A State-of-the-Art Microbur-Driven Non-Absorbable Epithelial SERT Antagonist to Treat Anxiety and Depression in Military Members and the General Public
Abstract
Depression and anxiety are common disabling conditions that have a huge negative impact on the military and society at large. Major depression (MD) affects 13.1% and 12% military members previously and currently deployed, respectively. Anxiety disorders (AD), including posttraumatic stress disorder (PTSD), are also highly prevalent in military members. MD and AD are linked to serious negative outcomes in military personnel including an increased risk of suicide and suicide attempts. The high prevalence and increased suicide risk associated with MD/AD magnifies the critical need for adequate therapies. Selective serotonin reuptake inhibitors (SSRIs) are the first line and most highly prescribed medications for MD and AD/PTSD. The SSRIs currently available, however, have key limitations that cause discontinuation or noncompliance, including: (1) low efficacy: SSRIs are partially or fully effective in <50% and approximately one-third of patients, respectively; (2) severe side effects including those that SSRIs are prescribed to prevent (depression and/or anxiety in <65%), as well as severe constipation and/or abdominal pain; and (3) children exposed to SSRIs in utero have a long-term increased risk of cognitive issues, mood disorders, and gastrointestinal (GI) problems (pain and constipation), among others. This limitation is key: pregnant military women are >33% more likely to suffer from mental illness including depression, and SSRIs are the preferred therapy. There is thus a critical need for new ways to treat MD/AD that: (1) increase efficacy; (2) avoid common severe side effects; and (3) prevent the long-term harmful effects of in utero exposure. Serotonin (5-HT) is a chemical produced by the body that is thought to help prevent and/or treat MD and AD. SSRIs work by increasing 5-HT through inhibition of its major inactivator, the 5-HT reuptake transporter (SERT). SERT is located in nerve cells in the (1) brain (central nervous system; CNS), (2) gut (enteric nervous system; ENS), as well as (3) cells lining the gut wall (gut epithelium). Current SSRIs are systemically absorbed through the intestine and thus increase 5-HT signaling in the CNS, ENS, and gut epithelium. A key obstacle to improving upon SSRIs is a lack of understanding of precisely where they act to induce their beneficial mood effects. Although it has been thought that the major direct target of SSRIs is the CNS, recent data suggest that gut 5-HT could modulate mood. We thus sought to examine whether blocking SERT selectively in the intestine (gut epithelium versus ENS) contributes to the beneficial mood-altering effects and/or the negative side effects of SSRIs. To do this, we created mice where SERT was selectively eliminated from the gut epithelium or ENS. We made three major discoveries: (1) SSRIs, when taken chronically, act on a 5-HT receptor in the CNS (5-HT2C) to decrease their antidepressant and anxiolytic abilities (SSRI exposure to the CNS can have negative effects on mood); (2) Targeted SERT blockade in the ENS causes anxiety and depression, constipation, and abdominal pain (SSRI exposure to the ENS results in the negative side effects associated with currently available systemic SSRIs); and (3) Targeted SERT blockade in the intestinal epithelium (mimicking an SSRI targeted exclusively to the gut epithelium and not absorbed into the blood and thus not accessing the CNS/ENS) is anxiolytic and anti-depressive and does not induce GI problems. These findings support the idea that blockade of intestinal epithelial SERT, with limited/no systemic absorption, will effectively treat anxiety and depression while avoiding negative side effects and placental SSRI transfer to a fetus. Development of a gut epithelium-specific non-absorbable SSRI may thus be more effective and safer. We have created and validated a state-of-the-art drug delivery system (MB-SSRI) to selectively block SERT in the intestinal epithelium. Our prelim
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310816
Entities
People
- Kara Gross-margolis
Organizations
- New York University
- United States Army