Depression Induced by Interferon

MeSci

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Relevant to another recent thread on interferon, and suggesting a remedy:

An Easy Preventive Treatment of Depression Induced by Interferon

Steven Dubovsky, MD reviewing Su K-P et al. Biol Psychiatry 2014 Jan 27.
Prophylaxis with omega-3s decreases the risk.

Pretreatment with antidepressants can prevent depression caused by interferon-α (IFN) treatment of hepatitis C and other disorders, but antidepressants can be complicated to use in this setting. To find an alternative prophylaxis, researchers examined the effect of omega-3 polyunsaturated fatty acids for just 2 weeks prior to 6 months of treatment with IFN and ribavirin. A total of 162 hepatitis C patients were randomized to eicosapentaenoic acid (EPA; 3.50 g), docosahexaenoic acid (DHA; 1.75 g), or placebo; 152 completed IFN treatment and were included in the analysis.

Over the course of IFN treatment, the incidence of depression was significantly lower with EPA pretreatment (10%) than with placebo (30%; DHA pretreatment, 28%). When IFN-induced depression did occur, onset was significantly delayed with EPA or DHA pretreatment (12 weeks vs. 5 weeks with placebo). DHA pretreatment increased DHA levels, whereas EPA pretreatment increased both EPA and DHA levels.

Comment
Interferon-α increases activity of pro-inflammatory cytokines such as tumor necrosis factor-α, levels of which are correlated with the risk for IFN-induced depression. Anti-inflammatory effects of EPA, which is metabolized to DHA, may prevent this process. In view of how well omega-3s are tolerated, brief pretreatment with EPA before starting a course of IFN seems indicated as an initial strategy, and antidepressants can be started during treatment if depression does occur.
I have done some reading up on interferon, depression and related issues and have decided to try 5-HTP for current low mood. I'm already taking omega-3s, and it may be that my leaky-gut regime (which I have been on for almost 2 years) is taking me back through the stages of developing ME and I am reaching my depressive early stage, which I seem to recall one of the numerous abstracts and papers I viewed today cited as being characterised by particularly-high interferon levels.

My brain is getting very tired, so for simplicity I will just paste my notes on what I have found:

Interferon and ME/CFS

Abstract here may be relevant:

http://www.jwatch.org/na33597/2014/...ion-induced-interferon?query=topic_depression

It says:

“February 13, 2014

An Easy Preventive Treatment of Depression Induced by Interferon

Steven Dubovsky, MDreviewing Su K-P et al. Biol Psychiatry 2014 Jan 27.

Prophylaxis with omega-3s decreases the risk.

Pretreatment with antidepressants can prevent depression caused by interferon-α (IFN) treatment of hepatitis C and other disorders, but antidepressants can be complicated to use in this setting. To find an alternative prophylaxis, researchers examined the effect of omega-3 polyunsaturated fatty acids for just 2 weeks prior to 6 months of treatment with IFN and ribavirin. A total of 162 hepatitis C patients were randomized to eicosapentaenoic acid (EPA; 3.50 g), docosahexaenoic acid (DHA; 1.75 g), or placebo; 152 completed IFN treatment and were included in the analysis.

Over the course of IFN treatment, the incidence of depression was significantly lower with EPA pretreatment (10%) than with placebo (30%; DHA pretreatment, 28%). When IFN-induced depression did occur, onset was significantly delayed with EPA or DHA pretreatment (12 weeks vs. 5 weeks with placebo). DHA pretreatment increased DHA levels, whereas EPA pretreatment increased both EPA and DHA levels.”

This abstract :

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2816380/?report=classic

Which I got by searching online for abstract from ME Research UK list of publications says:

“Kuibitang (identical to Chinese Gui-Pi-Tang, Japanese Kihi-to) markedly inhibits lipopolysaccharide-induced tumor necrosis factor-α, IL-10 and transforming growth factor-β1 production and increases interferon-γ production in the peripheral blood mononuclear cells of CFS patients (35).”

That also says :

“In animal experiments, treatment with Peony root (Paeonia lactiflora Pall.) inhibits 5-HT synthesis and tryptophan hydroxylase expression, which may reduce fatigue, both during exercise and the resting state (24).”

This seems inconsistent with associations between depression and fatigue. Why would reducing 5-HT synthesis reduce fatigue? Maybe an example of the unreliability of animal ‘models’.

Numerous abstracts in ME Research publications doc refer to interferons being high in ME/CFS.

So could reducing leaky gut actually increase interferon and thus depression, thus possibly explaining my development of mood swings about 2 years after starting leaky-gut regime? Is it just a phase? Should I take 5-HTP? Something breaks down tryptophan to kynurenine. This paper discusses this process:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3021918/

Paper here

http://www.cfids-cab.org/cfs-inform/Immunology/patarca-montero.etal01.pdf

says:

“Typical Th1‐type cytokines include IL‐2 and interferon‐gamma, and some of the therapies induce their production.”

So could that mean that my self-treatment is correcting the TH1/2 balance?

Relevant info about 5-HTP on Examine.com here:

http://examine.com/supplements/5-HTP/#ref22
http://examine.com/supplements/5-HTP/#ref22
NB there have been a number of references to kynurenine on the Resistant Starch thread recently but I can't recall the context. Will post another message or edit shortly.

Edit:

Maybe just do a search for 'tryptophan' or 'kynurenine' in this thread.
 
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MeSci

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3.5 g EPA, damn that's a high dose.
It does sound high, doesn't it?!

I checked in Examine.com here and it says that even higher doses can be taken, mentioning 6 g for example., although they confusingly treat EPA, DHA and 'fish oil' as synonymous.

(It annoys me no end that most sites, even supplement sites, list all omega-3 supplements under 'fish oil', thus giving people the impression that they must consume often-unsustainable animal products to get EPA and DHA. In fact there are algal sourced EPA and DHA available, and which I take.)
 

A.B.

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This seems inconsistent with associations between depression and fatigue. Why would reducing 5-HT synthesis reduce fatigue? Maybe an example of the unreliability of animal ‘models’.
The assertion that depression is directly related to reduced serotonin levels in the brain is little more than a marketing slogan by the pharmaceutical industry.

http://chriskresser.com/the-chemical-imbalance-myth
 

MeSci

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The assertion that depression is directly related to reduced serotonin levels in the brain is little more than a marketing slogan by the pharmaceutical industry.

http://chriskresser.com/the-chemical-imbalance-myth
I know that the way SSRIs work has been found not to be closely related to increases in serotonin. But if 5-HTP has reasonable evidence for efficacy in depression I think it's worth a try when that is a problem. How it does it is less important to me right now. It seems to have a corrective effect on some of the abnormalities seen in ME.

I'm starting with a lowish dose (100g) and a product without added Vitamin B6, as I didn't previously tolerate a supplement containing B6.
 

A.B.

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I know that the way SSRIs work has been found not to be closely related to increases in serotonin. But if 5-HTP has reasonable evidence for efficacy in depression I think it's worth a try when that is a problem. How it does it is less important to me right now. It seems to have a corrective effect on some of the abnormalities seen in ME.
Apples and oranges. The question as to why antidepressants work is different from the question how effective they are. I find the the cytokine hypothesis of depression credible.
 

adreno

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Interferon-gamma upregulates the 5-HT transporter, so it makes sense that increasing serotonin levels would ameliorate the depression.
 

MeSci

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Apples and oranges. The question as to why antidepressants work is different from the question how effective they are. I find the the cytokine hypothesis of depression credible.
So do I! Not sure what you are saying. We agree, I think!
 

MeSci

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Just looking through the info in Examine.com and one study claims that 5-HTP increases salivary cortisol. As we seem to have generally low cortisol, this is hopefully a good thing. Here is the abstract.

Psychopharmacology (Berl). 2002 Jun;161(4):365-9. Epub 2002 Apr 19.

L-5-hydroxytryptophan induced increase in salivary cortisol in panic disorder patients and healthy volunteers.

Schruers K1, van Diest R, Nicolson N, Griez E.

Author information

Abstract

BACKGROUND:

Hypersensitivity of brain serotonin receptors has been proposed as a causal mechanism in the pathophysiology of panic disorder. This theory can be tested, using serotonergic stimulation of the HPA axis. Up to now, plasma cortisol has generally been used as the outcome measure in such studies. Assessment of salivary cortisol is a non-invasive alternative to measure HPA axis activity.

METHOD:

Salivary cortisol levels were measured in 24 panic disorder patients and 24 healthy volunteers, following ingestion of 200 mg L-5-hydroxytryptophan or placebo.

RESULTS:

A significant rise in cortisol was observed in both patients and controls following ingestion of L-5-hydroxytryptophan. No such effects were seen in the placebo condition.

CONCLUSION:

The results show that L-5-hydroxytryptophan stimulated salivary cortisol is a useful probe of serotonin function in healthy volunteers as well as panic disorder patients, and provide some evidence against a serotonin receptor hypersensitivity in panic disorder.
 

MeSci

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Looking at more papers, specifically related to interferon and 5-HTP, and found an interesting one here.

Particularly interesting to me is this phrase:

...the reduction in serum 5-hydroxytryptophan (5-HTP) and serotonin levels is highly correlated to the degree of depression...
I am also very interested in this quote from the other interferon thread:

Interferon-gamma levels were much higher in cases ill < 3 years.
[ill for less than 3 years]

which supports my insane theory that I am moving back along the course of my illness, which is also supported by reappearance of symptoms which were present at the start but which had gone. :D

Highly speculative and optimistic, but...
 

MeSci

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Well, I have been taking 100g 5-HTP a day for almost 3 weeks.

EDIT: 100 mg!!!

Nothing observed at first, then slightly odd mentally for maybe 2-3 days starting maybe about 10 days after I started the 5-HTP, then there was a subtle but noticeable improvement in mood about 2 weeks after starting 5-HTP, which has continued. Things seem more bearable and manageable, and I can even think about sad events without plunging into profound sadness as I was before, and no longer getting the feeling of being hit in the chest or abdomen which I had had when getting those episodes of plummeting mood.

Although subtle, the improvement is very useful/helpful. No adverse effects except the temporary weirdness which was maybe my brain rewiring! No horrible agitation and insomnia like I had in 1996 after taking Prozac/fluoxetine. I feel calm and normal.
 
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MeSci

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I know that the way SSRIs work has been found not to be closely related to increases in serotonin. But if 5-HTP has reasonable evidence for efficacy in depression I think it's worth a try when that is a problem. How it does it is less important to me right now. It seems to have a corrective effect on some of the abnormalities seen in ME.

I'm starting with a lowish dose (100g) and a product without added Vitamin B6, as I didn't previously tolerate a supplement containing B6.
I keep saying 100g when I mean 100 mg! Please don't take 100g! :eek:
 

MeSci

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Just come across a possibly-very-relevant paper from 2008 - apologies if it has been posted elsewhere. I can only access the abstract but that provides clear details of associations:

(sorry about journal name!)

IFN-gamma mediated pathways in patients with fatigue and chronic active Epstein Barr virus-infection
Abstract
Background
Chronic active Epstein Barr virus (EBV)-infection is characterized by mononucleosis like symptoms including fatigue, lymphadenopathy and/or hepatosplenomegaly and serologic evidence for ongoing EBV replication. Interferon-gamma (IFN-γ) triggers several antiviral mechanisms in target cells including the induction of indoleamine-2,3-dioxygenase (IDO), which degrades the essential amino acid tryptophan to kynurenine. Because tryptophan is a precursor of the neurotransmitter 5-hydroxytryptamine (serotonin), tryptophan depletion by IDO can cause mood disturbances in patients with chronic immune activation.

Methods
This study investigated the tryptophan metabolism in 20 patients with chronic active EBV-infection, who were followed up for 4 to 8 months and in 10 healthy age-matched controls. The clinical suspicion of chronic active EBV infection was verified by the presence of circulating antibodies against EBV early antigen (EA) and virus capsid antigen (VCA).

Results
Patients with detectable EBV–DNA had higher serum neopterin (p < 0.01) and lower tryptophan concentrations (p = 0.01) than EBV–DNA negative patients. Serum concentrations of neopterin, indicating Th-1 mediated immune activation via IFN-γ, were positively correlated to enhanced tryptophan degradation (rs = 0.650, p < 0.001) in patients, but not in healthy individuals. Patients suffering from more severe symptoms (as assessed by questionnaires) tended to have aggravated tryptophan degradation.

Conclusion
Our data show that EBV viremia is associated with cell-mediated immune activation and increased tryptophan degradation, which may partly account for the symptoms found in this disorder.
I'm still on the 5-HTP and have no plans to stop.
 

heyitisjustin

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Sorry to hear that, hope things get better soon.
5HTP to serotonin is not rate limited and can occur in the body. Too much serotonin in the body can damage the heart and lead to Serotonin Syndrome. My Dr. says I'd probably have other symptoms first (e.g. digestive), but I am not risking him being wrong. If you are taking 5HTP (I am) you should consider taking carbidopa or EGCG to alleviate the chance of heart injury.