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Biological Psychiatry

Thursday, November 1, 2018

November 2018

Corroboration of a Major Role for Herpes Simplex Virus Type 1 in Alzheimer’s Disease

Frontiers in Aging Neuroscience


Strong evidence has emerged recently for the concept that herpes simplex virus type 1 (HSV1) is a major risk for Alzheimer’s disease (AD). This concept proposes that latent HSV1 in brain of carriers of the type 4 allele of the apolipoprotein E gene (APOE-ε4) is reactivated intermittently by events such as immunosuppression, peripheral infection, and inflammation, the consequent damage accumulating, and culminating eventually in the development of AD. Population data to investigate this epidemiologically, e.g., to find if subjects treated with antivirals might be protected from developing dementia—are available in Taiwan, from the National Health Insurance Research Database, in which 99.9% of the population has been enrolled. This is being extensively mined for information on microbial infections and disease. Three publications have now appeared describing data on the development of senile dementia (SD), and the treatment of those with marked overt signs of disease caused by varicella zoster virus (VZV), or by HSV. The striking results show that the risk of SD is much greater in those who are HSV-seropositive than in seronegative subjects, and that antiviral treatment causes a dramatic decrease in number of subjects who later develop SD. It should be stressed that these results apply only to those with severe cases of HSV1 or VZV infection, but when considered with the over 150 publications that strongly support an HSV1 role in AD, they greatly justify usage of antiherpes antivirals to treat AD. Three other studies are described which directly relate to HSV1 and AD: they deal respectively with lysosomal changes in HSV1-infected cell cultures, with evidence for a role of human herpes virus type 6 and 7 (HHV6 and HHV7) in AD, and viral effects on host gene expression, and with the antiviral characteristics of beta amyloid (Aβ). Three indirectly relevant studies deal respectively with schizophrenia, relating to antiviral treatment to target HSV1, with the likelihood that HSV1 is a cause of fibromyalgia (FM), and with FM being associated with later development of SD. Studies on the link between epilepsy, AD and herpes simplex encephalitis (HSE) are described also, as are the possible roles of APOE-ε4, HHV6 and HSV1 in epilepsy. 

Organophosphate exposures during pregnancy and child neurodevelopment: Recommendations for essential policy reforms

PLOS Medicine

• Widespread use of organophosphate (OP) pesticides to control insects has resulted inubiquitous human exposures.
• High exposures to OP pesticides are responsible for poisonings and deaths, particularly in developing countries.
• Compelling evidence indicates that prenatal exposure at low levels is putting children atrisk for cognitive and behavioral deficits and for neurodevelopmental disorders.To protect children worldwide, we recommend the following:
• Governments phase out chlorpyrifos and other OP pesticides, monitor watersheds andother sources of human exposures, promote use of integrated pest management (IPM)through incentives and training in agroecology, and implement mandatory surveillanceof pesticide-related illness.
• Health professions implement curricula on the hazards from OP pesticides in nursingand medical schools and in continuing medical education courses and educate theirpatients and the public about these hazards.
• Agricultural entities accelerate the development of nontoxic approaches to pest controlthrough IPM and ensure the safety of workers through training and provision of protec-tive equipment when toxic chemicals are to be used.

FDA approves new dosage strength of buprenorphine and naloxone sublingual film as maintenance treatment for opioid dependence

The U.S. Food and Drug Administration today approved Cassipa (buprenorphine and naloxone) sublingual film (applied under the tongue) for the maintenance treatment of opioid dependence. This action provides a new dosage strength (16 milligrams/4 milligrams) of buprenorphine and naloxone sublingual film, which is also approved in both brand name and generic versions and in various strengths.

“There’s an urgent need to ensure access to, and wider use and understanding of, medication-assisted treatment for opioid use disorder. The introduction of new treatment options has the potential to broaden access for patients. For example, the FDA recently described a streamlined approach to drug development for certain medication-assisted treatments that are based on buprenorphine. This streamlined approach can reduce drug development costs, so products may be offered at a lower price to patients and we can broaden access to treatment,” said FDA Commissioner Scott Gottlieb, M.D. “The FDA is committed to helping those with opioid use disorder transition to lives of sobriety. We’ve taken a number of steps to advance the development of new FDA-approved treatments for opioid dependence and encourage health care professionals to ensure patients are offered an adequate chance to benefit from these therapies. We’re also working to address the unfortunate stigma that’s sometimes associated with the use of opioid replacement therapy as one approach to the successful treatment of addiction. Despite what some may think, individuals who successfully transition onto medication-assisted treatment are not swapping one addiction for another. Opioid replacement therapy can be an important part of effective treatment. Opioid use disorder should be viewed similarly to any other chronic condition that is treated with medication.”

Medication-assisted treatment (MAT) is a comprehensive approach that combines FDA-approved medications (currently methadone, buprenorphine, or naltrexone) with counseling and other behavioral therapies to treat patients with opioid use disorder (OUD). Regular adherence to MAT with buprenorphine reduces opioid withdrawal symptoms and the desire to use opioids, without causing the cycle of highs and lows associated with opioid misuse or abuse. At proper doses, buprenorphine also decreases the pleasurable effects of other opioids, making continued opioid abuse less attractive. According to the Substance Abuse and Mental Health Services Administration, patients receiving MAT for treatment of their OUD cut their risk of death from all causes in half.

Determinants of suboptimal medication adherence in patients with a major depressive episode

Depression & Anxiety 



Major Depression (MD) is often a chronic condition requiring a long‐term pharmacologic treatment. Despite the efficacy of antidepressants, the medication adherence in those affected is usually very poor. In this scenario, further research concerning drivers of suboptimal adherence is needed. We aimed to explore medication adherence in patients with a MD episode, and to identify sociodemographic, clinical (psychiatric antecedents, comorbidities, medication, pain, and medication side effects), and psychosocial factors (negative life events, childhood trauma, and attitudes to medication) related to adherence status.

The Medication Adherence Rating Scale (MARS) was completed by 370 patients at hospital admission. Participants were divided into groups of optimal and suboptimal adherence based on the medication adherence behavior score (MARS's factor 1), and were compared with respect to the study variables.

Twenty‐nine percent of participants (n = 107) were found to be optimally adherents to their medication (score = 4/4). Compared to optimally adherents, suboptimally adherents (71%) presented a significantly higher depression severity, more psychiatric hospitalizations, suicidal ideation, physical pain, negative medication side effects, and antecedents of emotional maltreatment. Suboptimally adherents also had less favorable attitudes toward medication and were less in a relationship than optimally adherents. Multivariate analyses showed that depression severity, suicidal ideation, and physical pain increase the probability of belonging to the suboptimal adherent group.

These results suggest a vicious circle in which more vulnerable patients are less adherent to medication, which could worsen the clinical picture maintaining, in turn, low adherence. More efforts are needed to develop interventions aiming to improve medication adherence in MD patients.

Anxiety as a Risk Factor for Cognitive Decline: A 12-Year Follow-Up Cohort Study

The American Journal of Geriatric Psychiatry


Anxiety might be a risk factor for cognitive decline, but previous studies had short follow-up or small sample sizes or studied general or single cognitive domain functioning.

Anxiety symptoms were assessed with the Symptom Checklist-90 in 918 participants of the Maastricht Aging Study aged 50 years or older. Anxiety was analyzed both dichotomously (highest versus lower quartiles as a group) and continuously. Neuropsychological tests measured executive function, memory, speed of information processing, and verbal fluency. Linear mixed models were conducted with anxiety symptoms as predictor and change in cognitive scores as outcome. Differences of associations by age and gender were studied with three-way interactions.

Higher anxiety symptoms were significantly associated with more decline in verbal memory in those aged 65 years and older (delayed recall: χ2 = 9.30, df = 2, p = 0.01; immediate recall: χ2 = 11.81, df = 2, p = 0.003). There were sex differences in executive function (χ2 = 6.63, df = 2, p = 0.036), fluency (χ2 = 6.89, df = 2, p = 0.032), and processing speed (χ2 = 8.83, df = 2, p = 0.012), with lower performance in women over time.

In participants without cognitive impairments at baseline, anxiety symptoms were associated with a decline in verbal memory in older adults and with poorer performance in nonamnestic domains in women. Adequate treatment of anxiety symptoms could have a beneficial influence on the risk of developing neurodegenerative diseases. Further research is needed to elucidate whether this association is causal.

Mapping the Heterogeneous Phenotype of Schizophrenia and Bipolar Disorder Using Normative Models

JAMA Psychiatry


Schizophrenia and bipolar disorder are severe and complex brain disorders characterized by substantial clinical and biological heterogeneity. However, case-control studies often ignore such heterogeneity through their focus on the average patient, which may be the core reason for a lack of robust biomarkers indicative of an individual’s treatment response and outcome.

To investigate the degree to which case-control analyses disguise interindividual differences in brain structure among patients with schizophrenia and bipolar disorder and to map the brain alterations linked to these disorders at the level of individual patients.

Design, Setting, and Participants  
This study used cross-sectional, T1-weighted magnetic resonance imaging data from participants recruited for the Thematically Organized Psychosis study from October 27, 2004, to October 17, 2012. Data were reanalyzed in 2017 and 2018. Patients were recruited from inpatient and outpatient clinics in the Oslo area of Norway, and healthy individuals from the same catchment area were drawn from the national population registry.

Main Outcomes and Measures  
Interindividual differences in brain structure among patients with schizophrenia and bipolar disorder. Voxel-based morphometry maps were computed, which were used for normative modeling to map the range of interindividual differences in brain structure.

This study included 218 patients with schizophrenia spectrum disorders (mean [SD] age, 30 [9.3] years; 126 [57.8%] male), of whom 163 had schizophrenia (mean [SD] age, 31 [8.7] years; 105 [64.4%] male) and 190 had bipolar disorder (mean [SD] age, 34 [11.3] years; 79 [41.6%] male), and 256 healthy individuals (mean [SD] age, 34 [9.5] years; 140 [54.7%] male). At the level of the individual, deviations from the normative model were frequent in both disorders but highly heterogeneous. Overlap of more than 2% among patients was observed in only a few loci, primarily in frontal, temporal, and cerebellar regions. The proportion of alterations was associated with diagnosis and cognitive and clinical characteristics within clinical groups. Patients with schizophrenia, on average, had significantly reduced gray matter in frontal regions, cerebellum, and temporal cortex. In patients with bipolar disorder, mean deviations were primarily present in cerebellar regions.

Conclusions and Relevance  
This study found that group-level differences disguised biological heterogeneity and interindividual differences among patients with the same diagnosis. This finding suggests that the idea of the average patient is a noninformative construct in psychiatry that falls apart when mapping abnormalities at the level of the individual patient. This study presents a workable route toward precision medicine in psychiatry.


Translational Psychiatry


The menopause transition is a time when women experience an increased risk for new onset depression, as well as relapse of depression. While there are overlapping symptoms between major depression and depression during menopause, differences suggest ‘perimenopausal depression’ may be a unique subtype of depression associated with characteristic symptoms. There is currently no validated scale designed to measure perimenopausal depression. The aim of the current study was to develop and validate the ‘Meno-D’, a self-reporting or clinician rated questionnaire, designed to rate the severity of symptoms of perimenopausal depression. The development phase of the Meno-D involved literature review, clinical observation, and focus groups. A 12-item questionnaire was developed and clinically reviewed for face validity for content. The Meno-D was administered to women experiencing symptoms of perimenopausal depression as part of a larger baseline assessment battery. Validation involved confirmatory factor analysis (CFA). The development of the Meno-D resulted in 12 items. A total of 93 participants with perimenopausal depression were involved in the baseline assessments, 82 completed the Meno-D. Factor analysis identified five sub-scales of the Meno-D “somatic; cognitive; self; sleep; sexual” with high-internal consistency; discriminant validity and a good construct and convergent validity. The Meno-D provides a unique tool for clinicians and researchers to measure the presence of perimenopausal depression.



Vitamin D supplementation may help reduce depressive symptoms, new results of an updated meta-analysis show.

"People who were vitamin D deficient and depressed seemed to respond best to supplementation, but there was some evidence that supplementation improved depressive symptoms in people who had a normal level of vitamin D," Marissa Flaherty, MD, of the Department of Psychiatry, University of Maryland School of Medicine in Baltimore, told Medscape Medical News.

Globally, more than 300 million people suffer from depression. It's the number one cause of years lost to disability worldwide. In the United States, the overall prevalence of vitamin D deficiency hovers around 42%, with the highest rate seen in blacks.

"In my third year of residency, I noticed that a lot of my depressed patients had very low vitamin D levels, and when I supplemented their vitamin D, their depressive symptoms, particularly their fatigue and energy levels, would improve," Flaherty said.

To investigate further, Flaherty and her colleagues conducted a systematic review and meta-analysis of five randomized controlled trials published from 2011 to 2016 that examined the effect of vitamin D supplementation (vs no supplementation) on depressive symptoms, as measured by the Beck Depression Inventory and Hamilton Depression Rating Scale.


American Journal of Epidemiology


Acetaminophen is the analgesic and antipyretic most commonly used during pregnancy. Evidence of neurodisruptive properties is accumulating. Therefore, we sought to evaluate the risk for attention deficit hyperactivity disorder (ADHD) and autistic spectrum disorder (ASD) in the offspring of women exposed to acetaminophen during pregnancy. We searched MEDLINE, Embase, and Cochrane databases for relevant studies up to January 2017. Data were independently extracted and assessed by 2 researchers. Seven eligible retrospective cohorts included 132,738 mother-child pairs, with follow-up periods ranging from 3 to 11 years. The pooled risk ratio for ADHD was 1.34 (95% confidence interval (CI): 1.21, 1.47; I2 = 72%); for ASD, the risk ratio was 1.19 (95% CI: 1.14, 1.25; I2 = 14%), and for hyperactivity symptoms, it was 1.24 (95% CI: 1.04, 1.43; I2 = 93%). In meta-regression analysis, the association between exposure and ADHD increased with the child’s age upon follow-up (β = 0.03, 95% CI: 0.00, 0.07) and with the mean duration of exposure (β = 0.00, 95% CI: 0.00, 0.01). The available data is of observational nature only. Studies differed widely in exposure and outcome assessment. Acetaminophen use during pregnancy is associated with an increased risk for ADHD, ASD, and hyperactivity symptoms. These findings are concerning; however, results should be interpreted with caution given that the available evidence consists of observational studies and is susceptible to several potential sources of bias.


The Journal of the Alzheimer's Association


Lifetime risks are the probabilities of progressing to Alzheimer's disease (AD) dementia during one's lifespan. Here, we report the first estimates of the lifetime and ten-year risks of AD dementia based on age, gender, and biomarker tests for preclinical disease.

We used a multistate model for the disease process together with US death rates.

Lifetime risks of AD dementia vary considerably by age, gender, and the preclinical or clinical disease state of the individual. For example, the lifetime risks for a female with only amyloidosis are 8.4% for a 90-year old and 29.3% for a 65-year old. Persons younger than 85 years with mild cognitive impairment, amyloidosis, and neurodegeneration have lifetime risks of AD dementia greater than 50%.

Most persons with preclinical AD will not develop AD dementia during their lifetimes. Lifetime risks help interpret the clinical significance of biomarker screening tests for AD

Online Journals:

Biological Psychiatry - Volume 84, Issue 11, December 2018

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