April 15, 2022

By Tom Insel, MD, and Matthew Hirschtritt, MD, MPH

Good morning, Research Roundup readers. The studies we review this week cover a broad range of mental health research: We take a deep look at new genomic studies about schizophrenia and assess their impact (spoiler alert: not much yet). We have a hopeful study about the power of virtual reality to help people with serious mental illness overcome their often extreme social anxiety. And we have couple of studies that straddle the line between social sciences and health outcomes. One looks at an often invisible impact of gun violence: the huge increase in psychiatric and substance use disorders in those who survive being shot. And the other examines the large number of people being treated in psychiatric hospitals who previously have been arrested, often for nonviolent offenses, or for failing to appear in court. But first…a look at a new story released by MindSite News yesterday…

As depression, anxiety and suicide rates spike among kids, public schools are working feverishly to expand programs supporting their mental health. So why are well-heeled ‘grassroots’ groups trying to overturn that?

During the pandemic, Idaho students, teachers and families were hit hard by school closures, coronavirus breakouts, and a brewing mental health crisis. Suicide attempts among kids twelve and under were on the rise. And a 2021 report from the state’s hospital emergency departments suggested many youth in Idaho – like kids throughout the country – were struggling with thoughts of depression, self-harm and hopelessness.

Small wonder that Sherri Ybarra, the state’s Republican superintendent of public instruction, appeared frustrated last fall by protests about the state’s support for social-emotional learning (SEL) – an educational approach based on the idea that kids learn and do best when they feel safe, valued and connected. In October, a libertarian group called the Idaho Freedom Foundation assailed the education department’s SEL efforts as a stealth campaign  “to hide a vehicle for critical race theory from the public.” 

Read the rest of the story here.


The Virtual Doctor Will See You Now

Going grocery shopping. Visiting friends. Taking public transportation. Most of us wouldn’t think twice about doing these things, but for people with agoraphobia – a profound fear and avoidance of places that might make one feel trapped, helpless, or embarrassed, leading to a panic attack – everyday life looks like a minefield. Simply venturing out of the house can be overwhelming.

Photo: Shutterstock

Agoraphobia is classified as an anxiety disorder, not generally in the category of serious mental illness. Yet as many as two-thirds of treatment-seeking adults with psychotic disorders (like schizophrenia) have agoraphobia. For people who are already dealing with hallucinations, delusions, and problems thinking clearly, the world can be an intimidating place. Many people with psychosis experience serious victimization; fear of the outside world almost seems a reasonable response to a threatening environment. But avoidance of everyday activities makes it hard – if not impossible – to hold down a job or maintain relationships.

Could a virtual reality-based treatment hold the key to freeing people from agoraphobia’s firm grip? Abundant evidence supports the use of virtual reality interventions for people with agoraphobia who do not have a psychotic illness. Could this same approach work for people with psychotic disorders?

A UK-based team lead by Daniel Freeman of University of Oxford and the Oxford Health National Health Service Foundation Trust looked to answer that question with a fully automated VR program designed to address agoraphobia among people with psychosis. Patients who use the program participate in up to six, half-hour-long VR therapy sessions that allow them to explore everyday social situations and challenge automatic, negative thoughts. For instance, in one session, patients “walk” into a virtual café and engage with other customers, guided by a virtual coach.

In a clinical trial, the researchers randomly assigned 346 people in England ages 16 and older who had psychosis and strong fears of social situations to either VR with “usual care” (including antipsychotic medications and periodic visits with a psychiatrist or case manager) or just usual care on its own. Patients assigned to VR used the program once a week for up to six weeks; a therapist provided a little guidance about how to use the program but stepped aside once the patient was immersed in the virtual world.

People who used the VR program reported significantly lower social-situation avoidance and distress after six weeks. For instance, after six weeks, people randomized to usual care alone had an average distress score of about 46 (out of 80), whereas the VR group had an average score of 41. That difference might seem minor, but even a small change could mean the difference between staying inside all day or venturing outside to walk the dog. The researchers found that what was driving this change was two-fold: Users of the tech had fewer thoughts about potential threats and eased their defense behaviors, like rushing to leave a social situation quickly. Patients who came in with the highest levels of social fears benefited the most from the VR therapy.

If replicated in subsequent studies (especially in real-world settings), this VR-based treatment might point to the future of first-line treatment for agoraphobia. Digital therapeutics including chat-bots, video games, and other VR-based therapies are being developed for a range of behavioral health issues. Access to high-quality, affordable, effective psychological treatment is uneven at best in the US. New technologies hold the promise of expanding access and standardizing treatments to a wider range of patients. There may not be a digital therapeutic for every problem, but tech will undoubtably play an ever-increasing role in treating mental health problems.

Automated virtual reality therapy to treat agoraphobic avoidance and distress in patients with psychosis (gameChange): a multicentre, parallel-group, single-blind, randomised, controlled trial in England with mediation and moderation analyses  The Lancet Psychiatry, April 5, 2022.

– Matthew Hirschtritt


The Criminalization of Mental Illness

In the US, as many as 15% of prison and 20% of jail inmates have a serious mental illness like schizophrenia or bipolar disorder and a far greater number have other forms of mental illness. People who have been incarcerated and have serious mental illnesses or substance use disorders are also more likely to reoffend, especially if these conditions are left undertreated or not addressed at all. But there is little data available about the other direction – the criminal histories of people in mental health settings.

Michael Compton of Columbia University and colleagues used data from Georgia to understand the scope of law enforcement involvement among people with serious mental illnesses. The researchers recruited 240 adult patients who were psychiatrically hospitalized at either a Georgia state psychiatric hospital or one of two crisis stabilization units. To be included in this study, patients needed to have had a psychotic or mood disorder, at least two psychiatric hospitalizations in the last year and trouble doing everyday tasks (like taking care of personal finances).

Taking a close look at the patients’ RAP sheets, researchers found that 71% of them had been arrested in Georgia at least once. Among those who had been arrested, the median number of lifetime arrests was six and the median number of lifetime charges was seven. More than two in five (41%) of all 240 patients and over half (57%) of those who’d been arrested had a felony charge.

What predicts involvement with the criminal justice system? Having fewer than 12 years of education tripled risk of having an arrest history, compared with patients with more education. Patients who were female, Black, and had a substance-use or mood disorder were also more likely to have been arrested. Surprisingly, homelessness wasn’t significantly associated with an arrest history.

Perhaps the most intriguing finding here was the chronology of offenses. While earlier offenses including things like drug possession, DUIs, and shoplifting or burglary, more recent charges were dominated by probation violations, officer-obstruction charges, and failure to appear in court. So what’s the story here?

The researchers posit that “as more arrests and more charges accrue, the likelihood of failure to appear and probation violation increases, and such violations are also likely driven partly by the manifestations of long-term serious mental illnesses, including neurocognitive impairments and other symptoms, as well as lack of transportation and other social adversities.” In other words, by the very nature of their condition, people with mental illness may lack the organizational skills to remember to meet with their probation officer or appear in court, leading them to be re-arrested.

This study, though small and limited to a single state, highlights the need for more robust systems of mental health services for economically disadvantaged people to keep them from getting entangled in the justice system. And for those with serious mental illnesses who’ve been drawn into this system, providing high-quality and assertive mental health care and support is doubly essential.

Characterizing Arrests and Charges Among Individuals With Serious Mental Illnesses in Public-Sector Treatment Settings  Psychiatric Services, April 5, 2022.

– Matthew Hirschtritt


The Mental Health Consequences of Firearm Injury

The impact of gun violence in the U.S. doesn’t end with those killed ­– about 45,000 in 2021. Almost twice that number, roughly 85,000, are injured in non-fatal firearm incidents each year. What are the psychic, medical and financial costs to those survivors, their families and the health care system? In an important new study, Zirui Song from Harvard Medical School and colleagues examined these questions. His key finding: mental health and substance use disorders soared among those still living.

This study looked at 6498 survivors drawn from health care claims in commercial insurance or Medicare. It is not surprising that medical costs increase after a firearm injury, with pain diagnoses rising 40% in the year following the injury. What is surprising is the 51% jump in psychiatric disorders and the 85% increase in substance use disorders among gun-violence survivors. What do these percentages mean in absolute terms? For every 1,000 people injured by firearms, an additional 22 were diagnosed with psychiatric disorders and 14 with substance use disorders, compared with a control group of people demographically matched to those who were injured. The behavioral health impact rose the most for victims of intentional firearm injury. Family members were affected too – they had a 12% increase in psychiatric diagnoses.

The increase in health care costs was profound. Compared with the non-injured control group, medical costs, including care for behavioral health disorders, increased by roughly $30,000 in the year after injury. Extrapolating this to the 85,000 incidents each year, the authors estimate the total national cost at about $2.5 billion in the first year after injury. No doubt this cost would be higher if it included lost productivity (inability to work) and decreased quality of life.

This study is an important addition to the literature on the public health consequences of firearm injury because it looks at a large population with a well-matched control group and it includes family costs. However, it excludes Medicaid recipients and is limited to the first year after injury. Nevertheless, these new findings highlight the importance of behavioral health  issues for survivors of firearm injuries and their families. Knowing this risk is an important first step towards prevention and early intervention. 

Changes in Health Care Spending, Use, and Clinical Outcomes After Nonfatal Firearm Injuries Among Survivors and Family Members  Annals of Internal Medicine, April 5, 2022

-Tom Insel


New Gene Discoveries in Schizophrenia: Are They Meaningful?

Illustration: Shutterstock

Decades of studies of twins and families have shown that schizophrenia runs in families. But the genetic basis of schizophrenia has proven elusive, without a clear blueprint of the genetic architecture that might lead to new treatment targets. Two important advances in genomics research have promised to provide this blueprint. First, the speed and cost of genomic sequencing have changed markedly, making dense mapping feasible in large populations. And second, researchers from around the world have collaborated to create large cohorts of patients for genetic studies.

The fruits of this effort can be seen in two new papers in Nature. One paper, from the Psychiatric Genomics Consortium, uses an approach that has been popularly known as GWAS (Genome-Wide Association Study). GWAS maps common variants – single base changes in the DNA sequence that are common, occurring in at least 1% of us.

In a new report, researchers looked for these commonly shared variations in people with schizophrenia, and they found some ­– 287, to be precise – that occur slightly more often in people with schizophrenia. But most of these common variations in the genome may be difficult to interpret. They are far from actual genes and difficult to link to any biological function. Taken together, they may identify risk but the causal importance of any one of these 287 DNA variants is unclear and likely minimal.

A second study takes the opposite approach. Rather than mapping the common variation across the 3 billion “letters,” ­or pairs of nucleotides, in the entire genome, it uses exome sequencing to look at the small percentage – 1.5 percent – of letters that code for proteins and therefore affect biological function.

A global consortium called the Schizophrenia Exome Sequencing Meta-Analysis (SCHEMA) sequenced the exomes of nearly 25,000 people with schizophrenia and nearly 100,000 controls and found rare changes in 10 genes associated with schizophrenia. All of these genes make proteins that are found in neurons. Although most have not been implicated in neurodevelopment, these same genes have been associated with other neurodevelopmental disorders, like autism spectrum disorders and epilepsy. And many of these ultra-rare variants are in areas of the genome where common variants have been reported previously.

What should we make of these new findings? Do they point to mechanisms of the disorder or new treatment targets? Are they actionable? In a word, no. Whether they are focused on common, rare, or ultra-rare variants, genomic scientists are looking at associations, not causes. And they are looking in “germline DNA” – the inherited DNA that is found in every cell. This may help understand risk – which can be important for early intervention and prevention ­– but it is unlikely to reveal the mechanisms of disease or point to targets for treatment.

This is an important lesson learned from cancer genetics where the genetic changes that lead to cancer are usually the result of random (not inherited) mutations that happen in a small group of cells that develop into a tumor. Inherited variations to genes such as BRCA1 (a DNA repair gene) are useful for detecting risk, in this case for breast cancer. But BRCA1 is not a treatment target. Today, new molecular targets for treating breast cancer come from sequencing the DNA of the tumor, not the DNA of blood cells, where BRCA1 was detected.

Similarly, the molecular cause of schizophrenia may reside in a tiny population of cells in a very specific part of the brain – but not in blood cells. Finding those genetic changes, which some day might reveal a new treatment target, would require knowing where to look in the brain, not only at an anatomic level but at the resolution of specific cells. We are not there yet.

Mapping genomic loci implicates genes and synaptic biology in schizophrenia  Nature, April 8, 2022

Rare coding variants in ten genes confer substantial risk for schizophrenia  Nature, April 8, 2022

-Tom Insel


If you or anyone you know is considering suicide, call the National Suicide Prevention Lifeline at 1-800-273-8255. And if you’re a veteran, press 1.



Tom Insel, MD, is a psychiatrist, neuroscientist, and former director of the National Institute of Mental Health (NIMH). He is a donor to MindSite News and chair of its Editorial Advisory Board. Dr. Insel’s financial conflict of interest statement, which includes equity and advisory roles in several early-stage mental health technology companies, can be found here.

Matthew Hirschtritt, MD, MPH, is a clinical psychiatrist with the Permanente Medical Group, Inc., a mental health services researcher with the Division of Research, Kaiser Permanente Northern California, and assistant program director of the Kaiser Permanente Oakland Adult Psychiatry Training Program. His current research focuses on identification and treatment of patients with first-episode psychosis, as well as implementation of a telehealth-based mental health evaluation and referral program.

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