Do GLP-1s Work for Depression—or Is It Metabolism?

Bret: 
Welcome to the Metabolic Mind Podcast. I’m your host, Dr. Bret Scher. Metabolic Mind is a non-profit initiative of Baszucki Group where we’re providing information about the intersection of metabolic health and mental health and metabolic therapies, such as nutritional ketosis as therapies for mental illness.

Thank you for joining us. Although our podcast is for informational purposes only and we aren’t giving medical advice, we hope you will learn from our content and it will help facilitate discussions with your healthcare providers to see if you could benefit from exploring the connection between metabolic and mental health

GLP-1s are weight loss miracle drugs. It seems this has been the hottest topic in medicine for over the past couple years. But a large new study just published in The Lancet Psychiatry is maybe shifting that conversation towards the brain and mental health. So, do GLP-1s treat depression and anxiety? Yes and no. So, let’s get into it.

For this study, researchers in Sweden reviewed the electronic health records for 95,000 individuals with Type 2 diabetes and a diagnosis of depression or anxiety. And they compared those on GLP-1 agonists to those taking other diabetes medications, like SGLT2 inhibitors or DPP4 inhibitors. And they looked at the psychiatric hospitalizations, episodes of self-harm, or the escalation of depression and anxiety symptoms.

So, by looking at this study, I guess we could say, right away, we see it wasn’t an intervention trial. It was a records review. So, it can point to maybe an association, but it’s unlikely to demonstrate cause and effect. So, that’s point one. And it wasn’t comparing symptoms of an individual before starting the medication to after starting it.

They just registered the hospitalization, self-harm, and the other outcomes for everyone, and then compared those taking GLP-1s and those not. And the result was that those on the GLP-1s, and especially semaglutide, had a significantly lower risk of severe psychiatric outcomes compared to people on the other medications.

But here’s the nuance that many are missing. This study didn’t necessarily find that GLP-1s treat depression or that they provided improvement from baseline or a remission of depression, anxiety, anything like that. What the researchers observed was “less worsening of mental health” is how they called it in the study.

And since chronic metabolic disease is linked to worsening mental health, I can see the rationale for that approach. Plus, they had to work with the data they had access to, right? It was a huge study all from electronic health records. So, we just have to be clear that this isn’t an intervention study showing improvement in overall mental health.

But the results are still interesting. Less worsening still matters, right? It’s still better outcome than the comparator, which in this case was other diabetes medications. And the study still tells us something about this brain-body connection, and the role possibly of insulin resistance and neuroinflammation in mental health.

But interestingly, the study did not report some important things, like weight loss, blood sugar control, or other markers of insulin resistance. The paper actually explicitly mentions that they didn’t have access to that data, which is a big miss since we don’t know if the results were a function of better metabolic health or not.

Seems like an important piece of the puzzle. But look, I don’t mean to disparage the paper, right? They did the best with what they could, and they presented the paper as is. We just have to be clear about what it represents. And in a way, it fits with the emerging field of metabolic psychiatry.

It’s becoming increasingly clear that improving metabolic health often improves mental health. One question we need to better define is what’s the best way to improve metabolic health and improve psychiatric symptoms? So here at Metabolic Mind, we’ve shared a number of pilot studies, clinical experience, individual experience demonstrating the safety and efficacy of ketogenic therapy as an adjunct treatment for depression, schizophrenia, bipolar disorder, and other psychiatric diagnoses.

Does that mean ketogenic therapy is better than GLP-1s? They haven’t been compared head-to-head. So, we don’t know for sure. Given the direct beneficial effects of ketones on the brain, there’s reason to believe it would be more effective than GLP-1s, but we just don’t know yet. Now, another question is, how can the two interventions be used together?

So, the Coalition for Metabolic Health recently released a position statement on GLP-1s, and a key aspect to that position statement is how do we use GLP-1s together with effective metabolically directed lifestyle interventions, of which ketogenic therapy is one option. Again, we need more research in this area, but clinical practice is demonstrating an impressive synergy between ketogenic therapy and short-term or even micro-dosed GLP-1s.

Again, not as the only option, but certainly as an encouraging option. So, while based on this study, we can’t say GLP-1s treat depression and anxiety, we can say the evidence continues to grow that improving metabolic health can improve mental health

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