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Summary: Yes, new research shows a medication for constipation can help depression brain fog – i.e. cognitive deficits associated with major depressive disorder (MDD) – by acting on receptors present in the brain and the digestive system.

Key Points:

  • Research shows a relationship between receptors in the gastrointestinal tract and mental health disorders.
  • The relationship includes both positive and negative consequences for mental clarity and thinking, i.e. cognition.
  • Symptoms of depression not only include low mood, sadness, and other emotional states, but also include deficits in cognitive domains such as learning, memory, and executive function.

The Brain and the Gut: Is There a Connection?

Yes, there’s definitely a connection between the brain and the gut.

More specifically, there’s a direct relationship between the health of our gut microbiome and our mental health. The gut microbiome is the total of all the bacteria that inhabit our gastrointestinal tract. Research shows that over three thousand species of bacteria live in our digestive system, collectively known as the gut microbiome. When our gut microbiome is healthy, we experience a healthy symbiosis with the bacteria, but when our gut microbiome is unhealthy and imbalanced, we experience gut dysbiosis.

Research shows gut dysbiosis is associated with:

  • Elevated stress hormones including cortisol
  • Increased symptoms of anxiety
  • Increased symptoms of depression

This phenomenon interested a group of researchers in the United Kingdom, who designed a study called “Pro-Cognitive Effects Of 5-HT4 Receptor Agonism in Individuals With Remitted Depression,” which they describe as follows:

“Preclinical and human studies suggest that stimulating 5-HT4 receptors enhances neuroplasticity and improves cognition. This novel study examines the cognitive effects of 5-HT4R agonism in adults with a history of recurrent depression.”

This study is relevant because it advances our emerging knowledge of the connection between the gut microbiome and mental health and addresses factors in people with remitted depression, i.e. depression that has largely improved, rather than symptom relief in people with active, ongoing depression.

Study co-author Dr. Angharad de Cates from the University of Birmingham observes:

“Cognitive problems, or brain fog, are an important and often overlooked feature of depression, and can persist even when mood improves. Our study suggests that a targeted serotonin 5-HT4 receptor medication, already used for chronic constipation, may improve cognitive functioning in people with a history of depression”

Senior author Susannah Murphy the University of Oxford adds:

“For many people, recovery from depression is incomplete because difficulties with memory and concentration persist.”

Let’s take a look at the study – and learn more about the gut microbiome.

After Depressive Symptoms Fade, Cognitive Deficits May Persist

Mental health providers work to help patients with depression and other mental health disorders manage their symptoms, improve daily function, and restore the psychological and emotional balance to live a full and productive life on their own terms. The symptoms therapists and patients work on most often are those related to mood, emotion, and behavior, such as:

  • Sadness/hopelessness
  • Anger/irritation
  • Withdrawal from friends and family
  • Anhedonia
  • Suicidality, i.e. thinking about, talking about, or attempting suicide

However, significant cognitive symptoms accompany depression, in addition to emotional and behavioral symptoms, such as problems with:

  • Learning
  • Memory
  • Concentration
  • Decision-making

To learn more about the relationship between the gut microbiome and mental health, please read the following article on our blog:

Can Probiotics Help Depression Treatment?

The research team conducted the study – with the goal of improving cognitive outcomes for people with remitted major depressive disorder – by recruiting fifty participants who met the following criteria:

  • At least two major depressive episodes or depression diagnosis
  • Currently in remission from depressive symptoms

Researchers divided the participants into two groups:

  • Control group received an inactive placebo for 7-10 days
  • Experimental group, the 5-HT4group, received the medication prucalopride, which includes a 5-HT4 receptor agonist, designed to increase the action of the receptor.
  • Activation of receptor hypothesized to improve depressive symptoms.

Participants completed the following self-report questionnaires to obtain baseline measures of mood, affect, cognitive difficulties, anhedonia, and trait anxiety:

Post-intervention, at the start of the research testing visit, participants’ state anxiety and affect were measured using:

Cognitive assessments included measures of:

  • Verbal learning
  • Memory/working memory tasks
  • Executive functioning:
    • Attention
    • Processing speed

Before we share the results, let’s look more closely at the targeted receptor, 5-HT4.

The Role of the 5-HT4 Receptor in Mental Health

The review and reference article “5-HT4 Receptor: An Overview” indicates that 5-HT4 receptors are expressed in wide variety of tissues in the human body. In the brain, they appear in:

  • Basal ganglia: complex structure associated with learning, memory, processing input, movement, and coordinating motor function.
  • Hippocampus: plays a pivotal role in memory, spatial memory, learning, and emotion.
  • Neo-cortex: performs critical functions associated with attention, thought, perception, and memory.

In the rest of the body, they appear in:

  • Peripheral nervous system: everywhere our nervous system extends from our central nervous system
  • Enteric neurons in the gastrointestinal lining: high concentration throughout intestinal wall
  • Smooth muscles of gastrointestinal (GI) tract: high concentration in muscles associated with GI tract
  • Secretory cells: regulate the release of hormones into bloodstream

These receptors play a role in the following functions:

The medication containing a 5-HT4 receptor agonist – prucalopride – is effective in people with constipation of unknown cause. The action on the muscles of the digestive system promotes muscle contraction and helps move things along. The theory behind this study is that activating 5-HT4 receptors in people with remitted depression can leverage synaptic plasticity and promote the restoration of cognitive function in people with depression. In other words, the researchers in the study hypothesized that a medication for constipation can help depression brain fog.

Let’s see if the experiment confirmed, or disproved, this novel new hypothesis, thereby identifying a new medication for depression.

Medication For Constipation and Depression Brain Fog

The goal of the study was to find a medication that improves the cognitive deficits depression my cause. In addition, researchers assessed the impact of the medication – the 5-HT4 receptor agonist prucalopride – on mental health outcomes more commonly associated with depression. These include overall anxiety, affect, i.e. how a person expresses their emotion or current state of feeling, and mood.

We’ll look at those results first.

Impact of 5-HT4 Activation on Anxiety, Affect, Mood

Anxiety:

  • No significant difference between experimental group and placebo group

Affect:

  • No significant difference between experimental group and placebo group
  • Moderate impact during follow-up for experimental group:
    • Slightly improved PANAS scores

Mood:

  • No significant difference between experimental group and placebo group

The medication showed virtually no effect. In this study, that’s not a bad thing, because the primary goal was to assess its impact on cognitive outcomes, rather than outcomes associated with anxiety, affect, and mood.

We’ll review the cognitive outcomes now.

Impact of 5-HT4 Activation on Cognition

Learning/Verbal Recall:

  • Accuracy:
    • Improved for experimental group on all word recall tasks
    • No improvement in placebo group

Working verbal memory:

  • Speed:
    • Improved for experimental group on memory tasks
    • No improvement in placebo group
  • Accuracy:
    • Improved for experimental group on memory tasks
    • No improvement in placebo group

Executive function:

  • Attention:
    • Improved for experimental group on focus-oriented tasks
    • No improvement in placebo group
  • Speed:
    • Improved for experimental group on memory and processing tasks
    • No improvement in placebo group

As we can see, the experimental group showed improvement in key cognition metrics. Participants showed significant improvement in learning, memory, and basic cognitive tasks.

This study was a replication of previous research conducted by the same group of scientists that “demonstrated pro-cognitive effects following a single acute dose of prucalopride in healthy volunteers” with no previous history of depression.

Here’s how the study authors characterize their findings:

“These findings support further research into whether 5-HT4-targeting medications can be repurposed for depression, or whether similar drugs could be developed to support people with depression and other mental disorders. People with remitted depression have a broad range of cognitive deficits, and it should be investigated whether targeted treatment of these with pro-cognitive medications may have beneficial effects on both prognosis and functioning.”

We’ll discuss these results further, below.

The Importance of Ongoing Care for Depression and Other Mental Health Disorders

In the U.S., we have a habit of thinking that once our symptoms are gone, we’re not sick, and we don’t have to worry about whatever illness caused the symptoms. For most things, that’s true. That’s how it works: we get sick, we get better, we forget about it.

In major depressive disorder (MDD), though, there are symptoms that antidepressants and psychotherapy don’t often target, which the study authors identify as primarily cognitive in nature. What that means is that while a person may recovery from depression and enter remission – technically speaking – they may still experience negative consequences of the disorder.

That means they’re not fully recovered, because full recovery means thriving in all areas of life.

The outcome of this study gives us hope that we can help our patients achieve full recovery and help them to fully thrive in their lives. A person with depression who feels better emotionally but doesn’t feel all there cognitively can enhance their healing and growth by improving those cognitive deficits, which may be a critical step toward their total health. If we can help a person feel fully restored in their emotions, and fully restored in their ability to learn, remember, think, and make critical decisions, then we’re moving them toward the real goal, which is more than the absence of symptoms: it’s total health, and the ability to thrive – as we say above – in all areas of life.

Finding Help: Resources

If you or someone you know needs professional treatment and support for depression brain fog, please contact us here at Crownview Psychiatric Institute. We can help. In addition, you can find support through the following online resources:

About Angus Whyte

Angus Whyte has an extensive background in neuroscience, behavioral health, adolescent development, and mindfulness, including lab work in behavioral neurobiology and a decade of writing articles on mental health and mental health treatment. In addition, Angus brings twenty years of experience as a yoga teacher and experiential educator to his work for Crownview. He’s an expert at synthesizing complex concepts into accessible content that helps patients, providers, and families understand the nuances of mental health treatment, with the ultimate goal of improving outcomes and quality of life for all stakeholders.