DDW Editor Reece Armstrong speaks to Kara Margolis, MD, Director of the NYU Pain Research Center and Associate Professor at NYU College of Dentistry and NYU Grossman School of Medicine, and Mark Ansorge, Associate Professor of clinical neurobiology at Columbia University about recent research highlighting the importance between the gut and the brain, and what this means for the development of more targeted antidepressants.

Arecent study, published in the journal Gastroenterology, explored how increasing serotinin in the gut epithelium can improve symptoms of anxiety and depression in animals, potentially leading to better routes of administration for antidepressants, helping to reduce side effects such as gastrointestinal issues. The researchers also found that in humans, the use of antidepressants during pregnancy can increase the risk of digestive issues in children, making the research potentially important the improving the use of antidepressants taken by pregnant women. 

RA: How important is it to weigh the benefits of taking antidepressants for expectant mothers versus the potential side-effects these drugs might cause? 

KM: This is a really important question. With pregnant women, it is always very important to consider the risk:benefit ratio of medications taken, with the additional consideration of how the medication will affect foetal development. It is always recommended that pregnant women that suffer from depression receive psychotherapy and engage in other treatments that help depression in non-medical ways including a good diet, good sleep and a safe level of exercise. For some pregnant women, these options do not help mood symptoms effectively. At that point it is important to consider starting medical treatment, among which SSRIs are a first-line choice, because untreated maternal depression has also been shown to impart potentially negative effects of foetal development and long-term outcomes in things like mood, cognition and, as we recently showed, some disorders of gut-brain interaction.

RA: How does this study challenge traditional notions of the role SSRIs play in treating mental health disorders specifically with their targeting of the central nervous system? 

MA: In the 60s and 70s the first line pharmacotherapies for depression were inhibitors of the monoamine oxidase (monoamine oxidase inhibitors) and monoamine transporters (tricyclic antidepressants). In parallel, monoamines including serotonin were identified and characterised as neurotransmitters, molecules that communicate information between neurons. In the case of serotonin, its synthesis, storage, release, breakdown, and uptake were studied in biochemical experiments using brain tissue. With this converging information, researchers at Eli Lilly proposed to directly target the uptake of serotonin to develop a more specific antidepressant. As a result, fluoxetine was developed and published as the first selective serotonin reuptake inhibitor (SSRI) in 1974. In 1987 Fluoxetine was approved by the FDA for the treatment of depression. Because depression (as basically all psychiatric disorders) is understood as a disorder of the brain, the search for biological mechanisms that can explain the efficacy of fluoxetine (downstream of serotonin transporter blockade) focused on its action in the brain. And this search was productive. Key mechanisms in the brain have been identified over the past decades that play a role in the action of SSRIs, for example the induction of neurotrophic factors, neuroplasticity, and adult neurogenesis. Our findings now challenge these notions and findings in the sense that while prior findings explain part of the picture, they do not explain the entire picture. Our findings start to paint the entire picture. We add a previously unknown place of action that contributes to the efficacy of SSRIs – the gut. And even to our surprise, this place in the body that was previously underacknowledged for its role in mood regulation seems to have ground zero properties: blocking reuptake of serotonin in the gut epithelium is sufficient to produce at least some anxiolytic and antidepressant effects.

RA: Do current side-effects associated with anti-depressants lead to a reduction of patients continuing treatment? 

KM: Yes, side-effects can include, amongst others, anxiety and gastrointestinal issues like nausea, abdominal pain and diarrhea or constipation, particularly in the first few weeks of treatment. All of these factors lead to increased rates of noncompliance or prematurely stopping the medication. There is often a delay in treatment success; it can take weeks to months for SSRIs to reach their full effect-this is also a reason for patient discontinuation.

RA: Following that, by removing gastrointestinal side-effects associated with anti-depressants would you expect patients to remain longer on the treatment? 

KM: It would certainly increase rates of continuing the medications, particularly at the beginning of treatment.

RA: What are the drug delivery challenges of targeting the gut epithelium? 

MA: The body has developed physical barriers that protect it from harmful substances. The most prominent such barriers are the gut barrier and the blood-brain barrier. SSRIs have been developed to cross through these barriers to find their molecular targets in the brain. Specific compositions were generated to enable this ability. We are now developing novel compositions in order to prevent them from passing these barriers while maintaining their affinity and specificity for the serotonin transporter and their ability to block serotonin transport.

RA: How could this research help inform new drug discovery approaches in mental health treatments? 

KM: Our research suggests a novel approach to treat mental health disorders that may be safer for pregnant women (because such a drug would not be transferred through the placenta to a fetus) and may induce less side effects. It is possible that other psychiatric medications work in the same way-but this still needs to be tested.

RA: Have you got any plans to follow on from this research? 

KM: Yes! We are currently devising new gut-targeted drugs to treat mood disorders.

From DDW Volume 26 – Issue 2, Spring 2025 Read the digital issue

Biographies:

Kara Margolis, MD is a physician-scientist and Director of the NYU Pain Research Center. She has been seeing patients with gastrointestinal conditions, including disorders of gut-brain interaction, for 20 years. Her laboratory focuses on understanding how gut serotonin signalling can be modulated to impact abdominal pain and mood disorders.

Mark Ansorge, PhD, is an Associate Professor in the Department of Psychiatry at Columbia University. He runs a research lab studying developmental origins and circuit mechanisms of neuropsychiatric disorders. Specifically, his research aims at understanding the mechanism by which serotonin and dopamine signaling during development and in adulthood impact emotional and cognitive behaviour.