Inflammation Marker Linked to Slower Thinking in Newly Diagnosed Bipolar Disorder

People newly diagnosed with bipolar disorder who carry higher levels of C-reactive protein (CRP), a widely used marker of systemic inflammation, also tend to perform worse on certain tests of memory and mental processing, according to a peer-reviewed study published in BMC Psychiatry. The research, which focused on patients who had not yet received medication, adds to a growing body of work suggesting that inflammation may be intertwined with the cognitive difficulties that many people with bipolar disorder experience, even early in the course of the illness. The study enrolled 135 patients with a new diagnosis of bipolar disorder who were drug-naïve, meaning they had not yet been treated with psychotropic medication, along with 85 healthy controls.

The researchers corrected between-group comparisons for multiple testing using the Benjamini–Hochberg false discovery rate procedure, a statistical safeguard against spurious findings when many measures are examined at once. Patients with bipolar disorder had significantly higher CRP levels than the healthy controls, a difference that reached statistical significance at P = 0.020. The patients also performed more poorly than controls across multiple cognitive measures, consistent with the well-documented observation that cognitive dysfunction is common in bipolar disorder.

The most striking results emerged when the researchers examined how CRP related to cognition within the patient group. In analyses that did not adjust for other variables, higher CRP was associated with lower scores on the RBANS total index as well as on specific subtests measuring List Learning and List Recognition, and with poorer Stroop performance, including the Word-reading and Color-word conditions. These associations suggest that the inflammatory marker tracked with both memory-related and attention-related aspects of cognition.

Because CRP levels can be influenced by many factors, the investigators then ran multivariable linear regression models that adjusted for age, sex, education, body mass index, smoking status and depression severity as measured by the HAMD-17 rating scale. After these adjustments, higher log-transformed CRP remained significantly associated with lower RBANS total scores (standardized β = −0.214, P = 0.032) and with poorer Stroop Word-reading performance (β = −0.207, P = 0.029). The association with the Stroop total score was attenuated and no longer reached statistical significance (β = −0.168, P = 0.082), indicating that some of the apparent link between inflammation and that composite measure could be accounted for by the covariates.

The persistence of the CRP–cognition associations after adjustment is notable because the study population was drug-naïve. The authors emphasize, however, that the findings are cross-sectional and associative: they show that higher CRP and poorer performance on selected tests co-occur, not that inflammation causes cognitive impairment. Beyond the clinical measurements, the study included an exploratory molecular component.

The researchers performed RNA sequencing on peripheral blood mononuclear cells, immune cells obtained from blood, from six patients with bipolar disorder and six healthy controls. This analysis identified 617 candidate differentially expressed genes between the two groups, but only one gene remained significant after genome-wide false discovery rate correction, underscoring how stringent multiple-testing correction can dramatically shrink a list of candidate findings. To follow up on the sequencing results, the team used RT-qPCR, a laboratory technique that quantifies the expression of selected genes, and found significant differences in several candidate genes after false discovery rate correction.

Importantly, the concordance between the RT-qPCR results and the original RNA-seq directionality was incomplete, meaning that some genes did not shift in the same direction across the two methods. The authors are explicit that these transcriptomic findings should be considered hypothesis-generating rather than definitive, given the very small sequencing sample of six patients and six controls and the limited findings that survived correction. Taken together, the study offers a measured contribution to the debate over inflammation in bipolar disorder.

Its strengths include a relatively large clinical sample for the CRP analyses, the use of drug-naïve patients, careful adjustment for demographic and clinical covariates, and statistical correction for multiple comparisons. The authors conclude that higher peripheral CRP levels were associated with selected aspects of cognitive performance, specifically RBANS total score and Stroop Word-reading performance, in newly diagnosed, drug-naïve patients with bipolar disorder, while the peripheral molecular alterations they identified remain candidates for future, better-powered studies.

Subject of Research: Associations between peripheral C-reactive protein levels and cognitive function in newly diagnosed, drug-naïve bipolar disorder, with exploratory transcriptomic profiling

Article Title: C-reactive protein and cognitive function in bipolar disorder: clinical associations and exploratory transcriptomic profiling

Article References: Huang, M., Tang, R., Liu, S., Qiu, Y., Teng, Z., Wang, B., Chen, J., Li, S., & Wu, H. (2026). C-reactive protein and cognitive function in bipolar disorder: clinical associations and exploratory transcriptomic profiling. BMC Psychiatry. https://doi.org/10.1186/s12888-026-08792-6

Image Credits: AI Generated

DOI: 10.1186/s12888-026-08792-6

Keywords: bipolar disorder, C-reactive protein, inflammation, cognitive function, neuropsychological testing, RBANS, Stroop test, transcriptomics, RNA sequencing, drug-naïve patients, BMC Psychiatry, peripheral blood mononuclear cells