Search PubMed⌕ Search

Biomedical subjects

D J Nutt

Publications and source records attributed to D J Nutt.

At least 55 records · Page 3Linked to original sources
PubMed2001

Changes in regional cerebral blood flow elicited by craving memories in abstinent opiate-dependent subjects.

OBJECTIVE: The brain circuitry of opiate craving was investigated with positron emission tomography (PET) imaging of regional cerebral blood flow (rCBF). METHOD: Twelve abstinent opiate-dependent subjects listened to audiotaped autobiographical scripts of an episode of craving and a neutral episode while undergoing a PET scan with the tracer [(15)O]H(2)O. Statistical parametric mapping was used to analyze the PET images of rCBF changes. RESULTS: Comparison of the drug-related and neutral stimulus conditions revealed activation of rCBF in the left medial prefrontal and left anterior cingulate cortices and deactivation in the occipital cortex in response to the drug-related stimulus. A further statistical parametric mapping analysis with a subjective rating of craving as a covariate showed a positive association of between craving and rCBF in the left orbitofrontal cortex. CONCLUSIONS: The patterns of cerebral activation reflect the different brain regions mediating the salience of opiate-related stimuli and the subjective experience of craving for opiates.

Adult↗
PubMed2001

Venlafaxine occupation at the noradrenaline reuptake site: in-vivo determination in healthy volunteers.

Venlafaxine, a serotonin and noradrenaline reuptake inhibitor, is an effective antidepressant at doses of 75 mg p.o. daily and above. Preclinical and healthy volunteer studies have demonstrated that venlafaxine is more potent at the serotonin than at the noradrenaline reuptake site, with noradrenergic blocking effects being observed at doses >75 mg p.o. in man. We used the Multiple Organs Coincidences Counter and [11C] meta hydroxy ephedrine (MHED) to test whether significant occupation of cardiac sympathetic neurones was achieved in man in vivo after the acute administration of venlafaxine 75 mg p.o. in nine healthy volunteers. MHED is a tracer which binds at the noradrenaline reuptake site. This study demonstrates that the [11C]MHED signal is significantly reduced after the administration of venlafaxine 75 mg p.o. thus showing that noradrenaline reuptake blockade is observable at this dose. This effect is predominantly seen in volunteers who received > 1 mg/kg venlafaxine.

Adrenergic Uptake Inhibitors↗
PubMed2001

Crossover trial of pagoclone and placebo in patients with DSM-IV panic disorder.

Pagoclone is a cyclopyrrolone that is believed to act as a partial agonist at the gamma-aminobutyric acid (GABA)-A/benzodiazepine (BDZ) receptor. In theory, such partial agonists should be anxiolytic but lack the adverse side-effects of sedation, tolerance and withdrawal associated with full GABA-A/BDZ agonists. The objective of the randomized double-blind crossover study was to assess whether pagoclone was an effective anti-panic agent and also to assess its side-effect profile. Patients recruited had a diagnosis of Panic Disorder (DSM-IV) with at least one panic attack per week. Following a 2-week screening period, patients entered a 6-week trial consisting of two 2-week treatment periods, each followed by a 1-week washout. Patients were randomly assigned to receive either pagoclone 0.1 mg t.d.s. or placebo on their first treatment period and the converse on their second. The primary measure was daily panic attack dairy. Fourteen patients completed the study, the mean number of panic attacks during screening was 5.8+/-0.8 (SEM), this fell to 3.6+/-0.5 during treatment with pagoclone (p = 0.05) and 4.3+/-0.8 with placebo (p = 0.14). There was no significant difference on direct comparison of pagoclone with placebo or in any of the secondary measures (including Rickels withdrawal scale) or the adverse event profiles. The study provides preliminary evidence that pagoclone has anxiolytic properties in the absence of typical BDZ side-effects. This is consistent with its theoretical mode of action as a partial agonist at the GABA(A)/BDZ receptor.

Adult↗
PubMed2001

New insights into the role of the GABA(A)-benzodiazepine receptor in psychiatric disorder.

BACKGROUND: In the 40 years since the first benzodiazepine was brought into clinical use there has been a substantial growth in understanding the molecular basis of action of these drugs and the role of their receptors in disease states. AIMS: To present current knowledge about the role of the GABA(A)-benzodiazepine receptor in anxiety disorders, new insights into the molecular biology of the receptor complex and neuroimaging studies suggesting involvement of these receptors in disease states. METHOD: An overview of published literature, including some recent data. RESULTS: The molecular biology of this receptor is detailed. Molecular genetic studies suggesting involvement of the GABA(A)-benzodiazepine receptor in animal behaviour and learning are outlined; possible parallels with human psychopathology are discussed. CONCLUSIONS: Current insights into the role of the GABA(A)-benzodiazepine receptor in the action of benzodiazepines and as a factor in disease states, in both animals and humans, may lead to new, more sophisticated interventions at this receptor complex and potentially significant therapeutic gains.

Animals↗
PubMed2001

Neurobiological mechanisms in generalized anxiety disorder.

Generalized anxiety disorder (GAD) is a common and serious disorder. Despite this fact, there is no clear understanding of the exact neurobiological changes underlying the condition. To date, there are few studies of neurobiological function in patients with GAD, and only limited comparative data with depression are available. Advances in neuroanatomical imaging techniques are beginning to allow detailed study of regional blood flow and metabolism and may offer insights into the specific regions of the brain involved in GAD. Investigations into neurotransmitter dysfunction have implicated the gamma-aminobutyric acid/benzodiazepine, serotonergic, and noradrenergic systems in this disorder. Variations in sleep patterns have also been assessed and indicate a biological separation from depression.

Anxiety Disorders↗
PubMed2001

Consensus statement on generalized anxiety disorder from the International Consensus Group on Depression and Anxiety.

OBJECTIVE: To provide primary care clinicians with a better understanding of management issues in generalized anxiety disorder (GAD) and guide clinical practice with recommendations on the appropriate treatment strategy. PARTICIPANTS: The 4 members of the International Consensus Group on Depression and Anxiety were James C. Ballenger (chair), Jonathan R.T. Davidson, Yves Lecrubier, and David J. Nutt. Four additional faculty members invited by the chair were Karl Rickels, Hans-Ulrich Wittchen, Dan J. Stein, and Thomas D. Borkovec. EVIDENCE: The consensus statement is based on the 6 review articles that are published in this supplement and the scientific literature relevant to the issues reviewed in these articles. CONSENSUS PROCESS: Group meetings were held over a 2-day period. On day 1, the group discussed the review articles and the chair identified key issues for further debate. On day 2, the group discussed these issues to arrive at a consensus view. After the group meetings, the consensus statement was drafted by the chair and approved by all attendees. CONCLUSIONS: GAD is the most common anxiety disorder in primary care and is highly debilitating. Furthermore, it is frequently comorbid with depression and other anxiety disorders, which exacerbates functional impairment. Antidepressants (serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and nonsedating tricyclic antidepressants) are generally the most appropriate first-line pharmacotherapy for GAD, since they are also effective against comorbid psychiatric disorders and are suitable for long-term use. Cognitive-behavioral therapy is the preferred form of psychotherapy for GAD, although when GAD is comorbid with depression, pharmacotherapy is increasingly indicated.

Age of Onset↗
PubMed2001

Consensus statement on transcultural issues in depression and anxiety from the International Consensus Group on Depression and Anxiety.

OBJECTIVE: To provide primary care physicians with a better understanding of transcultural issues in depression and anxiety. PARTICIPANTS: The 4 members of the International Consensus Group on Depression and Anxiety were James C. Ballenger (chair), Jonathan R. T. Davidson, Yves Lecrubier, and David J. Nutt. Five faculty invited by the chair also participated: Laurence J. Kirmayer, Jean-Pierre Lepine, Keh-Ming Lin, Osamu Tajima, and Yutaka Ono. EVIDENCE: The consensus statement is based on the 5 review articles that are published in this supplement and the scientific literature relevant to the issues reviewed in these articles. CONSENSUS PROCESS: Group meetings were held over a 2-day period. On day 1, the group discussed the review articles, and the chair identified key issues for further debate. On day 2, the group discussed these issues to arrive at a consensus view. After the group meetings, the consensus statement was drafted by the chair and approved by all attendees. CONCLUSION: The consensus statement underlines the prevalence of depression and anxiety disorders across all cultures and nations while recognizing that cultural differences exist in symptom presentation and prevalence estimates. In all countries, the recognition of depression by clinicians in the primary care setting is low (generally less than 50%), and the consensus group recommends a 2-step process to aid the recognition and diagnosis of depression. In line with the low recognition of depression and anxiety disorders is the finding that only a small proportion of patients with depression or anxiety are receiving appropriate treatments for their condition. Biological diversity across ethnic groups may account for the differential sensitivity of some groups to psychotropic medication, but this area requires further investigation.

Anxiety Disorders↗
PubMed2000

Desipramine binding to noradrenaline reuptake sites in cardiac sympathetic neurons in man in vivo.

Noradrenergic reuptake blockade is a recognised mechanism of antidepressant action, but the extent of the blockade necessary for therapeutic effect is not known and plasma levels do not provide a guide to therapy. We report a method to assess noradrenaline reuptake blockade in vivo in man using [11C]meta-hydroxyephedrine and the multiple organs' coincidences counter. Eight healthy volunteers had two scans, one with tracer alone and one after preloading with desipramine 50-75 mg p.o. In all subjects, there was an increased washout rate of the radioligand from the heart following preloading (t=4.38; P<0.003) as well as a decrease of the area under the [11C]meta-hydroxyephedrine time activity curve (t=7. 4; P=0.001). In one subject who had three doses of desipramine, the increase in washout rate was dose-dependent. In conclusion, [11C]meta-hydroxyephedrine in the multiple organs' coincidences counter gives a valid, low radiation method to assess noradrenergic reuptake blockade in the clinic.

Adrenergic Uptake Inhibitors↗
PubMed2000

Isolation of RP-HPLC pure clonidine-displacing substance from NG108-15 cells.

A crude extract of clonidine-displacing substance (CDS) has previously been extracted from the NG108-15 cell line. This study aimed to purify CDS extracted from this cell line further, by the technique of reverse phase-HPLC (RP-HPLC), and subsequently determine whether this refined CDS bears any similarity to CDS's extracted from other tissues. Crude CDS was extracted from NG108-cells and fractionated by RP-HPLC eluting with a linear gradient of methanol (5-65%; 1 ml min(-1) flow rate) over 50 min., and collected at 1 min. intervals. The pharmacological activities of the CDS fractions were determined by their abilities to displace bound [3H]clonidine to alpha(2)-adrenoceptors in rat brain membranes. RP-HPLC analysis of CDS revealed a pharmacologically active fraction distinct from agmatine, eluting at 24 min, corresponding to an absorbance peak observed at this time. Collectively, these results confirmed that CDS was present in the NG108-15 cell line. However, the RP-HPLC analysis showed the pharmacological activity to elute at a more hydrophobic gradient than previously observed with CDS's extracted from bovine tissues. These results support the notion of the existence of several CDS's.

Animals↗
PubMed2000

Flumazenil challenge in social phobia.

The benzodiazepine antagonist, flumazenil, can provoke panic attacks in some panic disorder patients. It has been predicted that panic responses to flumazenil may be associated with situational fear. Patients with social phobia frequently experience situational anxiety and panic attacks. The current study tested whether flumazenil induces panic in patients with social phobia. Fourteen patients with social phobia (DSM-III-R) and 14 age- and sex-matched controls were tested in a single session, double blind crossover challenge design, using intravenous flumazenil 2 mg/20 ml or matched placebo infusions 1 hour apart. Panic attacks occurred during flumazenil challenge in 2/14 subjects with social phobia. The rate of panic attacks and the severity of panic symptoms following flumazenil were not significantly greater in patients than in controls. Situational fears that are provoked by social cues therefore do not predict panic responses to flumazenil.

Adult↗
PubMed2000

Sleep changes during long-term treatment of depression with fluvoxamine--a home-based study.

RATIONALE: The effects of antidepressants on sleep in depression have been extensively investigated, although to date there have been relatively few studies of newer drug classes such as specific serotonin reuptake inhibitors (SSRIs). All reported studies on SSRIs have been conducted in patients admitted to sleep laboratories and very few longitudinal studies have continued to measure sleep beyond 5 weeks of treatment. The growing trend towards outpatient and community care has highlighted the need for studies of sleep in depression in a more naturalistic setting, and during longer periods of treatment in line with recommended clinical practice. OBJECTIVES: To establish if the changes in sleep architecture and continuity described during early treatment with SSRIs persist after 3 months, to relate these changes to clinical state, and to establish whether home recordings would yield similar results to previous laboratory studies. METHODS: We have recorded objective sleep parameters in 12 depressed patients before and during 12-week treatment with an SSRI, fluvoxamine. All the sleep recordings were performed in the patients' own homes, using the Oxford Medilog system. RESULTS: At 12 weeks, 7/12 patients had responded (HAM-D decreased by > 50%). REM latency showed the expected increase early in treatment; this change was less obvious at weeks 3 and 12. Amount of REM sleep was decreased at day 2 and week 3, but returned to baseline by week 12. Slow wave sleep was slightly increased at day 2 and decreased at week 12. Of the sleep continuity measures, the only significant change was in sleep onset latency, which was increased at week 3; the other measures showed non-significant worsening at night 2 and week 3, but most were better than baseline by 12 weeks. Subjective sleep (the three sleep items on the HAM-D) showed a progressive improvement over time, especially in the responders. CONCLUSIONS: The effects of the SSRI fluvoxamine on objective sleep measures are in the direction predicted by its pharmacological actions and some persist for at least 12 weeks. In addition subjective appraisal of sleep is strongly affected by mood state. All patients found the home recording procedure acceptable and only minimally disruptive.

Adult↗
PubMed2000

Evaluation of [O-methyl-11C]RS-15385-197 as a positron emission tomography radioligand for central alpha2-adrenoceptors.

Carbon-11 labelled RS-15385-197 and its ethylsulphonyl analogue, RS-79948-197, were evaluated in rats as potential radioligands to image central alpha2-adrenoceptors in vivo. The biodistributions of both compounds were comparable with that obtained in an earlier study using tritiated RS-79948-197 and were consistent with the known localisation of alpha2-adrenoceptors. The maximal signals (total to non-specific binding) were, however, reduced, in the order [11C]RS-79948-197 < [11C]RS-15385-197 < [3H]RS-79948-197, primarily due to the difference in radiolabel position (O-methyl for carbon- 11 compared with S-ethyl for tritium). This resulted in the in-growth of radiolabelled metabolites in plasma, which, in turn, contributed to the non-specific component of brain radioactivity. Nonetheless, the signal ratio of approximately 5 for a receptor-dense tissue compared with the receptor-sparse cerebellum, at 90-120 min after radioligand injection, encouraged the development of [O-methyl-11C]RS-15385-197 for human positron emission tomography (PET). Unfortunately, in two human PET scans (each of 90 min), brain extraction of the radioligand was minimal, with volumes of distribution more than an order of magnitude lower than that measured in rats. Following intravenous injection, radioactivity was retained in plasma and metabolism of the radiolabelled compound was very low. Retrospective measurements of in vitro plasma protein binding and in vivo brain uptake index (BUI) in rats demonstrated a higher protein binding of the radioligand in human compared with rat plasma and a lower BUI in the presence of human plasma. It is feasible that a higher affinity of RS-15385-197 for human plasma protein compared with receptor limited the transport of the radioligand. Although one of the PET scans showed a slight heterogeneity in biodistribution of radioactivity which was consistent with the known localisation of alpha2-adrenoceptors in human brain, it was concluded that [O-methyl-11C]RS-15385-197 showed little promise for routine quantification of alpha2-adrenoceptors in man.

Adult↗
PubMed2000

The psychobiology of anxiolytic drugs. Part 1: Basic neurobiology.

The authors provide an overview of the current state of knowledge with regards to the neurobiological mechanisms involved in normal and pathological anxiety. A brief review of the classification and cognitive psychology of anxiety is followed by a more in-depth look at the neuroanatomical and neurochemical processes and their relevance to our understanding of the modes of action of anxiolytic drugs. The serotonergic, noradrenergic, and gamma-aminobutyric acidergic systems are reviewed. The numerous physiological and pharmacological methods of anxiety provocation and the increasing importance of functional neuroimaging are also examined. The review provides an overview of the biology and basic pharmacology of anxiolytic drugs, and compliments the more clinically oriented companion review.

Anti-Anxiety Agents↗
PubMed2000

The psychobiology of anxiolytic drug. Part 2: Pharmacological treatments of anxiety.

Benzodiazepines have been the mainstay of pharmacological treatment of anxiety over the last 4 decades. The problems associated with their use prompted the research for alternative agents that would be useful in anxiety conditions. Old classes of antidepressants, such as tricyclic antidepressants and monoamine oxidase inhibitors, showed effectiveness in some anxiety syndromes, even in areas where benzodiazepines were not very effective. Newer antidepressants, the selective serotonin-reuptake inhibitors, also appear very useful in some anxiety states, and their favourable side-effect profile has elevated them to first-line treatment tools in these conditions. However, the ideal anxiolytic does not exist. Research with other new compounds is very active, and some experimental drugs show promise for the future.

Anti-Anxiety Agents↗