IntroductionDepressive disorders are characterized by recurrent episodes and a substantial disease burden, often leading to chronic functional impairment and reduced quality of life [1, 2]. Approximately one-third of patients fail to achieve satisfactory remission despite appropriate treatment, including antidepressant medications, electroconvulsive therapy(ECT), and psychotherapy[3-5]. This results in TRD, a severely disabling psychiatric disorder that is often refractory to conventional treatments. Patients face increased treatment costs, complications, and the heightened risk of recurrent hospitalizations. TRD poses a major clinical challenge within psychiatric practice due to delayed onset of action and low remission rates following multiple antidepressant doses[6, 7].Treatment options remain limited due to the prevalence of adverse effects tied to pharmacological therapies, low accessibility to psychotherapy, and high tolerance levels for electroconvulsive therapy. New neuromodulation techniques, such as rTMS, may offer potential solutions to these limitations[8, 9]. The U.S. Food and Drug Administration (FDA) approved rTMS for TRD in 2008, and it is recognized in the latest Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines [10, 11]. However, not all patients benefit from standard rTMS regimens[10], with meta-analytic evidence indicating an average effectiveness of 29.3% for the left dorsal lateral prefrontal cortex (lDLPFC) using high-frequency rTMS [10]. The FDA-approved rTMS regimen for TRD operates at 10 Hz, with a minimum of 60,000 total pulses; higher doses of 15 Hz or 20 Hz may achieve more favorable outcomes[12].Various classes of antidepressants, including tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors (SNRIs) have been utilized in the treatment of depression [13]. However, the estimated rate of TRD persists above 30% after treatment with multiple antidepressant classes [4]. Currently available antidepressants are effective for treating depression; however, they are often accompanied by notable limitations. These include delayed onset of action, limited therapeutic efficacy (yielding moderate effectiveness ranging from 50% to 70%), and a lack of cognitive improvement. Consequently, there is a growing clinical need for safer and more effective antidepressant options [14, 15]. In recent years, the triple monoamine reuptake inhibition hypothesis has gained significant recognition as a potentially effective strategy for treating depression. Toludesvenlafaxine, also known as Ansofaxine, LY03005, or LPM570065, is a triple reuptake inhibitor (TRI) that has been integrated into clinical settings. It functions by inhibiting the reuptake of serotonin, dopamine, and norepinephrine in the central nervous system. The simultaneous activation of all three monoamine systems is believed to have a favorable impact on mood by alleviating symptoms such as loss of pleasure, irritability, and depressive symptoms. It also supports cognitive improvement, including better attention span, learning abilities, and memory, and addresses somatic symptoms by reducing fatigue, increasing energy, and addressing insomnia in individuals with depressive disorders. Preclinical studies suggest that toludesvenlafaxine exhibits superior efficacy and a favorable safety profile compared to traditional monoamine reuptake inhibitors. It shows promise for addressing the unmet needs in the treatment of TRD by alleviating symptoms that are resistant to current standard therapies. Toludesvenlafaxine is noted for its rapid antidepressant-like effects and is considered a promising treatment option[15-18].On the other hand, previous studies have demonstrated that DTMS demonstrates beneficial therapeutic outcomes on depressed patients who are already on medication[19, 20]. Additionally, there is an urgent need for a safe and effective treatment for TRD. Therefore, this study aims to utilize a newer rTMS regimen, such as DTMS, in combination with a novel triple monoaminergic reuptake inhibitor (toludesvenlafaxine) to augment efficacy and achieve the therapeutic remission of TRD patients. By focusing on novel treatment combinations and techniques, this approach seeks to provide a safe and effective treatment strategy for managing patients with TRD who have experienced limited success with traditional treatment trials.