According to the World Health Organization (WHO), 350 million people worldwide suffer from major depression disorder (MDD), and the incidence of MDD in China is increasing yearly. According to a recent cross-sectional epidemiological study, depression is one of the most common mental disorders in China and the second most common cause of mental disability (Huang et al., 2019). MDD, caused by psychological, physical, and social factors, is characterized by a high incidence, recurrence, disability, and suicide rate. Effective MDD prevention and treatment options are lacking. Depression is characterized by a marked and persistent low mood, a loss of interest in activities, and slow thinking, while physical symptoms include early awakening, loss of appetite, and weight loss. These symptoms threaten patients' ability to work and quality of life and maybe a heavy burden on the patients' families and society.

Despite decades of intensive research on the underlying pathogenesis of depression, treatment outcomes for depression may be unsatisfactory, and a proportion of patients are treatment-resistant. Despite the wide range of first-line pharmacological treatments and psychotherapies available for MDD, approximately 20–30 % of patients do not respond to multiple medication trials (Rush et al., 2006; Loerinc et al., 2015; Maneeton et al., 2020). rTMS therapy is a non-invasive and important non-pharmacological treatment for depression (Antonenko et al., 2019; Yin et al., 2020). Evidence suggests that rTMS has a positive effect on MDD treatment (Berman et al., 2000; Brunoni et al., 2017; Teng et al., 2017). In 2008, the U.S. Food and Drug Administration approved rTMS for refractory depression.

A previous review determined the accelerated and augmentative antidepressant effects of rTMS when combined with antidepressants (Berlim et al., 2013). Therefore, antidepressants combined with rTMS physiotherapy may improve MDD outcomes and reduce the incidence of refractory depression. It is important to investigate the neurobiological mechanisms of action of rTMS combined with antidepressants in patients with MDD.

With the rapid development of neuroimaging technology, blood oxygen level-dependent MRI has become more widely used in neuropsychiatric diseases due to its high spatial resolution and safety (Lyu et al., 2016). The principle of blood oxygen level-dependent (BOLD) magnetic resonance imaging is to detect changes in magnetic properties caused by alterations in local metabolism and blood oxygen levels following neuronal activity (Tian et al., 2020). The ALFF technique uses low-frequency (0.01–0.08 Hz) BOLD signals of spontaneous brain activity to detect the intensity of local brain activity in the resting state. This reflects spontaneous neurological brain functions and accurately locates changes in brain regions. ALFF is widely used in clinical research (Zou et al., 2008). Increased ALFF values indicate increased neuronal activity in the brain region (Zang et al., 2007).

We aimed to investigate brain functional changes and the clinical efficacy of MDD treated with rTMS combined with antidepressant medication therapy using the rs-fMRI method. We analyzed ALFF values based on the whole brain and examined the relationship between ALFF and clinical variables.