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Biomedical subjects

D J Nutt

Publications and source records attributed to D J Nutt.

At least 19 recordsLinked to original sources
PubMed2006

Evidence-based guidelines for management of attention-deficit/hyperactivity disorder in adolescents in transition to adult services and in adults: recommendations from the British Association for Psychopharmacology.

Attention-deficit/hyperactivity disorder (ADHD) is an established diagnosis in children, associated with a large body of evidence on the benefits of treatment. Adolescents with ADHD are now leaving children's services often with no readily identifiable adult service to support them, which presents problems as local pharmacy regulations often preclude the prescription of stimulant drugs by general practitioners (GPs). In addition, adults with ADHD symptoms are now starting to present to primary care and psychiatry services requesting assessment and treatment. For these reasons, the British Association for Psychopharmacology (BAP) thought it timely to hold a consensus conference to review the body of evidence on childhood ADHD and the growing literature on ADHD in older age groups. Much of this initial guidance on managing ADHD in adolescents in transition and in adults is based on expert opinion derived from childhood evidence. We hope that, by the time these guidelines are updated, much evidence will be available to address the many directions for future research that are detailed here.

Adolescent↗
PubMed2006

Current research priorities in chronic fatigue syndrome/myalgic encephalomyelitis: disease mechanisms, a diagnostic test and specific treatments.

Chronic fatigue syndrome (CFS) is an illness characterised by disabling fatigue of at least 6 months duration, which is accompanied by various rheumatological, infectious and neuropsychiatric symptoms. A collaborative study group has been formed to deal with the current areas for development in CFS research--namely, to develop an understanding of the molecular pathogenesis of CFS, to develop a diagnostic test and to develop specific and curative treatments. Various groups have studied the gene expression in peripheral blood of patients with CFS, and from those studies that have been confirmed using polymerase chain reaction (PCR), clearly, the most predominant functional theme is that of immunity and defence. However, we do not yet know the precise gene signature and metabolic pathways involved. Currently, this is being dealt with using a microarray representing 47,000 human genes and variants, massive parallel signature sequencing and real-time PCR. It will be important to ensure that once a gene signature has been identified, it is specific to CFS and does not occur in other diseases and infections. A diagnostic test is being developed using surface-enhanced, laser-desorption and ionisation-time-of-flight mass spectrometry based on a pilot study in which putative biomarkers were identified. Finally, clinical trials are being planned; novel treatments that we believe are important to trial in patients with CFS are interferon-beta and one of the anti-tumour necrosis factor-alpha drugs.

Fatigue Syndrome, Chronic↗
PubMed2005

GABA-benzodiazepine receptor function in alcohol dependence: a combined 11C-flumazenil PET and pharmacodynamic study.

RATIONALE: Gamma-aminobutyric acid (GABA)-benzodiazepine receptor function is hypothesised to be reduced in alcohol dependence. OBJECTIVES: We used positron emission tomography (PET) with [11C]flumazenil, a non-selective tracer for brain GABA-benzodiazepine (GABA-BDZ) receptor binding, to determine in vivo the relationship between BDZ receptor occupancy by an agonist, midazolam, and its functional effects. METHODS: Abstinent male alcohol dependent subjects underwent [11C]flumazenil PET to measure occupancy of BDZ receptors by midazolam whilst recording its pharmacodynamic effects on behavioural and physiological measures. Rate constants describing the exchange of [11C]flumazenil between the plasma and brain compartments were derived from time activity curves. RESULTS: A 50% reduction in electroencephalography (EEG)-measured sleep time was seen in the alcohol dependent group despite the same degree of occupancy by midazolam as seen in the control group. The effects of midazolam on other measures of benzodiazepine receptor function, increasing EEG beta1 power and slowing of saccadic eye movements, were similar in the two groups. No differences in midazolam or flumazenil metabolism were found between the groups. CONCLUSIONS: In summary, our study suggests that alcohol dependence in man is associated with a reduced EEG sleep response to the benzodiazepine agonist, midazolam, which is not explained by reduced BDZ receptor occupancy, and is consistent with reduced sensitivity in this measure of GABA-BDZ receptor function in alcohol dependence. The lack of change in other functional measures may reflect a differential involvement of particular subtypes of the GABA-BDZ receptor.

Adult↗
PubMed2005

Pharmacotherapy of anxiety.

The pharmacological treatment of anxiety has a long and chequered history, and recent years have seen a rich development in the options available to prescribers. Most of the currently used anxiolytic agents act via monoaminergic (chiefly serotonin) or amino acid (GABA or glutamate) neurotransmitters, and this chapter describes the pharmacology of the major drug groups. Clinical applications are discussed with respect to the five major anxiety disorders, as well as simple phobia and depression with concomitant anxiety. Prospective future developments in the field are considered.

Anti-Anxiety Agents↗
PubMed2004

Using sleep to evaluate comparative serotonergic effects of paroxetine and citalopram.

BACKGROUND: SSRIs suppress rapid eye movement (REM) sleep, probably by increasing serotonin in the brainstem, and also increase sleep fragmentation. Although in the UK, paroxetine (PAR) and citalopram (CIT) have recommended doses of 20 mg/day for the treatment of depression, the recommended dose of CIT in USA is higher (40 mg). If similar doses of PAR and CIT have similar effects on central serotonin then they should have similar effects on sleep measures in volunteers. METHOD: This was a randomised, double blind placebo controlled crossover study in 12 healthy volunteers. Subjects took PAR 20 mg mane, CIT 20 mg mane or placebo mane for 3 days and sleep was recorded overnight at home on the third night. Standard measures of sleep were derived. RESULTS: REM sleep was significantly suppressed and sleep fragmentation increased by both drugs. Measures of REM sleep and sleep continuity previously found to be altered by SSRIs were considered together and compared with placebo as a 'serotonin response'; this was significantly greater in the PAR group. CONCLUSIONS: Sleep effects typical of SSRIs were greater with PAR 20 mg/day than CIT 20 mg/day, suggesting greater effects on 5HT uptake blockade.

Adult↗
PubMed2004

Evaluation of actigraphy and automated telephoned questionnaires to assess hypnotic effects in insomnia.

This study aimed to explore new methodologies in insomnia research, namely whether actigraphy was suitable to show hypnotic effects over weeks in insomnia, and to compare an automated method of questionnaire data collection with traditional methods. Thirty-eight insomniacs took part in a 5-week, double-blind, placebo-controlled study of the effects of 2 weeks of administration of temazepam 20 mg on sleep. Outcome measures were actigraphy and daily St Mary's Hospital Sleep Questionnaires (SMHSQ). Actigraphy was performed using Actiwatch (CNT) and analysed using both the automated Actiwatch sleep analysis software and non-parametric analysis of rest-activity rhythms. The questionnaires were administered as straightforward pencil-and-paper for half of the time and an automated telephoned system for the other half. The experimental paradigm allowed within-subject comparison of traditional and automated data collection, both on and off drug. Actigraphy showed a high degree of inter-subject variability but, nevertheless, some sleep variables (Fragmentation Index, Actual Sleep Time %) showed significant improvement during drug treatment, and Sleep Efficiency and Actual Sleep Time were significantly worsened during the first post-drug week. Nonparametric circadian rhythm analysis showed no significant effect. Subjective data from the SMHSQ showed significant drug effects and there was no significant difference in scores between the automated and pencil-and-paper methods; automated data collection was slightly more acceptable to patients and minimized data entry and management. Effect sizes using within-subject and between-subject comparisons were calculated for the subjective and objective measures to inform future studies

Adolescent↗
PubMed2004

Invited review: the evolution of antidepressant mechanisms.

Present antidepressants are all descendents of the serendipitous findings in the 1950s that the monoamine oxidase inhibitor iproniazid and the tricyclic antidepressant imipramine were effective antidepressants. The identification of their mechanism of action, and those of reserpine and amphetamine, in the 1960s, led to the monoamine theories of depression being postulated; first, with noradrenaline then 5-hydroxytryptamine being considered the more important amine. These monoamine theories of depression predominated both industrial and academic research for four decades. Recently, in attempts to design new drugs with faster onsets of action and more universal therapeutic action, downstream alterations common to current antidepressants are being examined as potential antidepressants. Additionally, the use of animal models has identified a number of novel targets some of which have been subjected to clinical trials in humans. However, monoamine antidepressants remain the best current medications and it may be some time before they are dislodged as the market leaders.

Animals↗
PubMed2003

2-(4,5-dihydro-1H-imidazol-2-yl)indazole (indazim) derivatives as selective I(2) imidazoline receptor ligands.

A series of variously substituted 2-(4,5-dihydro-1H-imidazol-2-yl)indazoles 3a-j and 2-(4,5-dihydro-1H-imidazol-2-yl)-4,5,6,7-tetrahydroindazole 6 were prepared by the regiospecific heteroalkylation of corresponding indazoles 1a-k with 2-chloro-4,5-dihydroimidazole (2). Their affinity to imidazoline I(2) receptors and alpha(2)-adrenergic receptors was determined by radioligand binding assay carried out on P(2) membrane preparations obtained from rat whole brains. 4-Chloro-2-(4,5-dihydro-1H-imidazol-2-yl)indazole (3f, 4-Cl-indazim) showed a 3076-fold difference in affinity for the [(3)H]2BFI-labeled imidazoline I(2) receptors relative to the [(3)H]RX821001-labeled alpha(2)-adrenergic receptors. This highly selective compound should prove to be useful tool in further understanding the functions of the imidazoline I(2) receptors.

Animals↗
PubMed2003

Using saccadic eye movements as objective measures of tolerance in methadone dependent individuals during the hydromorphone challenge test.

Substitute methadone prescribing is one of the main modes of treatment for opiate dependence. This study examined the relationship between methadone dose (measured by daily dose and methadone's active (R)-enantiomer blood levels) and opiate receptor function. Nine subjects on substitute methadone (30 - 90 mg daily) received three subcutaneous injections 1.5 hours apart (saline, 5 mg and 10 mg hydromorphone, a short-acting opiate agonist) followed by measures of functional response in particular saccadic eye movements (SEMs), as well as self-report measures. Ten mg of hydromorphone significantly slowed SEM parameters (peak velocity by 15%, p < 0.005; peak acceleration by 20%, p < 0.025; peak deceleration by 26%, p < 0.025) and the SEM velocity changes correlated significantly with (R)-methadone levels (r = 0.844, p < 0.005) and with the oral dose of methadone being taken (r = 0.829, p < 0.005). Although a similar trend was observed for 5 mg, this was not significant. These finding suggest that, at higher methadone doses (resulting in higher plasma concentrations), there is significant tolerance to the action of agonists. Such studies may help in refining our understanding of the actions of methadone and the SEM measure could help in defining the degree of tolerance in individuals using street heroin.

Adult↗
PubMed2003

Addiction.

Alcohol and psycho-active substance misuse has far-reaching social, psychological and physical consequences. Advances in neuroimaging technology have allowed neurobiological theories of addiction to become better characterized. We describe the neurobiology of dependence, withdrawal, abstinence and craving states in alcohol, stimulant and opiate misuse. Structural neuroimaging techniques such as CT and MRI with new analytical approaches such as voxel-based morphometry have shown wide-spread changes in stimulant and opiate abuse and atrophy, particularly in the frontal lobes, in alcoholism. Functional neuroimaging techniques such as PET, SPECT and fMRI reveal altered regional cerebral activity by all drugs of abuse. The neurochemistry of addiction, particularly involving dopamine, serotonin, opiate and GABA, has been studied with PET and SPECT and similarities between all drugs of abuse have been found such as reduced dopaminergic markers. The evidence derived from these advances in neuroimaging is likely to herald the emergence of new biological treatments in this important field.

Brain↗
PubMed2003

Does the brain noradrenaline network mediate the effects of the CO2 challenge?

The inhalation of carbon dioxide (CO2) is commonly used in patients and volunteers as a means of producing anxiety or panic. It is generally believed that patients with panic disorder are more vulnerable to the effects of CO2 than patients with other anxiety disorders or healthy volunteers and there is speculation and debate as to the mechanism for this apparent sensitivity. Recent work from our group has shown that a single inhalation of 35% CO2 activates the hypothalamic-pituitary-adrenocortical (HPA) axis, increases blood pressure (BP) and increases subjective fear responses in healthy volunteers. Correlation analyses reveal a relationship between the changes in BP and the cortisol increase. These findings led us to postulate that a common mechanism may mediate these and the subjective responses to inhalation of CO2. We propose that the noradrenergic system, particularly the locus coeruleus (LC), but including the A1 and A2 cell groups, may be a key mediator of these responses. This article examines the evidence and discusses the results of studies from our laboratory in relation to a neuroanatomical model centring on the LC.

Administration, Inhalation↗
PubMed2003

Endogenous beta-carbolines as clonidine-displacing substances.

Endogenous beta-carbolines, such as harmane, are known to occur in mammalian species including humans. Radioligand binding studies have revealed that certain beta-carbolines display high affinity for both I(1) and I(2) imidazoline-binding sites (IBS). Functional studies have shown that the beta-carboline harmane elicits many characteristics expected of an endogenous ligand IBS. This article discusses the evidence relating to beta-carbolines as endogenous ligands and presents a case for harmane and related compounds as endogenous ligands for IBS.

Adrenergic alpha-Agonists↗
PubMed2003

Characterization of [(3)H]harmane binding to rat whole brain membranes.

This study investigates the binding of [(3)H]harmane to rat whole brain homogenates. Saturation studies revealed [(3)H]harmane labels a single, saturable, high-capacity population with high affinity. All the test compounds displaced [(3)H]harmane completely and in an apparently monophasic manner. The displacement profile of the test ligands indicated labeling of MAO-A. Given the high level of MAO-A binding, it is unlikely that a low-capacity I(2) site would be distinguishable from the total [(3)H]harmane population.

Animals↗
PubMed2003

BU98008, a highly selective imidazoline(1)-receptor ligand.

BU98008 (1-(4, 5-dihydro-1H-imidazol-2-yl)isoquinoline) is a novel isoquinoline derivative. Radioligand binding studies revealed it had high affinity for the I(1) receptor in rat kidney membranes but low affinity for the I(2) binding site and alpha(2)-adrenoceptor in rat brain membranes. Further evaluation of BU98008 in vivo revealed no effect on blood pressure following peripheral administration. These preliminary data suggest BU98008 may be an antagonist at I(1) receptors. Further evaluation following central administration must be performed before a hypotensive action can be excluded.

Adrenergic alpha-Agonists↗