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Biological Psychiatry

Saturday, August 6, 2016

August 2016

Individuals hospitalized with acute mania have increased exposure to antimicrobial medications 

Bipolar Disorders


We have preciously documented that many individuals with acute mania have immune activation. However, the sources of immune activation have not been identified. We investigated whether individuals hospitalized with acute mania have evidence of bacterial infections as determined by the prescription of systemic antimicrobial agents.

We assessed the recent prescription of systemic antimicrobial medications and the site of presumed bacterial infection in 234 individuals hospitalized for acute mania in either an inpatient unit or a day hospital. We also assessed individuals hospitalized for other psychiatric disorders (n=368) and controls (n=555). We employed logistic regression models to compare the rates of antibiotic prescription in individuals with the different diagnoses, employing demographic variables as covariates.

We found that individuals hospitalized with acute mania had a substantially increased rate of recent antimicrobial prescription, defined as exposure within three days of ascertainment (adjusted odds ratio=5.5, 95% confidence interval: 2.2–14.1, P<.0002). Overall, a total of 18 of the 234 (7.7%) individuals hospitalized for acute mania were prescribed antibiotics as opposed to seven of 555 (1.3%) controls. The prescription of antibiotics was associated with being on an inpatient unit as opposed to being in the day hospital, and having increased mania symptom severity but not with other clinical ratings, demographic variables, or psychiatric medications. Hospitalization for other psychiatric disorders was not associated with the recent prescription of antimicrobial medications. The urinary tract was the most common site of infection in women, while the respiratory tract and mucosal surfaces were the most common sites in men.

Individuals hospitalized with acute mania have a markedly increased rate of bacterial infections, as evidenced by the recent prescription of antimicrobial agents. The prevention and effective treatment of bacterial infections may be important interventions for the management of individuals with mania.

Reducing smoking reduces suicidality among individuals with psychosis

Psychiatry Research


This study sought to explore the impact of smoking reduction on suicidality (suicide ideation and behaviour) among people with a psychotic disorder (n=235) who participated in a randomized trial of a healthy lifestyle intervention trial. Suicidality, measured by item −4 of the Brief Psychiatric Rating Scale (BPRS) was the main variable of interest. Measures were collected by research assistants blind to treatment allocation at baseline, at 15 weeks (mid-intervention) and 12 months after baseline. Mediation analysis, adjusted for confounders, was used to determine the relationship between smoking reduction and suicidality and to explore whether this was mediated through depression. At 12 months, smoking reduction was found to be significantly associated with suicidality change; an association was also seen between smoking reduction and depression and depression and suicidality. After adjusting for depression, the association between smoking reduction and suicidality was attenuated but remained statistically significant; the proportion of the total effect that was mediated through depression was 30%. There was no significant association between suicidality and treatment group (vs. controls) over time. Our study suggests that smoking interventions may have benefits over and above those for improved physical health, by reducing suicidal ideation in people with psychosis.

White Matter Integrity Reductions in Intermittent Explosive Disorder



Intermittent explosive disorder (IED), as described in DSM-5, is the categorical expression of pathological impulsive aggression. Previous work has identified neurobiological correlates of the disorder in patterns of frontal-limbic brain activity and dysregulation of serotonergic neurotransmission. Given the importance of short- and-long range white matter connections of the brain in social and emotional behavior, studies of white matter connectivity in impulsive aggression are warranted. Diffusion tensor imaging (DTI) studies in the related conditions of antisocial and borderline personality disorder have produced preliminary evidence of disturbed white matter connectivity in these disorders, but to date there have been no DTI studies in IED. A total of 132 male and female adults between the ages of 18 and 55 years underwent Turboprop-DTI on a 3-Tesla MRI scanner. Of these, 42 subjects had IED, 40 were normal controls, and 50 were clinical psychiatric controls with psychiatric disorders without IED. All subjects were free of alcohol, psychotropic medications, or drugs of abuse. The diffusion tensor was calculated in each voxel and maps of fractional anisotropy (FA) were generated. Tract-based spatial statistics (TBSS) were used to compare FA along the white matter skeleton among the three subject groups. IED was associated with lower FA in two clusters located in the superior longitudinal fasciculus (SLF) when compared with the psychiatric and healthy controls. Impulsive aggression and borderline personality disorder, but not psychopathy or antisocial personality disorder, was associated with lower FA in the two clusters within the SLF. In conclusion, IED was associated with lower white matter integrity in long-range connections between the frontal and temporoparietal regions.

An Individualized Risk Calculator for Research in Prodromal Psychosis

The American Journal of Psychiatry
Approximately 20%–35% of individuals 12–35 years old who meet criteria for a prodromal risk syndrome convert to psychosis within 2 years. However, this estimate ignores the fact that clinical high-risk cases vary considerably in risk. The authors sought to create a risk calculator, based on profiles of risk indicators, that can ascertain the probability of conversion to psychosis in individual patients.

The study subjects were 596 clinical high-risk participants from the second phase of the North American Prodrome Longitudinal Study who were followed up to the time of conversion to psychosis or last contact (up to 2 years). The predictors examined were limited to those that are supported by previous studies and are readily obtainable in general clinical settings. Time-to-event regression was used to build a multivariate model predicting conversion, with internal validation using 1,000 bootstrap resamples.

The 2-year probability of conversion to psychosis was 16%. Higher levels of unusual thought content and suspiciousness, greater decline in social functioning, lower verbal learning and memory performance, slower speed of processing, and younger age at baseline each contributed to individual risk for psychosis. Stressful life events, trauma, and family history of schizophrenia were not significant predictors. The multivariate model achieved a concordance index of 0.71 and, as reported in an article by Carrión et al., published concurrently with this one, was validated in an independent external data set. The results are instantiated in a web-based risk prediction tool envisioned to be most useful in research protocols involving the psychosis prodrome.

A risk calculator comparable in accuracy to those for cardiovascular disease and cancer is available to predict individualized conversion risks in newly ascertained clinical high-risk cases. Given that the risk calculator can be validly applied only for patients who screen positive on the Structured Clinical Interview for Psychosis Risk Syndromes, which requires training to administer, its most immediate uses will be in research on psychosis risk factors and in research-driven clinical (prevention) trials.

A multi-modal parcellation of human cerebral cortex


Understanding the amazingly complex human cerebral cortex requires a map (or parcellation) of its major subdivisions, known as cortical areas. Making an accurate areal map has been a century-old objective in neuroscience. Using multi-modal magnetic resonance images from the Human Connectome Project (HCP) and an objective semi-automated neuroanatomical approach, we delineated 180 areas per hemisphere bounded by sharp changes in cortical architecture, function, connectivity, and/or topography in a precisely aligned group average of 210 healthy young adults. We characterized 97 new areas and 83 areas previously reported using post-mortem microscopy or other specialized study-specific approaches. To enable automated delineation and identification of these areas in new HCP subjects and in future studies, we trained a machine-learning classifier to recognize the multi-modal ‘fingerprint’ of each cortical area. This classifier detected the presence of 96.6% of the cortical areas in new subjects, replicated the group parcellation, and could correctly locate areas in individuals with atypical parcellations. The freely available parcellation and classifier will enable substantially improved neuroanatomical precision for studies of the structural and functional organization of human cerebral cortex and its variation across individuals and in development, aging, and disease.

Amyloid proteotoxicity initiates an inflammatory response blocked by cannabinoids


The beta amyloid (Aβ) and other aggregating proteins in the brain increase with age and are frequently found within neurons. The mechanistic relationship between intracellular amyloid, aging and neurodegeneration is not, however, well understood. We use a proteotoxicity model based upon the inducible expression of Aβ in a human central nervous system nerve cell line to characterize a distinct form of nerve cell death caused by intracellular Aβ. It is shown that intracellular Aβ initiates a toxic inflammatory response leading to the cell's demise. Aβ induces the expression of multiple proinflammatory genes and an increase in both arachidonic acid and eicosanoids, including prostaglandins that are neuroprotective and leukotrienes that potentiate death. Cannabinoids such as tetrahydrocannabinol stimulate the removal of intraneuronal Aβ, block the inflammatory response, and are protective. Altogether these data show that there is a complex and likely autocatalytic inflammatory response within nerve cells caused by the accumulation of intracellular Aβ, and that this early form of proteotoxicity can be blocked by the activation of cannabinoid receptors.

Hospital Readmission Rates Among Patients With Schizophrenia Treated With Long-Acting Injectables or Oral Antipsychotics

Psychiatric Service


This study analyzed hospital readmission rates of patients with schizophrenia who were treated with long-acting injectable antipsychotics (LAIs) or with oral antipsychotics after being discharged from a hospitalization.

Medical claims of patients with schizophrenia who were ages 18–64 and had a first hospitalization for a serious mental illness (index hospitalization, October 2007 through September 2012) and at least one prescription for a first- or second-generation antipsychotic were analyzed from the Truven Health MarketScan Multi-State Medicaid Database. Analyses were conducted for patients with a sole diagnosis of schizophrenia (N=1,450) and for all patients with schizophrenia (N=15,556), which added patients with a codiagnosis of bipolar disorder or major depressive disorder. Probability of rehospitalization for any cause at 30 and 60 days after the initial hospitalization was assessed with multivariate logistic regression and propensity score matching (PSM) methods. The PSM model matched age, preindex use of LAIs or short-acting injectables, and select comorbidities between the LAI and the oral antipsychotics groups.

LAIs were associated with significantly lower probability of rehospitalization compared with oral antipsychotics at 60 days for schizophrenia-only patients (adjusted odds ratio [AOR]=.60, 95% confidence interval [CI]=.41–.90) and for all patients (AOR=.70, CI=.52–.95). The absolute difference in probability of rehospitalization for all patients was significantly lower by 5.0% at 60 days in the LAI group compared with the oral antipsychotics group.

Compared with use of oral antipsychotics, use of LAIs was associated with fewer readmissions of Medicaid patients with schizophrenia within 60 days after an index hospitalization.

Gray matter maturation and cognition in children with different APOE ε genotypes



The aims of the current study were to determine whether children with the 6 different APOE ε genotypes show differences in gray matter maturation, particularly for those with ε4 and ε2 alleles, which are associated with poorer outcomes in many neurologic disorders.

A total of 1,187 healthy children (aged 3–20 years, 52.1% boys, 47.9% girls) with acceptable data from the cross-sectional Pediatric Imaging Neurocognition and Genetics Study were evaluated for the effects of 6 APOE ε genotypes on macroscopic and microscopic cortical and subcortical gray matter structures (measured with 3-tesla MRI and FreeSurfer for automated morphometry) and on cognition (NIH Toolbox).

Among APOE ε4 carriers, age-related changes in brain structures and cognition varied depending on genotype, with the smallest hippocampi in ε2ε4 children, the lowest hippocampal fractional anisotropy in younger ε4ε4 children, the largest medial orbitofrontal cortical areas in ε3ε4 children, and age-dependent thinning of the entorhinal cortex in ε4ε4 children. Younger ε4ε4 children had the lowest scores on executive function and working memory, while younger ε2ε4 children performed worse on attention tasks. Larger parietal gyri in the younger ε2ε4 children, and thinner temporal and cingulate isthmus cortices or smaller hippocampi in the younger ε4ε4 children, predicted poorer performance on attention or working memory.

Our findings validated and extended prior smaller studies that showed altered brain development in APOE ε4–carrier children. The ε4ε4 and ε2ε4 genotypes may negatively influence brain development and brain aging at the extremes of age. Studying APOE ε polymorphisms in young children may provide the earliest indicators for individuals who might benefit from early interventions or preventive measures for future brain injuries and dementia.

Relative hypocortisolism is associated with obesity and the metabolic syndrome in recurrent affective disorders

Journal of Affective Disorders


Cardiovascular disease (CVD) is one of the main causes of excess deaths in affective disorders. Affective disorders are associated with increased frequencies of CVD risk-factors such as obesity, dyslipidemia, and metabolic syndrome. Stress-induced chronic cortisol excess has been suggested to promote obesity and metabolic syndrome. Chronic stress with frequent or persisting hypothalamic-pituitary-adrenal-axis (HPA-axis) hyperactivity may, over time, lead to a state of low HPA-axis activity, also denoted hypocortisolism. A low-dose weight-adjusted dexamethasone-suppression-test (DST) is considered to be a sensitive measure of hypocortisolism.

245 patients with recurrent depression or bipolar disorder and 258 controls participated in a low-dose DST and were also examined with regard to metabolic status.

Patients with hypocortisolism (low post-DST cortisol) compared with patients without hypocortisolism (normal or high post-DST cortisol) exhibited increased odds ratios (OR) for obesity (OR=4.0), overweight (OR=4.0), large waist (OR=2.7), high LDL (OR=4.2), low HDL (OR=2.4), high LDL/HDL ratio (OR=3.3), high TC/HDL ratio (OR=3.4) and metabolic syndrome (OR=2.0). A similar pattern but less pronounced was also found in the control sample.

The cross sectional study design and absence of analyses addressing lifestyle factors.

Our findings suggest that a substantial portion of the metabolic disorders and cardiovascular risk factors seen in recurrent affective disorders are found among individuals exhibiting hypocortisolism. This might indicate that long-term stress is a central contributor to metabolic abnormalities and CVD mortality in recurrent affective disorders.

Association Between Diabetes-Related Eye Complications and Symptoms of Anxiety and Depression

JAMA Ophthalmology


This study is needed to clarify inconsistent findings regarding the association between diabetes-related eye complications and psychological well-being.

To examine the association between severity of diabetic retinopathy (DR) and diabetic macular edema (DME) with symptoms of depression and anxiety in adults with diabetes.

Design, Setting, and Participants  
A cross-sectional study was conducted in a tertiary eye hospital in Melbourne, Australia. The study comprised 519 participants with diabetes. The median duration of diabetes was 13.0 (interquartile range, 14.0) years. The study was conducted from March 1, 2009, to December 24, 2010.

Patients underwent a comprehensive eye examination in which dilated fundus photographs (disc and macula centered) were obtained and graded for the presence and severity of DR and DME. Presenting distance uniocular and binocular visual acuity were assessed using a 3-m logMAR chart.

Main Outcomes and Measures  
Symptoms of depression and anxiety were measured using the Hospital Anxiety and Depression Scale (HADS), which comprises 7 questions specific to anxiety and 7 specific to depression with scores ranging from 0 to 21; scores higher than 8 signify possible anxiety or depression. The ordinal raw scores of the HADS questionnaire were transformed to estimates of interval measure using Rasch analysis and evaluated as continuous variables. Participants also completed standardized interview-administered questionnaires. Blood samples were assessed for hemoglobin A1c, fasting blood glucose, and serum lipids. Multiple linear regression models were used to determine the associations between the severity of DR and DME with symptoms of anxiety and depression and commonality analysis was used to quantify the unique variance explained.

Of the 519 participants in the study, 170 individuals (32.8%) were female; mean (SD) age was 64.9 (11.6) years. Raw scores indicated that 80 individuals (15.4%) screened positive for depressive symptoms and 118 persons (22.7%) screened positive for symptoms of anxiety. In multivariate analysis using Rasch scores, severe nonproliferative DR (NPDR)/PDR was independently associated with greater depressive symptoms (regression coefficient [β] = 0.69; 95% CI, 0.03-1.34) after controlling for sociodemographic factors and clinical characteristics, including visual acuity. A history of depression or anxiety accounted for 60.6% (95% CI, 23.9%-83.2%) of the unique variance in depressive symptoms, and severe NPDR or PDR contributed to 19.1% (95% CI, 1.7%-44.4%) of the total explained variance of depressive symptoms. Diabetic macular edema was not associated with depressive symptoms. No association between DR and symptoms of anxiety was identified.

Conclusions and Relevance  
Severe NPDR or PDR, but not DME, was independently associated with depressive symptoms. The severity of DR could be an indicator to prompt monitoring of depression in at-risk individuals with diabetes. Further work is required to replicate these findings and determine the clinical significance of the association.

Online Journals:

Biological Psychiatry - Volume 80, Issue 5, September 2016

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