The influence of alprazolam on the monoaminergic neurotransmitter systems in dysthymic patients. Relationship to clinical response.

The effects of alprazolam (1.5 mg/die) on the levels of the monoaminergic neurotransmitter metabolites, on the activity of the hypothalamic-pituitary-adrenal axis and on clinical outcome in subjects with primary late-onset dysthymia were investigated. Drug treatment significantly decreased plasma and urinary cortisol levels, serotonin platelet-bound and urinary 3-methoxy-4-hydroxyphenylglycol concentrations, while it increased plasma homovanillic acid (HVA) concentrations. Significant relationships were observed between neurochemicals and global scores or some items of the Hamilton Depression Rating Scale, before and after treatment. Patients responded positively (73%) to the therapy; clinical outcome was significantly correlated with plasma and urinary HVA levels. Collected data seem to support the hypothesis that central monoaminergic systems are in part involved in therapeutic response to alprazolam.

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.

Opposing actions of D1- and D2-dopamine receptors on arachidonic acid release and cyclic AMP production in striatal neurons.

D1- and D2-dopamine receptors exert important physiological actions on striatal neurons, but the intracellular second messenger pathways activated by these receptors are still incompletely understood. Using primary cultures of rat striatal cells, we have examined the effects of activating D1 or D2 receptors on arachidonic acid (AA) release and cyclic AMP accumulation. In striatal neurons labeled by incubation with [3H]AA, D2-receptor stimulation enhanced release of [3H]AA produced by application of the Ca2+ ionophore A23187 or of the purinergic agonist ATP. By contrast, D1-receptor stimulation inhibited [3H]AA release. This inhibitory effect of D1 receptors was accompanied by stimulation of adenylyl cyclase activity, measured as accumulation of cyclic AMP, and was mimicked by application of the adenylyl cyclase activator forskolin. The results indicate the existence of a novel signaling pathway for D2 and D1 receptors in striatum, potentiation and inhibition, respectively, of Ca(2+)-evoked AA release.

Modulation of dopamine-induced cAMP production in rat striatal cultures by the calcium ionophore A23187 and by phorbol-12-myristate-13-acetate.

The modulation of cAMP formation by protein kinase C (PKC), activated by phorbol-12-myristate-13-acetate, and by Ca2+ entry, using the ionophore A23187, was investigated in rat striatal neurons grown in primary dissociated cell culture. Phorbol-12-myristate-13-acetate (PMA) potentiated forskolin-induced and dopamine-induced cAMP formation in a concentration-dependent manner. In contrast, the calcium ionophore A23187 inhibited dopamine-induced cAMP formation. When PMA and A23187 were tested simultaneously, the levels of cAMP were not statistically different from those found in the presence of dopamine alone. Furthermore, the decreasing effect of A23187 on cAMP formation was enhanced when PKC was desensitized by pretreating the neurons with 1 microM PMA for 18 h. These data indicate that in striatal neurons Ca2+ entry and PKC activation exert opposing effect on cAMP production.

Measurement of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in cultured rat mesencephalic neurons by high-performance liquid chromatography with electrochemical detection.

An HPLC method with electrochemical detection for the simultaneous measurement of serotonin (5-hydroxytryptamine) and 5-hydroxyindoleacetic acid in primary mesencephalic cell culture is described. The serotonin and 5-hydroxyindoleacetic acid cell content was measured on different days of growth in vitro; after twelve days in culture the amounts of serotonin and 5-hydroxyindoleacetic acid detected were 916.0 +/- 70.2 and 215.8 +/- 15.5 pg per well, respectively. The heterogeneity of neurons in our cultures and their capacity to take up serotonin were assessed by measuring the amounts of exogenous serotonin taken up in the presence of different monoamine uptake inhibitors. This method, sensitive and reliable, can represent a valid alternative to the use of labelled compounds.

Aspects of amitriptyline and nortriptyline plasma levels monitoring in depression.

Fifty-nine depressed female inpatients were treated with 100 mg amitriptyline (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.

Noradrenergic output and clinical response in depressed women during amitriptyline therapy.

The measurement of the urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG) in 59 unipolar depressed women before and during administration of 100 mg amitriptyline (AMT) i.m. daily for four weeks showed that the patients could be divided into high or low MHPG excretors. An analysis of the excretion course of MHPG and 3-methoxy-4-hydroxy mandelic acid during therapy showed, in most patients, a lower urinary excretion of both these noradrenaline (NA) metabolites in comparison with basal values. Therapy also decreased plasma noradrenaline concentrations and blood pressure values both at rest and on orthostatic challenge. Available evidence seems to suggest that AMT administration caused a lower overall noradrenergic output that might be partially responsible for a diminished sympathetic nervous activity. The authors were unable to confirm that the baseline MHPG level can predict the clinical response to antidepressant treatment and they found no significant correlations between changes in bio-chemical or physiological variables and drug plasma concentrations or clinical response. The possibility that depressed patients might be grouped according to their different NA metabolism needs to be validated in a larger patient sample.

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

Memory 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.

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. 2. Therapy induced an increase in pulse rate in supine and upright positions, a decrease of noradrenaline levels and modified standing systolic and (partially) diastolic blood pressure, particularly in elderly subjects. 3. No correlation between neurotransmitter or functional changes and drug plasma levels was noted. 4. The supposed lower noradrenergic output together with blood pressure drop in both positions suggests a reduced sympathetic tone.

Viloxazine in depressed women: clinical response and cardiovascular effects.

The antidepressant effect of viloxazine (300 and 500 mg/day) was investigated for 4 weeks in 26 depressed women. The decrease in the Hamilton Depression Rating Scale score indicated a prompt overall clinical improvement, the depressed mood and suicide items showing the highest percent diminution. The highest plasma level of viloxazine was reached at day 7 and decreased during treatment only with the 500 mg dosage. Blood pressure and pulse rate responses to orthostatic stress were slightly affected and showed few untoward cardiovascular reactions to drug treatment. The decrease of noradrenaline plasma levels in both postural positions might indicate a lower sympathetic nervous system tone.

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.

Assay of urinary vanilmandelic, homovanillic, and 5-hydroxyindole acetic acids by liquid chromatography with electrochemical detection.

A reversed-phase liquid chromatographic method with amperometric detection has been developed for the simultaneous determination of the noradrenaline metabolite, vanilmandelic acid, the dopamine metabolite, homovanillic acid, and the serotonin metabolite, 5-hydroxyindole acetic acid, in human urine. After purification by an extraction procedure, the metabolites were rapidly separated under isocratic conditions. Detection and quantification were performed with an electrochemical detector using a carbon paste electrode. The present method is sensitive, selective and, achieves a high degree of precision by the use of isovanilmandelic acid as an internal standard. This provides a suitable tool for clinical and research applications.

Urinary 3-methoxy-4-hydroxyphenylglycol determination using reversed-phase chromatography with amperometric detection.

A reversed-phase liquid chromatographic method with amperometric detection has been developed for the determination of urinary 3-methoxy-4-hydroxyphenylglycol. Before and after enzymatic deconjugation, it was purified by an extraction procedure and rapidly quantified under isocratic conditions. The 24-h excretion profile in normal human subjects (eight males and seven females) was determined; our results are consistent with those arrived at in a number of other studies. The present method is highly sensitive and selective; in addition, a good degree of precision is assured by use of 4-methoxy-3-hydroxyphenylglycol as internal standard.

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.

Amitriptyline, nortriptyline plasma levels and clinical response in women with affective disorders.

The relationship between the plasma levels of amitriptyline and its metabolite nortriptyline, as well as their side-effects and clinical response, were studied in 102 depressed female in-patients, treated with different dosages of amitriptyline. For 50 and 100 mg dosages, significant positive correlations were found between amitriptyline concentration and the Hamilton amelioration scores, as well as between Hamilton final values and side effects. For depressive neurosis and involutional melancholia best therapeutic responses were yielded at a dosage of 50 mg, while in the treatment of manic-depressive illness, comparable results occurred at a 150 mg dosage. In the depressive neurosis and in the involutional melancholia the upper plasma concentration limits for the therapeutic effect of nortriptyline were identified. The lower plasma concentration limits of amitriptyline and nortriptyline in the treatment of manic-depressive illness were also pointed out.