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[Fascinating] Depression: An Evolutionary Byproduct of Immune System?

Bob

Senior Member
Messages
16,455
Location
England (south coast)
Anyone noticed the link http://clinicaltrials.gov/ct2/show/NCT00463580#miller infliximab depressionto the clinical trial of infliximab in major depression? It's especially interesting because that study is completed and the authors speculate wether auto-immune medications may benefit people with treatment resistant depression. In other words, it's very likely that study is 'positive'.

Could you keep us updated with any developments with that trial please FancyMyBlood, if you are able to? It would be very interesting if they have had any success.
 

FancyMyBlood

Senior Member
Messages
189
There is actually a small study having tested infliximab for depression in patients with AS:

http://www.ncbi.nlm.nih.gov/m/pubmed/21079965/

Some effect on depression was found, although the effects did not correlate with any physiological markers of inflammation. Placebo?

Who knows. The clinical trial I referenced is placebo-controlled and measures more inflammatory markers (the study you referenced had no control froup and only measured ESR and CRP).

The correlation coefficient between changes in HDRS symptom score(measured numerically and as the ratio of change score to baseline score) and changes in the plasma concentrations of TNF-alpha, IL-6 and CRP. [ Time Frame: Between baseline and any study point ] [ Designated as safety issue: No ]

Between-group differences (mean SD) in the change of cortisol and ACTH slope, p.m. cortisol, diurnal plasma cytokine and cytokine receptor concentrations and sleep efficiency between baseline and study week 8. [ Time Frame: Between baseline and study week 8. ] [ Designated as safety issue: No ]

Correlation coefficients between changes in HDRS symptom score and changes in diurnal slope of cortisol and ACTH, p.m. cortisol plasma concentrations, diurnal plasma concentrations of inflammatory cytokines and their receptors and sleep efficiency [ Time Frame: Measured numerically and as the ratio of change score to baseline score ] [ Designated as safety issue: No ]

CRP, IL-6, TNF-alpha, TNFR 1 and 2 [ Time Frame: Baseline ] [ Designated as safety issue: No ]
Investigate the effects of baseline CRP (and IL-6, TNF-alpha, TNFR 1 and 2) on reduction in depressive symptoms in patients in the two treatment groups.
 

Bob

Senior Member
Messages
16,455
Location
England (south coast)
Well, there are things that don't fit together here. In major depression disorder, CBT and exercise has both been shown as effective treatments. So why wouldn't it work for CFS, if the inflammatory pathways involved are almost similar?

Just because there are some similarities in the inflammatory abnormalities, it doesn't mean that the two illnesses have share identical processes/pathways or that the two illnesses have the same underlying causes.
I don't think science yet knows much about the immune system, and the human body, and what makes it malfunction.
I think we only have a shallow understanding.
For example, we don't understand Parkinson's disease, arthritis, Multiple Sclerosis, Bi-polar depression etc. etc. etc.
 

FancyMyBlood

Senior Member
Messages
189
Could you keep us updated with any developments with that trial please FancyMyBlood, if you are able to? It would be very interesting if they have had any success.

Sure, I don't think it will take too long until it gets published. I'll definitely update this thread when I notice the paper is published ( if no one has already).

Btw, you can check it yourself too by searching Pubmed for "Miller AH"[Author] infliximab
 

FancyMyBlood

Senior Member
Messages
189
Thank you :thumbsup:

You're welcome. :)

I was just searching for some previous papers from this author and I stumbled upon a recent interesting one:

Molecular signatures of peripheral blood mononuclear cells during chronic interferon-? treatment: relationship with depression and fatigue.

Felger JC, Cole SW, Pace TW, Hu F, Woolwine BJ, Doho GH, Raison CL, Miller AH.


Source

Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA.


Abstract

BACKGROUND:

Interferon-alpha (IFN-?) treatment for infectious disease and cancer causes high rates of depression and fatigue, and has been used to investigate the impact of inflammatory cytokines on brain and behavior. However, little is known about the transcriptional impact of chronic IFN-? on immune cells in vivo and its relationship to IFN-?-induced behavioral changes.MethodGenome-wide transcriptional profiling was performed on peripheral blood mononuclear cells (PBMCs) from 21 patients with chronic hepatitis C virus (HCV) either awaiting IFN-? therapy (n=10) or at 12 weeks of IFN-? treatment (n=11).

RESULTS:

Significance analysis of microarray data identified 252 up-regulated and 116 down-regulated gene transcripts. Of the up-regulated genes, 2'-5'-oligoadenylate synthetase 2 (OAS2), a gene linked to chronic fatigue syndrome (CFS), was the only gene that was differentially expressed in patients with IFN-?-induced depression/fatigue, and correlated with depression and fatigue scores at 12 weeks (r=0.80, p=0.003 and r=0.70, p=0.017 respectively). Promoter-based bioinformatic analyses linked IFN-?-related transcriptional alterations to transcription factors involved in myeloid differentiation, IFN-? signaling, activator protein-1 (AP1) and cAMP responsive element binding protein/activation transcription factor (CREB/ATF) pathways, which were derived primarily from monocytes and plasmacytoid dendritic cells. IFN-?-treated patients with high depression/fatigue scores demonstrated up-regulation of genes bearing promoter motifs for transcription factors involved in myeloid differentiation, IFN-? and AP1 signaling, and reduced prevalence of motifs for CREB/ATF, which has been implicated in major depression.

CONCLUSIONS:

Depression and fatigue during chronic IFN-? administration were associated with alterations in the expression (OAS2) and transcriptional control (CREB/ATF) of genes linked to behavioral disorders including CFS and major depression, further supporting an immune contribution to these diseases.
 

Waverunner

Senior Member
Messages
1,079
Well, there are things that don't fit together here. In major depression disorder, CBT and exercise has both been shown as effective treatments. So why wouldn't it work for CFS, if the inflammatory pathways involved are almost similar?

You don't differentiate. In otherwise healthy people, depression can be caused by a traumatic event for example. Of course it involves the same inflammatory pathways as in other diseases where people suffer from depression but the cause for the inflammatory process is the traumatic event. If the burden/stress of the traumatic event can be lowered through CBT, this will improve the depression. What traumatic event do you want to treat in CFS, there is none!

If you say that depression in CFS, is inflammatory, caused by a change in the immune system, then it is the same as the kind of depression in the study you posted. And as you stated, there is only one kind of depression, the physiological one, again described in the evolutionary study. So how come that CBT and excercise works for inflammatory depression (as described in the study), but not the inflammatory depression seen in CFS? They are both of physiological origin, caused by inflammation, brought on by immune system changes.

As I said there is no traumatic cause of the inflammatory process in CFS, so what do you want to treat with CBT? Exercise lowers all sorts of inflammatory processes in otherwise healthy people. I addition to that it works as a natural anti-depressant by stimulating neurotransmitter release. You know that it's impossible for many PWCs to exercise, so it makes no sense to bring it up. If someone suffers from depression and can exercise, this should improve his situation. If someone suffers from a severe disease like CFS, exercise is no option unfortunately.

I'm not sure I agree that the general consensus is that depression is caused by purely psychological factors. This is not what psychiatry believes, and that reasoning would not have lead to the use of chemical antidepressants. For at least 50 years, antidepressants have been in use. I would think that the general opinion is that depression is caused by a chemical imbalance in the brain, usually directly translatable to the monoamine hypothesis, which has prevailed in psychiatry for decades. That is the old hypothesis, and the present one subscribes to the idea of neurodegeneration, which is again ameliorated by antidepressants (or CBT and exercise).

Antidepressants have been around for a long time and every psychologist knows that an imbalance or lack of neurotransmitters drives depression but this says nothing about the general consensus. I studied psychology for two semester and every professor had the same credo: In the short run we use antidepressants and exercise to alleviate the symptoms of our patients, in the long run psychotherapy is the only causative cure.

Of course these people acknowledged the existence of biochemical involvement, but they saw this rather as a consequence of the underlying traumatic event and not as symptom of another physical disease that is not caused by a stressful event. This thinking slowly changes, thanks to studies like this.

What I believe is the case, is that the evolutionary study in reality describes sickness behavior, which has many of the same symptoms as depression, but is yet different. Sickness behavior follows an infection, and infection is not involved in major depression disorder. But infection is likely involved in CFS. So, in essence, there are more similarities between sickness behavior and CFS, than there are between sickness behavior and depression.

That is also, I argue, why CBT and exercise works in depression, but not in CFS. It doesn't work for sickness behavior, either. So in my view, the theory that depression = sickness behavior, is false. There is also plenty of evidence showing that prolonged psychological stress can lead to depression, without any infection involved. In essence, stress can lead to inflammation and neurodegeneration. Genetic factors are likely involved in this.

If you use these definitions of sickness behavior and depression, then of course CFS would fall into the first group. In the end however your definitions do not exist. The word depression does not make statements about the cause. Depression can be caused by infection and it can be caused by a traumatic event, it's still depression. The same way as it doesn't matter if I break my leg in a car accident or when I fall down the stairs, in both cases it's still called a broken leg.
 

Enid

Senior Member
Messages
3,309
Location
UK
Makes sense to me this thinking - I don't recall depression (of the fed up type except now and again) but what is termed "clinical" depression when all systems slow to a virtual standstill. At that stage the body is conserving energies to fight off infections. I think the word depression is much misused (chiefly psyches who know no better). The word needs far better clarification than currently used.
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
Hmmmm, is it a coincidence that sickness behaviour occurs in people who are sick? Who have infections like TB or polio? Maybe depression and sickness behaviour are extreme ends of a spectrum? If so, as pointed out in this thread, conserving energy helps fight the infection. Severe fever does something similar.

What sets ME apart is neurological damage, although there is now growing evidence of autoantibodies that can attack the nervous system in depression (Maes).

Bye, Alex
 

adreno

PR activist
Messages
4,841
You don't differentiate. In otherwise healthy people, depression can be caused by a traumatic event for example. Of course it involves the same inflammatory pathways as in other diseases where people suffer from depression but the cause for the inflammatory process is the traumatic event. If the burden/stress of the traumatic event can be lowered through CBT, this will improve the depression. What traumatic event do you want to treat in CFS, there is none!



As I said there is no traumatic cause of the inflammatory process in CFS, so what do you want to treat with CBT? Exercise lowers all sorts of inflammatory processes in otherwise healthy people. I addition to that it works as a natural anti-depressant by stimulating neurotransmitter release. You know that it's impossible for many PWCs to exercise, so it makes no sense to bring it up. If someone suffers from depression and can exercise, this should improve his situation. If someone suffers from a severe disease like CFS, exercise is no option unfortunately.



Antidepressants have been around for a long time and every psychologist knows that an imbalance or lack of neurotransmitters drives depression but this says nothing about the general consensus. I studied psychology for two semester and every professor had the same credo: In the short run we use antidepressants and exercise to alleviate the symptoms of our patients, in the long run psychotherapy is the only causative cure.

Of course these people acknowledged the existence of biochemical involvement, but they saw this rather as a consequence of the underlying traumatic event and not as symptom of another physical disease that is not caused by a stressful event. This thinking slowly changes, thanks to studies like this.



If you use these definitions of sickness behavior and depression, then of course CFS would fall into the first group. In the end however your definitions do not exist. The word depression does not make statements about the cause. Depression can be caused by infection and it can be caused by a traumatic event, it's still depression. The same way as it doesn't matter if I break my leg in a car accident or when I fall down the stairs, in both cases it's still called a broken leg.

The article essentially equates depression with sickness behavior. And that, I believe, is wrong. Exercise improve depression, but it doesn't improve sickness behavior. For that, rest is needed. So in my view, they cannot be the same. Sickness behavior is also an acute state, whereas depression is prolonged. Sickness behavior is a healthy immune response, whereas depression is pathological.

Remember also, that although you refer to the article as a study, it really isn't. It's a hypothesis. The idea that depression is the immune system on high alert, anticipating a coming immune insult, makes no sense to me. The immune system is much less efficient this way. People with depression are much more prone to infections than healthy people, and have a shorter lifespan. To have prolonged inflammatory response is detrimental to health. A healthy immune system makes a strong response to immune insults, and then calms down quickly. Low baseline inflammation promotes health. Depression is essentially a prolonged inflammatory state, very detrimental to health.

Depression also don't need a traumatic event to trigger it. Genetic factors combine with environmental insults to create depression, just as in most other diseases. Depression is likely a neurodegenerative disorder. Prolonged environmental insult (stress) leads to neurogeneration. Sickness behavior is not a neurodegenerative disorder, because it is an acute response to infection. Unless the sickness behavior becomes chronic as in CFS. In that case neurodegeneration is likely involved.
 

Waverunner

Senior Member
Messages
1,079
The article essentially equates depression with sickness behavior. And that, I believe, is wrong. Exercise improve depression, but it doesn't improve sickness behavior. For that, rest is needed. So in my view, they cannot be the same. Sickness behavior is also an acute state, whereas depression is prolonged. Sickness behavior is a healthy immune response, whereas depression is pathological.

Remember also, that although you refer to the article as a study, it really isn't. It's a hypothesis. The idea that depression is the immune system on high alert, anticipating a coming immune insult, makes no sense to me. The immune system is much less efficient this way. People with depression are much more prone to infections than healthy people, and have a shorter lifespan. To have prolonged inflammatory response is detrimental to health. A healthy immune system makes a strong response to immune insults, and then calms down quickly. Low baseline inflammation promotes health. Depression is essentially a prolonged inflammatory state, very detrimental to health.

Depression also don't need a traumatic event to trigger it. Genetic factors combine with environmental insults to create depression, just as in most other diseases. Depression is likely a neurodegenerative disorder. Prolonged environmental insult (stress) leads to neurogeneration. Sickness behavior is not a neurodegenerative disorder, because it is an acute response to infection. Unless the sickness behavior becomes chronic as in CFS. In that case neurodegeneration is likely involved.

I completely agree that depression is not healthy, although it may increase the chances of survival in some situations. The sooner we find working treatments and the sooner we have a better understanding of the inflammatory mechanisms behind it, the better.
 

FancyMyBlood

Senior Member
Messages
189
Could you keep us updated with any developments with that trial please FancyMyBlood, if you are able to? It would be very interesting if they have had any success.

The paper was published last month! http://www.ncbi.nlm.nih.gov/pubmed/22945416

The results are not really mind-blowing but might be hopeful for depressed people with hs-CRP. It certainly points to an immune component in a subset of depressed people, but the sample size is pretty small. More studies are now needed...
 

Bob

Senior Member
Messages
16,455
Location
England (south coast)
The paper was published last month! http://www.ncbi.nlm.nih.gov/pubmed/22945416

The results are not really mind-blowing but might be hopeful for depressed people with hs-CRP. It certainly points to an immune component in a subset of depressed people, but the sample size is pretty small. More studies are now needed...

Oh, wow, you remembered my request from so long ago! :)

Thanks very much for that! :thumbsup:

And thanks for the comments about it.

I'll read it a little later.
 

FancyMyBlood

Senior Member
Messages
189
Oh, wow, you remembered my request from so long ago! :)

Thanks very much for that! :thumbsup:

And thanks for the comments about it.

I'll read it a little later.

I just noticed it was published and automatically remember you asked for it. It seems my long(er)-term memory is not really effected afterall :D