Acute bipolar depression and immune alterations

"Individuals with acute bipolar depression show immune alterations. Some of the alterations are similar to those found in acute mania."

That was the bottom line reported by Faith Dickerson and colleagues [1] following their analysis of blood samples provided by "82 individuals with acute bipolar depression, 147 with acute mania, and 280 controls." Looking for the presence of various antibodies to "human herpesviruses, gliadin, Toxoplasma gondii, and endogenous retroviruses as well as for C-reactive protein (CRP) and pentraxin-3" in said samples, researchers reported a few potentially important findings.

So: "The levels of CRP and IgG antibodies to an endogenous retrovirus, Mason-Pfizer monkey virus (MPMV), were significantly elevated in the bipolar depressed group." Further: "Levels of pentraxin-3 were reduced in both psychiatric groups." Researchers also reported that for 32 individuals who were hospitalised (and I assume treated) for bipolar depression, they "showed a significant decrease in the levels of MPMV antibodies, but not a change in the other markers."

Looking through the list of antigens included for analysis, without looking at the authorship list, I could have told you that the authors Faith Dickerson and/or Robert Yolken were involved in this study based on what has been discussed before on this blog (see here and see here for example). The work coming out of Johns Hopkins has been particularly interesting with their focus on "the role of infectious and inflammatory processes in complex psychiatric disease such as schizophrenia, bipolar disorder, and autism." Their most recent work on pentraxin-3 looks very interesting indeed (see here) and complements their most recent results.

The finding of elevations in the levels of CRP in the "bipolar depressed group" fits in well with the idea of inflammation being somehow involved in psychiatry (see here) and seemingly crossing diagnostic labels (see here). One might reasonable ask whether the research voices are indeed getting stronger for the potential usefulness of 'treating inflammation' when it comes to something like depression (see here) bearing in mind no clinical or medical advice is given or intended.

Finally, is that "endogenous retrovirus" finding reported by Dickerson et al. Regular readers of this blog might already know that I'm an avid [amateur] follower of the idea that all those fossil viruses that lurk in our genomes might be some much more than just junk DNA. With schizophrenia in mind (see here), with attention-deficit hyperactivity disorder (ADHD) in mind (see here), with autism in mind (see here), even with chronic fatigue syndrome / myalgic encephalomyelitis (CFS/ME) in mind (see here), I've covered the topic a few times on this blog. Although never coming across MPMV before, this is not the first time that antibodies to non-human primate viruses have been talked about with psychiatric / behavioural conditions in mind [2]. Indeed a previous paper from Dickerson and colleagues [3] even went as far as suggesting that as part of suite of inflammatory markers, the presence and elevation of MPMV antibodies is likely derived "from the activation of homologous endogenous retroviruses and to be a reflection of immune activation." Similar sentiments seem to carry over to the most recent results too.

Music: Doves - There Goes The Fear.

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[1] Dickerson F. et al. Immune alterations in acute bipolar depression. Acta Psychiatr Scand. 2015 Jun 9.

[2] Lillehoj EP. et al. Serum antibodies reactive with non-human primate retroviruses identified in acute onset schizophrenia. J Neurovirol. 2000 Dec;6(6):492-7.

[3] Dickerson F. et al. A combined marker of inflammation in individuals with mania. PLoS One. 2013 Sep 3;8(9):e73520.

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Dickerson F, Katsafanas E, Schweinfurth LA, Savage CL, Stallings C, Origoni A, Khushalani S, Lillehoj E, & Yolken R (2015). Immune alterations in acute bipolar depression. Acta psychiatrica Scandinavica PMID: 26061032

Predicting the onset of schizophrenia?

"A lower level of inflammatory response indicated by PTX3 [pentraxin-3] might be implicated in developing schizophrenia."

That was the primary conclusion reported by Natalya Weber and colleagues [1] (open-access here) who "tested preonset serum specimens from 160 US military service members who were later diagnosed with schizophrenia or bipolar disorder and 160 matched controls without psychiatric disorders."

PTX-3 by the way, is a compound of some note when it comes to the concept of inflammation, residing in the same family as a better known inflammatory-related compound, C-reactive protein (CRP) (see here). The difference between CRP and PTX-3 seems to be down to CRP being a 'short' pentraxin and PTX-3 being a 'long' one.

Weber et al assessed levels of PTX-3 in "first available serum specimens" of 160 military personnel who were "later diagnosed with schizophrenia or bipolar disorder" (n=80 respectively) and compared them with 160 matched controls. As per other work by authors on the Weber paper [2], using military cohorts has some significant advantages when it comes to potential biomarker work in this area (see here). They reported that: "PTX3 levels among subjects with schizophrenia were significantly lower... than the levels among their paired controls" thus indicating that prior to the onset of schizophrenia, PTX-3 levels might be something to watch for risk of developing the condition. The authors even went as far as to say that: "a level of PTX3 below the median (0.6 ng/ml) was associated with an OR [odds ratio] of 3.0 (CI, 1.6–5.7)" when it came to risk of subsequent schizophrenia.

This is interesting data which, as the authors point out, is strengthened by "including the follow-up of an initially disease-free population with subsequent complete and reliable case/control ascertainment" alongside the collection of biological samples "years before disease onset". Military personnel are screened and screened over their time serving, thus making this population about as valuable to research as all those archived newborn bloodspot cards that I'm so interested in (see here). The authors do caution that their results may not be entirely generalisable to the population at large as a result of their 'captive audience' (how many civvies spend their days like military personnel?) but the strengths of the study perhaps outweigh the limitations.

The idea that the immune system and the orchestration of its arsenal of compounds might be perturbed when it comes to a behavioural/psychiatric condition like schizophrenia is by no means a new idea (see here for example). That being said, science is still fumbling around trying to make sense of the idea that immune function / inflammation might impact on something like schizophrenia and the specific hows and whys of the relationship. Weber et al do speculate on what their results might mean as per comments that: "Long-lasting or temporal lack of PTX3 could potentially impact pathogen recognition, activation, and orientation of the adaptive immune response and/or antibody production." Further: "Impairment of any of these functions, particularly those where PTX3 plays its unique role, could lead to a vulnerability to the neurotropic pathogens associated with schizophrenia and bipolar disorder." Part of those 'neurotropic pathogens' must surely include the body of work referring to a possible role for Toxoplasma gondii in relation to some schizophrenia (see here).

Interestingly also the authors talk about how their findings might relate to the issue of autoimmunity and how their findings might be contributory to immune system "derailment into a dysregulated state of autoimmune activation and damage." As per my discussions on autism and autoimmunity (see here for example) I do think there is a lot more to see in this particular area with schizophrenia also in mind (see here), perhaps also mediated by some interesting connections to the human endogenous retroviruses (HERVs) among other things. And yes, before you ask, HERVs have been implicated in cases of schizophrenia and perhaps even with the words 'molecularly mimicry' and 'superantigen' in mind [3].

More research in this area please.

Music: Björk - Hyperballad.

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[1] Weber NS. et al. Predictors of the Onset of Schizophrenia in US Military Personnel. J Nerv Ment Dis. 2015 May;203(5):319-24.

[2] Niebuhr DW. et al. Association between bovine casein antibody and new onset schizophrenia among US military personnel. Schizophr Res. 2011 May;128(1-3):51-5.

[3] Brodziak A. et al. The role of human endogenous retroviruses in the pathogenesis of autoimmune diseases. Med Sci Monit. 2012 Jun;18(6):RA80-8.

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Weber NS, Larsen RA, Yolken RH, Cowan DN, Boivin MR, & Niebuhr DW (2015). Predictors of the Onset of Schizophrenia in US Military Personnel. The Journal of nervous and mental disease, 203 (5), 319-24 PMID: 25919381