It’s been a busy week for mental health news – with the Surgeon General issuing a sobering report about youth mental health – but also for mental health research. Ever wonder why exercise seems to relieve mild or even moderate depression? A new study in marathon mice might provide the answer. And if you thought the increased number of helpline calls during the pandemic were all about depression and anxiety, you’ll be surprised by a new study reported this week in Nature.  And there’s more…. Enjoy and don’t forget to ask a friend to subscribe to our Research Roundup newsletter. They can sign up here

By Tom Insel, MD

How does exercise help your brain? It may be in the clusterin.

Photo: Shutterstock

Exercise has long been considered both a preventive intervention and a treatment for mild or moderate depression. How does exercise help? A simple answer is “activation” of circuits in the brain. But what gets activated and how does this activation work to relieve depression? Neuroscientists have previously shown that exercise reduces inflammation, increases plasticity, and facilitates cell birth in the hippocampus, a part of the brain involved in learning and memory.

A fascinating study takes the study of exercise and brain function to a new level – at least in mice. Tony Wyss-Coray’s lab at Stanford has previously demonstrated the rejuvenating effects of blood transferred from young mice to aged mice. Now he and his team take this approach with running mice. Plasma from mice who’d spent 28 days running on a wheel was injected into test mice. These test mice not only had more hippocampal cell birth, they showed the same kind of improved learning and memory observed with exercise. No such change was found in test mice injected with plasma from mice that had not exercised. In addition, when the team looked at the pattern of gene expression in the hippocampus, they found marked reductions in pro-inflammatory genes and reduced markers of inflammation after injection of the plasma from the running mice.

So what’s the active ingredient here? The team found a family of proteins that inhibit inflammation and zeroed in on one called clusterin. When they injected clusterin into mice with an acute brain inflammation, they found reduced genetic markers of inflammation. And this may not be just a mouse story. Humans with cognitive impairment who participated in a 6-month exercise program were found to have elevated plasma clusterin.

Will clusterin, which is produced in the liver, confer all the benefits of exercise? That’s not clear. Nor is it evident that clusterin could serve as an antidepressant, either with or without exercise. But it is worth noting that depression has been associated with increased markers of inflammation and that every effective antidepressant has been shown to increase cell birth in the hippocampus. Both could explain the effects of exercise on depression.

So before asking for a plasma donation from your favorite ultra-marathoner for your sedentary friend with depression, we will need more evidence of effects in humans. Like the rejuvenation story, this is a remarkable finding, especially if you’re a mouse.  

Exercise plasma boosts memory and dampens brain inflammation via clusterin  Nature, Dec 8, 2021

Helpline Calls During the Covid-19 Pandemic

The Covid-19 pandemic has affected mental health profoundly – but often in ways that were unexpected and counter-intuitive. In the U.S., for example, suicides actually decreased modestly, while overdoses increased significantly. Not so surprising: Surveys have found increased rates of anxiety and depression, especially in youth and young adults.

Some surprises appeared this week in a paper in the journal Nature that looked at helplines in 14 European countries, the USA, China, Hong Kong, Israel and Lebanon – a dataset that covered 8 million individual calls between 2019 and 2021. Overall, the number of calls peaked six weeks after the onset of the pandemic at 35% above pre-pandemic level. No surprise there.

But the calls weren’t mostly about mental health – the increase was largely driven by fear of infection, loneliness, and physical health concerns. Calls about relationship issues and suicidal ideation were actually less prevalent than before the pandemic. “Issues linked directly to the pandemic therefore seem to have replaced rather than exacerbated underlying anxieties,” the authors wrote.

But later in the pandemic, as lockdowns caused deep economic woes, calls for suicide and self-harm rose, the helpline data show. This increase reversed with financial relief, demonstrating the effectiveness of these policies at improving population mental health.

Helpline data can’t replace epidemiological surveys or clinical assessments, but they complement these other approaches and offer a highly responsive way of assessing the fears and anxieties of a population at any given moment – a source, the authors suggest, “of real-time information on the state of public mental health.”

Mental health concerns during the COVID-19 pandemic as revealed by helpline calls  Nature, Dec 2, 2021

Sex, Social Cognition, and Schizophrenia: Not So Simple

Of the various biological factors that influence mind and brain, the sex of an individual is unquestionably one of the most powerful. It influences the prevalence of several disorders: males are more likely to be diagnosed with autism and ADHD; females are more likely to be diagnosed with anorexia nervosa and depression. The mechanism for these differences is not clear, but some have posited that females are better at processing social information, such as emotional expression, and therefore, less likely to show social deficits in disorders like autism or ADHD.

Are there also sex differences in schizophrenia? Relative to men, young women who develop schizophrenia generally have later onset and better functioning before and after they become ill. Several studies have demonstrated that people with schizophrenia have impairments in what clinicians call “social cognition” – the ability to identify or read emotions, a problem that impedes people’s overall ability to function.

Does this female advantage in social cognition protect young women who develop schizophrenia? Marta Ferrer-Quintero from Barcelona and her colleagues tried to answer this question with a series of cognitive tasks in both men and women, comparing people with schizophrenia to healthy control subjects. They used a wide range of tasks, seeing how well people could recognize facial emotion or expressions of empathy. In general, there were significant differences between people with schizophrenia and the control group, but no significant effect of sex.

This surprising lack of an effect of sex on social cognition in people with schizophrenia suggests there must be a different explanation for the tendency for women to function better. Could this advantage be due to the later onset or higher levels of functioning prior to onset? This study does not provide an explanation but it reveals that social cognition is not the source for better functioning in females, as men and women had equivalent deficits.

The effect of sex on social cognition and functioning in schizophrenia  npj Schizophrenia, Dec 1, 2021



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.