Earl L. Giller

Low urinary cortisol excretion in patients with posttraumatic stress disorder.

In the present study, we replicated and extended our previous findings of low urinary free-cortisol levels in PTSD. Cortisol was measured in 16 male patients (nine inpatients, seven outpatients) with posttraumatic stress disorder (PTSD) and in 16 nonpsychiatric control subjects. The mean cortisol level in the PTSD group was significantly lower, and the range narrower, than that observed in control subjects. Low cortisol in PTSD did not seem to be related to the presence or absence of major depressive disorder or to overall psychiatric symptomatology as assessed by the sum Brief Psychiatric Rating Scale score. In the outpatient group, there was a relationship between PTSD symptomatology and cortisol levels. The findings suggests a physiological adaptation of the hypothalamic-pituitary- adrenal axis to chronic stress.

Urinary free-cortisol levels in posttraumatic stress disorder patients.

Urinary free-cortisol levels (micrograms per day) were measured by radioimmunoassay at 2-week intervals during the course of hospitalization in the following patient groups: posttraumatic stress disorder (PTSD); major depressive disorder; bipolar I, manic; paranoid schizophrenia; and undifferentiated schizophrenia. The mean cortisol level during hospitalization was significantly lower in PTSD (33.3 ± 3.2) than in major depressive disorder (49.6 ± 5.9), bipolar I, manic (62.7 ± 6.7), and undifferentiated schizophrenia (50.1 ± 8.9), but was similar to that in paranoid schizophrenia (37.5 ± 3.9). The same differences across groups are evident in the first sample following hospital admission. This finding of low, stable cortisol levels in PTSD patients is especially noteworthy, first because of the overt signs of anxiety and depression, which would usually be expected to accompany cortisol elevations, and second because of the concomitant chronic increase in sympathetic nervous system activity shown in prior psychophysiological studies of PTSD and reflected in marked and sustained urinary catecholamine elevations previously reported in our own PTSD sample. The findings suggest a possible role of defensive organization as a basis for the low, constricted cortisol levels in PTSD and paranoid schizophrenic patients. The data also suggest the possible usefulness of hormonal criteria as an adjunct to the clinical diagnosis of PTSD.

Hypothalamic-pituitary-adrenal dysfunction in posttraumatic stress disorder.

Neuroendocrine studies examining the hypothalamic-pituitary-adrenal (HPA) axis under baseline conditions and in response to neuroendocrine challenges have supported the hypothesis of altered HPA functioning in posttraumatic stress disorder (PTSD). However, to date, there is much debate concerning the nature of HPA changes in PTSD. Furthermore, in studies showing parallel findings in PTSD and major depressive disorder there is controversy regarding whether the HPA alterations suggest a specific pathophysiology of PTSD, or, rather, reflect comorbid major depressive disorder. This review summarizes findings of HPA axis dysfunction in both PTSD and major depressive disorder, and shows distinct patterns of HPA changes, which are probably due to different mechanisms of action for cortisol and its regulatory factors.

Sustained urinary norepinephrine and epinephrine elevation in post-traumatic stress disorder

Urinary norepinephrine and epinephrine levels (microgram/day) were measured at two-week intervals during the course of hospitalization in the following patient groups: post-traumatic stress disorder (PTSD); major depressive disorder (MDD); bipolar I, manic (BP); paranoid schizophrenia (PS); and undifferentiated schizophrenia (US). The mean norepinephrine level during hospitalization was significantly higher in PTSD (76 +/- 10.4 micrograms/day) than in BP (60.6 +/- 8.4 micrograms/day), MDD (41.2 +/- 4.7 micrograms/day), PS (33.4 +/- 4.9 micrograms/day) and US (34.3 +/- 5.9 micrograms/day) groups, according to Duncans multiple range test, (F(4,39) = 6.94, p less than 0.0003). The norepinephrine elevations in the PTSD group were sustained throughout hospitalization. The only other group to show mean levels in this range was the BP group in the first sample after hospital admission. This finding supports prior psychophysiological studies indicating increased sympathetic nervous system activity in PTSD patients. The mean epinephrine level during hospitalization was also significantly higher in PTSD (22.7 +/- 2.4 micrograms/day) than in MDD (13.6 +/- 1.7 micrograms/day), PS (14.7 +/- 2.4 micrograms/day), and US (18.9 +/- 1.8 micrograms/day), but not higher than in BP (21.5 +/- 2.7 micrograms/day). The relationship of epinephrine levels among diagnostic groups was sustained throughout hospitalization. It appears likely that the main underlying mechanisms for elevations of both hormones are psychological, but further work will be required to establish the exact nature of these mechanisms.

Glucocorticoid receptor number and cortisol excretion in mood, anxiety, and psychotic disorders ☆

In the present study, we measured cytosolic lymphocyte glucocorticoid receptor and 24-hour urinary cortisol excretion in patients with major depressive disorder, bipolar mania, posttraumatic stress disorder, panic disorder, and schizophrenia. Patients with major depression had the smallest, and posttraumatic stress disordered patients the largest, mean number of glucocorticoid receptors per cell compared to patients in the other groups. Bipolar manic and panic patients did not differ from each other in regard to the number of lymphocyte glucocorticoid receptors. Bipolar manic and panic patients did have significantly more glucocorticoid receptors/cell than schizophrenic patients. The mean 24-hour urinary cortisol excretion was significantly higher in patients with major depression and bipolar mania than in those in the other diagnostic groups. Lymphocyte glucocorticoid receptor number and cortisol excretion tended to be inversely related, when the entire sample was considered as a whole, but this effect did not reach statistical significance. It is concluded that lymphocyte glucocorticoid receptors may be modulated by multiple influences, not just ambient cortisol levels. These preliminary data suggest that the assessment of lymphocyte glucocorticoid receptor number in tandem with cortisol levels may provide a more meaningful estimate of hypothalamic-pituitary-adrenal axis activity than is achieved using cortisol alone.

Pharmacotherapy for posttraumatic stress disorder using phenelzine or imipramine

Sixty male veterans with posttraumatic stress disorder (PTSD) participated in an 8-week, randomized trial comparing phenelzine (N = 19), imipramine (N = 23), and placebo (N = 18). Mean treatment retention was better on phenelzine (7.4 weeks) than on imipramine (5.6 weeks) or placebo (5.5 weeks). By week 5, both medications significantly reduced PTSD symptoms, as assessed by the Impact of Events Scale (IES), but the 44% improvement on phenelzine was greater than the 25% improvement on imipramine. The intrusion, but not the avoidance, subscale of the IES showed significant improvement, and the initial mild to moderate depressive symptoms did not significantly improve.

Elevation of urinary norepinephrine/cortisol ratio in posttraumatic stress disorder.

We have previously reported the unusual combination of low urinary free cortisol levels with high urinary norepinephrine excretion in posttraumatic stress disorder (PTSD) patients in comparison with four other patient groups: major depressive disorder, endogenous type; bipolar I, manic; paranoid schizophrenia; undifferentiated schizophrenia. Cortisol levels alone did not distinguish PTSD from paranoid schizophrenia patients and norepinephrine levels alone did not distinguish PTSD from bipolar I, manic, patients. In further consideration of these findings, we have found that combining the values for the two systems in a norepinephrine/cortisol (N/C) ratio provides a measure that significantly distinguishes PTSD from all the other patient groups throughout the hospitalization period. The N/C ratio was more than twice as high in the PTSD group than in all the other patient groups in the first sample following hospital admission, in the mean sample during hospitalization, and in the last sample before discharge. The mean N/C ratio for the PTSD group was 2.54, compared with a mean of .99 for the other four groups, which ranged from .81 to 1.18. The diagnostic sensitivity was 78% and the specificity was 94% for correct classification of PTSD in our sample. These preliminary findings yield further encouragement for exploring multivariate strategies, using hormonal ratios or profiles, in an effort to increase the diagnostic sensitivity of neuroendocrine criteria in the assessment of psychiatric patients.

Frequency of Positive Studies Among Fixed and Flexible Dose Antidepressant Clinical Trials: An Analysis of the Food and Drug Administraton Summary Basis of Approval Reports

The assumption that the design of an antidepressant clinical trial affects the outcome of that trial is based on sparse data. We sought to examine if the dosing schedule, either a fixed dose or a flexible dose type, in an antidepressant clinical trial affects the frequency with which antidepressants show statistical superiority over placebo. Randomized, placebo-controlled clinical trials of nine antidepressants approved by the Food and Drug Administration between 1985 and 2000 were reviewed. These trials comprised 9313 depressed patients who participated in 51 antidepressant clinical trials consisting of 92 treatment arms with eventual approved doses. In the flexible dose trials, 59.6% (34/57) of the antidepressant treatment arms were statistically significant compared to placebo, whereas in the fixed dose trials only 31.4% (11/35) of the antidepressant treatment arms were statistically significant compared to placebo (χ2=6.9, df=1, p<0.01). These data suggest that the antidepressant dose schedule may influence trial outcome due in part to a significantly lower magnitude of symptom reduction with placebo in flexible dose trials (F=4.08, df=1, 48, p<0.05) compared to fixed dose trials. Symptom reduction was similar with antidepressants in the flexible and fixed dose trials. Further, the primary function of finding a dose–response relationship was not found among the fixed dose studies.

Neurobiological aspects of PTSD: Review of clinical and preclinical studies

Although physiologic studies of post-traumatic stress disorder (PTSD) date to World War I, clinical neuroscience has only recently explored biological mechanisms involved in this disorder. This review will selectively consider clinical and preclinical studies pertaining to biological theories and pharmacological treatments for PTSD, highlighting the role of central noradrenergic systems in its pathophysiology.

Long-lasting hormonal alterations to extreme stress in humans: normative or maladaptive?

&NA; The biological consequences of stress have been studied for over half a decade, however, little is known about persistent biological alterations after extreme stress in humans. Posttraumatic stress disorder (PTSD) is a syndrome that occurs in some individuals after exposure to extreme stress. In this review, we summarize some of our studies of hypothalamic‐pituitary‐adrenal axis alterations in PTSD and compare and contrast these findings with knowledge concerning biological changes following stress.