A book review with some notes on my recent research, part I
I have stated before that I believe that the field of psychiatry may be more advanced in the approach of neuroinflammation as an underlying pathway to certain types of depression, than the field of neurodegenerative diseases. I might just be looking at the right places, but I believe I am seeing the first signs now of articles on chronic neuroinflammation and microglial activity in neurodegenerative diseases targeting a larger audience, so things may finally be changing. I am not yet seeing much convergence between ideas of academy in both fields, psychiatry on the one side and neurodegenerative diseases on the other side. But I am seeing some, and this includes Prof. Ed Bullmore’s book that I will review below and in an upcoming blog, Prof. Karl Herrup and his book ‘How not to study a disease’ which I will review later.
In the latest interview by Braun Capital, INmune’s CJ Barnum mentioned (as of min. 31) that he met world-renowned Prof. psychiatrist and behavioral sciences Andrew Miller at Emory University. Prof. Miller was in charge of the study on infliximab which showed benefit in depressed patients with evidence of inflammation based on measure of CRP (C-reactive protein), which I have covered here. His colleague Jennifer Felger has further discovered where in the brain these abnormalities occurred, including with imaging studies. This accessible page on the site of Emory University covers that research well, and a quote is below: “In patients with high CRP, Felger and her colleagues observed a lack of connectivity between the ventromedial prefrontal cortex and the ventral striatum. In contrast, patients with low CRP had robust connectivity, they write.” (link to full study here). Further confirmatory research on the link between high levels of CRP and efficacy of infliximab, a non-selective TNF inhibitor, was published by the both of them in 2021.
CJ Barnum adds that, when the National Institute of Health saw this grant request…well, as always, CJ says it better:
“When the time was right, we wrote a grant to the national institute of health who has really cracked down on drug development clinical trials because they've funded all these studies in psychiatry, and they've never learned anything. The drugs don't work, and they don't learn anything about biology. So they've really changed the way they do it, and they were only funding studies that if the drug doesn't work, you know a rationale for a target in the brain, and you're really going to be specific about. And, by the way, I didn't write this, I wrote it with them. The program officer said to me this is the best grant we've ever seen in our entire lives. We're really excited, you nailed exactly what we're looking for, your rationale is very strong, and we'd like to fund it.”
The Inflamed Mind, A Radical New Approach to Depression, by Prof. Ed Bullmore
And so it is from the field of psychiatry, already in 2018, that we got to see another excellence in the field of psychiatry, with +500 publications behind him, write a version of the state of the science which has been adapted for a larger audience, in the form of the afore-mentioned book. The book has been written on the old continent, and insofar as I understand, fully separate from the developments of INmune Bio, which were taking place on the new continent at the same time. I consider it a must read, and my blogs will not do it justice, so I would advise any investor here to take a look at it; the similarities with INMB’s approach are mind-blowing at times. Let's dive into it.
The shift to a new paradigm
In psychiatry, first successful drugs saw the light in the early nineties, with Prozac as the first one, and many others ensued. All these drugs essentially have similar mechanisms, in that they tweak serotonin levels. Apparently those drugs can’t treat every type of depression, as this disease is ever-expanding and is set to become the world’s leading cause of disability in 2030. One would need to take a different view, which came from the relationship between arthritis and depression and temporary, even local, inflammation and mood disorder. Taking it further, dozens of human reports and hundreds of animal studies have come out reporting a link between childhood adversity and inflammation, and inflammation being able to anticipate depression or depressive behaviors in later life. Under the influence of cytokines, nerve cells show less regeneration and are more prone to die. In an inflamed state, synapses are less able to learn, and inflammation reduces serotonin levels, with serotonin being a neurotransmitter. Add to that, patients who show signs of inflammation are less likely to respond well to treatment with traditional anti-depressants.
In a compelling forty pages, Prof. Bullmore mentions how the body’s immune system responds to infections and harm, what the underlying mechanism behind auto-immune diseases is, and how these numerous links between different diseases where bodily inflammation plays a major role but even going as far as coronary disease, HIV, cancer, stroke, or chronic bronchitis, somehow coincide with higher incidence of mental health issues, often leading to depression. And the doctor, or usual psychiatrist, often just doesn't focus on it when he hears that.
Note: So here we are, many years later, and in spite of the abundant amount of companies that are involved in trying to take psychedelic substances to the clinic, which I’ve reviewed finding none of them compelling, there is still not one drug that act on the immune system for the treatment of depression.
And so, Prof. Bullmore wrote in 2018 that he believes the dualist way of thinking about the body and the brain will probably pass, with the immune system becoming more central to novel ideas on treatment of depression, and with some decisive moves to come in the next five years or so.
Note: still, I don’t see many drugs in trials focusing on this treatment pathway. There is INmune Bio’s XPro, of course, and Prof. Bullmore leads a 2014-created consortium with GSK and Janssen, called NIMA. Janssen now has two anti-inflammatory drug candidates, P2X7 Antagonists JNJ-54175446 and JNJ-55308942, in trials for respectively depression and bipolar disorder, with these trials expected to end respectively end of 2023 and mid 2024. The drug candidates are brain penetrant P2X7 receptor antagonists. P2X7 is a microglial protein with as downstream function the release of pro-inflammatory cytokines, IL-1β and IL-18 through the recruitment of the NLRP3 inflammasome complex. Sound familiar? More publications here, here and here. They’re just confirmation of stuff I’ve been writing about, if you will; same scientific background, different targeted pathway. P2X7 has also been mentioned as a target for ALS, making the crossover from depression to neurodegenerative diseases complete. So, Janssen’s on board with the good approach, now for the rest of the world. And, yes, before J&J came around, Janssen was Belgian, and it’s still very much Belgian-style, just like me. Onboarding goes fast in this country, historically unencumbered by hierarchy and tradition, only by beers and chocolate 😊.
The link with traditional TNF-inhibitors
When the first drugs to treat arthritis came about in the late nineties, they were a slam-dunk. These were the traditional TNF-inhibitors, blocking both transmembrane and soluble TNF, and supposed to not cross the blood-brain barrier. Still, doctors and nurses reported that when given such drugs, patients cheered up, often rapidly. They called it the Remicade high. However, the Remicade high, even if it became common to speak about, has not yet been taken seriously, even though it could give us insight into how the brain reacts to TNF inhibitors. A similar effect was seen long before, in a tuberculosis drug called iproniazid in the 1950’s.
Note: for me, this is telling. Not only do we now have proof of some effect of traditional TNF inhibitors from the neurodegenerative side, but also from the psychiatric side, and these two have come about independently. Furthermore, they confirm the same; treatment will be effective in patients with signs of inflammation (more about that later). And more, the timeframe in which the drug shows efficacy is remarkably short, and this is consistent in all studies. Add to that, INmune Bio has shown that improvements continue with time, and this may in my humble opinion perhaps not hold true for non-selective TNF inhibitors or other drugs which may be immunosuppressive in the longer term.
Prozac’s aftermath and the lack of biomarkers
Back to Prozac, the first SSRI (selective serotonin reuptake inhibitor) and its aftermath. Prof. Bullmore sees the generation of drugs that came after Prozac this way:
“But, in the perfect light of hindsight, the launch of Prozac was the blazing sunset, not the dawn, of the golden age of anti-depressants. In the 30 years following the seminal and surprising observation that an antibiotic caused outbreaks of dancing in a TB sanatorium, industrial and academic researchers collectively produced many new drugs, and many new theories about how they worked. In the 30 years following Prozac, the field has not flourished but fizzled out.”
And why is that, in Prof. Bullmore's view? Because the scientific field did not take into account biomarkers, even though in most areas of medicine, practitioners are using biomarkers all the time, as measurements of biological or biochemical function in patients. Logic would command that the use of SSRI’s would be appropriate when measurements would show low levels of serotonin in the brain, and see how such levels would evolve weeks after first treatment, but either the diagnostic is too complex and expensive, or methods have been explored in research but have not been pursued in practice. And so, psychiatry continues to proceed by trial and error.
From the slowly-developing side of neuro-immunology, scientists have started to see a relationship between measurements of C-reactive protein and cytokines on the one hand and depressive behavior on the other hand. A relationship that perhaps isn’t always so strong, but still clearly there. One of the largest studies was done in Sweden, showing that the higher the dose of inflammation indicated by CRP, the greater the depressive response, with the chances that this relationship would be based on luck being assessed as less than one in a trillion. Then in 2014, an English study of 15,000 children showed that cytokine levels at the age of nine predicted risk of depression at the age of 18. Similar studies have been reported.
And in hepatitis B, a disease causing inflammation and damage to the liver for which treatment with interferon, an inflammatory cytokine, was prescribed, patients started becoming feverish, lethargic and anorexic immediately post treatment, with most patients recovering from the acute effects of interferon but a third of them becoming clinically depressed.
Note: Severe COVID is equivalent to 20 years of ageing – new study. Of course the article states, as so often, that the reasons behind this finding are unknown, but that it may be related to the immune system. In my humble opinion, since Covid, there is an even more pressing need to get drugs targeting the brain’s immune response to market in the correct way.
Microglia, and mens sana in corpore sano
How does this happen? Simply stated, the brain is not immune-privileged, there is free and easy connection between both body and brain. Prof. Bullmore puts it like this:
“What we know now (right) is that there are many channels of communication across the BBB. Inflammation of the body can cause activation of the inflammatory microglial cells in the brain, which in turn causes collateral damage to nerve cells in the amygdala, the cingulate and other hubs in the brain’s emotional network.”
Time and again, these microglia. Prof. Bullmore makes the comparison between macrophages as the resident immune cells in the body, and microglia as the resident immune cells in the brain. When these cells pick up inflammatory signals from the body in response to an insult, they start releasing cytokines themselves. Doing that, and certainly for prolonged periods of time, can kill nerve cells, hamper the neuroregenerative process, and make nerve cells less plastic. Synaptic plasticity has been considered important for learning and memory.
The link between microglial activation and serotonin levels
Not only does Prof. Bullmore establish a link between inflammation, microglial activation and cognition, but also between microglial activation and serotonin levels. Microglial activation may lead to loss of good synaptic transmitter signaling, especially for serotonin. Nerve cells make serotonin from tryptophan, but the overactivated microglial cells can instruct nerve cells to make other end-products, such as kynurenine, possibly interrupting normal serotonin signaling, and additionally kynurenine is toxic. Overactivation of nerve cells exhausts their metabolism and leads to nerve cell death.
“The net effect of microglial activation is that serotonin signaling is disabled and usurped.”
This mechanism could explain why patients with signs of inflammation, and therefore with overactivated microglia leading to lack of serotonin release in the synapses, respond badly to SSRI’s or other anti-depressants. And conversely, it could explain why treatment-resistant depressed patients are particularly likely to be inflamed.
Note: on June 6, 2022, that’s three days ago, a good article came about that was entitled ‘Microglia in depression: an overview of microglia in the pathogenesis and treatment of depression’.
In it, the authors further elucidate the pathways underlying microglial activation and leading to depression, and have also included two lists of anti-depressants and plant-derived compounds/formulations regulating microglia-regulated neuroinflammation. This includes SSRIs, tricyclic antidepressants (TCAs), other compounds such as minocycline, melation, FCPR16, pioglitazone, iptakalim, and caffeine, but on the natural side also flavonoids, ginsenosides (from ginseng), iridoid glycosides (from Rhadix rehmannnia – Chinese medicinal plant) and arctigenin (Chinese fruit with alleged medicinal properties). For example, treatment with SSRI’s saw decreases in microglial marker Iba-1, downregulation of pro-inflammatory factors (IL-1β, TNF-α, and NO), and upregulation of anti-inflammatory factors (IL-4, IL-10, Arg-1, and TGF-β1). Similar effects were seen in tricyclic antidepressants, but not in citalopram.
It comes as no surprise to me that there is such interplay, through the own mechanisms of action of these anti-depressants.
That’s it for part I. I’ve tried to keep it condense, hope you can appreciate that, and I hope you see the links with INMB's science and efforts like I did. The second part should follow soon.