CRP as a Biomarker of Antidepressant Efficacy

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RESEARCH UPDATE

CASE VIGNETTE

“Mr Fishburne” is a 35-year-old African American male with a history of major depressive disorder (MDD), recurrent, moderate, without psychosis. He was diagnosed approximately 1 year ago. He does not have any significant current medical problems and does not use tobacco or illicit substances. He completed a course of cognitive behavioral therapy, but had residual symptoms despite improvements in depression. His psychiatrist then started him on sertraline 3 months ago, which has been titrated to a dose of 150 mg daily. He felt the medication was initially helpful, but endorses ongoing symptoms of depression.

He presents for an outpatient clinic visit, and informs the psychiatrist that he would like to try a different medication. He also states that his primary care physician did routine blood work at his annual visit, and his C-reactive protein (CRP) level was 3 mg/L. As his psychiatrist, how would this additional information influence your decision on his next antidepressant trial? Some features of atypical depression, including hypersomnia, weight gain, and anxiety.

Approximately one-third of patients with MDD do not respond to an antidepressant trial of adequate dose and duration.¹ Presently, there are no established peripheral biomarkers of antidepressant treatment response, although neurotrophins, oxidative stress, and inflammation have been investigated.² Three previous clinical trials have investigated CRP, a hepatic acute phase reactant and inflammatory marker, as a predictor of antidepressant response. One study found better outcomes for patients with low CRP for escitalopram and high CRP for nortriptyline.³ Another study found that selective serotonin reuptake inhibitors (SSRI) monotherapy with was more effective than SSRI plus bupropion in patients with low CRP.⁴ A third study found that the serotonin-norepinephrine reuptake inhibitor (SNRI) duloxetine was more effective than sertraline in patients with high CRP.⁵ However, no previous studies have investigated CRP as a biomarker of antidepressant response in routine clinical practice.

The Current Study

Pan and colleagues investigated CRP and antidepressant efficacy in a real-world retrospective cohort study of outpatients and inpatients with depression in China.⁶ Inclusion criteria were ICD-10 diagnosis of depression; aged 12 to 60; antidepressant use for > 4 weeks; and blood CRP measured by turbidimetry. They excluded subjects with cerebrovascular disease, immune-inflammatory, or other serious disease; CRP not available or measured with nephelometry (which only reports a range); elevated CRP (> 5 mg/L); patient diagnosis or first-degree relative with schizophrenia or bipolar disorder; simultaneous use of 2 or more classes of antidepressants; substance dependence; or pregnancy. Patients had a single follow-up visit with an outpatient psychiatrist, either in person or over the phone.

Patients had a blood draw for CRP levels at baseline and were dichotomized based on CRP < 1 and ≥ 1 mg/L. CRP was also repeated at follow-up. Antidepressant efficacy (dichotomized as yes/no) was based on the Clinical Global Impression-Improvement (CGI-I) scale and was defined as either “significantly” or “very significantly” improved. Data on antidepressant treatment was obtained from patients, family members, and the electronic medical record. The authors compared the efficacy of SSRIs and SNRIs in the low and high CRP groups using chi-square test and Cox proportional hazards regression.

Baseline and follow-up data were available for n=918 patients, of whom 709 (77%) had low CRP and 209 (23%) high CRP. Mean subject age was 24, mean BMI was 22, and 35% of the sample was male. Patients were treated with SSRIs (n=725), SNRIs (n=138), agomelatine (n=32), and mirtazapine (n=11). In patients with high CRP, SNRIs were more efficacious than SSRIs (HR=1.65, 95% CI 1.03-2.65). In patients with low CRP, SSRIs were more efficacious than SNRIs (HR=1.26, 95% CI 1.00-1.57). There was no significant change in CRP levels before and after treatment.

Study Conclusions

The authors concluded that SNRIs were more efficacious in patients with high CRP, and SSRIs were more efficacious in patients with low CRP. This pattern of findings is broadly consistent with previous clinical trials.^3-5 Study strengths include the overall large sample size and the use of a real-world effectiveness sample. Study imitations include the retrospective design (including potential recall bias); nonstandardized follow-up; the use of dichotomous outcome measures; inadequate data on cigarette smoking as a potential confounding factor; and inadequate sample sizes to investigate non-SSRI or SNRI antidepressants, as well as specific agents.

The Bottom Line

Blood CRP levels may have utility as a biomarker of antidepressant efficacy. Findings warrant replication in a large, rigorously designed prospective study.

Dr Miller is professor in the Department of Psychiatry and Health Behavior, Augusta University, Augusta, Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for Psychiatric TimesTM. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute.

References

1. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163(11):1905-1917.

2. Gadad BS, Jha MK, Czysz A, et al. Peripheral biomarkers of major depression and antidepressant treatment response: current knowledge and future outlooks. J Affect Disord. 2018;233:3-14.

3. Uher R, Tansey KE, Dew T, et al. An inflammatory biomarker as a differential predictor of outcome of depression treatment with escitalopram and nortriptyline. Am J Psychiatry. 2014;171(12):1278-1286.

4. Jha MK, Minhajuddin A, Gadad BS, et al. Can C-reactive protein inform antidepressant medication selection in depressed outpatients? Findings from the CO-MED trial. Psychoneuroendocrinology. 2017;78:105-113.

5. Wang D, Yang XH, Zheng YS, et al. Serum level of hs-CRP in patients with depression and its predictive role for the efficiency of antidepressants. J Shandong Univ (Health Sci). 2018;56:51-57.

6. Pan Y, Luo R, Zhang S, et al. C-reactive protein couple predict the efficacy of SSRIs in clinical practice: a cohort study of large samples in the real world. J Affect Disord. 2022;313:251-259.