The Gut Could Be a New Target for Antidepressants
A gut-targeting SSRI could also provide an alternative approach for treating depression during pregnancy.
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Anxiety and depression affect four and five percent of the global population respectively, representing a major public health burden. Similarly, disorders of the gut–brain interaction (DGBIs), such as irritable bowel syndrome, are highly prevalent across the world.
Selective serotonin reuptake inhibitors (SSRIs), the first-line pharmacological treatment option for both mood disorders and DGBIs, are designed to increase levels of the serotonin neurotransmitter. Neurotransmitters are chemical messengers that transmit signals from one nerve cell to another. Once this message has been “delivered”, serotonin is typically reabsorbed. If a person is taking SSRI medication, however, the protein responsible for this reuptake is blocked, increasing the amount of free serotonin available to continue transmitting neuronal messages.
The molecular mechanisms underpinning the therapeutic effects – and adverse side effects – of SSRIs are still being figured out. While SSRIs are designed to systemically block serotonin receptors, much of the body’s serotonin is actually produced in the gut.
Dr. Kara Margolis, director of the New York University Pain Research Center and Dr. Mark Ansorge, associate professor of clinical neurobiology at Columbia University Vagelos College of Physicians and Surgeons, have been collaborating on research into gut–brain interactions for the last decade. Their latest body of work provides fundamental new insights into the role of serotonin signaling in the gut.
The research, published in Gastroenterology, provides new evidence supporting the targeting of the gut for mood disorder treatment and demonstrates the impact of in utero SSRI exposure.
Ansorge joined Technology Networks to discuss the design of the research project, its key findings and their implications for the treatment of mood disorders.
What key question did this research project aim to address?
Mark Ansorge, PhD (MA):
Serotonin serves many functions throughout the human body. SSRI antidepressants boost serotonin signaling, and they are among the most widely prescribed class of drugs worldwide. Their effects on mood are thought to stem from increased serotonin signaling in the brain. But interestingly, 90% of the body’s serotonin is produced in the gut, and we know that the brain and the gut are connected – they talk to each other.
Hence, we asked the question: does gut serotonin signaling impact emotional behavior? Within that question, we also asked if SSRIs might exert effects on mood via boosting serotonin signaling in the gut.
If we can understand where serotonin acts to influence mood and where SSRIs act to exert antidepressant and anxiolytic effects, we may be able to design novel drugs that target those regions more selectively and thereby improve efficacy and side effect profiles of existing treatments.
What is an anxiolytic?
A type of medication or alternative intervention that aims to treat anxiety.
MC:
How did you design the study to explore these questions?
MA:
To address the question of whether increasing serotonin signaling in the gut may impact gut–brain communication and ultimately mood, we tested mice using a combination of genetic engineering, surgery and pharmaceuticals.
The genetic engineering allowed us to target the serotonin manipulations selectively to the gut epithelium, something we cannot do currently with drugs. We for example, engineered mice to amplify serotonin signaling only at the gut epithelium, which mimicked an SSRI delivered selectively to the gut. By studying the behavior of those mice, and by comparing the behavior to those that did receive an SSRI, we could conclude on the effects that an SSRI targeted selectively to the gut epithelium would have.
In the latter part of the study, we conducted a prospective birth cohort study where we followed mothers who were depressed +/- SSRI use during pregnancy with non-depressed pregnant women (not taking SSRIs). We showed that in utero SSRI exposure is associated with an increased risk of a disorder of gut-brain interaction, functional constipation.
This is the first study showing that in utero SSRI exposure may have an impact on the way gut–brain communication develops.
MC:
What impact could this research have on the depression treatment landscape?
MA:
Antidepressants like ProzacTM (fluoxetine) and ZoloftTM (sertraline), which raise serotonin levels, are important first-line treatments and help many patients. However, they can sometimes cause side effects that patients can’t tolerate.
Our findings suggest that SSRIs produce therapeutic effects by working directly in the gut. Our findings also suggest that restricting SSRIs to interact only with intestinal cells could potentially avoid some of the side effects that lead people to discontinue currently available SSRI medications.
It is important to note, though, that we do not draw conclusions in the other direction. We know that SSRIs also exert some effects on behavior in mice by acting directly on specific brain regions. So, we will not know how a systemic SSRI compares to a gut-targeted SSRI in the clinic until we have results from appropriate clinical studies. However, our results are highly indicative that a gut-targeted SSRI will at least have some beneficial effects on mood while having fewer negative side effects when compared to systemic SSRIs.
One scenario where this outlook is especially promising and motivating is for pregnant mothers.
Current SSRIs do not just pass from the gut
into the bloodstream and from there across the blood–brain barrier into the
brain; they also pass through the placenta from the mother to the fetus. The
exposure of the fetal body and brain to SSRIs may produce effects that are not
beneficial to child development, with some studies suggesting mood, cognitive
and gastrointestinal problems later in childhood. It is critical to note,
however, that SSRIs are needed to treat depression and anxiety in pregnancy
because untreated maternal illness carries its own many risks for child
development.
It is thus important to underscore that our findings do not imply that mothers should stop taking SSRIs during pregnancy.
SSRIs are most likely the best option currently available to deal with this difficult situation. However, a gut-targeted SSRI would not find its way from the mother into the fetal system and could therefore be a better alternative during pregnancy.
Taken together, our findings indicate that we may be able to treat a mother’s depression or anxiety effectively without exposing the child, and we are working on drug-delivery technology that will hopefully help us achieve that.
