F. Zerbi

Blood noradrenaline and 5-HT levels in depressed women during amitriptyline or lithium treatment.

Noradrenaline levels and platelet and free serotonin concentrations were studied in depressed women in-patients (n=78) before and during amitriptyline (n=41) or lithium treatment (n=37). Pronounced monthly differences in platelet serotonin level have been shown in these subjects before treatment. In all clinical subgroups (neurotic, involutional, manic-depressive patients) a significant fall in platelet serotonin level was observed with amitriptyline medication while an increase was noted with lithium. No significant correlations between serotonin concentrations and clinical outcome were found. Amitriptyline treatment also produced a decrease in peripheral noradrenaline concentration in all subgroups, while an increase was observed with lithium. Some correlations between noradrenaline level and degree of depression were noted in patients treated with amitriptyline or lithium. A more extended analysis of blood amine levels could supply meaningful information on the peripheral action of antidepressive drugs on noradrenaline and serotonin concentrations in depression.

Catecholaminergic, Neuroendocrine and Anxiety Responses to Acute Psychological Stress in Healthy Subjects: Influence of Alprazolam Administration

We studied the effect of alprazolam (APZ) in 12 healthy volunteers on the psychological stress-induced activation of emotion and on the pituitary-adrenal, adrenomedullary and sympathoneuronal systems. After 3 days of placebo or APZ (1 mg/day orally) administration, we examined plasma levels of adrenocorticotropic hormone, cortisol, L-3,4 dihydroxyphenylalanine, dopamine, norepinephrine (NE), epinephrine, metanephrine, normetanephrine, homovanillic acid, vanillylmandelic acid, 3-methoxy-4-hydroxy phenyglycol, urinary levels of cortisol and catecholamines, circulatory responses and state anxiety levels in subjects undergoing psychological stress based on viewing horror, violence, danger and war film clips. Film viewing produced modest rises of state anxiety levels, of plasma NE concentration and of diastolic blood pressure in both the placebo and drug groups. APZ significantly reduced anxiety levels at the beginning of the experimental session and caused a decrease of noradrenergic and dopaminergic neurotransmitter and cortisol concentrations. Our data suggest that APZ reduced anxiety related to the expectation of the event, while the circuitry between structures responsible for anxiety and peripheral sympathoneural function was still found to be partly sensitive to film viewing.

Effects of pyridostigmine, corticotropin-releasing hormone and growth hormone-releasing hormone on the pituitary-adrenal axis and on growth hormone secretion in dementia

Alterations of neuroendocrinological indices determined by the impaired regulating effects of cholinergic neurotransmission have been described in primary dementia. In this study we have evaluated the effects of acetylcholinesterase inhibition by pyridostigmine on growth hormone (GH), adrenocorticotropic hormone (ACTH) and cortisol secretion and on their responses to GH-releasing hormone (GHRH) and corticotropin-releasing hormone (CRH) in 7 patients with primary degenerative dementia and in 8 sex- and age-matched controls. Demented subjects showed higher cortisol basal levels and lower ACTH levels than controls. Pyridostigmine increased the GH response to GHRH in both groups, the effect being significantly enhanced in patients. An increase of ACTH and cortisol levels was found in both groups after pyridostigmine and CRH administration. Pyridostigmine pretreatment significantly increased the ACTH response to CRH in controls but not in patients. The obtained data may indicate that a muscarinic receptor upregulation and an impairment of somatostatinergic function are operative in the regulation of GH secretion in dementia. An underlying hyperactivity of the hypothalamic-pituitary-adrenal axis impairs the responses of ACTH and cortisol to CRH in this disorder.

Aspects of amitriptyline and nortriptyline plasma levels monitoring in depression

Fifty-nine depressed female inpatients were treated with 100 mg amitriptiline (AMT) IM for 4 weeks. Depression ratings and determinations of the parent drug and nortriptyline (NT) were performed weekly. No direct relationship between plasma AMT + NT concentrations and therapeutic response was apparent, but beneficial therapeutic responses and significantly lower side-effect scores were more frequently noted in subjects with concentrations in the 100–200 ng/ml range. AMT + NT concentrations were significantly correlated with age. No significant difference was found in the number of responders between younger and older subjects with two clinical improvement criteria; however, a significant difference emerged when a third more restrictive clinical outcome criterion was adopted. The implications of the present findings for patient treatment and for the interpretation of previous studies are discussed. The data collected point to a possible usefulness of monitoring AMT and NT plasma levels, even if further investigations are needed.

Glutamate and GABA levels in CSF from patients affected by dementia and olivo‐ponto‐cerebellar atrophy

The modifications in the CSF content of glutamate and GABA in patients afflicted with primary degenerative dementia (PDD) and olivo‐ponto‐cerebellar atrophy (OPCA) have been evaluated. Control subjects (with disk erniation) were also included in the study. The amino‐acids assays were carried out utilizing enzymatic‐bioluminescence technique. GABA levels in controls were 803 ± 98 (n = 7) and in demented patients 702 ± 98 (n = 7) pmol/ml. Glutamate levels were 2067 ± 244 (n = 10) in controls, 1190 ± 81 (n = 16) pmol/ml (vs controls p<0.01) in demented patients, and 1116 ± 146 (vs controls p<0.01) in OPCA patients. These results suggest that CSF glutamate levels in severely demented patients might be a result of generalized neuronal loss in the brain with a reactive gliosis.

Cholinergic Modulation of Growth Hormone-Releasing Hormone Effects on Growth Hormone Secretion in Dementia

An impairment of cholinergic and somatostatinergic neurotransmission have been reported in dementia. Both acetylcholine and somatostatin are involved in the regulation of growth hormone (GH) secretion. The effects of GH-releasing hormone (GHRH) 1-44 on GH release have been studied before and after the pretreatment with pyridostigmine or pirenzepine in subjects with senile dementia of the Alzheimer type, multi-infarct dementia and mixed dementia. The data have been compared with those obtained in an age-matched healthy control group. The GH response to GHRH is similar in the patients and in the controls, though the peak occurrence is significantly delayed in dementia. The cholinesterase inhibitor pyridostigmine enhances significantly the GH response to GHRH in both groups. The responses obtained in demented subjects are significantly larger than those found in the controls. Pirenzepine, a muscarinic receptor blocker, inhibits the GHRH effect on GH secretion in both groups. The findings may be interpreted in terms of an underlying impairment of the hypothalamic cholinergic neurotransmission, with an acetylcholine receptor supersensitivity that becomes apparent when the cholinergic tonus is enhanced by the inhibition of cholinesterase by pyridostigmine. No significant differences, due to the type of dementia, have been observed.

Clinical and biochemical responses to therapy in Alzheimer's disease and multi-infarct dementia

SummaryMemory performance, central monoaminergic function and sympathetic nerve activity were studied in patients with dementia of the Alzheimer type (DAT) or with multi-infarct dementia before and after 4 weeks with single or combined drug therapy (choline-piracetam). Analysis of the levels of 3-methoxy-4-hydroxyphenylglycol (MHPG), 3-methoxy-4-hydroxyphenylacetic acid (HVA) and 5-hydroxyindolacetic acid in the cerebrospinal fluid (CSF) and also in urine (plus 3-methoxy-4-hydroxy mandelic acid) showed that the basal values of HVA in the CSF and urine were lower in the more severely demented compared with the mildly demented subjects in both groups. The combined drug treatment resulted in a statistically significant increase in the MHPG level in the CSF of mildly demented subjects of the DAT group, while it seemed not to influence the other monoamine metabolites. The sympathetic nerve activity was similar in both patient groups and was unchanged after therapy. These findings suggest a dopaminergic deficit in advanced stages of the disease and a possible enhancement of the central noradrenergic output with therapy. No effects of therapy on memory performance or correlations between monoamine levels and memory test scores were noted.

GROWTH HORMONE SECRETION IN PRIMARY DEGENERATIVE DEMENTIA: CORRELATIONS WITH COGNITIVE IMPAIRMENT

Changes in brain peptides and neurotransmitters are thought to elicit alterations of growth hormone (GH) secretion in dementia. Baseline GH levels and hormone responses to GH‐releasing hormone (GHRH)—administered alone or after pyridostigmine pretreatment—were evaluated in 17 patients, aged 52–83, with primary degenerative dementia quantified by the Clinical Dementia Rating (CDR) Scale and the Mini‐Mental State Examination (MMSE) with a view to detecting correlations between neuroendocrine and clinical data. Basal GH levels were not statistically different in patients and in age‐matched controls. However, when patients were split into the three CDR groups of disease severity, basal GH levels were significantly higher in those with more severe dementia than in all other patients and in controls. GH responses to GHRH, evaluated both in terms of peaks attained after simulation and of secretion areas under the curve (AUC), were significantly higher in patients than in controls after pyridostigmine pretreatment, but not after the infusion of GHRH alone. Patients with mild to moderate dementia had GH peaks after GHRH higher than more severe patients. Pyridostigmine did not potentiate GHRH effects in the more severe cases. The scores on Reys 15‐word test for memory function were directly correlated with GH peaks after GHRH. No correlations were found between GH data, age, body weight, disease duration and scores at other psychometric assessments such as MMSE, Ravens matrices, verbal fluency or WAIS tests.

Amitriptyline action on sympathetic neuronal function in depressed women.

1. Noradrenaline plasma levels and cardiovascular function modifications with orthostatic challenge during therapy were studied in 59 female depressed inpatients treated with 100 mg amitriptyline daily by intramuscular route for 4 weeks.

Amitriptyline and Nortriptyline Plasma Levels, Urinary 3-Methoxy-4-Hydroxyphenylglycol and Clinical Response in Depressed Women

Thirty-eight depressed female inpatients, treated intramuscularly with 100 mg/day amitriptyline (AMT), were monitored to investigate the relationships between plasma levels of the drug and its metabolite nortriptyline (NT), the urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG), side effects and clinical response. Considering the whole group, the clinical improvement was better within an intermediate range of AMT plus NT plasma concentrations (100-200 ng/ml). A more favorable outcome was also observed at NT plasma levels below 55 ng/ml. No significantly different percent clinical response among the patient clinical subgroups was observed as well as no significant correlations between MHPG decrease and drug plasma levels.