Highlights • Fluoxetine had no effects on the white matter and the myelinated fibers in the white matter of CUS rat model of depression. • Method with the transmission electron microscope technique and the unbiased stereological methods. • Atrophy of the white matter and disruption of the myelinated fibers in the white matter might contribute to the pathophysiology of depression. Abstract Objective To explore the pathogenesis of depression and the possible mechanism of the effects of selective serotonin reuptake inhibitors (SSRIs) on the myelinated fibers and myelin sheaths in the white matter during the antidepressant action of fluoxetine. Methods In this study, Sprague Dawley (SD) rats were divided into a Control group, a group treated with CUS and no drugs (CUS/Standard group) and a group treated with CUS and fluoxetine (CUS/FLX group). The CUS/FLX group was treated with fluoxetine at dose of 5 mg/kg for 21 days. The white matter volume, the myelinated fiber parameters and the myelin sheath volume in the white matter were calculated from transmission electron microscope images through unbiased stereological methods. Results The total volume and total length of myelinated fibers;and mean volume of white matter of the CUS/Standard group were significantly decreased compared to values from the control group (p = 0.025, p = 0.007, p = 0.000), whereas no significant differences in these stereological parameters were found between the CUS/Standard and CUS/FLX groups (p > 0.05). Conclusions Fluoxetine successfully treated depression-like behavior but had no effects on the white matter or its component myelinated fibers in the CUS rat model of depression. [ABSTRACT FROM AUTHOR]