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Saturday, March 5, 2016

March 2016

Incidence of Dementia over Three Decades in the Framingham Heart Study 

The New England Journal of Medicine


The prevalence of dementia is expected to soar as the average life expectancy increases, but recent estimates suggest that the age-specific incidence of dementia is declining in high-income countries. Temporal trends are best derived through continuous monitoring of a population over a long period with the use of consistent diagnostic criteria. We describe temporal trends in the incidence of dementia over three decades among participants in the Framingham Heart Study.

Participants in the Framingham Heart Study have been under surveillance for incident dementia since 1975. In this analysis, which included 5205 persons 60 years of age or older, we used Cox proportional-hazards models adjusted for age and sex to determine the 5-year incidence of dementia during each of four epochs. We also explored the interactions between epoch and age, sex, apolipoprotein E ε4 status, and educational level, and we examined the effects of these interactions, as well as the effects of vascular risk factors and cardiovascular disease, on temporal trends.

The 5-year age- and sex-adjusted cumulative hazard rates for dementia were 3.6 per 100 persons during the first epoch (late 1970s and early 1980s), 2.8 per 100 persons during the second epoch (late 1980s and early 1990s), 2.2 per 100 persons during the third epoch (late 1990s and early 2000s), and 2.0 per 100 persons during the fourth epoch (late 2000s and early 2010s). Relative to the incidence during the first epoch, the incidence declined by 22%, 38%, and 44% during the second, third, and fourth epochs, respectively. This risk reduction was observed only among persons who had at least a high school diploma (hazard ratio, 0.77; 95% confidence interval, 0.67 to 0.88). The prevalence of most vascular risk factors (except obesity and diabetes) and the risk of dementia associated with stroke, atrial fibrillation, or heart failure have decreased over time, but none of these trends completely explain the decrease in the incidence of dementia.

Among participants in the Framingham Heart Study, the incidence of dementia has declined over the course of three decades. The factors contributing to this decline have not been completely identified. (Funded by the National Institutes of Health).

Association of Proton Pump Inhibitors With Risk of Dementia

JAMA Neurology 


Medications that influence the risk of dementia in the elderly can be relevant for dementia prevention. Proton pump inhibitors (PPIs) are widely used for the treatment of gastrointestinal diseases but have also been shown to be potentially involved in cognitive decline.

To examine the association between the use of PPIs and the risk of incident dementia in the elderly.

Design, Setting, and Participants  
We conducted a prospective cohort study using observational data from 2004 to 2011, derived from the largest German statutory health insurer, Allgemeine Ortskrankenkassen (AOK). Data on inpatient and outpatient diagnoses (coded by the German modification of the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision) and drug prescriptions (categorized according to the Anatomical Therapeutic Chemical Classification System) were available on a quarterly basis. Data analysis was performed from August to November 2015.

Prescription of omeprazole, pantoprazole, lansoprazole, esomeprazole, or rabeprazole.

Main Outcomes and Measures  
The main outcome was a diagnosis of incident dementia coded by the German modification of the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision. The association between PPI use and dementia was analyzed using time-dependent Cox regression. The model was adjusted for potential confounding factors, including age, sex, comorbidities, and polypharmacy.

A total of 73 679 participants 75 years of age or older and free of dementia at baseline were analyzed. The patients receiving regular PPI medication (n = 2950; mean [SD] age, 83.8 [5.4] years; 77.9% female) had a significantly increased risk of incident dementia compared with the patients not receiving PPI medication (n = 70 729; mean [SD] age, 83.0 [5.6] years; 73.6% female) (hazard ratio, 1.44 [95% CI, 1.36-1.52]; P < .001).

Conclusions and Relevance  
The avoidance of PPI medication may prevent the development of dementia. This finding is supported by recent pharmacoepidemiological analyses on primary data and is in line with mouse models in which the use of PPIs increased the levels of β-amyloid in the brains of mice. Randomized, prospective clinical trials are needed to examine this connection in more detail.

Risk of suicide after a concussion

CMAJ  Canadian Medical Association Journal

Head injuries have been associated with subsequent suicide among military personnel, but outcomes after a concussion in the community are uncertain. We assessed the long-term risk of suicide after concussions occurring on weekends or weekdays in the community.

We performed a longitudinal cohort analysis of adults with diagnosis of a concussion in Ontario, Canada, from Apr. 1, 1992, to Mar. 31, 2012 (a 20-yr period), excluding severe cases that resulted in hospital admission. The primary outcome was the long-term risk of suicide after a weekend or weekday concussion.

We identified 235 110 patients with a concussion. Their mean age was 41 years, 52% were men, and most (86%) lived in an urban location. A total of 667 subsequent suicides occurred over a median follow-up of 9.3 years, equivalent to 31 deaths per 100 000 patients annually or 3 times the population norm. Weekend concussions were associated with a one-third further increased risk of suicide compared with weekday concussions (relative risk 1.36, 95% confidence interval 1.14–1.64). The increased risk applied regardless of patients' demographic characteristics, was independent of past psychiatric conditions, became accentuated with time and exceeded the risk among military personnel. Half of these patients had visited a physician in the last week of life.

Adults with a diagnosis of concussion had an increased long-term risk of suicide, particularly after concussions on weekends. Greater attention to the long-term care of patients after a concussion in the community might save lives because deaths from suicide can be prevented.

Systematic Review and Meta-Analysis: Dose-Response Relationship of Selective Serotonin Reuptake Inhibitors in Major Depressive Disorder

The American Journal of Psychiatry

Previous studies suggested that the treatment response to selective serotonin reuptake inhibitors (SSRIs) in major depressive disorder follows a flat response curve within the therapeutic dose range. The present study was designed to clarify the relationship between dosage and treatment response in major depressive disorder.

The authors searched PubMed for randomized placebo-controlled trials examining the efficacy of SSRIs for treating adults with major depressive disorder. Trials were also required to assess improvement in depression severity at multiple time points. Additional data were collected on treatment response and all-cause and side effect-related discontinuation. All medication doses were transformed into imipramine-equivalent doses. The longitudinal data were analyzed with a mixed-regression model. Endpoint and tolerability analyses were analyzed using meta-regression and stratified subgroup analysis by predefined SSRI dose categories in order to assess the effect of SSRI dosing on the efficacy and tolerability of SSRIs for major depressive disorder.

Forty studies involving 10,039 participants were included. Longitudinal modeling (dose-by-time interaction=0.0007, 95% CI=0.0001–0.0013) and endpoint analysis (meta-regression: β=0.00053, 95% CI=0.00018–0.00088, z=2.98) demonstrated a small but statistically significant positive association between SSRI dose and efficacy. Higher doses of SSRIs were associated with an increased likelihood of dropouts due to side effects (meta-regression: β=0.00207, 95% CI=0.00071–0.00342, z=2.98) and decreased likelihood of all-cause dropout (meta-regression: β=–0.00093, 95% CI=–0.00165 to −0.00021, z=−2.54).

Higher doses of SSRIs appear slightly more effective in major depressive disorder. This benefit appears to plateau at around 250 mg of imipramine equivalents (50 mg of fluoxetine). The slightly increased benefits of SSRIs at higher doses are somewhat offset by decreased tolerability at high doses.

Opioid Modulation With Buprenorphine/Samidorphan as Adjunctive Treatment for Inadequate Response to Antidepressants: A Randomized Double-Blind Placebo-Controlled Trial 

The American Journal of Psychiatry


Major depressive disorder has been associated with dysregulation of the endogenous opioid system. The authors sought to determine whether opioid modulation achieved through administration of ALKS 5461, a combination of a μ- and κ-opioid partial agonist, buprenorphine, and a μ-opioid antagonist, samidorphan, would exhibit antidepressant activity in patients with major depression.

A multicenter, randomized, double-blind, placebo-controlled, two-stage sequential parallel comparison design study was conducted in adults with major depression who had an inadequate response to one or two courses of antidepressant treatment. Participants were randomly assigned to receive adjunctive treatment with 2 mg/2 mg of buprenorphine/samidorphan (the 2/2 dosage group), 8 mg/8 mg of buprenorphine/samidorphan (the 8/8 dosage group), or placebo. Antidepressant effect was measured based on change from baseline to the end of 4 weeks of treatment on the 17-item Hamilton Depression Rating Scale (HAM-D), the Montgomery-Åsberg Depression Rating Scale (MADRS), and the Clinical Global Impressions severity scale (CGI-S).

Compared with the placebo group, there were significantly greater improvements in the 2/2 dosage group across the three depression outcome measures (HAM-D: −2.8, 95% CI=−5.1, −0.6; MADRS: −4.9, 95% CI=−8.2, −1.6; CGI-S: −0.5, 95% CI=−0.9, −0.1). There was also evidence of improvement in the 8/8 dosage group, although it did not achieve statistical significance. Overall, the buprenorphine/samidorphan combinations were well tolerated, and there was no evidence of opioid withdrawal on treatment discontinuation.

The buprenorphine/samidorphan combination is a novel and promising candidate for treatment of major depressive disorder in patients who have an inadequate response to standard antidepressants.

Yes or No: Prescribing Antidepressants to Pregnant Patients

Psychiatric News

Despite antidepressants being one of the most-studied classes of medications used during pregnancy, their use during pregnancy remains controversial. Numerous studies have explored the association between antidepressants and a variety of outcomes in the neonate including cardiac malformations, preterm birth, persistent pulmonary hypertension (PPHN), poor neonatal adaptation syndrome, and most recently autism.

Many of these studies have resulted in sensational headlines when there have been positive findings; however, there are a number of limitations in these studies that, when taken into account with other studies, resulted in negative findings that do not seem to make it into the headlines.

One significant limitation of the literature in this area is that the use of antidepressants during pregnancy can be considered a “marker” for a population of women that have very different associated behaviors and risk factors than the general population of pregnant women. These risk factors, if not controlled for, may influence the outcomes of studies attempting to examine the risks of in utero exposure of antidepressants. For example, diabetes, obesity, smoking, and substance use are more common in patients with a history of depression than in the general population of pregnant women...

Transcutaneous Vagus Nerve Stimulation Modulates Default Mode Network in Major Depressive Disorder

Biological Psychiatry


Depression is the most common form of mental disorder in community and health care settings and current treatments are far from satisfactory. Vagus nerve stimulation (VNS) is a Food and Drug Administration approved somatic treatment for treatment-resistant depression. However, the involvement of surgery has limited VNS only to patients who have failed to respond to multiple treatment options. Transcutaneous VNS (tVNS) is a relatively new, noninvasive VNS method based on the rationale that there is afferent/efferent vagus nerve distribution on the surface of the ear. The safe and low-cost characteristics of tVNS have the potential to significantly expand the clinical application of VNS.

In this study, we investigated how tVNS can modulate the default mode network (DMN) functional connectivity (FC) in mild or moderate major depressive disorder (MDD) patients. Forty-nine MDD patients were recruited and received tVNS or sham tVNS (stVNS) treatments.

Thirty-four patients completed the study and were included in data analysis. After 1 month of tVNS treatment, the 24-item Hamilton Depression Rating Scale score reduced significantly in the tVNS group as compared with the stVNS group. The FC between the DMN and anterior insula and parahippocampus decreased; the FC between the DMN and precuneus and orbital prefrontal cortex increased compared with stVNS. All these FC increases are also associated with 24-item Hamilton Depression Rating Scale reduction.

tVNS can significantly modulate the DMN FC of MDD patients; our results provide insights to elucidate the brain mechanism of tVNS treatment for MDD patients.

AKT1 genotype moderates the acute psychotomimetic effects of naturalistically smoked cannabis in young cannabis smokers

Translational Psychiatry


Smoking cannabis daily doubles an individual’s risk of developing a psychotic disorder, yet indicators of specific vulnerability have proved largely elusive. Genetic variation is one potential risk modifier. Single-nucleotide polymorphisms in the AKT1 and catechol-O-methyltransferase (COMT) genes have been implicated in the interaction between cannabis, psychosis and cognition, but no studies have examined their impact on an individual’s acute response to smoked cannabis. A total 442 healthy young cannabis users were tested while intoxicated with their own cannabis—which was analysed for delta-9-tetrahydrocannbinol (THC) and cannabidiol content—and also ±7 days apart when drug-free. Psychotomimetic symptoms and working memory were assessed on both the sessions. Variation at the rs2494732 locus of the AKT1 gene predicted acute psychotic response to cannabis along with dependence on the drug and baseline schizotypal symptoms. Working memory following cannabis acutely was worse in females, with some suggestion of an impact of COMT polymorphism on working memory when drug-free. These findings are the first to demonstrate that AKT1 mediates the acute response to cannabis in otherwise healthy individuals and implicate the AKT1 pathway as a possible target for prevention and treatment of cannabis psychosis.

Autism Linked to Air Pollution In Preschool Children

Psychiatric News

Could exposure to traffic-related air pollution contribute to autism? A study published online November 26, 2012, in Archives of General Psychiatry and funded by the National Institute of Environmental Health Sciences suggests so.

Traffic-related air pollution has been shown to induce inflammation. Inflammation may be involved in some forms of autism, according to emerging evidence.

Two years ago, Heather Volk, Ph.D., an assistant professor of research at the University of Southern California, and her colleagues found a provocative association between living near a freeway and autism. This association implied that traffic air pollution might be a culprit in autism.

They decided to conduct another study to test the hypothesis. The cohort included 279 preschool children with autism and 145 preschool children with typical development (controls). In addition to vehicle-emission rates, the researchers used local meteorological data, traffic volume, and road geometry to construct mathematical models of traffic-related air pollution in the areas where the subjects lived. The researchers then used the models as well as the addresses of the subjects to see whether they could find any links between traffic air pollution and autism.

They could. The children residing in areas with the highest levels of traffic air pollution were three times more likely to have autism than were the children residing in areas with the lowest levels. Moreover, the children with autism were twice as likely as controls to have been exposed to high levels of traffic air pollution during their mothers’ pregnancy and three times as likely as controls to have been exposed to high levels of traffic air pollution during the first year of life. Some specific traffic air pollutants—nitrogen dioxide and particulate matter—were likewise associated with autism during pregnancy and the first year of life. Finally, the findings remained solid even when demographic and socioeconomic factors as well as maternal smoking during pregnancy were considered...

Effects of Testosterone Treatment in Older Men

The New England Journal of Medicine

Testosterone concentrations in men decrease with increasing age.Many symptoms and conditions similar to those that are caused by low testosterone levels in men with pituitary or testicular disease become more common with increasing age. Such symptoms include decreases in mobility, sexual function, and energy. These parallels suggest that the lower testosterone levels in older men may contribute to these conditions.
Previous trials of testosterone treatment in men 65 years of age or older, however, have yielded equivocal results. Although testosterone treatment consistently increased muscle mass and decreased fat mass effects on physical performance sexual function and energy have been inconsistent.
In 2003, an Institute of Medicine panel concluded that there was insufficient evidence that testosterone treatment was beneficial in older men and recommended a coordinated set of clinical trials to determine whether testosterone would benefit older men who had low testosterone levels for no known reason other than age and who had clinical conditions to which low testosterone might contribute. The Testosterone Trials were designed to implement that recommendation...

Online Journals:

Biological Psychiatry - Volume 79, Issue 7, April 2016

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