Showing papers in "JAMA Psychiatry in 2013"
TL;DR: This proof-of-concept study suggests that TNF antagonism does not have generalized efficacy in treatment-resistant depression but may improve depressive symptoms in patients with high baseline inflammatory biomarkers.
Abstract: Context Increased concentrations of inflammatory biomarkers predict antidepressant nonresponse, and inflammatory cytokines can sabotage and circumvent the mechanisms of action of conventional antidepressants. Objectives To determine whether inhibition of the inflammatory cytokine tumor necrosis factor (TNF) reduces depressive symptoms in patients with treatment-resistant depression and whether an increase in baseline plasma inflammatory biomarkers, including high-sensitivity C-reactive protein (hs-CRP), TNF, and its soluble receptors, predicts treatment response. Design Double-blind, placebo-controlled, randomized clinical trial. Setting Outpatient infusion center at Emory University in Atlanta, Georgia. Participants A total of 60 medically stable outpatients with major depression who were either on a consistent antidepressant regimen (n = 37) or medication-free (n = 23) for 4 weeks or more and who were moderately resistant to treatment as determined by the Massachusetts General Hospital Staging method. Interventions Three infusions of the TNF antagonist infliximab (5 mg/kg) (n = 30) or placebo (n = 30) at baseline and weeks 2 and 6 of a 12-week trial. Main Outcome Measures The 17-item Hamilton Scale for Depression (HAM-D) scores. Results No overall difference in change of HAM-D scores between treatment groups across time was found. However, there was a significant interaction between treatment, time, and log baseline hs-CRP concentration (P = .01), with change in HAM-D scores (baseline to week 12) favoring infliximab-treated patients at a baseline hs-CRP concentration greater than 5 mg/L and favoring placebo-treated patients at a baseline hs-CRP concentration of 5 mg/L or less. Exploratory analyses focusing on patients with a baseline hs-CRP concentration greater than 5 mg/L revealed a treatment response (≥50% reduction in HAM-D score at any point during treatment) of 62% (8 of 13 patients) in infliximab-treated patients vs 33% (3 of 9 patients) in placebo-treated patients (P = .19). Baseline concentrations of TNF and its soluble receptors were significantly higher in infliximab-treated responders vs nonresponders (P Conclusions This proof-of-concept study suggests that TNF antagonism does not have generalized efficacy in treatment-resistant depression but may improve depressive symptoms in patients with high baseline inflammatory biomarkers. Trial Registration clinicaltrials.gov Identifier: NCT00463580.
1,282 citations
TL;DR: Differences suggest that distinct prediction and prevention strategies are needed for ideation, plans among ideators, planned attempts, and unplanned attempts.
Abstract: Context Although suicide is the third leading cause of death among US adolescents, little is known about the prevalence, correlates, or treatment of its immediate precursors, adolescent suicidal behaviors (ie, suicide ideation, plans, and attempts). Objectives To estimate the lifetime prevalence of suicidal behaviors among US adolescents and the associations of retrospectively reported, temporally primary DSM-IV disorders with the subsequent onset of suicidal behaviors. Design Dual-frame national sample of adolescents from the National Comorbidity Survey Replication Adolescent Supplement. Setting Face-to-face household interviews with adolescents and questionnaires for parents. Participants A total of 6483 adolescents 13 to 18 years of age and their parents. Main Outcome Measures Lifetime suicide ideation, plans, and attempts. Results The estimated lifetime prevalences of suicide ideation, plans, and attempts among the respondents are 12.1%, 4.0%, and 4.1%, respectively. The vast majority of adolescents with these behaviors meet lifetime criteria for at least one DSM-IV mental disorder assessed in the survey. Most temporally primary (based on retrospective age-of-onset reports) fear/anger, distress, disruptive behavior, and substance disorders significantly predict elevated odds of subsequent suicidal behaviors in bivariate models. The most consistently significant associations of these disorders are with suicide ideation, although a number of disorders are also predictors of plans and both planned and unplanned attempts among ideators. Most suicidal adolescents (>80%) receive some form of mental health treatment. In most cases (>55%), treatment starts prior to onset of suicidal behaviors but fails to prevent these behaviors from occurring. Conclusions Suicidal behaviors are common among US adolescents, with rates that approach those of adults. The vast majority of youth with suicidal behaviors have preexisting mental disorders. The disorders most powerfully predicting ideation, though, are different from those most powerfully predicting conditional transitions from ideation to plans and attempts. These differences suggest that distinct prediction and prevention strategies are needed for ideation, plans among ideators, planned attempts, and unplanned attempts.
1,244 citations
TL;DR: The relatively new field of HR research in psychosis has the potential to shed light on the development of major psychotic disorders and to alter their course and provides a rationale for service provision to those in need of help who could not previously access it.
Abstract: Context During the past 2 decades, a major transition in the clinical characterization of psychotic disorders has occurred. The construct of a clinical high-risk (HR) state for psychosis has evolved to capture the prepsychotic phase, describing people presenting with potentially prodromal symptoms. The importance of this HR state has been increasingly recognized to such an extent that a new syndrome is being considered as a diagnostic category in the DSM-5. Objective To reframe the HR state in a comprehensive state-of-the-art review on the progress that has been made while also recognizing the challenges that remain. Data Sources Available HR research of the past 20 years from PubMed, books, meetings, abstracts, and international conferences. Study Selection and Data Extraction Critical review of HR studies addressing historical development, inclusion criteria, epidemiologic research, transition criteria, outcomes, clinical and functional characteristics, neurocognition, neuroimaging, predictors of psychosis development, treatment trials, socioeconomic aspects, nosography, and future challenges in the field. Data Synthesis Relevant articles retrieved in the literature search were discussed by a large group of leading worldwide experts in the field. The core results are presented after consensus and are summarized in illustrative tables and figures. Conclusions The relatively new field of HR research in psychosis is exciting. It has the potential to shed light on the development of major psychotic disorders and to alter their course. It also provides a rationale for service provision to those in need of help who could not previously access it and the possibility of changing trajectories for those with vulnerability to psychotic illnesses.
1,213 citations
TL;DR: The effects of being bullied are direct, pleiotropic, and long-lasting, with the worst effects for those who are both victims and bullies.
Abstract: Importance Both bullies and victims of bullying are at risk for psychiatric problems in childhood, but it is unclear if this elevated risk extends into early adulthood. Objective To test whether bullying and/or being bullied in childhood predicts psychiatric problems and suicidality in young adulthood after accounting for childhood psychiatric problems and family hardships. Design Prospective, population-based study. Setting Community sample from 11 counties in Western North Carolina. Participants A total of 1420 participants who had being bullied and bullying assessed 4 to 6 times between the ages of 9 and 16 years. Participants were categorized as bullies only, victims only, bullies and victims (hereafter referred to as bullies/victims), or neither. Main Outcome Measure Psychiatric outcomes, which included depression, anxiety, antisocial personality disorder, substance use disorders, and suicidality (including recurrent thoughts of death, suicidal ideation, or a suicide attempt), were assessed in young adulthood (19, 21, and 24-26 years) by use of structured diagnostic interviews. Results Victims and bullies/victims had elevated rates of young adult psychiatric disorders, but also elevated rates of childhood psychiatric disorders and family hardships. After controlling for childhood psychiatric problems or family hardships, we found that victims continued to have a higher prevalence of agoraphobia (odds ratio [OR], 4.6 [95% CI, 1.7-12.5]; P Conclusions and Relevance The effects of being bullied are direct, pleiotropic, and long-lasting, with the worst effects for those who are both victims and bullies.
902 citations
TL;DR: To screen for depression in postpartum women and evaluate positive screen findings to determine the timing of episode onset, rate and intensity of self-harm ideation, and primary and secondary DSM-IV disorders to inform treatment and policy decisions.
Abstract: Importance The period prevalence of depression among women is 21.9% during the first postpartum year; however, questions remain about the value of screening for depression. Objectives To screen for depression in postpartum women and evaluate positive screen findings to determine the timing of episode onset, rate and intensity of self-harm ideation, and primary and secondary DSM-IV disorders to inform treatment and policy decisions. Design Sequential case series of women who recently gave birth. Setting Urban academic women's hospital. Participants During the maternity hospitalization, women were offered screening at 4 to 6 weeks post partum by telephone. Screen-positive women were invited to undergo psychiatric evaluations in their homes. Main Outcomes and Measures A positive screen finding was an Edinburgh Postnatal Depression Scale (EPDS) score of 10 or higher. Self-harm ideation was assessed on EPDS item 10: “The thought of harming myself has occurred to me” (yes, quite often; sometimes; hardly ever; never). Screen-positive women underwent evaluation with the Structured Clinical Interview for DSM-IV for Axis I primary and secondary diagnoses. Results Ten thousand mothers underwent screening, with positive findings in 1396 (14.0%); of these, 826 (59.2%) completed the home visits and 147 (10.5%) completed a telephone diagnostic interview. Screen-positive women were more likely to be younger, African American, publicly insured, single, and less well educated. More episodes began post partum (40.1%), followed by during pregnancy (33.4%) and before pregnancy (26.5%). In this population, 19.3% had self-harm ideation. All mothers with the highest intensity of self-harm ideation were identified with the EPDS score of 10 or higher. The most common primary diagnoses were unipolar depressive disorders (68.5%), and almost two-thirds had comorbid anxiety disorders. A striking 22.6% had bipolar disorders. Conclusions and Relevance The most common diagnosis in screen-positive women was major depressive disorder with comorbid generalized anxiety disorder. Strategies to differentiate women with bipolar from unipolar disorders are needed. Trial Registration clinicaltrials.gov Identifier: NCT00282776
720 citations
TL;DR: This article posits that this emphasis on psychosis is a conceptual fallacy that has greatly contributed to the lack of progress in the understanding of this illness and hence has hampered the development of adequate treatments.
Abstract: Schizophrenia is currently classified as a psychotic disorder. This article posits that this emphasis on psychosis is a conceptual fallacy that has greatly contributed to the lack of progress in our understanding of this illness and hence has hampered the development of adequate treatments. Not only have cognitive and intellectual underperformance consistently been shown to be risk factors for schizophrenia, several studies have found that a decline in cognitive functioning precedes the onset of psychosis by almost a decade. Although the question of whether cognitive function continues to decline after psychosis onset is still debated, it is clear that cognitive function in schizophrenia is related to outcome and little influenced by antipsychotic treatment. Thus, our focus on defining (and preventing) the disorder on the basis of psychotic symptoms may be too narrow. Not only should cognition be recognized as the core component of the disorder, our diagnostic efforts should emphasize the changes in cognitive function that occur earlier in development. Putting the focus back on cognition may facilitate finding treatments for the illness before psychosis ever emerges.
639 citations
TL;DR: These findings provide novel biological evidence that schizophrenia is characterized by a selective disruption of brain connectivity among central hub regions of the brain, potentially leading to reduced communication capacity and altered functional brain dynamics.
Abstract: Importance The human brain forms a large-scale structural network of regions and interregional pathways. Recent studies have reported the existence of a selective set of highly central and interconnected hub regions that may play a crucial role in the brain’s integrative processes, together forming a central backbone for global brain communication. Abnormal brain connectivity may have a key role in the pathophysiology of schizophrenia. Objective To examine the structure of the rich club in schizophrenia and its role in global functional brain dynamics. Design Structural diffusion tensor imaging and resting-state functional magnetic resonance imaging were performed in patients with schizophrenia and matched healthy controls. Setting Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, the Netherlands. Participants Forty-eight patients and 45 healthy controls participated in the study. An independent replication data set of 41 patients and 51 healthy controls was included to replicate and validate significant findings. Main Outcome(s) and Measures Measures of rich club organization, connectivity density of rich club connections and connections linking peripheral regions to brain hubs, measures of global brain network efficiency, and measures of coupling between brain structure and functional dynamics. Results Rich club organization between high-degree hub nodes was significantly affected in patients, together with a reduced density of rich club connections predominantly comprising the white matter pathways that link the midline frontal, parietal, and insular hub regions. This reduction in rich club density was found to be associated with lower levels of global communication capacity, a relationship that was absent for other white matter pathways. In addition, patients had an increase in the strength of structural connectivity–functional connectivity coupling. Conclusions Our findings provide novel biological evidence that schizophrenia is characterized by a selective disruption of brain connectivity among central hub regions of the brain, potentially leading to reduced communication capacity and altered functional brain dynamics.
587 citations
TL;DR: Patients with ADHD have consistent functional abnormalities in 2 distinct domain-dissociated right hemispheric fronto-basal ganglia networks, including the inferior frontal cortex, supplementary motor area, and anterior cingulate cortex for inhibition and dorsolateral prefrontal cortex, parietal, and cerebellar areas for attention.
Abstract: CONTEXT Functional magnetic resonance imaging studies in attention-deficit/hyperactivity disorder (ADHD) revealed fronto-striato-parietal dysfunctions during tasks of inhibition and attention. However, it is unclear whether task-dissociated dysfunctions exist and to what extent they may be influenced by age and by long-term stimulant medication use. OBJECTIVE To conduct a meta-analysis of functional magnetic resonance imaging studies in ADHD during inhibition and attention tasks, exploring age and long-term stimulant medication use effects. DATA SOURCES PubMed, ScienceDirect, Web of Knowledge, Google Scholar, and Scopus databases were searched up to May 2012 for meta-analyses. Meta-regression methods explored age and long-term stimulant medication use effects. STUDY SELECTION Twenty-one data sets were included for inhibition (287 patients with ADHD and 320 control subjects), and 13 data sets were included for attention (171 patients with ADHD and 178 control subjects). DATA EXTRACTION Peak coordinates of clusters of significant group differences, as well as demographic, clinical, and methodological variables, were extracted for each study or were obtained from the authors. DATA SYNTHESIS Patients with ADHD relative to controls showed reduced activation for inhibition in the right inferior frontal cortex, supplementary motor area, and anterior cingulate cortex, as well as striato-thalamic areas, and showed reduced activation for attention in the right dorsolateral prefrontal cortex, posterior basal ganglia, and thalamic and parietal regions. Furthermore, the meta-regression analysis for the attention domain showed that long-term stimulant medication use was associated with more similar right caudate activation relative to controls. Age effects could be analyzed only for the inhibition meta-analysis, showing that the supplementary motor area and basal ganglia were underactivated solely in children with ADHD relative to controls, while the inferior frontal cortex and thalamus were underactivated solely in adults with ADHD relative to controls. CONCLUSIONS Patients with ADHD have consistent functional abnormalities in 2 distinct domain-dissociated right hemispheric fronto-basal ganglia networks, including the inferior frontal cortex, supplementary motor area, and anterior cingulate cortex for inhibition and dorsolateral prefrontal cortex, parietal, and cerebellar areas for attention. Furthermore, preliminary evidence suggests that long-term stimulant medication use may be associated with more normal activation in right caudate during the attention domain.
582 citations
TL;DR: Exposure to traffic-related air pollution, nitrogen dioxide, PM2.5, and PM10 during pregnancy and during the first year of life was associated with autism.
Abstract: Context: Autism is a heterogeneous disorder with geneticandenvironmentalfactorslikelycontributingtoits origins. Examination of hazardous pollutants has suggested the importance of air toxics in the etiology of autism,yetlittleresearchhasexamineditsassociationwith local levels of air pollution using residence-specific exposure assignments. Objective:To examine the relationship between trafficrelated air pollution, air quality, and autism. Design: This population-based case-control study includes data obtained from children with autism and control children with typical development who were enrolled in the Childhood Autism Risks from Genetics and the Environment study in California. The mother’s addressfromthebirthcertificateandaddressesreportedfrom a residential history questionnaire were used to estimate exposure for each trimester of pregnancy and first year of life. Traffic-related air pollution was assigned to each locationusingaline-sourceair-qualitydispersionmodel.Regional air pollutant measures were based on the Environmental Protection Agency’s Air Quality System data. Logisticregressionmodelscomparedestimatedandmeasuredpollutantlevelsforchildrenwithautismandforcontrol children with typical development. Setting: Case-control study from California. Participants: A total of 279 children with autism and a total of 245 control children with typical development. Main Outcome Measures: Crude and multivariable adjusted odds ratios (AORs) for autism. Results: Children with autism were more likely to live at residences that had the highest quartile of exposure totraffic-relatedairpollution,duringgestation(AOR,1.98 [95%CI,1.20-3.31])andduringthefirstyearoflife(AOR, 3.10 [95% CI, 1.76-5.57]), compared with control children.Regionalexposuremeasuresofnitrogendioxideand particulate matter less than 2.5 and 10 m in diameter (PM2.5 and PM10) were also associated with autism during gestation (exposure to nitrogen dioxide: AOR, 1.81 [95% CI, 1.37-3.09]; exposure to PM2.5: AOR, 2.08 [95% CI, 1.93-2.25]; exposure to PM10: AOR, 2.17 [95% CI, 1.49-3.16) and during the first year of life (exposure to nitrogen dioxide: AOR, 2.06 [95% CI, 1.37-3.09]; exposure to PM2.5: AOR, 2.12 [95% CI, 1.45-3.10]; exposure to PM10: AOR, 2.14 [95% CI, 1.46-3.12]). All regional pollutant estimates were scaled to twice the standard deviation of the distribution for all pregnancy estimates. Conclusions: Exposure to traffic-related air pollution, nitrogen dioxide, PM2.5,andPM10during pregnancy and during the first year of life was associated with autism. Further epidemiological and toxicological examinations of likely biological pathways will help determine whether these associations are causal.
534 citations
TL;DR: Patients with bipolar disorder had increased mortality from cardiovascular disease, diabetes mellitus, chronic obstructive pulmonary disease (COPD), influenza or pneumonia, unintentional injuries, and suicide for both women and men and cancer for women only.
Abstract: Importance Bipolar disorder is associated with premature mortality, but the specific causes and underlying pathways are unclear. Objective To examine the physical health effects of bipolar disorder using outpatient and inpatient data for a national population. Design, Setting, and Participants National cohort study of 6 587 036 Swedish adults, including 6618 with bipolar disorder. Main Outcomes and Measures Physical comorbidities diagnosed in any outpatient or inpatient setting nationwide and mortality (January 1, 2003, through December 31, 2009). Results Women and men with bipolar disorder died 9.0 and 8.5 years earlier on average than the rest of the population, respectively. All-cause mortality was increased 2-fold among women (adjusted hazard ratio [aHR], 2.34; 95% CI, 2.16-2.53) and men (aHR, 2.03; 95% CI, 1.85-2.23) with bipolar disorder, compared with the rest of the population. Patients with bipolar disorder had increased mortality from cardiovascular disease, diabetes mellitus, chronic obstructive pulmonary disease (COPD), influenza or pneumonia, unintentional injuries, and suicide for both women and men and cancer for women only. Suicide risk was 10-fold among women (aHR, 10.37; 95% CI, 7.36-14.60) and 8-fold among men (aHR, 8.09; 95% CI, 5.98-10.95) with bipolar disorder, compared with the rest of the population. Substance use disorders contributed only modestly to these findings. The association between bipolar disorder and mortality from chronic diseases (ischemic heart disease, diabetes, COPD, or cancer) was weaker among persons with a prior diagnosis of these conditions (aHR, 1.40; 95% CI, 1.26-1.56) than among those without a prior diagnosis (aHR, 2.38; 95% CI, 1.95-2.90; P interaction = .01). Conclusions and Relevance In this large national cohort study, patients with bipolar disorder died prematurely from multiple causes, including cardiovascular disease, diabetes, COPD, influenza or pneumonia, unintentional injuries, and suicide. However, chronic disease mortality among those with more timely medical diagnosis approached that of the general population, suggesting that better provision of primary medical care may effectively reduce premature mortality among persons with bipolar disorder.
516 citations
TL;DR: Salience network hyperconnectivity may be a distinguishing feature in children with ASD and Quantification of brain network connectivity is a step toward developing biomarkers for objectively identifying children with Autism spectrum disorder.
Abstract: Importance Autism spectrum disorder (ASD) affects 1 in 88 children and is characterized by a complex phenotype, including social, communicative, and sensorimotor deficits. Autism spectrum disorder has been linked with atypical connectivity across multiple brain systems, yet the nature of these differences in young children with the disorder is not well understood. Objectives To examine connectivity of large-scale brain networks and determine whether specific networks can distinguish children with ASD from typically developing (TD) children and predict symptom severity in children with ASD. Design, Setting, and Participants Case-control study performed at Stanford University School of Medicine of 20 children 7 to 12 years old with ASD and 20 age-, sex-, and IQ-matched TD children. Main Outcomes and Measures Between-group differences in intrinsic functional connectivity of large-scale brain networks, performance of a classifier built to discriminate children with ASD from TD children based on specific brain networks, and correlations between brain networks and core symptoms of ASD. Results We observed stronger functional connectivity within several large-scale brain networks in children with ASD compared with TD children. This hyperconnectivity in ASD encompassed salience, default mode, frontotemporal, motor, and visual networks. This hyperconnectivity result was replicated in an independent cohort obtained from publicly available databases. Using maps of each individual’s salience network, children with ASD could be discriminated from TD children with a classification accuracy of 78%, with 75% sensitivity and 80% specificity. The salience network showed the highest classification accuracy among all networks examined, and the blood oxygen–level dependent signal in this network predicted restricted and repetitive behavior scores. The classifier discriminated ASD from TD in the independent sample with 83% accuracy, 67% sensitivity, and 100% specificity. Conclusions and Relevance Salience network hyperconnectivity may be a distinguishing feature in children with ASD. Quantification of brain network connectivity is a step toward developing biomarkers for objectively identifying children with ASD.
TL;DR: The findings suggest that treating maternal depression antenatally could prevent offspring depression during adulthood and that prioritizing less advantaged mothers postnatally may be most effective.
Abstract: Importance Some small studies suggest that maternal postnatal depression is a risk factor for offspring adolescent depression. However, to our knowledge, no large cohort studies have addressed this issue. Furthermore, only 1 small study has examined the association between antenatal depression and later offspring depression. Understanding these associations is important to inform prevention. Objective To investigate the hypothesis that there are independent associations between antenatal and postnatal depression with offspring depression and that the risk pathways are different, such that the risk is moderated by disadvantage (low maternal education) with postnatal depression but not with antenatal depression. Design, Setting, and Participants Prospective investigation of associations between symptoms of antenatal and postnatal parental depression with offspring depression at age 18 years in a UK community-based birth cohort (Avon Longitudinal Study of Parents and Children) with data from more than 4500 parents and their adolescent offspring. Main Outcomes and Measures Diagnosis of offspring aged 18 years with major depression using the International Classification of Diseases, 10th Revision . Results Antenatal depression was an independent risk factor. Offspring were 1.28 times (95% CI, 1.08-1.51; P = .003) more likely to have depression at age 18 years for each standard deviation increase in maternal depression score antenatally, independent of later maternal depression. Postnatal depression was also a risk factor for mothers with low education, with offspring 1.26 times (95% CI, 1.06-1.50; P = .01) more likely to have depression for each standard deviation increase in postnatal depression score. However, for more educated mothers, there was little association (odds ratio, 1.09; 95% CI, 0.88-1.36; P = .42). Analyses found that maternal education moderated the effects of postnatal but not antenatal depression. Paternal depression antenatally was not associated with offspring depression, while postnatally, paternal depression showed a similar pattern to maternal depression. Conclusions and Relevance The findings suggest that treating maternal depression antenatally could prevent offspring depression during adulthood and that prioritizing less advantaged mothers postnatally may be most effective.
TL;DR: Whether sex disparities in depression rates disappear when alternative symptoms are considered in the place of, or in addition to, more conventional depression symptoms is explored.
Abstract: RESULTS Men reported higher rates of anger attacks/aggression, substance abuse, and risk taking compared with women. Analyses using the scale that included alternative, male-type symptoms of depression found that a higher proportion of men (26.3%) than women (21.9%) (P = .007) met criteria for depression. Analyses using the scale that included alternative and traditional depression symptoms found that men and women met criteria for depression in equal proportions: 30.6% of men and 33.3% of women (P =. 57).
TL;DR: In MDD, the combination of tDCS and sertraline increases the efficacy of each treatment, and tDCS only (but not sERTraline only) was superior to placebo/sham tDCS.
Abstract: Importance Transcranial direct current stimulation (tDCS) trials for major depressive disorder (MDD) have shown positive but mixed results. Objective To assess the combined safety and efficacy of tDCS vs a common pharmacological treatment (sertraline hydrochloride, 50 mg/d). Design Double-blind, controlled trial. Participants were randomized using a 2 × 2 factorial design to sertraline/placebo and active/sham tDCS. Setting Outpatient, single-center academic setting in Sao Paulo, Brazil. Participants One hundred twenty antidepressant-free patients with moderate to severe, nonpsychotic, unipolar MDD. Interventions Six-week treatment of 2-mA anodal left/cathodal right prefrontal tDCS (twelve 30-minute sessions: 10 consecutive sessions once daily from Monday to Friday plus 2 extra sessions every other week) and sertraline hydrochloride (50 mg/d). Main Outcome Measures In this intention-to-treat analysis, the primary outcome measure was the change in Montgomery-Asberg Depression Rating Scale score at 6 weeks (end point). We considered a difference of at least 3 points to be clinically relevant. The analysis plan was previously published. Safety was measured with an adverse effects questionnaire, the Young Mania Rating Scale, and cognitive assessment. Secondary measures were rates of clinical response and remission and scores on other scales. Results At the main end point, there was a significant difference in Montgomery-Asberg Depression Rating Scale scores when comparing the combined treatment group (sertraline/active tDCS) vs sertraline only (mean difference, 8.5 points; 95% CI, 2.96 to 14.03; P = .002), tDCS only (mean difference, 5.9 points; 95% CI, 0.36 to 11.43; P = .03), and placebo/sham tDCS (mean difference, 11.5 points; 95% CI, 6.03 to 17.10; P Conclusions and Relevance In MDD, the combination of tDCS and sertraline increases the efficacy of each treatment. The efficacy and safety of tDCS and sertraline did not differ. Trial Registration clinicaltrials.gov Identifier: NCT01033084
TL;DR: If verified with prospective testing, the insula metabolism-based treatment-specific biomarker defined in this study provides the first objective marker, to the authors' knowledge, to guide initial treatment selection for depression.
Abstract: Importance Currently, fewer than 40% of patients treated for major depressive disorder achieve remission with initial treatment. Identification of a biological marker that might improve these odds could have significant health and economic impact. Objective To identify a candidate neuroimaging “treatment-specific biomarker” that predicts differential outcome to either medication or psychotherapy. Design Brain glucose metabolism was measured with positron emission tomography prior to treatment randomization to either escitalopram oxalate or cognitive behavior therapy for 12 weeks. Patients who did not remit on completion of their phase 1 treatment were offered enrollment in phase 2 comprising an additional 12 weeks of treatment with combination escitalopram and cognitive behavior therapy. Setting Mood and anxiety disorders research program at an academic medical center. Participants Men and women aged 18 to 60 years with currently untreated major depressive disorder. Intervention Randomized assignment to 12 weeks of treatment with either escitalopram oxalate (10-20 mg/d) or 16 sessions of manual-based cognitive behavior therapy. Main Outcome and Measure Remission, defined as a 17-item Hamilton Depression Rating Scale score of 7 or less at both weeks 10 and 12, as assessed by raters blinded to treatment. Results Positive and negative predictors of remission were identified with a 2-way analysis of variance treatment (escitalopram or cognitive behavior therapy) × outcome (remission or nonresponse) interaction. Of 65 protocol completers, 38 patients with clear outcomes and usable positron emission tomography scans were included in the primary analysis: 12 remitters to cognitive behavior therapy, 11 remitters to escitalopram, 9 nonresponders to cognitive behavior therapy, and 6 nonresponders to escitalopram. Six limbic and cortical regions were identified, with the right anterior insula showing the most robust discriminant properties across groups (effect size = 1.43). Insula hypometabolism (relative to whole-brain mean) was associated with remission to cognitive behavior therapy and poor response to escitalopram, while insula hypermetabolism was associated with remission to escitalopram and poor response to cognitive behavior therapy. Conclusions and Relevance If verified with prospective testing, the insula metabolism-based treatment-specific biomarker defined in this study provides the first objective marker, to our knowledge, to guide initial treatment selection for depression. Trial Registration Registered at clinicaltrials.gov (NCT00367341)
TL;DR: Dose reduction/discontinuation of antipsychotics during the early stages of remitted FEP shows superior long-term recovery rates compared with the rates achieved with MT, the first study showing long- term gains of an early-course DR strategy in patients with remitting FEP.
Abstract: Importance Short-term outcome studies of antipsychotic dose-reduction/discontinuation strategies in patients with remitted first-episode psychosis (FEP) showed higher relapse rates but no other disadvantages compared with maintenance treatment; however, long-term effects on recovery have not been studied before. Objective To compare rates of recovery in patients with remitted FEP after 7 years of follow-up of a dose reduction/discontinuation (DR) vs maintenance treatment (MT) trial. Design Seven-year follow-up of a 2-year open randomized clinical trial comparing MT and DR. Setting One hundred twenty-eight patients participating in the original trial were recruited from 257 patients with FEP referred from October 2001 to December 2002 to 7 mental health care services in a 3.2 million-population catchment area. Of these, 111 patients refused to participate and 18 patients did not experience remission. PARTICIPANTS After 7 years, 103 patients (80.5%) of 128 patients who were included in the original trial were located and consented to follow-up assessment. Intervention After 6 months of remission, patients were randomly assigned to DR strategy or MT for 18 months. After the trial, treatment was at the discretion of the clinician. Main outcomes and measures Primary outcome was rate of recovery, defined as meeting the criteria of symptomatic and functional remission. Determinants of recovery were examined using logistic regression analysis; the treatment strategy (MT or DR) was controlled for baseline parameters. Results The DR patients experienced twice the recovery rate of the MT patients (40.4% vs 17.6%). Logistic regression showed an odds ratio of 3.49 (P = .01). Better DR recovery rates were related to higher functional remission rates in the DR group but were not related to symptomatic remission rates. Conclusions and relevance Dose reduction/discontinuation of antipsychotics during the early stages of remitted FEP shows superior long-term recovery rates compared with the rates achieved with MT. To our knowledge, this is the first study showing long-term gains of an early-course DR strategy in patients with remitted FEP. Additional studies are necessary before these results are incorporated into general practice. Trial registration isrctn.org Identifier: ISRCTN16228411.
TL;DR: Autoimmune diseases and infections are risk factors for subsequent mood disorder diagnosis and seem compatible with an immunologic hypothesis for the development of mood disorders in subgroups of patients.
Abstract: Importance Mood disorders frequently co-occur with medical diseases that involve inflammatory pathophysiologic mechanisms. Immune responses can affect the brain and might increase the risk of mood disorders, but longitudinal studies of comorbidity are lacking. Objective To estimate the effect of autoimmune diseases and infections on the risk of developing mood disorders. Design Nationwide, population-based, prospective cohort study with 78 million person-years of follow-up. Data were analyzed with survival analysis techniques and adjusted for calendar year, age, and sex. Setting Individual data drawn from Danish longitudinal registers. Participants A total of 3.56 million people born between 1945 and 1996 were followed up from January 1, 1977, through December 31, 2010, with 91 637 people having hospital contacts for mood disorders. Main Outcomes and Measures The risk of a first lifetime diagnosis of mood disorder assigned by a psychiatrist in a hospital, outpatient clinic, or emergency department setting. Incidence rate ratios (IRRs) and accompanying 95% CIs are used as measures of relative risk. Results A prior hospital contact because of autoimmune disease increased the risk of a subsequent mood disorder diagnosis by 45% (IRR, 1.45; 95% CI, 1.39-1.52). Any history of hospitalization for infection increased the risk of later mood disorders by 62% (IRR, 1.62; 95% CI, 1.60-1.64). The 2 risk factors interacted in synergy and increased the risk of subsequent mood disorders even further (IRR, 2.35; 95% CI, 2.25-2.46). The number of infections and autoimmune diseases increased the risk of mood disorders in a dose-response relationship. Approximately one-third (32%) of the participants diagnosed as having a mood disorder had a previous hospital contact because of an infection, whereas 5% had a previous hospital contact because of an autoimmune disease. Conclusions and Relevance Autoimmune diseases and infections are risk factors for subsequent mood disorder diagnosis. These associations seem compatible with an immunologic hypothesis for the development of mood disorders in subgroups of patients.
TL;DR: Elevated levels of CRP are associated with increased risk for psychological distress and depression in the general population and in prospective analyses, increasing CRP levels were also associated with increasing risk for hospitalization with depression.
Abstract: CONTEXT The pathogenesis of depression is not fully understood, but studies suggest that low-grade systemic inflammation contributes to the development of depression. OBJECTIVE To test whether elevated plasma levels of C-reactive protein (CRP) are associated with psychological distress and depression. DESIGN We performed cross-sectional and prospective analyses of CRP levels in 4 clinically relevant categories using data from 2 general population studies. SETTING The Copenhagen General Population and the Copenhagen City Heart studies. PARTICIPANTS We examined 73 131 men and women aged 20 to 100 years. MAIN OUTCOME MEASURES We ascertained psychological distress with 2 single-item self-reports and depression using self-reported antidepressant use, register-based prescription of antidepressants, and register-based hospitalization with depression. RESULTS In cross-sectional analyses, increasing CRP levels were associated with increasing risk for psychological distress and depression (P = 3 × 10-8 to P = 4 × 10-105 for trend). For self-reported use of antidepressants, the odds ratio was 1.38 (95% CI, 1.23-1.55) for CRP levels of 1.01 to 3.00 mg/L, 2.02 (1.77-2.30) for 3.01 to 10.00 mg/L, and 2.70 (2.25-3.25) for greater than 10.00 mg/L compared with 0.01 to 1.00 mg/L. For prescription of antidepressants, the corresponding odds ratios were 1.08 (95% CI, 0.99-1.17), 1.47 (1.33-1.62), and 1.77 (1.52-2.05), respectively; for hospitalization with depression, 1.30 (1.01-1.67), 1.84 (1.39-2.43), and 2.27 (1.54-3.32), respectively. In prospective analyses, increasing CRP levels were also associated with increasing risk for hospitalization with depression (P = 4 × 10-8 for trend). CONCLUSIONS Elevated levels of CRP are associated with increased risk for psychological distress and depression in the general population.
TL;DR: Excessive microglial activation in multiple brain regions in young adult subjects with ASD is indicated, and similarities in the pattern of distribution of activated microglia in subjects with autism and control subjects may indicate augmented but not altered microglian activation in the brain in the Subjects with ASD.
Abstract: Context A growing body of evidence suggests that aberrant immunologic systems underlie the pathophysiologic characteristics of autism spectrum disorder (ASD). However, to our knowledge, no information is available on the patterns of distribution of microglial activation in the brain in ASD. Objectives To identify brain regions associated with excessively activated microglia in the whole brain, and to examine similarities in the pattern of distribution of activated microglia in subjects with ASD and control subjects. Design Case-control study using positron emission tomography and a radiotracer for microglia—[ 11 C](R)-(1-[2-chrorophynyl]- N-methyl- N-[1-methylpropyl]-3 isoquinoline carboxamide) ([ 11 C](R)-PK11195). Setting Subjects recruited from the community. Participants Twenty men with ASD (age range, 18-31 years; mean [SD] IQ, 95.9 [16.7]) and 20 age- and IQ-matched healthy men as controls. Diagnosis of ASD was made in accordance with the Autism Diagnostic Observation Schedule and the Autism Diagnostic Interview–Revised. Main Outcome Measures Regional brain [ 11 C](R)-PK11195 binding potential as a representative measure of microglial activation. Results The [ 11 C](R)-PK11195 binding potential values were significantly higher in multiple brain regions in young adults with ASD compared with those of controls (P 11 C](R)-PK11195 binding potential values in these brain regions of ASD and control subjects was similar, whereas the magnitude of the [ 11 C](R)-PK11195 binding potential in the ASD group was greater than that of controls in all regions. Conclusions Our results indicate excessive microglial activation in multiple brain regions in young adult subjects with ASD. The similar distribution pattern of regional microglial activity in the ASD and control groups may indicate augmented but not altered microglial activation in the brain in the subjects with ASD.
TL;DR: The ultra high-risk patients are at long-term risk for psychotic disorder, with the highest risk within the first 2 years of entry into the service, but individuals continued to be at risk up to 10 years after initial referral.
Abstract: Importance The ultra high-risk (UHR) criteria were introduced to prospectively identify patients at high risk of psychotic disorder. Although the short-term outcome of UHR patients has been well researched, the long-term outcome is not known. Objective To assess the rate and baseline predictors of transition to psychotic disorder in UHR patients up to 15 years after study entry. Design Follow-up study of a cohort of UHR patients recruited to participate in research studies between 1993 and 2006. Setting The Personal Assessment and Crisis Evaluation (PACE) clinic, a specialized service for UHR patients in Melbourne, Australia. Participants Four hundred sixteen UHR patients previously seen at the PACE clinic. Main Outcomes and Measures Transition to psychotic disorder, as measured using the Comprehensive Assessment of At-Risk Mental States, Brief Psychiatric Rating Scale/Comprehensive Assessment of Symptoms and History, or state public mental health records. Results During the time to follow-up (2.4-14.9 years after presentation), 114 of the 416 participants were known to have developed a psychotic disorder. The highest risk for transition was within the first 2 years of entry into the service, but individuals continued to be at risk up to 10 years after initial referral. The overall rate of transition was estimated to be 34.9% over a 10-year period (95% CI, 28.7%-40.6%). Factors associated with transition included year of entry into the clinic, duration of symptoms before clinic entry, baseline functioning, negative symptoms, and disorders of thought content. Conclusions and Relevance The UHR patients are at long-term risk for psychotic disorder, with the highest risk in the first 2 years. Services should aim to follow up patients for at least this period, with the possibility to return for care after this time. Individuals with a long duration of symptoms and poor functioning at the time of referral may need closer monitoring. Interventions to improve functioning and detect help-seeking UHR patients earlier also may be indicated.
TL;DR: Acutely ill patients with an initial schizophrenia diagnosis show an increased prevalence of NMDA-R antibodies and the repertoire of antibody subtypes in schizophrenia and MD is different from that with NMda-R encephalitis.
Abstract: Context: Evidence for symptomatic convergence of schizophrenia and N-methyl-D-aspartate glutamate receptor (NMDA-R) encephalitis highlights the need for an assessment of antibody prevalence and specificity for distinct disease mechanisms in patients with a diagnosis of schizophrenia among glutamatergic pathophysiologic abnormalities in psychiatric disorders. Objectives: To compare the specificity and prevalence of NMDA-R antibodies in schizophrenia (DSM-IV criteria) with those of other psychiatric diagnoses and to determine whether antibody subtypes characterize overlap withanddistinctionfromthoseinNMDA-Rencephalitis. Design: Serum from 459 patients admitted with acute schizophrenia, major depression (MD), and borderline personality disorder (BLPD) or individuals serving as matched controls was obtained from our scientific blood bank. To explore epitope specificity and antibody subtype, IgA/IgG/IgM NMDA-R (NR1a or NR1a/NR2b) and -amino-3-hydroxyl-5-methyl-4-isoxazole-propionatereceptors(AMPA-R)(GluR1/GluR2)serumantibodieswere determined. Participants:Twohundredthirtymatchedhealthycontrols were compared with patients (unmedicated for at least6weeks)withschizophrenia(n=121),MD(n=70), or BLPD (n=38). Main Outcome Measures: The primary outcome was theoverallnumberofseropositivecasesforNMDA-Rand AMPA-R antibodies; the secondary outcome was disease specificity of IgA/IgG/IgM antibodies and epitope specificity for clinical subgroups. Results: Diverse NMDA-R antibodies were identified in 15 subjects, primarily those with an initial schizophrenia diagnosis (9.9%), opposed to MD (2.8%), BLPD (0), and controls (0.4%). Retrospectively, 2 patients initially classifiedashavingcatatonicordisorganizedschizophreniawere reclassified as having misdiagnosed NMDA-R encephalitis(presenceofspecificserumandcerebrospinalfluidIgG NR1a antibodies). In all other seropositive cases, the antibodies consisted of classes IgA and/or IgM or were directedagainstNR1a/NR2b(notagainstNR1aalone).None ofthepatientsorcontrolshadantibodiesagainstAMPA-R. Conclusions: Acutely ill patients with an initial schizophrenia diagnosis show an increased prevalence of NMDA-R antibodies. The repertoire of antibody subtypesinschizophreniaandMDisdifferentfromthatwith NMDA-Rencephalitis.Thelatterdisordershouldbeconsidered as a differential diagnosis, particularly in young females with acute disorganized behavior or catatonia.
TL;DR: Evidence-based psychotherapies outperform usual care, but the EBP advantage is modest and moderated by youth, location, and assessment characteristics.
Abstract: Importance Research across more than 4 decades has produced numerous empirically tested evidence-based psychotherapies (EBPs) for psychopathology in children and adolescents. The EBPs were developed to improve on usual clinical interventions. Advocates argue that the EBPs should replace usual care, but this assumes that EBPs produce better outcomes than usual care. Objective To determine whether EBPs do in fact produce better outcomes than usual care in youth psychotherapy. We performed a meta-analysis of 52 randomized trials directly comparing EBPs with usual care. Analyses assessed the overall effect of EBPs vs usual care and candidate moderators; we used multilevel analysis to address the dependency among effect sizes (ES) that is common but typically unaddressed in psychotherapy syntheses. Data Sources We searched the PubMed, PsychINFO, and Dissertation Abstracts International databases for studies from January 1, 1960, through December 31, 2010. Study Selection We identified 507 randomized youth psychotherapy trials. Of these, the 52 studies that compared EBPs with usual care were included in the meta-analysis. Data Extraction and Synthesis Sixteen variables (participant, treatment, outcome, and study characteristics) were extracted from studies, and ESs were calculated for all comparisons of EBP vs usual care. We used an extension of the commonly used random-effects meta-analytic model to obtain an overall estimate of the difference between EBP and usual care while accounting for the dependency among ESs. We then fitted a 3-level mixed-effects model to identify moderators that might explain variation in ESs within and between studies by adding study or ES characteristics as fixed predictors. Main Outcomes and Measures Primary outcomes of our meta-analysis were mean ES estimates across all studies and for levels of candidate moderators. These ES values were based on measures of symptoms, functioning, and other outcomes assessed within the 52 randomized trials. Results Evidence-based psychotherapies outperformed usual care. Mean ES was 0.29; the probability was 58% that a randomly selected youth would have a better outcome after EBP than a randomly selected youth after receiving usual care. The following 3 variables moderated treatment benefit: ESs decreased for studies conducted outside North America, for studies in which all participants were impaired enough to qualify for diagnoses, and for outcomes reported by informants other than the youths and parents in therapy. For certain key groups (eg, studies of clinically referred samples and youths with diagnoses), significant EBP effects were not demonstrated. Conclusions and Relevance Evidence-based psychotherapies outperform usual care, but the EBP advantage is modest and moderated by youth, location, and assessment characteristics. The EBPs have room for improvement in the magnitude and range of their benefit relative to usual clinical care.
TL;DR: Clinically significant reductions in PTSD symptoms were achieved among male and female veterans of all war eras and veterans with combat-related and non-combat-related PTSD, and PE is effective in reducing depression symptoms, even though depression is not a direct target of the treatment.
Abstract: Importance Posttraumatic stress disorder (PTSD) is a pervasive and often debilitating condition that affects many individuals in the general population and military service members. Effective treatments for PTSD are greatly needed for both veterans returning from Iraq and Afghanistan and veterans of other eras. Prolonged exposure (PE) therapy has been shown to be highly efficacious in clinical trials involving women with noncombat trauma, but there are limited data on its effectiveness in real-world clinical practice settings and with veterans. Objective To evaluate the effectiveness of PE as implemented with veterans with PTSD in a large health care system. Design, Setting, and Participants This evaluation included 1931 veterans treated by 804 clinicians participating in the Department of Veterans Affairs (VA) PE Training Program. After completing a 4-day experiential PE training workshop, clinicians implemented PE (while receiving consultation) with a minimum of 2 veteran patients who had a primary diagnosis of PTSD. Main Outcomes and Measures Changes in PTSD and depression symptoms were assessed with the PTSD Checklist and the Beck Depression Inventory II, measured at baseline and at the final treatment session. Multiple and single imputation were used to estimate the posttest scores of patients who left treatment before completing 8 sessions. Demographic predictors of treatment dropout were also examined. Results Intent-to-treat analyses indicate that PE is effective in reducing symptoms of both PTSD (pre-post d = 0.87) and depression (pre-post d = 0.66), with effect sizes comparable to those reported in previous efficacy trials. The proportion of patients screening positive for PTSD on the PTSD Checklist decreased from 87.6% to 46.2%. Conclusions Clinically significant reductions in PTSD symptoms were achieved among male and female veterans of all war eras and veterans with combat-related and non–combat-related PTSD. Results also indicate that PE is effective in reducing depression symptoms, even though depression is not a direct target of the treatment.
TL;DR: The results suggest that strong selection exists against schizophrenia, autism, and anorexia nervosa and that these variants may be maintained by new mutations or an as-yet unknown mechanism.
Abstract: Context It is unknown how genetic variants conferring liability to psychiatric disorders survive in the population despite strong negative selection. However, this is key to understanding their etiology and designing studies to identify risk variants. Objectives To examine the reproductive fitness of patients with schizophrenia and other psychiatric disorders vs their unaffected siblings and to evaluate the level of selection on causal genetic variants. Design We measured the fecundity of patients with schizophrenia, autism, bipolar disorder, depression, anorexia nervosa, or substance abuse and their unaffected siblings compared with the general population. Setting Population databases in Sweden, including the Multi-Generation Register and the Swedish Hospital Discharge Register. Participants In total, 2.3 million individuals among the 1950 to 1970 birth cohort in Sweden. Main Outcome Measures Fertility ratio (FR), reflecting the mean number of children compared with that of the general population, accounting for age, sex, family size, and affected status. Results Except for women with depression, affected patients had significantly fewer children (FR range for those with psychiatric disorder, 0.23-0.93; P Conclusions Our results suggest that strong selection exists against schizophrenia, autism, and anorexia nervosa and that these variants may be maintained by new mutations or an as-yet unknown mechanism. Bipolar disorder did not seem to be under strong negative selection. Vulnerability to depression, and perhaps substance abuse, may be preserved by balancing selection, suggesting the involvement of common genetic variants in ways that depend on other genes and on environment.
TL;DR: Although incidence is no higher than in the general population, psychiatric patients are more likely to have metastases at diagnosis and less likely to receive specialized interventions, which may explain their greater case fatality and highlights the need for improved cancer screening and detection.
Abstract: Context There is a 30% higher case fatality rate from cancer in psychiatric patients even though their incidence of cancer is no greater than in the general population. The reasons are unclear, but if increased cancer mortality were due to lifestyle only, cancer incidence should be similarly increased. Other hypotheses include delays in presentation, leading to more advanced staging at diagnosis, and difficulties in treatment access following diagnosis. Objective To assess why psychiatric patients are no more likely than the general population to develop cancer but are more likely to die of it. Design, Setting, and Patients A population-based record-linkage analysis compared psychiatric patients with the Western Australian population, using an inception cohort to calculate rates and hazard ratios. Mental health records were linked with cancer registrations and death records from January 1, 1988, to December 31, 2007, in Western Australia. Main Outcome Measures Metastases, incidence, mortality, and access to cancer interventions. Results There were 6586 new cancers in psychiatric patients. Cancer incidence was lower in psychiatric patients than in the general population in both males (rate ratio = 0.86; 95% CI, 0.82-0.90) and females (rate ratio = 0.92; 95% CI, 0.88-0.96), although mortality was higher (males: rate ratio = 1.52; 95% CI, 1.45-1.60; females: rate ratio = 1.29; 95% CI, 1.22-1.36). The proportion of cancer with metastases at presentation was significantly higher in psychiatric patients (7.1%; 95% CI, 6.5%-7.8%) than in the general population (6.1%; 95% CI, 6.0%-6.2%). Psychiatric patients had a reduced likelihood of surgery (hazard ratio = 0.81; 95% CI, 0.76-0.86), especially resection of colorectal, breast, and cervical cancers. They also received significantly less radiotherapy for breast, colorectal, and uterine cancers and fewer chemotherapy sessions. Conclusions Although incidence is no higher than in the general population, psychiatric patients are more likely to have metastases at diagnosis and less likely to receive specialized interventions. This may explain their greater case fatality and highlights the need for improved cancer screening and detection.
TL;DR: The negative correlations between fear extinction deficits and Yale-Brown Obsessive-Compulsive Scale symptoms in OCD suggest that there may be other factors, in addition to fear extinction deficiency, that contribute to the psychopathology of OCD.
Abstract: Importance Obsessive-compulsive disorder (OCD) may be characterized by impaired self-regulation and behavioral inhibition. Elevated fear and anxiety are common characteristics of this disorder. The neurobiology of fear regulation and consolidation of safety memories have not been examined in this patient population. Objective To examine the psychophysiological and neurobiological correlates of conditioned fear extinction in patients with OCD. Design Cross-sectional, case-control, functional magnetic resonance imaging study. Setting Academic medical center. Participants Twenty-one patients with OCD and 21 healthy participants. Main Outcomes and Measures Skin conductance responses and blood oxygenation level–dependent responses. Results The between-group difference noted in our psychophysiological measure (skin conductance responses) was during extinction recall: patients with OCD showed impaired extinction recall relative to control subjects. Regarding the functional magnetic resonance imaging data, patients with OCD showed significantly reduced activation in the ventromedial prefrontal cortex across training phases. Moreover, reduced activation in the patients with OCD was noted in the caudate and hippocampus during fear conditioning, as well as in the cerebellum, posterior cingulate cortex, and putamen during extinction recall. Contrary to our prediction, OCD symptom severity was positively correlated with the magnitude of extinction memory recall. Also contrary to our prediction, functional responses of the ventromedial prefrontal cortex were positively correlated with symptom severity, and functional responses of the dorsal anterior cingulate cortex were inversely correlated with symptom severity. Conclusions and Relevance As expected, our study showed that fear extinction and its neural substrates are impaired in patients with OCD. However, this study also yielded some surprising and unexpected results regarding the correlates between extinction capacity and its neural substrates and the severity of symptoms expressed in this disorder. Thus, our data report neural correlates of deficient fear extinction in patients with OCD. The negative correlations between fear extinction deficits and Yale-Brown Obsessive-Compulsive Scale symptoms in OCD suggest that there may be other factors, in addition to fear extinction deficiency, that contribute to the psychopathology of OCD.
TL;DR: The associations between early gestation and mortality and psychiatric morbidity generally were robust when comparing differentially exposed siblings and controlling for statistical covariates, whereas the associations with academic and some social problems were greatly or completely attenuated in the fixed-effects models.
Abstract: Importance: Preterm birth is associated with increased mortality and morbidity. However, previous studies have been unable to rigorously examine whether confounding factors cause these associations ...
TL;DR: Symptoms of depression follow a U-shaped pattern across adulthood, and women reported more depressed affect at younger ages, but an interaction with age suggested that this gap disappeared in old age.
Abstract: Importance Long-term longitudinal studies are needed to delineate the trajectory of depressive symptoms across adulthood and to individuate factors that may contribute to increases in depressive symptoms in older adulthood. Objectives To estimate the trajectory of depressive symptoms across the adult life span; to test whether this trajectory varies by demographic factors (sex, ethnicity, and educational level) and antidepressant medication use; and to test whether disease burden, functional limitations, and proximity to death explain the increase in depressive symptoms in old age. Design Longitudinal study. Setting Community. Participants The study included 2320 participants (47.0% female; mean [SD] age at baseline, 58.1 [17.0] years; range, 19-95 years) from the Baltimore Longitudinal Study of Aging. Main Outcomes and Measures Estimated trajectory of depressive symptoms modeled from 10 982 assessments (mean [SD] assessments per participant, 4.7 [3.6]; range, 1-21) based on the Center for Epidemiologic Studies Depression scale and 3 subscales (depressed affect, somatic complaints, and interpersonal problems). Results The linear (γ 10 = 0.52; P 20 = 0.43; P Conclusions and Relevance Symptoms of depression follow a U-shaped pattern across adulthood. Older adults experience an increase in distress that is not due solely to declines in physical health or approaching death.
TL;DR: Altered paralimbic reward signals and impulsivity and/or carelessness may facilitate unplanned suicidal acts.
Abstract: IMPORTANCE—Suicide can be viewed as an escape from unendurable punishment at the cost of any future rewards. Could faulty estimation of these outcomes predispose to suicidal behavior? In behavioral studies, many of those who have attempted suicide misestimate expected rewards on gambling and probabilistic learning tasks.OBJECTIVES—To describe the neural circuit abnormalities that underlie disadvantageous choices in people at risk for suicide and to relate these abnormalities to impulsivity, which is one of the components of vulnerability to suicide.DESIGN—Case-control functional magnetic resonance imaging study of reward learning using are inforcement learning model.SETTING—University hospital and outpatient clinic.PATIENTS—Fifty-three participants 60 years or older, including 15 depressed patients who had attempted suicide, 18 depressed patients who had never attempted suicide (depressed control subjects), and 20 psychiatrically healthy controls.MAIN OUTCOMES AND MEASURES—Components of the cortical blood oxygenation level–dependent response tracking expected and unpredicted rewards.RESULTS—Depressed elderly participants displayed 2 distinct disruptions of control over reward-guided behavior. First, impulsivity and a history of suicide attempts (particularly poorly planned ones) were associated with a weakened expected reward signal in the paralimbic cortex,which in turn predicted the behavioral insensitivity to contingency change. Second, depression was associated with disrupted corticostriatothalamic encoding of unpredicted rewards, which in turn predicted the behavioral over sensitivity to punishment. These results were robust to the effects of possible brain damage from suicide attempts, depressive severity, co-occurring substance use and anxiety disorders, antidepressant and anticholinergic exposure, lifetime exposure to electroconvulsive therapy, vascular illness, and incipient dementia.CONCLUSIONS AND RELEVANCE—Altered paralimbic reward signals and impulsivity and/or carelessness may facilitate unplanned suicidal acts. This pattern, also seen in gambling and cocaine use, may reflect a primary deficit in the paralimbic cortex or in its mesolimbic input. The over reactivity to punishment in depression may be caused in part by a disruption of appetitive learning in the corticostriatothalamic circuits.
TL;DR: Brain response, alcohol craving, and relapse outcome measures indicate that disrupted vmPFC/ACC function plays a role in jeopardizing recovery from alcoholism and may serve as a neural marker to identify those at risk for alcohol relapse.
Abstract: Alcohol dependence is a chronic, relapsing illness, which contributes to significant global disease burden.1 The risk for relapse further perpetuates this disease burden and is increased in stress-related and alcohol-related contexts that promote anxiety and alcohol craving.2-6 Neuroendocrine studies have demonstrated that upregulated hypothalamic-pituitary-adrenal axis response during a neutral-relaxing condition and blunted cortisol responses to stress significantly contribute to chronic alcoholism and relapse.6-8 Evidence from electrophysiological studies also indicates disrupted electroencephalographic responses at rest during early recovery from alcoholism. For example, excessive alcohol use leads to neuroadaptations akin to a kindling-like process,9 resulting in a hyper-excitable neuronal state, particularly in frontal regions.10,11 Furthermore, alcohol-related neuroadaptations increase stress sensitivity2,12 and stress-related anxiety response.13 These studies suggest the importance of examining neural mechanisms of stress and nonemotional, neutral-relaxing states in assessing their contribution to alcohol relapse risk.
Although recent advances in neuroimaging techniques have provided insights into neuronal abnormalities in brain structure and function associated with chronic alcoholism, research on functional mechanisms associated with alcohol relapse has been rare and primarily focused on alcohol cue–related neural processes in the mesocortical-limbic pathways,14 with little attention to neural mechanisms involved in stress and neutral-relaxing states and their associations with alcohol craving and relapse. Because chronic alcohol-related neuroadaptations target prefrontal networks that include the corticostriatal motivation pathways,15 such neuroadaptations could promote increased craving and relapse risk.2,6,12,16 Alcohol-related dysfunction in frontal networks might particularly affect higher order executive function including response inhibition and decision-making functions.17-19 Furthermore, chronic alcohol-related hyperactivity of the mesolimbic dopamine-related impulsive pathways may further compromise the prefrontal self-control regions involved in the regulation of cravings and the will to resist relapse.17,19,20 However, the specific role of the prefrontal regions and their interconnected networks in alcohol craving and relapse risk in the context of stress and neutral-relaxing states is not known.
Integrating the previously mentioned theoretical and empirical perspectives, the current study aimed to identify neural correlates of alcohol craving and future relapse risk in the context of stress, alcohol cue, and neutral-relaxing situations in recovering alcohol-dependent (AD) patients using a combined functional magnetic resonance imaging (fMRI) and prospective clinical design study. We examined all 3 conditions known to influence alcoholism in previous studies to investigate patterns of differential neural responses during these conditions. The neutral-relaxing condition was included as an active comparison state because it does not increase alcohol craving,6 but it provides a context to assess changes in a resting-relaxed state while controlling for the non-specific effects of the experimental manipulation. In previous work, we identified disrupted neuroendocrine responses in the relaxed states in AD patients with a strong association with alcohol relapse.6 A second aim was to identify whether the same neural responses that are predictive of alcohol relapse show differences in brain responses when comparing recovering AD patients and demographically matched healthy control (HC) subjects.
For the relapse aim, 45 inpatient treatment–engaged, 4- to 8-week–abstinent, recovering AD individuals participated in an fMRI session. Participants were discharged from inpatient treatment following the fMRI session and prospectively followed up with repeated face-to-face assessments at days 14, 30, and 90 to assess relapse risk (Figure 1A). Relapse risk was assessed with the frequently used clinical outcome measures of time to first drink (relapse), time to heavy drinking relapse (5 or more drinks/occasion in men; 4 or more drinks/occasion in women), and alcohol relapse severity as measured by frequency of drinking days after first relapse. For group comparisons, we compared brain responses of age-matched, sex-matched, and intelligence-matched, right-handed, abstinent AD patients (a subgroup of the relapse sample) vs healthy, socially drinking individuals (30 in each group; eTable 1, http:www.jamapsych.com).
Figure 1
Study design. A, For relapse sample, all 45 alcohol-dependent (AD) patients resided in an inpatient treatment research facility for 6 weeks with functional magnetic resonance image (fMRI) testing in week 5, and patients were assessed with follow-up interviews ...
A block design approach that used a well-validated, individually calibrated, script-driven guided-imagery procedure (see Sinha article21 for review) was implemented to experimentally induce challenging stress and alcohol cue states and an active neutral-relaxing control state via exposure to 6 brief trials of 2 stress, 2 alcohol cue, and 2 neutral-relaxing scenarios (different scripts presented in randomized order). The same fMRI procedures were used with both the AD patients and HC subjects in the study.