January 21, 2022

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

Good morning, Research Roundup readers. This week, the big breakthrough in the world of brain disorders was a report in the journal Science about multiple sclerosis. A study of more than 10 million active-duty service members found that infection with Epstein Barr Virus, which causes infectious mononucleosis, increased the risk of multiple sclerosis by 32-fold, suggesting that EBV is the leading cause of multiple sclerosis.

From the world of mental health research, we uncovered some surprising leads. Stem cells from people with schizophrenia show abnormal features that correlate with clinical symptoms. New research on gender-affirming hormone treatment has clear implications for policy. And more: Why are most suicidal people not in treatment? Are mental health apps effective? And did you know that Covid survivors have higher levels of anxiety? Read on!

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Most People Who Are Suicidal Aren’t Getting Mental Health Care

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As many as two-thirds of people who die by suicide have not accessed mental health services in the year before their death, one of the reasons suicide mortality has climbed over the past two decades even though there are effective treatments. Why don’t suicidal people access treatment? They may believe they don’t need it, want to be self-reliant, have limited access, or have negative attitudes or negative prior experiences with the mental health system. All these factors may contribute, but we don’t really know because once someone has died, we can’t ask.

What we can do is investigate lack of care in people who have suicidal thoughts. Samantha Tang and colleagues from the Black Dog Institute in Sydney reviewed 35 studies that explored non-use of services in people with suicidal thoughts. As with people who die by suicide, those with suicidal thoughts are often not in care – that was the case in 44% to 72% of people in the U.S. studies. One of the most consistent findings across these studies was the lack of care for racial or ethnic minorities. Other predictors of people not getting treatment: lack of a psychiatric diagnosis, lower psychological distress, and better perceived general health.

And what about people who actually attempt suicide? Tanner Bommersbach and colleagues at the Yale School of Medicine reviewed suicide attempts from 2008 to 2019 in a national survey of nearly half a million non-institutionalized U.S. adults. Looking at 4,342 suicide attempts across these years, the team found a 17% increase in the annual rate, with the increase greatest in young adults (ages 18-25), women, individuals who were unemployed, never married, and substance abusers. Only about 40% received services in the year of their attempt and, in spite of the greater number of attempts, the rate of service utilization did not increase from 2008 to 2019.

So how do we reach people who are reluctant to engage the formal health care system or don’t know how to access it? Using peer supporters  and a more diverse set of providers who are able to connect with and understand people’s needs and cultural background could help. So could more creative use of online services.

Predictors of Not Receiving Mental Health Services Among People at Risk of Suicide: A Systematic Review Journal of Affective Disorders. January 12, 2022

National Trends of Mental Health Care Among US Adults Who Attempted Suicide in the Past 12 Months. JAMA Psychiatry, January 19, 2022

–Tom Insel

For Transgender Teens, Gender-Affirming Hormone Access Improves Adult Mental Health

Growing numbers of Americans define themselves as transgender, but what it does to their mental health when they are unable to get hormonal treatment that helps them conform to their gender identity?

A team of researchers led by Stanford psychiatrist Jack Turban went back and examined responses from 21,598 adults who took part in the pioneering U.S. Transgender Survey in 2015. Among other questions, the survey asked about access to gender-affirming hormones in early adolescence (ages 14-15), late adolescence (ages 16-17), and adulthood. Respondents also answered questions about their current level of psychological distress, substance use patterns, and various measures of suicidality.

Turban’s team compared adults who had used hormones with adults who wanted but didn’t get this type of treatment. In total, 78% of respondents told the survey team that they wanted gender-affirming hormonal treatment. Of those, 2% received hormones during early or late adolescence, 57% got it when they were adults and 41% never accessed it.

Turban’s reanalysis found that adults who accessed gender-affirming hormonal treatment reported lower odds of past-year suicidal thoughts and psychological distress than those who didn’t. What’s more, the relatively small number of people who had accessed hormonal treatment in adolescence were less likely to have had suicidal thoughts in the year prior to the survey than those who waited until adulthood to get the hormones. They also reported lower rates of severe psychological distress, recent binge drinking, and illicit drug use over the course of their lives.

Taken together, these results point to a pressing public health need to provide access to gender-affirming hormonal treatment for adolescents who desire it. They also, as the authors write, “argue against waiting until adulthood to offer GAH to transgender adolescents and suggest that doing so may put patients at greater mental health risk.” In this context, it’s especially distressing that more than 20 states have introduced bills recently to restrict access to healthcare for transgender youth, and 15 states have proposed anti-transgender bills in the 2022 legislative session alone. The need to protect the right to treatment for transgender youth has never been greater.

This study comes as surveys show a growing number of young people –1.8% of Gen Z’ers (born between 1997 and 2002) and 1.2% of millennials (born between 1981 and 1996) – identify as transgender, compared with 0.2% of older generations. It also comes as the World Professional Association for Transgender Health’s Standards of Care is being revised. The meaning of these findings is clear: Providing gender-affirming hormonal treatment for transgender youth has profound and positive mental health effects, now and into the future.

Access to gender-affirming hormones during adolescence and mental health outcomes among transgender adults. PLOS ONE, January 12, 2022.

Matthew Hirschtritt

Stem Cells and Schizophrenia

Image: Shutterstock

Neuroscientists increasingly consider schizophrenia a developmental brain disorder. By this, they mean that schizophrenia may start in utero when the brain is developing, perhaps two decades before the first symptoms. If this is a brain disorder that starts before birth, how can we study either the mechanisms for schizophrenia or develop preventive interventions?

Induced pluripotent stem cells (iPSCs), which were recognized with the Nobel Prize for Medicine and Physiology in 2012, provide part of the answer. Ordinary cells taken from the skin of an adult can be re-programmed to go back in time so they resemble embryonic stem cells, the cells that give rise to all other cells in the body. Then they can be differentiated to become neurons or other brain cells. This technique permits scientists to study brain development in a dish, literally watching the process by which stem cells become neurons and neurons create circuits.

This week, a team from the Lieber Institute for Brain Development reported the physiological properties of cortical neurons derived from iPSCs from adults diagnosed with schizophrenia. Several previous studies have documented differences in iPSCs or differentiated neurons from people with schizophrenia. The new report goes further by selecting people with high genetic risk and hunting for associations with specific clinical features. While the findings are based on only thirteen patients and fifteen controls, the results are intriguing.

While the neurons derived from patients and controls appeared identical in many ways, there were physiological differences. Surprisingly, some of these neuronal differences appeared to correlate with specific clinical features of schizophrenia. One electrophysiological pattern correlated with the intensity of hallucinations and delusions, while a second pattern mapped on to the cognitive deficits of the original thirteen patients.

The use of stem cells has already revealed important mechanisms for developmental brain disorders like Fragile X and Rett Syndrome. Schizophrenia, which is genetically complex, has proven more difficult to study. This new study, which attempts to link cellular physiology to clinical features, may be a first step toward connecting the dots between genetic risk, brain development, and the adult expression of the disorder. If differences are indeed already present in fetal development, then preventive interventions might begin years before what we currently recognize as the onset of the disorder.

Electrophysiological measures from human iPSC-derived neurons are associated with schizophrenia clinical status and predict individual cognitive performance Proceedings of the National Academy of Sciences, Jan 11, 2022

-Tom Insel

Smart Phones Hold Promise – Not a Panacea – for Mental Health

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Nearly all U.S. adults (97%) have a cellphone and 87% report owning a smartphone – up from 35% just 10 years ago. The explosion in smartphone access has brought a flurry of text- and mobile app-based interventions for mental health – as many as 10,000 to 20,000 by some estimates. Now a new review synthesizing previous research concludes that the data supporting the overall utility of these apps is limited, but there are some specific cases in which they may be helpful.

Simon Goldberg at the University of Wisconsin, Madison, and colleagues compiled data from 14 meta-analyses including a total of 145 randomized-controlled trials (RCTs) of mental health apps among 47,940 participants. The sample size may seem impressive, but the results were weak. Overall, the authors didn’t find convincing evidence that apps were effective, only “highly suggestive evidence” of efficacy for anxiety, stress, depression, and quality of life. Text-message based interventions for smoking cessation led to better rates of quitting compared with education about the hazards of tobacco use and other inactive controls. Perhaps not surprisingly, mental health apps looked more impressive when they were compared to a behavioral placebo – and less so when they were compared to other active interventions.

So what should consumers do with these data? With so many options available at the click of a button, the One Mind PsyberGuide offers objective reviews of 225 mental health apps, a small fraction of the total apps available. Similarly, the American Psychiatric Association’s App Advisor provides an app evaluation framework and sample evaluations. For researchers, there is a need for rigorous clinical trials that are not funded by the app creators. Finding the right match between what an app can offer and what a user needs is still a ways off.

Mobile phone-based interventions for mental health: A systematic meta-review of 14 meta-analyses of randomized controlled trials. PLOS Digital Health, January 18, 2022.

Matthew Hirschtritt

The Lingering Mental Health Effects from Covid-19 Infection

Every week another report links the Covid pandemic to poor mental health. This week we were struck by a study of a very specific link: People who have had a Covid infection report much higher rates of anxiety and depression.

We know that Covid long haulers – people who continue to suffer fatigue and brain fog months after the acute infection has passed –  may experience worsened mental health. But a review of studies published last year found relatively low rates of depression, anxiety and other psychiatric illness among people who had survived Covid infection.

Jagdish Khubchandani and colleagues used e-mail and social media sites to conduct a survey comparing 836 self-identified Covid survivors to 2797 people without a history of Covid infection. They found that people who survived an infection were 2.9 times more likely to have clinically significant anxiety and 1.8 times more likely to have depression than those who never had Covid. The survivors were also more than 2.5 times more likely to report moderate-to-severe psychological distress.

Survey data collected via the internet are subject to bias and this survey did not verify infection or psychological distress beyond a single self-report screen. Nevertheless, the findings suggest that infection with Covid-19, like other SARS viruses, could indeed have lingering mental health effects that make them one of the most enduring aftermaths of the pandemic.

Covid-19 Infection Survivors and the Risk of Depression and Anxiety Symptoms: A Nationwide Study of Adults in the United States European Journal of Internal Medicine, Jan 11, 2022

-Tom Insel



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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