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

1 INTRODUCTION

In the literature, there are many arguments for a special relationship between type 2 diabetes and hypertension. Indeed, the prevalence of hypertension may reach 56.7% in type 2 diabetics and that of type 2 diabetes is estimated at 38.7% in hypertensive individuals.1, 2 In addition, hypertension is a risk factor for type 2 diabetes whereas type 2 diabetes is associated with an increased risk of hypertension.3, 4 Although this particular relationship is not yet fully understood, the presence of some common pathophysiological mechanisms (deregulation of the renin-angiotensin-aldosterone system, oxidative stress, activation of pro-inflammatory mechanisms, and occurrence of dysfunctional innate/adaptive immune responses) could explain this frequent co-occurrence of type 2 diabetes and hypertension.5 Moreover, 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.

2 MATERIAL AND METHOD 2.1 Population

Three hundred and twenty three hypertensive individuals were recruited from the clinical database of the Erasme Hospital Sleep Laboratory, which contains the data of 3301 individuals who usually stayed at the Erasme Hospital Sleep Laboratory between 2017 and 2019. In our study, we did not recruit individuals without hypertension because our objective was to focus on the subpopulation of hypertensive individuals where the co-occurrence of type 2 diabetes may have a deleterious impact on life quality and cardiovascular outcome.

These hypertensive individuals were referred to the Sleep Laboratory by physicians specialised in sleep medicine after an outpatient consultation during which a preliminary assessment of their complaints related to sleep, their ongoing psychotropic/somatic treatments and their somatic/psychiatric comorbidities was systematically carried out in order to allow a first diagnostic hypothesis. These polysomnographic examinations were performed in these hypertensive individuals to allow an objective assessment of their sleep complaints and exclude the presence of comorbid sleep disorders negatively impacting blood pressure regulation.

The inclusion criteria were age ≥18 years and the presence of hypertension meeting the diagnostic criteria of the World Health Organisation.14

The exclusion criteria were the presence of diabetes other than type 2 diabetes (such as type 1 diabetes, gestational diabetes, latent autoimmune diabetes, maturity-onset diabetes of the young, and secondary or iatrogenic diabetes), the presence of severe psychiatric pathologies (psychotic or bipolar disorder), the presence of severe uncontrolled somatic pathologies (chronic liver pathologies, chronic pancreatic pathologies, chronic pulmonary pathologies, severe cardiovascular pathologies, severe renal pathologies, autoimmune pathologies, severe endocrine pathologies, severe neurological pathologies and pathologies altering the activity of the hypothalamic-pituitary-adrenal axis such as Cushing's syndrome), the presence of inflammatory or infectious diseases, the presence or history of head trauma, the presence or history of central nervous system damage that may affect the respiratory centres, the presence of craniofacial or thoracic malformations, the presence of ongoing pregnancy, the presence of obstructive sleep apnoea syndrome being treated before the sleep laboratory, the presence of predominantly central sleep apnoea syndrome, the presence of central hypersomnia, the presence of parasomnia, and the presence or history of drug addiction.

2.2 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 anti-hypertensive 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 included in this study completed a series of self-questionnaires to assess the severity of their subjective complaints of depression (Beck Depression Inventory [BDI-II]), state anhedonia (Anhedonia subscale of Beck Depression Inventory [BDI-II]), trait anhedonia (Temporal Pleasure Experience Scale), insomnia (Insomnia Severity Index), and daytime sleepiness (Epworth Sleepiness Scale) (detailed description available in Supplementary data - Annex 1).

Finally, in hypertensive individuals recruited for this study, a specific semi-structured sleep interview and a polysomnographic recording were performed to systematically diagnose their potential comorbid sleep disorders according to the diagnostic criteria of the American Academy of Sleep Medicine (detailed description available in Supplementary data - Annex 2).17

2.3 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.

3 RESULTS 3.1 Polysomnographic data (Table )

Compared to hypertensive individuals without type 2 diabetes, hypertensive individuals with type 2 diabetes had a reduction in slow-wave 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.

TABLE 1. Polysomnographic data (n = 323) Whole sample (n = 323) Hypertensive individuals without diabetes (n = 262) Hypertensive individuals with diabetes (n = 61) p-value Sleep latency (min) 50.0 (30.0–95.0) 55.5 (30.0–96.0) 39.0 (30.0–75.0) .115 Sleep efficiency (%) 73.0 (63.0–81.0) 74.0 (63.0–81.0) 72.0 (63.0–80.0) .479 Sleep period time (min) 441.0 (408.0–471.0) 435.0 (406.0–470.0) 454.0 (429.0–477.0) .025 Total sleep time (min) 378.0 (321.0–413.0) 378.0 (320.0–414.0) 380.0 (327.0–411.0) .677 % stage 1 8.0 (6.0–12.0) 8.0 (5.0–12.0) 9.0 (7.0–12.0) .236 % stage 2 51.0 (43.0–58.0) 50.0 (44.0–58.0) 53.0 (40.0–60.0) .988 % slow-wave sleep 7.0 (2.0–13.0) 7.0 (2.0–14.0) 6.0 (1.0–11.0) .035 % REM latency 15.0 (10.0–19.0) 15.0 (11.0–19.0) 14.0 (8.0–18.0) .101 REM latency (min) 90.0 (67.0–148.0) 89.5 (67.0–149.0) 91.0 (68.0–137.0) .721 % wake after sleep onset 12.0 (7.0–22.0) 12.0 (7.0–21.0) 16.0 (10.0–22.0) .011 Number of awakenings 26 (20–37) 26 (19–36) 27 (22–39) .100 Micro-arousal index 15 (9–23) 15 (9–23) 16 (9–27) .497 Apnoea-hypopnoea index 13 (4–30) 13 (4–30) 13 (7–28) .446 Oxygen desaturation index 4 (1–15) 4 (1–15) 7 (2–16) .251 Total time under 90% of SaO2 (min) 4.0 (.0–32.0) 4.0 (.0–24.0) 8.0 (1.0–62.0) .066 PLMs index 4 (0–15) 4 (0–15) 3 (0–14) .284 Median (P25-P75) Median (P25-P75) Median (P25-P75) Wilcoxon test Abbreviations: PLMs, periodic limb movements during sleep; REM, rapid eye movement. 3.2 Demographic data (Table )

The rate of type 2 diabetes was 18.9% (n = 61) in our sample of hypertensive individuals. Compared to hypertensive individuals without type 2 diabetes, hypertensive individuals with type 2 diabetes had higher body mass index, age, CRP levels and scores on the Anhedonia subscale of the Beck Depression Inventory (items 4, 12 and 21). In addition, body mass index ≥30 kg/m2, age ≥65 years, obstructive sleep apnoea syndrome with altered sleep maintenance, complicated hypertension, dyslipidaemia, cardiovascular comorbidities (excluding hypertension), CRP levels ≥1 mg/L and anhedonic subtype of MD were more frequent in hypertensive individuals with type 2 diabetes than in hypertensive individuals without type 2 diabetes. There were no significant differences between the two groups for other demographic parameters. Finally, the rate of non-anhedonic subtype of MD was 15.5% (n = 50) and that of anhedonic subtype of MD was 15.8% (n = 51) in our sample of hypertensive individuals.

TABLE 2. Sample description (n = 323) Variables Categories % Hypertensive individuals without diabetes Hypertensive individuals with diabetes p-value Chi-square Sex

Female (n = 117)

36.2% 37.0% 32.8% .535 Male (n = 206) 63.8% 63.0% 67.2%

BMI (kg/m2)

<30 (n = 153) 47.4% 51.2% 31.2% .005 ≥30 (n = 170) 52.6% 48.8% 68.8% Age (years) <50 (n = 134) 41.5% 42.8% 36.1% .015 ≥50 & < 65 (n = 150) 46.4% 47.7% 41.0% ≥65 (n = 39) 12.1% 9.5% 22.9% Benzodiazepine receptor agonists No (n = 278) 86.1% 84.7% 91.8% .151 Yes (n = 45) 13.9% 15.3% 8.2% Antidepressant therapy No (n = 256) 79.3% 80.5% 73.8% .241 Yes (n = 67) 20.7% 19.5% 26.2% Other psychotropic treatments No (n = 300) 92.9% 93.5% 90.2% .360 Yes (n = 23) 7.1% 6.5% 9.8% Smoking No (n = 256) 79.3% 80.2% 75.4% .411 Yes (n = 67) 20.7% 19.8% 24.6% Alcohol No (n = 146) 45.2% 42.8% 55.7% .127 Occasional (n = 137) 42.4% 45.0% 31.2% Regular (n = 40) 12.4% 12.2% 13.1% Snoring No (n = 43) 13.3% 14.1% 9.8% .375 Yes (n = 280) 86.7% 85.9% 90.2% OSAS No (n = 97) 30.0% 31.7% 23.0% .009 Without altered sleep maintenance (n = 91) 28.2% 30.5% 18.0% With altered sleep maintenance (n = 135) 41.8% 37.8% 59.0% Insomnia disorders No (n = 115) 35.6% 35.5% 36.0% .564 Sleep deprivation alone (n = 86) 26.6% 25.2% 32.8% With sleep duration ≥6 h (n = 81) 25.1% 26.3% 19.7% With sleep duration < 6 h (n = 41) 12.7% 13.0% 11.5%

Sleep movement disorders

No (n = 243) 75.2% 75.2% 75.4% .959 Moderate to severe PLMs alone (n = 40) 12.4% 12.6% 11.5% RLS alone or combined with PLMs (n = 40) 12.4% 12.2% 13.1% Excessive daytime sleepiness No (n = 194) 60.1% 59.5% 62.3% .693 Yes (n = 129) 39.9% 40.5% 37.7% Hypertension status Untreated (n = 153) 47.4% 49.2% 39.3% .376 Controlled (n = 95) 29.4% 28.2% 34.4% Uncontrolled (n = 75) 23.2% 22.6% 26.3% Complicated hypertension No (n = 253) 78.4% 82.1% 62.3% .001 Yes (n = 70) 21.6% 17.9% 37.7% Dyslipidemia No (n = 138) 42.7% 46.2% 27.9% .009 Yes (n = 185) 57.3% 53.8% 72.1% Cardiovascular comorbidities No (n = 261) 80.8% 84.4% 65.6% .001 Yes (n = 62) 19.2% 15.6% 34.4% CRP (mg/L) <1 (n = 85) 26.3% 29.0% 14.8% .023 ≥1 (n = 238) 73.7% 71.0% 85.2% Major depression No (n = 222) 68.7% 70.2% 62.3% .040 Non-anhedonic subtype (n = 50) 15.5% 16.4% 11.5% Anhedonic subtype (n = 51) 15.8% 13.4% 26.3% Type 2 diabetes No (n = 262) 81.1% Yes (n = 61) 18.9% Median (P25-P75) Wilcoxon test BMI (kg/m2) 30.5 (26.8–35.2) 29.8 (26.7–35.0) 33.1 (28.4–36.4) .004 Age (years) 52 (44–60) 52 (42–59) 55 (48–63) .006 Systolic blood pressure (mm Hg) 140 (130–145) 140 (130–145) 140 (120–150) .961 Diastolic blood pressure (mm Hg) 80 (70–90) 80 (70–90) 80 (70–90) .248 ESS 9 (5–13) 9 (5–13) 9 (5–12) .664 BDI 10 (5–17) 10 (5–16) 10 (6–21) .248 BDI–anhedonia 1 (0–3) 1 (0–3) 2 (1–4) .018 ISI

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