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Inflammation and clinical response to treatment in depression: A meta-analysis

Discussion in 'Other Health News and Research' started by Sidereal, Jul 15, 2015.

  1. Sidereal

    Sidereal Senior Member

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    http://www.ncbi.nlm.nih.gov/pubmed/26169573
     
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  2. anciendaze

    anciendaze Senior Member

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    Is anyone willing to admit they've been mistakenly treating inflammatory diseases with counseling and mood elevators, to say nothing of possible electroconvulsive therapy?
     
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  3. Woolie

    Woolie Senior Member

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    Interesting, @Sidereal. The more I learn about depression, the more I think its actually a messy mix of a number of very different chronic conditions, but our way of describing and diagnosing it is so blunt, we can't even see the differences.

    Important, too, to point out that despite the evidence suggesting a biomarker for this particular form of "treatment resistant depression", these authors still maintain that the cause of the depression is psychosocial:

    They then go on to give examples where inflammatory responses and depression-like symptoms have been induced by purely biological interventions, without psychosocial stressors (e.g., interferon). Which would seem to be a much simpler explanation.

    So instead of this:

    inflammation -> disorder that looks a bit like depression, but is fundamentally different (nice simple explanation)

    We have this:

    psychosocial stressors -> inflammation -> depression (byzantine model that pleases those with a biopsychosocial bent)

    Hey, you can have your cake and eat it - biomarkers and psychobabble!
     
  4. Sidereal

    Sidereal Senior Member

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    Why would that be a mistake? Antidepressants have anti-inflammatory effects. They work well for a minority of patients.

    I agree. Their own meta-analyses show extremely high levels of heterogeneity. In fairness, they do acknowledge that in the discussion.

     
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  5. Marco

    Marco Grrrrrrr!

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    Near Cognac, France
  6. Marco

    Marco Grrrrrrr!

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    Thankfully at least partially adressed in this particular genetics study. Large scale gene studies of 'undifferentiated' cases of depression found nothing.

    http://www.nature.com/news/first-robust-genetic-links-to-depression-emerge-1.17979
     
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  7. user9876

    user9876 Senior Member

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    I wonder if this is a problem in diagnosing without really trying to get to grips with the details of symptoms. Would all depressed patients describe depressed in the same way. Or with fatigue do all fatigued patients experience the same thing - is cancer fatigue the same as with ME?

    Sometimes I think doctors need to look in more detail rather than having some words with very broad semantics and a tick box diagnosis system.

    Could it be that we have event->inflammation -> ... -> depression (or other symptoms) but where the ....s are there is a transition where things are not quite working right as the inflammation (or other mechanisms) builds up. As things are not working correctly people get stressed because they can't get everything done they need to. So that to an observer they might see stress -> depression since other bits won't be observed. Of course there may just be an over reporting of stress due to the framing of doctors and hence it comes to patients minds.
     
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  8. A.B.

    A.B. Senior Member

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    The streetlight effect is a type of observational bias where people only look for whatever they are searching by looking where it is easiest.[1][2][3] The search itself may be referred to as a drunkard's search.

    Taken from an old joke about a drunkard who is searching for something he has lost, the parable is told several ways but typically includes the following details:

    A policeman sees a drunk man searching for something under a streetlight and asks what the drunk has lost. He says he lost his keys and they both look under the streetlight together. After a few minutes the policeman asks if he is sure he lost them here, and the drunk replies, no, and that he lost them in the park. The policeman asks why he is searching here, and the drunk replies, "this is where the light is."[2]

    https://en.wikipedia.org/wiki/Streetlight_effect

    Maybe depression is actually simple to explain but we've been searching under the streetlight for the last 100 years, and by now have research institutions that specialize in searching under streetlights.
     
    Last edited: Jul 16, 2015
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  9. anciendaze

    anciendaze Senior Member

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    Antidepressants started life as repurposed antibiotics aimed at treating tuberculosis. (See the history of isoniazid.) You have to go a long way in the literature before you encounter any mention of anti-inflammatory properties. There are multiple historical roots for antidepressant development, and the discovery that entirely different lines of development resulted in drugs with some anti-inflammatory properties, still not well understood, should have been an indication that the central tenets of their mechanisms of action were wrong. Most of these drugs exhibit immunomodulatory effects which are very poorly explained. Finally, we have the stunning discovery that SSRIs have powerful effects on enteroviruses, something that was emphatically never intended.

    This is particularly ironic because fluoxetine, the leading example of an SSRI, was described as the result of "rational drug design". Some consequences of sheer ignorance in this process would be hard to imagine without the aid of psychoactive substances.
     
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  10. Marco

    Marco Grrrrrrr!

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    'Fish on Prozac'

    Great name for a band!
     
  11. Sidereal

    Sidereal Senior Member

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    The treatments you dissed in your original post are effective for some patients with depression, some of whom have a severely disabling, treatment resistant and/or life-threatening illness. The fact that we don't know how they work or that MAO inhibitors and TCAs were serendipitously discovered or that SSRIs were developed based on the flawed serotonin hypothesis or that drugs have unintended effects is irrelevant. Everyone is wrong about disease and treatment mechanisms all the time, there is nothing unusual going on in that regard here. These treatments will continue to be used until better ones are developed because they are somewhat effective which is a preferable situation to disability or suicide.

    It is becoming evident that antidepressants ultimately work via an immunomodulatory mechanism. I would invite you to take a look at some of the newer work showing that the effect of SSRI is diminished if the patient is taking NSAID like ibuprofen at the same time.

    http://www.pnas.org/content/108/22/9262.full

    Immune modulators are being studied for depression now. For example, infliximab, a TNF-a antagonist, showed a signal in a subgroup analysis of patients with depression with elevated CRP at baseline in this small underpowered trial:

    http://archpsyc.jamanetwork.com/article.aspx?articleid=1356541

    You'll notice that the response rate to infliximab in this group of depressed patients was essentially the same as the response rate to rituximab in ME/CFS but in the depression trial the effect was not statistically significant because depression trials are plagued by a high placebo response rate which makes it very hard to detect treatment effects whereas the likelihood of placebo response in properly characterised ME cohorts is low.
     
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  12. duncan

    duncan Senior Member

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    The reasons treatments work, or do not, needs desperately to be relevant.

    If we are throwing treatments at patients without understanding the mechanisms behind their success, that is dangerous ground that threatens to lead to bad consequences.
     
  13. Sidereal

    Sidereal Senior Member

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    Agreed. A lot of psychiatry is a cargo cult science as far as I'm concerned. But that doesn't mean psychiatry should apologise for using currently available effective treatments for depression just because they were developed by accident or based on incorrect or incomplete hypotheses.
     
  14. anciendaze

    anciendaze Senior Member

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    @Sidereal

    The research you cite is still largely unknown to practitioners, or considered uncertain, as opposed to "proven treatments". Those who do not respond have "treatment-resistant depression", not a misdiagnosis. Psychiatric diagnoses may be falsified by discovery of physiological disease, but can seldom be falsified with any confidence within psychiatry. This is a clear weakness.

    What is far from hypothetical is the effect on patients with definite physiological disease thrown into this category. I know of a case in which a patient with miliary TB died during ECT. Patients with Wilson's disease may sit in back wards for years with complex psychiatric diagnoses before anyone notices the pathognomonic sign of a copper ring around the iris. This is not speculation; it has happened.

    I've gone one round with a local doctor concerning a patient with an actual clear diagnosis of POTS who committed suicide in a spectacular manner. Counseling and drugs to reduce anxiety were not the answer to the problem of her brain not getting oxygenated blood, with resulting poor decision making. The argument that she must have had hidden depression, since she killed herself, takes us into circular reasoning, and entirely beyond the scope of objective science.

    Doctors tend to interpret POTS as simply a problem with heart rate and anxiety. Neurally-mediated hypotension is often interpreted in terms of conventional numbers for systolic or diastolic pressure, and presumed mental problems. These are relatively simple physical problems producing objective measurements. I've repeatedly encountered doctors who flatly reject the idea that upright pulse pressure will decline over about 20 minutes, and refuse to make any measurements which might show this.

    When a patient showing such obvious signs of distress is faced with the prospect of being put in a locked ward, where serious physiological problems are regularly neglected, suicide becomes predictable.

    I'm not arguing that all cases of clinical depression are misdiagnoses, or that antidepressants do not have uses in keeping patients alive for the months that many cases last. I am arguing that we seldom know what is going on inside psychiatric patients, and must be especially careful about ignoring physiological causes of irrational behavior.
     
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  15. natasa778

    natasa778 Senior Member

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    Did you see that article I posted on central mediating role of serotonin in the effects of peripheral inflammation on CNS function.

    It could well be the case of that street lamp being in the middle of the park :)
     
  16. Sidereal

    Sidereal Senior Member

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    Sorry, I don't think I have. Could you post a link?
     
  17. natasa778

    natasa778 Senior Member

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    here is the original paper, I cannot find the link to the thread (I might have dreamt posting it :))

    http://www.jneuroinflammation.com/content/pdf/1742-2094-10-116.pdf

     
  18. Sidereal

    Sidereal Senior Member

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    Okay, a rat study. Nonetheless, it raises the important point that you require key additional factors to be present in the body in order to be capable of developing a major depressive episode when in a state of immune activation. You can observe this anecdotally in your social circle when people get infections. Some people get very irritable, foul mood, negative/irrational/perseverative cognitions, anxiety etc. when they have a cold while others get no apparent depressive symptoms despite having an infection/autoimmune disease/cancer/etc.
     
  19. Woolie

    Woolie Senior Member

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    Interesting and related observation: When I started on prednisone, I had a look at various forums to see if anyone had suffered depression on it (I saw it mentioned somewhere as a side effect of long-term use).

    But what I discovered was the opposite: a lot of people with depression who had never responded to antidepressants, but found when they took a course of prednisone (usually prescribed for something else entirely), they felt a marked and long-lasting relief from their depression.

    Given that corticosteroids are immune suppressants, just wondering is these guys might be the "non-responders" whose depression is inflammation-related?
     
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  20. A.B.

    A.B. Senior Member

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    Corticosteroids are known to improve mood in most people so this isn't very surprising.
     

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