Inflammation is part of Gulf War Syndrome

Although mostly trying to avoid any politics-talk on this blog I am going to make some reference to it in this post set in the context of the Persian Gulf War otherwise known at the First Iraq War.

The recent publication of the Chilcot report describing the case for the UK's involvement in the 2003 Iraq War (the second Iraq War) has further lit up an already illuminating year in British politics, by perhaps adding fuel to the notion that 'finishing the job' might have been an important link between the two conflicts...

Operation Desert Storm - the combat phase of the First Gulf War (1991) - described by some as 'the most toxic war in history' left a mark not just on the region where it was fought and its people but also on many of the returning service personnel, some of whom came back in a pretty poor state of health. Their various symptoms known collectively as Gulf War Syndrome or Illness, are still the topic of discussions and debate to this day despite increasing evidence that they are 'real' symptoms (see here) and not just some psychosomatic manifestation of combat stress for example, as advocated by some quite prominent figures. The possible reasons for illness are varied (see here) but when one uses the words 'sarin' in the context of potential exposures for example you get a flavour for what might have been involved [1] and their potential contributions to health or rather ill-health.

The paper by Gerhard Johnson and colleagues [2] (open-access) adds further credence to the idea that Gulf War Illness (GWI) is indeed a real phenomenon and specifically: "that inflammation is a component of the pathobiology of GWI." Based on the examination of a relatively small number of veterans (85 out of 500 deployed veterans who were invited to participate), researchers undertook a "structured interview" that "assessed their health status, and blood samples were obtained." They managed to divide veterans up into GWI+ (n=57) and GWI- (n=28) groupings dependent on whether or not they reached the Fukuda criteria [3] for a "a chronic multisymptom condition" linked to deployment to the Gulf War.

Results: over 80 specific analytes were assayed for from the blood samples provided by participants. Many compounds had an immunological slant in terms of being cytokines or being other markers of immune system (specifically inflammatory) 'activation'. "The results of the current study provide evidence of alterations in a number of blood parameters that are readily measurable in routine clinical laboratories" was the headline as six specific compounds, all with inflammation in mind, were ripe for further independent study: plasma C-reactive protein (CRP), leptin, brain-derived neurotrophic factor (BDNF), and matrix metalloproteinase-9 (MMP-9)  = higher in the GWI+ group. Heart-type fatty acid binding protein (H-FABP) and matrix metalloproteinase-2 (MMP-2) = lower in the blood of GWI+ subjects. Alongside "the distributions of peripheral blood lymphocyte, monocyte, neutrophil, and platelet counts were higher in GWI+ subjects" compared with GWI- participant data leading researchers to observe that "a model utilizing three readily measurable biomarkers [lymphocytes, monocytes, and C reactive protein]... appears to significantly augment the symptom-based case definition of GWI."

"The limitations of the study include small sample size, restricted geographic, ethnic, and sex composition of the study subjects, assay of blood parameters only once, some plasma protein assays, including cytokines, considered inevaluable due to a high percentage of assays below the level of detection, overlap of biomarker distributions within the normal range, absence of correction for multiple comparisons, a limited number of blood proteins found to be positively related to GWI+ status, and the absence of a confirmation cohort study." Apologies for just grafting a large chunk of text from the Johnson paper into this post, but when it comes to the limitations of their work, the authors do a pretty good job of cautioning against any over-hype and providing a roadmap to 'where next?'

And as part of that 'where next?' it appears that we might be talking quite soon about some findings if an associated ClinicalTrials.gov entry is anything to go by (see here) on the use of 'delayed-release prednisone' with this group. I say this without making any value judgements or providing anything that looks, sounds or smells like medical or clinical advice.

We wait and see.

And to close: "all is as the Force wills it" apparently...

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[1] Proctor SP. et al. Effects of sarin and cyclosarin exposure during the 1991 Gulf War on neurobehavioral functioning in US army veterans. Neurotoxicology. 2006 Dec;27(6):931-9.

[2] Johnson GJ. et al. Blood Biomarkers of Chronic Inflammation in Gulf War Illness. PLoS ONE 11(6): e0157855.

[3] Fukuda K. et al. Chronic multisymptom illness affecting Air Force veterans of the Gulf War. JAMA. 1998 Sep 16;280(11):981-8.

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Johnson GJ, Slater BC, Leis LA, Rector TS, & Bach RR (2016). Blood Biomarkers of Chronic Inflammation in Gulf War Illness. PloS one, 11 (6) PMID: 27352030

C-reactive protein "may be a causal risk factor for schizophrenia"

Although the public perception of science is that researchers go around 'proving' or 'disproving' that A leads to B or X causes Y, it is still surprisingly rare to see the word 'causal' in many areas of peer-reviewed research. Aside from the fact that science generally works around the concept of 'probability' - producing data pertinent to discussions on whether something is more or less likely to be true/false - most science is not so forthright in its conclusions. Certainly science covering the area of behaviour and medicine tends to be a little more 'shades of grey' than anything else when it comes to causality...

When I therefore see research articles talking about 'causality' particularly in the domain of psychiatry and behaviour, they tend to grab my attention. So it was when I stumbled across the paper by Masatoshi Inoshita and colleagues [1] (open-access) who, and I quote, reported that their cumulative findings "suggest that elevated CRP itself may be a causal risk factor for schizophrenia."

CRP refers to C-reactive protein, a pentraxin produced in the liver that "rises when there is inflammation throughout the body." In these days of layer upon layer of experimental evidence indicating that immune function may play an important role in psychiatry and behaviour (see here), it is not surprising to see a marker of systemic inflammation being linked to a complicated condition like schizophrenia given what research has already said about such a connection (see here).

The Inoshita study was an interesting one insofar as it represented yet another 'value-added' study where researchers first produced their own data on the topic and then undertook a meta-analysis on the topic of CRP and schizophrenia. I've covered such a method on at least two other occasions on this blog (see here and see here).

The first part of their study found that: "The mean serum CRP levels in the 408 patients with schizophrenia and the 1,247 control subjects were 0.36 mg/dl (SD = 0.81) and 0.03 mg/dl (SD = 0.01), respectively" = it was elevated in the schizophrenia group. Analysis was also undertaken taking into account genetics potentially affecting levels of CRP where "2 common SNPs... (rs2794520 in the CRP gene and rs1183910 in the HNF1 homeobox A (HNF1A) gene) were selected." Part of this included a Mendelian randomization analysis, the results of which [partially] "provided evidence for a causal association between elevated CRP levels and schizophrenia risk."

A meta-analysis was also carried out "of previous case-control studies between serum CRP levels and schizophrenia." Based on data from 14 case-control studies including "a total of 1,664 patients with schizophrenia and 3,070 control subjects", researchers found that "serum CRP levels were significantly higher in patients with schizophrenia than in the controls" (although with "significant heterogeneity among studies"). Cumulatively, they concluded, there is something to see when it comes to CRP and schizophrenia; indeed: "Our finding suggests that CRP levels are causally associated with not only late- and very-late-onset schizophrenia but also general schizophrenia."

From all the topics that I've covered on this blog, the association between elevated CRP and schizophrenia is perhaps one of the strongest insofar as the amount and direction of data/evidence that has been produced and documented; also crossing different geographies. Accepting that it may be slightly problematic to use the term 'schizophrenia' in these days of pluralised labels (see here) and that there may be 'outliers' ("we excluded from our association study any subjects who had a CRP concentration below the assay’s limit of 0.02 mg/dl (a total of 127 subjects; patients N = 9, controls N = 118)"), the time has surely come to start treating such data seriously. Not least because if higher levels of CRP are present, there may be ways and means to reduce them and potentially also impact on the presentation of symptoms. The authors seem well aware of this point: "several clinical studies have demonstrated the efficacy of anti-inflammatory drugs, such as aspirin and the cyclooxygenase-2 (COX-2) inhibitor celecoxib, on the symptoms in patients with schizophrenia" (with no medical or clinical advice given or intended).

I don't however doubt that CRP is merely one facet of quite a lot of schizophrenia (see here) nor that it is not a condition specific finding (see here and see here). That other pentraxins may also be linked to immune functions in cases of schizophrenia is also potentially important (see here) as are the multitude of other molecular targets that have been reported on down the years with an immune system feel to them [2].

The use of Mendelian randomization where "genetic variants that either alter the level of, or mirror the biological effects of, a modifiable environmental exposure that itself alters disease risk should be related to disease risk to the extent predicted by their influence on exposure to the environmental risk factor" seems to be in the research ascendancy these days as per other examples where important biological variables have been linked to something like schizophrenia [3]. I like the idea of what this statistical technique can bring but would perhaps take exception to the sole focus on structural genetics at the expense of other issues potentially affecting gene expression. That also it is not outside the realms of possibility that there may be a coincidence of factors linking something like CRP and vitamin D mentioned in the paper by Taylor and colleagues [3] is something else to consider (see here).

But, yet again, with CRP we have something testable and quantifiable to measure and potentially act upon where values fall outside of accepted reference ranges...

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[1] Inoshita M. et al. A significant causal association between C-reactive protein levels and schizophrenia. Sci Rep. 2016 May 19;6:26105.

[2] Chase KA. et al. The value of interleukin 6 as a peripheral diagnostic marker in schizophrenia. BMC Psychiatry. 2016; 16: 152.

[3] Taylor AE. et al. Investigating causality in the association between 25(OH)D and schizophrenia. Sci Rep. 2016 May 24;6:26496.

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Inoshita M, Numata S, Tajima A, Kinoshita M, Umehara H, Nakataki M, Ikeda M, Maruyama S, Yamamori H, Kanazawa T, Shimodera S, Hashimoto R, Imoto I, Yoneda H, Iwata N, & Ohmori T (2016). A significant causal association between C-reactive protein levels and schizophrenia. Scientific reports, 6 PMID: 27193331

Neonatal pain 'causing' autism? I'm not so sure...

I wasn't actually going to talk about the paper by Jin Hwan Lee and colleagues [1] on this blog and the suggestion that: "severe inflammatory pain in neonates and persistent inflammatory reactions may predispose premature infants to development delays and psychiatric disorders including ASD [autism spectrum disorder]." I changed my mind however when a piece appeared on-line titled: 'New Autism Dispute: Is Circumcision a Factor?' with mention of 'ritual circumcision and autism' being made based on some research a while back (see here) and a possible "pain-autism connection" being introduced.

From the outset I'll admit that I'm pretty unconvinced about sweeping notions that 'pain' in early infancy can later manifest as a complicated condition like autism. My viewpoint is based on the idea that (a) pain (different types of pain) is a fairly regular passenger for nearly all of us over our lifetime and (b) unfortunately, whilst some young infants do experience significant pain during their earliest days, not all go on to develop autism or other behavioural labels as a result of their pain. I'm not saying that pain can't have longer term effects when severe enough, just that plausible evidence of a link specifically with autism is currently quite sparse.

Bearing in mind my view, the Lee paper describes how rats were the participants in question when it came to their study on whether "repeated inflammatory pain experienced by preterm/premature babies could lead to acute and delayed brain damage that might be associated with social and behavioral abnormalities at the juvenile age." Aside from utilising an animal model, you'll note there is mention of the word 'inflammatory' in their hypothesis, which already implies that pain is not the only variable under investigation. I'll come back to this shortly.

Said rat pups whose age modelled the "brain developmental stage to human preterm infants" were rather unpleasantly given an injection of formalin (a fairly standard method of stimulating inflammatory pain) or saline and various measures including behavioural and physiological were assessed. Unfortunately, those physiological measures involved the rat brain so animals were eventually sacrificed.

Results: well, there were quite a few of them. Perhaps unsurprisingly, formalin treated rats "travelled less distance and showed a lower velocity than control rats" as a consequence of receiving their injection in their hindpaw. Behaviourally, the formalin treated group were also subsequently described as showing "more time engaging in repetitive behaviors such as self-grooming, repetitive jumping, and spontaneous muscle twitching" and "showed sleeping disorder, exhibited as marked increases in bouts of awake and sleep activities." Increases in various cytokines - chemical messengers of the immune system - were noted in treated rats: "increased levels of inflammatory cytokines, TNF-α, and IL-1β in the blood as well as in the brain, and increased microglia in the brain." The authors also noted "significant cell death" in parts of the brain in those treated rats. Interestingly however: "an anti-inflammation treatment using indomethacin (10 mg/kg, i.p.) at the time of formalin injections suppressed inflammatory responses and neuronal cell death." Finally: "the inflammatory pain led to long-term regulation of ASD [autism spectrum disorder]-associated genes NRXN1, FMR1, and oxytocin/oxytocin receptor in the brain."

Going back to point made a few paragraphs back about the concept of 'inflammation' or inflammatory processes/responses potentially being more important than 'pain' in these results, you can perhaps see what I was trying to get at. Indeed, in their discussion the authors note: "inflammation and pain are distinct insults although may sometimes reciprocal. The pathogenic effects of pain and inflammation may play distinctive roles in ASD, while this is unclear based on available data." Certainly, there is a growing recognition that inflammation/inflammatory processes do seem to show an important relationship to at least some autism (see here and see here for example) although there are some details that still need to be investigated. As part of a wider scheme of research implicating immune-related processes (see here) I'm tempted to err on the side of inflammatory issues being more pertinent to the Lee and other results over and above any 'memory of pain' having a large effect. I say all that accepting that rats are rats not people and that there is still a degree of not knowing...

In terms of the coverage of the paper by Frisch & Simonsen [2] talking about ritual circumcision potentially being associated with an increased risk for autism and 'a pain-autism connection', I'm gonna again link you back to what I said the last time I covered this work (see here). Namely, that studies of association where only a few variables are analysed together should always be treated with caution; also bearing in mind some important details were missing from their analysis on that occasion: "Unfortunately, we had no data available on analgesics or possible local anaesthetics used during ritual circumcisions in our cohort" so other potentially relevant hypotheses could still exert an effect [3].

Pain can very much be a feature of autism (see here) but on the question of pain 'causing' or leading to autism, I'm yet to be convinced with the currently available evidence...

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[1] Lee J-H. et al. Neonatal inflammatory pain and systemic inflammatory responses as possible environmental factors in the development of autism spectrum disorder of juvenile rats. Journal of Neuroinflammation. 2016; 13: 109.

[2] Frisch M. & Simonsen J. Ritual circumcision and risk of autism spectrum disorder in 0- to 9-year-old boys: national cohort study in Denmark. JRSM. 2015. 8 January.

[3] DiMaggio C. et al. Early childhood exposure to anesthesia and risk of developmental and behavioral disorders in a sibling birth cohort. Anesth Analg. 2011 Nov;113(5):1143-51.

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Lee JH, Espinera AR, Chen D, Choi KE, Caslin AY, Won S, Pecoraro V, Xu GY, Wei L, & Yu SP (2016). Neonatal inflammatory pain and systemic inflammatory responses as possible environmental factors in the development of autism spectrum disorder of juvenile rats. Journal of neuroinflammation, 13 (1) PMID: 27184741

The 'anti-neuroinflammatory activity' of oxytocin

Whilst the package inserts of the various drugs that modern medicine has at its disposal provides important information on potential mode of action, there is a growing realisation that drugs generally have quite a few more molecular targets than are perhaps listed. Take for example the quite commonly used (in some parts of the world anyway) compound called melatonin  that in some instances can provide almost miraculous relief when it comes to sleeping issues under certain circumstances. A derivative of the amino acid tryptophan, melatonin might however be quite the molecular handy-person when it comes to its biological targets including its actions on something called leaky gut for example...

The paper by Lin Yuan and colleagues [1] similarly suggests that everyone's favourite 'cuddle hormone' (oxytocin) might also have a wider range of biological effects than has hitherto been fully appreciated.  Drawing on cell line results and intra-nasal administration of oxytocin (OT) to [artificially] immune-stimulated mice, authors reported that "OT possesses anti-neuroinflammatory activity and might serve as a potential therapeutic agent for treating neuroinflammatory diseases."

One of the primary analytical targets of the Yuan study were microglia, those 'constant gardeners' according to one description, and how administration of OT might have some interesting effects on the activation of microglia under certain circumstances. "BV-2 cells and primary microglia were pre-treated with OT (0.1, 1, and 10 μM) for 2 h followed by LPS [lipopolysaccharides] treatment" we are told, and microglia activation and "pro-inflammatory mediators" subsequently monitored. The results tallied with those 'anti-neuroinflammatory' sentiments previously expressed as authors report on various possible reasons for such an effect: "OT suppressed the expression of TNF-α, IL-1β, COX-2, and iNOS at the mRNA and proteins levels and reduced the elevation of [Ca2+]i in LPS-stimulated microglia cells." If that wasn't enough, researchers also looked at what happened following OT pre-treatment when a certain strain of mouse was 'immune stimulated' again in terms of microglia activation and those pro-inflammatory mediators. We are similarly told that: "pre-treatment with OT showed marked attenuation of microglial activation and pro-inflammatory factor levels." So we have something of a match in the lab and in an animal model.

These are interesting results. Yet again, one has to be a little cautious about the use of mouse models or indeed, cell lines (humans are so much more than a group of cells in a petri dish) and further, independent investigations are indicated. But: "These data suggested that OT would be a potential therapeutic agent for alleviating neuroinflammatory processes in neurodegenerative diseases."

I was inclined to talk about the Yuan paper because of the various 'connections' that have been made between oxytocin and autism (see here). With a growing interest in the oxytocin-autism connection in the peer-reviewed literature, this nonapeptide (9 amino acids long) has attracted quite a few researchers to its cause [2] as a function of the idea that: "Oxytocin increases the salience of social stimuli and promotes parental nurturing and social bonds" [3]. As per my interpretation of the current state of the oxytocin-autism research base, there are some interesting results available but once again, universal 'effects' are nowhere to be seen - Autisms, people. Autisms. The Yuan and other results focusing on the 'anti-neuroinflammatory' activity of oxytocin perhaps add another dimension to the possible hows and whys of efficacy when it comes to a label like autism. That also a growing number of people are coming around to the idea that neuroinflammation might be a facet of 'some' autism (see here) and including some mention of microglia (see here) offers an additional correlate to add into the future research mix. Could those with autism who have more prominent signs of neuroinflammatory issues potentially be 'best responders' to oxytocin for example? I did also wonder whether the idea that inflammation or inflammatory issues might feature in complex behaviours like social cognitive processing (see here) could provide another explanation for some of the reported results observed following use of oxytocin in [some] autism?

Much more research is indicated but again the message is... don't be too dogmatic when it comes to pharmacological targets and actions of medicines indicated for conditions such as autism. You might just end up being surprised...

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[1] Yuan L. et al. Oxytocin inhibits lipopolysaccharide-induced inflammation in microglial cells and attenuates microglial activation in lipopolysaccharide-treated mice. Journal of Neuroinflammation. 2016; 13:77.

[2] Okamoto Y. et al. The Potential of Nasal Oxytocin Administration for Remediation of Autism Spectrum Disorders. CNS Neurol Disord Drug Targets. 2016 Apr 13.

[3] Young LJ. & Barrett CE. Neuroscience. Can oxytocin treat autism? Science. 2015 Feb 20;347(6224):825-6.

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Yuan L, Liu S, Bai X, Gao Y, Liu G, Wang X, Liu D, Li T, Hao A, & Wang Z (2016). Oxytocin inhibits lipopolysaccharide-induced inflammation in microglial cells and attenuates microglial activation in lipopolysaccharide-treated mice. Journal of neuroinflammation, 13 (1) PMID: 27075756

Schizophrenia and the constant (immune) gardeners

"Immune clue to preventing schizophrenia" went the BBC headline, as the paper by Peter Bloomfield and colleagues [1] garnered some significant media interest recently specifically tied into their findings suggesting that: "neuroinflammation is linked to the risk of psychosis and related disorders, as well as the expression of subclinical symptoms."

Based on the use of "second-generation radioligand [11C]PBR28 and PET to image microglial activity in the brains of participants at ultra high risk for psychosis", researchers reported on 56 participants looking to record their microglial activity. Microglia, as I've talked about before, are something like the constant gardeners of our immune defences in their role as macrophages (big eaters of the immune system) of the brain and spinal cord. Bloomfield et al reported that some of the highest levels of microglia activity were seen in those participants diagnosed with schizophrenia. There also appeared to be something of a potentially important dose related relationship between microglial activity and those at ultra-high risk of psychosis too. Ergo: "Microglial activity is elevated in patients with schizophrenia and in persons with subclinical symptoms who are at ultra high risk of psychosis and is related to at-risk symptom severity." Quite a nice write-up of the study can be read here.

It's not necessarily new news that immune activation and inflammatory processes may be part and parcel of at least some schizophrenia. I've covered the topic quite a few times on this blog (see here and see here for example). The novelty in the Bloomfield results is that researchers actually looked at neuroinflammation as being part of the process linked to excess immune activation in their cohort including people on the schizophrenia-psychosis spectrum.

Where next with this work? Well, replication - independent replication - is a must-have for this area and might also include some analysis of other more general circulating markers of inflammation such as C-reactive protein (CRP) and other pentraxins for example. That also the orchestra of immune-related chemicals that fall under the banner of cytokines (see here) might also be included in further work would also be a valuable scientific addition bearing in mind that not all schizophrenia/psychosis might be immune related: remember the schizophrenias (plural). I might also forward the idea that we might already have some clues as to the possible agents involved in such immune stimulation as per the interesting work looking at Toxoplasma gondii and some schizophrenia (see here).

With regards to the BBC and other media talking about possible treatments focused on some 'anti-inflammatory' action, this again is not new news as per reports such as the one by Friedrich [2]. With other psychiatric labels in mind also talking about inflammation as being part and parcel of pathology (see here) there may be a variety of anti-inflammatory strategies requiring scientific analysis within the context of schizophrenia and/or psychosis. Indeed, such work might overlap across various different labels (see here) and even point to some rather unorthodox intervention ideas (see here and see here).

The times are a changin' for psychiatry methinks.

Music: All I Wanna Do Is Have Some Fun...

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[1] Bloomfield PS. et al. Microglial Activity in People at Ultra High Risk of Psychosis and in Schizophrenia: An [11C]PBR28 PET Brain Imaging Study. American Journal of Psychiatry. 2015. Oct 16.

[2] Friedrich MJ. Research on Psychiatric Disorders Targets Inflammation. JAMA. 2014; 312: 474-476.

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Bloomfield, P., Selvaraj, S., Veronese, M., Rizzo, G., Bertoldo, A., Owen, D., Bloomfield, M., Bonoldi, I., Kalk, N., Turkheimer, F., McGuire, P., de Paola, V., & Howes, O. (2015). Microglial Activity in People at Ultra High Risk of Psychosis and in Schizophrenia: An [ C]PBR28 PET Brain Imaging Study American Journal of Psychiatry DOI: 10.1176/appi.ajp.2015.14101358

Immunosuppression as a therapeutic pathway of clozapine?

"Our data suggest that the superior therapeutic effect of clozapine may be a result of its presently shown immunosuppressive action."

So said the findings reported by Markus Larsson and colleagues [1] (open-access available here) who set about investigating "the effects of chronic treatment with antipsychotic drugs on brain levels of cytokines and KYNA [kynurenic acid]" in a rat model. The rationale for the study came in part from the idea that schizophrenia (or least some schizophrenia) may show more than a passing connection to a state of inflammation (see here) as well as a link to the kynurenine pathway (see here). Whether or not antipsychotic medication might show some 'effect' on these processes is still a little up in the air.

Then: "Rats were treated daily by intraperitoneally administered haloperidol (1.5 mg/kg, n = 6), olanzapine (2 mg/kg, n = 6), and clozapine (20 mg/kg, n = 6) or saline (n = 6) for 30 days." Kynurenic acid (KYNA) in brain tissue and levels of various cytokines (chemical messengers of the immune system) in cerebrospinal fluid (CSF) were assayed for among the various groups in comparison to a control group of animals receiving saline.

"Clozapine, but not haloperidol or olanzapine-treated rats displayed significantly lower cerebrospinal fluid (CSF) levels of interleukin-8 compared to controls." This is an interesting finding that needs to be treated with some caution given that aside from IL-8 all other cytokines were reported as being below the limits of detection of the analytical methods employed. Interleukin-8 (IL-8) is normally considered to be a pro-inflammatory cytokine specifically associated with acute inflammation [2]. With schizophrenia in mind, IL-8 has been tied into the whole maternal immune activation (MIA) theory of schizophrenia as per data such as those reported by Alan Brown and colleagues [3]. Brown et al reported on: "a significant association between maternal IL-8 level during the second trimester and risk of schizophrenia spectrum disorders in the offspring." More directly, IL-8 levels in relation to 'some' schizophrenia [4] have been reported in the research literature.

That rats treated with clozapine showed a lower level of IL-8 than following use of the other antipsychotics has been translated by the authors as possible evidence that clozapine may have an immunosuppressive action. Granted we don't have 'before and after' data in the Larsson study so we have to be a little careful about generalisation but I do find this to be a tantalising prospect. Whilst it might not be new news to some readers that clozapine might be doing quite a bit more than we expected when it comes to its use in a condition like schizophrenia, the idea that immune function might be 'affected' by administration [5] is a new one for me. A quick survey of some of the other literature on the immuno-modulatory aspects to clozapine indeed reveals that there is something to see here. Chen and colleagues [6] for example, talked about the anti-inflammatory possibilities attached to something like clozapine.

Within the various discussions about how several psychiatric labels might have an important 'inflammatory' component behind them (see here) it's not outside of the realms of possibility that the other pharmacological actions of the drug might also be complemented by such immunological alterations too. This might be a bit of a double-edged sword insofar as working out a more targeted 'use' for the drug whilst at the same time realising how complex the immune system truly is and why we should be cautious about tinkering too much with it.

Music: Passenger - I'll Be Your Man.

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[1] Larsson MK. et al. Chronic Antipsychotic Treatment in the Rat - Effects on Brain Interleukin-8 and Kynurenic Acid. Int J Tryptophan Res. 2015 Sep 20;8:49-52.

[2] Harada A. et al. Essential involvement of interleukin-8 (IL-8) in acute inflammation. J Leukoc Biol. 1994 Nov;56(5):559-64.

[3] Brown AS. et al. Elevated maternal interleukin-8 levels and risk of schizophrenia in adult offspring. Am J Psychiatry. 2004 May;161(5):889-95.

[4] Zhang XY. et al. Elevated interleukin-2, interleukin-6 and interleukin-8 serum levels in neuroleptic-free schizophrenia: association with psychopathology. Schizophr Res. 2002 Oct 1;57(2-3):247-58.

[5] Røge R. et al. Immunomodulatory effects of clozapine and their clinical implications: what have we learned so far? Schizophr Res. 2012 Sep;140(1-3):204-13.

[6] Chen ML. et al. Regulation of macrophage immune responses by antipsychotic drugs. Immunopharmacol Immunotoxicol. 2013 Oct;35(5):573-80.

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Larsson MK, Schwieler L, Goiny M, Erhardt S, & Engberg G (2015). Chronic Antipsychotic Treatment in the Rat - Effects on Brain Interleukin-8 and Kynurenic Acid. International journal of tryptophan research : IJTR, 8, 49-52 PMID: 26448689

Anti-NMDA-receptor encephalitis and autism: research ascendancy

The paper by Reza Kiani and colleagues [1] (open-access available here) detailing the presence of anti-N-methyl-d-aspartate (NMDA) receptor encephalitis in two people "with autism and intellectual disability presenting with neuropsychiatric symptoms of catatonia and neuroleptic malignant syndrome" caught my eye recently.

Having previously talked about anti-NMDA-receptor encephalitis and autism in a previous blog post (see here) back in 2013 with the emphasis on a possible link to 'autistic regression', I've been intrigued by the rise and rise of peer-reviewed material on this subject in the intervening years. Subsequent descriptions such as the one from González-Toro and colleagues [2] again talking about children diagnosed with anti-NMDA receptor encephalitis after suffering a "regression of previously acquired abilities that developed into autism" further adds to my interest in this potentially important connection. That also there may be several roads leading to a diagnosis of autism is also an important take-away point from such work.

Kiani et al continue with the idea that there may be an "aetiological role of the immune system in the pathogenesis of various psychiatric disorders" on the back of various studies looking at anti-NMDA receptor encephalitis. On this occasion, they detail two case reports where autism and learning (intellectual) disability were already diagnosed but deteriorations in behaviour were noted. The first case report of a woman in her early-30s who "presented with social withdrawal and a persistently low mood" that subsequently led into "objective evidence of hallucinations" illustrates how various tests followed various symptoms ultimately leading the authors to suspect anti-NMDA receptor encephalitis. Importantly, they detail how psychotropic medication was the first choice of intervention and how, only after this 'failed', did they look for anti-NMDA-receptor antibodies. Of importance to the female presentation of anti-NMDA receptor encephalitis were the further investigations looking for any signs of "an underlying tumour, particularly an ovarian teratoma" given previous suggestions of a possible link [3].

The second case report focused on a middle-aged man "with moderate intellectual disability, autism and a history of affective psychosis in remission." Again, antipsychotic medication was the first thing to be reached for when "his condition deteriorated and he displayed aggressive outbursts and insomnia." Alas, this did not improve his state and neuroleptic malignant syndrome (NMS) was eventually diagnosed as a result of such intervention. Anti-NMDA-receptor encephalitis was finally considered when "further investigations revealed positive anti-NMDA-receptor antibodies."

Of note for both these individuals was the effect of treating anti-NMDA receptor encephalitis. This involved the use of methylprednisolone, an anti-inflammatory compound, normally administered for various autoimmune conditions. Interestingly, as a corticosteroid, prednisolone (the un-methylated version of methylprednisolone) has been talked about with 'regressive autism' in mind before in the peer-reviewed literature (see here). Kiani et al note that delivery of methylprednisolone was associated with a gradual recovery in behavioural symptoms "with no evidence of psychosis or cognitive deficit."

"In both patients the diagnosis was made with delay owing to the complexity of their presentation." This is an important sentence from Kiani and colleagues. Not only in respect to the various behavioural and somatic issues that were present (including comorbid diagnoses) but also insofar as issues with communication for example. I've talked about similar things before on this blog (see here). Further, the authors reiterate "the complex presentation of anti-NMDA-receptor encephalitis in... patients with intellectual disability and autism" and how further research is required to see whether diagnostic conditions such autism and/or learning disability "are more prone to develop this type of encephalitis or have a worse prognosis in comparison with the rest of the population." I struggle to disagree with such sentiments.

Music: Hozier - Take Me To Church.

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[1] Kiani R. et al. Anti-NMDA-receptor encephalitis presenting with catatonia and neuroleptic malignant syndrome in patients with intellectual disability and autism. BJPsych Bull. 2015 Feb;39(1):32-5.

[2] González-Toro MC. et al. Anti-NMDA receptor encephalitis: two paediatric cases. Rev Neurol. 2013 Dec 1;57(11):504-8.

[3] Dabner M. et al. Ovarian teratoma associated with anti-N-methyl D-aspartate receptor encephalitis: a report of 5 cases documenting prominent intratumoral lymphoid infiltrates. Int J Gynecol Pathol. 2012 Sep;31(5):429-37.

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Kiani R, Lawden M, Eames P, Critchley P, Bhaumik S, Odedra S, & Gumber R (2015). Anti-NMDA-receptor encephalitis presenting with catatonia and neuroleptic malignant syndrome in patients with intellectual disability and autism. BJPsych bulletin, 39 (1), 32-5 PMID: 26191422

Depression and risk of coronary heart disease

"The results of our meta-analysis suggest that depression is independently associated with a significantly increased risk of CHD [coronary heart disease] and MI [myocardial infarction], which may have implications for CHD etiological research and psychological medicine."

No owners means - no heartbreak!

So said the conclusion of the paper by Yong Gan and colleagues [1] (open-access) and their synthesis of the peer-reviewed literature on the topic of heart health and depression. Granted, such findings are probably not particularly great news to anyone with depression, but as per similar research on health and psychology discussed on this blog (see here), getting the message out is often an important first stage in doing something about mitigating any enhanced risk.

Glancing through some of the previous entries on this blog covering depression - in all its different forms - I realise that this is a topic which has already been raised in a previous entry (see here). In that case based on the study by Amit Shah and colleagues [2] the suggestion was that: "In adults younger than 40 years, depression and history of attempted suicide are significant independent predictors of premature CVD [cardiovascular disease] and IHD [ischemic heart disease] mortality in both sexes." Again, slightly sombre reading.

"Participants with depression, compared with those free of it, experienced a significant
increased risk of 30% for CHD and MI. Furthermore, the association remained significant in
the groups adjusted for potential confounders, such as lifestyle factors and socio-demographic
factors." An important summary from Gan and colleagues highlighting how, whilst their data did point to an increased risk of CHD and MI in relation to depression, one has to be slightly careful in how one communicates the words 'increased risk' and what a 30% risk might translate into in the real world.

Without exceeding the scope of this blog, and in particular my caveats about not giving anything that looks, sounds or smells like medical or clinical advice, I was interested in some discussion by Gan on the potential role of antidepressants to "reduce the risk of development of CHD." They suggested that it may not be as easy as such intervention just impacting on heart health as well as psychological health even though other studies have suggested some beneficial effect [3] to be had from certain antidepressants. I've talked before on this blog about depression and some of the slightly more alternative ways that have been put forward to manage symptoms as per the rise and rise of something like anti-inflammatory strategies for example (see here). If for example, one is to assume that exercise (also included in that post on potential strategies to manage depression) might also be a potentially important tool for at least some types of depression, might it also have some effect to mitigate risk of adverse heart conditions too?

Music to close. When footballers sing.... Glenn & Chris - Diamond Lights (in the 1980s).

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[1] Gan Y. et al. Depression and the risk of coronary heart disease: a meta-analysis of prospective cohort studies. BMC Psychiatry 2014, 14:371

[2] Shah AJ. et al. Depression and history of attempted suicide as risk factors for heart disease mortality in young individuals. Archives of General Psychiatry. 2011: 68: 1135-1142.

[3] Pizzi C. et al. Meta-analysis of selective serotonin reuptake inhibitors in patients with depression and coronary heart disease. Am J Cardiol. 2011 Apr 1;107(7):972-9.

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Gan Y, Gong Y, Tong X, Sun H, Cong Y, Dong X, Wang Y, Xu X, Yin X, Deng J, Li L, Cao S, & Lu Z (2014). Depression and the risk of coronary heart disease: a meta-analysis of prospective cohort studies. BMC psychiatry, 14 (1) PMID: 25540022

An inflammatory autism subtype?

The paper from Harumi Jyonouchi and colleagues [1] (open-access) continues a theme from this author with their suggestion of "an imbalance in the production of inflammatory (IL-1ß and IL-6) and counterregulatory (IL-10) cytokines by ‘flare’ ASD-IS [autism spectrum disorder - inflammatory subtype] monocytes".

Panic on the streets of Birmingham...

'Flare' ASD-IS in this case refers to a coding given to a small participant group (n=24) who were: "defined as those with a history of fluctuating behavioral symptoms following immune insults (mainly microbial infection)" and who experienced: "worsening behavioral symptoms following immune insults, despite the resolution of acute conditions such as viral syndrome (that is, the resolution of other infectious symptoms if associated with a microbial infection, lack of fever, and no other acute physical symptoms associated with immune insults)".

Innate immune system functions (yes, cytokines again) were measured in flare ASD-IS and compared with results from other groups: (i) controls with autism with a history of "non-IgE mediated food allergy (NFA)" (n=20), (ii) ASD/non-NFA controls (n=20), and (iii) "three groups of non-ASD controls (non-ASD/NFA subjects (N =16), those diagnosed with pediatric acute onset-neuropsychiatric syndrome (PANS, N =18), and normal controls without NFA or PANS (N =16))". For those unfamiliar with the term PANS - pediatric acute onset-neuropsychiatric syndrome - this is a term originating from PANDAS (see here) and denotes an important condition bridging the link between infection and psychiatric symptomatology [2]. As if you needed telling...

Authors concluded that: "‘Flare’ ASD-IS PB Mo [peripheral blood monocytes] produced higher amounts of inflammatory cytokines (IL-1β and IL-6) without stimuli than ‘non-flare’ ASD-IS cells". They concluded that their findings: "support parental impression of worsening behavioral symptoms in the ‘flare’ state following immune insults" on the basis of the immune findings also linking in with behavioural descriptions at the time of sample collections.

Whilst including relatively small participant groups, it is the spread of presentations (not just based on diagnosis) which makes this paper stand out. I note that the authors also report that their results may: "indicate a possibility that monocytes from ASD-IS children also have intrinsic defects in regulatory mechanisms of IL-10 production". This is again, potentially important. Although there is still some misconception that cytokines are binary in function (either pro-inflammatory or anti-inflammatory) when the emerging data are suggesting it is very much more complicated than that (see here), the authors are hinting that inflammation with regards to autism may actually be down to issues with the opposing anti-inflammatory response over and above an upregulated pro-inflammatory response. Sort of like a fire tender not carrying enough water to put out a blaze. Indeed, work from this research team had previously hinted as much [3] (see also my previous post on this paper) as have other studies [4].

I am looking forward to seeing this research independently followed-up and reported on to further characterise those people with autism who such results are potentially relevant to. Whether gastrointestinal (GI) symptoms and dietary intervention might also be important factors [5] in such immune responses, also offers some potentially tantalising options for intervention...

Music to close: Rhapsody In Blue.

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[1] Jyonouchi H. et al. Cytokine profiles byperipheral blood monocytes are associated with changes in behavioral symptoms following immune insults in a subset of ASD subjects: an
inflammatory subtype? Journal of Neuroinflammation. 2014, 11:187

[2] Chang K. et al. Clinical Evaluation of Youth with Pediatric Acute Onset Neuropsychiatric Syndrome (PANS): Recommendations from the 2013 PANS Consensus Conference. J Child Adolesc Psychopharmacol. 2014 Oct 17.

[3] Jyonouchi H. et al. Immunological characterization and transcription profiling of peripheral blood (PB) monocytes in children with autism spectrum disorders (ASD) and specific polysaccharide antibody deficiency (SPAD): case study. J Neuroinflammation. 2012 Jan 7;9:4.

[4] Estes ML. & McAllister AK. Alterations in Immune Cells and Mediators in the Brain: It's Not Always Neuroinflammation! Brain Pathol. 2014 Nov;24(6):623-30.

[5] Jyonouchi H. et al. Dysregulated innate immune responses in young children with autism spectrum disorders: their relationship to gastrointestinal symptoms and dietary intervention. Neuropsychobiology. 2005;51(2):77-85.

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Jyonouchi H, Geng L, & Davidow AL (2014). Cytokine profiles by peripheral blood monocytes are associated with changes in behavioral symptoms following immune insults in a subset of ASD subjects: an inflammatory subtype? Journal of neuroinflammation, 11 (1) PMID: 25344730

Treating depression: exercise or anti-inflammatory meds?

Reiterating my primary caveat on this blog about not giving anything that looks, sounds or smells like medical and/or clinical advice, I'm bringing three papers to the research blogging table today, all published in the JAMA journal family and all talking about depression / depressive symptoms.

See my hat... @ Wikipedia 

First up is the paper by Ole Köhler and colleagues [1] reviewing "the antidepressant and possible adverse effects of anti-inflammatory interventions". Some media interest in this study can be found here. For those who might not know, there is a growing 'feeling' that the various links being made between inflammation or inflammatory mechanisms and psychiatry (see here) may well also extend into the area of depression or depressive symptoms. Far be it from me to say that inflammation and depression is a 'done deal' in scientific terms, but when reading research papers with titles like: 'So depression is an inflammatory disease, but where does the inflammation come from?' by Michael Berk and colleagues [2] (open-access) one kinda gets the impression that quite a lot of opinion has already come down on the side of a probable link.

The Köhler paper looked at the combined peer-reviewed literature on the use of various anti-inflammatory medication strategies previously trialled "in adults with depressive symptoms, including those who fulfilled the criteria for depression" including the use of "nonsteroidal anti-inflammatory drugs (NSAIDs)" and "cytokine inhibitors". Cytokines, inflammation and psychology is a topic which has graced this blog on previous occasions (see here). The authors concluded that whilst there is quite a bit more to do in this area: "This study supports a proof-of-concept concerning the use of anti-inflammatory treatment in depression. Identification of subgroups that could benefit from such treatment might be warranted". Touché.

Next up are the papers by Snehal M. Pinto Pereira and colleagues [3] and Umar Toseeb and colleagues [4] both talking about a possible role for physical activity and exercise when it comes to the presentation of depression. The results were a little mixed; Pinto Pereira et al concluding that during adult life "activity may alleviate depressive symptoms in the general population" as a function of "a trend of fewer depressive symptoms with more frequent activity". By contrast, Toseeb et al looking at physical activity (PA) "and depressive symptoms during 3 years of adolescence" noted no "longitudinal association between objectively measured PA and the development of depressive symptoms". Indeed they quite prominently recorded a lack of support for PA being protective against developing depressive-type symptoms in their teenage group.

There are some differences in the way that the Pinto Pereira and Toseeb research groups went about looking at their respective cohorts and the differences in age between their participants is certainly worth noting. Just correlating two variables is also likely to omit other significant factors (such as inflammation!) which might also show some involvement in the onset or continuation of depression/depressive symptoms. That being said I hark back to other reviews on this topic such as the meta-analysis by Mammen & Faulkner [5] as detailing the bigger picture, denoting some "promising evidence that any level of PA, including low levels (e.g., walking <150 minutes/weeks), can prevent future depression".

If we are to assume that anti-inflammatory medication and physical activity (at least for some) can impact on depression or depressive symptoms, the next question really needs to be: what could unite these two findings if anything? Yes, anti-inflammatory meds impact on inflammatory processes, but does this mean that exercise could be doing the same? I found quite a bit of peer-reviewed literature in this area talking about acute and chronic exercise and its short- and long-term effects on inflammation and inflammatory markers (see here for a summary). The long-and-short of it is that nobody really knows at present and, once again, there is quite a lot of merit for the N=1 in this area of study.

I might however also advance a couple of other ideas potentially worth looking into. First is the impact that inflammation / anti-inflammatory techniques and exercise have on an important region: the gut microbiota. Those trillions of wee beasties which reside in our deepest, darkest recesses doing so much more than just helping us digest our food are seemingly cropping up everywhere these days (see here for example). The idea that certain elements of our bacterial passengers might also show involvement with something like depression in a sort of gut-brain axis manner is by no means a new concept as per previous discussions on this blog (see here). Research hinting that exercise may also impact on the gut microbiota [6] particularly when it comes to the diversity of bacteria to be present, offers something a glimpse into how exercise may provide effects. Gut bacteria diversity and depression is however still wanting in research terms...

Second up, and potentially related to the gut microbiota [7] is the introduction of some epigenetic effect from both anti-inflammatory strategies and exercise when it comes to depression. The science of epigenetics has again been something of a talking point on this blog (see here and see here) from quite a few behavioural perspectives down the years. The idea being that above and beyond your structural genome, there is an added layer of chemical complexity pertinent to the switching on or off of genes which might influence risk for all manner of things. Hype aside, there is growing evidence looking at epigenetic mechanisms being potentially pertinent to depression [8] (open-access) although the precise hows and whys remain somewhat elusive. At the same time, the epigenetics of exercise is also an up-coming area [9] albeit with further investigation needed. Marrying the two concepts together - the epigenetics of exercise and depression - might be a good research idea because at present, there is something of a void in this area. That being said, the epigenetics of immune functions is an area of some note (see here).

I really hope that I've not gone beyond my blogging remit with this post in emphasising the potential links between depression, inflammation and physical activity. By no means did I intend to boil something like depression down to just a lack of exercise or inflammation running amok, given the complexity of the condition and the seemingly many ways that one can arrive at the condition. Similar things were noted in a recent post on zinc and depression (see here). At the very least, I'd like to think my musings are nothing like as sweeping as suggesting that major depression is "an infectious disease" [10]. I do however think that the further moves by disciplines like psychiatry to understanding conditions like depression as potential 'whole body' conditions (either in causation or manifestation) brings us closer to understanding how one might further alleviate the often severe symptoms of depression and, to some degree, potentially mitigate signs and symptoms before they ever get the chance to severely impact on a person's life.

Music to close, and what else but Physical by Olivia Newton-John.

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[1] Köhler O. et al. Effect of Anti-inflammatory Treatment on Depression, Depressive Symptoms, and Adverse Effects. JAMA Psychiatry. 2014. October 15.

[2] Berk M. et al. So depression is an inflammatory disease, but where does the inflammation come from? BMC Med. 2013; 11: 200.

[3] Pinto Pereira SM. et al. Depressive Symptoms and Physical Activity During 3 Decades in Adult Life. JAMA Psychiatry. 2014. October 15.

[4] Toseeb U. et al. Exercise and Depressive Symptoms in Adolescents. JAMA Pediatrics. 2014. October 13.

[5] Mammen G. & Faulkner G. Physical activity and the prevention of depression: a systematic review of prospective studies. Am J Prev Med. 2013 Nov;45(5):649-57.

[6] Clarke SF. et al. Exercise and associated dietary extremes impact on gut microbial diversity. Gut. 2014 Jun 9. pii: gutjnl-2013-306541.

[7] Stilling RM. et al. Microbial genes, brain & behaviour - epigenetic regulation of the gut-brain axis. Genes Brain Behav. 2014 Jan;13(1):69-86.

[8] Vialou V. et al. Epigenetic Mechanisms of Depression and Antidepressants Action. Annu Rev Pharmacol Toxicol. 2013; 53: 59–87.

[9] Ntanasis-Stathopoulos J. et al. Epigenetic regulation on gene expression induced by physical exercise. J Musculoskelet Neuronal Interact 2013; 13(2):133-146

[10] Canli T. Reconceptualizing major depressive disorder as an infectious disease. Biology of Mood & Anxiety Disorders 2014, 4:10.

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Ole Köhler, Michael E. Benros, Merete Nordentoft, Michael E. Farkouh, Rupa L. Iyengar, Ole Mors, & Jesper Krogh (2014). Effect of Anti-inflammatory Treatment on Depression, Depressive Symptoms, and Adverse Effects JAMA Psychiatry : doi:10.1001/jamapsychiatry.2014.1611



Snehal M. Pinto Pereira, Marie-Claude Geoffroy, & Christine Power (2014). Depressive Symptoms and Physical Activity During 3 Decades in Adult Life JAMA Psychiatry : doi:10.1001/jamapsychiatry.2014.1240





Toseeb, U., Brage, S., Corder, K., Dunn, V., Jones, P., Owens, M., St Clair, M., van Sluijs, E., & Goodyer, I. (2014). Exercise and Depressive Symptoms in Adolescents JAMA Pediatrics DOI: 10.1001/jamapediatrics.2014.1794