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Hey everybody, it's Mikki here. You're listening to Mini Mikkipedia and today I'm excited to chat through a paper that was published just last week looking at the effects of GLP-1s specifically to Zephytide and anhedonia and basically when weight loss comes at the cost of motivation. So imagine

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briefly that someone is doing everything right on to Zepatide. Weight is coming off exactly the way it's supposed to, the scales finally cooperating, blood pressure's better, energy on paper should be better. Every metric that a clinician would look at would say that it was working. And yet, the gym bag sits in the corner. The hobby that used to light someone up isn't done anymore. Dinner with friends, something you used to look forward to all week, this is something that happens now. Nothing is wrong exactly.

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Nothing is sad exactly. It's more like the volume has been turned down on everything, including the things that used to matter. And if you felt some version of this on a GLP-1 light medication, or you're prescribing these medications and a patient has described something to you, I think this most recently published paper and today's episode will be super insightful. It's a new case series out in the journal Obesity Pillars that has been published

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by Dr. Spencer Nadolski who has been on this podcast. He is such a wealth of knowledge in the space of GLP-1 for weight loss medications. He's an obesity specialist, has been working in the field for 15, 20 years at this point. In addition to Summer Kessel, who is a dietitian I follow on Instagram, another wealth of information when it comes to weight loss and application of GLP-1s.

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with lifestyle and diet change as well. And another author in the paper is Grant Tinsley, who is a body composition expert that I've also had on Wikipedia. So today, what are we talking about? Anhedonia and GLP-1 medications, specifically as I said, high dose to zeppetide. This one is for, I guess, three groups of people all at once, right? People currently on GLP-1, people thinking about starting one, and the prescribers who manage it. So.

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The paper is a case series about three women on high dose trisepatide who described a real specific pattern of reduced motivation and flatness despite the medication working as intended for weight loss. So first I want to go through what anhedonia actually means clinically because it isn't just another way of saying feeling low. And then I want to go through the three cases themselves because the details matter, I think.

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m And of course, this is case series. We've got that information. And then we can chat about how much weight this evidence can actually carry. Because of course, as noted by the authors as well, three patients isn't a landmark study. However, it is a start looking at something that people are seeing clinically, which clearly motivated the authors to actually publish on it. And I do want to talk about the proposed mechanism, where the dopamine reward system fits in, and where researchers in the space

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actually, you know, they do disagree with each other. And then finally, the practical takeaways as noted in the paper, depending on sort of which seat you're sitting in as a patient, someone interested or as a prescriber. So anhedonia, it isn't feeling sad. Two authors, Amy Dirt-Avakian and Athena Markow's work on the neurobiology of this describes it as markedly diminished interest or pleasure. And it's really a reward processing problem.

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more than it is a mood problem in the classic sense. Michael Treadway and Jessica Zull's research draws a line between wanting and liking. Wanting is the drive to go pursue something, the motivation and anticipation that gets you off the couch. Liking is the pleasure you feel once you're actually doing the thing. So these are separate systems in the brain and most of what shows up clinically as anhedonia is actually a wanting problem. People aren't necessarily incapable of enjoying things once they start,

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they just can't seem to generate the drive to start. So do hold on to that distinction because it does map perfectly onto what these three patients describe. There are evidence limitations, of course, and even measuring anhedonia is actually difficult. So a researcher, Sakina Revsey's work on assessment tools, points out that different scales can disagree with each other and there isn't one clean universally accepted way to quantify it.

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This is worth knowing clearly because this particular case series didn't use a standardized scale at all. It relied on clinical interviews. So let's chat about what these cases found individually. Patient one was 62 years old, classified as a class one obesity and hypertensive with no prior history depression or mood disorders. Over 19 months working with the clinic on strength training and body composition, she lost 26 % of her body weight.

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working up to a maximum dose of 15 milligrams of tzepetide a week. She started noticing a real loss of motivation to exercise and interest in hobbies she'd previously enjoyed. Her doctors dropped her to 10 milligrams for four months and things improved. However, frustrated with her weight loss stall that occurred with the drop in medication, she chose to self-escalate her own dose back up to 12.5 and then back to 15 milligrams over the following four months.

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Then the anhedonia came back quickly and she got no further weight loss for the trouble. Back down to 10 milligrams for four months, some improvement in motivation, but lingering flatness, then down further to five milligrams for another four months, at which everything resolved completely and her weight loss held. So that was like a self-run re-challenge experiment really. She went up in terms of her dose, symptoms returned with no benefit. She went down, they resolved.

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and the weight stayed off. Now, patient two was 36 years old with class one obesity and existing history of depression and anxiety. And she had used bupropion, I think that's how I say it, it's an antidepressant, years earlier, unrelated to this actually. Over 24 months at 15 milligrams of tizepatide, she lost 23 % of her body weight, but noticed a flatness she was careful to describe as genuinely different from her prior depression.

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an awareness that she should be exercising paired with this inability to make herself do it. What's notable here is how she found her way to the clinic. She'd seen other patients discussing to a type related and hedonia online before her own doctor had raised it with her. The patient community was ahead of the literature on this one. Now the clinic I'm referring to is uh Vinyard, which is clinic created by Spence and Adolfsgill, which we talked about in our podcast.

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So with patient number two, she was at that 15 milligrams. They then spent one month at 10 milligrams and it did bring some improvement. Four months at 10 milligrams, plus 150 milligrams of bupropion did help further, but didn't fully resolve things.

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Propion was increased to 300 mg while two zeppotides was dropped to 7.5 mg. Over the following 4 months she lost another 15 pounds, about 7 % of her original weight and described feeling like herself again. Patient 3 was 64 years old, Class 3 obesity, no prior mood history and the most dramatic transformation of all three. She lost 57 % of her body weight at 15 mg. That's about 190 pounds from the paper.

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that was enough to eventually need skin removal surgery. She hadn't actually registered a mood disturbance until she stopped the medication for four weeks around the time of the surgery and restarted at a lower dose of 7.5 milligrams. Only in hindsight did she recognize that she had scaled back things like food preparation and exercise down to the bare minimum without ever consciously clocking it as a symptom.

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Once she was back on the lower dose, her interest in cooking and looking forward to exercise returned, and over three further months, her weight held, or her motivation in daily engagement clearly improved. And I think patient three's case is super important actually, because she didn't notice that the anhedonia was setting in. It was retrospective. So of course, the uncomfortable question is,

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How many people are living with a milder version of this and have no comparison point because nothing ever prompted the dose reduction that would have shown them what they'd actually lost. So I think that's super important. One thing I will say though, I was on Twitter where I found this paper, or X, I'm sorry, and a few people commented underneath Spencer's post and they'd said, well, can we just reframe this actually? It's not anhedonia, it's just maybe a normalization of the

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brain circuitry pathways. Like maybe the wanting was just too much initially. And you hear a lot about food noise, about food addiction and things like that. So maybe this is just a recalibration back to where it needs to be. So I think that's an interesting point. And I mean, I don't have a lot more to say other than that that was something that people on the drug have mentioned that, yes, I feel different, but it's not necessarily a bad thing. So I did want to actually point that out as well.

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not part of the paper, but something I'd seen online. Anyway, how did they actually diagnosis? It isn't just because the patient said that they felt flat. All three patients were specifically interviewed about their treatment history, their weight trajectory, and changes in mood and motivation. Critically, anhedonia was only established after ruling out organic causes, things like hormonal issues, anemia, nutritional deficiencies, sleep disturbance, and after ruling out

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depression as a primary driver. So that is a differential diagnosis process, even without a formal scale attached to it. And you know, it does preempt the obvious pushback that, you know, maybe these people were just depressed and had nothing to do with the drugs. So there was a lot of rigor attached to the diagnosis of anhedonia. And in the paper, the authors are upfront about their own limitations.

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Obviously three patients is not generalizable, there's no control or comparison group, so we can't make strong causal claims. Individual variability in physiology and psychology could plausibly explain some or all of what was observed, and anhedonia was assessed by clinical interview rather than a validated instrument, which obviously these real subjectivity baked into how these cases were characterized. However, what I think is really important is

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there's a pattern, and specifically with patient one's accidental re-challenge, right? So when she went back up in dose, symptoms returned quickly and predictably with zero further weight loss benefit, which was interesting. So more isn't always more with that regard. And when she came back down in dose, the symptoms of anhedonia resolved again, twice. That kind of dose response relationship repeated in the same person

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I think is stronger piece of evidence than just an isolated anecdote, even though of course it's a sample size of one, but it is worth mentioning. Obviously it doesn't prove causation because you can't, but it's the kind of signal that does warrant some properly controlled follow-up study rather than just being sort of dismissed out of hand. So what might be going on biologically? And I think that there's a bit of disagreement here actually. So GLP-1 receptors aren't confined to the gut.

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that we know. They're expressed in the mesolimbic and mesocortical dopamine circuits, the pathways running from the ventral tegmental area to the nucleus accumbens and prefrontal cortex. So these are the circuits behind wanting the drive to go pursue a reward or the drive reward paradox. So the proposed mechanism in this paper is that the same dopamine dampening effect that quiets

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Food cravings and reduces addictive wanting behavior may, at high enough doses in susceptible people, generalize past food into a broader blunting of motivation. Exercise, hobbies, daily tasks, all running through the same underlying circuitry. Which of course makes sense actually, because if you look at other emerging published research in the space, there people who are no longer interested in alcohol, in shopping, in gambling, and other addictive behaviors.

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Obviously, that's a definite mechanism. There's a useful analogy here from the dopamine deficit states more broadly, actually. So work on Parkinson's disease and on dopamine-lesioned animal models show that reduced dopamine signaling impairs the effortful pursuit of things, including pursuing food, without necessarily reducing how much that food is enjoyed once it's actually obtained. Same wanting versus liking split that we talked about earlier, just from a different underlying cause.

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One distinction the authors are careful to draw is that it's not the same phenomenon as the nausea and fatigue that shows up during initial dose escalation, which comes from a different set of brain stem circuits and typically resolves as people acclimate. All three of these patients had already settled into the drug and were describing something that emerged later, at or near the maximal maintenance dose, well after the usual GI side effects had faded.

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Some preclinical research does show GLP-1 receptor agonists suppressing dopamine release in response to rewarding stimuli, but other studies have found nominal or even increased dopamine responses to valuable rewards under the same drug class. So this whole sort of mechanism is an unresolved area of research and I don't doubt that we're going to learn so much more over the next few years. Now, I think this is interesting because it's easy to hear that anhedonia

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distinct from depression is not a mood or a disissue. And walk away thinking GLP ones are basically fine for mental health across the board. So the picture could be messier than that actually. The authors themselves state that this anhedonia phenomenon is distinct from clinical depression, anxiety, and suicidality. And they cite research broadly associating GLP receptor agonists with non-significant, even improved mood outcomes on average. But there are some

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studies that complicate that sort of reassurance. And you've probably heard about them before. There's a Swedish national cohort study found an association between GLP-1 receptor agonist use and worsening mental illness, specifically in people who already had depression or anxiety. uh A JAMA psychiatry meta-analysis by Ebrahimi and colleagues looked specifically at suicide and self-harm events associated with this drug class. And

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a nationwide self-controlled case series by Stanislaus and colleagues examined suicide and suicide attempt risk directly. What I would say is that while population level reassurance, the fact that these are tiny, like this is just a tiny subset of people who might react negatively to the drug, it's still a tiny subset of people, I suppose. So I think this is important.

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for anyone at risk of depression and anxiety to consider if they're going to go on a drug like tuzepatide or as a prescriber, and clearly this will be part of your notes anyway, to have a think about the mental health history of someone before prescribing it. Like, yes, at a population level, the meta-analyses and the national cohort study, you know, they're very small numbers, but they were still there. So I just think it's worth...

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acknowledging that as part of this whole discussion. Now, interesting on bupropion, because I didn't know, I mean, I don't know medications that well, clearly. I'm a nutritionist. So I was interested to hear them talk about this one. So it's a norepinephrine dopamine reuptake inhibitor. It's approved for depression and for smoking cessation. And mechanistically, it pushes in roughly the opposite direction from what this paper proposes is happening with the high dose to zepatide, increasing the

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availability of exactly the neurotransmitters that may be getting dampened. And bupropion is also an obesity medication paired with naltrexone in the combination sold as Contrave. We have that here in New Zealand. So the logic here is that naltrexone blocks an opioid mediated feedback loop that would otherwise limit bupropion's effect on its own. And the combination together produces meaningfully more weight loss than either drug alone.

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And for context on where it sits relative to the GLP-1 class, Naltrexone bupropion produces around 4 % average weight loss compared with roughly 15 % for semaglutide and about 20 % for terzepatide. So it's useful, but it's much more modest than the other two. And even though bupropion is part of an obesity medication sort of combo,

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I think you'll know that it was used in this context to help alleviate those symptoms of anhedonia. Just wanted to mention that. so just something worth considering. If you're currently taking one of these medications, just think about these. So this was just three patients out of millions of people on this drug class. So it's not a reason to panic and absolutely not a reason to stop taking your medication unilaterally. And when I hear the likes of Spencer talk about this on his podcast, Docs Who Lift, he

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describes it as, you know, it's something that happens. It's not common, but it's not infrequent enough not to notice. And quieter food noise, less mental chatter around eating. This is expected and clearly welcomed by people who experience these issues, but a broader flattening, reduced interest in exercise or in the people around you, in your usual hobbies or your work, especially if it comes on gradually near your maximum dose.

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and well after those initial nausea and GI side effects, that is a different thing entirely and it is worth chatting to your prescriber about it. Thirdly, and this is what I said at the beginning about patient three, is that you might not notice this happening until it's already lifted. So it is good just to check in on yourself when you're on these things as to, it gonna make a difference to how do I feel on a sort of month by month basis?

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because if you do notice some of your motivation for some of the things you enjoy sort of lacking a little bit, I think that's also worth taking note of. And also the paper had a note for the clinicians, which is always really interesting. So they suggest building a check for motivation, reward, and daily engagement into routine follow-ups, particularly at higher maintenance doses and after longer stretches on the medication, not just a standard norzerine GI review.

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Be clear with patients that these symptoms are distinct from and shouldn't be conflated with the early dose escalation side effects most people already expect and tolerate. And know that dose reduction with or without adjunctive bupropion, preserved weight loss outcomes in all three of these cases. So that's super interesting. Reducing the dose isn't automatically a trade off against efficacy. And it'll be interesting to see what happens

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when some of the more potent dual and triple agonists that are already in the pipeline come to market because they likely hit these brain neural pathways much more heavily than some agglutide or even tuzepatide do. So in summary, the GLP-1 receptor agonists are reward pathway drugs every bit as much as they are gut hormone drugs. And that's exactly why they work as well as they do for cravings and food noise.

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And of course, quietening down the food noise is of course a goal for a lot of people taking these medications, but you don't want to quieten down and turn the dimmer down on your entire life. Based on these three case studies, it is worth checking in on yourself if you're on these drugs or checking in on your patients if you're prescribing these drugs and establish sort of how that sits on any particular dose of tizepatide, but particularly in those higher

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sort of more maintenance doses. All right guys, well, I found that interesting. know, even if you're not on these drugs and you just have a bit of a fascination with them like I do, hopefully you did as well. And I don't doubt that there'll be more emerging in this space. And for what it's worth, I looked around for any sort of prevalence numbers of this occurring, but it is so new. I don't even know that there are other papers. And in fact, that's one of the reasons why the authors probably sort of leaned heavily on literature.

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around other mental health issues because it's just not a lot on the anhedonia which obviously prompted them to sort of publish this paper. But I'd love to hear your thoughts. I'm over on Instagram threads and X @mikkiwilliden, Facebook @mikkiwillidennutrition or head to my website, @mikkiwilliden.com. Scroll right down to the bottom, pop your email in the box to jump on my weekly email list. All right guys, you have the best week. See you later.