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