M. Michele Murburg

Effect of desipramine on cerebrospinal fluid concentrations of corticotropin-releasing factor in human subjects

To assess the effect of desipramine (DMI) on corticotropin-releasing-factor (CRF) activity in the central nervous system, we measured cerebrospinal fluid (CSF) concentrations of CRF in healthy volunteers following short-term administration of DMI or placebo. DMI administration for 2 days was associated with a significant dose-related reduction in CRF concentrations. There was a nonsignificant 6% reduction in CRF concentrations among the 10 subjects who received 50 mg DMI (delta CRF: -3 +/- 2 pg/ml) and a significant 14% fall in the CRF concentrations of the eight subjects who received 100 mg DMI (delta CRF: -8 +/- 3 pg/ml). The mean CSF concentration of CRF was unchanged in the six subjects randomized to placebo (delta CRF: 1 +/- 5 pg/ml). DMI administration had no effect on CSF norepinephrine concentrations (n = 24) or on plasma cortisol (n = 25). We conclude that short-term administration of DMI in healthy volunteers is associated with a dose-related reduction in CSF concentrations of CRF.

Basal sympathoadrenal function in posttraumatic distress disorder

Research has consistently shown that patients with posttraumatic stress disorder (PTSD) manifest greater changes in heart rate, blood pressure, and plasma epinephrine than controls when exposed to trauma-related laboratory stressors. However, findings are equivocal as to whether PTSD subjects differ from controls on basal, or tonic, measures of autonomic activity. In this study, PTSD patients (n = 11) and asymptomatic controls (n = 11) were compared on measures of basal sympathoadrenal function, including plasma norepinephrine and epinephrine as well as heart rate and blood pressure. Results showed that PTSD patients were not significantly different from control subjects on any measure. Although phasic alterations in autonomic function in PTSD have been consistently found in previous research, this study suggests that tonic sympathetic nervous system activity in PTSD patients may not differ from that of healthy controls.

Antipsychotic drugs and plasma vasopressin in normals and acute schizophrenic patients

Elevated plasma vasopressin concentrations have been documented in antipsychotic drug-treated patients as well as a drug-free acutely psychotic patients. To evaluate the effects of antipsychotic drugs on plasma vasopressin, we measured vasopressin response to a single dose of intramuscular chlorpromazine or intravenous haloperidol in normal individuals and to 2 weeks of oral antipsychotics in patients with acute schizophrenia. Neither intramuscular chlorpromazine nor intravenous haloperidol affected plasma vasopressin in normals, except in one subject who developed high plasma vasopressin concentrations coincident with marked hypotension following chlorpromazine. Prior to antipsychotics, two acute schizophrenia patients had elevated plasma vasopressin concentrations, which normalized during antipsychotic drug treatment. We conclude that antipsychotics do not directly stimulate vasopressin release, but may indirectly stimulate vasopressin release by well-described baroreceptor reflex mechanisms if hypotension occurs. Also, acute schizophrenia may be associated with increased plasma vasopressin levels in some patients.

Plasma norepinephrine kinetics in patients with posttraumatic stress disorder

To determine whether basal sympathetic nervous system (SNS) function is increased in patients with posttraumatic stress disorder (PTSD), we used a radioisotope dilution technique to assess basal arterialized plasma norepinephrine (NE) kinetics in 12 men who were Viet Nam combat veterans with PTSD and six normal controls. In addition to determining the rates of appearance of NE into, and clearance of NE from, plasma, we measured basal arterialized plasma levels of epinephrine (EPI), and also vital signs, in both groups. Patients with PTSD actually manifested lower arterialized plasma levels of NE, and had lower rates of appearance of NE into plasma, than did controls. The rate of NE clearance from plasma was unaltered in PTSD patients. Patients with PTSD also showed a trend toward lower arterialized EPI levels than controls, but manifested a trend toward higher diastolic blood pressure. Our data indicate that basal SNS activity is not increased in patients with PTSD and that previous reports of increased resting SNS activity in this population may instead reflect SNS reactivity.

Haloperidol increases plasma beta endorphin-like immunoreactivity and cortisol in normal human males☆

To investigate possible central dopaminergic regulation of beta-endorphin-like immunoreactivity (beta E-LI) and adrenocorticotropin (ACTH) release in humans, we gave the dopamine antagonist haloperidol or placebo intravenously to twelve normal male subjects and measured beta E-LI and cortisol for 120 minutes following injection. Haloperidol, but not placebo, produced significant increases in plasma beta E-LI and cortisol. These findings suggest that central dopaminergic pathways such as the tuberohypophyseal system may participate in regulation of the secretion of beta E and ACTH from the human pituitary.

Psychophysiologic and neuroendocrine findings in posttraumatic stress disorder: A review of theory and research

Abstract Psychophysiologic and neuroendocrine investigations of posttraumatic stress disorder (PTSD) are reviewed. Patients with PTSD have higher resting heart rate and blood pressure than asymptomatic controls, and urinary catecholamines are more elevated in PTSD subjects than in psychiatric patients without PTSD. Combat veterans with PTSD, when exposed to combat-related laboratory stressors, exhibit greater autonomic arousal than do various groups of control subjects. Diagnostic sensitivity in discriminating PTSD from non-PTSD subjects using biological variables is moderate, although specificity is substantially greater. The evidence supports models of conditioned autonomic nervous system arousal in PTSD.

An analysis of criteria used by VA clinicians to diagnose combat-related PTSD

The diagnostic criteria for post-traumatic stress disorder (PTSD) were consensually derived from the expert opinions of a small group of DSM-III-R Task Force and advisory committee members. In this study, 448 psychiatrists and psychologists were surveyed to assess their opinions of the criteria they utilize to assign a diagnosis of PTSD to veterans of war. The various DSM-III-R criteria for PTSD were perceived by clinicians as being differentially useful in making diagnostic judgments. Evidence of exposure to traumatic stress and symptoms of reexperiencing the trauma were consistently rated as more influential than criteria of avoidance/numbing and increased arousal. Moreover, symptoms that are directly ascribed to the traumatic event were rated more influential than those not directly referenced to the traumatic experience. Clinicians report they utilize supplemental information that extends beyond the DSM-III-R criteria to diagnose PTSD, and that this information is as important as many official DSM-III-R symptom criteria.

Adrenocortical responsiveness to infusions of physiological doses of ACTH is not altered in posttraumatic stress disorder

Early studies of posttraumatic stress disorder (PTSD) reported that abnormal function of the hypothalamic–pituitary–adrenocortical (HPA) system was associated with the disorder. However, subsequent studies attempting to identify a specific aspect of HPA dysfunction that characterizes PTSD have been marked by considerable inconsistency of results. A facet of HPA regulation that has been considered but not definitively investigated is the possibility that the responsiveness of the adrenal cortex to physiological concentrations of adrenocorticotropin (ACTH) is diminished in PTSD. Relationships between PTSD and the adrenal androgen dehydroepiandrosterone (DHEA) have also been postulated. In this study we investigated the magnitude and time course of changes in concentrations of plasma cortisol and DHEA in response to bolus infusions of physiological doses of ACTH 1–24 in PTSD patients and control subjects. We found no evidence for PTSD-related alterations in cortisol or DHEA secretion in response to stimulation by low doses of ACTH and conclude that adrenocortical responsiveness is normal in PTSD. Results from this and other studies suggest that the occurrence of defects in HPA function in PTSD may be specific responses to particular combinations of trauma type, genetic susceptibility, and individual history.