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This website is made possible by third party financial support from Sage Therapeutics, Inc. and Biogen Inc.

Challenges of Current Pharmacotherapy in Major Depressive Disorder (MDD)

Challenges of Current Pharmacotherapy in Major Depressive Disorder (MDD)

March 30, 2023

To address the challenges of current pharmacotherapy in MDD, a multifaceted approach is necessary.

Pharmacotherapy 2

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Major Depressive Disorder (MDD) is a widespread mental health condition characterized by persistent low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities (anhedonia).1 With a lifetime prevalence of 15%, and an annual incidence of approximately 7%, MDD is a significant public health concern.2 Although newer generation antidepressant drugs have improved safety and tolerability compared to tricyclic antidepressants, they have not eliminated the challenges associated with the pharmacotherapy of MDD.3 This article aims to provide an overview of these challenges and explore the impact of biological and social factors on treatment outcomes.

Underdiagnosis and Undertreatment

One of the primary challenges of treating MDD is the frequent underdiagnosis and undertreatment by clinicians.4 This results from the heterogeneity of depressive symptoms, stigma surrounding mental health disorders, and the reluctance of patients to seek help.4

Biologic Factors

MDD is categorized as a mood disorder, but physical symptoms are commonly observed in patients with this condition. These physical symptoms—such as insomnia, appetite and weight changes, psycho-motor retardation/agitation, and lethargy/fatigue—can serve as important indicators of depression, as they may be either the cause or consequence of depression.5 Research has shown that most depressed patients report experiencing physical symptoms, including fatigue, nausea, pain, and more.4 In fact, rates of fatigue, insomnia, and nausea among patients with depression have been reported to be as high as 86%, 79%, and 51%, respectively. Physical symptoms are also highly associated with MDD and anxiety, regardless of the presence of underlying medical conditions, as indicated by a recent study conducted in China.4

Interestingly, physical symptoms are not associated with the severity of MDD. Patients often become aware of changes in physical symptoms before psychological symptoms, making these somatic symptoms the a sign of MDD.6 Due to the wide range of physical symptoms, patients may consult primary physicians rather than psychiatrists for help. However, physical examinations may not show significant results, leading to the suggestion that the symptoms may be related to MDD. This indirect route of help-seeking may delay a referral to a psychiatrist and the diagnosis and treatment of MDD, resulting in poor treatment outcomes. In fact, it has been reported that approximately 30% of patients with MDD experience physical symptoms for more than five years before receiving an accurate diagnosis.4

Social Factors

According to the National Comorbidity Survey Replication Study, which was conducted through face-to-face household surveys of 9090 respondents, most patients with MDD experience impairment in their social functioning. Impairments related to social roles were the most common, with 43.4% of respondents reporting severe or very severe impairment, while those related to work roles were the least common, with only 28.1% of respondents reporting severe or very severe impairment. Additionally, patients with MDD reported missing an average of 35.2 days of work in the past year due to impaired functioning caused by MDD. Social and physical functioning are both impaired by MDD, and social functioning is significantly more impaired by MDD than it is by other chronic illnesses such as hypertension, diabetes, and arthritis. The degree of impairment in the domains of work, home, relationships, and/or other social functions is closely related to the severity of MDD.4

In the United States, 7.2% of employees experience at least one depressive episode each year, resulting in significant productivity and economic losses. Depressed individuals curtail their usual activities or stay in bed for an average of 66.4 days per year, and depressed workers lose an average of 27.2 workdays per year, leading to a loss of $36.6 billion in productivity. The treatment costs for these individuals are also significant, totaling $27 billion. Depressed workers report working at only 70% of their peak productivity.4

Strategies for Overcoming Challenges

To address the challenges of current pharmacotherapy in MDD, a multifaceted approach is necessary. This approach should include a collaborative approach that involves systematic support from mental health providers in primary care settings. This collaborative approach should focus on populations of patients identified with depression, uses measurement-based care, treatment to target, and stepped care to adjust treatments systematically, to help significantly improve patient satisfaction and health outcomes. The principles of collaborative care align with the concepts of patient-centered medical homes (PCMH) and accountable care, making it an effective tool for primary care practices to adapt to health care reform, and changes in health care delivery and financing. Overall, adopting a multifaceted approach that includes a collaborative care model can help health care providers overcome the challenges of current pharmacotherapy in MDD and improve treatment outcomes for patients.7


1. Brown CH. Pharmacotherapy of major depressive disorder. US Pharmacist. 2011;36(11):HS3-HS8. Accessed March 29, 2023.

2. Ceskova E. Current pharmacotherapy of depression – focused on multimodal/multifunctional antidepressants. Expert Opin Pharmacother. 2016; 17(14) 1835-1837. doi:10.1080/14656566.2016.1219340

3. Dupuy JM, Ostacher MJ, Huffman J, Perlis RH, Nierenberg AA. A critical review of pharmacotherapy for major depressive disorder. Int J Neuropsychopharmacol. 2011;14(10):1417-1431. doi:10.1017/S1461145711000083

4. Sato S, Yeh TL. Challenges in treating patients with major depressive disorder: the impact of biological and social factors. CNS Drugs. 2013;27(Suppl):S5–10. doi:10.1007/s40263-012-0028-8

5. Cronkleton E. Depression and its physical symptoms. Medical News Today. October 7, 2021. Retrieved March 29, 2023.

6. Psychosomatic disorder. Cleveland Clinic. Reviewed April 30, 2021. Accessed March 30, 2023.

7. Unützer J, Park M. Strategies to improve the management of depression in primary care. Prim Care. 2012;39(2):415-431. doi:10.1016/j.pop.2012.03.010