Blunted growth hormone response to clonidine in post-traumatic stress disorder

Abstract

Hyperactivity of the sympathetic and noradrenergic systems is thought to be a feature of post-traumatic stress disorder (PTSD). Assessment of noradrenergic receptor function can be undertaken by measuring the growth hormone (GH) response to the α₂-agonist clonidine. The aim of this study was to examine whether subjects with combat-related PTSD (with or without co-morbid depression) have a blunted growth hormone response to clonidine, compared to a combat-exposed control group.

Twenty-three Vietnam veterans suffering from PTSD alone, 27 suffering from PTSD and co-morbid depression, and 32 veteran controls with no psychiatric illness were administered 1.5 μg/kg clonidine i.v. Plasma growth hormone was measured every 20 min for 120 min.

The growth hormone response to clonidine was significantly blunted in the non-depressed PTSD group compared to both the depressed PTSD group and the control group as measured by peak growth hormone, delta growth hormone and AUC growth hormone. Subjects with PTSD and no co-morbid depressive illness show a blunted growth hormone response to clonidine. This suggests that post-synaptic α₂-receptors are subsensitive. This finding is consistent with other studies showing increased noradrenergic activity in PTSD.

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.