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Biomedical subjects

A J Cleare

Publications and source records attributed to A J Cleare.

At least 19 recordsLinked to original sources
PubMed2000

Integrity of the growth hormone/insulin-like growth factor system is maintained in patients with chronic fatigue syndrome.

GH deficiency states and chronic fatigue syndrome (CFS) share several characteristics, and preliminary studies have revealed aspects of GH dysfunction in CFS. This study assessed indexes of GH function in 37 medication-free CFS patients without comorbid psychiatric illness and 37 matched healthy controls. We also assessed GH function before and after treatment with low dose hydrocortisone, which has been shown recently to reduce fatigue in CFS. We measured basal levels of serum insulin-like growth factor I (IGF-I), IGF-II, IGF-binding protein-1 (IGFBP-1), IGFBP-2 and IGFBP-3 together with 24-h urinary GH excretion. We also performed 2 dynamic tests of GH function: a 100-microg GHRH test and an insulin stress test using 0.15 U/kg BW insulin. There were no differences between patients and controls in basal levels of IGF/IGFBP or in urinary GH excretion. GH responses to both the GHRH test and the insulin stress test were no different in patients and controls. CFS patients did have a marginally reduced suppression of IGFBP-1 during the insulin stress test. Hydrocortisone treatment had no significant effect on any of these parameters. There is no evidence of GH deficiency in CFS. At the doses used, hydrocortisone treatment appears to have little impact on GH function.

Adult↗
PubMed1999

Low-dose hydrocortisone in chronic fatigue syndrome: a randomised crossover trial.

BACKGROUND: Reports of mild hypocortisolism in chronic fatigue syndrome led us to postulate that low-dose hydrocortisone therapy may be an effective treatment. METHODS: In a randomised crossover trial, we screened 218 patients with chronic fatigue. 32 patients met our strict criteria for chronic fatigue syndrome without co-morbid psychiatric disorder. The eligible patients received consecutive treatment with low-dose hydrocortisone (5 mg or 10 mg daily) for 1 month and placebo for 1 month; the order of treatment was randomly assigned. Analysis was by intention to treat. FINDINGS: None of the patients dropped out. Compared with the baseline self-reported fatigue scores (mean 25.1 points), the score fell by 7.2 points for patients on hydrocortisone and by 3.3 points for those on placebo (paired difference in mean scores 4.5 points [95% CI 1.2-7.7], p=0.009). In nine (28%) of the 32 patients on hydrocortisone, fatigue scores reached a predefined cut-off value similar to the normal population score, compared with three (9%) of the 32 on placebo (Fisher's exact test p=0.05). The degree of disability was reduced with hydrocortisone treatment, but not with placebo. Insulin stress tests showed that endogenous adrenal function was not suppressed by hydrocortisone. Minor side-effects were reported by three patients after hydrocortisone treatment and by one patient after placebo. INTERPRETATION: In some patients with chronic fatigue syndrome, low-dose hydrocortisone reduces fatigue levels in the short term. Treatment for a longer time and follow-up studies are needed to find out whether this effect could be clinically useful.

Adult↗
PubMed1999

Peripheral hormonal responses to D-fenfluramine as a probe of central serotonergic function in humans.

We tested the hypothesis that D-fenfluramine (DFEN)-elicited cortisol (CORT) release in humans may be mediated by a direct effect on the adrenal gland by pretreating subjects with dexamethasone (DEX), to prevent release of ACTH from the pituitary, followed by a DFEN challenge test. Eight healthy subjects (four males; four female) (mean age = 38.1 +/- 8.4 years (SD)] were studied > 1 week apart (same phase of menstrual cycle) and testing order was randomised. On the with-DEX day (DEX+), subjects took 2 mg DEX orally at 10 p.m.; 30 mg DFEN was then given orally at 9 a.m. and samples were taken at 0-5 h for PRL and CORT. Peak hormone responses (delta values) were calculated by subtracting baseline values from the maximum levels post-DFEN administration. Peak and baseline hormonal values were compared between the two test conditions; DFEN-induced CORT and PRL responses were compared across all time points, with and without DEX. There was no significant difference in delta PRL between the two test conditions (DEX- and DEX+), but delta CORT values were significantly reduced after DEX: mean delta CORT DEX- = 68.4 +/- 26.3 nmol/l; DEX+ = 0.0 nmol/l (all blunted) (df 7,1; P = 0.03). The completely blunted peripheral cortisol response indicates that DFEN cortisol responses are of central origin only.

Adrenocorticotropic Hormone↗
PubMed1999

Tryptophan enhancement/depletion and reactions to failure on a cooperative computer game.

Twenty-eight high trait hostility male volunteers played a "cooperative" computer game 4.5 hours after an amino acid drink enhanced with, or depleted of, tryptophan. Each trial involved steering a tank through minefields following directions from an unknown "partner." Failure was experienced when the tank hit a mine or when time ran out. Subjects' moods, verbal aggression, attributions of blame, vocal acoustics, and blood pressure were assessed. Differences between tryptophan groups were not significant for primary measures of anger and verbal aggression. However, depleted subjects reported greater increases in feelings of restlessness and incompetence, were less successful in avoiding mines and showed greater increases in blood pressure during the game. Subjects in both groups sent more negative ratings when they lost the game by virtue of hitting a mine rather than losing by running out of time. However, ratings of the depleted group were less influenced by the reason for losing the game. Also, vocal acoustics showed a group X reason-for-losing interaction in the high-frequency band. Tryptophan-depleted subjects with high scores on Behavioral-Activation-System-Drive were most likely to send negative ratings and those scoring high on Buss-Durkee Hostility Inventory Assault and Guilt to report increased anger after the game.

Adult↗
PubMed1999

The 1microg short Synacthen test in chronic fatigue syndrome.

OBJECTIVE: Many studies suggest mild hypocortisolism in chronic fatigue syndrome (CFS), usually assumed to be due to reduced suprahypothalamic drive to the hypothalamo-pituitary-adrenal (HPA) axis. We wished to explore further the state of the HPA axis in CFS using the 1 microg low dose short Synacthen test. DESIGN: Subjects received an intravenous bolus of 1 microg Synacthen; samples for cortisol estimation were taken at baseline and 2, 10, 20, 30, 40 and 60 minutes after injection. PATIENTS: We tested 20 subjects suffering from CFS according to the criteria of the Center for Diseases Control without psychiatric comorbidity and 20 matched healthy controls. All subjects were drug free for at least 1 month. MEASUREMENTS: We calculated the cortisol responses to the test as the maximum cortisol attained, the incremental rise in cortisol over baseline (Deltavalue) and as the integrated area under the curve. RESULTS: There were no significant differences in baseline cortisol or cortisol responses between patients and controls. However, responses generally were low, and many subjects' peak responses were prior to the standard 30 minute sampling time., CONCLUSIONS These results do not lend support to the theory that patients with chronic fatigue syndrome have a low adrenal reserve. However, results from studies assessing the HPA axis are proving to be inconsistent. We suggest that many other factors may be contributing to HPA axis alterations in chronic fatigue syndrome, including sleep disturbance, inactivity, altered circadian rhythmicity, illness chronicity, concomitant medication and comorbid psychiatric disturbance. These sources of heterogeneity need to be considered in future studies, and may explain the inconsistent findings to date.

Adult↗
PubMed1999

Trait hostility and prolactin response to tryptophan enhancement/depletion.

This study investigated the relationship between trait hostility and aspects of serotonergic function by assessing the prolactin (PRL) response to acute tryptophan depletion and enhancement in 28 healthy male volunteers. Serum PRL was assessed immediately before, and 4.5 h after, administration of an amino acid drink enhanced with, or depleted of, the 5-HT precursor tryptophan. Trait hostility and DeltaPRL (value at 4.5 h minus baseline) correlated negatively following enhancement and positively following depletion, indicating that the higher the hostility the smaller the change in PRL in either direction. This is consistent with previous research reporting an association between aggression and blunted neuroendocrine responses to serotonergic agents. The results indicate the possibility that, in people high on hostility, part of the serotonergic pathway that leads to modulation of PRL release is characterised by a stage with either low capacity relative to input availability or a strong negative feedback component.

Adolescent↗
PubMed1999

Plasma tryptophan and trait aggression.

Many studies have reported correlations between measures of aggression and indices of serotonergic function, but most have studied patient or offender populations and relatively few have investigated plasma concentrations of the serotonin precursor tryptophan. This study investigates the relationship between plasma concentrations of tryptophan and trait hostility, depression and anxiety in male healthy volunteers. Sixty-seven healthy male volunteers gave blood samples and completed trait questionnaires. Plasma tryptophan was positively correlated with the Buss-Durkee Hostility Inventory Total score and Motor Aggression subscale, but not with the Attitudinal Hostility subscale or with trait anxiety or depression. In conclusion, there is evidence for an association between high concentrations of plasma tryptophan and aggressive behaviour in men, presumably mediated by some aspect of central serotonergic function, which seems unlikely to be explained by high trait anxiety or depression.

Adult↗
PubMed1998

Assessment of serotonergic function in major depression using d-fenfluramine: relation to clinical variables and antidepressant response.

BACKGROUND: d-Fenfluramine, a specific serotonin (5-HT)-releasing agent without the catecholamine effects of d,l-fenfluramine, was used as a serotonergic neuroendocrine challenge in subjects with unipolar major depression. METHODS: Patients were given 30 mg of d-fenfluramine orally, and prolactin and cortisol responses were measured over the following 5 hours. Endocrine responses were examined in relation to clinical variables and subsequent response to antidepressant treatment. RESULTS: 5-HT-mediated cortisol responses at baseline were inversely correlated with depression severity on the Montgomery Asberg Depression Rating Scale, Bech Melancholia Scale, and Clinical Global Impression scale. Prolactin responses were inversely correlated with anxiety on the Brief Symptom Inventory. A higher initial cortisol response to d-fenfluramine predicted a subsequent good antidepressant response. CONCLUSIONS: We conclude that: a) the severity and symptom profile in major depression may be closely related to 5-HT dysfunction; and b) higher cortisol responses to d-fenfluramine predict a preferential response to treatment.

Adult↗
PubMed1998

Abnormal 5-HT1D receptor function in major depression: a neuropharmacological challenge study using sumatriptan.

BACKGROUND: Sumatriptan, a specific agonist at 5-HT1D receptors, stimulates release of growth hormone (GH) and inhibits release of prolactin (PRL). METHODS: We gave sumatriptan (6 mg subcutaneously) to 11 patients with unipolar major depression and 11 control subjects matched for age, sex, weight and menstrual cycle phase. Serum GH and PRL were measured at 0, 15, 30, 45, 60 and 90 min after injection. RESULTS: The maximal rise in GH was significantly reduced in the depressed patients, with 60% showing no increase over baseline compared with 18% of controls. There were no significant differences in PRL responses. CONCLUSIONS: These results suggest reduced sensitivity of 5-HT1D receptors in major depression. Our results and those of studies investigating 5-HT1A receptors imply that both 5-HT1A and 5-HT1D autoreceptors may show reduced function in major depression.

Adult↗
PubMed1998

Neuroendocrine and hypothermic effects of 5-HT1A receptor stimulation with ipsapirone in healthy men: a placebo-controlled study.

The neuroendocrine effects of 5-hydroxytryptamine-1A (5-HT1A) receptor stimulation remain uncertain in humans, in respect to both anterior and posterior pituitary hormone release. This is important because these endocrine responses are often used as indications of 5-HT1A receptor sensitivity. The link between receptor stimulation and subsequent hormone release is more direct with posterior pituitary hormones because there is no intermediate hypothalamic peptide in the pathway. Theoretically, therefore, posterior pituitary hormones should be more valid indicators of central 5-HT1A receptor sensitivity. We used the 5-HT1A receptor partial agonist ipsapirone (20 mg) as an oral serotonergic challenge drug in a random-order, double-blind placebo-controlled study of 12 healthy men. Blood sampling occurred at 30 min intervals up to 180 min after the administration of drug or placebo. Ipsapirone caused clear and significant elevations in adrenocorticotrophin (ACTH), cortisol (CORT), prolactin (PRL), and growth hormone (GH) release. Peak hormone and ipsapirone blood levels both occurred at 60 min after ipsapirone administration. Release of the posterior pituitary hormone oxytocin was also stimulated, but less robustly and with more baseline variation. Temperature fell significantly more after ipsapirone than placebo. These results contrast with previous studies, which found no effect of ipsapirone on PRL and GH release in humans, but are in accordance with data using other 5-HT1A agonist drugs. The presence of an oxytocin response to ipsapirone suggests that oxytocin is a potential marker for serotonergic function in neuroendocrine challenge studies, but this awaits further study.

Administration, Oral↗
PubMed1997

Does central serotonergic function correlate inversely with aggression? A study using D-fenfluramine in healthy subjects.

Much research has investigated possible links between serotonergic function and aggression in violent or personality disordered populations, but few studies have looked at healthy subjects. In this study we administered 30 mg of the specific 5-HT releasing agent D-fenfluramine to 35 healthy subjects, along with questionnaire measures of hostility and aggression. Prolactin and cortisol responses were used as indices of central 5-HT function. In males, there were significant inverse correlations between 5-HT mediated cortisol responses and both the Buss-Durkee Hostility Inventory total score and the aggression factor. There were no such relations in female subjects or using prolactin responses. There was also an inverse relation between basal cortisol levels and both prolactin and cortisol responses, but no relation between basal cortisol levels and aggressive measures. These results provide some support for the existence of an inverse relationship between central serotonin function and aggression/hostility in healthy males, similar to that seen in previous studies using violent or highly aggressive populations.

Adult↗
PubMed1997

Reduced whole blood serotonin in major depression.

Whole blood serotonin (WBS) was measured in 17 patients with DSM-III-R major depression and compared to a healthy control group of 57. Values were significantly lower in the depressed group, but there was no correlation with the degree of depression. Four patients with a history of suicide attempts had even lower levels, but this was not statistically significant. Across all subjects, there was an effect of season of sampling, with values in spring significantly higher than those in autumn. Since blood serotonin is primarily produced peripherally, these results suggest that some aspect of peripheral serotonin metabolism is abnormal in major depression.

Adult↗
PubMed1997

Do noradrenergic reuptake inhibitors affect serotonergic function in depression?

d-Fenfluramine, a specific 5-HT releasing agent without the catecholamine effects of d,l-fenfluramine, was used as a serotonergic neuroendocrine challenge in subjects with unipolar major depression. Prolactin and cortisol responses to 30 mg d-fenfluramine were measured in patients at baseline. Patients were then randomly assigned to treatment for 6 weeks with a specific noradrenergic reuptake inhibitor, a tricyclic antidepressant, or placebo. Response to antidepressant treatment was assessed, and patients underwent further testing with d-fenfluramine. Prolactin responses were increased by treatment, but this was independent of whether or not patients' depression responded to treatment. Seven patients were treated with a specific noradrenergic reuptake inhibitor. These patients showed a significant rise in 5-HT-mediated cortisol responses after treatment, independent of whether their depression improved. We conclude that antidepressants which selectively modify noradrenergic function also have effects on 5-HT function as measured by neuroendocrine testing.

Adrenergic Uptake Inhibitors↗
PubMed1997

Serotonergic function and negative and depressive symptomatology in schizophrenia and major depression.

BACKGROUND: Serotonergic abnormalities are found in both major depressive disorder (MDD) and schizophrenia. Depressive symptoms commonly occur alongside the negative or defect symptoms in schizophrenia and antiserotonergic drugs may be particularly effective in their treatment. We wished to explore whether these symptoms could be distinguished biologically by directly comparing serotonergic function in these two illnesses. METHOD: Fifteen patients with MDD and 13 patients with schizophrenia underwent testing with the specific serotonin releasing agent D-fenfluramine (D-FEN). Prolactin and cortisol responses were measured to ascertain central serotonergic function. Individual patient results were compared with their own carefully matched control to correct for the effect of age, sex, weight and menstrual cycle, before the two patient groups were then compared. RESULTS: Prolactin responses differed significantly between the two patient groups, being lower in MDD patients and higher in schizophrenia patients than their individually matched controls. Cortisol responses did not differ. Within the schizophrenia group, increased serotonergic function correlated positively with depressive symptoms, but there was no such correlation with defect symptoms. Depressive scores were negatively correlated with the presence of negative symptoms in the schizophrenic group. CONCLUSIONS: Schizophrenia and MDD have distinct and opposite neuroendocrine responses to D-FEN. There is no evidence that depressive symptoms in these two conditions have a common serotonergic basis. Moreover, these responses distinguished between negative and depressive symptoms in our schizophrenic group.

Adult↗