Inflammation an Accurate Biomarker for Bipolar Disorder?

Nancy A. Melville

November 22, 2016

Levels of C-reactive protein (CRP), a known biomarker of inflammation, are elevated across all mood states in patients with bipolar disorder, with higher levels occurring during periods of mania, new research shows.

"In my opinion, CRP shows great promise as a biomarker, helping to define who would benefit most from treatments that target inflammation, which is one of the major goals of precision medicine ― defining who will, and will not, benefit from each treatment," senior author Brisa S. Fernandes, PhD, of the Deakin University School of Medicine, in Geelong, Victoria, Australia, told Medscape Medical News.

The study was published online November 9 in Lancet Psychiatry.

CRP Screening Warranted?

Currently there are no reliable biomarkers for bipolar disorder, although evidence points to CRP as a possible candidate. According to the "immune hypothesis," an increase in immune activation could be associated with a number of psychiatric illnesses, including bipolar disorder.

For the meta-analysis and systemic review, the authors identified 27 studies, which included 2161 patients with bipolar disorder and 81,932 healthy control persons.

Evaluation of data regarding CRP concentrations showed that for those with bipolar disorder, CRP levels were higher during periods of depression (Hedges' adjusted g, 0.67; P = .003), euthymia (Hedges' adjusted g, 0.65; P < .0001), and, more significantly, mania (Hedges' adjusted g, 0.87; P < .0001).

Increases in CRP concentrations were not related to symptom severity in mania or depression; however, concentrations were moderately decreased after resolution of an index manic episode (P = .02) and were slightly decreased after an index depressive episode (P = .002).

CRP concentrations were not found to increase with duration of bipolar disorder.

Although psychiatric medications have been associated with increases in CRP concentrations, the analysis showed that in those patients taking medications for mania and depression, CRP concentrations were lower than in those patients who were not receiving medication.

Those findings are consistent with previous evidence indicating benefits in the treatment of some psychiatric disorders with anti-inflammatory medication, such as aspirin and statins.

In a meta-analysis published this year by the same team of researchers, statins showed efficacy as an add-on treatment of symptoms in moderate to severe depression and warranted further investigation.

"Whether statins and other anti-inflammatory agents have a role in the treatment of depression in the context of bipolar disorder remains to be determined," the authors note.

Dr Fernandes said CRP appears to represent an important measure to consider in the treatment of bipolar disorder.

"As a psychiatrist myself, I would assess CRP levels in all of my patients," she said.

"High CRP levels are a well-defined [marker] of cardiovascular risk, and the use of drugs such as statins decrease CRP levels and incidence of myocardial infarction and stroke.

"Since bipolar disorder is also associated with increased cardiovascular risk, that would be another reason for the routine evaluation of CRP in the disorder."

Supporting Evidence

The authors of an accompanying commentary point out that medications for bipolar disorder, including lithium and valproic acid, as well as some antidepressants have been shown to have anti-inflammatory effects. One intriguing study suggested that for patients who respond to lithium, CRP concentrations may be significantly reduced after treatment compared to patients who do not respond.

Another important study of the use of the anti-inflammatory agent infliximab as an add-on therapy for patients with depression found no effect overall, with an important exception of patients with CRP levels higher than 5 mg/L. Those patients experienced significant reductions in depressive symptoms.

"[The findings] suggest that CRP could be a marker for treatment response, which is interesting," editorial coauthor Marie Wium-Andersen, MD, of the Psychiatric Center Frederiksberg, in Denmark, told Medscape Medical News.

An even more important question the research raises is whether elevations in CRP concentrations and inflammation play a causative role in bipolar disorder. If so, anti-inflammatory treatment could have a preventive effect.

But Dr Wium-Andersen notes the importance of distinguishing between CRP and inflammation as causative factors in considering such theories.

"The first would suggest that, could the CRP level alone be lowered, risk of bipolar disorder would decrease, which I don't really believe," she said.

"Rather, I think inflammation is a risk factor for bipolar disorder, but, importantly, not the only one, and maybe only in a subgroup of vulnerable patients," Dr Wium-Andersen explained.

She compared the relationship between inflammation and bipolar disorder to the relationship between diabetes and cardiovascular disease (CVD), for which diabetes is a risk factor.

"Not all patients with cardiovascular disease have diabetes, and lowering the blood glucose level in all CVD patients may not be beneficial.

"At the moment, too little is really known about how inflammation may cause bipolar disorder and how it may be treated or prevented."

The authors of the study and the commentary have disclosed no relevant financial relationships.

Lancet Psychiatry. Published online November 9, 2016. Abstract, Commentary

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