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Biomedical subjects

Trevor R Norman

Publications and source records attributed to Trevor R Norman.

At least 19 recordsLinked to original sources
PubMed2006

The heritability of melatonin secretion and sensitivity to bright nocturnal light in twins.

The super-sensitivity of the neurohormone melatonin to light in patients with bipolar disorder provides evidence of the circadian nature of the disorder. This response has been proposed as an endophenotype for identifying people at risk of the disorder and guiding investigations of molecular genetic targets. However, before this response is used as an endophenotypic marker, the heritable nature of melatonin sensitivity in the normal population must be established. The aim of this study was to investigate the heritability of nocturnal melatonin secretion and sensitivity to light in monozygotic and dizygotic twins with no psychiatric history. This study investigated overall melatonin levels (between 2000 and 2400 h) and suppression by 500 lx of light (between 2400 and 0100 h) in 20 pairs of twins (nine monozygotic, 11 dizygotic). The results indicate that melatonin secretion is highly heritable with secretion in one twin being a significant predictor of secretion in their twin in both monozygotic and dizygotic pairs. In relation to light sensitivity, genetic loading appears to play a significant role with the greatest concordance between monozygotic twins, followed by dizygotic twins and finally low concordance in unrelated individuals. This provides additional support for the usefulness of melatonin sensitivity to light as a potential endophenotypic marker of bipolar affective disorder.

Adolescent↗
PubMed2006

Prospects for the treatment of depression.

Antidepressant drugs represent the principal form of treatment for major depressive disorder. While there are a plethora of medications available for this task, current drugs have many shortcomings. In the face of these deficiencies there is an ongoing search for new agents. The search has been guided, in part, by drug design based on existing agents and their putative mechanism of action. This has been less than fruitful in addressing inadequacies of existing medications as it has not produced compounds which are novel in terms of pharmacological mechanisms. Recent insights from molecular biological approaches hold promise for the discovery of novel compounds, in particular the so-called neurogenesis hypothesis suggests novel therapeutic approaches. Although significantly modified over the years, the monoamine hypothesis of depression and antidepressant drug action still remains an important driving force behind the development of new compounds. Several recently marketed agents and some in early-phase development tend to conform to these existing mechanistic hypotheses. Clearly the place of these agents in the treatment of depression is dependent on issues such as short- and long-term safety and efficacy. Duloxetine has been developed as a dual monoamine re-uptake inhibitor. Agomelatine is a compound with major effects on the circadian system as well as effects on subtypes of the serotonin receptor system. While the mechanism of action of this compound is not certain, recent evidence would suggest that the drug exerts its effects through antagonist actions at serotonin receptors. Compounds based on the hypothalamic pituitary adrenal axis, substance P antagonism and other neuropeptides have potential application for the treatment of depression but require further development before that potential is realized.

Acetamides↗
PubMed2006

A comparative study of sertraline dosages, plasma concentrations, efficacy and adverse reactions in Chinese versus Caucasian patients.

This prospective 6-week study examined the differences in dosage and steady state plasma concentrations of sertraline in Chinese versus Caucasian depressed patients. Two groups of Chinese patients from different geographical sites and a group of Caucasian patients were evaluated with clinical measures during an initial dose of 50 mg/day, with subsequent doses adjusted clinically. The results of 17 Australian Chinese (ACHI), 13 Malaysian Chinese (MCHI) and 15 Australian Caucasians (AC) were analysed. Despite controlling for weight, the AC subjects received a significantly higher dose than both the ACHI (P = 0.002) and the MCHI groups (P = 0.012). However, the mean sertraline concentration to dose ratios at weeks 1 and 6 were not significantly different between the three groups. Sertraline was effective and well tolerated in both ethnic groups with few adverse events. Although there was a lack of difference between groups in the pharmacokinetic results, Chinese depressed patients appeared to require lower dosages with consequently lower plasma concentrations of sertraline compared to Caucasian patients to achieve clinical efficacy. Further studies of the dosages, kinetics and adverse effects of selective serotonin reuptake inhibitors linked with genotyping are necessary.

Adult↗
PubMed2006

A double-blind placebo-controlled randomised pilot study of nocturnal melatonin in tracheostomised patients.

BACKGROUND AND AIM: Patients in the intensive care unit often suffer from lack of sleep at night. We hypothesised that nocturnal melatonin may increase observed nocturnal sleep in tracheostomised patients. DESIGN: Double-blind, randomised, placebo-controlled pilot study. SETTING: ICU of a tertiary hospital. PARTICIPANTS: Thirty-two ICU patients with tracheostomy who were not receiving continuous sedation. METHODS: We administered either oral melatonin (3mg) or placebo at 20:00. We collected pre- and post-dosage blood samples on Days 1 and 3 to confirm drug delivery. Primary outcome measure was number of hours of observed sleep at night, assessed by the bedside nurse. Secondary outcome measures included comparison of the incidence of agitation, assessed by score on the Riker Sedation-Agitation Scale, and requirement for sedatives or haloperidol to settle agitation. RESULTS: Pre-treatment melatonin levels in the two groups were similarly low: 4.8 pg/mL (95% CI, 2.4-7.5) for melatonin versus 2.4 (95% CI, 1.6-3.2) for placebo (P=0.13). Post-treatment, melatonin levels increased significantly in the melatonin group compared with the placebo group (3543 pg/mL versus 3 pg/mL; P<0.0001). However, subsequent observed nocturnal sleep was similar in the two groups: 240 minutes (range, 75-331.3) for melatonin v 243.4 minutes (range, 0-344.1) for placebo (P=0.98). Observed diurnal sleep was also similar: 138.7 minutes (range, 50-230) with melatonin v 104 minutes (range, 0-485) for placebo (P=0.42). The incidence of agitation was non-significantly higher in the melatonin group (31% v 7%; P=0.11), while the requirement for extra sedation or use of haloperidol was slightly higher in the placebo group (57% versus 46%; P=0.56). CONCLUSION: Melatonin is well absorbed, and a standard dose increases blood levels approximately 1000-fold. However, in this pilot assessment, these high levels failed to increase observed nocturnal sleep or induce other observable benefits in tracheostomised ICU patients.

Aged↗
PubMed2005

Brain serotonin depletion by lesions of the median raphe nucleus enhances the psychotomimetic action of phencyclidine, but not dizocilpine (MK-801), in rats.

We have previously shown that brain serotonin depletion by lesions of the median raphe nucleus (MRN) causes enhancement of phencyclidine-induced locomotor hyperactivity [S. Kusljic, D.L. Copolov, M. van den Buuse, Differential role of serotonergic projections arising from the dorsal and median raphe nuclei in locomotor hyperactivity and prepulse inhibition, Neuropsychopharmacology 28 (2003) 2138-2147]. In this study, we extend our previous work by (1) comparing the effect of phencyclidine with that of another NMDA receptor antagonist, dizocilpine (MK-801); (2) investigate behavioral changes in more detail; (3) assess in detail the effect of raphe lesions on regional serotonin levels in the brain. Male Sprague-Dawley rats received microinjection of the serotonergic neurotoxin 5,7-dihydroxytryptamine into the MRN or dorsal raphe nucleus (DRN). The effects of treatment with saline, phencyclidine and MK-801 on locomotor activity were determined 2 weeks after the surgery. MRN lesions caused serotonin depletion in the dorsal hippocampus, whereas DRN lesions caused serotonin depletion in the frontal cortex, striatum and ventral hippocampus. There was a significant increase in phencyclidine-induced locomotor hyperactivity in the MRN-lesioned group compared to sham-operated controls. Further analysis of behavior showed that phencyclidine-induced hyperambulation, but not stereotypy or rearing, was significantly higher in MRN-lesioned rats compared to controls. In contrast, there was no significant effect of the lesions on the psychotomimetic effect of MK-801. These results indicate that a hyposerotonergic state induced by destruction of projections from the MRN leads to altered brain circuitry that is responsible for the regulation of phencyclidine-but not MK-801-induced locomotor hyperactivity. Thus, MRN projections may play an inhibitory role in mechanisms involved in symptoms of schizophrenia.

5,7-Dihydroxytryptamine↗
PubMed2005

Attenuation of benzodiazepine withdrawal anxiety in the rat by serotonin antagonists.

Administration of benzodiazepines is known to be associated with tolerance and a withdrawal syndrome on abrupt cessation. The aetiology of the withdrawal syndrome is not known but a role for the serotonin (5HT) system is suspected. The aim of the current study was to investigate the usefulness of 5-HT2 antagonists in the treatment of benzodiazepine withdrawal syndrome in the rat. Male Wistar rats were treated with either diazepam (4 mg/kg) or vehicle for 14 days, then abruptly withdrawn for 24h. Animals were tested in the social interaction paradigm and elevated plus maze. Some diazepam-withdrawn rats were pre-treated with 5HT2 antagonists 60 min before behavioural testing. Acute withdrawal from benzodiazepines significantly reduced social interaction between pairs compared to vehicle or diazepam-treated animals. Similarly, for the elevated plus maze withdrawn animals made fewer entries and spent less time on the open arms than did vehicle or diazepam-treated animals. Single doses of 5-HT2 antagonists, mianserin (5mg/kg) and ritanserin (1mg/kg), effectively ameliorated withdrawal anxiety in the rat, returning behavioural function in the social interaction test and elevated plus maze to levels comparable to vehicle-treated animals.

Animals↗
PubMed2005

Low doses of lithium carbonate reduce melatonin light sensitivity in healthy volunteers.

Sensitivity of the pineal hormone melatonin to bright light at night has been posited as a putative marker of affective disorders. Research demonstrates melatonin supersensitivity to light in bipolar disorder, however the role that lithium carbonate plays in this response is unclear. This study assessed the effect of lithium on nocturnal melatonin secretion and sensitivity to light in healthy adults. Ten participants, tested on two nights, had blood samples drawn between 20:00 and 02:30 hours. On testing nights participants were exposed to 200 lux of light between 24:00 and 01:00 hours. Participants took 250 mg of lithium daily for 5 d between testing nights. The results indicated that lithium had a significant effect on sensitivity to light but not on overall melatonin synthesis. This finding has implications on the true magnitude of the melatonin light response in people with bipolar disorder and may elucidate possible mechanisms of action of lithium.

Adult↗
PubMed2005

Effect of sodium valproate on nocturnal melatonin sensitivity to light in healthy volunteers.

Sensitivity of the pineal hormone melatonin to bright light at night has been proposed as a putative marker of bipolar affective disorder. Patients with bipolar disorder have a super-sensitive melatonin response to light. No studies have investigated whether super-sensitivity is due to agents used to treat the illness or is associated with the disorder per se. We investigated the effect of valproate on this phenomenon. Melatonin sensitivity to light was determined on two nights in 12 healthy volunteers (5M, 7F). Between testing nights participants received 200 mg of valproate b.d. for 5 days. Valproate significantly decreased the sensitivity of melatonin to light. On the other hand, valproate had no effect on overall melatonin secretion or dim light melatonin onset. The ability of valproate to decrease the sensitivity of melatonin to light may relate to its therapeutic effect in bipolar disorder--an ability to lengthen circadian period similar to that of lithium.

Adolescent↗
PubMed2004

The treatment of depression with different formulations of venlafaxine: a comparative analysis.

Venlafaxine is the first of a group of antidepressants that show dual reuptake inhibition of serotonin and noradrenaline (SNRIs). Originally marketed in an immediate release (IR) formulation a microencapsulated, extended release (XR) formulation is now available. Significant differences exist between these two formulations with respect to pharmacokinetic parameters which have an impact on clinical use. The XR has lower maximum plasma concentrations (Cmax) and achieves these at a later time (higher Tmax). The longer apparent elimination half-life of the drug after single XR doses suggests that it is suitable for once daily dosing compared with the twice daily dosing regimen required by the IR formulation. With respect to antidepressant efficacy the XR formulation is equivalent to other marketed antidepressants and to the IR formulation. Consistent with its pharmacokinetic properties the use of the XR formulation is associated with less nausea and dizziness at the initiation of therapy. While in clinical usage XR might be expected to increase compliance with medication and to reduce discontinuation syndromes there are few comparative studies for which this has been evaluated. The XR formulation of venlafaxine is no worse than the IR form with respect to tolerability and offers some benefits to patients in terms of ease of use. On the other hand there does not appear to be any increase in the efficacy of the active agent.

Antidepressive Agents, Second-Generation↗
PubMed2004

Selective effects of acute serotonin and catecholamine depletion on memory in healthy women.

There is converging evidence that brain serotonin and dopamine may selectively modulate learning and memory in humans. However, this has not been directly demonstrated. In the current study, we used the method of amino acid precursor depletion to explore the effects of low serotonin and catecholamine function on memory in healthy female volunteers. Participants completed three experimental sessions: (i) tryptophan depletion (TD to lower 5-HT); (ii) tyrosine and phenylalanine depletion (TPD to lower catecholamines); and (iii) a balanced control condition (Bal). All testing was conducted in a double-blind, placebo-controlled, crossover design. Cognitive and mood assessments were performed at baseline and 5 h after ingesting the amino acid mixture. Consistent with previous studies, TD impaired declarative memory consolidation on a structured word-learning task, while TPD, acting to lower brain dopamine availability, impaired spatial working memory. No secondary deficits were observed on measures of attention, short-term memory or subjective mood state. These findings suggest that low brain serotonin versus dopamine selectively impairs memory performance in humans. This may shed light on the role of these neurotransmitters in disorders that are characterized by significant memory impairment.

Adult↗
PubMed2004

New formulations of existing antidepressants: advantages in the management of depression.

For nearly 50 years, antidepressant drugs have been the first-line treatment for various forms of depression. Despite their widespread use, these medications have significant shortcomings, in particular problems of patient compliance due to adverse effects. The introduction of new formulations of existing antidepressant medications may provide patients with benefits in terms of convenience of use. As a consequence, improvements in compliance may lead to better antidepressant efficiency.An orally disintegrating formulation of mirtazapine (mirtazapine SolTab), a once-weekly formulation of fluoxetine, an enantiomer-specific formulation of citalopram (escitalopram), an extended-release formulation of venlafaxine (venlafaxine XR), a controlled-release formulation of paroxetine (paroxetine CR) and intravenous formulations of some of the newer antidepressants have all been evaluated in limited clinical trials. In this article, a review of the pharmacokinetics and clinical evaluations of these formulations is presented. While there do not appear to be major clinical advantages for the new formulations in terms of antidepressant efficacy, none of them is less efficacious than their older counterpart. Indeed, some of the new formulations are more acceptable to patients (fluoxetine once-weekly, paroxetine CR), others have pharmacokinetic advantages (venlafaxine XR, paroxetine CR), while others may have a faster onset of effect (mirtazapine SolTab, intravenous formulations). Further evaluation of some formulations is still required (mirtazapine SolTab, fluoxetine once-weekly), while others (venlafaxine XR, escitalopram) are finding widespread acceptance in clinical practice.

Animals↗
PubMed2004

International Congress of Biological Psychiatry. 8-13 February 2004, Sydney, Australia.

Approximately 1500 psychiatrists, psychologists and basic scientists attended the International Congress of Biological Psychiatry with a specialist interest in the biological aspects of psychiatry. There was relatively little information on new medications for the treatment of psychiatric disorders but the congress emphasized approaches to treatment based on medications and physical therapies, as well as advances in the understanding of the biological basis of psychiatric illnesses. Around 800 abstracts were presented in symposia, sponsored satellite sessions, free communications and poster sessions. The poster sessions were particularly well attended and provided many lively discussions. Of particular interest were sessions devoted to new antipsychotics for the treatment of schizophrenia, management of mood and anxiety disorder, Alzheimer's disease and bipolar disorder. This report describes information on the new antipsychotic drug aripiprazole, novel targets for the treatment of mood disorders and psychoses, GABAA receptors in the treatment of panic disorder, and poster presentations on bipolar disorder.

Animals↗
PubMed2003

Comparative cognitive and psychomotor effects of single doses of Valeriana officianalis and triazolam in healthy volunteers.

OBJECTIVES: To assess the cognitive and psychomotor effects of single oral doses of valerian in healthy volunteers in comparison with a placebo and the hypnotic agent triazolam. METHODS: In a double-blind, placebo-controlled, four-way crossover study nine healthy subjects (5 males, 4 females) received in random order valerian 500 mg, valerian 1000 mg, triazolam 0.25 mg and placebo. Doses were separated by a wash-out period of at least 1 week. Subjects were tested before each dose and at 2, 4 and 8 h after the dose of each compound using the critical flicker fusion (CFF), choice reaction time (CRT), digit symbol substitution test (DSST), symbol search test (SST), digit span test (DST) and visual analogue scales of mood. RESULTS: Repeated measures ANOVA was used to examine the changes in performance on tests over time and significant effects were further analysed using simple main effects analysis with least significant difference corrections. Statistically significant differences were only noted for the cognitive tests: SST (F(3, 8)=3.182, p<0.05) and DSST (F(3, 8)=9.688, p<0.005). In both cases the differences between groups were due to the effects of triazolam. CONCLUSION: These data confirm that at recommended therapeutic doses, triazolam has detrimental effects on cognitive processes in healthy volunteers as found in previous studies. Valerian was without effect on either cognitive or psychomotor performance in healthy volunteers at the doses used in this study. Should the hypnotic activity of valerian be confirmed in randomized double-blind trials it may be a less troublesome alternative to benzodiazepines in the treatment of insomnia.

Adult↗
PubMed2002

Effects of serotonin and catecholamine depletion on interleukin-6 activation and mood in human volunteers.

There is increasing evidence that depression and related neurotic illnesses are associated with alterations in immune function that may contribute to their pathogenesis. For example, clinical and experimental studies have shown that abnormal HPA-axis activation and monoamine neurotransmission may be related to an increased release of proinflammatory cytokines from stimulated lymphocytes in the periphery and brain. In the present investigation, the effects of tryptophan depletion (TD) on unstimulated plasma interleukin-6 (IL-6) concentrations were investigated in order to determine whether acute changes in serotonin (5-HT) neurotransmission would induce a proinflammatory response in healthy individuals. The effects of TD were compared with the analogous procedure of tyrosine depletion (TPD), which reduces catecholamine metabolism in humans. Thirteen female participants completed three experimental sessions: TD, TPD and a balanced-control condition (B). Mood-ratings and blood sampling were performed at baseline and 5 h after the administration of the mixtures. Analyses revealed that TD and TPD markedly reduced tryptophan and tyrosine/phenylalanine levels, respectively. No changes in plasma IL-6 production or ratings of lowered mood were observed, however, subjects did report feeling more fatigued after TD. These findings indicate that a transient disruption in global monoamine function does not stimulate a proinflammatory response of IL-6 in normal volunteers.

Adult↗
PubMed2002

Olanzapine excretion in human breast milk: estimation of infant exposure.

Newer antipsychotic drugs offer significant clinical advantages for the treatment of psychosis. In particular for the treatment of postpartum disorders newer agents may be suited due to their favourable side-effect profiles. Of concern is the passage of the drugs into breast milk and what potential risks this poses for an infant who is breastfed. The excretion of olanzapine into the breast milk of five lactating women with postpartum psychosis was examined in this study. Nine pairs of plasma and breast-milk samples were collected and the concentration of olanzapine determined by high-performance liquid chromatography. Single-point milk-to-plasma ratios were calculated and ranged from 0.2 to 0.84 with a mean of 0.46. The median relative infant dose was 1.6% (range 0-2.5%) of the weight-adjusted maternal dose. During the study period, there were no apparent ill effects on the infant as a consequence of exposure to these doses of olanzapine. As with other antipsychotic drugs this study demonstrates that olanzapine passes into breast milk. The long-term effects of exposure in infants exposed to olanzapine requires further investigation.

Adult↗