The comorbidity of mental and physical illnesses is on the rise, particularly with the co-occurrence of major depression (MD) and type 2 diabetes mellitus (T2DM). Patients with DM exhibit a significantly elevated risk for MD, with the interplay of inflammatory responses, activation of the hypothalamic-pituitary-adrenal axis, oxidative stress, and abnormalities within the kynurenine pathway contributing to the pathophysiology of both diseases. Inflammatory cytokines and vascular endothelial growth factor abnormalities have emerged as critical factors common to MD and T2DM. Effective pharmacological treatments such as selective serotonin reuptake inhibitors and cognitive-behavioral therapy (CBT) are available, with CBT demonstrating particularly beneficial effects on medication adherence and glycemic control. This review aims to elucidate the complex interplay between MD and T2DM, highlighting the shared mechanisms of pathophysiology and their therapeutic implications, ultimately informing clinical practice for better management of comorbid conditions.
The comorbidity of mental and physical illnesses poses a significant public health concern, with increasing prevalence attributed to rising life expectancy and various other socioeconomic factors. The prevalence of major depression (MD) is notably elevated among patients with chronic physical illnesses, with varying complication rates based on the specific physical illness and its severity. The overall prevalence of MD in this population ranges from 13% to 79%. Among patients with coronary artery disease, for instance, the prevalence of MD ranges from 34.6% to 51%. Elevated rates of MD are also observed in individuals suffering from cancer and chronic obstructive pulmonary disease. This review article focuses on the comorbidity of MD and type 2 diabetes mellitus (T2DM), both of which have escalated in prevalence in recent years [1]. MD is nearly twice as prevalent in individuals with T2DM compared to those without; specifically, only 2,574 of 68,739 patients without T2DM developed MD (3–7%). Furthermore, the risk of developing MD in patients with T2DM is significantly higher than in those without T2DM, as indicated by a hazard ratio (HR) of 1.61 (95% CI: 1.49–1.77). This demonstrates a close relationship between T2DM and MD [2]. Particularly, MD and T2DM share common pathophysiological mechanisms, including inflammation, abnormal stress responses/hypothalamus pituitary adrenal (HPA) axis, neurotransmitter changes, oxidative stress, impaired insulin signaling, and others, which contribute to the risk of comorbidity and the severity of both diseases. An integrated treatment strategy targeting these mechanisms is considered important for improving both diseases [3].
Current clinical guidelines do not adequately elucidate the pathophysiological mechanisms underlying the concurrent occurrence of T2DM and MD, nor do they provide comprehensive therapeutic protocols for managing these conditions [4]. In this review article, we discuss the epidemiology, common pathophysiology, and treatment approaches for the complications associated with T2DM and MD.
A meta-analysis investigating the mean point prevalence of T2DM revealed that the prevalence of MD in patients with T2DM was 14.5% (95% CI: 7.9–25.3; I² = 99.65), significantly higher than that in the general population (odds ratio [OR]: 1.73, 95% CI: 1.38–2.16) [5]. Roy and Lloyd reported that the prevalence of MD was more than three times greater in patients with Type 1 diabetes mellitus (T1DM) compared to those without (12%, range 5.8–43.3% vs. 3.2%, range 2.7–11.4%, respectively), and nearly double in patients with T2DM compared to those without (19.1%, range 6.5–33% vs. 10.7%, range 3.8–19.4%, respectively) [6]. Additionally, women with diabetes demonstrated a higher prevalence of MD compared to men. A recent systematic review of studies conducted in India reported considerable variation in the prevalence of MD in patients with DM across studies, with rates ranging from 2% to 84% (T1DM: 2% to 7%; T2DM: 8% to 84%) [7]. The coexistence of DM and MD has been associated with several factors, including advanced age, female sex, lower literacy, lower socioeconomic status, rural residence, marital status, duration of diabetes exceeding 2 years, diabetes-related complications, poor glycemic control, lack of exercise, and inadequate self-care. A nationwide retrospective analysis from 2002 to 2014 used the Inpatient Sample database to examine prevalence, temporal trends, and risk factors for comorbid MD among adult DM inpatients. That analysis demonstrated that the proportion of MD among patients with T2DM increased from 7.6% in 2002 to 15.4% in 2014, and in T1DM, it rose from 8.7% to 19.6%. High rates of MD were particularly noted among women, non-Hispanic whites, younger patients, and those with five or more comorbidities associated with DM [8].
The pathophysiology of MD and T2DM is intricate, involving mechanisms such as inflammatory responses, activation of the HPA axis, and oxidative stress. Elevated levels of inflammatory cytokines (e.g., interleukin [IL]-6, tumor necrosis factor [TNF]α) are prevalent in both conditions, contributing to their pathological progression. Dysregulation of the HPA axis and hypersecretion of cortisol have been observed in patients with MD and T2DM, with hypercortisolemia being correlated with insulin resistance and hyperglycemia. Oxidative stress similarly impacts both diseases, leading to cellular and tissue damage via excessive production of reactive oxygen species (ROS) in the body. Additionally, ROS plays a role in the pathogenesis of depression through several mechanisms, including oxidative stress, inflammation, neurotransmitter imbalances, and neuronal plasticity, all of which can contribute to the emergence of depressive symptoms. The kynurenine (KYN) pathway, implicated in both diseases, mediates effects related to insulin resistance and inflammation. The following sections will elaborate on the shared pathophysiological features, concentrating on inflammation, HPA axis dysregulation, oxidative stress, the KYN pathway, and vascular endothelial dysfunction (Figure 1).
VEGF: vascular endothelial growth factor, CRP: C-reactive protein, MD: major depression, T2DM: type 2 diabetes mellitus, HPA: hypothalamus pituitary adrenal.
Elevated serum and plasma levels of inflammatory cytokines such as IL-1 β, IL-6, IL-10, and TNFα are observed in DM [9–11]. Correspondingly, elevation of serum and plasma levels of IL-6 and TNFα have been documented in the context of MD [12, 13]. Additionally, chemokines are involved in MD pathogenesis; a meta-analysis comparing patients with MD to healthy controls reported significantly higher levels of C-C motif chemokine 2/monocyte chemoattractant protein-1 (MCP-1) in patients with MD [13]. Furthermore, a cumulative meta-analysis of 58 studies in patients with MD affirmed the elevation of IL-6 levels, a finding supported by another meta-analysis focusing exclusively on IL-6 [14]. In addition, high-sensitive C-reactive protein (hs-CRP) levels are similarly elevated in patients with MD. Peripheral TNFα concentrations are heightened in patients with MD who are not undergoing pharmacological treatment. However, no differences in levels of hs-CRP, interferon-gamma (INF-γ), and MCP-1 are noted between MD and healthy cohorts [14, 15]. As aforementioned, the pathophysiological mechanisms common to DM and MD include increased levels of inflammatory cytokines; both conditions lead to heightened levels of cytokines such as TNFα and IL-6, adversely affecting insulin signaling at the pancreatic cell level, as well as neural and synaptic plasticity in the brain.
The HPA axis, which serves as a biological system mediating the relationship between stress and physiological function, is closely regulated to manage acute and chronic stress. It has been reported that there is no alteration in early morning cortisol levels between MD and healthy participants. Moreover, alterations to the diurnal cortisol rhythm, specifically flattening the cortisol circadian rhythm, are associated with insulin resistance and T2DM. The connection between stress and MD appears to be bidirectional, as both factors heighten the risk of developing T2DM. Negative glucocorticoid feedback is impaired in patients with T2DM, resulting in activation of the HPA axis and subsequent hypercortisolemia [16–19]. Hypercortisolemia has deleterious effects on glucose homeostasis in peripheral tissues, consequently leading to hyperglycemia. In glucocorticoid-sensitive peripheral tissues, including the liver, skeletal muscle, adipose tissue, and pancreas, the glucocorticoid receptor (GR) mediates the dysregulation of glucose production, uptake, and insulin signaling by glucocorticoids. In contrast to the increased sensitivity of GR in peripheral tissues, impaired GR signaling within peripheral blood mononuclear cells of patients with T2DM is associated with hyperglycemia, hyperlipidemia, and heightened inflammation. The parallel alterations in glucocorticoid receptors in immune cells and the brain suggest that impaired GR function in the brain may contribute to stress response, HPA axis hyperactivity, hypercortisolemia, and hyperglycemia. Furthermore, genetic polymorphisms in GR have been linked to metabolic disturbances in T2DM [20]. MicroRNAs known to target GRmRNAs have been reported to be dysregulated [21].
Oxidative stress (OS) represents a metabolic dysfunction characterized by an imbalance between biochemical processes that results in increased production of ROS and a compromised antioxidant defense system. Alterations often influence diseases associated with metabolic dysfunction in redox balance. Recently, compelling evidence has emerged linking OS to the pathogenesis of T2DM [22–24]. DM results from either impaired insulin secretion or diminished sensitivity to insulin, or both. ROS, including hydrogen peroxide and superoxide, negatively affects pancreatic beta-cell islets, subsequently impacting insulin production. In hyperglycemic environments, various signaling pathways—such as nuclear factor kappa-light-chain-enhancer of activated B cells and protein kinase C—are activated by ROS, further contributing to insulin resistance. Additionally, OS due to hyperglycemia plays a substantial role in complications, including diabetic nephropathy; patients with DM are at increased risk of developing atherosclerotic macrovascular and microvascular disease [25]. The augmentation of OS is observed in patients with both T2DM and MD; increased ROS leads to cellular injury that may exacerbate insulin resistance and contribute to neuronal dysfunction [26]. Excessive ROS generation and depletion of antioxidant defenses lead to heightened inflammatory signaling and induction of cellular apoptosis. The brain is particularly vulnerable to ROS due to its high oxygen consumption, high lipid content, and relatively weak antioxidant defenses; ROS are one of the main causative agents affecting neuroplasticity, potentially inducing MD. In this context, the synergistic effects of ROS and increased inflammatory signaling may represent one of the underlying etiologies of MD, underscoring the intricate relationship between oxidative stress and inflammation [27]. Another cytokine-associated mechanism widely acknowledged to be linked with MD is the KYN pathway, which is responsible for maintaining equilibrium between neuroprotective and neuroregenerative processes within the brain, thus intertwining the pathophysiology of DM and MD [28].
The Tryptophan-KYN pathway is a principal route for tryptophan conversion in the brain and peripheral systems [29]. The functional effects of KYN are contingent on its local concentration, cellular environment, and intricate positive and negative feedback mechanisms. KYN has been implicated in the etiology of various neurodegenerative diseases, MD, and metabolic diseases, including DM [30]. Mild inflammation associated with DM can influence KYN pathway function; conversely, KYN may modulate immune responses [31]. Key enzymes and metabolites within the tryptophan metabolic pathway are critically involved in DM pathogenesis, impacting pancreatic function, insulin resistance, intestinal barrier integrity, and angiogenesis [32]. Tryptophan metabolic imbalance has been identified in individuals with DM and its complications, rendering it an emerging focus in the prevention and treatment of DM [32]. In patients with MD, inflammation is believed to underpin serotonin deficiency through the induction of the extrahepatic tryptophan-degrading enzyme indoleamine 2,3-dioxygenase, which is activated by inflammatory cytokines. However, not all patients with MD exhibit immune activation, and in those that do, inflammation is often mild [33]. While aberrations in the KYN pathway have been the pathophysiology of MD, a meta-analysis [34] assessing KYN pathway metabolites reported that levels of kynurenic acid (KYNA) and KYN were lower in patients with MD than those in healthy controls, whereas quinolinic acid (QUIN) levels did not differ between the two groups. In patients with MD not receiving antidepressants, KYNA levels were lower, while QUIN levels were elevated in comparison to healthy controls. Our previous study investigated the effects of inflammatory cytokines on the KYN and serotonin pathways in two groups: those with T2DM-complicated MD (n = 13) and those with uncomplicated MD (n = 27) [35]. We measured the concentrations of inflammatory cytokines IL-6, TNFα, and metabolites in the KYN pathway. In univariate (P = 0.044) and multivariate (P = 0.036) analyses, TNFα levels were significantly higher in patients with combined MD and T2DM than in those with MD alone; TNFα showed significant interaction with quinolinic acid/tryptophan (QUIN/Typ) and serotonin in both groups (β = 1.029, adjusted P < 0.001; β = –1.444, adjusted P = 0.047, respectively). These results suggest that the T2DM-complicated MD group may be more affected by the activation of the KYN pathway through inflammatory depressive components and inflammatory cytokines than those with uncomplicated MD.
Vascular endothelial dysfunction in DM results from a range of disturbances in vascular endothelial cells caused by prolonged hyperglycemia. Elevated glucose levels contribute to increased oxidative stress, facilitate inflammatory responses, and contribute to endothelial cell dysfunction [27]. Detrimental consequences of endothelial cell dysfunction encompass reduced vascular relaxation capacity, increased thrombus formation, and accelerated vascular inflammation [36]. In response to vascular endothelial dysfunction, the body attempts to produce vascular endothelial growth factor (VEGF) to facilitate vascular repair; however, excessive VEGF production can have adverse effects depending on the disease context. In the case of DM, sustained hyperglycemia inflicts chronic damage to vascular endothelial cells, resulting in dysfunction. Additionally, VEGF increases vascular permeability, heightening the risk for complications such as diabetic retinopathy and nephropathy [37, 38]. Neurotrophic factors play critical roles in the pathophysiology of MD. VEGF has been shown to promote neurogenesis, neuroprotection, and synaptic transmission [39]. Previous research examining VEGF levels in depressed patients has yielded inconsistent results [40]. VEGF has been implicated in the development of major depressive disorder. Recently, a genome-wide association study identified four VEGF-related single nucleotide polymorphisms (SNPs) (rs4416670, rs6921438, rs6993770, and rs10738760) that are independently associated with circulating VEGF levels [41]. In a separate investigation, the relationship between brain volume and these four SNPs was evaluated in 38 patients with first-episode, drug-naïve MD and 39 healthy controls, with high-resolution T1-weighted imaging employed for assessment. All four SNPs were associated with whole-brain cortical thickness and sub-hippocampal area volume. Genotype-diagnosis interactions were evaluated for each of the four SNPs; a significant interaction was identified only for rs6921438 (specifically in left sub-hippocampal area volume between patients with MD and healthy controls possessing G/G genotype and A carrier genotype; P < 0.05). Scores on the “hypochondriac” measure of the Hamilton Depression Rating Scale were significantly higher in patients with the G/G genotype compared to those with the A carrier genotype. An association was identified between the VEGF-related SNP rs6921438 and pituitary atrophy in first-time patients with drug-naive MD [42]. Furthermore, a 4-week treatment regimen with duloxetine, a serotonin and norepinephrine reuptake inhibitor, did not increase serum VEGF concentrations [43]. No significant association was observed between the VEGF-related SNP rs6921438 and VEGF atrophy. These findings imply that genetic polymorphisms in VEGF may be implicated in the response to antidepressants.
Telemonitoring interventions may be a better option than usual care in improving glycated haemoglobin control of patients with T2DM [44]. In another study, physicians, nurses, and psychiatrists worked together to provide “collaborative care” to patients with depression and chronic illnesses such as diabetes, reporting significant improvement in the patients’ depressive symptoms and improved glycemic control [45]. A recent report has shown that integrated lifestyle interventions (diet, exercise, psychological support, and medical management) for T2DM patients are effective in improving anxiety and depression symptoms. In particular, it has been suggested that a multifaceted approach that includes psychological support contributes to the improvement of depression in T2DM patients [46]. To summarize the above, there have been reports that treatment of MD (cognitive behavioral therapy and the use of antidepressants) for T2DM patients has improved blood sugar control. There have also been cases where diabetes management programs have had a positive impact on MD.
Pharmacotherapy
The first-line medications for MD without uncomplicated T2DM are SSRIs, SNRIs, mirtazapine, and bupropion [47, 48], with a few caveats for MD patients with comorbid T2DM. According to a systematic review by Roopan and Larsen [49], SSRIs are regarded as the first-line pharmacological treatment for MD in patients with T2DM. However, careful monitoring for SSRI-induced hypoglycemia is warranted. Mirtazapine, paroxetine, and tricyclic antidepressants are advised against due to concerns regarding weight gain, insulin sensitivity, and glycemic control [50]. When the use of tricyclic antidepressants becomes necessary, vigilant monitoring of blood glucose levels is recommended to prevent exacerbation of hyperglycemia [51]. Given the involvement of inflammation in the pathogenesis of both T2DM and MD, it has been proposed that a combination of antidepressants with anti-inflammatory agents may enhance treatment efficacy. Studies indicate that this combination could be beneficial for treatment-resistant depression [52–54], while conflicting data exist regarding its efficacy [55]. In specific cases, particularly among patients with MD and T2DM, renal function may be compromised, necessitating further rigorous studies with larger sample sizes to clarify these outcomes. No evidence exists to support the efficacy of concomitantly administering vitamins C, E, and polyphenols, which are noted for their roles in scavenging ROS.
Cognitive Behavioral Therapy
In a cohort of 87 patients with T2DM and MD and who had inadequate glycemic control, the implementation of 9 to 11 sessions of cognitive-behavioral therapy (CBT) alongside enhanced treatment as usual (ETAU)—which included medication adherence, self-monitoring of blood glucose, and lifestyle counseling—led to significantly higher rates of adherence to oral medication and blood glucose self-monitoring. Additionally, reductions on the Montgomery-Asberg Depression Rating Scale were markedly greater in the group receiving CBT compared to the ETAU-only cohort. These findings indicate that CBT may be an effective intervention for improving adherence, glycemic control, and alleviating depressive symptoms [56]. A preliminary study investigating the impact of a 6-session internet CBT (iCBT) program over a 10-week span among individuals with comorbid MD and DM reported that while iCBT was effective in reducing depression, it did not significantly enhance adherence. This study suggests that an iCBT program supported by therapists via telephone and email could provide an effective and accessible treatment avenue for patients with comorbid DM and MD [55]. Recent systematic reviews have demonstrated that psychotherapy, group therapy, and comprehensive care strategies yield positive outcomes in patients with T2DM and MD. Nonetheless, limitations exist within these interventions, including insufficient sample sizes and the inclusion of patients with subthreshold MD, indicating a need for clarity regarding more rigorous intervention methodologies in subsequent research.
This review focused on the public health challenges posed by the comorbidity of type 2 diabetes mellitus (T2DM) and major depression (MD), discussing their epidemiology, shared pathophysiology, and treatment approaches. The prevalence of MD in T2DM patients is approximately twice as high as in the general population, significantly impacting patient outcomes. Common pathophysiological mechanisms include elevated inflammatory cytokines, dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis, oxidative stress, alterations in the tryptophan-kynurenine pathway, and vascular endothelial dysfunction. In particular, inflammation and oxidative stress contribute to both insulin resistance and impaired neuroplasticity, exacerbating the progression of T2DM and MD. Selective serotonin reuptake inhibitors (SSRIs) are recommended as the first-line pharmacological treatment, while cognitive behavioral therapy (CBT) and other psychosocial interventions have also shown efficacy. Future directions include developing inflammation-targeted therapies, leveraging digital health technologies, and advancing personalized medicine. This review aims to deepen the understanding of T2DM and MD comorbidity, supporting advancements in clinical management and research.
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Not applicable as no new data were generated in this review.
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The authors confirm their contribution to the paper as follows: all authors reviewed the paper and approved the final version of the manuscript.
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