Susan Jeffrey

May 22, 2013

SAN FRANCISCO — A new study shows a link between elevated levels of C-reactive protein (CRP) and increased risk for late- and very-late-onset schizophrenia.

CRP has previously been linked to increased risk for cardiovascular disease, and more recently, in a study by these same researchers, with risk for depression. In this prospective study, elevated baseline levels of CRP were associated with a significantly increased risk for late-onset and very-late-onset schizophrenia in a general population in Denmark.

"These are novel findings," the researchers, with lead author Marie Kim Wium-Andersen, MD, from the Department of Clinical Biochemistry at Herlev Hospital and the Copenhagen University Hospital in Denmark, conclude.

"We had up to 19 years of follow-up, and after adjusting for all the other factors that would also increase CRP — smoking, body mass index, alcohol, education, income, diabetes, and all risk factors — we still saw significantly increased risk of schizophrenia; for those who had even very small elevations of CRP, they still have a 6-times increased risk for schizophrenia," Dr. Wium-Andersen told Medscape Medical News.

Their findings were presented here at the American Psychiatric Association's 2013 Annual Meeting.

Inflammatory Markers

Previous studies have shown that people with autoimmune disease and severe infections have elevated inflammatory markers and an increased risk for schizophrenia, the researchers note. "That's actually what our study supports, but also that you see it for only very minor elevations of inflammatory markers," Dr. Wium-Andersen notes. Although a frank infection may increase CRP to levels on the order of 30 to 100 mg/L, they were examining the association of schizophrenia with chronic CRP elevations of 2 to 3 mg/L.

Dr. Marie Kim Wium-Andersen

For this study, they used data on CRP measured in 78,810 randomly selected men and women between the ages of 20 and 100 years participating in 2 large population-based studies, the Copenhagen General Population Study, and the Copenhagen City Heart Study.

During 19 years of follow-up, they recorded information on hospitalizations for schizophrenia — mainly late- and very-late-onset schizophrenia — and schizophrenialike psychosis from the national Danish Patient Registry. In all, there were 37 hospitalizations for schizophrenia, and 86 for schizophrenialike psychosis.

"And what we found is that those in the fourth quartile (of CRP) were very significantly more at risk of being hospitalized for schizophrenia in the future," Dr. Wium-Andersen said.

Table. Adjusted Risk for Hospitalization for Schizophrenia by C-Reactive Protein Level

Quartile Odds Ratio 95% Confidence Interval
Quartile 1 1.00 (reference)  
Quartile 2 1.6 0.3 - 8.4
Quartile 3 1.7 0.3 - 8.6
Quartile 4 5.9 1.4 - 24


In addition, the cumulative incidence of schizophrenia was increased among those with a CRP level in the fourth quartile vs the first to the third quartile, the authors report. Those with schizophrenia also had increased plasma levels of CRP, about 68% higher than those without schizophrenia.

Dr. Wium-Andersen pointed out that CRP is a marker of inflammation, and inflammatory markers such as cytokines affect neurotransmitters in the brain, particularly perhaps dopamine and serotonin. "It's also one of the mechanisms by which inflammation might contribute to depression, too," she noted.

One limitation of their study is that they did not have any data on the kinds of symptoms actually associated with CRP, she added. Because other studies have shown, for example, an association with especially positive symptoms or negative symptoms, it could be interesting to have further data on what symptoms are most related to elevated CRP. "Also, because we know that inflammation is associated with a lot of different psychiatric diseases, to know the mechanisms better, I think it would be interesting to know the symptoms which are affected or caused by the inflammation."

Pathogenesis of Schizophrenia

Asked for comment on these findings, R. Scott Hamilton, MD, a psychiatrist at the Mclean County Center for Human Services in Bloomington, Illinois, called them interesting, and he said he anticipates that CRP testing would be relatively inexpensive, which would make it attractive as a screening test.

Dr. R. Scott Hamilton

"The question I would have is what percentage of the late-onset schizophrenia sufferers have elevated CRP," he told Medscape Medical News. "Even though individuals in the highest quartile are 4.7 times more likely to be afflicted, it still may be a small percentage, in which case it would not be a very good screening tool."

"What might be of more use is if these results might help us understand the pathogenesis of schizophrenia and/or help differentiate subtypes and treatment response," Dr. Hamilton said.

The American Psychiatric Association's 2013 Annual Meeting. Abstract NR10-23. Presented May 21, 2013.


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