The interplay between mental and physical health has been a subject of long-standing exploration, and recent reports indicated that depression is intricately linked to heightened morbidity and mortality. Rather than a mere mood dysregulation confined to the mind, depression should be viewed as a “whole body disease”.
Major depressive disorder (MDD) stands as one of the most common and severe psychiatric disorders, with a surge in global prevalence from 193 million individuals prior to the onset of COVID-19 pandemic to an alarming 246 million in its aftermath.1 According to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5), major depressive disorder is characterised by the presence of either a persistently depressed mood or a loss of interest or pleasure, accompanied by additional symptoms including changes in appetite and body weight, disruption in sleep patterns, fatigue, psychomotor agitation or retardation, feelings of worthlessness or excessive guilt, difficulty concentrating, and recurrent thoughts of death2. These symptoms typically last for more than two weeks, and lead to clinically significant distress or impairment in daily functioning.
Cardiovascular disease
The interplay between mental and physical health has been a subject of long-standing exploration, and recent reports indicated that depression is intricately linked to heightened morbidity and mortality. Rather than a mere mood dysregulation confined to the mind, depression should be viewed as a “whole body disease”. One well-established association exist between depression and cardiovascular disease, demonstrating a bidirectional relationship. A meta-analysis found that depression post myocardial infarction was significantly associated with all-cause mortality and a 2- to 2.5-fold increased risk of impaired cardiovascular outcomes3. In another study among individuals diagnosed with major depressive disorder, comorbid cardiovascular disease was identified in two-thirds of the patients, underscoring the significance of detecting major depressive disorder among middle- and older-aged adults4. In depression, dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system may give rise to the development of hypertension, platelet dysfunction, the release of pro-inflammatory cytokines, and left ventricular hypertrophy5. Moreover, long-term depression can increase the incidence of sub-clinical cardiovascular disease by influencing levels of glucose, serum lipids, body mass index (BMI) and physical activities6. These physiological alterations, in turn, predispose individuals to arrhythmias and myocardial infarction7. Depression can also increase the risk of adopting unhealthy lifestyle, including smoking and alcohol intake, and non-adherence to medication, further contributing to the risk of cardiovascular disease8. These findings emphasize the critical importance of early identification and management of major depressive disorder especially within the context of coronary heart disease patients.
Diabetes
Diabetes emerges as another notable physical comorbidity presenting a higher risk among individuals with depression. Diabetes is defined by a condition of chronic hyperglycaemia which can lead to both microvascular damage (retinopathy, neuropathy, nephropathy) and macrovascular complications (stroke, peripheral vascular disease and ischemic heart disease) in the absence of treatment. By the year of 2030, the total number of people with diabetes is projected to increase to 366 million9. Diabetes and depression are interrelated in a bidirectional way10. Up to 30% of individuals with diabetes were found to have depressive symptoms 11. Additionally, those experiencing depression from early adulthood are at a higher risk of developing Type 2 diabetes. The biochemical changes in depressive individuals, specifically via the dysregulation of hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system contribute to the development of diabetes. In severe or melancholic depression subtypes, excess glucocorticoids levels can lead to insulin resistance and resulting in diabetes12. Secondly, akin to the development of cardiovascular disease, individuals with depression exhibit higher concentrations of inflammatory cytokines in particularly interleukin-6, which have been associated with a higher risk of diabetes13. Thirdly, studies have found a significant association between depression and insulin resistance14. Lastly, depression is associated with poorer diet, smoking, lower physical activity, higher body mass index BMI), and all these factors could have collectively contributed to an increased risk of diabetes. The coexistence of depression and diabetes is linked to higher diabetes complications, increased disability and loss of years of life 15. It is also associated with increased risk of diabetes complications, treatment nonadherence, poorer self-management, and heightened utilization of healthcare services and associated medical costs16. Poorly controlled diabetes, in turn, can lead to myocardial infarction and other cerebrovascular diseases. On the contrary, individuals with diabetes face a higher risk of developing depression, likely attributed to the psychological burden of diabetes17.
Nonalcoholic fatty liver disease (NFALD)
A dysfunctional HPA axis in depression has various implications, affecting psychological, endocrine, and visceral domains within the human body. The elevated levels of cortisol hormone in dysregulated HPA axis can lead to mood alterations, inflammation, metabolic syndrome, and nonalcoholic fatty liver disease (NFALD). Notably, population studies have established a dose-dependent correlation between the severity of depression and the histological stage of NAFLD 18. Additionally, even after the remission of a depressive episode, residual cognitive deficits persist19. It is noteworthy that individuals with NAFLD face a significantly higher risk of cognitive impairment compared to healthy individuals. Besides this, the presence of a chronic inflammatory state can induce insulin resistance, resulting in an excess of circulating free fatty acids (FFA) that bind to toll-like receptors, triggering an inflammatory cascade and further exacerbating insulin resistance. This inflammatory phenomenon posits that the combined presence of depression and obesity constitutes a greater risk factor for NAFLD than either condition in isolation 18.
Pain
Among patients with chronic pain, 40% to 60% were found to have depression 20. Severity of pain was found to be positively correlated with depression severity21. A few hypotheses have been investigated on the correlation between these two conditions. Depression can lead to lowered pain thresholds and increased pain sensitivity, resulting in pain as a presenting symptom in depression. Secondly, depression and chronic pain may share common pathological changes, which are both upon the neuroanatomical and neurochemical basis. In the neuroanatomical basis, the processing of emotions and pain involve areas of the brain which may overlap22. The part of the brain involve in emotions processing are the hypothalamus, amygdala, and anterior cingulate gyrus. Signals from these areas are transmitted to the periaqueductal grey matter and ventromedial medulla, both areas involved in pain modulation. In the neurochemical level, both depression and chronic pain have various neurotransmitters in common, in particularly serotonin and norepinephrine. In both depression and chronic pain, a reduction in presynaptic serotonin (5-HT) is found. This can lead to the development of depression, and also resulting in more pain due to a reduction in the activity of the descending pain control pathways22. On the other hand, the presence of pain can be a predictive factor for the development of depression23. Chronic pain can worsen an individual’s mood and may potentially alter the levels of physical and social activities, leading to social isolation. Besides that, painful physical symptoms and heart or chest pain was found to be significant indicators for first episode MDD in adults without physical disease24. The presence of both conditions often results in poorer outcomes. This relationship underscores the need for comprehensive care strategies that address both mental health and diabetes management to improve overall health outcomes in affected individuals.
Autoimmune diseases
Numerous studies have highlighted the contributory role of pro-inflammatory cytokines, metabolic markers, and endocrine factors in the onset of major depressive disorders25. Consequently, it is not surprising to observe a higher incidence of depression in diseases involving inflammatory processes. Auto-immune diseases such as multiple sclerosis and rheumatoid arthritis, for example, demonstrate the incidence of depression as high as 50% 26,27.
Neurocognitive disorder
In the elderly population, a significant association between the onset of depressive symptoms and a higher risk for developing functional disability in daily activities was establisehd 28. Earlier-life depression is also associated with a more than twofold increase in dementia risk 29 However, the relationship between depression and dementia remains complex. Some studies reported that late-life depression is associated with the development of dementia 30 while others suggest that late-life depression might act as a prodrome to dementia rather than a risk factor. There are also studies that found no clear association between depression and dementia31. Further research is warranted to investigate the complexity of this association and develop effective treatments for this demographic.
Pharmacological side effects
Antidepressants stand as the first-line option in managing moderate to severe major depressive disorder. However, it is important to acknowledge the variability in adverse events associated with these medications, including the cardiometabolic effects and weight gain. The antihistamic and anticholinergic effects of antidepressants are likely contributors to weight-gain. Drugs that have a high affinity for H1 receptor blockage have been linked to increased carbohydrate craving, consequently increasing food intake and promoting weight gain. The impact of antidepressants on weight modulation, specifically those involving serotonin, varies depending on the duration of treatment. In a narrative review by Hartej et al. (2020), antidepressants that have been identified to have weight-gain effects are tricyclic antidepressants (TCA: amitriptyline and nortriptyline), monoamine oxidase inhibitor (MAOI: phenelzine), selective serotonin reuptake inhibitor (SSRI: citalopram, paroxetine) and noradrenaline and specific serotonergic antidepressants (NaSSA” mirtazapine). Conversely, antidepressants that were found to be at low-risk for weight-gain are TCA (imipramine), MAOI (tranylcypromine, moclobemide), SSRI (fluoxetine), SNRI (venlafaxine, levomilnacipran, desvenlafaxine), and multimodal antidepressant (vortioxetine, vilazodone, trazodone)32.
Conclusion
Understanding the intricate relationship between depression and physical health carries profound implications for patients, caregivers, healthcare providers, and society at large. Patient education is paramount in promoting treatment adherence, while caregivers can adopt healthier lifestyles to support patient recovery and mitigate caregiver burden33. Among physicians, enhancing knowledge in identifying and treating both depression and physical health is a crucial step toward achieving remission. By performing early detection and intervention, the depression’s effects on physical illness can be lowered. Intervention strategies such as lifestyle modification, increased social support, encouragement of physical activities, and the reduction of alcohol use and obesity contribute to lowering morbidity and mortality.
In conclusion, major depressive disorder exerts a significant impact on physical health and prognosis of illnesses, and this illuminates a complex interplay that extends far beyond the conventional confines of mental health. By recognizing the interconnections between mental and physical well-being, it empowers physicians to employ a holistic approach in the treatment of patients.
