The Evolving Science on Depression and Inflammation with Dr. Adrian Lopresti and Professor Michael Berk

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The Evolving Science on Depression & Inflammation with Dr Adrian Lopresti and Professor Michael Berk

In 2020, up to 15% of Australians aged between 16-85 year reported high or very high levels of psychological distress and 3.4 million people sought saw a health professional for mental health support. In our latest podcast, Professor Michael Berk and Dr. Adrian Lopresti share the latest research on the association between inflammation and mental health conditions.  They discuss the latest treatments for common mental health conditions and the associated research, as well as covering the challenges associated with trials, and the strength of their outcomes. 

Covered in this episode

[00:39] Welcoming Professor Michael Berk
[01:44] Connections between inflammation and mental health
[05:58] does everybody with depression have inflammation?
[08:54] The differences in cortisol-induced vs inflammatory-induced depression
[10:38] Why research results into inflammatories for depression can be inconsistent
[12:42] Should reducing inflammation be a first line treatment?
[21:24] Discussing the evidence around aspirin and depression
[24:45] SSRI’s are anti-inflammatory
[26:19] Symptoms of atypical depression
[29:46] Oxidative stress and mood disorders
[34:56] NAC for schizophrenia and OCD
[40:42] Thanking Michael and closing remarks

Key takeaways 

  • There is a considerable body of evidence connecting markers of inflammation to the presentation of depression and other psychiatric disorders. 
  • An improvement in mood is associated with a reduction in inflammation. Treatment resistance is generally associated with inflammation. 
  • Increased inflammatory markers may be associated with mental health conditions, however, there are still patients who present with the diagnostic criteria for a mental health condition without the presence of inflammatory markers. 
  • Current evidence suggests that inflammation may cause depression based on a study where participants were infused with inflammatory cytokines inducing depression features. 
  • Lifestyle risk factors for depression include physical inactivity, low vitamin D levels, stress, trauma and poor diet among others which are all associated with inflammation.  
  • Brenda Penninx from the Amsterdam University Medical Centre has categorised depression into two types: immunometagbolic depression and cortisol-related depression.
  • Immunometabolic/atypical depression  
    • Linked to inflammation  
    • Often present in people with obesity, hyperphagia, atypical depressive symptoms and involves inflammation. 
    • Patients experience hypersomnia, hyperphagia, may be overweight or obese and likely to have high inflammatory cytokines 
    • More common phenotype for bipolar depression than unipolar depression 
  • Cortisol-related/typical/melancholic pattern depression  
    • Patients experience a loss of appetite and weight and insomnia.  
    • Typical markers include elevated cortisol, loss of diurnal rhythm, abnormal dexamethasone suppression test results 
  • Inflammation is not a disorder specific function. Inflammation is  essential to life and is involved in signalling and defence throughout the body and also involved in disease pathophysiology.  
  • Lifestyle, psychological and pharmacological strategies are important for the management of mental health conditions. 
  • Depression is a risk factor for cardiovascular disease. First line therapies including diet, exercise, smoking cessation and stress reduction. Statin therapy to reduce the cardiovascular disease risks may support a reduction in depression by reducing inflammation. 
  • Lifestyle factors are critical for the treatment of mental health conditions and form the first-line recommendations from the Australia College guidelines
  • The anti-inflammatory effects of minocycline and supports neurogenesis, with studies to support its benefit to the treatment of depression.
  • Research into the preventative benefits of aspirin for the treatment of depression determined no benefit to patients.  
  • Oxidative stress is connected with inflammation with similar drivers. Both relate to a suppression of mitochondrial function. 
  • N-acetyl cysteine (NAC) replenishes glutathione levels. There are several studies associating improvements in the presentation of schizophrenia over an extended period of time with 2-3 g/day NAC treatment. 
  • NAC may also provide modest benefit to depression and bipolar patients over a longer treatment period at 2 g/day. 
  • Professor Michael Berk and Dr Adrian Lopresti were part of a taskforce convened by the World Federation of Societies of Biological Psychiatry (WFSBP) and the Canadian Network for Mood and Anxiety Disorders (CANMAT) and have recently been involved in the release of the Clinician guidelines for the treatment of psychiatric disorders with naturaceuticals and phytoceuticals. These guidelines are both a must-read, and an essential reference for all practitioners working with mental health patients. Full link to the study 

Resources Discussed 

Professor Michael Berk
IMPACT: The Institute for Mental and Physical Health and Clinical Translation
Brenda Penninx | Study: Depression Heterogeneity and Its Biological Underpinnings: Toward Immunometabolic Depression (Milaneschi, et al., 2020)
Study: Inflamed moods: a review of the interactions between inflammation and mood disorders (Rosenblat, et al., 2014)
Royal Australian College of General Practitioners Mental Health Guidelines
Study: Adjunctive minocycline treatment for major depressive disorder: A proof of concept trial (Dean, et al., 2017)
The ASPREE Project
Bipolar Depression Rating Scale 
Study: Genetic Polymorphism Associated Prefrontal Glutathione and Its Coupling With Brain Glutamate and Peripheral Redox Status in Early Psychosis (Xin, et al., 2016)
Study: N-Acetyl Cysteine as a Glutathione Precursor for Schizophrenia—A Double-Blind, Randomized, Placebo-Controlled Trial (Berk, et al., 2008)
Study: Meta-analysis of randomised controlled trials with N-acetylcysteine in the treatment of schizophrenia (Ob Yolland, et al., 2020)
Study: N-acetylcysteine for major depressive episodes in bipolar disorder (Magalhães, et al., 2011)
Study: N-acetyl cysteine (NAC) augmentation in the treatment of obsessive-compulsive disorder: A phase III, 20-week, double-blind, randomized, placebo-controlled trial (Sarris, et al., 2022)


Adrian: Hi, and welcome to FX Medicine, where we bring you the latest in evidence-based integrative, functional and complementary medicine. I'm Dr. Adrian Lopresti, and today, I have the great pleasure of speaking with Professor Michael Berk. 

Michael Berk is an NHMRC senior principal research fellow and is Alfred Deakin chair of psychiatry at Deakin University and Barwon Health, where he heads IMPACT the Institute for Mental and Physical Health and Clinical Translation. He has gathered an incredibly impressive list of awards over the course of his career, and he's listed by Thomas Reuters as amongst the world's most influential scientific minds. He is authored or co-authored over 1,300 papers on a wide variety of mental health topics, including how inflammation and oxidative stress affects mental health and using N-acetylcysteine for the treatment of mental health disorders like bipolar disorder. It is a great privilege to have him with us today, where we'll talk about some of his amazing work. 

Welcome to FX Medicine, Michael. Thank you for joining us.

Michael: Adrian, it's an absolute pleasure to be able to chat to you.

Adrian: So, Michael, I'm an avid follower of your work, and I know you've done a lot of work in the area of inflammation and mental health. Can you tell me a bit about the relationship between inflammation and mental health and the area of immunopsychiatry?

Michael: Absolutely. This is now a very interesting and hot topical area. But 20, 30 years ago, this was an area that was treated with some scepticism, the idea that inflammation was present in mental health disorders, A, and B, that it had any impact on mental health disorders was rather disbelieved. But what's happened in the last couple of decades is a substantial body of evidence has accumulated showing that depression - and for that matter, most other psychiatric disorders - are associated with increased levels of markers of inflammation.

Adrian: Yes.

Michael: So the problem, however, is that there are many people who meet diagnostic criteria for those illnesses who do not have markers of inflammation. And those markers of inflammation are positive in quite a diverse range of psychiatric disorders, as well as in many medical comorbidities, many of those comorbidities also being common in people with depression. So it's a complicated area.

Adrian: Yeah, certainly that relationship between inflammation and mental health, there's also the relationship between inflammation and physical health disorders, cardiovascular disease, for example. So, obviously, there was research showing that there's a relationship between inflammation and mental health. Does that then necessarily mean that inflammation can cause depression or mental health disturbances, or is it just purely a relationship?

Michael: That is a really important point. I think probably the best evidence we've got that inflammation can cause depression comes from experimental studies, where inflammatory cytokines are infused into volunteers. And that induces many of the signature features of depression. That's probably some of the very best evidence that we have. 

There's also indirect evidence from conditions that are principally inflammatory, and almost every one of these is associated with an increased risk for depression. But it's a bit more complicated than that because many of the lifestyle risk factors for depression... So these are things like physical inactivity, low vitamin D, stress, trauma, poor diet, all of these actually can increase inflammation. 

So that makes it a little bit unclear whether inflammation is the mediator or the marker. But I think there is a general acceptance in the field that, although there are many other pathways involved in the genesis of depression, inflammation is a critical one, at least for a subset of people, at least for a subset of people.

Adrian: Because those studies where they induced inflammation, I mean, that's interesting. Some of those studies, it created changes in the way people think, didn't it? Or even in terms of how people perceive the world, if you... I've seen some of those research where they gave TNF-alpha or lipopolysaccharides to induce inflammation and people would be more sensitive to criticism and social rejection and things like that. So that was fascinating work that's been done.

Michael: Yeah. So the interesting thing is that those cytokines reproduce not only the psychological stuff, which you mentioned, like negative thinking, it's a personal sensitivity, but also the classical physical symptoms, like fatigue, sleep disturbance, loss of appetite. 

So that implies that cytokines really have an important role in the genesis of depression. Saying that, if you look at the biology of depression, it's actually very hard to find a system that isn't involved in depression at least to some modest degree. So it's a very complicated process.

Adrian: Absolutely. And so it's a simple “inflammation causes depression.” There's obviously a whole bunch of other factors that are going on that complicate the picture, isn't there?

Michael: Absolutely.

Adrian: So, with inflammation, it's becoming more aware that there's a relationship between inflammation and mental health. And particularly, I suppose the largest body of evidence is around probably depression. So does everybody with depression have inflammation? Is it what the research shows?

Michael: No. Absolutely not. So one of the problems is that only about a half of the people who have depression… If you look at the scatter plots of the studies comparing controls to people who are depressed, there's huge overlap between those groups. The mean is clearly higher in the depression group than the control group. But if you look at the dots, the individual subjects, there's huge overlap. 

So like many biomarkers in psychiatry, sensitivity and specificity of inflammation as a biomarker of depression is quite poor. So it's not sensitive, in that a lot of depressed people don't have it, and it's not specific because a lot of people who have schizophrenia, obesity, PTSD will also have increased inflammation. The only evidence I'm aware of that suggests that it's associated with a specific phenotype of depression is the work of the Amsterdam group led by Brenda Penninx. So Brenda has done some very interesting work, where she's divided depression into two types, what she calls an immunometabolic depression and a cortisol-related depression.

Adrian: Okay.

Michael: So immunometabolic depression is the depression which she links to inflammation. So these are people who tend to have obesity, hyperphagia, so atypical depressive symptoms, and they have increased inflammation. Whereas the group who have classical typical depression, loss of appetite, insomnia, they tend to have more disturbance in cortisol systems. 

Now, a keen observer would step back and say, "Actually, both cortisol, and for that matter, inflammatory systems are both stress response systems in different ways." And I think it's really important for us to stop thinking about inflammation purely as a bug-flagging system, and rather think about cytokines and inflammation as part of a broader stress response system, which is really where much more tightly linked to the whole construct of depression.

Adrian: So it's not as simple as just going, “Okay, this person that's presenting here might be cortisol-induced depression, and this one here might be inflammation-induced depression. So let's treat accordingly.” Unfortunately, it's not as simple as that.

Michael: Well, that's the next step. That's the next step. No one's done that yet.

Adrian: Okay. So how do you determine whether somebody's more cortisol-induced and somebody's more inflammatory-induced?

Michael: So, your typical markers of cortisol dysregulation, so it's elevated cortisol, loss of the diurnal rhythm, abnormal dexamethasone suppression test, that's much more likely to current people with classical, typical, melancholic pattern depression, at least according to Brenda. And I have to say her hypothesis has not yet been replicated externally. And then atypical depression, your hypersomnia, hyperphagia, overweight, obese people are more likely to have high levels of cytokines.

Adrian: Okay.

Michael: That would suggest that you could use anti-cortisol treatments like RU 486 in the former group, and you could be using classical anti-inflammatory strategies in the latter group. So that's a very clear maybe that arises from that understanding, but that has to be tested in trials.

Adrian: Okay. All right. And that hasn't been done yet.

Michael: Oh, no, that hasn't been done yet.

Adrian: At the moment, that's really kind of differentiating term. Okay, because that's really what's got me... Initially, I remember looking at some of the studies, an issue around celecoxib for the treatment of depression, and when it was used as an adjunct to anti antidepressants. There was a study there where there was greater improvement in depressive symptoms when you used the anti-inflammatory and the antidepressant together. And then that was what really led me into kind of looking into kind of natural anti-inflammatories in curcumin, and we certainly can go into that later on.

Michael: That's triggered a whole lot of areas of interest and trialling a whole lot of different compounds with quite variable success rates.

Adrian: Yeah, yeah, because the research is not consistent, isn't it? It's not just a matter of just then, "Well, let's give an anti-inflammatory and we're going to see improvements in depressive symptoms." That's not necessarily the case, is it?

Michael: That is not the case. So there's an awful lot of people, firstly, who have depression, who don't have elevated levels of inflammation. So, at least in theory then, if you stratify for inflammation, you should be able to get better results. And two or three studies have tried to do this and failed. So there's a study by Roger McIntyre, and a few others where people have tried to stratify for inflammation and see if anti-inflammatories work better. Unfortunately, that hasn't been a spectacular success that people might have hoped. 

Now, again, trials are complicated beasts. I always think of Tolstoy's law of clinical trials. So Tolstoy wrote, "Happy families are all alike. Unhappy families are all unique in their misery." And the same is true in clinical trials. So successful trials are all alike, you get everything right. But unsuccessful trials can fail for any one of a million reasons. It could be that the idea you have at the get-go is wrong, but it's very common that there are methodological problems that preclude you from detecting the signals. So a negative study doesn't necessarily mean that your idea was bad. Studies can fail for many reasons.

Adrian: Yeah, yeah. And it's often those negative studies that they kind of lead you into more understanding and help you to develop a different study that maybe improves upon what was already studied already. So not necessarily a bad thing, isn't it?

Michael: Although if you muck up the design of a study and you end up with a negative study and that's a false negative, it can pour enough cold water in the field that nobody goes back there again because...

Adrian: Yeah, exactly.

Michael:'s hard to get funding for a study when somebody says that somebody else has published on this and it was convincingly negative.

Adrian: Now, I just want to just go back just a little bit because you mentioned obviously, there's a relationship between inflammation and mental health, but you can get then people who have, let's say, for example, high levels of cytokines or CRP, and then some will develop depression, others get bipolar disorder or others get schizophrenia. And what's going on there? There's obviously different mechanisms going on, or is it genetics?

Michael: Yeah, absolutely. And some will get...they have heart attacks and some will get diabetes, which are also disorders linked to inflammation. So it's really complicated, and I think there's an interplay between... 
I think it's also important to remember that inflammation is not a disorder-specific thing. So these are ubiquitous pathways involved in regulation of signalling and defence in every bodily system and therefore, are likely to play a role in almost any disease that you care to mention.

Adrian: Yes.

Michael: So, once you conceptualise these inflammatory pathways as ubiquitous, life essential, signalling pathways, then it becomes less reasonable to assume that you're going to find a signal specific to any one disorder. And I think that's what the evidence is now showing.

Adrian: So I know that, obviously, things like inflammation affects your HPA axis activity, and it can impact on neurotransmitter activity, and neurotrophins, and oxidative stress, obviously, yeah, there's that interplay between all those different mechanisms, isn't there?

Michael: Absolutely. And I think one has to accept that the body doesn't really work with one system subserving one function. It's a bit like you can have a limitless number of books written using the same 26 letters of the alphabet.

Adrian: I see.

Michael: So there's a language whereby these complicated systems and processes interact at the tissue-specific level that conveys a message and has a function that is unique to that system. In a different context with other partners in a different relationship, all these signals can have entirely different meanings to a particular tissue.

Adrian: And that's what makes it complicated, doesn't it? I remember initially reading the literature and go, "Oh, wow, inflammation, mental health, that's great. Now, what we need to do is reduce inflammation, and that's going to be the key.” And while that's certainly...

Michael: Everything seems so simple. It isn't.

Adrian: Exactly. All right. So let's...

Michael: And the only thing I'm sure about is that no matter how complicated we think it is, it's much, much more complicated than that.

Adrian: Absolutely. So, let's say, okay, I'm a clinician. I'm seeing somebody with depression. Okay. They're coming into my office, or some other mental health condition, and I'm thinking, "Okay..." Or maybe inflammation has a role. We don't know necessarily whether it's a major role, but inflammation has a role. What am I looking for? Are they particular tests I'm doing? Are they, like you said, particular symptoms?

Michael: I think at this stage of the game, we don't know enough to suggest that a jobbing clinician seeing a real patient should be measuring inflammation and that this should guide treatment. I think it's too early to do so. I would love to be able to say, "Oh, yeah, you should be measuring C reactive protein. And if it's elevated, we should be using an anti-inflammatory strategy, and these are the ones that are evidence-based." I think the field's not there yet. A lot of people are hoping that it'll get there. I'm certainly one of them. But to be honest, I think we are not quite there yet. 

That's not to say clinicians can't think of anti-inflammatory strategy as an augmentation. But given this current state of play, I would say that they're pretty low down the algorithm of lifestyle, psychological, and pharmacological strategies. You would have to fail an awful lot first. I think the science is probably too early.

Adrian: No. All right. Okay. Yeah.

Michael: But saying that, there's an awful lot of people that you and I have seen who have failed 10 treatments already. So, in that group of patients, and they're not a small group, I think a clinician would be justified in using one. So, the place that I think a jobbing clinician could think about an anti-inflammatory strategy would be this kind of scenario. 

So you've got a patient who's got treatment-refractory depression, they've failed a bazillion things. Fair overweight, they're obese, they've got atypical pattern of depression. They smoke, they've got high blood pressure, and they're diabetic, and their cholesterol's not looking so good, you should put them on a statin. So there's already a rationale for cardiovascular prevention proactively because we know that depression is a more potent risk factor for cardiovascular disease than smoking.

Adrian: Wow.

Michael: It's one of the most robust predictors of cardiovascular disease. So if you already have cardiovascular risk factors and your cholesterol's not looking too pretty, let's assume even it's at the margins of should I/shouldn’t I treat, I would argue that because the statins are anti-inflammatory agents, and we know that there's meta-analytic level of evidence that they have modest benefits for depression, you should be prescribing a statin because you've got a conventional justification for the statin plus an added psychiatric possible benefit. 

So that's the one scenario that I think routine prescription of an anti-inflammatory agent would be indicated, understanding that from a psychiatric point of view, statins are anti-inflammatory agents. From a cardiovascular point of view, they're cholesterol reducing agents.

Adrian: Okay. So you're using the statin potentially to treat the cardiovascular disease, and, potentially, it might have mood-enhancing effects. Is that what you're saying?

Michael: Correct. Yes, that's the kind of rationale where I think today we would be in a position to say that in people's depression who have other cardiovascular risk factors, we should be proactively and aggressively using statins because there's substantially increased cardiovascular risk in our patients. That's why people with schizophrenia die 10 years, 15 years younger than the general population. It's a cardiovascular disease. If I had schizophrenia, I would want to take a statin anyway because it's cardiovascular disease that's going to make me die at age 60, not schizophrenia.

Adrian: Okay. Yeah.

Michael: So I think that there's a rationale for aggressive early use of statins in cardiovascular prevention, understanding that there is meta-analytic level of evidence that they have benefit for schizophrenia as well as for depression.

Adrian: Wow. I mean, obviously, for our listeners, it's not just a statin that you'd be suggesting, there'd be all the lifestyle and psychological base interventions that we need to also encourage too.

Michael: Oh, absolutely. I mean, we are focusing on medication in our consultation.

Adrian: Yeah. Absolutely.

Michael: But as a clinical treatment, the statin is not first line. First line is diet exercise smoking cessation, all the lifestyle stuff. If you look at the most recent Australian College guidelines, that is now, to use their wording, a non-negotiable first line, which is quite remarkable. 

Adrian: Yes.

Michael: It's a massive change in the way we are thinking about this because there's evidence that individually, exercise is a useful antidepressant agent. Smoking cessation helps mental health. Diet modification has evidence of having antidepressant efficacy. So, if you bundle that lot together, together with the health benefits for all the highly comorbid and disproportionately more common medical conditions that plague our patients, diabetes, cardiovascular disease, stroke. Lifestyle is critical for all of the above.

Adrian: So you've got your statins, and obviously, you've mentioned the lifestyle, which is integral and should be the initial part. There's also, you’ve done some work around other medications like aspirin and minocycline and antidepressants too?

Michael: Yeah. Absolutely. Yeah.

Adrian: What's the evidence showing around that?

Michael: These are really complicated agents, and they're all very different. So minocycline is work led by Olivia Dean. And minocycline is an old antibiotic. It's a tetracycline antibiotic. But minocycline is complicated because it has many effects, one of which is anti-inflammatory. But it also has very robust effects on neurogenesis. So it's one of the agents that is the most potent triggers of new neuronal growth and development. So all of a sudden, minocycline is looking like a very interesting potentially anti-inflammatory agent. 

We did work with aspirin, and came to a very different conclusion. What attracted us to aspirin is 100 milligrams of aspirin, baby aspirin, is thought of as being very well tolerated and is understood to have many additional health benefits. So, when I heard that there was a study being planned to look at aspirin as the preventive agent in the elderly, the so-called ASPREE study led by John McNeil. We were very keen to add on depression as an endpoint, and we were lucky enough to get the grant-funded to do so. To cut a very long story short, aspirin failed to display benefit for any of the medical outcomes that they were interested in from all cause mortality to cardiovascular death, to dementia. And for depression, we were initially interested in aspirin as a preventive strategy. The reason being this was an otherwise healthy group, and we wanted to see whether aspirin prevented depression. And it spectacularly failed to do so that the lines were completely superimposed. It had no benefit whatsoever in the prevention of depression.

Adrian: Wow.

Michael: But then, because the sample size was 19,114, it was at the time the biggest study ever done in psychiatry. There were enough people or just under 2,000 who were depressed at baseline.

Adrian: Yes.

Michael: And so, we thought maybe aspirin treats these people. And not only did it not treat those people, but they actually did worse.

Adrian: Wow.

Michael: Which really made us scratch our heads to think why the hell might aspirin be doing this. And paradoxically, this cycles back to inflammation because our hypothesis, and we don't have good evidence to prove this, is that what aspirin was doing was what it's known to do as a side effect, is that it irritates the gut and it increases permeability of the gut.

Adrian: Yeah.

Michael: And by increasing permeability, it allows translocation of lipopolysaccharide and other bacterial products into the circulation. And it might actually drive inflammation.

Adrian: Wow.

Michael: That's what we suspect might be happening, but we don't know whether that's happening. But either way, low dose aspirin is pretty much dead in the water as a therapy for depression after that study.

Adrian: And so what about pharmaceutical antidepressants, selective serotonin reuptake inhibitors and other antidepressants? Do they have anti-inflammatory effects?

Michael: Yes, they do. So there's quite a lot of evidence, prepost administration suggesting that conventional SSRIs reduced circulating anti-inflammatory levels. What's not 100% clear to me is whether this is the direct effect of the SSRIs themselves, or whether this is a state-dependent marker, such that you have more inflammation in the depressive phase than in the euthymic phase. And the transition from depression to euthymia is lowering inflammatory markers. I'm not completely clear of that.

Adrian: So is there research showing that people who improve in mood, do they also have a reduction in inflammation, or is the evidence not…?

Michael: Yeah, they do.

Adrian: They do.

Michael: The best evidence comes from studies of electroconvulsive therapy because there is no medications involved.

Adrian: Yep.

Michael: So, if you give somebody ECT and their mood improves, inflammation goes down.

Adrian: Okay. Wow.

Michael: Which is really interesting.

Adrian: Okay. And so if the inflammation doesn't go down, does that mean that they're more likely to be treatment-resistant?

Michael: Well, inflammation is associated with treatment resistance, generally...

Adrian: Okay. Yeah.

Michael: ...but not in the... I don't know that that's ever been shown in the context of ECT.

Adrian: Okay. So, just to recap some of the things you've...before we move into some of the treatments. But just to recap some of the things that you've mentioned, there's certainly a relationship between inflammation and depression. Not everybody with depression or mental health disturbances have inflammation, but you mentioned maybe around the research indicates around 50% of people who have some form of elevated inflammation. 

And then you mentioned that if we are looking at people who are more likely to have inflammation, they've got maybe lifestyle-based obesity and maybe poor sleep and things like that. You mentioned also that they are more likely to have atypical depression. So, can you just recap atypical depression? What are the symptoms of atypical depression?

Michael: So, atypical depression... Well, let me start with talking about what typical depression is.

Adrian: Yeah.

Michael: So typical depression is you can't sleep, you can't eat. So you either got classical sleep disturbances midterm. You wake up in the middle of the night, and you're waking up much earlier than normal and can't get back to sleep, and loss of appetite, loss of weight. So that's typical or melancholic pattern depression. 

Atypical is the opposite. So atypical depression, historically, was defined as having four symptoms. They included increased appetite, increased sleep, rejection sensitivity, and marked fatigue. Some people call this “lead and paralysis.” Some people just felt completely exhausted and could not move. So that's atypical depression. Interestingly, there's a signal that atypical depression might be more common as a phenotype of bipolar than unipolar depression. I don't know that anybody has systematically studied this and certainly studied anti-inflammatory strategies differentially across the two. But that is an interesting differentiation.

Adrian: Wow. Okay. So, obviously, anybody then presenting with that atypical depression, which is quite common, isn't it? It's not quite atypical...

Michael: It's not common at all.

Adrian: Yeah. So, yeah.

Michael: It's one of the problems with atypical depression, right? It's ignored and missed, and people don't pay attention to it. And the reason being that our conventional rating skills for depression, like the Montgomery and the Hamilton have no items for atypical depression. So they don't measure it.

Adrian: Wow.

Michael: The people ignore it. It's the usual story. If you don't measure it, nobody does anything about it. So one of the things we did many moons ago is develop a... Particularly because it's more of an issue for bipolar disorder, atypical symptoms, the first person who really drew much attention to this was Phil Mitchell. And he writes about the bipolar signature, which includes a lot of atypical symptoms. And so we developed a specific rating scale called the Bipolar Depression Rating Scale, which measures atypical symptoms because most rating scales don't.

Adrian: And so can people get access to that rating scale?

Michael: Oh, yeah. It's on the web. It's free.

Adrian: Okay. So just type in bipolar rating scale.

Michael: Bipolar Depression Rating Scale.

Adrian: Okay. All right. So a good tool to potentially use in practice if people want to assess that.

Michael: Yeah. Yeah, for sure.

Adrian: Okay. All right. I'll just touch on this, but I know that you also have done a lot of work on oxidative stress and mitochondrial dysfunction and mental health. They obviously are the potential drivers of mood disorders?

Michael: Absolutely, and they're not disconnected. So, for example, oxidative stress is tightly interconnected with inflammation. The drivers of inflammation and the drivers of oxidative stress are very similar, and both interact very tightly with mitochondrial function. High levels of inflammation are amongst the most potent suppresses of mitochondrial function. And in a way, that is nature working because if you have an infection, the body needs to quarantine all its energy for fighting the inflammation. And if you're using that energy running marathons, you're going to die. So nature evolved to shut down mitochondrial energy generation if you've got high levels of systemic inflammation. 

The consequence in an inflammatory disorder like depression is you then have persistent rate inflammation and you then have persistently suppressed mitochondrial function. And that leads to all kinds of other problems, not only the symptoms like fatigue, but it also then ties into other medical disorders where mitochondrial functioning is critical, like diabetes or cardiovascular disease.

Adrian: So that's got me thinking a little bit. If we go out and go, "Okay, let's give a whole bunch of anti-inflammatories because we think inflammation's going on," and that potentially reduces the inflammation, and we're not treating the drivers of the inflammation. We might then be reducing inflammation and doing more harm than good because the inflammation's in there as an adaptive response. There's something going on, either lifestyle-wise or biologically-wise that we really need to identify and treat. And if we just reduce inflammation by giving all these anti-inflammatories, we might potentially be doing more harm than good.

Michael: Well, that's possible. It's an entirely plausible thought. However, there are many examples where even though it's physiological, there's clinical benefit in doing so. So we give people who've got infections Panadol because it reduces symptoms and people feel better and there's no deleterious consequences. But you are right in as much as, if the inflammation is coming from physical inactivity, smoking, obesity, poor diet, inflammatory diet, then, yes, you'd imagine that the deleterious effects of those lifestyle behaviours may well not be compensated by simply taking a pill.

Adrian: Yeah. Then that's really where that personalised care comes into place. We obviously need to really do good assessments and really go, "Okay, well, what's going on for this individual? Whether inflammation's going on or not, what are the potential drivers of this person's low mood? Is it poor sleep? Is it physical inactivity? Is it diet related?" And we really need to kind of target those areas, don't we?

Michael: Absolutely. Which is why I agree with the College Guidelines that lifestyle modification should be routine in the work that we do. And it doesn't have to be dramatic or overly comprehensive. If you can convey to people, just the advice that, “You know, Mr. Smith, your smoking might be contributing to your depression, and there's good evidence that quitting smoking is going to improve your mental health. So, instead of thinking about smoking in the two hard basket, you should be thinking about smoking as low-hanging fruit and really trying to quit.” And there was a misperception many moons back that people with psychiatric disorders are less likely to quit. That is not the case. So we need to be doing this and we need to be giving that kind of routine counselling, similarly around physical activities, similarly around diet.

Adrian: Yeah.

Michael: And the rules around diet don't have to be complicated. They can be really simple.

Adrian: Certainly. And then obviously when they're feeling depressed, and motivated, and fatigued, complicating it can make them feel worse potentially. So we really need to be aware of where they're at and ensure that the treatment recommendations we offer are reasonable for them. 

I'll just also go back. You mentioned smoking. This is what I was alluding to before was like you got somebody smoking and they go, "Mr Smith, you're smoking. So, therefore, we know that they can cause oxidative stress. So here is a whole bunch of antioxidants to combat your smoking, the damaging effects of your smoking." We really got to be careful about doing that, don't we?

Michael: Well, I think there's almost no evidence that that kind of strategy is helpful.

Adrian: Yeah, exactly. Are you able to kind of tell me...? I know you've done a lot on N-acetylcysteine. Can you tell me a bit about the NAC, the N-acetylcysteine work that you've done and what the research is saying about that?

Michael: Well, we came to N-acetylcysteine, we were working with Ashley Bush at the Flory at the time, and a paper came out by Kim Do from Lausanne in Switzerland, which said that people with schizophrenia had dramatically lowered levels of glutathione in their brains. The glutathione is the brain's major antioxidant, and N-acetylcysteine is the juice that replenishes glutathione. So we thought, "Well, there’s a simple solution to a complex problem. Let's give him NAC." And we did a trial in schizophrenia, and we showed significant but modest benefits in schizophrenia, particularly negative symptoms. But it took an awful long time for that to work. So it was really only significant at the six-month time point.

Adrian: Okay.

Michael: And since then, a number of studies have come out, some of them negative, some of them positive. But reassuringly, more recent meta-analyses of just over half a dozen studies are out there suggest that it is effective. And just yesterday, a Network meta-analysis came out of nutraceuticals for schizophrenia suggesting that NAC was the most effective nutraceutical for the treatment of schizophrenia, which is kind of heartening. I also have to say a caveat with NAC that it is very slow to work. We are looking at six months before you really notice anything. And the effect sizes are modest.

Adrian: Yeah.

Michael: It's no Clozapine, it's not going to take somebody something... It's not a cure but in people with significant schizophrenia, particularly negative symptoms, it does offer modest benefits. But that's better than you get for most other therapies, which do not work, particularly for negative symptoms. There really no good treatments for negative symptoms. So I still think it's useful to the field.

Adrian: What was the dosage that you used for NAC?

Michael: So we use 2 grams a day. Other studies have gone up a bit. Some have used 3, some have used 2.4, but that's kind of the ballpark where most people are sitting there.

Adrian: So NAC, potentially, for schizophrenia, what's the research say around depression and bipolar?

Michael: So, again, there are now about a half a dozen studies of bipolar disorder as well. Some of those studies... Our initial study was quite robustly positive. More recent studies, including studies we've been involved in have not been positive. But meta-analysis have been variable. So depending on which studies you put in and how you do your math, they are positive and now negative meta-analyses. So the story of bipolar depression is probably a little bit more uncertain. But again, probably you get modest benefit, and, again, probably with extended periods of treatment. But the bipolar story is a little bit more uncertain than the schizophrenia story.

Adrian: Okay. All right. So it certainly needs to be used on a… If it's going to work, it seems like it needs to be on a longer-term basis and around that 2 gram level.

Michael: Two grams. And the advice is you don't look at the speedometer until you've hit six months.

Adrian: Oh, okay.

Michael: You really can't assess for an awful long time.

Adrian: Does it impact on the manic phase or is it more the depressive symptoms?

Michael: Nobody's done a trial in mania.

Adrian: Oh, yeah.

Michael: So, in our original depression study, we've done subgroup analysis, post-hoc, at manic symptoms. And at least post-hoc, there was a reduction in YMRS scores, the paper by Pedro Magalhães. But nobody's looked at Mania that I'm aware of.

Adrian: And I know NAC, there was studies initially with OCD, wasn't there with NAC, with obsessive-compulsive disorder?

Michael: So there are a number of studies in OCD. One of them was led by Jerome Sarris and colleagues at The Melbourne Clinic. But there are half a dozen OCD studies. And the picture is really similar, in as much as that there's a modest benefit, interestingly, in obsessions, not compulsions. And that's useful because behaviour therapy targets compulsions, not obsessions.

Adrian: Absolutely. Wow, yeah.

Michael: But again, the benefits, if they are there, because the data is soft, are relatively modest. But the advantage that NAC has is its tolerability and safety appears to be pretty good.

Adrian: Yeah, it'd be interesting to look at NAC as adjunct to response prevention therapy or psychological therapy. That'd be interesting to see whether it adds anything.

Michael: Oh, absolutely. There's so many things one could look at.

Adrian: Yeah, absolutely. What the research then, and our clinical experience indicates that really we need to really look at what factors are driving a person's mental health disturbances, and obviously lifestyle-based factors, and sleep hygiene, and diets, and exercise, and obviously social connections, and being outside in nature, I mean, they are the things that really we need to be targeting.

Michael: Oh, absolutely. That's a really biggie.

Adrian: Yeah. And they're the things that I think we're definitely going to get some benefit there with our clients if we really target those areas, for sure. 

So, Michael, thank you very much for joining us today to talk about inflammation and how it affects mental health. It's really no wonder that so many of these disorders are on the rise, but at least we have people like you out there doing the important research of lifestyle, dietary, and nutraceutical options that can be employed to lower inflammation and possibly improve mental health. Today, you provided us with lots of great information about treatment options that our listeners will definitely appreciate. So thank you for all of that and allocating some time today to be with us today.

Michael: Absolute pleasure, Adrian. Thanks for chatting.

Adrian: And thanks, everyone, for listening today. Don't forget that you can find all the show notes, transcripts, and other resources from today's episode on the FX Medicine website. I'm Dr. Adrian Lopresti, and thanks for joining us. We'll see you next time.

About Professor Michael Berk

Michael Berk is an NHMRC Senior Principal Research Fellow, and is Alfred Deakin Chair of Psychiatry at Deakin University and Barwon Health, where he heads IMPACT, the Institute for Mental and Physical Health and Clinical Translation. On the bibliometric resource expertscape, he is ranked #1 in psychiatry globally, and in both depression and bipolar disorder, he is ranked 2nd globally and 1st in Australia. Nationally, between 2014-2019, CIA Berk was the top ranked author in citations in Australia for the FOR codes Psychology and Cognitive Sciences (SciVal) and 11th globally. He is past president of the International Society for Bipolar Disorders and the Australasian Society for Bipolar and Depressive Disorders. He is listed by Thompson Reuters as amongst the world’s most influential scientific minds (2015-2019), was awarded the Brain & Behaviour (NARSAD) Colvin Award for Mood Disorders in 2015, and Victoria Prize for Life Sciences in 2019 and the International Society for Bipolar Disorders Bob Post award for mentorship in 2020. He holds grants from the National Institutes of Health (US), Simon Autism Foundation, NHMRC CRE and Project Grants, Beyondblue, ARC Hub and Stanley Medical Research Institute and was a lead investigator in a Collaborative Research Centre. He generated $79M in total funding. His major interests are in the discovery and implementation of novel therapies.


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Dr Adrian Lopresti

Dr. Adrian Lopresti is a Clinical Psychologist in private practice and senior researcher at Murdoch University, Western Australia. He has over 20 years of clinical experience working with children and adults suffering from a range of mental health conditions.

Dr. Lopresti has experience in a range of psychological therapies and has received extensive training in nutritional and lifestyle treatments for mental-health disorders. Dr. Lopresti regularly publishes in peer-reviewed and high-impact journals on the effects of diet, nutraceuticals, sleep, and exercise for the treatment and prevention of depression, anxiety, attention deficit hyperactivity disorder (ADHD), and bipolar disorder. He has completed several clinical trials investigating the effects of curcumin, saffron, and ashwagandha for the treatment of anxiety and depression in children and adults. Dr. Lopresti is also the founder of Personalised Integrative Therapy, and regularly conducts educational workshops both nationally and internationally.