Hypertension is considered as the leading cause of cardiovascular (CV) mortality and based on American data, it is in the second place in the list of the preventable causes of all-cause mortality as well [1, 2]. Mood disorders such as depression and anxiety represent a growing public health problem and their association with adverse CV outcome is well-established [3,4,5].

The association between hypertension, depression and anxiety are controversially discussed in diverse studies [6, 7]. The background of this observation can be based on the differences of the studied patient populations, the application of different psychometric measures, the heterogenous pathophysiological background of hypertension or the presence of different hypertension phenotypes in the cohorts. Such phenotypes are white-coat hypertension (WhHT), masked hypertension, chronic, treatment-resistant hypertension (ResHT) and chronic, non-resistant hypertension (non-ResHT). In WhHT patients blood pressure is increased in office, but normal during out-of office measurements. In masked hypertension home results are elevated, while in the office, blood pressure is normal [8]. In ResHT blood pressure is above 140/90 mmHg in the office in spite of the use of 3 antihypertensive drugs of different classes including a diuretic. ResHT also includes patients whose blood pressure is controlled with the use of more than 3 medications [9]. It was demonstrated that both controlled and uncontrolled ResHT are accompanied with higher CV risk compared with non-ResHT [10].

Anxiety was found to be associated with white-coat effect during blood pressure measurement [11, 12], while resistant hypertension was also associated with anxiety [13]. Recently we described similarities in affective temperament patterns between WhHT and ResHT [14]. However, until now the level of depression and anxiety was not evaluated in a cohort of individuals with different hypertension phenotypes.

The aim of our study was to measure depression and anxiety in healthy controls, in untreated subjects with white-coat effect and in chronic hypertension with or without the presence of resistant hypertension. Based on our recent findings we hypothesized similarities between subjects with white-coat and resistant hypertension.

Methods.

Our present results are part of an additional analysis of a previously published cohort [14], including the results of the depression and anxiety questionnaires.

In the setup of a cross-sectional study, altogether 363 Caucasian patients were involved between August 2012 and January 2019, in three primary care practices in Budapest, Hungary. Four categories of the enrolled subjects were defined: healthy controls (Cont, n = 82); white-coat hypertensive patients (WhHT, n = 44); chronic, non-resistant hypertensive patients (non-ResHT, n = 200); and patients with chronic, resistant hypertension (ResHT, n = 37). The diagnosis of resistant hypertension was always confirmed by ambulatory blood pressure monitoring (ABPM) or by home blood pressure monitoring (HBPM). The definition of non-resistant hypertension required the following criteria: chronic (the onset is longer than 3 months), treated (with the maximum use of 3 antihypertensive agents) and controlled hypertension.

As in this cohort carotid–femoral pulse wave velocity was also measured (data are not shown in the present publication), patients with atrial fibrillation were excluded from the study. Other exclusion criteria were treated depression, anxiety, or other psychiatric conditions (bipolar disorder, schizophrenia) and also dementia to avoid mistakes or misunderstanding of the questionnaires. The chronic, moderate use of alprazolam (< 0.5 mg/day) was not an exclusion criterion when it was added to the hypertension therapy protocol by other specialists, without the diagnosis of anxiety.

Subjects were recruited into the study during the screening visit when blood pressure was measured with a validated oscillometric device (Omron M3) and written informed consent was collected. At the end of the screening visit an autoquestionnaire was handed out to the subjects including a questionnaire for the evaluation of family and personal history and also for depression. The autoquestionnaires were collected from the patients in the day of the clinical measurements.

After the screening visit within the maximum of a 2-week period an appointment was scheduled for 7.00. a.m. for repeated office and/or ambulatory blood pressure measurement and also for blood sampling. Finally the evaluation of anxiety was completed in the form of an interview with the examiner.

The Beck Depression Inventory (BDI) was used to evaluate the severity of depression. It is one of the most widely used instruments including a 21-question multiple-choice self-report questionnaire with ratings on a four-point scale, where a higher score correlates with more severe depression [15].

The Hamilton Anxiety Scale (HAM-A) was used to study the severity of anxiety. During the evaluation the examiner reports the subject. Its scale consists 14 items, each item is scored on a scale of 0 (not present) to 4 (severe anxiety) [16].

Before the clinical measurements overnight fasting, refrain from smoking and drinking caffeine-containing beverages were required, but patients were asked to take their usual antihypertensive medication. In sitting position after 5 min of rest, two brachial blood pressure measurements were taken in 1-min interval on each arm with an oscillometric device (Omron M3, validated). In the detailed analysis the mean value of the higher side of arms was further used as brachial systolic (SBP) and diastolic (DBP) blood pressures and heart rate. Pulse pressure (PP) was also calculated as SBP minus DBP. Next, untreated subjects, who had elevated office blood pressure during the screening visit, were fitted with a 24-h ABPM device (Mobil-O-Graph, I.E.M. GmbH, Germany). The cuff was placed on the left arm. Finally venipuncture was performed on the right arm for blood sampling. The 24-h ABPM and blood test results were discussed with the patient on the following day. In case of treated hypertensive patients with increased office blood pressure, where the diagnosis of ResHT was considered, it was confirmed within 2 weeks with HBPM or with ABPM.

Descriptive data are expressed as mean ± standard deviation or median with interquartile ranges. Kolmogorov–Smirnov test was used test the normality of continuous parameters. ANOVA was applied for normally distributed parameters to compare differences between the four groups (Cont, WhHT, non-ResHT, ResHT). Tukey's test was used for post-hoc analysis. Kruskal–Wallis test was applied to compare non-normally distributed parameters.

To study the association of depression and anxiety with ResHT, chronic hypertensive patient groups (non-ResHT plus ResHT) were dichotomized based on the 75% quartile of the depression and anxiety scores of the patients. Next, with binary regression analysis, the association with ResHT of the patient groups reaching different BDI and HAM-A scores was studied with the adjustment for traditional CV risk factors, such as age, sex, smoking, diabetes, body mass index and total cholesterol. Finally, in the merged group of Cont plus WhHT, with binary regression analysis the association with WhHT of the patients reaching different BDI and HAM-A points was also studied with the adjustment for sex, smoking and BMI.

In all analyses p < 0.05 was considered as the border of significance. SPSS 22.0 for Windows was used throughout the calculations.