Background: Several lines of evidence indicate that circadian rhythm disruption is associated with bipolar disorder (BPD). This strong association, along with evidence from genome wide association studies (GWAS) implicating clock and clock controlled genes with BDP and efficacy of lithium treatment, suggests that BPD circadian rhythm disruption may represent a core etiology feature. Lower morning expression of the neuropeptide somatostatin (SST) has been previously reported in the brain and cerebral spinal fluid of subjects with BPD, coinciding with increased morning severity of anxiety and depression. We aimed to test the hypothesis that levels of neuropeptides involved in circadian rhythm regulation, including somatostatin (SST), neuropeptide-Y (NPY), arginine vasopressin (AVP), vasoactive intestinal peptide (VIP) and cortisol levels, are altered in blood samples collected in the morning from patients BPD. Method: Thirty nine patients diagnosed as BPD according to DSM-5, and 38 healthy controls were enrolled in the study. Blood were collected at 9 AM from all subjects. Serum levels of SST, NPY, AVP, VIP and cortisol were measured. Results: We observed significantly lower levels of SST (p = 0.001), NPY (p = 0.001), VIP (p = 0.001) and cortisol levels (p = 0.001) in the morning in subjects with BPD compared to control subjects. Significant positive effects of Young Mania Rating Scale and lithium treatment with cortisol, SST, and VIP levels were observed. Conclusion: Our study suggests that lower morning levels of SST, NPY, VIP and cortisol may represent biomarkers underlying disrupted biological rhythms and behavioral and sleep disturbances observed in patients with BPD.