The objective of the study was to explore the presentation of symptoms in patients suffering from treatment-resistant mood disorder (TRMD), and associated clinical features, including age, gender, and comorbid conditions, that lead towards the development of treatment-resistant mood disorder. Furthermore, the study analyses the available psychotherapeutic treatment modalities and evidence-based non-medical treatment approaches for TRMD.The current study utilized a systematic review approach where 37 articles were studied and three articles were theoretically sampled to authenticate and signify the findings. PRISMA guidelines were followed and the review was conducted by searching social sciences databases and electronic libraries including Google Scholar, Sage Journal, and Science Direct (1990-2020).The results suggested that psychotherapeutic interventions including cognitive behavior therapy, mindful-based cognitive therapy; and interpersonal and social rhythm therapeutic interventions are efficacious modalities for treatment when in augmentation with psychopharmacological treatment. Bipolar diathesis and comorbid conditions of anxiety and personality disorders are possible causal factors in developing the condition of treatment resistance in mood disorders. The prevalence rate of TRMD is more common in females and in late adulthood. The analysis also suggests that there are numerous risk factors contributing to making a mood disorder treatment-resistant over a period of time; the most observed conditions were physical and psychological comorbidity, inaccurate diagnosis, lack of proper medical treatment, illness severity, and late age diagnosis. In evidence-based non-medical treatment approaches aerobics demonstrated promising results in improving the condition of complex mood disorders.It was concluded that psychotherapeutic interventions in augmentation with pharmacological modalities enhance the efficacy of treatment.