Biopsychosocial and Nutritional Factors of Depression among Type 2 Diabetes Mellitus Patients: A Systematic Review

The rising prevalence of depression among Type 2 Diabetes Mellitus (T2DM) patients has triggered an alarming situation, and further actions need to be taken by health care professionals and policymakers to curb the issue. There is a lack of evidence review in terms of the biopsychosocial and nutritional factors that are related to depression among T2DM. Hence, this review aimed to identify available evidence on the biopsychosocial and nutritional factors associated with depression among T2DM patients based on the existing literature. Articles were systematically searched from four databases, namely PubMed, Scopus, Web of Science, and EBSCOHost. The approach for the identification of the final articles followed PRISMA guidelines. The selected full-text articles were published between 2017 and 2021 in the English language, and included studies focused on depression among T2DM patients. Using AXIS tools, the eligible articles were evaluated to assess the quality of studies. A total of 19 studies were included in the review, and information related to research questions and associated factors was extracted. Biological, psychological, social, and nutritional factors were shown to be linked with depression among T2DM patients. Future studies need to considered using the biopsychosocial model and incorporating nutritional factors to manage the issues of depression among T2DM patients.


Introduction
Type 2 Diabetes Mellitus (T2DM) is an emerging public health issue with a high prevalence worldwide. The prevalence of T2DM is increasing, with a significant increase in low-and middle-income countries, including Southeast Asian countries [1]. T2DM a health challenge and has affected 415 million patients globally [2]. Moreover, it is predicted that by 2040, the number of people with T2DM will increase to 642 million worldwide [3]. Recently, mental health among T2DM patients has become a topic of clinical discussion and policymaking [4].
Despite microvascular and macrovascular complications, T2DM was found to negatively affect the mental health status of patients, contributing to mental health outcomes such as depression [5]. Moreover, T2DM patients had a three-times higher risk of developing depression than those who did not have Diabetes Mellitus [6]. Individuals with T2DM and depression were found to have more severe long-term effects than those who did not have T2DM [5]. Depression was found to affect patients in terms of (i) quality of life, (ii) economic impact, and (iii) morbidity and mortality. In terms of quality of life, depression influences adherence to treatment and indirectly contributes to poor sugar control, as well as reduced productivity [7]. In addition, depression among T2DM patients was found to increase the risk of developing coronary heart disease up to 36.8% and the risk of heart-related deaths around 47.9% [2,7].
According to a biopsychosocial model developed by George Engel in 1977, the development of illness or disease occurs through a combination of biological factors, namely genetic and physiological [8]. For psychological factors, the development of illness or disease is linked to health beliefs, lifestyle, personality, and behaviour. In addition, social factors include family relationships, socioeconomic status and social support [8]. Thus, this model suggests that biological, psychological, and social factors are associated in the development of illness [9].
Based on the previous literature, nutritional factors play an important role in mental health. Poor dietary habits and nutritional factors may put T2DM patients at a higher risk for developing depressive symptoms [10]. Studies conducted in Iran have shown that depression was associated with low protein and high fat intake in an individual dietary pattern [11]. T2DM patients with low carbohydrate diet showed a significant association with mental health status [12]. Otherwise, there is still a lack of reviews discussing in detail biopsychosocial and nutritional factors in relation to depression among T2DM patients. Therefore, this review aimed to identify available evidence on biopsychosocial and nutritional factors associated with depression among T2DM patients.

Materials and Methods
This review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) review protocol [13]. NAM and ZMI started the review by formulating appropriate research question. The process conducted for systematic searching consists of identification, screening, and eligibility processes. During the identification process, four primary databases, namely Scopus, Web of Science, PubMed, and EBSCOHost, were used. Most articles were open-access articles, which provided full original articles. Full original articles were selected to extract the relevant information and findings to answer the research question. In term of the quality of the selected articles, the articles were screened and evaluated using the Appraisal tool for Cross-Sectional Studies (AXIS) [14].

Formulation of the Research Question
In this review, the formulation of research questions was based on the PICo concept, which stands for the population, interest, and context [15]. This tool is used to guide authors in forming a suitable research question for the systematic review [15]. These components are the crucial elements in constructing the research question. Based on this concept, "population" refers to Type 2 Diabetes Mellitus patients, "interest" refers to depression, and "context" refers to biopsychosocial and nutritional factors or determinants. The PICo guided the formulation of the main research question in this review: "What are the biopsychosocial and nutritional factors associated with depression among T2DM patients?"

Systematic Searching Strategies
The systematic searching strategy in this review is based on PRISMA flow, which consists of the identification, screening, and eligibility stages ( Figure 1).

Identification
During the identification stage, keywords were chosen using synonyms and variations that were found when searching for articles in databases. All authors (NAM, ZMI, and NA) screened the titles and abstracts independently according to their relevance based on the research question. The search string was use in the identification process, as shown in Table 1. The systematic literature search was conducted between 20 December and 27 December 2021, and involved four primary databases, namely Scopus, Web of Science, PubMed, and EBSCOHost, which resulted in the retrieval of 418 records. The records were retrieved from the databases and organised in an Excel sheet for screening. During the procedure, any duplicated articles and unrelated titles that deviated from the study question were deleted. Following that, the abstracts were reviewed before the unrelated articles were removed.

Identification
During the identification stage, keywords were chosen using synonyms and variations that were found when searching for articles in databases. All authors (NAM, ZMI, and NA) screened the titles and abstracts independently according to their relevance based on the research question. The search string was use in the identification process, as shown in Table 1. The systematic literature search was conducted between 20 December and 27 December 2021, and involved four primary databases, namely Scopus, Web of Science, PubMed, and EBSCOHost, which resulted in the retrieval of 418 records. The records were retrieved from the databases and organised in an Excel sheet for screening. During the procedure, any duplicated articles and unrelated titles that deviated from the study question were deleted. Following that, the abstracts were reviewed before the unrelated articles were removed. Table 1. Keyword search in the identification process.

Screening Using Inclusion and Exclusion Criteria
The title and abstract of each article were examined by all authors (NAM, ZMI, and NA) for relevance based on the inclusion and exclusion criteria for this review. The inclusion criteria for article selection were: (1) published between 2017 and 2021, (2) full original article, (3) written in English, and (4) study focused on identifying factors associated with depression among T2DM patients. Systematic reviews, conference proceedings, book chapters, editorial letters, and reports were excluded. The screening process excluded 319 articles, and the retrieval of full-text eligibility proceeded for the remaining 35 articles.

Eligibility
A total of 30 full text articles were successfully retrieved for eligibility. NAM, ZMI, and NA reviewed all full-text articles and removed non-related articles. The remaining 19 articles were reviewed with the quality appraisal process.

Quality Assessment
The Appraisal tool for Cross-Sectional Studies (AXIS tool) is designed for non-experimental research and includes 20 components measuring each aspect of the study's quality [14]. This tool determines whether the findings of a study are credible and reliable, and should related to the aims, methods, and analysis of what is reported and not on the interpretation (e.g., discussion and conclusion) of the study. This tool does not provide a numerical scale for evaluating the quality of the study. The benefit of the AXIS tool is that it provides the opportunity to assess each aspect of study design to provide an overall assessment of the quality of the study. This tool offers more flexibility in incorporating quality of reporting and risk of bias when making assessment on the quality of a paper. Based on the assessment, a total of 19 articles were included. The total number of "yes" appraisals was recorded for each study, as the tool guide does not specify a standardized scoring measure or numerical scale. For this review, the mean total quality score was 16 (range: 15-17) out of 20, as presented in Tables A1 and A2 in Appendix A. The authors were able to conclude that included (19 studies) had clear study objectives and used the appropriate study design and methods.

Data Abstraction and Analysis
The authors independently extracted information from the selected studies, including the author's names, year, country, study objectives, study designs, sample size, depression instrument, factors associated with depression among T2DM patients, and limitations. Data abstracted from all studies were compiled in an appropriate matrix table ( Table 2). The authors (NAM, ZMI, and NA) reviewed the matrix tables for both consistencies and inconsistencies to generate themes and findings for the review. Similar or related information were grouped together as one characteristic, and the technique was repeated to form reasonable findings for interpretation.

Crosssectional study
To assess the predictors of depression as well as its prevalence in T2DM patients, the authors conducted a cross sectional study entitled "DEPression in DIABetes" (DEPDIAB).

T2DM patients from Eastern India
Patient Health Questionnaire-9 (PHQ-9) and Beck depression scales Younger age , female, low socioeconomic status, poor compliance, hypoglycaemia, and difficulty in managing day-to-day activities Biological, Social (1) It was conducted in the tertiary care centres and not in the community set-up, which may limit its generalizability. (2) The assessment of depression was performed via a questionnaire-based screening tool rather than by a psychiatrist.

3.
Kant et al. [18], India  (2) The depressive and anxiety symptoms were measured by self-reported tools rather than diagnostic interviews.

Crosssectional study
This study aimed to assess the prevalence of Diabetes Mellitus (DM)-related distress and depression and their associated factors in Saudi people with T2DM in Jazan, Saudi Arabia.
It also aimed to assess the association between glycaemic control and DM-related distress and depression.
300 Saudi patients with T2DM randomly from primary healthcare centres in Jazan, Saudi Arabia

17-item Diabetes Distress Scale and the Patient Health
Questionnaire-9 Female, patients aged < 45, physical inactivity, DM duration < 5 years, and smoking were significantly associated with DM-related distress and depression.
Biological, Social, Psychological Cross-sectional study The cross-sectional design is inadequate to assess the direction of the relationship between depression, anxiety, and stress and T2DM.

Crosssectional study
To evaluate the relationship between T2DM-related factors and the degree of depression based on gender in elderly patients with T2DM. We also evaluated and considered other possible factors that can affect depression, such as cognitive function, physical function, education level, and other personal factors.

patients with T2DM
The Geriatric Depression Scale-Korean version (SGDS-K) Poorer glycemic control and a longer duration of DM in elderly male patients with T2DM.

Biological
(1) The study was cross sectional; (2) The sample size was relatively small, and the participants were enrolled from several general hospitals, raising concern about the generalizability of the results.
(3) They relied on the SGDS-K without an accompanying diagnostic interview by a professional

Results
After the screening and selection process, a total of 19 studies which fulfilled the inclusion criteria were included in this systematic review ( Table 2). The selected articles comprised four articles from India, three articles from Saudi Arabia, two articles from Malaysia, and two articles from Ethiopia. The remaining articles were from China, Korea, Nepal, Kuwait, Singapore, Turkey, and Pakistan, respectively. Eighteen articles of these quantitative studies were cross-sectional studies, and one was a cohort study. The review found various measurements used for depression and its related factors among T2DM patients ( Table 2). The extracted articles were published from 2017 to 2021.

Factors Associated with Depression among T2DM Patients
All findings were summarized into biological, psychological, social, and nutritional factors in Table 3. The review showed that age, the female sex, a long duration of diabetes, high body mass index, high HbA1c levels, the presence of comorbidities, diabetic complications, a mild impairment of cognitive function, and sexual dysfunction were biological factors. Psychological factors included the fear of diabetic complications, anxiety, low satisfaction with treatment, and physical inactivity. For social factors, depression was associated with alcohol intake, poor social support, low educational status, smoking habits, being single, living arrangement, and low socioeconomic status. As for nutritional status, low albumin was with depression among T2DM patients.

Discussion
To our knowledge, this is the first review discussing the factors associated with depression among T2DM patients based on the biopsychosocial model. This review comprised 19 articles identified multiple factors associated with depression among T2DM patients. These factors were then further divided into four major categories, namely (1) biological factors, (2) psychological factors, (3) social factors, and (4) nutritional factors.

Biological Factors
Based on the biopsychosocial model, biological factors, including genetic and physiological factors, cause the occurrence of a disease [8]. Referring to a study conducted by Habtewold et al. [4] which used this model, the biological factors included age, gender, fasting blood sugar levels, body mass index, comorbidity disease, and diabetes complications [4]. In terms of age (less than 65 years old), the female sex was among the contributing factors in the incidence of depression among people with T2DM [34]. Based on previous studies, patients who were older and had various chronic diseases faced more stress [35]. In terms of gender, women had a higher risk and were more prone to depression and anxiety compared to men [20,36].
A study in the United States showed that various comorbidities increase the risk of depression among T2DM patients [37]. The presence of comorbidities, such as hypertension and coronary heart disease, is among the contributing factors [22,38]. In the long term, T2DM may cause various complications, such as diabetes nephropathy, neuropathy, and retinopathy. The presence of complications has caused the patients to face more stress related to their health condition, thus contributing to depression and anxiety [20,33]. Diabetic complications, such as diabetic retinopathy, diabetic nephropathy, and neuropathy, predispose patients to depression. Studies have shown that the positive association between diabetes complications and depressive symptoms is persistent and mediated by diabetes distress [39]. Diabetic complications occur due to the long duration of diabetes. In other aspects, a long period of illness is also a contributing factor of depression among T2DM patients [33].
Metabolic problems in T2DM may contribute to the incidence of depression. Persistent hyperglycaemia and severe hypoglycaemia among T2DM patients can alter function, neuronal transmission, or brain structure, hence predisposing T2DM patients to depressive disorder [40]. Obesity is linked to anxiety and depression [25]. Obesity has been found to negatively affect self-confidence, economic status, and social status, and further contributes to psychological problems [40]. One study showed an association between obesity and depression due to the presence of genes contributing to depression, such as genes that encode glucocorticoids, leptin, and dopamine receptors [41]. Depression was associated with an increased risk of macrovascular complications, mortality, suicide, and all-cause mortality among patients with incident T2DM [42].
In other aspects, sexual disorders among T2DM patients have a significant association with the incidence of depression. Sexual disorders are more common in diabetics than non-diabetics [43]. Sexual disorders were more frequent among older T2DM patients and those with a longer duration of diabetes [43]. In addition, sexual dysfunction can negatively impact marital relationships and treatment outcomes [44].
In addition, depression, anxiety, and apathy are prevalent neuropsychiatric symptoms in mild cognitive impairment, and they have been associated with cognitive and functional deterioration in daily tasks, as well as disease progression [45]. In individuals with diabetes, depression is associated with a higher risk of dementia and poor cognition [46].

Psychological Factors
Psychological factors involve health beliefs and lifestyle [9]. The psychological factors in the study conducted by Habtewold et al. [4] included physical activity and the fear of complications of the disease and treatment. The fear of diabetic complications and anxiety also play an important role in depression among T2DM patients. Patients with anxiety symptoms are more inclined toward depression [6]. In addition, patients not only feel burdened by the disease but also fear further Diabetes Mellitus complications [22]. The increased burden of treatment cost is also among the psychological factors that contribute to anxiety and depression among patients with T2DM [47].
Life satisfaction is a necessary component in achieving positive mental health and is a predictor of several life outcomes [48]. Low satisfaction with treatment was shown a predisposing factor for depression among T2DM patients [24]. Patients with T2DM having moderate satisfaction with their treatments had greater medication adherence and a better quality of life [49]. Physician-patient interaction satisfaction is an important outcome in health care delivery, and most important determinant for patient satisfaction and medication adherence [50].
Generally, physical inactivity is linked with a higher mortality rate, as well as coronary disease, stroke, T2DM, and poor mental health [51]. Physical activity plays an important role in preventing depression [52]. A previous study showed that a sedentary lifestyle is a contributing factor to depression [19]. According to World Health Organization guidelines, adults aged between 18 and 64 years old should perform at least 150 min of moderateintensity physical activity throughout the week for at least 5 days each week and for at least 30 min per day [53]. Excessive high-intensity physical activity can lead to fatigue and increase the risk of depression. Moreover, moderate-intensity physical activity is ideal to improve quality of life and can reduce the prevalence of depression [25]. Promoting exercise in addition to drug treatment has been shown to offer significant advantages in managing the symptoms of depression [54]. Exercise has therapeutic effects on depression among all age groups, mainly those between 18 and 65 years old, as a monotherapy, adjuvant therapy, or combination therapy in which the advantages of exercise therapy are comparable to conventional depression treatments [55].

Social Factors
Based on the biopsychosocial model, social factors consist of socioeconomic status, education level, marital status, and social support [4] In terms of financial status, patients from low-income families have a higher risk of depression [7]. Low socioeconomic status, poor education, and divorce are among the factors involved in the incidence of depression [38]. For employment status, unemployed individuals are more prone to the risk of anxiety and depression [56]. This is expected, as not having work is itself a depressing factor. In addition, the disease itself imposes a financial burden [57]. The association between lower educational status and T2DM can be attributed to a lack of understanding of the disease's severity, drug compliance, and dietary management, which makes individuals vulnerable to complications [57].
Unhealthy lifestyles, such as smoking and the consumption of alcohol, are highly interrelated with depression, whereby depression may elicit and exacerbate unhealthy lifestyles. Moreover, people with unhealthy lifestyles are more likely to become depressed over time [58]. In a longitudinal study, smoking on a daily and non-daily basis and heavy alcohol consumption were associated with depression [58].
Loneliness is one of the risk factors for T2DM [59]. Being single was associated with depression among T2DM patients [19]. Living arrangement also plays an important role. Living arrangements, such as living alone, may be related to the incidence of T2DM [60]. Patients who lived with their children were found to be significantly less depressed compared to those who lived alone [28]. It has been postulated that living with children has a protective effect from depression, as patients receive good support and attention from the children.
Social support is very important to maintain good physical and mental health. Overall, positive and high-quality social support is crucial to prevent any occurrence of depression and mental stress [61]. Previous studies have shown that poor social support is significantly associated with depressive symptoms. Individuals with poor social support from family, neighbours, and friends are six-times more susceptible to depressive symptoms than individuals with strong social support [6]. The coping mechanism is crucial in order to adapt to any stressful situation [62]. T2DM is associated with a high prevalence of depression, which is influenced by personality factors and coping styles [63]. Poor coping mechanisms predispose T2DM patients to a higher incidence of depression [63]. Negative coping methods, such as protest or isolation, were associated with a lower quality of life, whereas avoidance was associated with increased diabetes-related distress and depressive symptoms [62]. Those who used positive coping techniques, and demonstrated high levels of personal and treatment control had lower levels of depression [64]. Other reviews have suggested that T2DM patients may benefit from psychoeducational interventions, such as supportive psychotherapy, in managing the complications of diabetes [63].

Nutritional Factors
Nutritional factors and dietary habits can affect physical health and illnesses [65]. The percentage of macronutrients consumed in daily life may be associated with the occurrence of depression [65]. High fruit and vegetable consumption was associated with a decreased incidence of T2DM, hypertension, dyslipidaemia, osteoarthritis, and depression in both men and women [66]. Studies in the United States have shown an association between protein and fat intake and depression [67]. Carbohydrates are one of the sources of energy for the population in Asian countries [68]. Carbohydrates play an important role in controlling sugar levels, and contribute to the incidence of T2DM and complications of Diabetes Mellitus [12].
Overall, a high amount of calorie intake and increased sugar intake in food were found to correlate with anxiety and depression symptoms [69]. Patients who consume fewer carbohydrates have better sleep quality and are less likely to suffer from mental illnesses [12]. Studies conducted in Iran have shown that depression is associated with low protein and high fat intake in individual dietary patterns [11]. A study showed that total protein intake and protein intake from milk and milk products might reduce the risk of depressive symptoms, but protein intake from red meat, poultry, fish, grain products, and legumes did not have the same result [70].
In this review, lower albumin levels due to poor nutritional status contributed to depression among T2DM patients [29]. Albumin is a protein that supports a variety of functions in the human body. Many studies have found that lower serum albumin levels are related to depression in distinct groups of psychiatric and non-psychiatric patients [71]. As summarised, nutritional factors play a crucial role in terms of mental health, especially depression, among T2DM patients.

Strength and Limitations
This review provides an overview of the biopsychosocial and nutritional factors that are associated with depression among T2DM patients based on the existing literature. In this review, the research was limited to articles published in English only. The systematic literature only extracted articles from 2017 to 2021. Most of the studies were observational studies, including cross-sectional studies and one cohort study. Despite being conducted using PRISMA guidelines for systematic reviews and using four different databases to perform the systematic search, this study still has some limitations. The review included only open-access articles; thus, it may not represent all available literature linked to the topic. In addition, some studies may have focused on similar topics that were eliminated during the screening process due to the different keywords and titles used by the studies.

Conclusions
This systematic review identified multiple factors that contributed to depression among T2DM patients from multiple countries. The findings revealed that biopsychosocial and nutritional factors had a greater impact on depression among T2DM patients. All identified factors can facilitate health care professionals in taking the necessary preventive measures. Using the biopsychosocial model, a better and more holistic approach can be devised to manage the issues of depression among T2DM patients.     Table A2. Quality assessment of included studies using the AXIS tool.

Discussion Other
Author, Country Were the basic data adequately described?
Does the response rate raise concerns about non-response bias?
If appropriate, was information aboutnonresponders described?
Were the results internally consistent?
Were the results for the analyses described in the methods, presented?
Were the authors' discussions and conclusions justified by the results? Were