Elsevier

Journal of Affective Disorders

Volume 196, 15 May 2016, Pages 190-199
Journal of Affective Disorders

Research paper
Stress reactivity predicts symptom improvement in children with anxiety disorders

https://doi.org/10.1016/j.jad.2016.02.022Get rights and content

Highlights

  • The stress response is a possible predictive biomarker in child anxiety disorders.

  • Pre-treatment HPA and ANS reactivity are associated with symptom improvement.

  • SCL reactivity to stress predicts anxiety symptoms at one-year follow-up.

  • Cortisol reactivity to stress predicts depressive symptoms at one-year follow-up.

Abstract

Background

We examined the longitudinal associations of autonomic nervous system (ANS) and hypothalamic-pituitary-adrenal (HPA) axis rest and reactivity measures with anxiety and depressive symptoms at one-year follow-up in children with anxiety disorders.

Methods

In a clinical sample of 152 children with a primary DSM-IV anxiety disorder, aged 8 to 12 years, anxiety and depressive symptoms were assessed with the Multidimensional Anxiety Scale for Children and the Children's Depression Inventory at pre-treatment baseline and one year later, after treatment with cognitive behavioral therapy. At baseline, children participated in a 70 min stress task. Salivary cortisol was measured directly prior to and 20 min post stress task. Skin conductance level (SCL), heart rate and high frequency heart rate variability (HRV) were continuously measured during rest and the stress task. To investigate if rest or reactivity measures predicted anxiety and depressive symptoms at one year follow-up, linear regression analyses were conducted for rest and reactivity measures of SCL, heart rate, HRV and cortisol separately.

Results

Higher SCL reactivity predicted less decrease of anxiety symptoms at one-year follow-up. Cortisol reactivity showed a weak association with depressive symptoms at one-year follow-up: lower cortisol reactivity predicted less decrease in depressive symptoms.

Limitations

Only self-reported anxiety and depressive symptoms were used. However, all predictors were objective biological measures, hence there is no risk of shared method variance bias.

Conclusions

These findings suggest that pre-treatment HPA and ANS responsiveness to stress are predictive biomarkers for a lack of symptom improvement in children with a clinical anxiety disorder.

Introduction

Anxiety disorders are among the most prevalent types of psychiatric disorders experienced by children and adolescents (Bittner et al., 2007, Verhulst et al., 1997), with separation anxiety disorder, specific phobia, social phobia, and generalized anxiety disorder being the most frequent childhood anxiety disorders (Beesdo-Baum and Knappe, 2012). Childhood anxiety has been associated with a range of negative outcomes, including academic underachievement, drug dependency, and an increased risk for developing other psychiatric disorders (Bittner et al., 2007, Woodward and Fergusson, 2001).

Cognitive behavioral therapy (CBT) is the treatment of choice for children with an anxiety disorder, with a remission rate of 59% following treatment (James et al., 2013). A 7–19 year follow-up study of the long-term outcomes of treated childhood anxiety disorders showed that patients with a poorer response to CBT, had higher rates of panic disorder, substance abuse and dependency in adulthood than the successfully treated controls (Benjamin et al., 2013). It is, therefore, important to identify predictors of symptom improvement in treated children with an anxiety disorder.

Several studies tried to gain insight into clinical predictors of treatment outcome in children with anxiety disorders. Some studies reported that higher anxiety severity predicts a less favorable outcome (Compton et al., 2014, Hudson et al., 2013, Last et al., 1998, Liber et al., 2010). A few studies showed that children with comorbid mood disorders are more likely to retain their primary anxiety disorder following treatment (Hudson et al., 2013, Liber et al., 2010). Various studies examined the role of parental characteristics as predictors of treatment outcome in children, but an inconsistent pattern of findings resulted (Compton et al., 2014, Hudson et al., 2013, Legerstee et al., 2008). Because clinical characteristics are weak or inconsistent indicators of response to CBT, there is an increasing interest in identifying biomarkers to predict differential treatment response (Lester and Eley, 2013).

Physiological stress response systems have been implicated as possible important biological state markers for childhood anxiety. It can be hypothesized that children with an anxiety disorder function under conditions of persistent stress, with an excessive and prolonged stress system activation (Dieleman et al., 2015). Alterations in the autonomic nervous system (ANS) have been associated with anxiety disorders in children; children with an anxiety disorder show a pattern of heightened activity of the sympathetic nervous system (Dieleman et al., 2015, Kossowsky et al., 2012, Schmitz et al., 2011) and diminished parasympathetic control (Dieleman et al., 2015, Schmitz et al., 2011), although some studies failed to show this difference (Kossowsky et al., 2012, Kristensen et al., 2014). Another major physiological stress response system is the hypothalamic-pituitary-adrenal (HPA) axis. Glucocorticoids can act both to augment and suppress autonomic mediated changes. Cross-sectional studies related HPA axis functioning to childhood anxiety disorders, but provided inconsistent findings (Dieleman et al., 2015, Dietrich et al., 2013, Feder et al., 2004, Forbes et al., 2006, Krämer et al., 2012). This may reflect the variable methods of sampling, resting state versus stress paradigms, differences in age, developmental status, and diagnostic status of the study populations. Furthermore, differences in functioning of the HPA axis could depend on the chronicity or the severity of the disorder (Dieleman et al., 2015, Pervanidou, 2008).

Despite the evidence of altered pre-treatment HPA axis and autonomic functioning in anxiety-disordered children, studies that have assessed stress physiology as a predictor of therapy outcome in childhood anxiety disorders are lacking. This study aims to investigate the longitudinal association of stress physiology at pre-treatment baseline with anxiety and depressive symptoms at one year follow-up in a clinical sample of anxiety disordered children treated with CBT. We hypothesize that anxiety-disordered children with a stronger autonomic stress response, i.e. heightened activity of the sympathetic and diminished activity of the parasympathetic nervous system, show persistence of anxiety symptoms one year later. Also, we explore the longitudinal association between cortisol levels and anxiety symptoms at one-year follow-up, but formulate no specific hypothesis, given the inconsistent results of previous studies. Furthermore, since comorbid depressive symptoms have been associated with a less favorable treatment outcome in children with anxiety disorders (Hudson et al., 2013, Liber et al., 2010) and in previous work we observed that cortisol reactivity was specifically associated with depressive symptoms (Dieleman et al., 2010), we will also explore the longitudinal association of stress physiology with depressive symptoms.

Section snippets

Participants

This study included 152 children, aged 8–12 years, referred to the outpatient clinic of the Department of Child and Adolescent Psychiatry of Erasmus Medical Center in Rotterdam or the University Medical Center in Leiden, The Netherlands. These hospitals serve as secondary or tertiary referral centers of South-West Netherlands. Children had a primary diagnosis of separation anxiety disorder (n=57), generalized anxiety disorder (n=47), social phobia (n=29) or specific phobia (n=19). All children

Cortisol assessment

Cortisol samples were assessed with solid-phase radioimmunoassay (RIA, Diagnostic Products Corporation, Los Angeles; n=83) and Enzyme-Linked Immuno Sorbent Assay (ELISA, DRG-kits, Marburg, Germany; n=69) as the laboratory changed the standard technique during data collection. To test for possible effects of measurement thirty-one cortisol samples were analyzed by both RIA and ELISA. Correlation between both assays was high (R=.99). The slope was not equal to 1, therefore the concentrations in

Data analysis

Measures of depressive symptoms, SCL, cortisol and HRV were log-transformed to approach a normal distribution. Means of heart rate, HRV and SCL were defined for two periods: minutes 7–10 of the first resting period and minutes 17–20 of the re-experiencing part of the social competence interview. Subsequently, stress reactivity in heart rate, HRV and SCL were calculated by subtracting the rest value from the value during the social competence interview. To characterize cortisol reactivity to

Sample characteristics

Group characteristics, diagnoses and comorbidity at pre-treatment and at one-year follow-up are presented in Table 1. Thirty-seven percent had a primary diagnosis of separation anxiety disorder, 30.5% a primary diagnosis of generalized anxiety disorder, 18.8% a primary diagnosis of social phobia and 12.3% a primary diagnosis of specific phobia. Comorbidity rates at pre-treatment were high; 55.3% had a single clinical anxiety disorder only, 30.9% had two clinical anxiety disorders, 11.8% had

Principal findings

This clinical study of pediatric anxiety disorders showed that children with higher pre-treatment SCL reactivity to stress, as a proxy of sympathetic reactivity, responded less to treatment. Their anxiety symptoms decreased less over a one-year period as compared to children with a lower pre-treatment SCL reactivity. Furthermore, children with lower pre-treatment cortisol reactivity showed less decrease of depressive symptoms.

Autonomic nervous system

To our knowledge, this is the first longitudinal study that uses ANS

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