GH response to intravenous clonidine challenge correlates with history of childhood trauma in personality disorder

https://doi.org/10.1016/j.jpsychires.2015.11.009Get rights and content

Highlights

  • Personality disorder itself is not associated with increased or decreased GH response to clonidine challenge.

  • Childhood Trauma is positively correlated with Growth Hormone response to clonidine Among the CTQ subscale scores, the strongest relationships were for Emotional Abuse, Physical Abuse, and Physical Neglect.

  • The findings were not driven by PTSD or MDD.

Abstract

Background

Childhood trauma is a risk factor for personality disorder. We have previously shown that childhood trauma is associated with increased central corticotrophin-releasing hormone concentration in adults with personality disorder. In the brain, the release of corticotrophin-releasing hormone can be stimulated by noradrenergic neuronal activity, raising the possibility that childhood trauma may affect the hypothalamic-pituitary adrenal (HPA) axis by altering brain noradrenergic function. In this study, we sought to test the hypothesis that childhood trauma is associated with blunted growth hormone response to the α-2 adrenergic autoreceptor agonist clonidine.

Methods

All subjects provided written informed consent. Twenty personality disordered and twenty healthy controls (without personality disorder or Axis I psychopathology) underwent challenge with clonidine, while plasma Growth Hormone (GH) concentration was monitored by intravenous catheter. On a different study session, subjects completed the Childhood Trauma Questionnaire and underwent diagnostic interviews.

Results

Contrary to our a priori hypothesis, childhood trauma was associated with enhanced GH response to clonidine. This positive relationship was present in the group of 40 subjects and in the subgroup 20 personality disordered subjects, but was not detected in the healthy control subjects when analyzed separately. The presence of personality disorder was unrelated to the magnitude of GH response.

Discussion

Childhood trauma is positively correlated with GH response to clonidine challenge in adults with personality disorder. Enhanced rather that blunted GH response differentiates childhood trauma from previously identified negative predictors of GH response, such as anxiety or mood disorder.

Introduction

Childhood trauma, in the form of parental neglect and/or abuse, is a risk factor for later personality disorder symptoms (Luntz and Widom, 1994, Horwitz et al., 2001, Johnson et al., 1999, Johnson et al., 2006a, Johnson et al., 2006b). While there is an emerging recognition that the development of personality disorder emerges from a complex but not fully understood interaction of genetic and environmental factors (Johnson et al., 2006a, Johnson et al., 2006b), childhood trauma may provide a clue regarding which neurobiological factors have a mechanistic role in personality disorder. Research across preclinical and clinical domains has identified the hypothalamic-pituitary axis as one of the primary mediators of the effect of early life trauma on altered adult stress reactivity. Our previous work has examined the relationship between reported early life trauma and adult stress hormone function in adults with personality disorder, finding that childhood trauma is associated with increased central drive of the stress hormone corticotropin-releasing hormone (CRH; Lee et al., 2012). Given that the hypothalamic-pituitary axis can be stimulated by noradrenergic neurons, and that the release of norepinephrine is part of the acute stress response, it is biologically plausible that trauma also has lasting effects on noradrenergic function. The hypothalamic pituitary axis can be activated by the central noradrenergic system, consistent with the role of noradrenergic cell bodies in dynamically modulating arousal and attention to the environment. Other stress-related psychopathologies such as post-traumatic stress disorder have been found to have components of both noradrenergic and HPA-axis dysfunction. There is reason to believe that the noradrenergic system may play a role in trauma-related personality psychopathology. However, empirical data regarding this are not available.

An animal study modelling the effects of maternal maternal care and early life stress on the stress system found evidence that maternal care and stress differentially affect noradrenergic receptor binding in the noradrenergic cell body regions of the brain (Liu et al., 2000). In this study, post-natal handling was found to increase expression of α-2 receptor levels in the locus coeruleus and nucleus tractus solitarius. Extended maternal separation, an animal model of maternal neglect, was not associated with altered α-2 receptor expression, but was found to be associated with greater norepinephrine in dialysate of the paraventricular nucleus of the hypothalamus following restraint stress. Although no clinical research studies have yet examined the relationship between central adrenergic function and childhood trauma, lastingly elevated measures of central catecholamine function have repeatedly been found to be associated with both pediatric and adult post-traumatic stress disorder (reviewed by Pervanidou, 2008).

The growth hormone (GH) response to clonidine challenge has been previously utilized as a pharmacological probe of central α-2 adrenergic receptor function. The α-2 adrenergic receptor is a pre-synaptic autoreceptor in the locus coeruleus; stimulation of the receptor with clonidine results in decreased firing of noradrenergic neurons. Via stimulation of hypothalamic α-2 receptors, clonidine also facilitates the release of growth hormone via induced release of Growth Hormone Releasing Hormone (GHRH) (Checkley, 1980, Muller et al., 1999). On the basis of this neuroendocrine effect, the GH response to clonidine is considered to be an indirect measure of α-2 receptor sensitivity. The magnitude of GH response has been found to reflect plasma clonidine level (Cubeddu and Hoffman, 1987), as well as the dynamic adrenergic receptor environment (Eriksson et al., 1982).

It remains unknown if history of childhood trauma is associated with abnormal noradrenergic function in non-PTSD adults with personality disorder. To investigate this, a clinical research study was performed using the GH response to clonidine as a probe of central alpha-2 adrenergic receptor function in adults with and without personality disorder. History of childhood trauma was measured using a retrospective instrument, the Childhood Trauma Questionnaire. Based on the existing animal and human data mentioned above, it was hypothesized that the severity of childhood trauma would be related to blunted GH response to clonidine.

Section snippets

Subjects

Twenty subjects with personality disorder and twenty healthy control volunteer subjects participated in this study. All subjects were medically healthy and were systematically evaluated in regard to impulsive, aggressive, suicidal, and other behaviors as part of a larger program designed to study the biological correlates of impulsive aggressive, and other personality-related, behaviors in personality disordered subjects. Personality disordered subjects were recruited by newspaper and public

Results

Demographic, functional, and behavioral data for the PD and HV subjects are displayed in Table 2. While the two groups displayed a small, though significant difference in age (PD > HC), the two groups did not differ significantly in the distribution of gender, race, or in socioeconomic class. As expected, however, PD subjects had lower global functioning scores and trend higher scores on CTQ Total and EPQ Neuroticism compared with the HV subjects.

Discussion

In this sample of medication and drug-free male and female adults with and without personality disorder, the magnitude of GH response to acute challenge was positively correlated with the severity of childhood trauma. The relationship was not caused by personality disorder itself, as it remained strong in the sub-sample of personality disordered adults, and was not statistically related to presence or absence of personality disorder. The relationship was also not due to concurrent posttraumatic

Role of the funding source

This work was supported in part by grants from the National Institute of Mental Health: RO-1 MH46848 (Dr. Coccaro).

Contributors

Royce Lee was critical to the design and analysis of the results as well as preparation of the manuscript. Jennifer Fanning was critical to the statistical analysis of the results. Dr. Coccaro was critical in the design and execution of the research.

Conflicts of interest

Dr. Coccaro reports that he is on the Scientific Advisory Board of Azevan Pharmaceuticals., Inc. and that he has stock options in Azivan Pharmaceuticals, Inc., through this role. Dr. Lee reports that he has received a research grant from Azivan Pharmaceuticals, Inc.

Acknowledgments

We thank Richard Hauger, M.D. for the RIA GH assays of the plasma samples.

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