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Tuesday, July 3, 2018

July 2018

Deprescribing benzodiazepine receptor agonists

The Oficial Journal of the College of Family Physicians of Canada


To develop an evidence-based guideline to help clinicians make decisions about when and how to safely taper and stop benzodiazepine receptor agonists (BZRAs); to focus on the highest level of evidence available and seek input from primary care professionals in the guideline development, review, and endorsement processes.

The overall team comprised 8 clinicians (1 family physician, 2 psychiatrists, 1 clinical psychologist, 1 clinical pharmacologist, 2 clinical pharmacists, and 1 geriatrician) and a methodologist; members disclosed conflicts of interest. For guideline development, a systematic process was used, including the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Evidence was generated by conducting a systematic review of BZRA deprescribing trials for insomnia, as well as performing a review of reviews of the harms of continued BZRA use and narrative syntheses of patient preferences and resource implications. This evidence and GRADE quality of evidence ratings were used to generate recommendations. The team refined guideline content and recommendations through consensus and synthesized clinical considerations to address front-line clinician questions. The draft guideline was reviewed by clinicians and stakeholders.

We recommend that deprescribing (tapering slowly) of BZRAs be offered to elderly adults (≥ 65 years) who take BZRAs, regardless of duration of use, and suggest that deprescribing (tapering slowly) be offered to adults aged 18 to 64 who have used BZRAs for more than 4 weeks. These recommendations apply to patients who use BZRAs to treat insomnia on its own (primary insomnia) or comorbid insomnia where potential underlying comorbidities are effectively managed. This guideline does not apply to those with other sleep disorders or untreated anxiety, depression, or other physical or mental health conditions that might be causing or aggravating insomnia.

Benzodiazepine receptor agonists are associated with harms, and therapeutic effects might be short term. Tapering BZRAs improves cessation rates compared with usual care without serious harms. Patients might be more amenable to deprescribing conversations if they understand the rationale (potential for harm), are involved in developing the tapering plan, and are offered behavioural advice. This guideline provides recommendations for making decisions about when and how to reduce and stop BZRAs. Recommendations are meant to assist with, not dictate, decision making in conjunction with patients. 

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FDA approves Lofexidine, the first non-opioid treatment for management of opioid withdrawal symptoms in adults


The U.S. Food and Drug Administration approved Lucemyra (lofexidine hydrochloride) for the mitigation of withdrawal symptoms to facilitate abrupt discontinuation of opioids in adults. While Lucemyra may lessen the severity of withdrawal symptoms, it may not completely prevent them and is only approved for treatment for up to 14 days. Lucemyra is not a treatment for opioid use disorder (OUD), but can be used as part of a broader, long-term treatment plan for managing OUD.

“As part of our commitment to support patients struggling with addiction, we’re dedicated to encouraging innovative approaches to help mitigate the physiological challenges presented when patients discontinue opioids,” said FDA Commissioner Scott Gottlieb, M.D. “We’re developing new guidance to help accelerate the development of better treatments, including those that help manage opioid withdrawal symptoms. We know that the physical symptoms of opioid withdrawal can be one of the biggest barriers for patients seeking help and ultimately overcoming addiction. The fear of experiencing withdrawal symptoms often prevents those suffering from opioid addiction from seeking help. And those who seek assistance may relapse due to continued withdrawal symptoms. The FDA will continue to encourage the innovation and development of therapies to help those suffering from opioid addiction transition to lives of sobriety, as well as address the unfortunate stigma that’s sometimes associated with the use of medication-assisted treatments.”

Opioid withdrawal includes symptoms — such as anxiety, agitation, sleep problems, muscle aches, runny nose, sweating, nausea, vomiting, diarrhea and drug craving — that occur after stopping or reducing the use of opioids in anyone with physical dependence on opioids. Physical dependence to opioids is an expected physiological response to opioid use. These symptoms of opioid withdrawal occur both in patients who have been using opioids appropriately as prescribed and in patients with OUD.

In patients using opioid analgesics appropriately as prescribed, opioid withdrawal is typically managed by slow taper of the medication, which is intended to avoid or lessen the effects of withdrawal while allowing the body to adapt to not having the opioid. In patients with OUD, withdrawal is typically managed by substitution of another opioid medicine, followed by gradual reduction or transition to maintenance therapy with FDA-approved medication-assisted treatment drugs such as methadone, buprenorphine or naltrexone; or by various medications aimed at specific symptoms, such as over-the-counter remedies for upset stomach or aches and pains. Other treatments may also be prescribed by a patient’s health care provider.

“Today’s approval represents the first FDA-approved non-opioid treatment for the management of opioid withdrawal symptoms and provides a new option that allows providers to work with patients to select the treatment best suited to an individual’s needs,” said Sharon Hertz, M.D., director of the Division of Anesthesia, Analgesia and Addiction Products in the FDA’s Center for Drug Evaluation and Research.

Lucemyra is an oral, selective alpha 2-adrenergic receptor agonist that reduces the release of norepinephrine. The actions of norepinephrine in the autonomic nervous system are believed to play a role in many of the symptoms of opioid withdrawal. The safety and efficacy of Lucemyra was supported by two randomized, double-blind, placebo-controlled clinical trials of 866 adults meeting Diagnostic and Statistical Manual-IV criteria for opioid dependence who were physically dependent on opioids and undergoing abrupt opioid discontinuation. The studies evaluated benefit using the Short Opiate Withdrawal Scale of Gossop (SOWS-Gossop), which is a patient-reported outcome instrument that assesses opioid withdrawal symptoms. These symptoms include feeling sick, stomach cramps, muscle spasms/twitching, feeling of coldness, heart pounding, muscular tension, aches and pains, yawning, runny eyes and insomnia/problems sleeping.  

Metabolic Effects of Antipsychotics on Adiposity and Insulin Sensitivity in Youths

JAMA Psychiatry
Antipsychotic medications are commonly used to treat nonpsychotic disruptive behavioral disorders in youths.

To characterize the metabolic effects of first exposure to antipsychotics in youths using criterion standard assessments of body composition and insulin sensitivity.

Design, Setting, and Participants  
This randomized clinical trial recruited antipsychotic-naive youths aged 6 to 18 years in the St Louis, Missouri, metropolitan area who were diagnosed with 1 or more psychiatric disorders and clinically significant aggression and in whom antipsychotic treatment was considered. Participants were enrolled from June 12, 2006, through November 10, 2010. Enrolled participants were randomized (1:1:1) to 1 of 3 antipsychotics commonly used in children with disruptive behavioral disorders and evaluated for 12 weeks. Data were analyzed from January 17, 2011, through August 9, 2017.

Twelve weeks of treatment with oral aripiprazole (n = 49), olanzapine (n = 46), or risperidone (n = 49).

Main Outcomes and Measures  
Primary outcomes included percentage total body fat measured by dual-energy x-ray absorptiometry (DXA) and insulin sensitivity in muscle measured via hyperinsulinemic clamps with stable isotopically labeled tracers. Secondary outcomes included abdominal adiposity measured by magnetic resonance imaging (MRI) and adipose and hepatic tissue insulin sensitivity measured via clamps with tracers.

The intention-to-treat sample included 144 participants (98 males [68.1%]; mean [SD] age, 11.3 [2.8] years); 74 (51.4%) were African American, and 43 (29.9%) were overweight or obese at baseline. For the primary outcomes, from baseline to week 12, DXA percentage total body fat increased by 1.18% for risperidone, 4.12% for olanzapine, and 1.66% for aripiprazole and was significantly greater for olanzapine than risperidone or aripiprazole (time by treatment interaction P < .001). From baseline to week 12, insulin-stimulated change in glucose rate of disappearance increased by 2.30% for risperidone and decreased by 29.34% for olanzapine and 30.26% for aripiprazole, with no significant difference across medications (time by treatment interaction, P < .07). This primary measure of insulin sensitivity decreased significantly during 12 weeks in the pooled study sample (effect of time, F = 17.38; P < .001). For the secondary outcomes from baseline to week 12, MRI measured abdominal fat increased, with subcutaneous fat increase significantly greater for olanzapine than risperdone or aripiprazole (time by treatment, P = .003). Behavioral improvements occurred with all treatments.

Conclusions and Relevance  
Adverse changes in adiposity and insulin sensitivity were observed during 12 weeks of antipsychotic treatment in youths, with the greatest fat increases on olanzapine. Such changes, likely attributable to treatment, may be associated with risk for premature cardiometabolic morbidity and mortality. The results inform risk-benefit considerations for antipsychotic use in youths.

Greater depressive symptoms, cognition, and markers of brain aging



We examined whether greater depressive symptoms were associated with domain-specific cognitive performance, change in cognition, and MRI markers of brain atrophy and subclinical cerebrovascular disease in a diverse sample of older adults from the Northern Manhattan Study.

Data were analyzed from the Northern Manhattan Study, a prospective cohort study of mostly Caribbean Hispanic, stroke-free, older adults. A total of 1,111 participants had baseline measures of depressive symptoms, measured as the Center of Epidemiological Studies–Depression Scale, MRI markers, and cognitive function. A Center of Epidemiological Studies–Depression score ≥16 was considered indicative of greater depressive symptoms. Multivariable linear and logistic regression models were used to examine the associations of interest.

Results At baseline 
22% of participants had greater depressive symptoms. Greater depressive symptoms were significantly associated with worse baseline episodic memory in models adjusted for sociodemographic, vascular risk factor, behavioral, and antidepressive medication variables (β [95% confidence interval] = −0.21 [−0.33 to −0.10], p = 0.0003). Greater depressive symptoms were also associated with smaller cerebral parenchymal fraction (β [95% confidence interval] = −0.56 [−1.05 to −0.07], p = 0.02) and increased odds of subclinical brain infarcts (odds ratio [95% confidence interval] = 1.55 [1.00–2.42], p = 0.05), after adjustment for sociodemographic, behavioral, and vascular risk factor variables. Greater depressive symptoms were not significantly associated with white matter hyperintensity volume, hippocampal volume, or change in cognition over an average of 5 years. Results were unchanged when stabilized inverse probability weights were applied to address selective attrition during the study period.

In this sample of mostly Caribbean Hispanic, stroke-free, older adults, greater depressive symptoms were associated with worse episodic memory, smaller cerebral volume, and silent infarcts.

Multiscale Analysis of Independent Alzheimer’s Cohorts Finds Disruption of Molecular, Genetic, and Clinical Networks by Human Herpesvirus



Investigators have long suspected that pathogenic microbes might contribute to the onset and progression of Alzheimer’s disease (AD) although definitive evidence has not been presented. Whether such findings represent a causal contribution, or reflect opportunistic passengers of neurodegeneration, is also difficult to resolve. We constructed multiscale networks of the late-onset AD-associated virome, integrating genomic, transcriptomic, proteomic, and histopathological data across four brain regions from human post-mortem tissue. We observed increased human herpesvirus 6A (HHV-6A) and human herpesvirus 7 (HHV-7) from subjects with AD compared with controls. These results were replicated in two additional, independent and geographically dispersed cohorts. We observed regulatory relationships linking viral abundance and modulators of APP metabolism, including induction of APBB2, APPBP2, BIN1, BACE1, CLU, PICALM, and PSEN1 by HHV-6A. This study elucidates networks linking molecular, clinical, and neuropathological features with viral activity and is consistent with viral activity constituting a general feature of AD.

3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for post-traumatic stress disorder in military veterans, firefighters, and police officers: a randomised, double-blind, dose-response, phase 2 clinical trial

The Lancet Psychiatry


Post-traumatic stress disorder (PTSD) is prevalent in military personnel and first responders, many of whom do not respond to currently available treatments. This study aimed to assess the efficacy and safety of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for treating chronic PTSD in this population.

We did a randomised, double-blind, dose-response, phase 2 trial at an outpatient psychiatric clinic in the USA. We included service personnel who were 18 years or older, with chronic PTSD duration of 6 months or more, and who had a Clinician-Administered PTSD Scale (CAPS-IV) total score of 50 or greater. Using a web-based randomisation system, we randomly assigned participants (1:1:2) to three different dose groups of MDMA plus psychotherapy: 30 mg (active control), 75 mg, or 125 mg. We masked investigators, independent outcome raters, and participants until after the primary endpoint. MDMA was administered orally in two 8-h sessions with concomitant manualised psychotherapy. The primary outcome was mean change in CAPS-IV total score from baseline to 1 month after the second experimental session. Participants in the 30 mg and 75 mg groups subsequently underwent three 100–125 mg MDMA-assisted psychotherapy sessions in an open-label crossover, and all participants were assessed 12 months after the last MDMA session. Safety was monitored through adverse events, spontaneously reported expected reactions, vital signs, and suicidal ideation and behaviour. This study is registered with, number NCT01211405.

Between Nov 10, 2010, and Jan 29, 2015, 26 veterans and first responders met eligibility criteria and were randomly assigned to receive 30 mg (n=7), 75 mg (n=7), or 125 mg (n=12) of MDMA plus psychotherapy. At the primary endpoint, the 75 mg and 125 mg groups had significantly greater decreases in PTSD symptom severity (mean change CAPS-IV total scores of −58·3 [SD 9·8] and −44·3 [28·7]; p=0·001) than the 30 mg group (−11·4 [12·7]). Compared with the 30 mg group, Cohen's d effect sizes were large: 2·8 (95% CI 1·19–4·39) for the 75 mg group and 1·1 (0·04–2·08) for the 125 mg group. In the open-label crossover with full-dose MDMA (100–125 mg), PTSD symptom severity significantly decreased in the group that had previously received 30 mg (p=0·01), whereas no further significant decreases were observed in the group that previously achieved a large response after 75 mg doses in the blinded segment (p=0·81). PTSD symptoms were significantly reduced at the 12-month follow-up compared with baseline after all groups had full-dose MDMA (mean CAPS-IV total score of 38·8 [SD 28·1] vs 87·1 [16·1]; p<0·0001). 85 adverse events were reported by 20 participants. Of these adverse events, four (5%) were serious: three were deemed unrelated and one possibly related to study drug treatment.

Active doses (75 mg and 125 mg) of MDMA with adjunctive psychotherapy in a controlled setting were effective and well tolerated in reducing PTSD symptoms in veterans and first responders.

Development and validation of a new rating scale for perimenopausal depression—the Meno-D

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 Ease 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.

Prenatal Exposure to Acetaminophen and Risk for Attention Deficit Hyperactivity Disorder and Autistic Spectrum Disorder: A Systematic Review, Meta-Analysis, and Meta-Regression Analysis of Cohort Studies

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.

Estimation of lifetime risks of Alzheimer's disease dementia using biomarkers for preclinical disease

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 2, July 2018

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