Watch out! Got inflammation? The it's aggressive meds for you!

[ebethc]

My hunch is that it may depend on which areas of the brain have inflammation / immune activation. The nature of the mental symptoms will likely depend on which brain areas are involved.

yep... it's complex... some mycotoxins cross the blood brain barrier (trich.)... I've been reading about microglia lately.. just starting... I have a lot to learn

 

[Skippa]

Well looking at Professor Carmine Pariante's list of publications, these papers mostly seem to be trying to link mental symptoms with physiological correlates such as inflammation, reactive oxygen species, HPA axis dysfunction, immune system genes, and so forth. I don't see any psychosomatic models there (apart from the stress stuff, but that's the side of psychosomatic research I think is valid).

For example, this paper by Pariante:
Are mood and anxiety disorders inflammatory diseases? - Research Portal, King's College, London

Professor Pariante is head of the King's College Stress, Psychiatry and Immunology Laboratory.

This is a different research group to the King's College NIHR Biomedical Research Centre, where you find Wessely School members Simon Wessely, Trudie Chalder, Anthony Cleare and Anthony David.





I should think it does not matter that much whether the neuroinflammation its initiated within the CNS, or whether the source of the neuroinflammation is further afield in the body: provided the source somehow causes inflammation in the brain, you might expect neuroinflammation-associated mental symptoms such as depression to arise.

It is now known that infection / inflammation in the body peripheries such as the gut can trigger neuroinflammation in the brain, by signals transmitted along the vagus nerve (and via other routes). This may explain why, for example in irritable bowel syndrome you can experience anxiety and depression: the inflammation in the gut may be triggering inflammation in the brain by a vagus nerve mechanism.

I sudden got significant and chronic anxiety symptoms after developing IBS, which did not make sense to me at the time, but now knowing about the vagus nerve connection from gut to brain, the pieces start to fall into place.


The source of inflammation I should think is important in terms of treatment, though: if a large component of your brain inflammation-induced anxiety or depression actually derives from the gut, then you may be better off treating the gut rather than the brain.

I found that supplements like prebiotics and probiotics which reduce gut inflammation significantly reduced my IBS-associated anxiety.

But therein lies the problem (re vagus nerve stuff). The psyche crowd (and by extension GPs) have previously, and continue to, treat it the other way around... that a 'disease' called anxiety or depression CAUSES problems in the gut. It's looking more and more likely that poor gut health (flora and fauna et al) are causing problems including anxiety and depression as symptoms, but they STILL hand out SSRI's by the bucket load for IBS hoping that treating the psyche disorder will cure the gut.

I worry that all this new research you point out won't lead to things like IBS or other inflammatory diseases being treated as physiological, but somehow through twisted logic will strengthen the resolve of psychos and GPs to treat as mental, with 'new' physiological evidence to back them up.

 

[A.B.]

Well looking at Professor Carmine Pariante's list of publications, these papers mostly seem to be trying to link mental symptoms with physiological correlates such as inflammation, reactive oxygen species, HPA axis dysfunction, immune system genes, and so forth. I don't see any psychosomatic models there (apart from the stress stuff, but that's the side of psychosomatic research I think is valid).

I can't get a copy of that paper but the list of publications looks like the stuff you would expect. Attempts to make-believe that psychological factors cause inflammation, and no discussion about alternative explanations. In other words: working backwards from a conclusion! Where is the discussion on autoimmunity, immune system dysregulation, infection, etc?

 

[Dichotohmy]

These TRD diagnosed patients eventually find themselves abandoned by psychiatry, because none of the psychiatric treatments work. Medical doctors won't try to help them either, because they are diagnosed psych patients.

A TRD diagnosis means long term abandonment by the medical system with no treatment. It's appalling.

This is one of the big reasons I won't take a depression diagnosis. I have already trialed and not responded to over 5 antidepressants from 3 or more drug classes, without a depression diagnosis mind you. By the basis of that drug failure, I would quite possibly be diagnosed as treatment resistant depression.

I agree with pretty much everything you say here, @Dichotohmy. Except that I feel calling it neuro-inflammation begs the question. Its inflammation, pure and simple. Makes people feel tired and yuk. Looks to a doctor like depression (and maybe even feels a bit like that). Whether than inflammation is initiated within the CNS, I haven't yet seen any convincing evidence..

I agree, the term neuroinflammation is kind of too specific and is maybe not the best terminology.
Psychiatric disorders can be caused by an immune response outside the CNS, like the gut, after all.

My understanding is that the association between neuroinflammation and psychiatric diseases has only come to light in recent years. For example, this 2015 article talks of:

However, I don't know how well the studies on this cortisol resistance were conducted, so don't know how valid this finding is.

The link has been around since at least the late 80s and 90s. There has been a lot more research on cytokines and immunity in relation to psychiatric disorders in the last 10 years or so, though. Still, the research hasn't really gained traction or changed the medical world much as can be seen in how psychiatric disorders are usually treated today. Here's just one paper (an abstract) from 1995 for example.

http://www.sciencedirect.com/science/article/pii/027858469400101M

 

[wastwater]

I have mostly been refused the depression label by psychiatrists even though ive trialled every modern antidepressant over 21 years and still take them,so maybe it isn't depression.

 

[Hip]

But therein lies the problem (re vagus nerve stuff). The psyche crowd (and by extension GPs) have previously, and continue to, treat it the other way around... that a 'disease' called anxiety or depression CAUSES problems in the gut. It's looking more and more likely that poor gut health (flora and fauna et al) are causing problems including anxiety and depression as symptoms.

I totally agree. It's looking much more like gut abnormalities in conditions such as IBS are affecting the brain via the vagus nerve and other body-to-brain pathways, thereby giving rise to symptoms such as anxiety and depression, rather than the reverse, where mental symptoms like anxiety cause gut issues.

There are at least four known pathways (the vagus nerve being one of them) by which peripheral infection and inflammation in the body can affect the brain, and trigger neuroinflammation.

I think it is these body-to-brain pathways that are paramount in conditions like IBS-associated anxiety — ie, physical conditions in the body affecting the brain, and then leading to mental symptoms like anxiety — rather than the other way around, where mental symptoms like anxiety trigger physical effects in the body like IBS diarrhea.


Having said that, when I first developed severe IBS-D, for years I had no solid digestion whatsoever, only extremely watery diarrhea (sorry to be graphic). The only treatment I found that returned my digestion back to normal was yoga. I used to do yoga regularly anyway, so I am very familiar with it. What I found was that on the days that I did an hour or so of yoga, my digestion was perfect. On all other days, I just had very watery diarrhea.

So you could argue that the mental relaxation afforded by yoga improved my IBS; however, with yoga it's not really clearcut, since yoga also affects the body, and in particular is known to activate the parasympathetic nervous system; so the benefits of yoga for my IBS might have been mediated purely through its physical effects on the body and parasympathetic activity.

but they STILL hand out SSRI's by the bucket load for IBS hoping that treating the psyche disorder will cure the gut.

Looking at the NHS guidelines for treating IBS, I don't think that is that is the case. Low dose antidepressants are very briefly mentioned, but other factors such as diet, low FODMAP diet, probiotics, exercise, etc are given more emphasis as treatments. In any case, if it has ben found empirically that low dose antidepressants can help IBS, that is a good enough rationale to give them.

Giving antidepressants does not necessarily imply that the cause of IBS is mental or in the brain. The "second brain" in the gut (enteric nervous system), which contains 100 million neurons and is part of the autonomic nervous system, controls peristalsis (the muscle contractions that move food along the intestinal tract). Although there does not seem to be much research in this area, it very likely that antidepressants will also effect the "second brain," and thereby may have benefits for IBS.

As an aside, it's interesting that IBS has been found to be associated with autoantibodies to vinculin.

I would not surprised if all functional disorders turn out to be caused by autoantibodies: in functional disorders, there are major physical symptoms, but very little pathophysiology to be found in the body, which has always been the mystery; but these normally unseen microscopic autoantibodies that can throw a huge spanner in the workings of the body would nicely explain that.

I worry that all this new research you point out won't lead to things like IBS or other inflammatory diseases being treated as physiological, but somehow through twisted logic will strengthen the resolve of psychos and GPs to treat as mental, with 'new' physiological evidence to back them up.

Not with members of this forum shooting down in flames every paper that purports to explain physical symptoms in terms of mental causes!

But I agree, researchers do need to increase the focus on finding physical causes for even purely mental disorders.

 

[Hip]

The link has been around since at least the late 80s and 90s.

I know the idea that mental illness might be an infectious disease goes way back. But the more specific idea that mental illness is caused by inflammation (which may itself derive from a chronic infection) I believe is relatively new.

 

[erin]

I think there are a huge number of factors playing into this. Some scientific, some cultural, some just poor reasoning.

First the science:

1. The brain is so very hard to study. The complexity is extreme, and the tools cannot handle that. Its about the hardest thing we have ever studied in science.

2. The issues cross specialties. Psychiatrists, for example, don't have a sufficient skill set. It takes a team, and a team across disciplines.

3. Because of the difficulty with this research, psychiatry has accepted low grade methodology. For example, if using standards in biomedicine I do not think ANY diagnosis in DSM would survive. The standards are very very low. A lot of psychiatry uses and tolerates very poor study methodology, as exemplified by the PACE trial. They use scientific trappings and claims, and in my view this makes much of it pseudoscience at best.

4. Evidence based approaches fail here because of three main reasons:
A. Evidence based on what diagnosis? If the diagnostic criteria are highly flawed, with poor diagnostic accuracy, then what can be said about studies based on them?
B. There are biases in a lot of psychiatric research, that act to increase the probability of making a positive finding. PACE is loaded with them. When you do a review or meta-analysis using EB methods then you risk reinforcing results due to bias. EBM is designed to minimize biases, that is the goal, but if you allow poor methodology, with entrenched biases, then you risk rubber stamping poor research.
C. Vested interests can distort the research base, and this is more worrying when this is due to funding bias and political support, which ties in with Zombie Science. If there are only 10 RCTs, and they were all funded by a small group of interests, then simply doing a review or meta-analysis will fail due to funding bias. Its a huge problem. Again, methodology counts.

I am not anti-psychiatry. I am indeed anti-bad-psychiatry. Psychiatry could be greatly improved, but as has already been posted on this thread that will not happen fast unless they acknowledge and keep working on the issues.


Cultural factors:

1. Psychiatry has failed to embrace science. They kind of do science, and hence its pseudoscience. We NEED something like psychiatry, its a travesty for poor research standards to be accepted.

2. Science used to proceed on the philosophy of logical positivism. Keep supporting your claims, its up to others to prove you are wrong. Most of science moved on from this in the middle of last century, instead moving to critical rationalism. (For the record, I am a pancritical rationalist, which is related to this.) Critical rationalism basically says that ideas need to be tested, and the better the tests the more sure you can be of the results, but you can never be certain. So methodology is critical, again.

3. Doctors do not, as a generalization, complain nearly enough about poor research. They tolerate it. I think this happens in psych a lot due to lack of confidence, and fear of failure. If they complain of other's poor research methodology, what then of their own methodology?

4. Medical culture suppresses dissent. There is this notion of not doing harm to the profession. There is a long history of ignoring or covering up mistakes.

5. Doctors are given privileged status under law. That has to change. Its abused for too often. Just look at the patients with ME or CFS who have been sectioned against their will. Look at the outcomes.

Just to be clear, in case anyone is thinking I am anti-doctor, my heroes are doctors. Top of that list is Barry Marshall, who almost lost his medical licence because he was a "quack". He later shared the Nobel prize. Most doctors who make my list have either had additional education, or worked hard to expand beyond traditional medical roles. Many are researchers.


Low standards of reasoning:

1. Much of medical reasoning is heuristic, designed for fast approximate answers. Time is often critical, either due to a medical crisis or due to insurance or bureaucratic demands. Such reasoning is fast, but its subject to serious flaws. Those flaws are often difficult to see. This kind of thing has been most investigated in economics, but I think it applies in many disciplines.

2. Doctors are not adequately trained in logical reasoning. They fail to see fallacies. Medicine has heavily embraced the dogma and fallacy known as Appeal to Authority. The PACE trial, especially when you consider not just the papers but press releases and interviews, is a morass of so many layered fallacies that I wanted to write a book on it. Maybe my health will improve and I will finish one day.

3. Most doctors do not adequately understand statistics. According to Gigerenzer that is about 80%+ in the USA.

4. Many doctors do not understand the reasoning behind EBM. RCTs are not actually the gold standard, you have to add a string of caveats. Anecdotal evidence is still evidence. Etcetera. Understanding why certain things are done in EBM tells you how the rules should be applied, and also when they do not apply.

5. As a special case of my comment on EBM, bureaucratic and insurance authorities misapply evidence based findings. Those findings are generalizations, and they limit the options of both doctors and patients if applied dogmatically. Even if some guideline (and they call them guidelines but sometimes treat them as hard rules) is 95% useful, then that still means that one in twenty patients will be poorly served by them. Doctors need the flexibility, training and resources to adapt to patients who do not fit the neat pigeonholes. We see that in the ME and CFS community a lot. Doctors are being trained to be inflexible. The bureaucrats want inflexible doctors.


I may no longer be capable of writing my book right now, but I can still give you some pieces of my analysis along the way.

Thanks for the very good analysis. The flows of the medical system is just like the other systems as usual. They become the reason to exist themselves, forgetting the real reason, i.e. in case of the medicine to heal the ill. Maybe they just don't want to do it. Maybe this is population control. I am not saying that every worker in the medical system is consciously aware and working towards it. But it is organized in a v

 

[Woolie]

I'm wondering if this second group has a whole host of other symptoms but only the mood ones are being reported or taken notice of.

I looked into this, @ukxmrv. I found this paper that said:

Associations between inflammatory markers and individual depressive symptoms such as fatigue, cognitive dysfunction, and impaired sleep have also been described (7, 8 and 9).

Notice how the depressive symptoms are not really depressive symptoms at all, not related to the core psychological construct, just correlates that we've come to treat as central symptoms.

I looked at papers 7, 8 and 9 mentioned above.

Paper 7 doesn't look at depression at all. It examines a sample of cancer patients and finds that increases in certain inflammatory cytokines etc. are associated with higher self-reported fatigue.

Paper 8 set out to find that the presence of markers of inflammation was related to depression. They used a sample of patients with major depression. They found that inflammation was associated only with sleep disturbance, not with the central, psychological features of depression itself.

Paper 9 also examined cancer patients. They found that the presence of certain inflammatory cytokines was associated with greater self-reported fatigue, but was not associated with depression scores on a self-report measure.

So there's not much evidence yet that chronic inflammation causes depression, not as we normally understand the word - persistent low mood, loss of hope, pleasure, self-esteem. (Acute inflammation might lower your mood, but we still don't know about not chronic depression). Chronic inflammation seems to influence the degree to which other, ancillary symptoms are present.

 

[alex3619]

So there's not much evidence yet that chronic inflammation causes depression, not as we normally understand the word - persistent low mood, loss of hope, pleasure, self-esteem. (Acute inflammation might lower your mood, but we still don't know about not chronic depression). Chronic inflammation seems to influence the degree to which other, ancillary symptoms are present.

Depression remains a mystery, as does fatigue and pain. I think depression, like fatigue and pain, covers a wide range of physiological mechanims, and as such is always a highly heterogeneous cohort unless additional restrictions are applied, such as in post-cancer patients.

 

[Hip]

So there's not much evidence yet that chronic inflammation causes depression, not as we normally understand the word - persistent low mood, loss of hope, pleasure, self-esteem.

This is a nice paper about the link between inflammation and depression:

From inflammation to sickness and depression: when the immune system subjugates the brain

This paper concludes that:

Taken together, these findings indicate that pro-inflammatory cytokines can cause depression by several mechanisms, including activation of IDO.

Some other excerpts:

In humans, major depressive disorders develop in roughly a third of patients who are treated with the recombinant human cytokines IL-2 and interferon-α (IFN-α). In agreement with these findings, major depressive disorders are more prevalent in patients afflicted with conditions that lead to chronic inflammation (such as cardiovascular diseases, type 2 diabetes and rheumatoid arthritis) than in the general population.

Nearly twenty years ago, when the recom- binant human cytokines IL-2 and IFN-α were first used chronically to boost the immune system to eliminate tumours that resisted chemotherapy and radiotherapy, or to clear hepatitis C virus, clinicians noted the occur- rence of severe neuropsychiatric changes, including major depressive disorders, after treatment onset in a significant percentage of patients

Also in mice, chronic stimulation of the immune system by inoculation with an attenuated form of Mycobacterium bovis induces a sustained elevation in circulating levels of IFN-γ and a chronic activation of IDO. Both of these events are associated with depression-like behaviour.

The prevalence of co-morbid depression in patients with coronary heart disease, a disease in which inflammation is now recognized as a major contributing factor, is three times higher than in the general population.

Depression has long been known to be a risk factor for subsequent cardiac events and mortality, which is usually explained by the detrimental effects of depression on illness behaviour including adherence to treatment. However, this traditional view of the relationship between inflammation and morbidity/mortality in physically ill patients is challenged by the new hypothesis, set out in this Review, that depression can actually be caused by inflammation in vulnerable patients.

 

[Woolie]

@Hip, that's an interesting paper. I wouldn't want to claim that inflammation can't affect people's mood and psychological status. It clear it can affect both. What I was responding to really was @ukxmrv's point that it might not be exactly the same disorder as occurs in people without inflammation. It might have slightly different qualities - more fatigue and insomnia ("somatic" components, if you like), and less of the central negative cognitions (loss of hope, low self-esteem, lack of motivation).

The clinical definition is so broad that lots of different states and conditions can end up with this single generic label. This paper doesn't seem to help much there, because is assumes depression is just one thing.

 

[Hip]

What I was responding to really was @ukxmrv's point that it might not be exactly the same disorder as occurs in people without inflammation.

That seems very likely. The research cited at the beginning of this thread is also saying that inflammation-associated depression is a different entity to non-inflammatory depression.

It's possible, however, that different precipitating causes of depression (such as inflammation) trigger the same final pathway of depression (a final pathway such as the activation of IDO). So it is conceivable that the precipitating causes are different, but the depression experienced is more or less the same, because it goes through the same final pathway.

If so, it makes sense that antidepressants are used as a treatment, if those antidepressants are targeting the same final pathway. Although if inflammation is the precipitating cause of depression in a percentage of patients, you may get better results by targeting the inflammation in those cases, as inflammation is probably lower down on the causal chain.


This is why I think my anti-inflammatory anti-anxiety treatments such as NAG work well: because I believe these treatments may be tackling anxiety at a point lower down on the causal chain: tackling anxiety at its inflammatory roots, rather than the final pathway of anxiety, which I think may be elevated glutamate in the amygdala.

By contrast, anxiety treatments such as benzodiazepines I think only tackle anxiety at the final pathway point: benzos increase the calming GABAergic response, which I think works to counter the excitatory actions of excess glutamate.

But by lowering inflammation in the brain, I think you stop excess excitatory glutamate being produced in the first place.


Of course, if you want to go down even lower down on the causal chain, you could try to tackle the viral infections that may be causing the inflammation in the first place. My severe generalized anxiety disorder appeared after catching a suspected enteroviral infection that persisted chronically. But as we know, it's not that easy to tackle chronic viral infections with the current state of medical technology and current crop of pharmacological drugs. So quelling virally-induced inflammation may be the next best thing.

 

[Hip]

One thing of interest is my experience with immunomodulators: when I first tried these, they would often trigger pretty significant depression, often within a few hours of taking them. The depression would then quickly abate when I stopped taking them.

The worst depression-inducer was Epicor (Saccharomyces cerevisiae, brewers yeast), but immunomodulators like oxymatrine, inosine, astragalus and beta sitosterol all rapidly caused depression significant enough to force me to stop taking them.

So from my experience, the immune system seems closely linked to the depression I sometimes experience alongside ME/CFS. Interestingly, since my ME/CFS improved a bit of the last few years, most of these immunomodulators no longer cause depression, or only cause very mild depression.

 

[Woolie]

It's possible, however, that different precipitating causes of depression (such as inflammation) trigger the same final pathway of depression (a final pathway such as the activation of IDO). So it is conceivable that the precipitating causes are different, but the depression experienced is more or less the same, because it goes through the same final pathway.

Yea, that could turn out to be true. Its just that we don't know.

And, as you say, even if the depression is exactly the same, this doesn't mean it will respond to the same treatments. It might, if those treatment work in a really generic way. But it might not, if they operate on a causal factor that is important in "regular" depression but not in an inflammation related disorder.

 

[alex3619]

This paper doesn't seem to help much there, because is assumes depression is just one thing.

This, I think, is at the core of why psychiatry, and medicine in general, fails to find answers. It may not be any different from saying there is only one kind of pain, or one kind of fatigue.

 

[alex3619]

And, as you say, even if the depression is exactly the same, this doesn't mean it will respond to the same treatments. It might, if those treatment work in a really generic way. But it might not, if they operate on a causal factor that is important in "regular" depression but not in an inflammation related disorder.

Plus genetic and acquired variations in activating and deactivating enzymes for the drug, dealing with breakdown products, effects on associated pathways etc. Co-morbidities also matter. Every factor that interplays with the biochemical efficacy with a given drug in a given patient can totally change its impact. In the end this is something that personalized medicine is hoping to change ... if we can have reliable predictions of drug efficacy and side effects then the guesswork will be reduced.

 

[alex3619]

I am happy to talk of final pathways with biochemical reactions. I am not happy to discuss brain function and final pathways. The brain is far too complex for that to be a likely scenario. So if the biochemistry is altered, then a final pathway would make sense. But if brain function, aside from biochemistry, is altered, then I doubt final pathways might exist. A spectrum of final pathways in the brain is more likely, but I suspect it would wind up a multidimensional spectrum.

 

[Hip]

A spectrum of final pathways in the brain is more likely, but I suspect it would wind up a multidimensional spectrum.

You may well be right.

The other thing is that there are many types of depression other than the regular major depression: this page lists 9 different types of depression (click "View all" towards bottom left).