Blunted growth hormone response to clonidine in post-traumatic stress disorder
Introduction
Historically there has been interest in the role of sympathetic nervous system activity in psychological disturbance following trauma. Early descriptions of syndromes analogous to what we now consider as post-traumatic stress disorder (PTSD) featured symptoms related to autonomic reactivity, including palpitations, fatigue, anxiety and an increased startle response which often generalised beyond direct reminders of the traumatic experience.
More recently, investigators have made biological measurements of sympathetic activity in patient groups with combat-related PTSD. The majority of studies have focussed on indirect measures. Studies of 24-h urinary noradrenaline excretion have yielded conflicting results. Some studies find increased noradrenergic levels (Kosten et al., 1987, Yehuda et al., 1992), while others find no difference between PTSD subjects and controls (Pitman and Orr, 1990, Mellman et al., 1995). Plasma noradrenaline levels in PTSD subjects were not different to controls in two studies (McFall et al., 1990, Blanchard et al., 1991), but were increased in PTSD in one report, although only in patients without co-morbid secondary depression (Yehuda et al., 1998). An investigation of peripheral α2-adrenoceptors found a reduced number on platelets taken from PTSD patients compared to controls (Perry et al., 1987), a finding consistent with increased noradrenergic activity. In the only direct study of central noradrenaline activity, serial CSF noradrenaline levels in PTSD subjects who were not clinically depressed at the time, were found to be significantly increased when compared to healthy controls (Geracioti et al., 2001).
Studies of central noradrenergic function using pharmacological probes (desipramine, clonidine and yohimbine) possessing α2-adrenergic receptor activity have been reported. Two studies (Dinan et al., 1990, Yatham et al., 1996) examined central α2-adrenoceptor function in non-combat PTSD using the growth hormone (GH) response to desipramine challenge. These studies found no significant difference in growth hormone responses between the PTSD patients and age and sex matched controls. There has been one single case report using clonidine, an α2-agonist, in PTSD (Hansenne et al., 1991). A clonidine growth hormone challenge test prior to psychiatric admission showed a blunted response that normalised after successful treatment of the patient with cognitive behavioural therapy.
In a series of investigations using yohimbine, an α2-antagonist, in combat-related PTSD, Southwick and colleagues demonstrated greater behavioural, cardiovascular and biochemical responses to yohimbine in PTSD subjects compared with controls (Southwick et al., 1993, Southwick et al., 1997). In particular, Southwick et al. (1993) found a significantly greater increase in plasma levels of the noradrenaline metabolite, methoxy-hydroxy-phenyl-glycol (MHPG) in response to yohimbine challenge in Vietnam veterans with PTSD. Bremner et al. (1997), using positron emission tomography (PET), found a significant decrease in cerebral metabolism in prefrontal, temporal, parietal and orbitofrontal cortices following yohimbine administration in PTSD patients compared to healthy subjects, a finding consistent with enhanced yohimbine-stimulated noradrenaline release in the brain in PTSD. Another study from the same group (Rasmussen et al., 2000) found low baseline and blunted yohimbine-stimulated plasma neuropeptide Y in combat-exposed PTSD subjects in comparison with healthy controls. Neuropeptide Y is co-localised with noradrenaline in most sympathetic nerves and in the locus coeruleus. The authors suggest that this neuropeptide may mediate, in part, the hyperreactivity in the noradrenergic system observed in studies of combat-related PTSD.
Overall, the literature concerning noradrenergic function in PTSD is suggestive of an increased reactivity of the noradrenergic system (Southwick et al., 1999). Not all studies support this hypothesis, but this may be in part related to a failure to control for co-morbid depressive illness. Some studies indicate whether PTSD patients have concurrent depressive diagnoses or symptoms, but in all but one study (Yehuda et al., 1998) the depressed subgroup has not been analysed separately. In the study by Yehuda et al. (1998), only the non-depressed PTSD subjects had increased plasma noradrenaline levels compared to controls and depressed PTSD subjects.
In the present study, we evaluated central noradrenergic function in combat-related PTSD using the clonidine growth hormone challenge test. Subjects diagnosed with PTSD were also assessed for the presence of current depressive disorder. Since overactivity of the sympathetic nervous system and increased noradrenergic reactivity appear to be a feature of PTSD, we anticipated that patients with PTSD would show de-sensitised or down-regulated central noradrenergic receptors. Thus, we hypothesised that patients with PTSD would show a significantly blunted growth hormone response to the α2-adrenergic agonist clonidine compared with controls.
Section snippets
Patient subjects
Male combat-exposed Vietnam war veterans were recruited from the Austin Repatriation Medical Centre Veterans’ Psychiatry Unit, the Vietnam Veterans’ Association and the Returned and Servicemen’s League. Patient subjects were eligible if they had a current diagnosis of PTSD subsequent to war service and significant PTSD symptomatology (see below). Patient subjects were excluded if they had (i) other current psychiatric disorders other than major depression, (ii) acute or serious medical illness
Results
Eighty-two male combat-exposed subjects met the inclusion criteria for the study. Fifty subjects had a diagnosis of PTSD. Of this group, 23 were not depressed and 27 were depressed. Thirty-two subjects were non-psychiatric controls. The means (±S.D.) of each group for age, body mass index (BMI), and clinical characteristics are presented in Table 1.
There were no significant differences in age, BMI or cognitive function between groups. There were differences across groups for CES ratings. The
Discussion
This is the first study of the growth hormone response to the α2-agonist clonidine in subjects with combat-related PTSD. The main finding of this study was a blunted growth hormone response in non-depressed PTSD subjects when compared to subjects suffering from PTSD and concurrent depression and to a healthy control group. As clonidine stimulates growth hormone secretion via action on post-synaptic α2-receptors in the hypothalamus and pituitary axis (Matussek et al., 1980), the implication of
Acknowledgements
The authors would like to thank Sophie Ignatiadis for recruiting the subjects and performing the neuroendocrine challenge tests. Debbie Lynch assisted in the preparation of the manuscript. The study was funded by the Australian Department of Veterans’ Affairs and the Weary Dunlop Research Foundation. We would like to thank all veterans for their typically generous participation.
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