Attention-deficit/hyperactivity disorder symptoms and stress-related biomarkers
Introduction
Attention-Deficit/Hyperactivity Disorder (ADHD) is a chronic psychiatric disorder characterized by symptoms of inattention, hyperactivity, and impulsivity (APA, 2013). ADHD has been shown to persist into adulthood in about two-thirds of cases (Simon et al., 2009), affecting approximately 3.4% of the adult general population (Fayyad et al., 2007).
There are several indications that dysregulations in stress-related mechanisms play a role in the pathophysiology of ADHD. These stress-related mechanisms include the hypothalamic-pituitary-adrenal (HPA) axis, the autonomic nervous system (ANS), the immune system, and brain-derived neurotrophic factor (BDNF), amongst others (Gold, 2015). First of all, dysregulations of these mechanisms have been related to the core symptoms of ADHD and their severity (Buske-Kirschbaum et al., 2013, Koenig et al., 2016, Ramos-Quiroga et al., 2016, Shim et al., 2008). For instance, a disturbed HPA-axis may lead to attention difficulties (Ramos-Quiroga et al., 2016). Second, these mechanisms are linked to dopamine regulation, the main neurotransmitter affected in ADHD (Ahs et al., 2009, Corominas-Roso et al., 2013, Donfrancesco et al., 2016, Ramos-Quiroga et al., 2016). Third, genetic studies provide evidence for a role of some of these mechanisms in the etiology of ADHD (Cho et al., 2010, Donev and Thome, 2010, Fortier et al., 2012, Lanktree et al., 2008). Finally, ADHD is associated with somatic comorbidities, such as obesity and cardiovascular diseases (Bijlenga et al., 2013), which could be partly the result of disturbances of stress-related mechanisms (Penninx et al., 2013).
However, results of studies that examined the association of ADHD with dysregulated stress-related mechanisms have conflicting results (Baird et al., 2012, Corominas-Roso et al., 2013, Donfrancesco et al., 2016, Freitag et al., 2009, Gispen-de Wied et al., 1998, Hatzinger et al., 2007, Hirvikoski et al., 2009, Holtmann et al., 2013, Imeraj et al., 2012, Isaksson et al., 2012, Kaneko et al., 1993, Koenig et al., 2016, Oades et al., 2010, Pesonen et al., 2011, Ramos-Quiroga et al., 2016, Rash and Aguirre-Camacho, 2012, Scassellati et al., 2014, Shim et al., 2008, Sondeijker et al., 2007). Previous studies were mainly performed in children or adolescents and not in adults, or were restricted by a small sample size (n < 100; e.g., Donfrancesco et al., 2016, Scassellati et al., 2014). Moreover, prior studies did not adjust for a wide range of confounders, such as affective disorders (e.g., Scassellati et al., 2014). ADHD is highly comorbid with affective disorders (Fayyad et al., 2007), and affective disorders have also been linked to dysregulations of the stress-related mechanisms. More specifically, meta-analyses found that, compared with controls, depressed patients had higher salivary cortisol levels both in the morning and in the evening (Stetler and Miller, 2011), more autonomic dysregulation such as a reduced heart rate variability (HRV) (Kemp et al., 2010), elevated levels of inflammation markers (Howren et al., 2009), and lower BDNF levels (Molendijk et al., 2014). Although the relationship between anxiety disorders and dysregulated stress-related mechanisms has been studied less, compared to depression, some evidence also suggests dysregulation of these mechanisms in anxiety (Chalmers et al., 2014, Elnazer and Baldwin, 2014, Molendijk et al., 2012, Vogelzangs et al., 2013). Hence, it is interesting to study ADHD in relation to the stress-related mechanisms, not only before taking into account current or remitted depressive and anxiety disorders, in order to examine a sample with different stages of depression and/or anxiety, but also after taking into account depressive and anxiety disorders, in order to investigate if ADHD has an independent association with dysregulation of stress-related mechanisms.
In this study, the relationship between adult ADHD symptoms and dysregulation of stress-related mechanisms will be analyzed, using a cohort of adults with and without affective disorders. The stress-related mechanisms are reflected by the following biomarkers: (1) HPA-axis indicators (salivary cortisol awakening curve, evening cortisol, 0.5 mg dexamethasone cortisol suppression ratio); (2) ANS measures (heart rate, pre-ejection period, respiratory sinus arrhythmia); (3) inflammatory markers (C-reactive protein (CRP), interleukin (IL)-6, and tumor necrosis factor-alpha (TNF-α)); and (4) BDNF. Our aims were: (a) to examine whether Attention-Deficit/Hyperactivity Disorder (ADHD) symptoms were associated with dysregulation of stress-related mechanisms before and after adjusting for affective disorders, and (b) since our sample for a large part consists of persons with varying stages of affective disorders, it is particularly suitable to examine whether ADHD symptoms interact with affective disorders in their association with dysregulated stress-related mechanisms. Aim a was divided into three parts: we used the dichotomous measure of ‘High ADHD symptoms’ yes/no, i.e., a score above the clinical relevant cut-off on the Conners’ Adult ADHD Rating Scale (CAARS-S:SV; (Connors et al., 1999)) to determine any relationship between ADHD symptoms and dysregulations of the stress-related mechanism biomarkers (aim a, part one). Next, we used three continuous scores: both symptom dimensions (Inattentive symptoms and Hyperactivity/Impulsivity symptoms) to examine whether one of the symptom dimensions of ADHD was associated with dysregulations of the stress-related mechanism biomarkers (aim a, part two); and the ADHD index score to investigate any dose-response relationship between ADHD symptoms and dysregulated stress-related mechanism biomarkers (aim a, part three).
Section snippets
Sample
Data were derived from the Netherlands Study of Depression and Anxiety (NESDA), an ongoing longitudinal cohort study on the predictors, course and consequences of depressive and anxiety disorders. The NESDA baseline sample included 2981 participants aged 18–65 years, and consisted of healthy controls and for a large part of persons with varying stages of affective disorders (i.e., those with a parental history of depression or anxiety, those with subthreshold affective symptoms, and those with
Sample characteristics
Table 1 presents sociodemographics, ADHD symptomatology, health factors, stress-related mechanism biomarkers measures, and mechanism-specific covariates. The mean age of the whole study sample (N = 2307) was 42.2 ± 13.1 years; 66.3% was female; and mean years of education was 12.4 ± 3.2. Of the persons without lifetime depressive and/or anxiety disorders, there were only 4 cases with High ADHD symptoms.
Aim 1: are ADHD symptoms associated with dysregulation of stress-related mechanisms?
Table 2 presents the outcomes of the linear regression analyses associating the dichotomous and
Discussion
To our knowledge, this is the first study to examine (a) the association between ADHD symptoms and a set of stress-related mechanisms biomarkers in an adult population with varying stages of affective disorders, in which thus correction for depressive and anxiety disorders was possible; and (b) to examine whether ADHD symptoms interact with affective disorders in their association with dysregulated stress-related mechanisms. Some associations were observed between ADHD symptoms and
Contributors
B.P. contributed to the design of the NESDA study. S.V. analyzed the data, and wrote the main drafts of the manuscript. D.B., J.V., T.B., A.B., J.K., B.P. interpreted the data and provided critical revisions. All authors contributed to and have approved the final version of the article.
Disclaimer
A.T.F Beekman has been a speaker for Lundbeck and Eli Lilly and received research grants from Astra Zeneca, Eli Lilly and Shire for other studies. B.W.J.H. Penninx has received research grants from NWO, BBRMI-NL, NIMH, and the EU-FP7 program for research in NESDA. J.J.S. Kooij, D. Bijlenga, J. Verduijn, T.I. Bron, and S.W.N. Vogel declare no conflicts of interest.
Acknowledgements
This study is funded by the Netherlands Foundation for Mental Health (grant number 2013-6777). The infrastructure for the NESDA study (www.nesda.nl) is funded through the Geestkracht Program of the Netherlands Organization for Health Research and Development (Zon-Mw, grant number 10-000-1002). This organization had no further role in study design, collection, analysis and interpretation of data, writing of the report, and in the decision to submit the paper for publication. NESDA is supported
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