Introduction

Microscopic Colitis (MC) affects about 2 per 10000 persons in the United States and is associated with chronic diarrhoea in combination with histopathological markers of inflammation in the large intestine₁. Sertraline, an antidepressant commonly prescribed for depressive and anxiety disorders, appears to increase the risk of MC. As such, health professionals should be aware of this link and conduct the appropriate investigations in individuals taking Sertraline who present with chronic diarrhoea, especially if they have other risk factors for MC.

MC is a type of chronic intestinal inflammation characterised by chronic non-bloody watery diarrhoea alongside an absence of macroscopic lesions on colonoscopy. It encompasses two related conditions, known as collagenous colitis and lymphocytic colitis. Upon histological analysis of colonic tissue, both illnesses are associated with an abnormal infiltration of white blood cells – indicating inflammation in the large intestine. Additionally, in collagenous colitis, only a visible deposition of collagen in the intestinal connective tissue is visible, which is most likely associated with repair mechanisms in response to inflammation-related lesions. Microscopic colitis affects 700000 people in the United States₃. In the UK, studies estimate there are as many as 17000 new diagnoses every year. Risk factors include >45 years old, female sex, cigarette smoking, certain medications and comorbid autoimmune disease. Most patients respond well to treatment with corticosteroids alongside antidiarrheals for symptom management. In some cases, however, bowel resection is necessary to remove sites of intractable inflammation.

On the other hand, Sertraline is a commonly used antidepressant medication belonging to the class of Selective Serotonin Reuptake Inhibitors (SSRIs). SSRIs are used to treat different psychopathologies, such as depression, anxiety, Obsessive Compulsive Disorder (OCD), and premenstrual dysphoria, among others. These drugs work by blocking the proteins that remove excess Serotonin from synapses, allowing more molecules of this neurotransmitter to reach adjacent neurons and activate their respective receptors. How this contributes to alleviating psychiatric symptoms is still poorly understood. Sertraline is generally considered safe and well tolerated with a side effect profile similar to other SSRIs - these most commonly include dry mouth, insomnia, excessive sweating, low sex drive and gastrointestinal disturbances. Sertraline is unique amongst SSRIs, however, in its relatively higher propensity to increase the risk of MC.

This association is important to address and investigate due to how common Sertraline use is amongst different age groups and populations. In fact, in 2021, Sertraline was the 11th most-prescribed drug in the US. In England, Sertraline is the most used Psychotropic medication, with almost 22 Million prescriptions in 2022. There is also a global trend of ever-increasing antidepressant use; as such, it is more important than ever to understand its health implications and identify the risks of prevalent medicines and how to combat them. At the same time, microscopic colitis is often debilitating and potentially dangerous due to diarrhoea-related complications such as weight loss and dehydration.

Microscopic colitis

Microscopic colitis was first described in 1982 based on the observation that some individuals with chronic symptoms of intestinal inflammation had no macroscopic changes seen on conventional tests. It encompasses two slightly different diagnoses – lymphocytic and collagenous colitis. They have similar symptoms, risk factors, treatment, and prognosis but slightly different microscopic features, with Lymphocytic colitis also being twice as common₁.

Sertraline

Sertraline is a commonly prescribed antidepressant medication that has been available in the UK and US since 1990 and 1991, respectively. Since then, Sertraline prescriptions have been exponentially increasing, with it being the most commonly prescribed psychiatric medication in several countries. It is currently approved to treat a vast array of mental illnesses, including:

• Major Depressive Disorder
• General Anxiety Disorder
•  Panic Attack Disorder
• Obsessive-Compulsive Disorder, including in children and adolescents
• Post-traumatic stress Disorder
• And PremenstrualPremenstrual Dysphoria

Sertraline is an SSRI, meaning it blocks the Serotonin Transporter (SERT), which under normal circumstances, recycles synaptic Serotonin molecules. This allows for more Serotonin to activate its postsynaptic receptors, such as the 5HT1A and 5HT2A, which have been linked to stress coping and amelioration of chronic helplessness – an animal model of psychopathology. Compared to other SSRIs, Sertraline may be slightly more effective at treating melancholic depression, characterised by anhedonia and lack of motivation. This may be related to its disputed unique action at the Dopamine Transporter, which may increase levels of this neurotransmitter that's traditionally associated with the experience of reward and pleasure.

Sertraline and other SSRIs are usually better tolerated and safer than older antidepressants. However, they are still associated with some side effects. The undesirable effects most commonly reported by patients on Sertraline are:

• Nausea
• Headache
• Insomnia
• Diarrhoea
• Dizziness
• Dry mouth
• Fatigue
• Tremor
• Sexual dysfunction
• And increased sweating

Connection between microscopic colitis and sertraline

Several studies have documented an increased risk of MC in patients taking Sertraline, which appears to be more significant than with any other SSRI. Sertraline-induced Microscopic Colitis is most frequently of the Lymphocytic subtype and presents with a 1-3-month history of chronic watery diarrhoea, generally within a few months of initiating Sertraline treatment. Other symptoms commonly reported are abdominal pain, faecal incontinence and weight loss. Usually, they resolve within three months of quitting Sertraline. In some cases, upon discussing their specific situation with a health professional, they may find it is more beneficial to stay on the drug alongside treatment for MC.

The mechanism by which Sertraline causes MC is poorly understood. Studies have shown that MC is associated with an increase in Serotonin-secreting intestinal Enterochromaffin cells. Increasing the levels of Serotonin not only in the brain but also in the gut mucosa, where SERT is also found, Sertraline, and presumably other SSRIs, may promote intestinal inflammation and diarrhoea. This is in line with evidence showing that gut serotonin stimulates the release of pro-inflammatory mediators. Additionally, it accelerates gastrointestinal motility by inducing peristalsis and facilitating Chloride and water secretion into the gut lumen.

It is important to note, however, that over 10% of patients taking Sertraline experience some form of diarrhoea, which more often than not is not indicative of Microscopic Colitis. Certain populations may be at a higher risk of developing Sertraline-induced Microscopic Colitis, particularly older females, those with a history of Autoimmune Disease and cigarette smokers. 

Summary

MC is a condition characterised by intestinal inflammation that can only be identified under the microscope through histological analysis of gut tissue. It usually causes a pattern of chronic non-bloody watery diarrhoea potentially associated with stomach pain and incontinence. Several medications have been linked to the development of MC, one of which is the antidepressant Sertraline, used to treat several different psychiatric illnesses.

In the future, it would be important to further investigate the connection between SSRIs and gastrointestinal inflammation. Diarrhoea is a very common side effect of these medications. Thus, more research is needed to understand what percentage of these cases are related to lymphocyte infiltration. Future studies shall hopefully also shed some light on why this seems to occur more frequently with Sertraline than with other SSRIs.

As MC can strongly worsen the quality of life and lead to potentially dangerous complications, health professionals should be aware of this known risk and undertake the necessary examinations on medicated patients that fit the criteria. Switching to a different medication class or an SSRI with lower MC risk could be considered if deemed appropriate by a Doctor.