The association between type 2 diabetes and anhedonic subtype of major depression in hypertensive individuals

Abstract Given the limited data in the literature, the aim of this study was to investigate the association between type 2 diabetes and anhedonic subtype of major depression in hypertensive individuals. Demographic and polysomnographic data from 323 hypertensive individuals recruited from the database of the Erasme Hospital Sleep Laboratory were analysed. Only individuals with a diagnosis of type 2 diabetes according to the diagnostic criteria of the American Diabetes Association at admission were included in the “diabetes group”. Logistic regression analyses were used to study the association between type 2 diabetes and anhedonic subtype of major depression in hypertensive individuals. The rate of type 2 diabetes was 18.9% in our sample of hypertensive individuals. After adjusting for major confounding factors, multivariate logistic regression analyses demonstrated that unlike the non‐anhedonic subtype of major depression, only the anhedonic subtype of major depression was significantly associated with higher likelihood of having type 2 diabetes in hypertensive individuals. In this study, the authors demonstrated that the anhedonic subtype of major depression is significantly associated with type 2 diabetes in hypertensive individuals, which could potentially open up new perspectives for the development of therapeutic strategies complementary to conventional treatments for type 2 diabetes in this subpopulation at high risk of complications related to the co‐occurrence of this metabolic disorder.


INTRODUCTION
the co-occurrence of these two pathologies is associated with negative impact on life quality and cardiovascular outcome (development of resistance to antihypertensive drugs, increased risk of cardiovascular diseases and higher cardiovascular mortality). 6,7 Given these various elements, the occurrence of type 2 diabetes in hypertensive individuals is therefore a major public health problem, which justifies the realisation of additional investigations to identify the potential factor associated with type 2 diabetes in hypertension.
In the literature, it has been shown that major depression (MD) may promote the development of type 2 diabetes. 8 Nonetheless, this particular relationship between MD and type 2 diabetes appears to be mediated by some specific depressive symptoms. 9 Among the depressive symptoms implicated in this association of MD with type 2 diabetes, 10 anhedonia is a central symptom of MD that may allow to categorise this psychiatric disorder into two distinct subtypes according to anhedonic status both in the general population and in subpopulations with cardiovascular diseases: the non-anhedonic subtype of MD (characterised by the maintenance of the ability to feel positive emotions during pleasant life situations) and the anhedonic subtype of MD (characterised by the loss of the ability to feel positive emotions during life situations previously considered to be pleasant). 11,12 However, despite a significant prevalence of anhedonia complaints in hypertensive individuals, 13 no study has currently investigated the association between type 2 diabetes and anhedonic subtype of MD in hypertension. Thus, given this lack of validated data in the literature, it would be interesting to study the association between type 2 diabetes and anhedonic subtype of MD in hypertensive individuals to allow a better understanding of the frequent co-occurrence of hypertension and type 2 diabetes.
The objective of this study was therefore to empirically investigate the association between type 2 diabetes and anhedonic subtype of MD in a large sample of hypertensive individuals. The goal of this approach was to provide healthcare professionals caring for hypertensive individuals with reliable data regarding the association between type 2 diabetes and anhedonic subtype of MD in order to allow the establishment of more targeted therapeutic strategies and better prevention of the negative consequences related to the co-occurrence of type 2 diabetes in this particular subpopulation.

Medical, psychiatric, and sleep assessment of participants
A review of their medical records and a complete somatic assessment (including blood test, electrocardiogram, day electroencephalogram and urinalysis) were performed in hypertensive individuals included in this study during their admission to the Erasme Hospital Sleep Laboratory in order to allow a systematic diagnosis of their potential somatic pathologies.
Following this somatic assessment, hypertension was defined as present if one of the following criteria were present: biologically documented self-reported diagnosis of hypertension; taking antihypertensive medication; mean systolic blood pressure ≥140 mm Hg; mean diastolic blood pressure ≥90 mm Hg. Systolic and diastolic blood pressures were manually measured at the right arm after 5 min of rest in a sitting position by well-trained nurses. For individuals with a systolic blood pressure ≥140 mm Hg and/or a diastolic blood pressure ≥90 mm Hg, blood pressures were again measured twice after a systematic rest period of five additional minutes. The first measurement was excluded whereas the second and third measurements were averaged in order to minimize the impact of white coat effect. In the absence of prior diagnosis of hypertension, pathological blood pressures were confirmed by repeated measurements during the stay at the sleep laboratory. 14 Type 2 diabetes was considered as present when the patient at admission has reported a biologically documented diagnosis of type 2 diabetes previously established by a diabetologist according to the diagnostic criteria of the American Diabetes Association. 15 Patients were also assessed as type 2 diabetics when one or more of the following criteria was present at their admission: glycated haemoglobin (HbA1c) ≥6.5%; fasting plasma glucose ≥126 mg/dl (fasting is defined as no calorie intake for at least 8 h); 2-h plasma glucose ≥200 mg/dl during an oral glucose tolerance test; plasma glucose ≥200 mg/dl in patients with classic symptoms of hyperglycaemia; hyperglycaemic crisis. In the absence of unequivocal hyperglycaemia, criteria 1-3 should be confirmed by repeat testing. In addition, diabetes must have begun in adulthood. 15 Thereafter, a unit psychiatrist performed a complete psychiatric assessment in hypertensive individuals recruited for this study in order to systematically diagnose their potential psychiatric disorders according to the diagnostic criteria of the DSM 5. 16 The diagnoses of anhedonic or non-anhedonic major depressive episodes were therefore made during this systematic psychiatric assessment based on the diagnostic criteria of the DSM 5. 16 In addition, hypertensive individuals

Statistical analyses
Statistical analyses were performed using Stata 14. The normal distribution of the data was verified using histograms, boxplots, and quantile-quantile plots whereas the equality of variances was checked using the Levene test.
In order to allow our analyses, we divided our sample of hypertensive individuals into a control group without type 2 diabetes and a patient group with type 2 diabetes. Only hypertensive individuals with a diagnosis of type 2 diabetes according to the diagnostic criteria of the American Diabetes Association were included in the "diabetes" group. 15 Categorical data were described by percentages and numbers whereas continuous variables were described by their median and P25-P75. Since most continuous data followed an asymmetric distribution, we decided to use non-parametric tests for all these variables (Wilcoxon test) in order to highlight significant differences between the medians (P25-P75) observed in the different groups of hypertensive individuals. Finally, the categorical data were described by percentage and were analysed with Chi-square tests.
Univariate logistic regression models were used to study the association between type 2 diabetes and anhedonic subtype of MD and to identify potential confounding factors (detailed description available in Supplementary Data -Annex 3). In multivariate logistic regression models, the association between type 2 diabetes and anhedonic subtype of MD was only adjusted for significant confounding factors during univariate analyses. These different confounding factors were introduced hierarchically in the different multivariate logistic regression models.
The adequacy of the final model was verified by the Hosmer and Lemeshow test whereas the specificity of the model was verified by the Link test.
The results were considered significant when the p-value was < .05.

Polysomnographic data (Table 1)
Compared to hypertensive individuals without type 2 diabetes, hypertensive individuals with type 2 diabetes had a reduction in slowwave sleep as well as an increase in wake after sleep onset and sleep period time. The two groups did not differ significantly for the other polysomnographic parameters.

Multivariate regression analyses (Table 4)
After adjustment for the main significant confounding factors during univariate analyses, multivariate logistic regression analyses showed that unlike to the non-anhedonic subtype of MD, only the anhedonic subtype of MD was significantly associated with higher likelihood of having type 2 diabetes in hypertensive individuals.

DISCUSSION
The rate of type 2 diabetes was 18.9% in our sample of hypertensive individuals. This rate appears to be lower than that of the studies by potential deleterious consequences related to the co-occurrence of type 2 diabetes in this particular subpopulation. 28 In this study, we demonstrated that the rate of anhedonic subtype of MD was 15.8% in our sample of hypertensive individuals, which seems to be consistent with the limited data available in the literature on the frequent occurrence of anhedonia complaints in this particular subpopulation. 29,30 In addition, similar to some subpopulations, 10 we demonstrated that unlike to the non-anhedonic subtype of MD, only the anhedonic subtype of MD was significantly associated with  (Table 4) had only a limited effect on the higher likelihood of having type 2 diabetes associated with the anhedonic subtype of MD demonstrated in our sample of hypertensive individuals, which seems to indicate that in this particular subpopulation, this higher likelihood of having type 2 diabetes associated with the anhedonic subtype of MD could be mainly mediated by pathophysiologic mechanisms specific to anhedonia that occur independently of these main confounding factors. Indeed, in major depressed individuals, anhedonia seems to favour a higher consumption of "comfort" foods characterised by high levels of refined sugar and saturated fat, which could correspond to an attempt at self-medication to increase the hedonic tone. 34,35 In addition, alongside these dietary changes, anhedonia also appears to be associated with more sedentary lifestyle characterised by decreased physical activity. 36 However, the occurrence of these deleterious behavioural changes related to anhedonia (combination of high-calorie diet and more marked sedentary behaviours) may directly promote the development of insulin resistance that plays a central role in the pathophysiology of type 2 diabetes. 37 Thus, following these different elements, it seems essential to screen more systematically and adequately treat the anhe-  46,47 However, in this particular subpopulation, the use alone or in combination of antihypertensive drugs with a demonstrated positive impact on the reduction of cardiovascular mortality (angiotensin-converting-enzyme inhibitors, angiotensin receptor blockers, thiazide-like diuretics and dihydropyridine calcium channel blockers) should be preferred based on the initial severity of hypertension, the goal of blood pressure control and potential comorbid conditions. 46,47 Thus, given the potential positive effect of therapies targeting anhedonia on glycaemic control, the implementation of these therapies targeting anhedonia in addition to an adequate combined treatment of type 2 diabetes and hypertension could be a promising therapeutic option to potentiate conventional glycaemic control strategies in anhedonic major depressed hypertensive individuals with type 2 diabetes.

Limitations
The results obtained in our study come from retrospective data that, even if they have been encoded in a systematic manner, cannot be verified directly with the patient in most cases, which means that our results need to be replicated in prospective studies. Furthermore, since other types of diabetes were exclusion criteria in our study, our results are only applicable to type 2 diabetes, which may possibly limit their generalisation. In addition, we only focused on the anhedonic and nonanhedonic subtypes of MD, which means that our results cannot be generalised to other subtypes of MD. Finally, our database only contains hypertensive individuals who have agreed to perform a sleep laboratory, which may also limit the generalisation of our results.

CONCLUSIONS
In our sample of hypertensive individuals, the prevalence of type 2 diabetes was 18.9%, which seems to confirm that type 2 diabetes is a frequent comorbidity in hypertension. In addition, we have shown that unlike the non-anhedonic subtype of MD, only the anhedonic subtype of MD was significantly associated with higher likelihood of having type 2 diabetes in hypertensive individuals, which could potentially open up new perspectives for the development of therapeutic strategies complementary to conventional treatments for type 2 diabetes in this subpopulation at high risk of complications related to the co-occurrence of this metabolic disorder.

ACKNOWLEDGMENTS
We want to thank the Sleep Laboratory team from the Erasme Hospital for technical support. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

CONFLICT OF INTEREST
The authors have no conflicts of interest with the work carried out in this study.