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1.  The bi-directional associations between psychotic experiences and DSM-IV mental disorders 
The American journal of psychiatry  2016;173(10):997-1006.
While it is now recognized that psychotic experiences (PEs) are associated with an increased risk of later mental disorders, we lack a detailed understanding of the reciprocal time-lagged relationships between first onsets of PEs and mental disorders.
The WHO World Mental Health (WMH) surveys assessed lifetime prevalence and age-of-onset of PEs and 21 common DSM-IV mental disorders among 31,261 adult respondents from 18 countries.
Temporally primary PEs were significantly associated with subsequent first onset of 8 of the 21 mental disorders (major depressive disorder, bipolar disorder, generalized anxiety disorder, social phobia, post-traumatic stress disorder, adult separation anxiety disorder, bulimia nervosa, alcohol abuse), with ORs (95%CI) ranging from 1.3 (1.2–1.5; major depressive disorder) to 2.0 (1.5–2.6; bipolar disorder). In contrast, 18 of 21 primary mental disorders were significantly associated with subsequent first onset of PEs, with ORs (95% CI) ranging from 1.5 (1.0–2.1; childhood separation anxiety disorder) to 2.8 (1.0–7.8; anorexia nervosa).
While temporally primary PEs are associated with an elevated risk of several subsequent mental disorders, we found that most mental disorder are associated with an elevated risk of subsequent PEs. Further investigation of the underlying factors accounting for these time-order relationships might shed light on the etiology of PEs.
PMCID: PMC5175400  PMID: 26988628
2.  Management of Alcohol Use Disorder in Patients Requiring Liver Transplant 
The American journal of psychiatry  2015;172(12):1182-1189.
Alcoholic liver disease is the second most common indication for orthotopic liver transplantation in western countries. The majority of patients with alcoholic liver disease, however, are not referred for transplant evaluation. If evaluated, a 6 month period of sobriety is required before waitlisting for transplant. The consequences of relapse to alcohol use in patients on the waitlist are usually removal from the list. Therefore, identification and treatment of alcohol use disorder in patients with end-stage liver disease greatly impacts quality of life, treatment options and survival in patients’ course with this grave illness. Psychosocial and behavioral interventions prior to transplant appear to reduce drinking in the period before the surgery as well as reduce relapse rates post-transplant. Only one of the three medications approved by the Food and Drug Administration, acamprosate, seems feasible for use in patients with end-stage liver disease, while several other medications currently under investigation for the treatment of alcohol use disorder can be considered for use in this population. While only baclofen has been formally studied in alcoholic patients with end-stage liver disease with positive results for safety and efficacy, other medications also hold promise to treat alcohol use disorder in this population. Transplant programs with addictions specialists who function as an integral part of the treatment team may offer better outcomes to patients in terms of success of maintaining sobriety both pre- and post-transplant.
PMCID: PMC4930850  PMID: 26619772
3.  Prospective Longitudinal Evaluation of the Effect of Deployment-Acquired Traumatic Brain Injury on Posttraumatic Stress and Related Disorders: Results From the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) 
The American journal of psychiatry  2015;172(11):1101-1111.
Traumatic brain injury (TBI) is increasingly recognized as a risk factor for deleterious mental health and functional outcomes. The purpose of this study was to examine the strength and specificity of the association between deployment-acquired TBI and subsequent posttraumatic stress and related disorders among U.S. Army personnel.
A prospective, longitudinal survey of soldiers in three Brigade Combat Teams was conducted 1–2 months prior to an average 10-month deployment to Afghanistan (T0), upon redeployment to the United States (T1), approximately 3 months later (T2), and approximately 9 months later (T3). Outcomes of interest were 30-day prevalence postdeployment of posttraumatic stress disorder (PTSD), major depressive episode, generalized anxiety disorder, and suicidality, as well as presence and severity of postdeployment PTSD symptoms.
Complete information was available for 4,645 soldiers. Approximately one in five soldiers reported exposure to mild (18.0%) or more-than-mild (1.2%) TBI(s) during the index deployment. Even after adjusting for other risk factors (e.g., predeployment mental health status, severity of deployment stress, prior TBI history), deployment-acquired TBI was associated with elevated adjusted odds of PTSD and generalized anxiety disorder at T2 and T3 and of major depressive episode at T2. Suicidality risk at T2 appeared similarly elevated, but this association did not reach statistical significance.
The findings highlight the importance of surveillance efforts to identify soldiers who have sustained TBIs and are therefore at risk for an array of postdeployment adverse mental health outcomes, including but not limited to PTSD. The mechanism(s) accounting for these associations need to be elucidated to inform development of effective preventive and early intervention programs.
PMCID: PMC5125442  PMID: 26337036
4.  Pediatric-Onset and Adult-Onset Separation Anxiety Disorder Across Countries in the World Mental Health Survey 
The American journal of psychiatry  2015;172(7):647-656.
The age-at-onset criterion for separation anxiety disorder was removed in DSM-5, making it timely to examine the epidemiology of separation anxiety disorder as a disorder with onsets spanning the life course, using cross-country data.
The sample included 38,993 adults in 18 countries in the World Health Organization (WHO) World Mental Health Surveys. The WHO Composite International Diagnostic Interview was used to assess a range of DSM-IV disorders that included an expanded definition of separation anxiety disorder allowing onsets in adulthood. Analyses focused on prevalence, age at onset, comorbidity, predictors of onset and persistence, and separation anxiety-related role impairment.
Lifetime separation anxiety disorder prevalence averaged 4.8% across countries (interquartile range [25th–75th percentiles]=1.4%–6.4%), with 43.1% of lifetime onsets occurring after age 18. Significant time-lagged associations were found between earlier separation anxiety disorder and subsequent onset of internalizing and externalizing DSM-IV disorders and conversely between these disorders and subsequent onset of separation anxiety disorder. Other consistently significant predictors of lifetime separation anxiety disorder included female gender, retrospectively reported childhood adversities, and lifetime traumatic events. These predictors were largely comparable for separation anxiety disorder onsets in childhood, adolescence, and adulthood and across country income groups. Twelve-month separation anxiety disorder prevalence was considerably lower than lifetime prevalence (1.0% of the total sample; interquartile range=0.2%–1.2%). Severe separation anxiety-related 12-month role impairment was significantly more common in the presence (42.4%) than absence (18.3%) of 12-month comorbidity.
Separation anxiety disorder is a common and highly comorbid disorder that can have onset across the lifespan. Childhood adversity and lifetime trauma are important antecedents, and adverse effects on role function make it a significant target for treatment.
PMCID: PMC5116912  PMID: 26046337
5.  Smoking and Schizophrenia in Population Cohorts of Swedish Women and Men: A Prospective Co-Relative Control Study 
The American journal of psychiatry  2015;172(11):1092-1100.
The purpose of this study was to clarify the causes of the smoking-schizophrenia association.
Using Cox proportional hazard and co-relative control models, the authors predicted future risk for a diagnosis of schizophrenia or nonaffective psychosis from the smoking status of 1,413,849 women and 233,879 men from, respectively, the Swedish birth and conscript registries.
Smoking was assessed in women at a mean age of 27 and in men at a mean age of 18. The mean age at end of follow-up was 46 for women and 26 for men. Hazard ratios for first-onset schizophrenia were elevated both for light smoking (2.21 [95% CI=1.90–2.56] for women and 2.15 [95% CI=1.25–3.44] for men) and heavy smoking (3.45 [95% CI=2.95–4.03] for women and 3.80 [95% CI=1.19–6.60] for men). These associations did not decline when schizophrenia onsets 3–5 years after smoking assessment were censored. When age, socioeconomic status, and drug abuse were controlled for, hazard ratios declined only modestly in both samples. Women who smoked into late pregnancy had a much higher risk for schizophrenia than those who quit early. Hazard ratios predicting nonaffective psychosis in the general population, in cousins, in half siblings, and in full siblings discordant for heavy smoking were, respectively, 2.67, 2.71, 2.54, and 2.18. A model utilizing all relative pairs predicted a hazard ratio of 1.69 (95% CI=1.17–2.44) for nonaffective psychosis in the heavy-smoking member of discordant monozygotic twin pairs.
Smoking prospectively predicts risk for schizophrenia. This association does not arise from smoking onset during a schizophrenic prodrome and demonstrates a clear dose-response relationship. While little of this association is explained by epidemiological confounders, a portion arises from common familial/genetic risk factors. However, in full siblings and especially monozygotic twins discordant for smoking, risk for nonaffective psychosis is appreciably higher in the smoking member. These results can help in evaluating the plausibility of various etiological hypotheses for the smoking-schizophrenia association.
PMCID: PMC4651774  PMID: 26046339
7.  Marijuana and Adolescence: What Can We Learn From Primates? 
The American journal of psychiatry  2014;171(4):381-383.
PMCID: PMC5074382  PMID: 24577331
8.  Contact With Mental Health and Primary Care Providers Before Suicide: A Review of the Evidence 
The American journal of psychiatry  2002;159(6):909-916.
This study examined rates of contact with primary care and mental health care professionals by individuals before they died by suicide.
The authors reviewed 40 studies for which there was information available on rates of health care contact and examined age and gender differences among the subjects.
Contact with primary care providers in the time leading up to suicide is common. While three of four suicide victims had contact with primary care providers within the year of suicide, approximately one-third of the suicide victims had contact with mental health services. About one in five suicide victims had contact with mental health services within a month before their suicide. On average, 45% of suicide victims had contact with primary care providers within 1 month of suicide. Older adults had higher rates of contact with primary care providers within 1 month of suicide than younger adults.
While it is not known to what degree contact with mental health care and primary care providers can prevent suicide, the majority of individuals who die by suicide do make contact with primary care providers, particularly older adults. Given that this pattern is consistent with overall health-service-seeking, alternate approaches to suicide-prevention efforts may be needed for those less likely to be seen in primary care or mental health specialty care, specifically young men.
PMCID: PMC5072576  PMID: 12042175
9.  Risperidone Nonadherence and Return of Positive Symptoms in the Early Course of Schizophrenia 
The American journal of psychiatry  2011;168(3):286-292.
This study examined the effect of medication nonadherence on the return of positive symptoms among recent-onset schizophrenia patients.
Three sets of operational criteria for medication nonadherence with differing levels of severity were compared for their ability to predict relapse. Explicit operational criteria are provided with the hope that they will be adopted by others. Psychotic symptoms were prospectively rated on a frequent basis, and systematic criteria were applied using a computer scoring program to identify periods of psychotic symptom return. In addition, a specialized statistical survival analysis method, optimal for examining risk periods and outcomes that can recur during the follow-up assessment, was used.
As hypothesized, medication nonadherence robustly predicted a return of psychotic symptoms during the early phase of schizophrenia (hazard ratios=3.7–28.5, depending on the severity of nonadherence).
Even brief periods of partial nonadherence lead to greater risk of relapse than what is commonly assumed. Patients in the early phase of schizophrenia should be cautioned about the possible consequences of partial or relatively brief periods of antipsychotic medication nonadherence.
PMCID: PMC5069345  PMID: 21205805
10.  In Vivo Measurement of GABA Transmission in Healthy Subjects and Schizophrenia Patients 
The American journal of psychiatry  2015;172(11):1148-1159.
Postmortem studies in schizophrenia reveal alterations in gene products that regulate the release and extracellular persistence of GABA. However, results of in vivo studies of schizophrenia measuring total tissue GABA with magnetic resonance spectroscopy (MRS) have been inconsistent. Neither the postmortem nor the MRS studies directly address the physiological properties of GABA neurotransmission. The present study addresses this question through an innovative positron emission tomography (PET) paradigm.
The binding of [11C]flumazenil, a benzodiazepine-specific PET radiotracer, was measured before and after administration of tiagabine (0.2 mg/kg of body weight), a GABA membrane transporter (GAT1) blocker, in 17 off-medication patients with schizophrenia and 22 healthy comparison subjects. Increased extracellular GABA, through GAT1 blockade, enhances the affinity of GABAA receptors for benzodiazepine ligands, detected as an increase in [11C]flumazenil tissue distribution volume (VT).
[11C]Flumazenil VT was significantly increased across all cortical brain regions in the healthy comparison group but not in the schizophrenia group. This lack of effect was most prominent in the antipsychotic-naive schizophrenia group. In this subgroup, [11C]flumazenil ΔVT in the medial temporal lobe was correlated with positive symptoms, and baseline [11C] flumazenil VT in the medial temporal lobe was negatively correlated with visual learning. In the healthy comparison group but not the schizophrenia group, [11C]flumazenil ΔVT was positively associated with gamma-band oscillation power.
This study demonstrates, for the first time, an in vivo impairment in GABA transmission in schizophrenia, most prominent in antipsychotic-naive individuals. The impairment in GABA transmission appears to be linked to clinical symptoms, disturbances in cortical oscillations, and cognition.
PMCID: PMC5070491  PMID: 26133962
11.  Molecular Mechanisms and Timing of Cortical Immune Activation in Schizophrenia 
The American journal of psychiatry  2015;172(11):1112-1121.
Immune-related abnormalities are commonly reported in schizophrenia, including higher mRNA levels for the viral restriction factor interferon-induced transmembrane protein (IFITM) in the prefrontal cortex. The authors sought to clarify whether higher IFITM mRNA levels and other immune-related disturbances in the prefrontal cortex are the consequence of an ongoing molecular cascade contributing to immune activation or the reflection of a long-lasting maladaptive response to an in utero immune-related insult.
Quantitative polymerase chain reaction was employed to measure mRNA levels for immune-related cytokines and transcriptional regulators, including those reported to regulate IFITM expression, in the prefrontal cortex from 62 schizophrenia and 62 healthy subjects and from adult mice exposed prenatally to maternal immune activation or in adulthood to the immune stimulant poly(I:C).
Schizophrenia subjects had markedly higher mRNA levels for interleukin 6 (IL-6) (+379%) and interferon-β (+29%), which induce IFITM expression; lower mRNA levels for Schnurri-2 (−10%), a transcriptional inhibitor that lowers IFITM expression; and higher mRNA levels for nuclear factor-κB (+86%), a critical transcription factor that mediates cytokine regulation of immune-related gene expression. In adult mice that received daily poly(I:C) injections, but not in offspring with prenatal exposure to maternal immune activation, frontal cortex mRNA levels were also markedly elevated for IFITM (+304%), multiple cytokines including IL-6 (+493%), and nuclear factor-κB (+151%).
These data suggest that higher prefrontal cortex IFITM mRNA levels in schizophrenia may be attributable to adult, but not prenatal, activation of multiple immune markers and encourage further investigation into the potential role of these and other immune markers as therapeutic targets in schizophrenia.
PMCID: PMC5063256  PMID: 26133963
12.  Is adult ADHD a childhood-onset neurodevelopmental disorder? Evidence from a 4-decade longitudinal cohort study 
The American journal of psychiatry  2015;172(10):967-977.
Despite a prevailing assumption that adult ADHD is a childhood-onset neurodevelopmental disorder, no prospective-longitudinal study has described the childhoods of the adult-ADHD population. We report follow-back analyses of ADHD cases diagnosed in adulthood, alongside follow-forward analyses of ADHD cases diagnosed in childhood, in one cohort.
Participants belonged to a representative birth cohort of 1,037 individuals born in Dunedin, New Zealand in 1972-73 and followed to age 38, with 95% retention. Symptoms of ADHD, associated clinical features, comorbid disorders, neuropsychological deficits, GWAS-derived polygenic risk, and life impairment indicators were assessed. Data sources were participants, parents, teachers, informants, neuropsychological testing, and administrative records. Adult ADHD diagnoses used DSM5 criteria, apart from onset-age and cross-setting corroboration, which were study outcomes.
As expected, the childhood-ADHD group showed 6% prevalence, male excess, childhood comorbid disorders, neurocognitive deficits, polygenic risk, and, despite having outgrown their ADHD diagnosis, residual adult life impairment. As expected, the adult-ADHD group showed 3% prevalence, gender balance, adult substance dependence, adult life impairment, and treatment contact. Unexpectedly, the childhood-ADHD and adult-ADHD groups comprised virtually non-overlapping sets; 90% of adult-ADHD cases lacked a history of childhood ADHD. Also unexpectedly, the adult-ADHD group did not show tested neuropsychological deficits in childhood or adulthood, nor did they show polygenic risk for childhood ADHD.
Findings raise the possibility that adults presenting with the ADHD symptom picture may not have a childhood-onset neurodevelopmental disorder. If this finding is replicated, then the disorder's place in the classification system must be reconsidered, and research must investigate the etiology of adult ADHD.
PMCID: PMC4591104  PMID: 25998281
13.  Psychosis Prevention: A Modified Clinical High Risk Perspective From the Recognition and Prevention (RAP) Program 
The American journal of psychiatry  2015;172(10):986-994.
Early intervention and prevention of psychosis remain a major challenge. Prediction would be greatly advanced with improved ability to identify individuals at true risk, which, at present, is moderate at best. The authors tested a modified strategy to improve prediction by selecting a more homogeneous high-risk sample (attenuated positive symptom criteria only, age range of mid-teens to early 20s) than is currently standard, combined with a systematic selection of neurodevelopmental deficits.
A sample of 101 treatment-seeking adolescents (mean age, 15.9 years) at clinical high risk for psychosis were followed clinically for up to 5 years (mean follow-up time, 3.0 years, SD=1.6). Adolescents were included only if they exhibited one or more attenuated positive symptoms at moderate to severe, but not psychotic, severity levels. Cox regression was used to derive a risk index.
The overall conversion rate to psychosis was 28.3%. The final predictor model, with a positive predictive validity of 81.8%, consisted of four variables: disorganized communication, suspiciousness, verbal memory deficits, and decline in social functioning during follow-up. Significant effects also suggest narrowing the risk age range to 15–22 years.
Clinical high risk criteria that emphasize disorganized communication and suspiciousness while also including compromised verbal memory and declining social functioning have the potential to improve predictive accuracy compared with attenuated positive symptoms used alone. On the resulting risk index (a weighted combination of the predictors), low scores were interpreted as signifying minimal risk, with little treatment necessary, high scores as suggesting aggressive intervention, and intermediate scores, although less informative, as supporting psychosocial treatment.
PMCID: PMC4993209  PMID: 26046336
15.  Distress During Pregnancy: Epigenetic Regulation of Placenta Glucocorticoid-Related Genes and Fetal Neurobehavior 
The American journal of psychiatry  2016;173(7):705-713.
Increased risk of psychopathology is observed in children exposed to maternal prenatal distress, and elevated maternal cortisol and epigenetic regulation of placental glucocorticoid-pathway genes are potential mechanisms. The authors examined maternal distress and salivary cortisol in relation to fetal movement and heart rate (“coupling”) and DNA methylation of three glucocorticoid pathway genes—HSD11B2, NR3C1, and FKBP5—in term placentas.
Mood questionnaires and salivary cortisol were collected from 61 women between 24–27 gestational weeks, and fetal assessment was conducted at 34–37 weeks. Placental CpG methylation in the three genes was analyzed using 450K Beadchips and bisulfite sequencing; correlations between maternal and fetal variables and DNA methylation were tested; and maternal distress effects on fetal behavior via DNA methylation were investigated.
Perceived stress (Perceived Stress Scale), but not cortisol, was associated with altered CpG methylation in placentas. In the highest tertile of the Perceived Stress Scale, the Beadchip data revealed modestly elevated methylation of HSD11B2, associated with lower fetal coupling (β=−0.51), and modestly elevated methylation of FKBP5, also with lower fetal coupling (β=−0.47). These increases in methylation were validated by bisulfite sequencing, where they occurred in a minority of clones.
This is the first study to link the effects of pregnant women’s distress on the fetus and epigenetic changes in placental genes. Since increased DNA methylation in HSD11B2 and FKBP5 are seen in a minority of bisulfite sequencing clones, these epigenetic changes, and functional consequences, may affect subpopulations of placental cells.
PMCID: PMC5026410  PMID: 27013342
16.  Neural Circuitry of Impaired Emotion Regulation in Substance Use Disorders 
The American journal of psychiatry  2016;173(4):344-361.
Impaired emotion regulation contributes to the development and severity of substance use disorders (substance disorders). This review summarizes the literature on alterations in emotion regulation neural circuitry in substance disorders, particularly in relation to disorders of negative affect (without substance disorder), and it presents promising areas of future research. Emotion regulation paradigms during functional magnetic resonance imaging are conceptualized into four dimensions: affect intensity and reactivity, affective modulation, cognitive modulation, and behavioral control. The neural circuitry associated with impaired emotion regulation is compared in individuals with and without substance disorders, with a focus on amygdala, insula, and prefrontal cortex activation and their functional and structural connectivity. Hypoactivation of the rostral anterior cingulate cortex/ventromedial prefrontal cortex (rACC/vmPFC) is the most consistent finding across studies, dimensions, and clinical populations (individuals with and without substance disorders). The same pattern is evident for regions in the cognitive control network (anterior cingulate and dorsal and ventrolateral prefrontal cortices) during cognitive modulation and behavioral control. These congruent findings are possibly related to attenuated functional and/or structural connectivity between the amygdala and insula and between the rACC/vmPFC and cognitive control network. Although increased amygdala and insula activation is associated with impaired emotion regulation in individuals without substance disorders, it is not consistently observed in substance disorders. Emotion regulation disturbances in substance disorders may therefore stem from impairments in prefrontal functioning, rather than excessive reactivity to emotional stimuli. Treatments for emotion regulation in individuals without substance disorders that normalize prefrontal functioning may offer greater efficacy for substance disorders than treatments that dampen reactivity.
PMCID: PMC4979988  PMID: 26771738
17.  Change in neuropsychological functioning is associated with the trajectory of ADHD severity and impairment in early childhood 
The American journal of psychiatry  2013;170(10):1205-1211.
This longitudinal study examined whether changes in neuropsychological functioning were associated with the trajectory of ADHD-related symptoms and impairment between preschool and school-age.
The sample consisted of 3- and 4-year-old children (N=138) who were identified as being “at-risk” for ADHD based on parent and teacher reports. Neuropsychological functioning was measured annually using the NEPSY at four points of time (Mean ages: 4.19, 5.36, 6.35 and 7.35 years). ADHD symptoms and impairment were assessed using semi-annual parent and teacher reports on the ADHD-RS-IV and the Children’s Problems Checklist over 10 points of time (Mean age at baseline and final assessment = 4.19 and 8.81 years, respectively). Hierarchical linear modeling was used to assess the trajectories of change in neuropsychological functioning and ADHD severity as well as the association of change in neuropsychological functioning with change in ADHD severity over time.
Baseline neuropsychological functioning was not significantly associated with the slope of change in ADHD severity. However, the magnitude of change in neuropsychological functioning was linearly associated with the trajectory of ADHD symptom severity and impairment such that individuals with greater neuropsychological growth over time had a greater diminution of ADHD severity and impairment. Family socioeconomic status at baseline was significantly associated with initial ADHD severity and impairment but not with change over time.
Interventions that enhance neuropsychological functioning from an early age may be beneficial to attenuating long-term ADHD severity and impairment.
PMCID: PMC4963820  PMID: 23897408
ADHD; neuropsychology; preschool; longitudinal study; developmental trajectory
18.  An Epidemiological Contribution to Clinical Understanding of Anxiety 
The American journal of psychiatry  2015;172(7):601-602.
PMCID: PMC4912126  PMID: 26130198
19.  Functional neuroimaging of avoidance habits in OCD 
The American journal of psychiatry  2014;172(3):284-293.
The goal of this study was to determine the neural correlates of excessive habit formation in obsessive-compulsive disorder (OCD). We aimed to (i) test for neurobiological convergence with the known pathophysiology of OCD and (ii) infer, based on abnormalities in brain activation, whether these habits arise from dysfunction in the goal-directed or habit system.
Thirty-seven OCD patients and 33 controls learned to avoid shocks while undergoing a functional Magnetic Resonance Imaging (fMRI) scan. Following 4 blocks of training, we tested if the avoidance response had become a habit by removing the threat of shock and measuring continued avoidance. We tested for task-related differences in brain activity in 3 ROIs, the caudate, putamen and medial orbitofrontal cortex at a statistical threshold of p<.05, family-wise error (FWE) corrected.
We observed excessive habit formation in OCD patients, which was associated with hyper-activation in the caudate. Activation in this region was also associated with subjective ratings of increased urge to perform habits. The OCD group, as a whole, showed hyper-activation in the medial orbitofrontal cortex (mOFC) during the acquisition of avoidance, however this did not relate directly to habit formation.
OCD patients exhibited excessive habits that were associated with hyper-activation in a key region implicated in the pathophysiology of OCD, the caudate nucleus. Prior studies suggest that this region is important for goal-directed behavior, suggesting that habit-forming biases in OCD may be a result of impairments in this system, rather than differences in the build up of stimulus-response habits themselves.
PMCID: PMC4910868  PMID: 25526600
20.  Additive Effects of HIV and Chronic Methamphetamine Use on Brain Metabolite Abnormalities 
The American journal of psychiatry  2005;162(2):361-369.
Proton magnetic resonance spectroscopy (1H-MRS) showed decreased neuronal marker N-acetylaspartate and increased glial marker myo-inositol in subjects with chronic methamphetamine use and in subjects infected with HIV. The authors sought to determine whether HIV and a history of chronic methamphetamine use might have additive or interactive effects on brain metabolite abnormalities.
1H-MRS was performed in 68 HIV-positive subjects (24 with a history of chronic methamphetamine use with a lifetime exposure of a mean of 2,167 g [SD=2,788] and last use a mean of 4.9 months earlier [SD=6.0]; 44 with no history of drug abuse) and 75 HIV-negative subjects (36 with a history of chronic methamphetamine use with a lifetime exposure of a mean of 8,241 g [SD=16,850] and last use a mean of 6.3 months earlier [SD=7.8]; 39 with no history of drug abuse). Concentrations of N-acetylaspartate, creatine, choline, and myo-inositol were measured in the frontal cortex, frontal white matter, and basal ganglia.
HIV-negative subjects with a history of chronic methamphetamine use showed lower concentrations of the neuronal marker N-acetylaspartate in the frontal white matter and basal ganglia and higher concentrations of choline compounds and the glial marker myo-inositol in the frontal cortex, relative to subjects with no history of drug abuse. HIV-positive status was associated with lower concentrations of N-acetylaspartate and creatine in the frontal cortex and higher concentrations of myo-inositol in the white matter, compared with HIV-negative status. Compared to the mean concentrations of metabolites in HIV-negative subjects with no history of drug abuse, the mean concentrations in subjects with HIV and chronic methamphetamine use showed additive effects on N-acetylaspartate in all three regions (−9% in the basal ganglia, −7% in the frontal white matter, and −6% in the frontal gray matter), on creatine in the basal ganglia (−7%), and on myo-inositol in the frontal white matter (+11%).
The combined effects of HIV and chronic methamphetamine use were consistent with an additive model, suggesting additional neuronal injury and glial activation due to the comorbid conditions.
PMCID: PMC4899042  PMID: 15677602
21.  Cerebral small vessel disease is associated with a higher incidence of depressive symptoms in a general elderly population: the AGES-Reykjavik Study 
The American journal of psychiatry  2015;172(6):570-578.
The vascular depression hypothesis postulates that cerebral small vessel disease (CSVD) leads to depressive symptoms via disruption of brain structures involved in mood regulation. However, longitudinal data on the association between CSVD and depressive symptoms are scarce. We investigated the association between CSVD and incident depressive symptoms.
Longitudinal data are from the AGES-Reykjavik study of 1,949 participants free of dementia and without baseline depressive symptoms (74.6 years/56.6% women). MRI markers of CSVD, detected at baseline (2002–2006) and follow-up (2007–2011), included white matter hyperintensity volume (WMHV), subcortical infarcts, cerebral microbleeds, Virchow-Robin spaces and total brain parenchyma volume. Incident depressive symptoms were defined by the 15-item Geriatric Depression Scale (GDS-15) score≥6 and(or) use of antidepressant medication.
Depressive symptoms occurred in 10.1% of the participants. The association for a greater onset of depressive symptoms was significant for participants having a 1 standard deviation increase in WMHV over time, new subcortical infarcts, new Virchow-Robin spaces, a 1 standard deviation lower total brain volume at baseline, or a 1 standard deviation decreased total brain volume over time, after adjustments for cognitive function, socio-demographic and cardiovascular factors. Results were qualitatively similar when change in the GDS-15 over time was used as the outcome instead of incident depressive symptoms.
Most markers of progression of CSVD over time and some markers of baseline CSVD are associated with concurrently developing new depressive symptoms. This study supports the vascular depression hypothesis.
PMCID: PMC4451386  PMID: 25734354
22.  Triparental Families: A New Genetic-Epidemiological Design Applied to Drug Abuse, Alcohol Use Disorders, and Criminal Behavior in a Swedish National Sample 
The American journal of psychiatry  2015;172(6):553-560.
The authors sought to clarify the sources of parent-offspring resemblance for drug abuse, alcohol use disorders, and criminal behavior, using a novel genetic-epidemiological design.
Using national registries, the authors identified rates of drug abuse, alcohol use disorders, and criminal behavior in 41,360 Swedish individuals born between 1960 and 1990 and raised in triparental families comprising a biological mother who reared them, a “not-lived-with” biological father, and a stepfather.
When each syndrome was examined individually, hazard rates for drug abuse in offspring of parents with drug abuse were highest for mothers (2.80, 95% CI=2.23–3.38), intermediate for not-lived-with fathers (2.45,95%CI=2.14–2.79), and lowest for stepfathers (1.99, 95% CI=1.55–2.56). The same pattern was seen for alcohol use disorders (2.23, 95% CI=1.93–2.58; 1.84, 95% CI=1.69–2.00; and 1.27, 95% CI=1.12–1.43) and criminal behavior (1.55, 95% CI=1.44–1.66; 1.46, 95%CI=1.40–1.52; and1.30, 95% CI=1.23–1.37). When all three syndromes were examined together, specificity of cross-generational transmission was highest for mothers, intermediate for not-lived-with fathers, and lowest for stepfathers. Analyses of intact families and other not-lived-with parents and stepparents showed similar cross-generation transmission for these syndromes in mothers and fathers, supporting the representativeness of results from triparental families.
A major strength of the triparental design is its inclusion, within a single family, of parents who provide, to a first approximation, their offspring with genes plus rearing, genes only, and rearing only. For drug abuse, alcohol use disorders, and criminal behavior, the results of this study suggest that parent-offspring transmission involves both genetic and environmental processes, with genetic factors being somewhat more important. These results should be interpreted in the context of the strengths and limitations of national registry data.
PMCID: PMC4451407  PMID: 25698436
23.  Association of Protein Phosphatase PPM1G With Alcohol Use Disorder and Brain Activity During Behavioral Control in a Genome-Wide Methylation Analysis 
The American journal of psychiatry  2015;172(6):543-552.
The genetic component of alcohol use disorder is substantial, but monozygotic twin discordance indicates a role for nonheritable differences that could be mediated by epigenetics. Despite growing evidence associating epigenetics and psychiatric disorders, it is unclear how epigenetics, particularly DNA methylation, relate to brain function and behavior, including drinking behavior.
The authors carried out a genome-wide analysis of DNA methylation of 18 monozygotic twin pairs discordant for alcohol use disorder and validated differentially methylated regions. After validation, the authors characterized these differentially methylated regions using personality trait assessment and functional MRI in a sample of 499 adolescents.
Hypermethylation in the 3′-protein-phosphatase-1G (PPM1G) gene locus was associated with alcohol use disorder. The authors found association of PPM1G hypermethylation with early escalation of alcohol use and increased impulsiveness. They also observed association of PPM1G hypermethylation with increased blood-oxygen-level-dependent response in the right subthalamic nucleus during an impulsiveness task.
Overall, the authors provide first evidence for an epigenetic marker associated with alcohol consumption and its underlying neurobehavioral phenotype.
PMCID: PMC4827248  PMID: 25982659
25.  Moderation of the Relationship Between Reward Expectancy and Prediction Error-Related Ventral Striatal Reactivity by Anhedonia in Unmedicated Major Depressive Disorder: Findings From the EMBARC Study 
The American journal of psychiatry  2015;172(9):881-891.
Anhedonia, disrupted reward processing, is a core symptom of major depressive disorder. Recent findings demonstrate altered reward-related ventral striatal reactivity in depressed individuals, but the extent to which this is specific to anhedonia remains poorly understood. The authors examined the effect of anhedonia on reward expectancy (expected outcome value) and prediction error-(discrepancy between expected and actual outcome) related ventral striatal reactivity, as well as the relationship between these measures.
A total of 148 unmedicated individuals with major depressive disorder and 31 healthy comparison individuals recruited for the multisite EMBARC (Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care) study underwent functional MRI during a well-validated reward task. Region of interest and whole-brain data were examined in the first- (N=78) and second- (N=70) recruited cohorts, as well as the total sample, of depressed individuals, and in healthy individuals.
Healthy, but not depressed, individuals showed a significant inverse relationship between reward expectancy and prediction error-related right ventral striatal reactivity. Across all participants, and in depressed individuals only, greater anhedonia severity was associated with a reduced reward expectancy-prediction error inverse relationship, even after controlling for other symptoms.
The normal reward expectancy and prediction error-related ventral striatal reactivity inverse relationship concords with conditioning models, predicting a shift in ventral striatal responding from reward outcomes to reward cues. This study shows, for the first time, an absence of this relationship in two cohorts of unmedicated depressed individuals and a moderation of this relationship by anhedonia, suggesting reduced reward-contingency learning with greater anhedonia. These findings help elucidate neural mechanisms of anhedonia, as a step toward identifying potential biosignatures of treatment response.
PMCID: PMC4858169  PMID: 26183698

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