Data support the notion that 40–60% of patients with bipolar disorder (BD) have neurocognitive deficits. It is increasingly accepted that functioning in BD is negatively impacted by these deficits, yet they have not been a successful target for treatment. The biomarkers that predict cognitive deficits in BD are largely unknown, however recent evidence suggests that inflammation may be associated with poorer cognitive outcomes in BD. We measured C-reactive protein (CRP), a marker of systemic inflammation and risk of inflammatory disease, in 222 euthymic BD patients and 52 healthy controls. Within the patient sample, using multivariate analyses of covariance (MANCOVA) we compared cognitive performance of those with high CRP (≥5 mg/L) versus the remaining subjects (<5 mg/L) on a battery of cognitive tests. We evaluated relationships with several other relevant clinical features. We also examined the role of CRP in cognitive decline using a proxy cognitive decline metric, defined as the difference between premorbid and current IQ estimates, in a logistic regression analysis. Approximately 80% of our sample were BD-I, and the remainder were BD-II and 42.6% of our sample had a history of psychosis. We found a statistically significant effect of CRP on cognitive performance on a broad range of tests; participants with CRP ≥ 5 mg/L had worse performance on several measures of executive functioning, MATRICS processing speed and MATRICS reasoning and problem solving relative to those with lower CRP. We also identified CRP as a significant positive predictor of proxy cognitive decline. Our results indicate that elevated CRP is associated with a broad cognitive dysfunction in affectively remitted BD patients. These results may point to a subgroup of patients who might benefit from treatments to reduce inflammation.
Subscribe to Journal
Get full journal access for 1 year
only $62.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Leboyer M, Soreca I, Scott J, Frye M, Henry C, Tamouza R, et al. Can bipolar disorder be viewed as a multi-system inflammatory disease? J Affect Disord. 2012;141:1–10.
Berk M, Kapczinski F, Andreazza AC, Dean OM, Giorlando F, Maes M, et al. Pathways underlying neuroprogression in bipolar disorder: focus on inflammation, oxidative stress and neurotrophic factors. Neurosci Biobehav Rev. 2011;35:804–17.
Burdick KE, Ketter TA, Goldberg JF, Calabrese JR. Assessing cognitive function in bipolar disorder: challenges and recommendations for clinical trial design. J Clin Psychiatry. 2015;76:e342–50.
Burdick EK, Russo M, Frangou S, Mahon K, Braga JR, Shanahan M, et al. Empirical evidence for discrete neurocognitive subgroups in bipolar disorder: clinical implications. Psychol Med. 2014;44:3083–96.
Depp AC, Dev S, Eyler TL. Bipolar depression and cognitive impairment: shared mechanisms and new treatment avenues. Psychiatr Clin North Am. 2016;39:95–109.
Duffy A. Toward a comprehensive clinical staging model for bipolar disorder: integrating the evidence. Can J Psychiatry. 2014;59:659–66.
Budde M, Schulze TG. Neurocognitive correlates of the course of bipolar disorder. Harv Rev Psychiatry. 2014;22:342–7.
Samamé C, Martino DJ, Strejilevich SA. Longitudinal course of cognitive deficits in bipolar disorder: a meta-analytic study. J Affect Disord. 2014;164:130–8.
Misiak B, Stanczykiewicz B, Kotowicz K, Rybakowski KJ, Samochowiec J, Frydecka D. Cytokines and C-reactive protein alterations with respect to cognitive impairment in schizophrenia and bipolar disorder: a systematic review. Schizophr Res. 2018;192:16–29.
Dantzer R. Cytokine, sickness behavior, and depression. Immunol Allergy Clin North Am. 2009;29:247–64.
Fernandes BS, Steiner J, Molendijk ML, Dodd S, Nardin P, Gonçalves CA, et al. C-reactive protein concentrations across the mood spectrum in bipolar disorder: a systematic review and meta-analysis. Lancet Psychiatry. 2016;3:1147–56.
Howren MB, Lamkin DM, Suls J. Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom Med. 2009;71:171–86.
Prins BP, Abbasi A, Wong A, Vaez A, Nolte I, Franceschini N, et al. Investigating the causal relationship of C-reactive protein with 32 complex somatic and psychiatric outcomes: a large-scale cross-consortium Mendelian randomization study. PLoS Med. 2016. https://doi.org/10.1371/journal.pmed.1001976.
Johnsen E, Fathian F, Kroken AR, Steen MV, Jorgensen AH, Gjestad R, et al. The serum level of C-reactive protein (CRP) is associated with cognitive performance in acute phase psychosis. BMC Psychiatry. 2016;16. http://www.ncbi.nlm.nih.gov/pubmed/26973142.
Dickerson F, Stallings C, Origoni A, Vaughan C, Khushalani S, Yolken R. Elevated C-reactive protein and cognitive deficits in individuals with bipolar disorder. J Affect Disord. 2013;150:456–9.
HAMILTON M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23:56–62.
Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry. 1978;133:429–35.
Cannon-Spoor HE, Potkin SG, Wyatt RJ. Measurement of premorbid adjustment in chronic schizophrenia. Schizophr Bull. 1982;8:470–84.
Nuechterlein KH, Green MF, Kern RS, Baade LE, Barch DM, Cohen JD, et al. The MATRICS consensus cognitive battery, part 1: test selection, reliability, and validity. Am J Psychiatry. 2008;165:203–13.
Burdick EK, Goldberg ET, Cornblatt AB, Keefe SR, Gopin BC, Derosse P, et al. The MATRICS consensus cognitive battery in patients with bipolar I disorder. Neuropsychopharmacol Publ Am Coll Neuropsychopharmacol. 2011;36:1587–92.
Corporation TP. Wechsler Abbreviated Scale of Intelligence (WASI) manual. San Antonio, TX; The Psychological Corporation 1999.
Wilkinson GS. Wide Range Achievement Test 3. Wilmington, DE: Wide Range, Inc.; 1993.
Golden CJ. Stroop Color and Word Test: a manual for clinical and experimental uses. Chicago, IL: Stoelting, Co.; 1978.
Benton AL, Hamsher K, Rey GL, Sivan AB. Multilingual aphasia examination. Iowa City, IA: AJA Associates; 1994.
BERG EA. A simple objective technique for measuring flexibility in thinking. J Gen Psychol. 1948;39:15–22.
GRANT DA, BERG EA. A behavioral analysis of degree of reinforcement and ease of shifting to new responses in a Weigl-type card-sorting problem. J Exp Psychol. 1948;38:404–11.
Baron-Cohen S, Jolliffe T, Mortimore C, Robertson M. Another advanced test of theory of mind: evidence from very high functioning adults with autism or asperger syndrome. J Child Psychol Psychiatry. 1997;38:813–22.
Goldberg TE, Torrey EF, Gold JM, Bigelow LB, Ragland RD, Taylor E, et al. Genetic risk of neuropsychological impairment in schizophrenia: a study of monozygotic twins discordant and concordant for the disorder. Schizophr Res. 1995. https://doi.org/10.1016/0920-9964(95)00032-H.
Kremen WS. The ‘3 Rs’ and neuropsychological function in schizophrenia: an empirical test of the matching fallacy. Neuropsychology. 1996. https://doi.org/10.1037/0894-4188.8.131.52.
Bernstein DP, Fink L. Childhood trauma questionnaire: a retrospective self-report: manual. Orlando: Harcourt Brace & Co: Orlando; 1998. https://www.worldcat.org/title/childhood-trauma-questionnaire-a-retrospective-self-report-manual/oclc/728667748. Accessed 30 Jul 2019.
Chung K-H, Huang S-H, Wu J-Y, Chen P-H, Hsu J-L, Tsai S-Y. The link between high-sensitivity C-reactive protein and orbitofrontal cortex in euthymic bipolar disorder. Neuropsychobiology. 2013;68:168–73.
Kapczinski F, Magalhães PVS, Balanzá-Martinez V, Dias VV, Frangou S, Gama CS, et al. Staging systems in bipolar disorder: an International Society for Bipolar Disorders Task Force Report. Acta Psychiatr Scand. 2014;130:354–63.
Gibson-Smith D, Bot M, Paans NPG, Visser M, Brouwer I, Penninx BWJH. The role of obesity measures in the development and persistence of major depressive disorder. J Affect Disord. 2016. https://doi.org/10.1016/j.jad.2016.03.032.
Wium-Andersen MK, Ørsted DD, Nordestgaard BG. Elevated C-reactive protein and late-onset bipolar disorder in 78,809 individuals from the general population. Br J Psychiatry. 2016. https://doi.org/10.1192/bjp.bp.114.150870.
Baumeister D, Akhtar R, Ciufolini S, Pariante CM, Mondelli V. Childhood trauma and adulthood inflammation: a meta-analysis of peripheral C-reactive protein, interleukin-6 and tumour necrosis factor-α. Mol Psychiatry. 2015;21:642–9.
Hoofnagle JH, Seeff LB. Peginterferon and ribavirin for chronic hepatitis C. N Engl J Med. 2006;355:2444–51.
Udina M, Castellví P, Moreno-España J, Navinés R, Valdés M, Forns X, et al. Interferon-induced depression in chronic hepatitis C: a systematic review and meta-analysis. J Clin Psychiatry. 2012;73:1128–38.
Valkanova V, Ebmeier KP, Allan CL. CRP, IL-6 and depression: a systematic review and meta-analysis of longitudinal studies. J Affect Disord. 2013;150:736–44.
Gimeno D, Kivimäki M, Brunner EJ, Elovainio M, De Vogli R, Steptoe A, et al. Associations of C-reactive protein and interleukin-6 with cognitive symptoms of depression: 12-year follow-up of the Whitehall II study. Psychol Med. 2009;39:413–23.
Felger JC, Haroon E, Patel TA, Goldsmith DR, Wommack EC, Woolwine BJ, et al. What does plasma CRP tell us about peripheral and central inflammation in depression? Mol Psychiatry. 2018. https://doi.org/10.1038/s41380-018-0096-3.
Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008;9:46–56.
Hsuchou H, Kastin AJ, Mishra PK, Pan W. C-reactive protein increases BBB permeability: implications for obesity and neuroinflammation. Cell Physiol Biochem. 2012;30:1109–19.
Kim H-W, Rapoport IS, Rao SJ. Altered expression of apoptotic factors and synaptic markers in postmortem brain from bipolar disorder patients. Neurobiol Dis. 2010;37:596–603.
Rao SJ, Harry JG, Rapoport IS, Kim WH. Increased excitotoxicity and neuroinflammatory markers in postmortem frontal cortex from bipolar disorder patients. Mol Psychiatry. 2010;15:384–92.
Rosenblat JD, Kakar R, Berk M, Kessing LV, Vinberg M, Baune BT, et al. Anti-inflammatory agents in the treatment of bipolar depression: a systematic review and meta-analysis. Bipolar Disord. 2016. https://doi.org/10.1111/bdi.12373.
Rapado-Castro M, Dodd S, Bush AI, Malhi GS, Skvarc DR, On ZX, et al. Cognitive effects of adjunctive N-acetyl cysteine in psychosis. Psychol Med. 2017. https://doi.org/10.1017/S0033291716002932.
Raison CL, Rutherford RE, Woolwine BJ, Shuo C, Schettler P, Drake DF, et al. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry. 2013;70:31–41.
Leboyer M, Kupfer DJ. Bipolar disorder: new perspectives in health care and prevention. J Clin Psychiatry. 2010;71:1689–95.
Raison CL, Pikalov A, Siu C, Tsai J, Koblan K, Loebel A. C-reactive protein and response to lurasidone in patients with bipolar depression. Brain Behav Immun. 2018;73:717–24.
Yatham LN, Mackala S, Basivireddy J, Ahn S, Walji N, Hu C, et al. Lurasidone versus treatment as usual for cognitive impairment in euthymic patients with bipolar I disorder: a randomised, open-label, pilot study. Lancet Psychiatry. 2017;4:208–17.
Gunstad J, Bausserman L, Paul RH, Tate DF, Hoth K, Poppas A, et al. C-reactive protein, but not homocysteine, is related to cognitive dysfunction in older adults with cardiovascular disease. J Clin Neurosci. 2006;13:540–6.
Kilbourne AM, Cornelius JR, Han X, Pincus HA, Shad M, Salloum I, et al. Burden of general medical conditions among individuals with bipolar disorder. Bipolar Disord. 2004;6:368–73.
Petrovsky N, McNair P, Harrison LC. Diurnal rhythms of pro-inflammatory cytokines: regulation by plasma cortisol and therapeutic implications. Cytokine. 1998;10:307–12.
Rifai N, Ridker PM, Rifai N, Price N, Dinges DF, Mullington JM. Proposed cardiovascular risk assessment algorithm using high-sensitivity C-reactive protein and lipid screening. Clin Chem. 2001;47:28–30.
Grant funding support is R01MH100125 and R01CX000995-01 (both to KEB). CEM is partially supported by the Sackler Scholars in Psychobiology Program through Harvard University.
Conflict of interest
KEB has served on advisory boards for Sunovion, Sumitomo Dainippon Pharma, and Neuralstem. The other authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Millett, C.E., Perez-Rodriguez, M., Shanahan, M. et al. C-reactive protein is associated with cognitive performance in a large cohort of euthymic patients with bipolar disorder. Mol Psychiatry (2019). https://doi.org/10.1038/s41380-019-0591-1