Julie Bowen

Exposure to adversities, such as parental divorce, during childhood and adolescence may increase the risk of substance abuse in persons with a particular gene mutation.

University of Oklahoma College of Medicine

 focused on a common variant of the gene for the enzyme catecholâOâmethyltransferase (

, Val158Met, rs4680) in their study, which was published in 

Alcoholism: Clinical and Experimental Research

 gene are more vulnerable to the effects of stress in their early lives. The heightened vulnerability often leads to the consumption of alcohol and drugs before the age of 15 years, which is one of the key independent predictors of addiction.

“Early-life adversity doesn’t make everyone an alcoholic,” said senior study author William R. Lovallo, PhD, Professor of Psychiatry and Behavioral Sciences, OU College of Medicine, Oklahoma City, OK, in a 

 “But this study showed that people with this genetic mutation are going to have a higher risk for addiction when they had a stressful life growing up.”

The study included 480 healthy young adults (average age, 23.5 years; 50% females), who had experienced no, one, or two or more types of early-life adversity during childhood and adolescence. The participants provided information on their use of alcohol and recreational drugs, and they were genotyped for the Val158Met polymorphism.

Exposure to early-life adversity was an independent predictor of earlier age at first drink (

<.0001). This effect was larger in Metâallele carriers (

<.00001) and smaller in Val homozygotes (

=.02). The effects of early-life adversity on recreational drug use were similar.

These results point to an interplay between the 

 158Met allele and early environmental factors that contributes to the development of alcohol and drug abuse.

“There is no such thing as a gene for addiction, but there are genes that respond to our environment in ways that put us at risk,” said Dr Lovallo. “You have to have the right combination to develop the risk factors.”

1. Lovallo WR, Cohoon AJ, Sorocco KH, et al. 

Early-life adversity and blunted stress reactivity as predictors of alcohol and drug use in persons with COMT (rs4680) Val158Met genotypes

. 2019;43:1519-1527. doi: 10.1111/acer.14079.

Researcher discovers gene mutation that contributes to addiction

 [press release]. Oklahoma City, OK: University of Oklahoma College of Medicine; August 16, 2019.

Articles

An interplay between genetic and early environmental factors contributes to the development of substance abuse.

Gene Mutation Can Raise Risk of Alcohol and Drug Abuse

About 50% of psychiatrists in a recent survey believe that artificial intelligence (AI) and machine learning will significantly transform the way they work, but only 4% think that future autonomous technology will replace them. 

, a global networking platform open to licensed physicians, conducted the survey in partnership with psychiatry and health technology researchers at 

The pilot survey included 791 psychiatrists in 22 countries. Respondents were asked to assess the likelihood that future technology would be able to replace-not just assist-physicians in performing complex tasks. Psychiatrists were also asked about the benefits and risks of future technologies in mental health and the impact on their daily work.

Among the salient findings of the survey:
	• Only 4% of psychiatrists felt that future technology would make their jobs obsolete
	• Only 17% believed technology is likely to replace a human’s role in providing empathetic care
	• More women (48%) psychiatrists than men (35%) were uncertain that the benefits of AI and machine learning would outweigh the risks
	• More US psychiatrists (46%) than those in other countries (32%) were uncertain that the benefits of future autonomous technology would outweigh the risks

The majority of psychiatrists also indicated that future technology would be unlikely to replace physicians for complex tasks such as a mental status examination (67%), assessing the risk of violence (58%), and determining the need for hospitalization (55%).

There were only two tasks that the majority felt technology would likely replace:
	• Providing patient documentation, such as updating medical records (75%)
	• Synthesizing patient information to reach diagnoses (54%)

“It is time for us to stop thinking about AI as a battle of machines versus humans. We need to instead focus on how AI can optimize and improve clinicians’ abilities to deliver better care,” said study author Murali Doraiswamy, MBBS, Professor of Psychiatry and Medicine at Duke University School of Medicine, in a 

The skepticism and uncertainty expressed by physicians in the survey could result from several factors. One possibility is that they place high value on human interaction and personalized professional analysis. Another possible explanation is that respondents are underestimating the pace of technological change.

“The findings from this survey also raise questions about the preparedness of the profession to navigate technological change in the delivery of patient care,” said study author Charlotte Blease, PhD, Research Fellow in General Medicine at Harvard Medical School, in a 

While physicians were skeptical about the prospects of AI and machine learning replacing them, one in two psychiatrists felt that future technologies would significantly transform their jobs. Psychiatrists also predicted that AI and machine learning could help ensure more accurate diagnosis, reduce administrative burden, provide 24/7 monitoring, individualize drug targets to reduce adverse effects, and integrate new streams of data from wearables and genetics.

Survey respondents had many ethical and safety concerns about AI, however. “This should be a high priority for research, since even a single line of bad code could have serious repercussions,” cautioned Dr Doraiswamy.

The full scientific report can be accessed at 

1. Doraiswamy PM, Blease C, Bodner K. Artificial intelligence and the future of psychiatry: insights from a global physician survey. 

. Submitted July 29, 2019. Accessed July 31, 2019.

First global survey of psychiatrists on the impact of artificial intelligence

 [press release]. New York, NY: Sermo; July 30, 2019.

Results of the first global survey of psychiatrists on the impact of future autonomous technology.

What Psychiatrists Think About Artificial Intelligence

Alkermes plans to expand its New Drug Application (NDA) for olanzapine/samidorphan (ALKS 3831) to include treatment of bipolar I disorder in addition to schizophrenia. The novel combination drug is designed to provide the efficacy of olanzapine while mitigating the weight gain associated with the atypical antipsychotic.

“Olanzapine is one of the most effective antipsychotics,” writes Brian Miller, MD, PhD, MPH, Associate Professor of Psychiatry, Augusta University, Georgia, in 

. “However, the adverse metabolic effects of olanzapine have limited its clinical utility.”

The ALKS 3831 NDA, which Alkermes plans to submit in the fourth quarter of 2019, will include data from the completed ALKS 3831 ENLIGHTEN clinical development program in patients with schizophrenia as well as pharmacokinetic bridging data comparing ALKS 3831 and ZYPREXA

ENLIGHTEN-2 is a multicenter, double-blind, randomized phase 3 study that compared the weight gain profile of ALKS 3831 with that of olanzapine over 6 months in 561 patients with stable schizophrenia. Alkermes announced the topline results in a 

Patients who received olanzapine (n=272) had a 57% higher mean percent weight change at 6 months compared with those who received ALKS 3831 (n=266), (6.59% for olanzapine versus 4.21% for ALKS 3831, 

=.003). The proportion of patients who gained 10% or more of their baseline body weight was 29.8% for olanzapine versus 17.8% for ALKS 3831 (

=.003). Thus, patients in the olanzapine treatment group had two times the risk of gaining 10% or more of their baseline body weight at 6 months compared with those who received ALKS 3831.

The ALKS 3831 NDA will include data to support an indication for the treatment of manic or mixed episodes associated with bipolar I disorder as a monotherapy or adjunct to lithium or valproate and for maintenance treatment of bipolar I disorder; and an indication for the treatment of schizophrenia. The proposed fixed dosage strengths for ALKS 3831 include 10 mg of samidorphan co-formulated with 5 mg, 10 mg, 15 mg, or 20 mg of olanzapine.

“Bipolar I disorder is a complicated and often misdiagnosed disease, characterized by severe shifts in mood and energy that can impact a person’s ability to complete day-to-day activities. Antipsychotics are a mainstay treatment option for many people living with bipolar I disorder; however, new treatments with differentiated efficacy and tolerability profiles are needed,” said Roger S. McIntyre, MD, Professor of Psychiatry and Pharmacology at the University of Toronto, and Head of the Mood Disorders Psychopharmacology Unit at the University Health Network in Toronto, Canada, in a 

. “A potential new medication like ALKS 3831 would be a meaningful addition to the bipolar I disorder treatment landscape.”

Alkermes expands planned New Drug Application for ALKS 3831 to include treatment of bipolar I disorder

 [press release]. Dublin, Ireland: Alkermes plc; July 15, 2019.

Mitigation of olanzapine-induced weight gain: not the sami old thing

Alkermes announces positive topline results from ENLIGHTEN-2 phase 3 study of ALKS 3831 in patients with schizophrenia

 [press release]. Dublin, Ireland: Alkermes plc; November 29, 2018.

The novel combination drug is designed to mitigate the weight gain associated with olanzapine.

New Drug Application for Olanzapine/Samidorphan Expanded to Include Bipolar I

An experimental drug safely lowered levels of the mutant protein associated with Huntington disease, reported a team of international researchers. Their findings were recently published in the 

The drug, IONIS-HTTRx, inhibits expression of the huntingtin (

) gene and thereby reduces concentrations of huntingtin protein (HTT). This is the first therapy to target the primary mechanism of Huntington disease; currently available treatments address only symptoms.

“This is a tremendously exciting and promising result for patients and families affected by this devastating genetic brain disorder,” said study author Blair Leavitt, MD, Director of Research at the Centre for Huntington Disease, University of British Columbia, Vancouver, in a 

. “For the first time, we have evidence that a treatment can not only decrease levels of the toxic disease-causing protein in patients, but that it is also safe and very well tolerated.”

The phase 1/2a trial included 46 adults with early Huntington disease. Thirty-four patients received HTT

 in doses ranging from 10 to 120 mg, while 12 patients were given placebo. Each participant received a total of four bolus intrathecal injections, which were administered at 4-week intervals.

The researchers found dose-dependent reductions in the concentration of mutant HTT protein in the cerebrospinal fluid (CSF) of patients who received HTT

. Specifically, there were reductions of 20%, 25%, 28%, 42%, and 38% in those given doses of 10 mg, 30 mg, 60 mg, 90 mg, and 120 mg, respectively. In contrast, patients who received placebo had an increase of 10% in CSF levels of mutant HTT.

No serious adverse events were reported in the patients who received HTT

. Most of the events (83%) were mild, and the remainder were moderate in severity. The most common adverse events in those who received HTT

 were procedural pain and post–dural puncture headache.

After the study ended, participants were given the opportunity to enroll in a 15-month, open-label extension trial to assess the effects of intrathecal administration of 120 mg of HTT

Questions remain, however, about whether the reduction in CSF levels of mutant HTT will translate into clinical benefits. The researchers themselves noted the limitations of their trial: “Functional, cognitive, psychiatric, and neurologic clinical outcomes were generally unchanged at the dose-group level during the trial, and no meaningful differences were observed between patients who received placebo and patients who received HTT

“Larger studies of greater duration will be needed to determine whether HTT

-mediated reduction of the concentration of mutant HTT in CSF is associated with a treatment effect on the disease course, which is typically slow, with changes on standard outcomes generally occurring over a period of years,” the authors concluded.

This article was originally published 6/20/19 and has since been updated.

This study was funded by Ionis Pharmaceuticals and F. Hoffmann–La Roche.

1. Tabrizi SJ, Leavitt BR, Landwehrmeyer GB, et al. 

Targeting huntingtin expression in patients with Huntington’s disease

. 2019;380:2307-2316. doi: 10.1056/NEJMoa1900907.

Huntington drug successfully lowers levels of disease-causing protein

 [press release]. Vancouver, BC: University of British Columbia; May 6, 2019.

The first therapy to target the primary mechanism of the disease is safe and well tolerated, say study investigators.

New Treatment Reduces Levels of Protein Linked to Huntington Disease

Is work stress driving doctors to drink? A survey of British physicians found that 44% binge drink (consume six or more alcoholic drinks on one occasion) and 5% meet the criteria for alcohol dependence.

 The findings were recently published in 

The survey was conducted to examine the effects of occupational distress (including burnout, depression, and maladaptive coping strategies) on substance abuse and other health problems. Researchers analyzed data from 417 physicians in the United Kingdom. The mean age of the participants was 47 years, and 52% were women.

“Our research shows that 55% of doctors have burnout, and this has real health consequences,” said study author Caroline Kamau, PhD, at 

About 34% of physicians in the survey reported that they drank alcohol to cope with work-related stress, and 22% used substances to deal with stressful events. Less experienced physicians and those who worked in hospitals were more likely to engage in binge drinking. Binge eating was another coping strategy reported by physicians: up to 29% experienced negative emotions after overeating and 8% had a binge eating disorder.

Burnout was a significant predictor of sleep disorders (odds ratio ≥1.344; P≤.03). Overall, 12% of physicians in the survey reported insomnia. Work stress also contributed to general ill health, including fatigue, nausea, headache, heartburn, eye strain, diarrhea, and tinnitus, but not back pain, in this study.

“Work-related stress is often ignored as not being a priority, but our research shows that stress among doctors is associated with health problems and risky health behaviors like alcohol use. Stress can no longer be ignored because it can lead to doctors suffering severe health problems,” said study author Asta Medisauskaite, PhD, at 

This article was originally published 5/16/19 and has since been updated.

Does occupational distress raise the risk of alcohol use, binge-eating, ill health and sleep problems among medical doctors? A UK cross-sectional study

. 2019;9:e027362. doi: 10.1136/bmjopen-2018-027362

The fallout from burnout: alcohol dependence, binge eating, sleep disorders, and general ill health.

Work Stress Takes a Toll on Physicians’ Health

A specific circuit of young adult-born neurons in the brain plays a key role in the recognition of safe versus hazardous situations, according to researchers. Their findings, recently published in 

, could pave the way for more targeted treatments for conditions such as 

 that are associated with hypervigilance and recurrent distressing memories.

“Without these cells, we would be incapable of distinguishing similar situations from each other, a process sometimes termed pattern separation, which is critical not only for forming novel memories but also for discriminating between safe and dangerous contexts,” said the study’s senior investigator, RenÃ© Hen, PhD, of 

 conducted in adult mice, Hen and colleagues

 looked at how young adult-born neurons in the hippocampus either excite or inhibit the dentate gyrus via metabotropic glutamate receptors or 

-methyl-D-aspartate receptors, respectively. These opposing mechanisms have profound effects on memory, learning, and mood.

The neural circuit controlled by the young neurons is involved in the development of PTSD, anxiety disorders, and phobias. According to Hen, identification of the neurotransmitters and receptors in this circuit “gives us the information we need to develop drugs that could mimic the young neurons.” He noted that neurogenesis is crucial to the mechanism of action of SSRIs but that these medications require 4 to 6 weeks to take effect.

The results of this study may lead to the development of rapid-acting treatments that directly target the neural circuits involved in mood and memory.

Funding for this study was provided by the 

This article was originally published 5/13/2019 and has since been updated.

 Luna VM, Anacker C, Burghardt NS, et al. 

Adult-born hippocampal neurons bidirectionally modulate entorhinal inputs into the dentate gyrus

Recent findings could pave the way for targeted therapies for conditions associated with hypervigilance and recurrent distressing memories.