Importance Major depressive disorder (MDD) and bipolar disorder (BD) are often misdiagnosed during depressive episodes, therefore, exploring biomarkers for differential diagnosis is important.

Objective To identify circadian biomarker signatures in patients’ peripheral blood that differentiate MDD from BD during depressive states.

Design, setting, and participants This case-control study recruited patients with MDD and BD at depressive state diagnosed by the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) and Health control (HC) subjects from January 2021 to May 2023. We collected serum samples to detect levels of Period (PER)1/PER2/phosphorylated cAMP reaction element binding protein (pCREB).

Main outcomes and measures Participants’ clinical data were evaluated by HAMD-17 and MDQ scales. Blood samples (n = 100) were collected and extracted for serum followed by detecting serum PER1, PER2 and pCREB levels by ELISA.

Results There were 100 participants in the cohort, including 40 in the MDD group, 30 in the BD group and 30 in the health control (HC) group. 71% were female in the cohort. The mean (SD) serum PER1 level in the HC group was 12.05 (2.96) ng/mL, in the MDD group was 8.41 (2.96) ng/mL, significantly decreased vs the HCs, and in the BPD group that was 16.05 (3.60) ng/mL, significantly increased vs the HCs (adjusted P < 0.0001). The serum pCREB level in the HC group was 205.2 (49.57) ng/mL, in the MDD group was 192.6 (38.52) ng/mL, and that in the BPD group was 290.0 (72.10) ng/mL, which was significantly increased vs the HCs and vs the MDD group. For the differential diagnosis between MDD and BPD, PER1 & pCREB (AUC, 0.9858) show similar high diagnostic efficiency as combined biomarkers of PER1, PER2 & pCREB (AUC, 0.9906).

Conclusions and relevance This study reveals the importance of serum PER1, combined use of serum PER1 and pCREB as well as that of serum pCREB, PER1 and PER2 in differentiating MDD from BPD.

Question Can major depressive disorder (MDD) be distinguished from bipolar disorder (BD) during their depressive episodes by circadian biomarkers in patient’s peripheral blood?

Findings In this case-control study of 100 participants, serum PER1 levels were significantly decreased in the MDD group but were significantly increased in the BPD group, serum PER2 levels were significantly elevated in both MDD and BPD groups, and serum pCREB levels were significantly increased in the BPD group, compared with the HC group. Besides, In the MDD group, serum PER1 levels were significantly positively associated with mood disorder questionnaire (MDQ) scores; and serum pCREB levels were significantly negatively associated with MDQ scores. In the BPD group, serum pCREB levels were significantly negatively associated with HAMD-17 scores. The combined use of serum pCREB and PER1 and the three biomarkers (pCREB, PER1 and PER2) had similar diagnostic values in differentiating MDD from BPD.

Meaning The serum PER1 has great value for differentiating MDD from BPD, and combined use of serum biomarkers of pCREB/PER1 or pCREB/PER1/PER2 shows higher efficacy in differentiating MDD from BPD.

The authors have declared no competing interest.

This work was supported by Natural Science Foundation of China (82071181), Zhejiang Province TCM Modernization Special Project (2020ZX012) to WC, Key Research & Development Program of Zhejiang Province (2020C03021 to WC and 2018C03023 to YDS), Science and Technology Program of Hangzhou Municipality (20212013B02, Z20200051) to YDS, and Natural Science Foundation of China (82201682) to XLW.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

This study was approved by the Ethics Committee of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine (No. 20191203-13). All study participants were informed of the purpose and methods of the study, and each participant provided informed consent before enrolment.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

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The original data of this project is available upon reasonable request from the corresponding author, Dr. Wei Chen (srrcwzju.edu.cn).