OBJECTIVES: Major depressive disorder affects approximately 10-15% of the population and is associated with significant morbidity and mortality. It is one of the leading causes of disability in young adults. A large proportion of the burden can be attributed to treatment-resistant depression (TRD). To understand the prevalence and disease burden of TRD in Western European countries, the US and Canada, a systematic literature search was performed. METHODS: OVID, the Cochrane Library and the CRD database were used to retrieve TRD publications in English language from January 2003-October 2013. In total, 6306 abstracts were identified. Predefined selection criteria regarding study design, patient population (age ≥12 years; US, Canada, Germany, Italy, France, Spain or UK; TRD defined as one treatment failure and high symptom severity e.g. MADRS ≥31, or an inadequate response to ≥ two antidepressants) and outcomes of interest were applied. RESULTS: Only seven studies included prevalence and/or disease burden data. Five studies provided prevalence estimates which adhered to the strict TRD definition used for this review. Study design and definition of the patient population were critical in determining the prevalence rates, with the lowest rates found in US employer claims databases (11-15%), higher rates in commercial health insurance databases (29-31%) and the highest rates in a European multicenter study (51-56%). The database studies mainly included employed patients thereby likely underestimating the prevalence, whereas the European study likely overestimated the prevalence due to a less stringent TRD definition. Inconsistent data were reported regarding treatment outcomes, comorbidities, hospitalization and work productivity. There was no information on other outcomes such as health-related quality of life or functioning. CONCLUSIONS: No consistent data were found in the literature from January 2003-October 2013 regarding the epidemiology and disease burden of TRD. To determine the prevalence and disease burden for TRD, further studies are needed.