Nutrition and Mental Health: Part III

Summary

Recent reports in both healthcare professional venues and public media sources have reported mental health benefits attributable to GLP-1 receptor agonists. The methodology of the study needs to be scrutinized. The conclusions of the study need further review. All of us, health care professionals and the general public, should become informed consumers.

Nutrition and Mental Health: Part III

I did not anticipate discussing the intersection of medications, nutrition, and mental health. The recent headlines, both in professional venues and in the public media, prompted me to include this subject as it seems topical for our world.

A recent study has led to news reports touting the “benefits” of a specific class of diabetes medications for anxiety and depression, with one article mentioning this medication class as potential future “treatments” for anxiety and depression.

GLP-1 Receptor Agonists

These medications were designed to treated diabetes. It was noticed that they can lead to weight loss. They have been re-envisioned to address “obesity”.

Weight Gain

Let’s consider some variables that lead to weight gain. The literature has substantiated a link between weight gain and the following: genetics; and the epigenetic effects of sedentary lifestyle, environmental exposures, sleep deprivation, diet, alcohol intake, and medications. We have become increasingly aware of the connection between inflammation, oxidative stress, metabolism, hypoxia, and other pathways with obesity/weight gain. Some of these pathways have been implicated in the development of mental health symptoms and to the experience of trauma.

The following article beautifully summarizes the literature: An Overview of Epigenetics in Obesity: The Role of Lifestyle and Therapeutic Interventions, Mahmoud, 2022, https://www.mdpi.com/1422-0067/23/3/1341

A discussion of obesity as a disease and as a cultural concept is not to be ignored. Different schools of thoughts surround this discussion, including the approach of Health at All Sizes. I am not going to pretend to be able to provide an exhaustive exposé of this topic. Please become informed via the multiple resources available to us.

(Nota bene: I am using the terms GLP-1 receptor agonist and GLP-1 agonist interchangeably.)

GLP-1 Receptor Agonists: Depression and Anxiety

Before jumping on the bandwagon of support for these medications, let’s take a look at the recent study noting a correlation with the use of GLP-1 receptor agonists and a reduction in the diagnosis of depression and of anxiety.

Epic Research released a report on February 8, 2024, opining that GLP I agonists (glucagon-like peptide-1 receptor agonists) are “correlated” with a “lower likelihood” of anxiety and depression.

https://www.epicresearch.org/articles/most-glp-1-medications-correlated-with-a-lower-likelihood-of-anxiety-and-depression-diagnoses

My choice of parentheses and my framing the report as reflecting an opinion are deliberate. The study methodology was not the gold standard for research studies, RCT (randomized control study). Nor was it a multivariate analysis or a longitudinal study. The researchers reviewed the charts (medical records) of over 3 million people with a diagnosis of diabetes and over 900 000 people who did not have a diagnosis of diabetes.

Pretty impressive numbers for a study. Again, consider the methodology.

The groups were controlled for age, “sex”, and history of depression or anxiety, for both groups. For the group with a diagnosis of diabetes, the researchers adjusted for hemoglobin A1C (hemoglobin with an attached sugar, reflecting glucose level for the person for the previous three months) and other diabetes medications. For those persons with a diagnosis of diabetes, the researchers compared patients who were prescribed GLP-1 agonists to patients with a documented hemoglobin A1C. (Um, does that even make sense? I am not sure.)

Now I am chomping at the bit and would like the see the research paper, not just what was reported in Epic Research.

Let’s continue.

For persons without a diagnosis of diabetes, the researchers compared patients prescribed GLP-1 agonists for weight management to patients prescribed a different type of medication for weight management. (Okay. I am seeing the light.)

The results are prettily presented in dot plots with confidence intervals and different colours. Nice touch.

The researchers arrive at the following conclusions: patients with a diagnosis of diabetes who were prescribed a GLP-1 agonist had a lower likelihood of being diagnosed with depression or anxiety compared to patients with diabetes who were not prescribed a GLP-1 agonist. Patients prescribed a particular GLP-1 agonist (tirzepatide) showed the “greatest reduction in likelihood of being diagnosed” with depression or anxiety. Among patients with a diagnosis of diabetes, those prescribed any of the GLP-1 agonists showed a lower likelihood of being diagnosed with depression than patients with diabetes not prescribed a GLP-1 agonist. Among patients without a diagnosis of diabetes, those who were prescribed a particular GLP-1 agonist (semaglutide) had a lower likelihood of being diagnosed with anxiety.

Again, I chose my words deliberately because the report is not clear in its language. Ultimately, I consulted the full research article:

https://epicresearchblob.blob.core.windows.net/cms-uploads/pdfs/most-glp-1-medications-correlated-with-a-lower-likelihood-of-anxiety-and-depression-diagnoses.pdf

Scrolling down to the definition sections, I smile. Finally, information about timeframe of study. There is the Index date defined as the date of the GLP-1 agonist order. The Censorship date is defined as 1 year following the Index date, the death date, or the last outpatient follow up date, whichever comes first. The End date is 1 month after the Censorship date or 1 month after completion of the GLP-1 agonist, whichever comes first.

Red Flags About The Study

I notice morphing in the choice of the language in the headlines from the Epic Research group report to the language in a professional online source, MDedge, February 12, 2024, Study Suggests Mind-Body Benefits of GLP-1s (https://www.mdedge.com/clinicianreviews/article/267775/obesity/study-suggests-mind-body-benefits-glp-1s) and, then, to the language in a non-clinical source, ABC News, in which the term correlate is switched to link which, in my opinion, carries a stronger sense of association than correlate (https://abcnews.go.com/Health/weight-loss-drugs-linked-lower-likelihood-depression-anxiety/story?id=107000659). And, in this article, the potential of using GLP-1 receptor agonists for treatment of depression and anxiety is mentioned.
The study has unclear endpoints related to when the patients in the study stopped taking a GLP-1 receptor agonist.
The study report does not document controlling for variables that are associated with depression and anxiety risks: socio-economic status; occupation; income; housing situation; relationship status; life changes; trauma history; medications that can induce depression or anxiety symptoms; medications for the treatment of depression or anxiety; marginalized population membership; eating disorders; …
The study report does not mention any consultation with specialists in the fields of eating disorder treatment or nutrition/dietetics, who might have recommended a different set of variables to be considered in the study.
The study report does not mention consultation with mental health professionals about the study’s design.
The study report mentions how the FDA recently noted no connection between suicidal ideation and the GLP-1 receptor agonists.
Do we know if the patients in the study even took the GLP-1 receptor agonists or is the study based entirely on the fact they were prescribed a GLP-1 receptor agonist?

Number 6 confounds me the most. The study emerged on the wings of bad press for the GLP-1 agonists. The side effect profile; the cost of the medications; the shortage of the medications for persons with diabetes now that prescribers are initiating the GLP=1 agonists for weight loss; and the FDA report on January 30, 2024, determining there is no causal link between GLP -1 agonists and suicidal ideation

(https://www.fda.gov/drugs/drug-safety-and-availability/update-fdas-ongoing-evaluation-reports-suicidal-thoughts-or-actions-patients-taking-certain-type).

Of note, as of December 2023, the European Medicines Agency was requesting additional data before deciding on the risk of suicidal ideation with GLP-1 agonists (https://www.reuters.com/business/healthcare-pharmaceuticals/eu-watchdog-seeks-more-data-glp-1-drugmakers-suicidal-thoughts-2023-12-01/).

Takeaways

We need information to make decisions. The information in the EPIC research report requires a close read.

Read the original research article, if you can understand it. If you do not understand information, consult a licensed dietitian nutritionist or a registered dietitian nutritionist and consult your health care professional team. If you are a health care professional, discuss the research with your colleagues.

Informed consent for treatment requires healthcare professionals to be informed about data that can or may not inform our practice, as well as the information we relay to clients, allowing them to make informed decisions.

Let’s all be informed consumers.