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Background: Depression is a common mental health disorder that affects millions of people worldwide. Globally, major depressive disorder (MDD) is a public health concern; nearly, it affects more than 300 million people. The coronavirus disease 2019 (COVID-19) pandemic lockdown, travel restrictions, social distancing, and COVID-19 vaccine acceptance have aggravated psychological disorders, such as depression and suicidal tendencies. Treatment-resistant depression (TRD) is typically defined as a lack of response to at least two different antidepressant medications or psychotherapies. TRD is common and has been associated with higher comorbidities and prolonged duration of illness, leading to a substantial medical and economic burden., Materials and Methods: A cross-sectional study was designed to determine the epidemiology and estimate the prevalence of TRD in Abha City, Assir Region, Kingdom of Saudi Arabia. The study includes adult patients who were attended to the psychiatry department and aged 18-65 years diagnosed with major depressive depression. A total of 651 study participants were recruited., Results: Of the total 651 depressive disorder cases, 134 (20.6%) were reported as TRD and the remaining 517 (79.4%) were nontreatment-resistant depressive cases. Of the 651 depression participants, 176 (27%) were males and 475 (73%) were females. More than one-quarter (180 (28%)) had been associated with chronic morbidity. One-tenth of the depressive patients were suffering from thyroid disorders, followed by hypertension (10%), autoimmune diseases (10%), and diabetes mellitus (8%)., Conclusions: TRD emerged as a threat to public health and challenging psychiatric care providers, and further innovative techniques and effective newer drugs to treat depression need to be researched. The treatment complaint mechanism is warranted, encouraging people to get treatment from the psychiatrist by removing the stigma of mental illness, which is needed to improve the quality of life of TRD patients., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Journal of Education and Health Promotion.)