#458 The Forgotten Role of Creatine and Exercise in Depression - Nicholas Fabiano, MD

Nicholas Fabiano (0:00)

In a depressed state or in an anxious state, your brain has learned to make automatic associations between different things. Imagine you see someone laughing in public. Someone with anxiety or depression may automatically assume these people are laughing at me because I'm a loser, or because I look weird, or something like that. What I see exercise to do is it allows your brain to enter almost this neuroplastic state where you're more amenable to unlearn some things, and you may see additional benefits in things like therapy. When you're going there and able to unlearn some of these wired thought patterns. When depressed, when in this increased metabolic state, your body's processes to make energy through the form of ATP are impaired. And this is where creatine comes in, and it's able to essentially quickly replace that ATP, or energy level in the brain, to help with some of the symptoms of depression.

Siim Land (0:44)

Nicholas, welcome to the show.

Nicholas Fabiano (0:46)

Thank you for having me.

Siim Land (0:47)

Yeah, I'm excited to have you in the show. And on X or Twitter, I see you post a lot about the effects of creatine, and exercise, and mental health, which is very popular right now with creatine, having shown to be more than just a muscle building supplement. There's a lot of research about the brain benefits, but many people aren't aware that it also has mental health benefits. And you've written some nice papers about this, reviewing those effects. So yeah, we'll be talking all things about mental health with the fundamentals of improving mental health with some exercise and creatine and some other things. So we'll have a good discussion.

Nicholas Fabiano (1:31)

Yeah, no, thank you. And I think, yeah, it's definitely been an interesting area that's been developing from both the creatine and exercise side. And like you said, I think traditionally, we've more seen creatine to be this fitness supplement for muscles. And there's been a paradigm shift recently where we're being more interested beyond even mental health, but just the brain gains, for lack of a better word, for creatine. But I think a big question that remains is, what is the optimal dosing protocol? What are the expected benefits? Because there are hundreds, if not thousands, of papers from a physical performance perspective, but there is only very preliminary literature for cognition and mental health. And most of the mental health literature for creatine is, again, largely focused on depression. And that's kind of how we usually see a lot of different studies come out is first, starting with the last of the, quote unquote, severe mental illness, where we start with depression, and then we move on to other things like schizophrenia and the such, but it's very exciting to see it starting up.

Siim Land (2:27)

Yeah. What was the, maybe you're going to give an overview about the recent paper you made about creatine.

Nicholas Fabiano (2:33)

Yeah. So with the recent paper, we published it in the European Neuropsychopharmacology, and essentially what we did was provided a brief overview of how creatine may work in depression, and highlighted some of the key trials that have been conducted so far. So in that paper, to speak from a clinical lens first, we highlighted two trials that were completed with creatine. And the first one, what they did was essentially pair creatine with an antidepressant agent, and they compared it to just placebo plus the antidepressant. And what they found was that there was a pretty early response where we saw antidepressant effects as early as two weeks, more so than that of the antidepressant alone, which is very promising because in psychiatry and mental health, we know that these antidepressant agents can take a long time to have an effect and sometimes don't even have a noticeable effect after many, many weeks. So if there's an agent that can be paired with some of these treatments to help, I think that's very promising. And that was repeated in a number of other trials where they paired creatine with an antidepressant and saw improved antidepressant response. But one of the newer trials that came out was just in 2025, again, in European neuropsychopharmacology by Sherpa et al. And they combined creatine with cognitive behavioral therapy. And this is one of the first line therapies for the treatment of depression. And they found a very similar fact where at the end of eight weeks, there was an improved antidepressant benefits. And what we did was in this paper, beyond just summarizing some of the results of it, we also wanted to speak mechanistically in terms of maybe what is creatine doing in the brain. And from that, the way we framed it was very similar to muscle. We know that creatine, it's stored as something called phosphocreatine within the muscles.