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Biomedical subjects

P J Cowen

Publications and source records attributed to P J Cowen.

At least 19 recordsLinked to original sources
PubMed1999

Symptomatic relapse in bulimia nervosa following acute tryptophan depletion.

BACKGROUND: Preclinical and clinical studies suggest that lowered brain serotonin neurotransmission may contribute to the pathophysiology of bulimia nervosa (BN). The aim of our study was to test this hypothesis by examining the psychological effects of a dietary-induced impairment in serotonin activity in subjects known to be at risk for manifestation of the clinical syndrome of BN. METHODS: An 85.8 g amino acid mixture lacking the serotonin precursor tryptophan and a balanced mixture were administered to 10 clinically recovered, medication-free female subjects with a history of BN in a double-blind, crossover design. Twelve healthy female subjects with no history of psychiatric disorder were studied as a comparison group. Observer and self-rated measures of mood and eating disorder cognitions were made for the 7 hours following administration of each amino acid mixture. RESULTS: Compared with healthy controls, subjects with a history of BN had significant lowering of mood, increases in ratings of body image concern, and subjective loss of control of eating following the tryptophan-free mixture. CONCLUSIONS: Our results suggest that diminished serotonin activity may trigger some of the cognitive and mood disturbances associated with BN. Our findings support suggestions that chronic depletion of plasma tryptophan may be one of the mechanisms whereby persistent dieting can lead to the development of eating disorders in vulnerable individuals.

Acute Disease↗
PubMed1999

Effect of a tyrosine-free amino acid mixture on regional brain catecholamine synthesis and release.

We report the effects of a tyrosine (and phenylalanine)-free amino acid mixture on tyrosine levels, ex vivo catecholamine synthesis and in vivo catecholamine release in brain regions of the rat. Administration of a tyrosine-free amino acid load reduced tissue levels of tyrosine (-50% after 2 h) in all brain regions examined (frontal cortex, hippocampus, striatum). The tyrosine-free amino acid mixture also reduced DOPA accumulation: this effect was most marked in striatum (-44%) and nucleus accumbens (-34%), areas with a predominantly dopaminergic innervation. Smaller decreases (-20-24%) were detected in other areas (cortex, hippocampus and hypothalamus). The effect on DOPA accumulation was prevented by supplementing the mixture with tyrosine/phenylalanine. The tyrosine-free amino acid mixture did not alter 5-HTP accumulation in any region. In microdialysis experiments, the tyrosine-free amino acid mixture did not consistently alter striatal extracellular dopamine under basal conditions but markedly, and dose-dependently, reduced the release of dopamine induced by amphetamine. In contrast, the tyrosine-free amino acid mixture did not alter either basal or amphetamine-evoked release of noradrenaline in hippocampus. Overall, these studies indicate that administration of a tyrosine-free amino acid mixture to rats depletes brain tyrosine to cause a decrease in regional brain catecholamine synthesis and release. Dopaminergic neurones appear to be more vulnerable to tyrosine depletion than noradrenergic neurones.

Amino Acids↗
PubMed1998

Basal activity of the hypothalamic-pituitary-adrenal axis in patients with the chronic fatigue syndrome (neurasthenia).

BACKGROUND: Impairments in both basal activity and activation of the hypothalamic-pituitary-adrenal axis (HPA) have been reported in chronic fatigue syndrome (CFS; neurasthenia). We sought to replicate these findings and examined basal activity of the HPA in a carefully selected sample of patients with CFS. METHODS: Basal activity of the HPA was assessed using salivary and urinary cortisol collection over a 24-hour period in 22 (12 male; 10 female) patients meeting criteria for CFS and appropriate controls. RESULTS: Salivary and urinary cortisol measures did not differ between CFS patients and controls. CONCLUSIONS: Basal activity of the HPA was not reduced in CFS patients. Reasons for the failure to replicate previous findings are discussed.

Adult↗
PubMed1998

Lack of effect of hydrocortisone treatment on d-fenfluramine-mediated prolactin release.

The prolactin responses to the serotonin (5-HT) releasing agent d-fenfluramine (30 mg orally) were studied in 11 male normal volunteers after administration of hydrocortisone (20 mg orally, twice daily for 10 days) using a double-blind, placebo-controlled, cross-over design. While hydrocortisone treatment significantly elevated 24-h urinary cortisol excretion, it did not lower the prolactin response to d-fenfluramine. Plasma levels of d-fenfluramine and d-norfenfluramine were not altered by hydrocortisone treatment. These findings show that following 10 days administration of hydrocortisone, the prolactin responses to d-fenfluramine are not changed.

Adult↗
PubMed1998

Antidepressant-like effect of Hypericum perforatum (St John's wort) on the sleep polysomnogram.

We studied the effect of two doses (0.9 mg and 1.8 mg) of Hypericum perforatum (St John's wort) on the sleep polysomnogram of healthy subjects using a placebo-controlled, cross-over design. Both doses of hypericum significantly increased the latency to rapid eye movement (REM) sleep without producing any other effect on sleep architecture. Our data are consistent with the proposed clinical antidepressant efficacy of hypericum, and raise the possibility that its pharmacological mechanism of action may be similar to that of conventional antidepressant medication.

Adult↗
PubMed1998

Clomipramine enhances the cortisol response to 5-HTP: implications for the therapeutic role of 5-HT2 receptors.

We measured the cortisol response to the 5-HT precursor, 5-hydroxytryptophan, (5-HTP) in seven patients with major depression before and after 8 weeks treatment with the tricyclic antidepressant, clomipramine. The cortisol response to 5-HTP was significantly increased following clomipramine treatment, suggesting that clomipramine, like selective serotonin re-uptake inhibitors (SSRIs), enhances this 5-HT2 receptor mediated response. Because other tricyclic antidepressants do not increase 5-HTP-mediated cortisol release, it seems unlikely that enhancement of 5-HT2 receptor function is a critical mechanism for antidepressant action. However, facilitation of neurotransmission at 5-HT2 receptors could account for the efficacy of clomipramine and SSRIs in the treatment of obsessive compulsive disorder and also for their liability to cause orgasmic dysfunction.

5-Hydroxytryptophan↗
PubMed1998

Electrophysiological and neurochemical evidence that pindolol has agonist properties at the 5-HT1A autoreceptor in vivo.

1. It has been hypothesized that 5-HT1A autoreceptor antagonists may enhance the therapeutic efficacy of SSRIs and other antidepressants. Although early clinical trials with the beta-adrenoceptor/5-HT1 ligand, pindolol, were promising, the results of recent more extensive trials have been contradictory. Here we investigated the actions of pindolol at the 5-HT1A autoreceptor by measuring its effect on 5-HT neuronal activity and release in the anaesthetized rat. 2. Pindolol inhibited the electrical activity of 5-HT neurones in the dorsal raphe nucleus (DRN). This effect was observed in the majority of neurones tested (10/16), was dose-related (0.2-1.0 mg kg(-1), i.v.), and was reversed by the 5-HT1A receptor antagonist, WAY 100635 (0.1 mg kg(-1), i.v.), in 6/7 cases tested. 3. Pindolol also inhibited 5-HT neuronal activity when applied microiontophoretically into the DRN in 9/10 neurones tested. This effect of pindolol was current-dependent and blocked by co-application of WAY 100635 (3/3 neurones tested). 4. In microdialysis experiments. pindolol caused a dose-related (0.8 and 4 mg kg(-1), i.v.) fall in 5-HT levels in dialysates from the frontal cortex (under conditions where the perfusion medium contained 1 microM citalopram). In rats pretreated with WAY 100635 (0.1 mg kg(-1), i.v.), pindolol (4 mg kg(-1), i.v.) did not decrease, but rather increased 5-HT levels. 5. We conclude that, under the experimental conditions used in this study, pindolol displays agonist effects at the 5-HT1A autoreceptor. These data are relevant to previous and ongoing clinical trials of pindolol in depression which are based on the rationale that the drug is an effective 5-HT1A autoreceptor antagonist.

Action Potentials↗
PubMed1998

Effect of venlafaxine on pineal melatonin and noradrenaline in the male rat.

Studies in vitro indicate that the antidepressant drug, venlafaxine (VEN), inhibits the reuptake of both serotonin (5-hydroxytryptamine, 5-HT) and noradrenaline (NA) but has little activity on other neurotransmitter receptors. There are, however, few studies on the effects of VEN on monoamine neurotransmission in vivo. In the present study we examined the effect of VEN treatment on the melatonin content of the rat pineal gland because the synthesis of melatonin is regulated by the release of NA onto pinealocyte beta-adrenoceptors. Acute treatment with higher doses (15 mg/kg) of VEN significantly increased pineal melatonin and NA but this effect was attenuated by subchronic treatment. These data are consistent with in vitro data suggesting that VEN increases NA neurotransmission at higher doses and that repeated treatment can desensitize pinealocyte beta-adrenoceptors.

Animals↗
PubMed1998

Brain 5-HT neurotransmission during paroxetine treatment.

BACKGROUND: Animal experimental studies suggest that repeated administration of selective serotonin reuptake inhibitors (SSRIs) produces complex adaptive changes in brain serotonin (5-HT) pathways. The effect of these adaptive changes on different aspects of brain 5-HT neurotransmission and their clinical consequences are not well understood. METHOD: We studied the effect of repeated administration of the SSRI, paroxetine (20 mg daily), on the cortisol responses to the 5-HT precursor, 5-hydroxytryptophan (5-HTP), in healthy subjects and depressed patients. RESULTS: In healthy subjects, following one week of paroxetine treatment there was a large increase in the cortisol response to 5-HTP. This increase had all but disappeared following 3 weeks treatment. In contrast, in depressed patients treated with paroxetine for 8 weeks, the cortisol response to 5-HTP was significantly increased. CONCLUSIONS: SSRI treatment in depressed patients produces a persistent increase in the cortisol response to 5-HTP, a probable measure of neurotransmission at central 5-HT2 receptors. Potentiation of 5-HT2 neurotransmission is unlikely to account for the efficacy of SSRIs in major depression but might underlie their actions in obsessive-compulsive disorder and also perhaps certain of their adverse effects, notably sexual dysfunction.

Adult↗
PubMed1998

Reduced latent inhibition in people with schizophrenia: an effect of psychosis or of its treatment.

BACKGROUND: People with schizophrenia show impaired attention. This could result from reduced latent inhibition (a measure of ability to filter out irrelevant stimuli). Previous studies have found reduced auditory latent inhibition in people with acute schizophrenia: we tested whether this results from psychosis or from drug treatment. METHOD: We measured auditory latent inhibition in two studies. One compared antipsychotic-naive people with acute schizophrenia with patients within two weeks of starting antipsychotic treatment. The second compared healthy volunteers given either saline or 1.0 mg haloperidol, intravenously. RESULTS: Latent inhibition was absent in treated patients, but was clearly present in patients who were naive to antipsychotics. Latent inhibition was absent in volunteers given haloperidol, but was clearly present in those given saline. CONCLUSIONS: The reduced auditory latent inhibition seen in acute schizophrenia is more plausibly due to antipsychotic treatment than to the disorder. Unless neuropsychological models of schizophrenia incorporate evidence from drug-free patients and drug-treated healthy controls, they may be invalid.

Adult↗
PubMed1997

Relapse of depression after rapid depletion of tryptophan.

BACKGROUND: Major depression is a common disorder but the pathophysiology is poorly understood. Current hypotheses implicate deficient function of brain serotonin pathways because drugs that selectively increase brain serotonin activity are effective antidepressants. However, there is no direct evidence that lowered serotonin function causes major depression. We aimed to assess whether lowering of brain serotonin activity by depletion of its amino acid precursor, tryptophan, could provoke a short-term relapse of clinically significant symptoms in women vulnerable to major depressive disorder. METHODS: We studied 15 women who had suffered recurrent episodes of major depression but had recovered and were no longer on drug treatment. Patients received two amino acid mixtures in a double-blind crossover design. One of the mixtures was nutritionally balanced and contained tryptophan and the other was identical except it contained no tryptophan. Participants were scored on the Hamilton rating scale for depression (HAMD) before and 7 h after drinking each mixture. They also completed hourly self-rated measures of mood during this period. Blood samples were also taken at baseline and 7 h for measurement of plasma tryptophan. FINDINGS: The tryptophan-free mixture produced a 75% reduction in plasma tryptophan concentration. After drinking the tryptophan-free mixture, ten of the 15 women experienced temporary but clinically significant depressive symptoms. The mean difference in total HAMD scores (7 h minus baseline) were significantly higher after the tryptophan-free mixture than after the nutritionally balanced mixture (7.3 vs 0.15 [95% CI 4.5-9.9]; p < 0.001). No changes in mood were seen after taking the nutritionally balanced mixture. INTERPRETATION: We conclude that rapid lowering of brain serotonin function can precipitate clinical depressive symptoms in well, untreated individuals who are vulnerable to major depressive disorder. The findings support a key role for deficient serotonin function in the aetiology of depression.

Adult↗
PubMed1997

Sumatriptan decreases food intake and increases plasma growth hormone in healthy women.

We studied the effect of the 5-HT1B/ID receptor agonist sumatriptan (6 mg s.c.) on plasma growth hormone and prolactin and food intake in 15 healthy female subjects using a double-blind, placebo-controlled, cross-over design. Sumatriptan significantly elevated plasma growth hormone but did not alter plasma prolactin. Sumatriptan also significantly lowered total food intake in a buffet meal, particularly decreasing the intake of fat. Our results indicate that 5-HT1B/ID receptors may be involved in the regulation of food intake in humans. In addition, while activation of 5-HT1B/ID receptors stimulates growth hormone release in both men and women, sumatriptan lowers plasma prolactin only in men, suggesting sex differences in the 5-HT regulation of prolactin release.

Adult↗
PubMed1997

Effect of paroxetine and nefazodone on 5-HT1A receptor sensitivity.

Animal experimental studies suggest that the therapeutic effect of selective serotonin re-uptake inhibitors (SSRIs) may involve neuroadaptive changes in pre- and post-synaptic serotonin1A (5-HT1A) receptors. We used the endocrine and hypothermic responses to the 5-HT1A receptor agonist, gepirone (20 mg orally), to assess 5-HT1A receptor sensitivity in 37 healthy male volunteers who were studied before and following random double-blind, allocation to treatment with paroxetine, nefazodone or placebo for 17 days. Following antidepressant drug treatment, hypothermic responses to gepirone were markedly decreased by paroxetine but only slightly diminished by nefazodone. Paroxetine also lowered the growth hormone and cortisol responses to gepirone. There was no change in either hypothermic or endocrine response following placebo treatment. Our results suggest that paroxetine treatment produces a striking attenuation of measures of both pre- and post-synaptic 5-HT1A receptor function. Nefazodone appears to decrease the sensitivity of 5-HT1A autoreceptors to some extent and this effect may contribute to its antidepressant activity.

Adult↗
PubMed1997

Haloperidol enhances latent inhibition in visual tasks in healthy people.

We have previously shown that 0.5 mg haloperidol (i.v.) increased latent inhibition in one of two visual tasks. The present study analysed the effects of a higher dose of haloperidol (1.0 mg, i.v.) on latent inhibition in these two visual tasks in healthy volunteers in a randomised controlled trial. In the task where 0.5 mg haloperidol had enhanced latent inhibition, 1.0 mg had the same effect, thus replicating the previous result. In the task where 0.5 mg haloperidol had been ineffective, 1.0 mg haloperidol enhanced latent inhibition in high schizotypal subjects only. This indicates that subjects with higher schizotypy scores are more sensitive to dopamine blockade. A comparison of the results from the studies at the two different doses suggests a dose dependence of haloperidol's effects on latent inhibition that parallels results from animal work.

Adult↗