Sunday, September 4, 2016

September 2016

Development of a blood-based molecular biomarker test for identification of schizophrenia before disease onset 


Translational Psychiatry

Abstract

Recent research efforts have progressively shifted towards preventative psychiatry and prognostic identification of individuals before disease onset. We describe the development of a serum biomarker test for the identification of individuals at risk of developing schizophrenia based on multiplex immunoassay profiling analysis of 957 serum samples. First, we conducted a meta-analysis of five independent cohorts of 127 first-onset drug-naive schizophrenia patients and 204 controls. Using least absolute shrinkage and selection operator regression, we identified an optimal panel of 26 biomarkers that best discriminated patients and controls. Next, we successfully validated this biomarker panel using two independent validation cohorts of 93 patients and 88 controls, which yielded an area under the curve (AUC) of 0.97 (0.95–1.00) for schizophrenia detection. Finally, we tested its predictive performance for identifying patients before onset of psychosis using two cohorts of 445 pre-onset or at-risk individuals. The predictive performance achieved by the panel was excellent for identifying USA military personnel (AUC: 0.90 (0.86–0.95)) and help-seeking prodromal individuals (AUC: 0.82 (0.71–0.93)) who developed schizophrenia up to 2 years after baseline sampling. The performance increased further using the latter cohort following the incorporation of CAARMS (Comprehensive Assessment of At-Risk Mental State) positive subscale symptom scores into the model (AUC: 0.90 (0.82–0.98)). The current findings may represent the first successful step towards a test that could address the clinical need for early intervention in psychiatry. Further developments of a combined molecular/symptom-based test will aid clinicians in the identification of vulnerable patients early in the disease process, allowing more effective therapeutic intervention before overt disease onset.


FDA warns about serious risks and death when combining opioid pain or cough medicines with benzodiazepines; requires its strongest warning


US FDA

A U.S. Food and Drug Administration (FDA) review has found that the growing combined use of opioid medicines with benzodiazepines or other drugs that depress the central nervous system (CNS) has resulted in serious side effects, including slowed or difficult breathing and deaths. Opioids are used to treat pain and cough; benzodiazepines are used to treat anxiety, insomnia, and seizures. In an effort to decrease the use of opioids and benzodiazepines, or opioids and other CNS depressants, together, we are adding Boxed Warnings, our strongest warnings, to the drug labeling of prescription opioid pain and prescription opioid cough medicines, and benzodiazepines.
Health care professionals should limit prescribing opioid pain medicines with benzodiazepines or other CNS depressants only to patients for whom alternative treatment options are inadequate. If these medicines are prescribed together, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. Warn patients and caregivers about the risks of slowed or difficult breathing and/or sedation, and the associated signs and symptoms. Avoid prescribing prescription opioid cough medicines for patients taking benzodiazepines or other CNS depressants, including alcohol.



The Effect of Concomitant Treatment With SSRIs and Statins: A Population-Based Study


The American Journal of Psychiatry

Abstract

Objective
Both preclinical studies and clinical trials have indicated that the combination of a selective serotonin reuptake inhibitor (SSRI) and a statin may have superior antidepressant effects compared with SSRI treatment alone. The authors sought to assess whether this beneficial effect can be generalized to a more heterogeneous population of SSRI users.

Method
In a nationwide cohort study that included all incident SSRI users in Denmark between 1997 and 2012, the authors compared people who had periods of concomitant use of SSRIs and statins with people who had periods of SSRI treatment alone. Outcomes included the rates of psychiatric hospital contacts (any cause), psychiatric hospital contacts due to depression, suicidal behavior, and all-cause mortality. Using Cox regression and competing risk analysis, the authors calculated crude and adjusted hazard ratios for these outcomes.

Results
The authors identified 872,216 incident SSRI users, of whom 113,108 (13.0%) used a statin concomitantly. Compared with SSRI treatment alone, the combined use of an SSRI and a statin was associated with a significantly lower risk for both psychiatric hospital contacts (adjusted hazard ratio=0.75 (95% CI=0.69, 0.82) and psychiatric hospital contacts due to depression (adjusted hazard ratio=0.64, 95% CI=0.55, 0.75). Compared with SSRI treatment alone, the concomitant use of SSRIs and statins was not associated with significant increases in all-cause mortality (adjusted hazard ratio=1.04, 95% CI=0.96, 1.12) or suicidal behavior (adjusted hazard ratio=0.85, 95% CI=0.61, 1.18).

Conclusions
In a large naturalistic cohort, concomitant treatment with SSRIs and statins resulted in robust advantages compared with SSRIs alone.



Association of Acetaminophen Use During Pregnancy With Behavioral Problems in Childhood


JAMA Pediatrics
  
Importance  
Acetaminophen (paracetamol) is used by a large proportion of pregnant women. Research suggests that acetaminophen use in pregnancy is associated with abnormal fetal neurodevelopment. However, it is possible that this association might be confounded by unmeasured behavioral factors linked to acetaminophen use.

Objective  
To examine associations between offspring behavioral problems and (1) maternal prenatal acetaminophen use, (2) maternal postnatal acetaminophen use, and (3) partner’s acetaminophen use.

Design, Setting, and Participants  
From February 2015 to March 2016, we collected and analyzed data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a prospective birth cohort. We studied 7796 mothers enrolled in ALSPAC between 1991 and 1992 along with their children and partners.

Exposures  
Acetaminophen use was assessed by questionnaire completion at 18 and 32 weeks of pregnancy and when the child was 61 months old.

Main Outcomes and Measures  
Maternal reports of behavioral problems using the Strengths and Difficulties Questionnaire (SDQ) when the children were 7 years old. We estimated risk ratios for behavioral problems in children after prenatal, postnatal, and partner’s exposure to acetaminophen and mutually adjusted each association.

Results  
Maternal prenatal acetaminophen use at 18 (n = 4415; 53%) and 32 weeks of pregnancy (n = 3381; 42%) was associated with higher odds of having conduct problems (risk ratio [RR], 1.42; 95% CI, 1.25-1.62) and hyperactivity symptoms (RR, 1.31; 95% CI, 1.16-1.49), while maternal acetaminophen use at 32 weeks was also associated with higher odds of having emotional symptoms (RR, 1.29; 95% CI, 1.09-1.53) and total difficulties (RR, 1.46; 95% CI, 1.21-1.77). This was not the case for maternal postnatal (n = 6916; 89%) or partner’s (n = 3454; 84%) acetaminophen use. We found the associations between maternal prenatal acetaminophen use and all the SDQ domains unchanged even after adjusting for maternal postnatal or partner’s acetaminophen use.

Conclusions and Relevance  
Children exposed to acetaminophen prenatally are at increased risk of multiple behavioral difficulties, and the associations do not appear to be explained by unmeasured behavioral or social factors linked to acetaminophen use insofar as they are not observed for postnatal or partner’s acetaminophen use. Although these results could have implications for public health advice, further studies are required to replicate the findings and to understand mechanisms.



Identification of 15 genetic loci associated with risk of major depression in individuals of European descent


Nature Genetics

Despite strong evidence supporting the heritability of major depressive disorder (MDD), previous genome-wide studies were unable to identify risk loci among individuals of European descent. We used self-report data from 75,607 individuals reporting clinical diagnosis of depression and 231,747 individuals reporting no history of depression through 23andMe and carried out meta-analysis of these results with published MDD genome-wide association study results. We identified five independent variants from four regions associated with self-report of clinical diagnosis or treatment for depression. Loci with a P value <1.0 × 10−5 in the meta-analysis were further analyzed in a replication data set (45,773 cases and 106,354 controls) from 23andMe. A total of 17 independent SNPs from 15 regions reached genome-wide significance after joint analysis over all three data sets. Some of these loci were also implicated in genome-wide association studies of related psychiatric traits. These studies provide evidence for large-scale consumer genomic data as a powerful and efficient complement to data collected from traditional means of ascertainment for neuropsychiatric disease genomics.



Suicide Attempt as a Risk Factor for Completed Suicide: Even More Lethal Than We Knew


The American Journal of Psychiatry

Objective
While suicide attempt history is considered to robustly predict completed suicide, previous studies have limited generalizability because of using convenience samples of specific methods/treatment settings, disregarding previous attempts, or overlooking first-attempt deaths. Eliminating these biases should more accurately estimate suicide prevalence in attempters.

Method
This observational retrospective-prospective cohort study using the Rochester Epidemiology Project identified 1,490 (males, N=555; females, N=935) Olmsted County residents making index suicide attempts (first lifetime attempts reaching medical attention) between January 1, 1986, and December 31, 2007. The National Death Index identified suicides between enrollment and December 31, 2010 (follow-up 3–25 years). Medical records were queried for sex, age, method, and follow-up care for index attempt survivors. Coroner records yielded data on index attempt deaths.

Results
During the study period, 81/1,490 enrollees (5.4%) died by suicide. Of the 81, 48 (59.3%) perished on index attempt; 27 of the surviving 33 index attempt survivors (81.8%) killed themselves within a year. Males were disproportionately represented: 62/81 (11.2% of men, 76.5% of suicides) compared with 19/81 (2.0% of women, 23.5% of suicides). Of dead index attempters, 72.9% used guns, yielding an odds ratio for gunshot death, compared with all other methods, of 140 (95% CI=60–325). When adjusted for covariates, survivors given follow-up psychiatric appointments had significantly lower likelihood of subsequent suicide (odds ratio=0.212, 95% CI=0.089–0.507).

Conclusions
At 5.4%, completed suicide prevalence in this community cohort of suicide attempters was almost 59% higher than previously reported. An innovative aspect of this study explains the discrepancy: by including index attempt deaths—approximately 60% of total suicides—suicide prevalence more than doubled. We contend that counting both index and subsequent attempt deaths more accurately reflects prevalence. Our findings support suicide attempt as an even more lethal risk factor for completed suicide than previously thought. Research should focus on identifying risk factors for populations vulnerable to making first attempts and target risk reduction in those groups.



Paradoxical Trend for Improvement in Mental Health With Aging


The Journal of Clinical Psychiatry

Abstract

Objective 
Studies of aging usually focus on trajectories of physical and cognitive function, with far less emphasis on overall mental health, despite its impact on general health and mortality. This study examined linear and nonlinear trends of physical, cognitive, and mental health over the entire adult lifespan.

Methods 
Cross-sectional data were obtained from 1,546 individuals aged 21–100 years, selected using random digit dialing for the Successful AGing Evaluation (SAGE) study, a structured multicohort investigation that included telephone interviews and in-home surveys of community-based adults without dementia. Data were collected from 1/26/2010 to 10/07/2011 targeting participants aged 50–100 years and from 6/25/2012 to 7/15/2013 targeting participants aged 21–100 years with an emphasis on adding younger individuals. Data included self-report measures of physical health, measures of both positive and negative attributes of mental health, and a phone interview–based measure of cognition.

Results 
Comparison of age cohorts using polynomial regression suggested a possible accelerated deterioration in physical and cognitive functioning, averaging 1.5 to 2 standard deviations over the adult lifespan. In contrast, there appeared to be a linear improvement of about 1 standard deviation in various attributes of mental health over the same life period.

Conclusions 
These cross-sectional findings suggest the possibility of a linear improvement in mental health beginning in young adulthood rather than a U-shaped curve reported in some prior studies. Lifespan research combining psychosocial and biological markers may improve our understanding of resilience to mental disability in older age and lead to broad-based interventions promoting mental health in all age groups.



Early Improvement in Work Productivity Predicts Future Clinical Course in Depressed Outpatients


The American Journal of Psychiatry

Abstract

Objective
Depression symptom severity, the most commonly studied outcome in antidepressant treatment trials, accounts for only a small portion of burden related to major depression. While lost work productivity is the biggest contributor to depression’s economic burden, few studies have systematically evaluated the independent effect of treatment on work productivity and the relationship between changes in work productivity and longer-term clinical course.

Method
Work productivity was measured repeatedly by the Work Productivity and Activity Impairment self-report questionnaire in 331 employed participants with major depression enrolled in the Combining Medications to Enhance Depression Outcomes trial. Trajectories of change in work productivity during the first 6 weeks of treatment were identified and used to predict remission at 3 and 7 months.

Results
Participants reported reduced absence from work and increased work productivity with antidepressant treatment even after controlling for changes in depression severity. Three distinct trajectories of changes in work productivity were identified: 1) robust early improvement (24%), 2) minimal change (49%), and 3) high-impairment slight reduction (27%). Compared with other participants, those with robust improvement had 3–5 times higher remission rates at 3 months and 2–5 times higher remission rates at 7 months, even after controlling for select baseline variables and remission status at week 6.

Conclusions
In this secondary analysis, self-reported work productivity improved in depressed patients with antidepressant treatment even after accounting for depressive symptom reduction. Early improvement in work productivity is associated with much higher remission rates after 3 and 7 months of treatment.



Antipsychotic Use in Pregnancy and the Risk for Congenital Malformations


JAMA Psychiatry

Abstract

Importance  
The frequency of antipsychotic (AP) use during pregnancy has approximately doubled during the last decade. However, little is known about their safety for the developing fetus, and concerns have been raised about a potential association with congenital malformations.

Objective  
To examine the risk for congenital malformations overall and cardiac malformations associated with first-trimester exposure to APs.

Design, Setting, and Participants  
This nationwide sample of 1 360 101 pregnant women enrolled in Medicaid with a live-born infant constituted the pregnancy cohort nested in the Medicaid Analytic Extract database, which included data from January 1, 2000, to December 31, 2010. Participants were enrolled in Medicaid from 3 months before their last menstrual period through at least 1 month after delivery. Relative risks (RRs) were estimated using generalized linear models with fine stratification on the propensity score to control for the underlying psychiatric disorders and other potential confounders. Data were analyzed during 2015.

Exposures  
Use of APs during the first trimester, the etiologically relevant period for organogenesis.

Main Outcomes and Measures  
Major congenital malformations overall and cardiac malformations identified during the first 90 days after delivery.

Results  
Of the 1 341 715 pregnancies that met inclusion criteria (mean [SD] age of women, 24.02 [5.77] years), 9258 (0.69%) filled at least 1 prescription for an atypical AP and 733 (0.05%) filled at least 1 prescription for a typical AP during the first trimester. Overall, 32.7 (95% CI, 32.4-33.0) per 1000 births not exposed to APs were diagnosed with congenital malformations compared with 44.5 (95% CI, 40.5-48.9) per 1000 births exposed to atypical and 38.2 (95% CI, 26.6-54.7) per 1000 births exposed to typical APs. Unadjusted analyses suggested an increased risk for malformations overall for atypical APs (RR, 1.36; 95% CI, 1.24-1.50) but not for typical APs (RR, 1.17; 95% CI, 0.81-1.68). After confounding adjustment, the RR was reduced to 1.05 (95% CI, 0.96-1.16) for atypical APs and 0.90 (95% CI, 0.62-1.31) for typical APs. The findings for cardiac malformations were similar. For the individual agents examined, a small increased risk in overall malformations (RR, 1.26; 95% CI, 1.02-1.56) and cardiac malformations (RR, 1.26; 95% CI, 0.88-1.81) was found for risperidone that was independent of measured confounders.

Conclusions and Relevance  
Evidence from this large study suggests that use of APs early in pregnancy generally does not meaningfully increase the risk for congenital malformations overall or cardiac malformations in particular. The small increase in the risk for malformations observed with risperidone requires additional study.



FDA allows marketing of first-of-kind computerized cognitive tests to help assess cognitive skills after a head injury


US FDA

The U.S. Food and Drug Administration today permitted marketing of two new devices to assess a patient’s cognitive function immediately after a suspected brain injury or concussion. The Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) and ImPACT Pediatric are the first medical devices permitted for marketing that are intended to assess cognitive function following a possible concussion. They are intended as part of the medical evaluation that doctors perform to assess signs and symptoms of a head injury.
ImPACT and ImPACT Pediatric are not intended to diagnose concussions or determine appropriate treatments. Instead the devices are meant to test cognitive skills such as word memory, reaction time and word recognition, all of which could be affected by a head injury. The results are compared to an age-matched control database or to a patient’s pre-injury baseline scores, if available.

“These devices provide a useful new tool to aid in the evaluation of patients experiencing possible signs of a concussion, but clinicians should not rely on these tests alone to rule out a concussion or determine whether an injured player should return to a game,” said Carlos Peña, Ph.D., M.S., director of the division of neurological and physical medicine devices at the FDA’s Center for Devices and Radiological Health.



Online Journals:




Biological Psychiatry - Volume 80, Issue 7, October 2016



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