The latest generation of antidepressants relieves symptoms by mimicking steroids produced by the brain to ensure neurons are effectively talking to each other. How these neurosteroids are linked to depression and why they work is still to be determined.

The new study finds that chronic stress reduces a mouse’s ability to produce and respond to these important molecules, specifically allopregnanolone. The research appears in the journal Biological Psychiatry.

“Our findings suggest that the behavioral deficits following chronic stress involve impaired neurosteroid synthesis and signaling,” says lead author Najah Walton, a PhD student in neuroscience at the Tufts University Graduate School of Biomedical Sciences. “We found that mice subjected to chronic unpredictable stress had an impairment in allopregnanolone production within the basolateral amygdala, a brain region crucial for mediating emotional responses.”

To confirm the link, Walton and colleagues in the Maguire Lab at the School of Medicine used CRISPR technology to adjust the enzymes necessary for allopregnanolone production. Mice with abnormally low levels of the neurosteroid showed depressive behaviors like those that had experienced chronic stress, while their counterparts with abnormally high levels of allopregnanolone showed more resilience to chronic stress.

“The potential implications of these findings suggest that synthetic neurosteroid analogs might exert a beneficial effect in individuals with depression by virtue of their ability to target part of the underlying neuropathology that leads to the condition,” says senior author Jamie Maguire, professor of neuroscience at the Tufts School of Medicine.

Less than half of patients with major depression respond to classic antidepressants, such as selective serotonin reuptake inhibitors, and the benefits are known to take weeks or months to take effect. “This study suggests that endogenous neurosteroid synthesis may be an alternative therapeutic target,” says Maguire.

How chronic stress impacts the genes responsible for producing allopregnanolone, how neurosteroids may be involved in the emergence of depression, and how neurosteroid-based treatments benefit the brain will be the focus of the group’s future work.

“For people with depression or experiencing chronic stress, this research could provide some hope that we are making progress in understanding the neurobiology that contributes to the emergence of psychiatric disease,” says Walton.

The work had support from the National Institute of Mental Health, a division of the National Institutes of Health and a sponsored research agreement with SAGE Therapeutics. Complete information on authors, funders, and conflicts of interest is available in the published paper. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Low-carbohydrate, high-fat diets can raise levels of ‘bad’ LDL cholesterol in the blood and lead to serious cardiovascular problems, a new study finds.

Following a keto-like diet that is low in carbohydrates and high in fats could more than double the risk of cardiovascular issues such as chest pain (angina), blocked arteries requiring stents (tiny coils that open arteries), heart attacks, and strokes, according to a new study.

The findings, presented at the American College of Cardiology’s Annual Scientific Session, suggest that a keto-style eating plan could lead to increased levels of LDL (low-density lipoprotein) — also known as “bad” cholesterol — which in turn may heighten the likelihood of cardiovascular disease.

“If you are following a carbohydrate-restricted diet, our data suggest that it may be important to monitor your cholesterol levels,” says senior study author Liam Brunham, MD, medical lead with the Healthy Heart Program Prevention Clinic at St. Paul’s Hospital in Vancouver and associate professor in the department of medicine at the University of British Columbia in Canada.

“If cholesterol levels are super high, consult with your doctor because there may really need to be careful attention paid to managing the risk of heart disease,” Dr. Brunham adds.

To conduct the study (which is considered preliminary because it has not yet been peer-reviewed for publication in a medical journal), Brunham and his research team analyzed information from more than 70,000 people in the United Kingdom who’d  completed a one-time, self-reported, 24-hour diet questionnaire. At the same time, the researchers did blood draws to check the subjects’ cholesterol levels.

From the questionnaire responses, 305 participants indicated they followed a low-carbohydrate, high-fat diet.

How a Low-Carbohydrate, High-Fat Diet Works

When people restrict their consumption of carbohydrates (found in foods such as bread, pasta, baked goods, and certain fruits and vegetables) and proteins, the body uses its own fat reserves for fuel; this produces chemicals called ketones that the body then uses as energy. Because this process, called ketosis, burns stored fat, it can help people lose weight.

The International Food Information Council estimates that as many as 8 percent of Americans were on a ketogenic diet in 2020.

People following a strict ketogenic diet will typically get 70 to 80 percent of their daily calories from fat, 5 to 10 percent from carbohydrates, and 10 to 20 percent from protein, according to the Harvard T.H. Chan School of Public Health. To include enough subjects to make meaningful conclusions, the Canadian investigators looked for people following a keto-like diet that includes more than 45 percent of daily calories from fat and no more than 25 percent from carbs.

The 305 subjects consuming a low-carbohydrate, high-fat diet were matched with 1,220 individuals who reported eating a standard diet consisting of just over 50 percent of daily calories from carbs and nearly 31 percent from fat.

For each group (keto and standard), about three-quarters were women and the average age was 54.

Higher LDL and More Heart Trouble for the Keto Group

After an average of nearly 12 years of follow-up, individuals on a keto-like diet had more than double the risk of having several major cardiovascular events, such as blockages in the arteries that needed stents, heart attack, stroke, and peripheral arterial disease. In all, 9.8 percent in the low-carbohydrate, high-fat group experienced a new cardiac event, compared with 4.3 percent on a standard diet.

In contrast to subjects on a standard diet, those on a low-carbohydrate, high-fat diet had significantly higher levels of both LDL cholesterol and apolipoprotein B (apoB), a protein on the surface of cholesterol, which may be a more accurate indicator of cardiovascular risk than LDL alone, per research.

When looking at the percentage of people in each dietary group that would be defined as having severe high cholesterol, the scientists recorded 5 percent in the standard diet group versus nearly 10 percent in the low-carb, high-fat group.

“Probably the diet in which there’s a large consumption of saturated fats from animal products is likely contributing to the increase in cholesterol,” says Brunham.

The Connection Between LDL Cholesterol and Heart Disease

Christopher Gardner, PhD, a nutrition scientist and professor of medicine at Stanford School of Medicine who has published research on the effects of low-fat, low-carbohydrate diets but was not involved in the latest study, was not surprised by the keto study results.

“My division chief is a preventive cardiologist. He sees this all the time — people coming in saying they are on keto, and their LDL cholesterol is through the roof,” says Dr. Gardner. “Every time you’re on a keto diet, you have high saturated fat and low fiber — there’s no other way to do it. So LDL goes up.”

As the Centers for Disease Control and Prevention describes it, too much LDL in the body can lead to a buildup of plaque in the blood vessels, causing them to become narrowed or blocked.

As far as major study limitations are concerned, Gardner points out that the investigation was based on a single, 24-hour dietary report, and while the research can show increased risks from a keto-like diet, it can’t prove that the diet itself causes these outcomes.

Still, he finds the researchers’ conclusions concerning. “If you’re going to try a ketogenic diet, you should do it under physician supervision so they can see what’s happening to your LDL cholesterol,” he says.