Can Micronutrient Supplements Help With Anxiety, Depression & Emotional Regulation? (SNP55)

0:00Sigma Nutrition: Welcome to Sigma Nutrition Radio. In this episode, Alan and I are going to be taking a look at some of the trials that have been done relating to micronutrient supplementation and some mental health-related outcomes. Specifically, we'll be looking at three trials that have come from Professor Julia Rucklidge's group that look at outcomes like anxiety, depression, irritability, emotional dysregulation in a few different population types. this comes off the back of a question that we received from one of our sigma nutrition premium subscribers asking about some of this work and how that might connect or not to some of the previous conversations we've had around diet and mental health because that's a topic where there are a lot of strong claims and narratives online but very scarce evidence of there being much to that so we're going to take a look at three specific trials they will be linked in the description where you're listening right now, going through them and seeing what we can potentially take from them.

0:59Sigma Nutrition: And is there something to this emerging area of looking at high dose micronutrient supplementation for some of these specific outcomes that we're going to look at? Now, this is a premium exclusive episode of the podcast, meaning to listen to it in its entirety, as well as receiving a set of detailed study notes, you will need to be a Sigma Nutrition premium subscriber and listening over on the premium feed of the podcast so if you are listening right now on the public feed of the podcast and you're a premium subscriber you'll need to switch over to your premium feed if you are not a premium member and you want to get these extra podcast episodes we do an extra episode every month we also take in questions from our premium subscribers which serve for both question and answer type episodes as well as full episodes like this one and for all our podcast episodes you receive a set of detailed study notes and an edited transcript so if you're interested in those types of things to advance your learning as you are listening to this podcast then check out what we offer with a membership to sigma nutrition premium and in the meantime please enjoy this preview of our latest premium exclusive episode where we're discussing some of this really interesting work.

2:16Sigma Nutrition: So without further ado, let's get into this episode.

2:31Sigma Nutrition: Hello and welcome to Sigma Nutrition Radio. My name is Danny Lennon and with me is Dr. Alan Flanagan. Alan, how are you doing?

2:40Professor Julia Rucklidge: I'm very well, thank you. Yeah, I'm taking over nicely with the research and nothing gets me ready for Halloween like reading more nutrition research.

2:49Sigma Nutrition: So you're very much in the Halloween mood at the moment. Today we're going to be taking a look at an area that was actually sparked by one of our premium subscribers. Rachel had submitted a question to us on nominally the topic around nutrition and mental health. Rachel had mentioned that she really enjoyed a previous episode that we had done that you were the lead on, Alan, looking at some of the research in the area around depression and nutrition, and particularly looking at the SMILES trial, which we may mention a bit later on, and some of the limitations in that and the drawing of conclusions from that.

3:22Sigma Nutrition: Off the back of that, Rachel is wondering for our insight on some of the work done by Julia Rutledge's group that uses high-dose supplements of micronutrients and looking at various different mental health conditions. For long-time listeners of the podcast, you may remember that Professor Rutledge was on this podcast probably close to 10 years ago, at least, I think back in episode 117, if people want to look at that. In the time since then, that group has done a lot more work and has done a number of trials, and that is the center of Rachel's question. So we're going to be looking at three of those today that look a couple of different outcomes across depression anxiety and then some emotional dysregulation we'll go through those trials and see what is in there what we can take from them how they were done and maybe give an insight into these types of studies that are looking at micronutrition and some of these different outcomes that we've mentioned and maybe as a precursor before we talk about any of that stuff alan to get people up to speed with maybe what you discussed previously some of the shortcomings we have tended to see in the more broad area around nutrition and mental health, whether that's outcomes of anxiety or depression.

4:39Sigma Nutrition: We see oftentimes big headlines in different outlets that come from some types of studies. One that has got a lot of popularity is that SMILES trial you've addressed before. Can you give people a bit of a lay of land of generally what we have seen in this area and then some of the potential issues that you might have flagged previously?

4:59Professor Julia Rucklidge: Yeah, I think the issues that we discussed before are very much, I think, overall still live in this area. I think there's various ways that we can think about some of the limitations to diet and nutrition interventions in the overarching area of mental health as outcomes. The first is the definition of the outcomes itself and what is specifically being looked at, whether that is depression or anxiety or another related diagnosis, ADHD or otherwise. The sensitivity and specificity with which that outcome is measured, this is an area with a dizzying array of different instruments that have been developed to nominally capture what we are interested in as an outcome in that context, depression, anxiety, multiple scales for each of these that all reflect different strengths, limitations, different psychometric validity, different alignment with diagnostic criteria, different convergent validity and sensitivity with in terms of are they actually capturing what they're intending to capture, and different levels of interrated and internal reliability to the construct itself within a given instrument.

6:25Professor Julia Rucklidge: So that creates an interesting issue that is basically a live issue in any of these trials, right? What do they measure to capture what they're hoping to actually assess as an outcome? Within that, there are some interesting discrepancies within behavioral interventions between patient rating scales and clinician rating. So that's another relevant component to how the outcome is assessed. It's not simply the construct validity and reliability of the instrument that is used to capture anxiety, depression, ADHD, irritability, whatever it is. There's also then how that is administered. So those outcome-related issues are always live.

7:12Professor Julia Rucklidge: And then there's the methodological component of the purpose of randomization and randomized trials, which is to isolate an independent effect of your intervention or your treatment. And in behavior trials, which are complex interventions in contrast to simple interventions like pharmacological trials, the assumptions that underpin that inference of the independence of outcome effects downstream from your treatment or intervention are very difficult and often untenable. How we see this translate in some of the evidence in this area is a real imbalance between an intervention group and a control group, where a control group are left to something like usual care, quote unquote, whatever that looks like, and an intervention group have substantial imbalances in their favor in terms of number of practitioner contacts, monitoring, and potentially additional, in the context of mental health outcomes, counselling support, all of which introduces enormous bias towards the intervention group.

8:18Professor Julia Rucklidge: That means that no real independent effect of a dietary or nutritional supplement intervention can truly be demonstrated in that context. And that issue colours so much of the evidence from human intervention trials in this area. And then there is, of course, the nature of the population that you are looking at itself. And this is also crucial. In behavioral interventions, we see consistent discrepancies in the magnitude of effects relative to the baseline severity of the sample that you're looking at. And for example, in pharmacotherapy trials in mental health, the baseline cutoffs for some of the instruments, like the Hamilton Raging Scale of Depression, for example, are often higher than they are for behavioral non-pharmacological trials.

9:10What this means is that in behavioral non-pharmacological

9:15Professor Julia Rucklidge: trials, you often have non-clinical samples. So you have samples of individuals that have non-clinical depression rather than major depressive disorder, or sometimes even a mix within the one study sample. And this is particularly relevant because generally with some of these interventions, you can actually see more robust effects in individuals that have clinically diagnosed depression, for example, or whatever the specific outcome is you are looking at. Whereas in non-clinical samples, you might get slightly more underwhelming effect sizes and estimates. So the baseline severity and the actual kind of the diagnostic criteria for whatever it is you're interested in seeing a change in in your population sample is particularly relevant.

10:08Professor Julia Rucklidge: So they're the kind of major points for me always when looking at this overall area of diet and nutrition interventions with mental health, broadly speaking, irrespective of what the specific outcome is. There's the population itself, the severity of the population. There's the intervention design and the importance then of either placebo effects or ensuring equal balance of behavioral components of an intervention between your two groups. And then there's the outcome itself and the sensitivity of the outcome, both on its own as a specific instrument, and then also the potential distinction between clinician rated outcomes versus, for example, parent or participant or patient rated outcomes.

11:00Sigma Nutrition: Perfect. And that gives us a great starting point because I think those are the things that people listening should bear in mind as we go through each of these studies and we can see to what degree each of those is addressed and how that has implications for how we might interpret these particular trials. and like I mentioned a bit earlier we've taken three specific trials from this group so led by professor Julia Rucklage across three related but distinct different outcomes and population types as you mentioned so the first we'll look at is called the nomad rct which is in adults and we have outcomes related to anxiety and depressive symptoms we'll look then at nutrimum which is more in antenatal depressive symptoms.

11:43Sigma Nutrition: And then the third being BEAM, which is related to irritability, emotional dysregulation in adolescent population. So three distinct different types of trials. And hopefully with those things Alan has outlined, people can bear those in mind as we walk through this. So Alan, let's maybe start with the NOMAD RCT. So again, this is published 2023. I'll put a link to this in the description for everyone listening. You can go and read the full text there that really looks at whether this formulation of a broad spectrum micronutrient can have an impact on what they term functionally impairing anxiety and depressive symptoms.

12:23Sigma Nutrition: Now when we, first before we get to any of the results around this, one of the noteworthy things that relates to what you just said is in the severity of the actual symptoms. In this case we have a situation where we're not looking at, let's say, true diagnosis of a severe depression, let's say, but rather we're looking at this group that is medication-free and are out in the community. What are some of those elements of that setup, let's say, of the study design that we're looking at here that are probably most relevant to what you've just said of the things that people should bear in mind?

13:04Professor Julia Rucklidge: So in this particular trial, there's several aspects to the design that are noteworthy and are a positive in the context of what we have just said, particularly the fact that both groups received the same level of monitoring and contact. This was deliberately for the purposes of the NOMAD trial kept minimal. So all participants were monitored by a clinical psychologist, which is the principal investigator. And then the contact consisted of baseline assessments and end of trial interview, and then weekly reminder texts to complete their online questionnaires. So there wasn't formal psychological therapy or counseling, but neither group received that.

13:50Professor Julia Rucklidge: And it was primarily administrative and monitoring contact, but that was identical between the two groups. So the minimal contact design was intentional because the study was looking specifically, again, unlike some of the other complex behavioral interventions where you have multiple moving parts, you have a dietary component, you have maybe additional counseling or therapy in conjunction with that. They were really looking to identify whether the provision of the micronutrient supplement, multivitamin mineral supplement itself had an effect rather than being combined with additional modalities of behavioral therapy, for example.

14:35Professor Julia Rucklidge: That, I think, in the context of what we said about the design aspect is a positive aspect to the design of the trial. In terms of the outcome and the two primary outcomes here were the PHQ-9 and the GAD-7. The PHQ-9 is the Patient Health Questionnaire 9, which is a very widely used nine-item self-reporting scale to screen and diagnose and measure severity of depression. The real strength of the PHQ-9 over, for example, other tools that can be used to assess depression is that it actually has very high sensitivity and specificity for detecting major depressive disorder.

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