Pituitary-adrenal-system regulation and psychopathology during amitriptyline treatment in elderly depressed patients and normal comparison subjects.

OBJECTIVE: This study was done to compare the effects of 6-week treatment with amitriptyline on hypothalamic-pituitary-adrenocortical (HPA) regulation in elderly depressed patients and age-matched comparison subjects. METHOD: A combined dexamethasone-suppression/CRH-stimulation (dexamethasone/CRH) test was administered before initiation of amitriptyline treatment and at the end of weeks 1, 3, and 6 of treatment. Thirty-nine depressed inpatients, mean age = 69 years, completed the study. Fourteen normal volunteers, mean age = 67 years, served as comparison subjects. RESULTS: In relation to the comparison subjects, the depressed patients had a profoundly abnormal HPA response, in particular an exaggerated cortisol release in the dexamethasone/CRH test. This abnormality began to disappear after 1 week of treatment with amitriptyline. In contrast, amitriptyline did not affect neuroendocrine regulation in the comparison subjects at any time during the test period. CONCLUSIONS: The data suggest that amitriptyline affects HPA regulation in hypercortisolemic depression only, and they raise the possibility that normalization of its feedback control is related to the antidepressive effect of amitriptyline.

Combined dexamethasone/corticotropin-releasing hormone test in acute and remitted manic patients, in acute depression, and in normal controls: I.

Hypothalamic-pituitary-adrenal system (HPA)-function in patients with mania (n = 11), depression (n = 11, unipolar) and in control subjects (n = 11) was studied; six of the acutely manic patients were reevaluated after a symptom-free interval of at least 6 months. The combined dexamethasone-suppression/human CRH-challenge test was used to probe HPA-system function. After CRH and dexamethasone pretreatment, ACTH and cortisol release were significantly increased in both manic and depressed patients in comparison to the control group. In the remitted patients with mania, a significant decrease in hormonal release after DEX and CRH was evident when compared to the acute manic episode, but the degree of CRH-stimulated hormone secretion in these remitted patients was still significantly larger than in normal controls. This study demonstrates that acute and remitted manic episodes are associated with a profoundly dysregulated HPA-system activity.

Combined dexamethasone/corticotropin-releasing hormone test in patients with schizophrenia and in normal controls: II.

Hypothalamic-pituitary-adrenal system (HPA) function was tested in 24 patients with schizophrenia and compared to 24 age-matched healthy volunteers using the combined dexamethasone-suppression (DST/CRH) corticotropin-releasing hormone stimulation test (DST/CRH). After stimulation with CRH, the dexamethasone-pretreated patients released significantly more cortisol, but a similar amount of adrenocorticotropic hormone (ACTH) in comparison to controls. No association between DST status and degree of severity of illness and/or current medication was found. However, in comparison to unmedicated patients, those patients currently receiving antipsychotics, who were also those with a lesser degree of severity of illness, showed a decreased release of CRH-stimulated cortisol and ACTH. This study demonstrates that schizophrenic patients have a dysregulation of the HPA system as assessed with the DEX/CRH test. Overall, however, the degree of HPA-system dysfunction in schizophrenic patients seems to be of a lesser magnitude than in patients with affective disorders.

Amitriptyline metabolism in elderly depressed patients and normal controls in relation to hypothalamic-pituitary-adrenal system function.

The pharmacokinetics of amitriptyline (AMI) have been extensively studied, and a large interindividual variability between oral dose and concentration of the drug in plasma has been documented. The aim of this study was twofold: first, to compare AMI kinetics in depressed patients with those of healthy controls and, second, to describe the relationship between AMI levels in plasma and hypothalamic-pituitary-adrenal (HPA) system changes during depression. Thirty-eight patients with a DSM-III-R diagnosis of major depression and 13 healthy control persons received 75 mg of AMI daily for 6 weeks. Levels of AMI and nortriptyline in plasma were determined, and neuroendocrine testing with the combined dexamethasone-suppression/CRH-stimulation test (DST) was done before AMI administration and after weeks 1, 3, and 6 of medication. AMI levels in plasma were significantly higher in the patient group compared with controls during the entire treatment period, whereas nortriptyline levels did not differ between the two groups. Drug levels correlated significantly with age, but gender had no effect on the concentration of the drug in plasma. Twenty-two patients remitted after treatment. There was no difference in drug levels between responders and nonresponders. Fifteen patients were DST nonsuppressors before treatment; 23 patients and all controls suppressed cortisol after dexamethasone. DST suppressors had significantly higher AMI levels in plasma at weeks 3, 5, and 6 compared with DST nonsuppressors. In comparison to patients with high AMI levels in plasma, those with low drug concentration had higher postdexamethasone cortisol and adrenocorticotropic hormone levels and an increased hormone release after additional CRH.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypothalamic-pituitary-adrenal system function in patients with Alzheimer's disease.

The neuropathologic hallmarks of Alzheimer's disease (AD) are very prominent in the hippocampus, a brain site which is pivotal for the regulation of the hypothalamic-pituitary-adrenal (HPA) system. Thus, the combined dexamethasone-suppression/CRH-stimulation-test outcome in patients with AD was compared to that of healthy elderly controls to assess--with a more refined neuroendocrine challenge procedure--HPA function in AD. Cortisol secretion after dexamethasone (DEX) pretreatment and before CRH was increased in Alzheimer's patients and 21% of this group were DST-nonsuppressors. None of the healthy control subjects escaped DEX-induced suppression of cortisol. However, after additional CRH administration, AD patients released significantly less cortisol and ACTH than the control subjects. No correlations were found between any of the endocrine parameters and degree of severity of dementia. It is concluded that the DST part of the DEX/CRH test better reflects glucocorticoid feedback disturbances, probably at a suprapituitary level. The CRH part of the DEX/CRH-test outcome might indicate the loss of endogenous CRH-Arginine-Vasopressin (AVP) synergism of the HPA system of these patients.

Age-associated changes of pituitary-adrenocortical hormone regulation in humans: importance of gender.

In the present study the hypothesis was tested that in normal human aging an insensitivity of the glucocorticoid feedback signals is acquired. Thus, 40 healthy elderly (mean age: 69 +/- 5 years) and 20 younger (mean age: 34 +/- 8 years) individuals underwent a combined dexamethasone suppression/CRH-stimulation test. Cortisol secretion after dexamethasone (DEX) pretreatment and before CRH was increased in the older age group, but none of the subjects escaped DEX-induced suppression of cortisol. However, after additional CRH administration to the DEX-pretreated volunteers, the older group released significantly more cortisol than their young counterparts. Within the group of the elderly only, a positive correlation between BASAL, DEX-pretreated cortisol concentration and post-CRH steroid responses was found. Gender profoundly affected DEX/CRH-test outcome: females, regardless of age, had an increased hormonal secretion in comparison to males. It is concluded that, during human aging, adaptive changes in glucocorticoid receptors take place, allowing for the system to maintain "peripheral" glucocorticoid homeostasis, but that more sophisticated challenge procedures such as the DEX/CRH test reveal an age-related increase in HPA system activity.

Growth hormone secretion in Alzheimer's disease: 24-hour profile of basal levels and response to stimulation and suppression studies.

The 24-h growth hormone secretory pattern and GH response to growth hormone releasing hormone, the alpha 2-adrenoceptor agonist clonidine and the somatostatin-analogue SMS 201-995 were evaluated in 9 patients with Alzheimer's disease and 9 age- and body body-matched control subjects. The secretory profile did not differentiate between patients and controls. Both secreted the largest amount of GH during the early nighthours between 22.00-02.00, whereas the majority of daytime GH levels were below the assay's detection limit (0.4 ng/ml). No difference was found in GH response to GHRH between patients and controls. All subjects showed significantly enhanced GH secretion after GHRH. Dividing the patients into two groups according to age-of-onset (less than 60 years greater than), there was a trend toward larger GH responses to GHRH for the early-onset group. No other parameter differentiated the groups. GH levels after clonidine were blunted in all subjects but one AD patient, probably due to an age-dependent attenuation frequently observed in subjects over 45 years of age. Finally, the administration of the somatostatin-analogue did not render conclusive results, since spontaneous decline of GH concentration was already beginning 2 hours before the drug was given and continued steadily throughout the observation period. In conclusion, patients with only mild to moderate degree of Alzheimer's disease have no prominent changes in GH regulation.

The limbic-hypothalamic-pituitary-adrenal axis in Huntington's disease.

The functional integrity of the limbic-hypothalamic-pituitary-adrenal (LHPA) axis was studied in 10 patients with Huntington's disease (HD) and 10 age- and weight-matched control subjects by measuring basal ACTH and cortisol secretion, analyzing the subjects' ACTH and cortisol responses to corticotropin-releasing hormone (CRH) challenge, and by means of the dexamethasone-suppression test (DST). Basal cortisol and ACTH levels were significantly higher in patients with HD compared with controls. Following CRH administration, ACTH responses tended to be blunted in concert with normal cortisol levels. Two patients with HD and one control subject were DST nonsuppressors. Post-DST plasma dexamethasone levels were 57% lower among patients compared with the control group. Only in the HD group age was there an important variable in influencing spontaneous cortisol secretion as well as plasma dexamethasone levels during DST. These results suggest that patients with HD have an endogenous CRH overdrive, possibly due to a loss of (GABA) gamma-aminobutyric acid-containing neurons, and that age might have an effect on the outcome of LHPA axis function tests in patients only.

Somatostatin replacement therapy for Alzheimer dementia.

Somatostatin is consistently diminished in brains of patients with Alzheimer's disease. To evaluate whether pharmacological restoration of this transmitter deficit has therapeutic value, the synthetic analogue octreotide was administered intravenously to 14 Alzheimer patients under double-blind, placebo-controlled conditions. At the highest dose administered, spinal fluid concentrations approximated those found in brains of experimental animals receiving behaviorally effective amounts of the drug. Neuropsychological testing, however, showed no clinically significant improvement. Coadministration of octreotide and physostigmine to 1 patient also failed to improve cognition. Positron emission tomographic studies in 6 patients revealed a generalized decrease in glucose metabolism as a result of octreotide infusion. These findings suggest that stimulation of the somatostatin system has no value in the symptomatic treatment of Alzheimer dementia.

Hypothalamic-pituitary-adrenal axis function in elderly endurance athletes.

To explore the effects of repeated episodes of hypercortisolemia on hypothalamic-pituitary-adrenal axis regulation, we studied plasma ACTH and cortisol (CORT) responses to 100 micrograms human CRH (hCRH) in 10 dexamethasone (1.5 mg)-pretreated elderly endurance athletes who had abstained from physical activity for at least 48 h before testing and 13 sedentary age-matched controls. Basal CORT and ACTH levels were indistinguishable between runners and sedentary controls, whereas CORT responses to hCRH were significantly increased in endurance athletes, and ACTH responses tended to be higher in this group. Comparing the dexamethasone/hCRH test results of the runners with those of an age-matched sample of previously studied depressed patients (n = 9), similar hormone responses to CRH challenge were noted. The mechanisms underlying these alterations may either be a stepwise decrease in corticotropic sensitivity to the negative feedback signal leading to a switch to positive glucocorticoid feedback, an enhanced cosecretion of ACTH secretagogues such as vasopressin, or a combination of both. In conclusion, hypothalamic-pituitary-adrenal axis physiology seems to be determined by previous stressful events associated with hypercortisolemia, regardless of its etiology.

Comparison of the clinical pharmacology of (-)NPA and levodopa in Parkinson's disease.

Direct acting dopamine agonists are generally less effective than levodopa in relieving symptoms of Parkinson's disease. In an attempt to quantitate and explain this situation, the acute motor responses to intravenous injections of the dopamine agonist, (-)-N-n-propyl-norapomorphine hydrochloride (NPA), were compared with those of the dopamine precursor, levodopa. At optimum dose levels, the acute anti-Parkinsonian efficacy of NPA averaged only about 50% of maximum, while essentially total symptom suppression was obtained with levodopa in patients previously treated with the amine precursor. Dyskinesia severity, however, was similar with the two drugs. These differences in anti-Parkinsonian efficacy may reflect the fact that while NPA acts mainly on D-2 dopamine receptors, levodopa results in stimulation of both the D-1 and D-2 subsets of receptors at a more physiological ratio. Future efforts to develop dopamine agonists for the treatment of Parkinsonian symptoms may thus have to consider focusing on drugs having pharmacological profile more similar to that of dopamine.

Anxiety disorders in patients with Parkinson's disease.

To study the prevalence and importance of anxiety disorders in patients with idiopathic Parkinson's disease, the authors systematically evaluated 24 parkinsonian patients for the presence of DSM-III-R axis I syndromes. Nine subjects (38%) had a clinically significant current anxiety disorder. Severity of anxiety was not correlated with severity of parkinsonian symptoms, cumulative duration of L-dopa exposure, or current dose of L-dopa. These findings suggest that anxiety disorders should be considered in the medical evaluation and treatment of parkinsonian patients and that further attention should be paid to the role of the dopaminergic system in anxiety and phobic disorders.

Modification of central dopaminergic mechanisms by continuous levodopa therapy for advanced Parkinson's disease.

The management of fluctuations in motor function complicating advanced Parkinson's disease with continuously administered dopaminomimetics was studied in 12 patients. In response to 7 to 12 days of round-the-clock intravenous infusions of levodopa, fluctuations in motor performance gradually diminished, ultimately by more than 40%. The beneficial effect persisted for about 6 days after withdrawal of continuous parenteral treatment and resumption of standard oral therapy. Clinical improvement was associated with changes in several pharmacological indices: Acute dose-response studies of intravenous levodopa showed a shift of the curve to the right in the immediate postinfusion phase compared to preinfusion studies; the therapeutic index improved significantly as patients demonstrated about 76% increased beneficial antiparkinsonian response with an equal degree of toxic dyskinetic effects; and the duration of action of levodopa was prolonged by 30%. These results suggest that changes in central dopaminergic mechanisms contributing to motor complications in advanced Parkinson's disease can be modified by procedures that provide continuous dopamine replacement. Presumably these modifications underlie the gradual amelioration of motor fluctuations over several days of round-the-clock therapy. Results of the present study also suggest potential deleterious effects of chronic intermittent oral treatment in the development of motor complications and thus support the role of long-term, continuous administration of dopaminomimetics.

Rationale for continuous dopaminomimetic therapy of Parkinson's disease.

Levodopa combined with carbidopa (Sinemet) remains the most effective approach to the symptomatic relief of Parkinson's disease. Over time, however, an increasing number of parkinsonian patients evidence motor response complications, notably abnormal involuntary movements and motor fluctuations. Clinical pharmacologic studies suggest that these phenomena may arise as a consequence of factors reflecting both natural disease progression and levodopa toxicity. Simple wearing-off responses appear primarily related to advancing degenerative changes afflicting the dopamine system. The appearance of peak-dose dyskinesias and complex, random motor fluctuations of the on-off type, on the other hand, may signal secondary postjunctional changes arising as a consequence of chronic intermittent excitation of postsynaptic dopamine receptors that are normally tonically stimulated. Therapeutically, prompt correction of wearing-off fluctuations can ordinarily be achieved by measures that deliver dopaminomimetics continuously to the central nervous system. In contrast, fluctuations of the on-off type initially persist despite stable circulating levodopa levels. With continuous levodopa treatment, however, the threshold for dyskinesias begins to rise and the dose-response relation shifts to the right; clinically, the severity of both dyskinesias and on-off fluctuations tends to diminish. It is thus tempting to speculate that the early and continuing treatment of Parkinson's disease with compounds providing a relatively constant level of central dopamine stimulation will preclude wearing-off phenomena and mitigate on-off fluctuations and severe dyskinesias.

No changes in central quinolinic acid levels in Alzheimer's disease.

Levels of the endogenous excitotoxin quinolinic acid were measured in brain and lumbar spinal fluid from Alzheimer patients and age-matched controls. Values in post mortem brain tissue, unlike those in spinal fluid, showed considerable variability among subjects. In the control group, frontal cortex and caudate nucleus had higher concentrations of quinolinic acid compared to other regions studied. No significant differences were found between Alzheimer brains and controls in any of the regions analyzed. Studies in lumbar spinal fluid showed no gradient for quinolinic acid along the neuraxis, a trend for increasing levels with normal aging, and no difference between Alzheimer patients and age-matched control subjects. The lack of increased central quinolinic acid levels in Alzheimer's disease does not necessarily negate the possibility of excitotoxins contributing to cell death in this disorder.

Pathogenesis of dyskinesias in Parkinson's disease.

Abnormal involuntary movements complicate the management of a majority of patients with advanced Parkinson's disease. The ability of levodopa to induce dyskinesias and alleviate parkinsonism has generally been considered a continuous dose-dependent pharmacological spectrum. In this study, the acute dose-response profile of intravenously administered levodopa for both inducing dyskinesia and alleviating parkinsonism, and its duration of action on these motor manifestations were evaluated in 52 parkinsonian patients. The minimum dose of levodopa required to produce mild dyskinetic movements was significantly lower in patients with fluctuations in motor response compared with those who had a stable response to standard oral therapy; the minimum dose for antiparkinsonian benefit, however, failed to show significant differences. The rate of disappearance of dyskinetic movements was faster than the rate of reappearance of parkinsonian signs following withdrawal of a steady-state infusion of levodopa. The dissociation of the pharmacodynamic profile of the two major motor effects of levodopa suggests their mediation through two different central pharmacological mechanisms, perhaps involving the two classes of dopamine receptors or other transmitter systems, and could have important implications for the design of future antiparkinsonian agents.