Journal of psychiatry and brain science最新文献

Background: Results from studies using medical record data indicate chronic (>90 days) opioid analgesic use (OAU) is associated with new depressive episodes (NDE), worsening depression and risk for depression recurrence. This body of evidence is based on retrospective cohort studies and medical record data. Limitations of existing research are overcome in a new prospective cohort study of the opioid-depression relationship.

Methods: Prospective cohort of 1500 adult patients recruited from two health care systems. Eligible subjects started a new period of OAU and have 30 to 90 days of OAU at baseline. Diagnostic assessments for psychiatric disorders, structured measures of pain, pain functioning, opioid use, social support, sleep and impulsivity will be obtained at baseline, 6-month and 12-month follow-up. Baseline participants will be invited to 12 monthly brief assessments of pain-related functioning, depression symptoms and opioid use.

Innovation: Robust control for confounding by indication and detailed phenotyping of depression and opioid use disorder.

Anticipated results: Chronic OAU will be associated with new onset of a depression phenotype characterized by anhedonia and somatic symptoms. This relationship will be partly, but not completely explained by impaired functioning and low social support.

Conclusions: Although the annual number of opioid prescriptions in the United States has decreased, over 190 million patients have OAU each year. If chronic OAU leads to a clinically meaningful affective disorder, independent of pain, then we need to consider depression an important adverse effect of chronic OAU and adjust care for chronic pain accordingly.

ADHD is defined by behavioral symptoms that are not well characterized in relation to ADHD's neurobiological mechanisms. This approach has limited our ability to define ADHD nosology and predict outcomes because it does not systematically examine facets of the disorder such as the inability to maintain cognitively effortful activities, as promoted in the NIMH RDoC approach. Existing data indicate ADHD is associated with differences in reward valuation and processing, but we do not know whether ADHD is also associated with higher levels of aversion to exerting cognitive effort and/or altered reward x effort interactions. Our ongoing study addresses this knowledge gap by examining individuals' preferences between rewards associated with minimal effort and reward alternatives with a higher payoff but higher effort costs ("effort discounting"); thereby permitting us to characterize differences in biases and tradeoffs during effort-related decision-making in ADHD. The study takes advantage of a well-defined sample of ADHD-diagnosed and healthy control individuals to address three aims. First, we determine whether ADHD is associated with steeper discounting of larger, more effortful rewards. Second, we examine the subjective perception of effort in youth diagnosed with ADHD and healthy controls using tasks requiring varying levels of cognitive effort. Third, we explore relationships amongst indices of effort discounting, theoretically-related traits (e.g., grit, distress tolerance), biomarkers of effort-related decision-making (eye movements and pupil size), and various cognitive measures. Successful completion of the aims will permit us to better characterize ADHD-healthy control differences and lay a foundation for more computational approaches to ADHD diagnostic criteria.

Schizophrenia and other psychotic disorders are serious psychiatric disorders that are associated with substantial societal, family, and individual costs/distress. Evidence suggests that early intervention can improve prognostic outcomes; therefore, it is essential to accurately identify those at risk for psychosis before full psychotic symptoms emerge. The purpose of our study is to develop a brief, valid screening questionnaire to identify individuals at risk for psychosis in non-clinical populations across 3 large, community catchment areas with diverse populations. This is a needed study, as the current screening tools for at-risk psychotic populations in the US have been validated only in clinical and/or treatment seeking samples, which are not likely to generalize beyond these specialized settings. The specific aims are as follows: (1) to determine norms and prevalence rates of attenuated positive psychotic symptoms across 3 diverse, community catchment areas and (2) to develop a screening questionnaire, inclusive of both symptom-based and risk factor-based questions. Our study will develop an essential screening tool that will identify which individuals have the greatest need of follow-up with structured interviews in both research and clinical settings. Our study has the potential for major contributions to the early detection and prevention of psychotic disorders.

We report on the ongoing project "A Novel Therapeutic to Ameliorate Chronic Pain and Reduce Opiate Use." Over 100 million adults in the U.S. suffer from intermittent or constant chronic pain, and chronic pain affects at least 10% of the world's population. The primary pharmaceuticals for treatment of chronic pain have been natural or synthetic opioids and the use of opioids for pain treatment has resulted in what has been called an "epidemic" of opioid abuse, addiction and lethal overdoses. We have, through a process of rational drug design, generated a novel chemical entity (NCE) and have given it the name Kindolor. Kindolor is a non-opiate, non-addicting molecule that was developed specifically to simultaneously control the aberrant activity of three targets on the peripheral sensory system that are integral in the development and propagation of chronic pain. In our initial preclinical studies, we demonstrated the efficacy of Kindolor to reduce or eliminate chronic pain in five animal models. The overall goal of the project is to complete the investigational new drug (IND)-enabling preclinical studies of Kindolor, and once IND approval is gained, we will proceed to the clinical Phase Ia and 1b safety studies and a Phase 2a efficacy study. The work is in its second year, and the present report describes progress toward our overall goal of bringing our compound to a full Phase 2 ready stage.

Major depressive disorder (MDD) is a serious public health problem that has, at best, modest treatment response-potentially due to its heterogeneous clinical presentation. One way to parse the heterogeneity is to investigate the role of particular features of MDD, an endeavor that can also help identify novel and focal targets for treatment and prevention efforts. Our R01 focuses on the feature of psychomotor disturbance (e.g., psychomotor agitation (PmA) and retardation (PmR)), a particularly pernicious feature of MDD, that has not been examined extensively in MDD. Aim 1 is comparing three groups of individuals-those with current MDD (n = 100), remitted MDD (n = 100), and controls (n = 50)-on multiple measures of PmR and PmA (assessed both in the lab and in the subjects' natural environment). Aim 2 is examining the structural (diffusion MRI) and functional (resting state fMRI) connectivity of motor circuitry of the three groups as well as the relation between motor circuitry and the proposed indicators of PmR and PmA. Aim 3 is following up with subjects three times over 18 months to evaluate whether motor symptoms change in tandem with overall depressive symptoms and functioning over time and/or whether baseline PmR/PmA predicts course of depression and functioning. Aim 3 is particularly clinically significant. Finding that motor functioning and overall depression severity co-vary over time, or that motor variables predict subsequent change in overall depression severity, would support the potential clinical utility of these novel, reliable, and easily administered motor assessments.

Social dysfunction is an intractable problem in a wide spectrum of psychiatric illnesses, undermining patients' capacities for employment, independent living, and maintaining meaningful relationships. Identifying common markers of social impairment across disorders and understanding their mechanisms are prerequisites to developing targeted neurobiological treatments that can be applied productively across diagnoses and illness stages to improve functional outcome. This project focuses on eye gaze perception, the ability to accurately and efficiently discriminate others' gaze direction, as a potential biomarker of social functioning that cuts across psychiatric diagnoses. This premise builds on both the monkey and human literatures showing gaze perception as a basic building block supporting higher-level social communication and social development, and reports of abnormal gaze perception in multiple psychiatric conditions accompanied by prominent social dysfunction (e.g., psychosis-spectrum disorders, autism-spectrum disorders, social phobia). A large sample (n = 225) of adolescent and young adult (age 14-30) psychiatric patients (regardless of diagnosis) with various degrees of impaired social functioning, and demographically-matched healthy controls (n = 75) will be recruited for this study. Participant's psychiatric phenotypes, cognition, social cognition, and community functioning will be dimensionally characterized. Eye gaze perception will be assessed using a psychophysical task, and two metrics (precision, self-referential bias) that respectively tap into gaze perception disturbances at the visual perceptual and interpretation levels, independent of general deficits, will be derived using hierarchical Bayesian modeling. A subset of the participants (150 psychiatric patients, 75 controls) will additionally undergo multimodal fMRI to determine the functional and structural brain network features of altered gaze perception. The specific aims of this project are three-fold: (1) Determine the generality of gaze perception disturbances in psychiatric patients with prominent social dysfunction; (2) Map behavioral indices of gaze perception disturbances to dimensions of psychiatric phenotypes and core functional domains; and (3) Identify the neural correlates of altered gaze perception in psychiatric patients with social dysfunction. Successfully completing these specific aims will identify the specific basic deficits, clinical profile, and underlying neural circuits associated with social dysfunction that can be used to guide targeted, personalized treatments, thus advancing NIMH's Strategic Objective 1 (describe neural circuits associated with mental illnesses and map the connectomes for mental illnesses) and Objective 3 (develop new treatments based on discoveries in neuroscience and behavioral science).

Background: Depression is associated with a broad range of cognitive deficits, including processing speed (PS) and executive functioning (EF). Cognitive symptoms commonly persist with the resolution of affective symptoms and increase risk of relapse and recurrence. The cognitive control network is comprised of brain areas implicated in EF and mood regulatory functions. Prior research has demonstrated the effectiveness of computerized cognitive training (CCT) focused on PS and EF in mitigating both cognitive and affective symptoms of depression.

Methods: Ninety participants aged 18-29 with a current diagnosis of major depressive disorder or persistent depressive disorder, or a Hamilton Depression Rating Scale score ≥12, will be randomized to either PS/EF CCT, verbal CCT, or waitlist control. Participants in the active groups will complete 15 min of training 5 days/week for 8 weeks. Clinical and neuropsychological assessments will be completed at baseline, week 4, week 8, and 3-month follow-up. Structural and functional magnetic resonance imaging (fMRI) will be completed at baseline and week 8. We will compare changes in mood, cognition, daily functioning, and fMRI data. We will explore cognitive control network functioning using resting-state and task-based fMRI.

Results: Recruitment began in October 2019; we expect to finish recruitment by April 2022 and subsequently begin data analysis.

Conclusions: This study is innovative in that it will include both active and waitlist control conditions and will explore changes in neural activation. Identifying the neural networks associated with improvements following CCT will allow for the development of more precise and effective interventions.

Trial registration: ClinicalTrials.gov NCT03869463; https://clinicaltrials.gov/ct2/show/NCT03869463.

This report describes the protocol for an ongoing project funded by the National Institutes of Health (R01MH108155) that is focused on effects of childhood maltreatment (MALTX) on neurocircuitry changes associated with adolescent major depressive disorder (MDD). Extant clinical and neuroimaging literature on MDD is reviewed, which has relied on heterogeneous samples that do not parse out the unique contribution of MALTX on neurobiological changes in MDD. Employing a 2 × 2 study design (controls with no MALTX or MDD, MALTX only, MDD only, and MDD + MALTX), and based on a cohesive theoretical model that incorporates behavioral, cognitive and neurobiological domains, we describe the multi-modal neuroimaging techniques used to test whether structural and functional alterations in the fronto-limbic and fronto-striatal circuits associated with adolescent MDD are moderated by MALTX. We hypothesize that MDD + MALTX youth will show alterations in the fronto-limbic circuit, with reduced connectivity between the amygdala (AMG) and the prefrontal cortex (PFC), as the AMG is sensitive to stress/threat during development. Participants with MDD will exhibit increased functional connectivity between the AMG and PFC due to self-referential negative emotions. Lastly, MDD + MALTX will only show changes in motivational/anticipatory aspects of the fronto-striatal circuit, and MDD will exhibit changes in motivational and consummatory/outcome aspects of reward-processing. Our goal is to identify distinct neural substrates associated with MDD due to MALTX compared to other causes, as these markers could be used to more effectively predict treatment outcome, index treatment response, and facilitate alternative treatments for adolescents who do not respond well to traditional approaches.

Psychotic disorders are severe, debilitating, and even fatal. The development of targeted and effective interventions for psychosis depends upon on clear understanding of the timing and nature of disease progression to target processes amenable to intervention. Strong evidence suggests early and ongoing neuroprogressive changes, but timing and inflection points remain unclear and likely differ across cognitive, clinical, and brain measures. Additionally, granular evidence across modalities is particularly sparse in the "bridging years" between first episode and established illness-years that may be especially critical for improving outcomes and during which interventions may be maximally effective. Our objective is the systematic, multimodal characterization of neuroprogression through the early course of illness in a cross-diagnostic sample of patients with psychosis. We aim to (1) interrogate neurocognition, structural brain measures, and network connectivity at multiple assessments over the first eight years of illness to map neuroprogressive trajectories, and (2) examine trajectories as predictors of clinical and functional outcomes. We will recruit 192 patients with psychosis and 36 healthy controls. Assessments will occur at baseline and 8- and 16-month follow ups using clinical, cognitive, and imaging measures. We will employ an accelerated longitudinal design (ALD), which permits ascertainment of data across a longer timeframe and at more frequent intervals than would be possible in a single cohort longitudinal study. Results from this study are expected to hasten identification of actionable treatment targets that are closely associated with clinical outcomes, and identify subgroups who share common neuroprogressive trajectories toward the development of individualized treatments.

It is now well documented that schizophrenia is associated with impairments in visual processing at all levels of vision, and that these disturbances are related to deficits in multiple higher-level cognitive and social cognitive functions. Visual remediation methods have been slow to appear in the literature as a potential treatment strategy to target these impairments, however, in contrast to interventions that aim to improve auditory and higher cognitive functions in schizophrenia. In this report, we describe a National Institute of Mental Health (NIMH)-funded R61/R33 grant that uses a phased approach to optimize and evaluate a novel visual remediation intervention for people with schizophrenia. The goals of this project are: (1) in the R61 phase, to establish the optimal components and dose (number of sessions) of a visual remediation intervention from among two specific visual training strategies (and their combination) for improving low and mid-level visual functions in schizophrenia; and (2) in the R33 phase, to determine the extent to which the optimal intervention improves not only visual processing but also higher-level cognitive and role functions. Here we present the scientific background for and innovation of the study, along with our methods, hypotheses, and preliminary data. The results of this study will help determine the utility of this novel intervention approach for targeting visual perceptual, cognitive, and functional impairments in schizophrenia.