Friday, 11 July 2014

Maternal C-Reactive Protein (CRP) and offspring schizophrenia

A big quote to start this post: "This finding provides the most robust evidence to date that maternal inflammation may play a significant role in schizophrenia, with possible implications for identifying preventive strategies and pathogenic mechanisms in schizophrenia and other neurodevelopmental disorders".
Ophelia @ Wikipedia 

The source for this quote was the paper by Sarah Canetta and colleagues [1] based on an analysis of serum samples from mums for C-reactive protein (CRP) as part of the Finnish Prenatal Study of Schizophrenia cohort under the leadership (well, grant holding) of Prof. Alan Brown. Some media interest in this paper can be seen here.

Regular readers of this blog might have heard me talk about some of Prof. Brown's previous research, again with CRP in mind but with an autism research slant (see here). I'll come back to some of that work shortly alongside some more recent research [2] in that area.

In this latest paper, archived maternal serum samples related to nearly 800 people (offspring) diagnosed with schizophrenia or schizo-affective disorder were assayed for CRP and results compared with maternal CRP levels related to a similarly sized asymptomatic control group. "Increasing maternal C-reactive protein levels, classified as a continuous variable, were significantly associated with schizophrenia in offspring (adjusted odds ratio=1.31, 95% confidence interval=1.10-1.56)". Even after controlling for confounders including a parental "history of psychiatric disorders" results remained significant. Ergo, one marker of inflammation present and elevated in spot sera samples of mums may have some implications for subsequent development of offspring.

Having recently heard the sad news about the death of Paul Patterson (see his obituary here) my first thoughts turned to his valuable contributions to this area and the proposed maternal immune activation hypothesis of schizophrenia and autism [3] (open-access here). You'll note that Prof. Brown was the co-author on that last citation with Prof. Patterson, giving you a feel for how such research connections might fit together.

My second thought was slightly more of a critical one with the realisation that CRP whilst a good marker of the acute-phase response linked to inflammation [4] may not necessarily present the whole picture when measured in a spot sample fashion or without reference to the multitude of other compounds reactive to an inflammatory status. Think cytokines for example (see here). I note also in the latest paper that maternal levels of CRP were the focus, and not specifically CRP levels in offspring with and without a diagnosis of schizophrenia. It would be interesting to see how the two measurements might correlate (or not). That being said, and as I've reported before, there is quite a body of evidence suggestive of on-going issues with CRP in at least a proportion of people on the schizophrenia spectrum. Inflammation and psychiatry seem to have some common ground (see here).

Going back to the CRP work with autism in mind, I do think there is a pattern emerging from the available peer-reviewed evidence suggestive that inflammation (excess inflammation or elevated markers of inflammation?) during critical periods of pregnancy might have some connection with later offspring outcomes. The processes potentially relevant to any association are still the source of some speculation, as are the various ways that inflammation might come about: air pollution (see here), maternal obesity (see here), etc. Take yer pick, accepting that genetics and/or epigenetics are probably also going to play a role. What remains to be seen is how the idea of mitigating inflammation - however one goes about doing this - during those critical periods of pregnancy may impact on offspring risk of developmental or psychiatric outcomes. Indeed, as the paper from Patterson and Brown [3] concluded: "It has been suggested that the overall decline in bacterial illnesses due to antibiotic therapy and the initiation of immunization programs may be at least partially responsible for the reduction in the incidence of schizophrenia in certain countries in the last several decades". Does this mean such strategies have already impacted on some of the prevalence figures?


[1] Canetta S. et al. Elevated Maternal C-Reactive Protein and Increased Risk of Schizophrenia in a National Birth Cohort. Am J Psychiatry. 2014 Jun 27. doi: 10.1176/appi.ajp.2014.13121579.

[2] Brown AS. et al. Elevated maternal C-reactive protein and autism in a national birth cohort. Mol Psychiatry. 2014 Feb;19(2):259-64.

[3] Brown AS. & Patterson PH. Maternal infection and schizophrenia: implications for prevention. Schizophr Bull. 2011 Mar;37(2):284-90.

---------- Canetta, S., Sourander, A., Surcel, H., Hinkka-Yli-Salomäki, S., Leiviskä, J., Kellendonk, C., McKeague, I., & Brown, A. (2014). Elevated Maternal C-Reactive Protein and Increased Risk of Schizophrenia in a National Birth Cohort American Journal of Psychiatry DOI: 10.1176/appi.ajp.2014.13121579