Alpha-2-adrenoceptor sensitivity in early alcohol withdrawal.

Growth hormone (GH), blood pressure, and pulse rate responses to clonidine (100 micrograms IV) were studied three times during the first week of alcohol withdrawal in 19 alcohol-dependent patients. Fifteen healthy men were used as controls. The results suggest reduced sensitivity of the alpha-2-adrenoceptors involved in GH secretion for at least 1 week after the end of alcohol intake. In contrast, very short-lasting subsensitivity was found in the alpha-2-adrenoceptors regulating blood pressure.

Guanfacine as an alpha-2-agonist inducer of growth hormone secretion--a comparison with clonidine.

Doses of 0.5 mg and 1.0 mg of the alpha-2-adrenoceptor agonist guanfacine (GUA) and NaCl were administered intravenously (IV) in a randomized order to 18 healthy male subjects. GUA induced growth hormone (GH) secretion in a dose-dependent manner without affecting blood pressure or heart rate or inducing sedation. The effects of GUA 1.5 mg i.v. was compared with those of another alpha-2-adrenoceptor agonist, clonidine (CLON) 150 micrograms i.v. in six other male volunteers. Both alpha-2-agonists increased GH to similar levels. CLON reduced both systolic and diastolic blood pressure levels, whereas GUA reduced only systolic levels. Sedation was significantly more pronounced after CLON. The results suggest that the GUA/GH-test (1.5 mg GUA i.v.) may be an alternative to the CLON/GH-test in neuroendocrine assessment of alpha-2-adrenoceptor sensitivity.

Treatment-resistant mania with primary hypothyroidism: a case of recovery after levothyroxine.

A manic-depressive woman was unresponsive to treatment with lithium and neuroleptics during a period of mania. Additional levothyroxine treatment of her primary hypothyroidism resulted in rapid and complete recovery from her mania.

Neuroendocrine evidence for increased responsiveness of dopamine receptors in humans following electroconvulsive therapy.

The previous finding that electroconvulsive therapy (ECT) enhances effects of dopamine (DA) agonists was further investigated in the present clinical experiment using neuroendocrine techniques. Apomorphine chloride (AP) (0.18-0.24 mg IV) induced stimulation of growth hormone (GH) and suppression of prolactin (PRL), as shown 2-3 days before and after ECT in mentally depressed patients (N = 12) and therapy-resistant parkinsonian patients with on-off phenomena (N = 9). AP-stimulated GH secretion was not significantly affected by ECT, whereas AP-induced suppression of PRL, expressed as percentage of baseline PRL levels, was significantly enhanced after ECT. Changes in clinical and hormonal parameters were not significantly correlated. Control patients not receiving ECT showed no significant changes in AP-induced GH secretion or PRL suppression in repeated investigations. The results support the view that ECT increases responsiveness of DA receptors and indicates that AP-induced suppression of PRL is a useful model to reflect these changes in humans.

Changes in dopamine receptor sensitivity in humans after heavy alcohol intake.

Dopamine (DA) sensitivity, assessed through maximal growth hormone (GH) response to stimulation by apomorphine (APO) (0.18-0.24 mg iv) was studied in 16 chronic alcoholics newly admitted after a period of heavy alcohol intake. Repeated hormonal tests were thereafter performed during a 2-month period under strictly controlled conditions to avoid relapse into alcohol consumption. Eight healthy volunteers with alcohol consumption slightly less than that of the general population were used as controls. It was found that DA sensitivity in the early abstinence phase was higher than later in the 2-month recovery period but not significantly different from control values. The relatively higher DA sensitivity in the early abstinence phase might be responsible for a lower threshold for psychotic symptoms and neuroleptic-induced extrapyramidal side effects. The results of this study give further evidence of a prolonged recovery phase after heavy alcohol intake.

Regulation of the hypothalamic-pituitary-adrenal axis in dementia disorders.

In 163 patients with dementia disorders, subdivided into Alzheimer's disease with early onset (AD; n = 40), senile dementia of the Alzheimer type (SDAT; n = 56), vascular dementia (VAD; n = 45) and dementia of unspecified type (NUD; n = 22) the dexamethasone suppression test (DST) was performed. The patients were rated according to the DSM-III-R criteria as having mild, moderate or severe dementia and were also assessed using the GBS scale which gives a profile of the dementia syndrome. In the total group of dementia there were significant correlations between severity of dementia and post-DST levels. The frequency of pathological DST also correlated significantly with the severity of dementia. In the subgroups of dementia a strong correlation between severity of dementia and high post-DST cortisol levels was found only in the VAD group. Between the subgroups of dementia disorders there were no significant differences in basal cortisol levels. The percentage of pathological DST was lowest in the AD group (40%). It was somewhat higher in the VAD group (49%), still higher in the SDAT group (54%) and highest in the NUD group (59%). When the relationship between post-DST cortisol levels and GBS scores was analyzed, significant correlations were found mainly in the VAD group. There intellectual impairment, anxiety, fear-panic and restlessness correlated significantly with post-DST cortisol levels. The results indicate hypothalamic overactivity in a substantial number of demented patients. In VAD and to a certain extent also in SDAT a disconnection between cortical areas, including the hippocampus, and the hypothalamus is assumed. Overactivity in the hypothalamic-pituitary-adrenal (HPA) axis is due to stress, and an insufficient feedback system leads to chronic stress adaptation failure.

Further neuroendocrine evidence for reduced D2 dopamine receptor function in alcoholism.

D2 dopamine receptor function, as assessed by growth hormone (GH) responses to apomorphine (APO; 0.18-0.24 mg i.v.), was investigated in 15 male alcoholics with reported long-term abstinence. Results from only nine subjects could be evaluated. These subjects had been heavy alcohol consumers for a mean of 15 +/- 10 years and had thereafter been abstinent for a mean of 7 +/- 6 years prior to the investigation. Eight male healthy subjects, all of whom were light social drinkers, were selected as controls. The maximum GH responses to APO were significantly lower in the alcoholics (5.8 +/- 5.8 mU/l) than in the controls (22.1 +/- 19.2 mU/l). This finding gives neuroendocrine evidence for reduced D2 dopamine receptor function in alcoholics with long-term abstinence.

Relationship between central serotonergic neurotransmission and reduction in alcohol intake by citalopram.

The relationship between the effect of citalopram on alcohol intake and central serotonergic neurotransmission, as assessed by prolactin (PRL) response to fenfluramine, was investigated in 17 male heavy drinkers. A positive correlation was obtained, suggesting that the status of central serotonergic neurotransmission in individuals is associated with the treatment response to citalopram. When the group of subjects were divided into those with high and low PRL response (above and below median, respectively) to fenfluramine, those with high PRL response had a significant reduction in alcohol intake during citalopram treatment, whereas those with low PRL response had no such effect. Thus, in subjects with evidence of unimpaired or only slightly impaired central serotonergic neurotransmission (high PRL response) citalopram may have beneficial effect on alcohol consumption, whereas in those with more evidently impaired serotonergic neurotransmission (low PRL response) citalopram treatment may have no effect on or may even increase the alcohol consumption.

Subsensitive alpha-2-adrenoceptor function in male alcohol-dependent individuals during 6 months of abstinence.

Postsynaptic alpha-2-receptor function, as assessed by growth hormone (GH) response to clonidine (CLON), has been shown to be downregulated in patients investigated in acute but also in late withdrawal after heavy alcohol intake. The results are however sometimes conflicting. The question whether this changed receptor function is a trait or state marker is not fully investigated so far. A total of seven male patients with alcohol dependence according to DSM-IV were assessed for the postsynaptic alpha-2-receptor function with the CLON/GH test (2.0 microg/kg body weight; i.v.) starting immediately after a period of heavy drinking. Neuroendocrine tests were repeated after 7 days, 2 and 6 months. A total of six healthy males were used as controls. The maximum GH responses to CLON were significantly lower on all four test occasions in the patient group as compared to the controls. Furthermore, in the patient group all neuroendocrine test results showed blunted GH responses to CLON. Thus, patients with downregulated alpha-2-receptor function during acute withdrawal after heavy alcohol intake showed similar subsensitive receptor function abnormality after a prolonged period of abstinence. The findings in this study indicate that alcohol dependent individuals have a persistent subsensitive alpha-2-adrenoceptor function which may constitute a trait factor for alcohol dependence.

Six-month open trial with Zimelidine in alcohol-dependent patients: reduction in days of alcohol intake.

In an open study, 14 alcohol-dependent male patients were treated with the selective serotonin reuptake inhibitor (SSRI) Zimelidine, 200 mg daily, for six months. They were given psychosocial therapy before and during the study. The number of days of alcohol intake was statistically significantly reduced from a mean of 14 days per month before to 1-5 days during drug treatment. No effect was observed on the amount of daily alcohol intake on drinking days. No tolerance to the effect of Zimelidine was observed during the study. The findings suggest an effect of combined psychosocial support with SSRI treatment that seems to be of clinical significance.

Dexamethasone suppression test in alcohol withdrawal: relationship to depression and liver function.

The relationship between dexamethasone suppression test (DST) response, depressive symptoms and liver function tests was investigated in 15 male alcohol-dependent patients for 2 weeks during alcohol withdrawal. Six of the patients relapsed into drinking within the investigation period. There was no association between DST response and relapse, which suggests that abnormal DST response has no predictive value for relapse into drinking. About 50% of the patients had abnormal DST responses during the first week of alcohol withdrawal. There was no relationship between DST response and depression or depressive symptoms. Depression remitted within 1-2 weeks, whereas DST responses remained abnormal for at least 2 weeks in 2 of the non-relapsing 9 patients. Abnormal DST response in alcohol withdrawal is unlikely to be due to alterations in liver function but may be attributable to the effect of alcohol on the hypothalamic-pituitary-adrenocortical axis.

Hypothalamic dysfunction in dementia.

In 40 patients with Alzheimer's disease (AD) 56 patients with senile dementia of Alzheimer type (SDAT) and 45 patients with vascular dementia (VAD) degree of dementia was rated into mild, moderate and severe according to DSM-III-R and on the GBS scale. Basal cortisol levels were determined and a dexamethasone test (DST) performed. Basal cortisol levels were high in all the dementia groups. Forty percent of AD patients, 54% of SDAT patients and 49% of VAD patients were non suppressors. Significant correlations between post DST cortisol levels and rated variables were seen mainly in the VAD group. The pathological DST could hardly be explained by presence of depression. In dementia, especially those with white matter disturbances, disconnections between cortical areas (hippocampus) and hypothalamus can be assumed explaining a reduced inhibitory tone on hypothalamus. When characterizing VAD patients with pathological DST these patients were significantly more intellectually impaired, showed higher degree of anxiety, restlessness and fear-panic than VAD patients with normal DST. Some behaviourial disturbances in dementia disorders may be a consequence of HPA over activity rather than a consequence of the dementia process itself.

Neuroendocrine evidence for decreased function of alpha 2-adrenergic receptor after electroconvulsive therapy.

Growth hormone (GH) and hypotensive responses to clonidine (150 micrograms, i.v.) were investigated before and after electroconvulsive therapy (ECT) in 16 depressed patients. Because of high baseline serum GH concentrations, results from only 10 patients could be evaluated. The level of GH secretion induced by clonidine was significantly reduced after ECT, but the hypotensive responses to clonidine remained unchanged. The results indicate downward regulation of the sensitivity of alpha 2-adrenergic receptors in the hypothalamus after ECT.

Growth hormone responses to the alpha 2-adrenoceptor agonist guanfacine and to growth hormone releasing hormone in depressed patients and controls.

Growth hormone (GH) responses to the alpha 2-adrenoceptor agonist guanfacine and to GH releasing hormone (GHRH) were measured in 13 patients fulfilling Research Diagnostic Criteria and DSM-III criteria for major depressive disorder and in 13 controls matched for age and sex. Dexamethasone suppression tests were performed in all subjects. The peak GH response to guanfacine correlated to the peak GH response to GHRH both in depressed patients and in controls. Neither the response to guanfacine nor the response to GHRH was significantly lower in depressed patients than in controls. Dexamethasone suppression tests, which were performed about 3 days before the GH stimulation tests, were abnormal in 61% (8/13) of the depressed patients but in none of the controls. No difference between dexamethasone suppressors and nonsuppressors with respect to GH response to guanfacine or GHRH was observed. The data are discussed in relation to the blunted GH response to clonidine described in depression.

No evident neuronal damage after electroconvulsive therapy.

Electroconvulsive therapy (ECT) is regarded as one of the most effective treatments for major depressive disorder but has also been associated with cognitive deficits possibly reflecting brain damage. The aim of this study was therefore to evaluate whether ECT induces cerebral damage as reflected by different biochemical measures. The concentrations in the cerebrospinal fluid (CSF) of three established markers of neuronal/glial degeneration, tau protein (tau), neurofilament (NFL) and S-100 beta protein, were determined in nine patients who fulfilled DSM-IV criteria for major depression. CSF samples were collected before and after a course of six ECT sessions. The CSF/serum (S) albumin ratio reflecting potential blood-brain barrier (BBB) dysfunction was also determined at these time points. The treatment was clinically successful with a significant decline of depressive symptoms in all patients as assessed by the Montgomery-Asberg Rating Scale for Depression. Several patients had signs of BBB dysfunction and/or neuronal damage before the start of treatment. Levels of CSF-tau, CSF-NFL and CSF-S-100 beta levels were not significantly changed by ECT. Also the CSF/S albumin ratio was found to be unchanged after the course of ECT. In conclusion, no biochemical evidence of neuronal/glial damage or BBB dysfunction could be demonstrated following a therapeutic course of ECT.

Cardiovascular responses to clonidine in alcohol withdrawal: are they related to psychopathology and mental well-being?

The possible relationships between alpha-2-adrenoceptor function, as assessed by blood pressure, heart rate, and sedative responses to clonidine (CLON; 1.5 microg/kg, i.v.), and psychopathology and mental well-being were investigated in 19 patients with alcohol-dependence in the early withdrawal period (days 1 and 7). An age-matched control group was used (n=17). CLON-induced maximum reduction of systolic blood pressure was less day 1 in the alcohol-dependent patients compared to controls. CLON was found to induce less sedation at day 7 compared to day 1 and to controls. No relationships were seen between the parameters for alpha-2-adrenoceptor function and psychopathology and mental well-being. These findings suggest that CLON-induced changes in blood pressures and heart rate reflect the cardiovascular situation in alcohol withdrawal and not aspects of behavior.

No effect of the cortisol-synthesis inhibitor metyrapone on alcohol drinking: a pilot study.

Two bases for this study were the theory of stress as a provoking factor for high alcohol consumption in human being and findings that the stress hormones stimulate ethanol intake in rats. We therefore investigated whether the cortisol-synthesis inhibitor metyrapone could reduce high alcohol consumption in socially stable subjects who reported drinking mainly for relaxation purposes. Most of the investigated subjects were found to be alcohol dependent (81%), with moderately high levels of intake, yet they had not reported more severe life problems. All subjects reported their daily alcohol consumption during 2-week baseline, medication, and postmedication periods. Sixteen subjects were given 1 g of metyrapone orally daily for 14 days, and 15 subjects received placebo. Morning serum cortisol concentration was assessed four times in the course of the study period. Metyrapone treatment was not found to reduce alcohol consumption more than placebo. Serum cortisol concentrations remained within the laboratory reference interval during the study and did not differ between the study groups. In this study, we found that a cortisol-synthesis inhibitor had no effect on alcohol consumption. One reason may be that cortisol secretion has no role in the maintenance of high alcohol consumption. On the other hand, because this study is the first of its kind, further studies using other doses of treatment and treatment schedules are suggested.