. Kamran Ikram; M. Arfan Ikram

    Objective: Identification of individuals at high risk of dementia is essential for development of prevention strategies, but reliable tools are lacking for risk stratification in the population. The authors developed and validated a prediction model to calculate the 10-year absolute risk of developing dementia in an aging population. Methods: In a large, prospective population-based cohort, data were collected on demographic, clinical, neuropsychological, genetic, and neuroimaging parameters from 2,710 nondemented individuals age 60 or older, examined between 1995 and 2011. A basic and an extended model were derived to predict 10-year risk of dementia while taking into account competing risks from death due to other causes. Model performance was assessed using optimism-corrected C-statistics and calibration plots, and the models were externally validated in the Dutch population-based Epidemiological Prevention Study of Zoetermeer and in the Alzheimer’s Disease Neuroimaging Initiative cohort 1 (ADNI-1). Results: During a follow-up of 20,324 person-years, 181 participants developed dementia. A basic dementia risk model using age, history of stroke, subjective memory decline, and need for assistance with finances or medication yielded a C-statistic of 0.78 (95% CI=0.75, 0.81). Subsequently, an extended model incorporating the basic model and additional cognitive, genetic, and imaging predictors yielded a C-statistic of 0.86 (95% CI=0.83, 0.88). The models performed well in external validation cohorts from Europe and the United States. Conclusions: In community-dwelling individuals, 10-year dementia risk can be accurately predicted by combining information on readily available predictors in the primary care setting. Dementia prediction can be further improved by using data on cognitive performance, genotyping, and brain imaging. These models can be used to identify individuals at high risk of dementia in the population and are able to inform trial design.

    更新日期:2019-07-01
  • Evidence for Network-Based Cortical Thickness Reductions in Schizophrenia
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-06-05
    Cassandra M.J. Wannan; Vanessa L. Cropley; M. Mallar Chakravarty; Chad Bousman; Eleni P. Ganella; Jason M. Bruggemann; Thomas W. Weickert; Cynthia Shannon Weickert; Ian Everall; Patrick McGorry; Dennis Velakoulis; Stephen J. Wood; Cali F. Bartholomeusz; Christos Pantelis; Andrew Zalesky

    Objective: Cortical thickness reductions in schizophrenia are irregularly distributed across multiple loci. The authors hypothesized that cortical connectivity networks would explain the distribution of cortical thickness reductions across the cortex, and, specifically, that cortico-cortical connectivity between loci with these reductions would be exceptionally strong and form an interconnected network. This hypothesis was tested in three cross-sectional schizophrenia cohorts: first-episode psychosis, chronic schizophrenia, and treatment-resistant schizophrenia. Methods: Structural brain images were acquired for 70 patients with first-episode psychosis, 153 patients with chronic schizophrenia, and 47 patients with treatment-resistant schizophrenia and in matching healthy control groups (N=57, N=168, and N=54, respectively). Cortical thickness was compared between the patient and respective control groups at 148 regions spanning the cortex. Structural connectivity strength between pairs of cortical regions was quantified with structural covariance analysis. Connectivity strength between regions with cortical thickness reductions was compared with connectivity strength between 5,000 sets of randomly chosen regions to establish whether regions with reductions were interconnected more strongly than would be expected by chance. Results: Significant (false discovery rate corrected) and widespread cortical thickness reductions were found in the chronic schizophrenia (79 regions) and treatment-resistant schizophrenia (106 regions) groups, with more circumscribed reductions in the first-episode psychosis group (34 regions). Cortical thickness reductions with the largest effect sizes were found in frontal, temporal, cingulate, and insular regions. In all cohorts, both the patient and healthy control groups showed significantly increased structural covariance between regions with cortical thickness reductions compared with randomly selected regions. Conclusions: Brain network architecture can explain the irregular topographic distribution of cortical thickness reductions in schizophrenia. This finding, replicated in three distinct schizophrenia cohorts, suggests that the effect is robust and independent of illness stage.

    更新日期:2019-07-01
  • Association of Choroid Plexus Enlargement With Cognitive, Inflammatory, and Structural Phenotypes Across the Psychosis Spectrum
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-06-05
    Paulo Lizano; Olivia Lutz; George Ling; Adam M. Lee; Seenae Eum; Jeffrey R. Bishop; Sinead Kelly; Ofer Pasternak; Brett Clementz; Godfrey Pearlson; John A. Sweeney; Elliot Gershon; Carol Tamminga; Matcheri Keshavan

    Objective: The choroid plexus is an important physiological barrier and produces CSF and neurotrophic, angiogenic, and inflammatory factors involved in brain development. Choroid plexus abnormalities have been implicated in both schizophrenia and bipolar disorder. A previous choroid plexus transcriptomic analysis of schizophrenia identified an upregulation of immune and inflammatory genes that correlated with peripheral inflammatory markers. The purpose of this study was to examine choroid plexus volume in probands across the psychosis spectrum and in their first-degree and axis II cluster A relatives, as well as choroid plexus familiality and choroid plexus covariance with clinical, cognitive, brain, and peripheral marker measures. Methods: Choroid plexus volume was quantified (using FreeSurfer) in psychosis probands, their first-degree and axis II cluster A relatives, and healthy control subjects, organized by DSM-IV-TR diagnosis. Analyte, structural connectivity, and genotype data were collected from a subset of study subjects. Results: Choroid plexus volume was significantly larger in probands compared with first-degree relatives or healthy control subjects; first-degree relatives had intermediate enlargement compared with healthy control subjects; and total choroid plexus volume was significantly heritable. Larger volume was associated with worse cognition, smaller total gray matter and amygdala volume, larger lateral ventricle volume, and lower structural connectivity in probands. Associations between larger volume and higher levels of interleukin 6 in probands was also observed. Conclusions: These findings suggest the involvement of the choroid plexus across the psychosis spectrum with a potential pathophysiological mechanism involving the neuroimmune axis, which functions in maintaining brain homeostasis and interacting with the peripheral immune and inflammatory system. The choroid plexus may be an important target in future research.

    更新日期:2019-07-01
  • Reports to the Membership
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-07-01

    The following are edited/abbreviated versions of the annual reports of the APA Secretary, Treasurer, CEO and Medical Director, Speaker, and Speaker-Elect and the chairpersons of the APA Committee on Bylaws, Membership Committee, Committee of Tellers, and Elections Committee. The full reports were presented at the APA Annual Business Meeting in San Francisco, May 18, 2019.

    更新日期:2019-07-01
  • Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study
    Am. J. Psychiatry (IF 13.655) Pub Date : 2019-05-21
    Vanina Popova; Ella J. Daly; Madhukar Trivedi; Kimberly Cooper; Rosanne Lane; Pilar Lim; Christine Mazzucco; David Hough; Michael E. Thase; Richard C. Shelton; Patricio Molero; Eduard Vieta; Malek Bajbouj; Husseini Manji; Wayne C. Drevets; Jaskaran B. Singh

    Objective: About one-third of patients with depression fail to achieve remission despite treatment with multiple antidepressants. This study compared the efficacy and safety of switching patients with treatment-resistant depression from an ineffective antidepressant to flexibly dosed esketamine nasal spray plus a newly initiated antidepressant or to a newly initiated antidepressant (active comparator) plus placebo nasal spray. Methods: This was a phase 3, double-blind, active-controlled, multicenter study conducted at 39 outpatient referral centers. The study enrolled adults with moderate to severe nonpsychotic depression and a history of nonresponse to at least two antidepressants in the current episode, with one antidepressant assessed prospectively. Confirmed nonresponders were randomly assigned to treatment with esketamine nasal spray (56 or 84 mg twice weekly) and an antidepressant or antidepressant and placebo nasal spray. The primary efficacy endpoint, change from baseline to day 28 in Montgomery-Åsberg Depression Rating Scale (MADRS) score, was assessed by a mixed-effects model using repeated measures. Results: Of 435 patients screened, 227 underwent randomization and 197 completed the 28-day double-blind treatment phase. Change in MADRS score with esketamine plus antidepressant was significantly greater than with antidepressant plus placebo at day 28 (difference of least square means=−4.0, SE=1.69, 95% CI=−7.31, −0.64); likewise, clinically meaningful improvement was observed in the esketamine plus antidepressant arm at earlier time points. The five most common adverse events (dissociation, nausea, vertigo, dysgeusia, and dizziness) all were observed more frequently in the esketamine plus antidepressant arm than in the antidepressant plus placebo arm; 7% and 0.9% of patients in the respective treatment groups discontinued study drug because of an adverse event. Adverse events in the esketamine plus antidepressant arm generally appeared shortly after dosing and resolved by 1.5 hours after dosing. Conclusions: Current treatment options for treatment-resistant depression have considerable limitations in terms of efficacy and patient acceptability. Esketamine is expected to address an unmet medical need in this population through its novel mechanism of action and rapid onset of antidepressant efficacy. The study supports the efficacy and safety of esketamine nasal spray as a rapidly acting antidepressant for patients with treatment-resistant depression.

    更新日期:2019-06-03
Contents have been reproduced by permission of the publishers.
导出
全部期刊列表>>
2020新春特辑
限时免费阅读临床医学内容
ACS材料视界
科学报告最新纳米科学与技术研究
清华大学化学系段昊泓
自然科研论文编辑服务
中国科学院大学楚甲祥
中国科学院微生物研究所潘国辉
中国科学院化学研究所
课题组网站
X-MOL
北京大学分子工程苏南研究院
华东师范大学分子机器及功能材料
中山大学化学工程与技术学院
试剂库存
天合科研
down
wechat
bug