New study explores safer antidepressants for pregnant women

Mood disorders, including depression and anxiety, affect millions of people worldwide. Selective serotonin reuptake inhibitors (SSRIs) are the most prescribed treatments for these conditions. However, these medications often cause side effects, particularly gastrointestinal issues, and raise concerns when used during pregnancy due to potential risks to the developing foetus. As researchers explore alternatives, growing evidence highlights the crucial role of the gut-brain connection in mental health. Recent findings reveal that serotonin, a neurotransmitter long associated with the brain, also plays a significant role in the gut. 

A study led by Dr Kara Margolis and Dr Mark Ansorge proposes that targeting serotonin in the gut could revolutionise treatments for mood disorders, offering pregnant women a safer and more effective alternative.

A new approach to antidepressant treatment

Dr Kara Margolis, Associate Professor of Molecular Pathobiology at NYU College of Dentistry and a paediatric gastroenterologist specialising in gut-brain axis disorders, has dedicated nearly two decades to investigating the intricate relationship between the gut and brain. Alongside Dr Mark Ansorge, Associate Professor of Psychiatry at Columbia University, they have uncovered groundbreaking insights into how gut serotonin could transform antidepressant therapy.

(Left) Dr Kara Margolis, Associate Professor of Molecular Pathobiology at NYU College of Dentistry | (Right) Dr Mark Ansorge, Associate Professor of Psychiatry at Columbia University

Traditionally, it has been thought that SSRIs alleviate depression and anxiety by increasing serotonin levels in the brain. However, they are absorbed systemically, entering the bloodstream and, in pregnant women, crossing the placenta to affect the developing foetus. Some studies suggest a link of maternal SSRI use to altered brain development and increased risks of cognitive, mood, and gastrointestinal disorders in children, prompting potential safety concerns for pregnant users.

Margolis and Ansorge’s research suggest a novel solution: targeting serotonin in the gut epithelium rather than the brain. By bypassing the bloodstream, this approach could minimise potential risks to the foetus while maintaining therapeutic benefits.

“Maternal SSRI exposure has been associated in some human studies with developmental changes in the brain and increased risks of cognitive, mood, and gastrointestinal disorders, as well as functional constipation,” Margolis explains. “By developing SSRIs that don’t enter the bloodstream, these foetal risks could be significantly reduced.”

Why the gut matters

Serotonin is well-known for regulating mood in the brain, but most of the body’s serotonin is produced in the gut, where it governs gastrointestinal motility. Conventional SSRIs elevate serotonin levels system-wide, often causing side effects like diarrhoea or constipation. Targeting the gut epithelium specifically could avoid these issues while still benefiting mood regulation.

The gut epithelium – a layer of cells lining the intestine – plays a vital role in digestion. Work done previously by Margolis and others has shown that serotonin produced in the gut profoundly impacts gut movement via the enteric nervous system (ENS), a network of neurons in the gut. Importantly, targeting serotonin exclusively to the epithelium avoids unintended effects on the ENS or brain.

In mouse studies, by avoiding the ENS, this targeted approach did not induce diarrhoea or constipation, suggesting that a gut-specific SSRI could eliminate common side effects of traditional treatments. “By targeting SSRIs to the gut epithelium and avoiding direct contact with the ENS or brain, we could avoid many negative effects,” Margolis says.

Reducing risks during pregnancy

Margolis and Ansorge’s research has profound implications for the safety of antidepressants during pregnancy. A different  population-based study by Margolis, Talati et al. linked in utero SSRI exposure to an increased risk of disorders of gut-brain interaction (DGBI) in children, persisting into adolescence. While untreated maternal depression carries its own risks, these findings underscore the need for safer antidepressant options for expectant mothers.

This gut-focused approach could balance the risks of maternal depression with concerns over foetal drug exposure, offering a safer alternative without compromising efficacy.

Next steps in drug development

Margolis and Ansorge are already developing new therapeutic targets based on their findings, aiming to accelerate drug development for safer, gut-specific antidepressants.

“We’re working on novel therapeutic targets,” Margolis shares. Their goal is to create treatments that serve populations like pregnant women, who have long lacked medications that are both highly effective and do not pose any potential risks to a fetus.

The implications of their research extend beyond pregnancy, potentially benefiting anyone affected by mood disorders or gastrointestinal issues. Their research into the gut-brain connection could usher in a new generation of antidepressants, designed to be both safer and more effective for people at all stages of life.