Search PubMed⌕ Search

Biomedical subjects

David J Nutt

Publications and source records attributed to David J Nutt.

At least 73 records · Page 4Linked to original sources
PubMed2003

Functional connectivity analysis of the neural circuits of opiate craving: "more" rather than "different"?

We investigated the functional connectivity of brain regions activated during opiate craving. Previously we used recorded autobiographical scripts to induce opiate craving in 12 abstinent opiate-dependent subjects while they were undergoing positron emission tomography (PET) scanning using the regional cerebral blood flow (rCBF) tracer H2 15O. SPM99 was used to examine the connectivity patterns associated with the primary brain regions activated in response to drug-craving memories (anterior cingulate, AC) and correlated with opiate craving (orbitofrontal cortex, OFC). Two separate connectivity patterns were identified associated with the OFC and AC regions. The AC region was associated with activity in the left temporal region. The left OFC region activity correlated with activity in the right OFC, and left parietal and posterior insular regions. There was also a positive association with the hippocampus and brainstem. Both the AC and OFC regions showed a negative association with posterior visual areas. We suggest that the patterns of functional connectivity reflect the ability of drug-related stimuli to activate attentional and memory circuits to a greater degree than non-drug-related stimuli. This argues that neural circuits of dependence and craving are not specific "craving" or "addiction" brain regions but are "normal" circuits activated to a greater degree.

Brain Stem↗
PubMed2003

WCA recommendations for the long-term treatment of obsessive-compulsive disorder in adults.

What are the latest psychotherapeutic and pharmacotherapeutic treatment recommendations for obsessive-compulsive disorder (OCD)? OCD is a relatively common disorder with a lifetime prevalence of approximately 2% in the general population. It often has an early onset, usually in childhood or adolescence, and frequently becomes chronic and disabling if left untreated. High associated healthcare utilization and costs, and reduced productivity resulting in loss of earning, pose a huge economic burden to OCD patients and their families, employers, and society. OCD is characterized by the presence of obsessions and compulsions that are time-consuming, cause marked distress, or significantly interfere with a person's functioning. Most patients with OCD experience symptoms throughout their lives and benefit from long-term treatment. Both psychotherapy and pharmacotherapy are recommended, either alone or in combination, for the treatment of OCD. Cognitive-behavioral therapy is the psychotherapy of choice. Pharmacologic treatment options include the tricyclic antidepressant clomipramine and the selective serotonin reuptake inhibitors (SSRIs) citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline. These have all shown benefit in acute treatment trials; clomipramine, fluvoxamine, fluoxetine, and sertraline have also demonstrated benefit in long-term treatment trials (at least 24 weeks), and clomipramine, sertraline, and fluvoxamine have United States Food and Drug Administration approvals for use in children and adolescents. Available treatment guidelines recommend first-line use of an SSRI (ie, fluoxetine, fluvoxamine, paroxetine, sertraline, or citalopram) in preference to clomipramine, due to the latter's less favorable adverse-event profile. Further, pharmacotherapy for a minimum of 1-2 years is recommended before very gradual withdrawal may be considered.

Adult↗
PubMed2003

WCA recommendations for the long-term treatment of panic disorder.

What are the symptoms of panic disorder and how is the disorder most effectively treated? One of the most commonly encountered anxiety disorders in the primary care setting, panic disorder is a chronic and debilitating illness. The core symptoms are recurrent panic attacks coupled with anticipatory anxiety and phobic avoidance, which together impair the patient's professional, social, and familial functioning. Patients with panic disorder have medically unexplained symptoms that lead to overutilization of healthcare services. Panic disorder is often comorbid with agoraphobia and major depression, and patients may be at increased risk of cardiovascular disease and, possibly, suicide. Research into the optimal treatment of this disorder has been undertaken in the past 2 decades, and numerous randomized, controlled trials have been published. Selective serotonin reuptake inhibitors have emerged as the most favorable treatment, as they have a beneficial side-effect profile, are relatively safe (even if taken in overdose), and do not produce physical dependency. High-potency benzodiazepines, reversible monoamine oxidase inhibitors, and tricyclic antidepressants have also shown antipanic efficacy. In addition, cognitive-behavioral therapy has demonstrated efficacy in the acute and long-term treatment of panic disorder. An integrated treatment approach that combines pharmacotherapy with cognitive-behavioral therapy may provide the best treatment. Long-term efficacy and ease of use are important considerations in treatment selection, as maintenance treatment is recommended for at least 12-24 months, and in some cases, indefinitely.

Adult↗
PubMed2003

WCA Recommendations for the long-term treatment of posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) is a common and disabling condition. In addition to combat-related PTSD, the disorder occurs in civilians exposed to severe traumatic events, with the community prevalence rate for the combined populations reaching as high as 12%. If left untreated, PTSD may continue for years after the stressor event, resulting in severe functional and emotional impairment and a dramatic reduction in quality of life, with negative economic consequences for both the sufferer and society as a whole. Although PTSD is often overlooked, diagnosis is relatively straightforward once a triggering stressor event and the triad of persistent symptoms-reexperiencing the traumatic event, avoiding stimuli associated with the trauma, and hyperarousal have been identified. However, comorbid conditions of anxiety and depression frequently hamper accurate diagnosis. Treatment for PTSD includes psychotherapy and pharmacotherapy. The latter includes selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, and monoamine oxidase inhibitors. Only SSRIs have been proven effective and safe in long-term randomized controlled trials. Current guidelines from the Expert Consensus Panel for PTSD recommend treatment of chronic PTSD for a minimum of 12-24 months.

Antidepressive Agents, Tricyclic↗
PubMed2003

WCA recommendations for the long-term treatment of social phobia.

What is the best approach for treating patients with social phobia (social anxiety disorder) over the long term? Social phobia is the most common anxiety disorder, with reported prevalence rates of up to 18.7%. Social phobia is characterized by a marked and persistent fear of being observed or evaluated by others in social performance or interaction situations and is associated with physical, cognitive, and behavioral (ie, avoidance) symptoms. The onset of social phobia typically occurs in childhood or adolescence and the clinical course, if left untreated, is usually chronic, unremitting, and associated with significant functional impairment. Social phobia exhibits a high degree of comorbidity with other psychiatric disorders, including mood disorders, anxiety disorders, and substance abuse/dependence. Few people with social phobia seek professional help despite the existence of beneficial treatment approaches. The efficacy, tolerability, and safety of the selective serotonin reuptake inhibitors (SSRIs), evidenced in randomized clinical trials, support these agents as first-line treatment. The benzodiazepine clonazepam and certain monoamine oxidase inhibitors (representing both reversible and nonreversible inhibitors) may also be of benefit. Treatment of social phobia may need to be continued for several months to consolidate response and achieve full remission. The SSRIs have shown benefit in long-term treatment trials, while long-term treatment data from clinical studies of clonazepam are limited but support the drug's efficacy. There is also evidence for the effectiveness of exposure-based strategies of cognitive-behavioral therapy, and controlled studies suggest that the effects of treatment are generally maintained at long-term follow-up. In light of the chronicity and disability associated with social phobia, as well as the high relapse rate after short-term therapy, it is recommended that effective treatment be continued for at least 12 months.

Adult↗
PubMed2003

WCA recommendations for the long-term treatment of generalized anxiety disorder.

What are the current recommendations for the long-term treatment of generalized anxiety disorder (GAD)? GAD is a common disorder with a lifetime prevalence of 4% to 7% in the general population. GAD is characterized by excessive, uncontrollable worry or anxiety about a number of events or activities that the individual experiences on more days than not over a 6-month period. Onset of GAD symptoms usually occurs during an individual's early twenties; however, high rates of GAD have also been seen in children and adolescents. The clinical course of GAD is often chronic, with 40% of patients reporting illness lasting >5 years. GAD is associated with pronounced functional impairment, resulting in decreased vocational function and reduced quality of life. Patients with GAD tend to be high users of outpatient medical care, which contributes significantly to healthcare costs. Currently, benzodiazepines and buspirone are prescribed frequently to treat GAD. Although both show efficacy in acute treatment trials, few long-term studies have been performed. Benzodiazepines are not recommended for long-term treatment of GAD, due to associated development of tolerance, psychomotor impairment, cognitive and memory changes, physical dependence, and a withdrawal reaction on discontinuation. The antidepressant venlafaxine extended-release (XR) has received approval for the treatment of GAD in the United States and many other countries. Venlafaxine XR has demonstrated efficacy over placebo in two randomized treatment trials of 6 months' duration as well as in other acute trials. Paroxetine is the first of the selective serotonin reuptake inhibitors (SSRIs) to receive US approval for the treatment of GAD. Paroxetine demonstrated superiority to placebo in short-term trials, and investigations into the use of other SSRIs are ongoing. This suggests that other SSRIs, and serotonin and noradrenaline reuptake inhibitors, are likely to be effective in the treatment of GAD. Of the psychological therapies, cognitive-behavioral therapy (CBT) shows the greatest benefit in treating GAD patients. Treatment gains after a 12-week course of CBT may be maintained for up to 1 year. Currently, no guidelines exist for the long-term treatment of GAD.

Antidepressive Agents, Tricyclic↗
PubMed2003

Psychotropic drugs, cardiac arrhythmia, and sudden death.

A variety of drugs targeted towards the central nervous system are associated with cardiac side effects, some of which are linked with reports of arrhythmia and sudden death. Some psychotropic drugs, particularly tricyclic antidepressants (TCAs) and antipsychotic agents, are correlated with iatrogenic prolongation of the QT interval of the electrocardiogram (ECG). In turn, this is associated with the arrhythmia (TdP). This review discusses the association between psychotropic agents, arrhythmia and sudden death and, focusing on TCAs and antipsychotics, considers their range of cellular actions on the heart; potentially pro-arrhythmic interactions between psychotropic and other medications are also considered. At the cellular level TCAs, such as imipramine and amitriptyline, and antipsychotics, such as thioridazine, are associated with inhibition of potassium channels encoded by In many cases this cellular action correlates with ECG changes and a risk of TdP. However, not all psychotropic agents that inhibit HERG at the cellular level are associated equally with QT prolongation in patients, and the potential for QT prolongation is not always equally correlated with TdP. Differences in risk between classes of psychotropic drugs, and between individual drugs within a class, may result from additional cellular effects of particular agents, which may influence the consequent effects of inhibition of repolarizing potassium current.

Animals↗
PubMed2003

Caffeine and central noradrenaline: effects on mood, cognitive performance, eye movements and cardiovascular function.

There have been numerous studies on the effects of caffeine on behaviour and cardiovascular function. It is now important to clarify the mechanisms that underlie such effects, and the main objective of the present study was to investigate whether changes in central noradrenaline underlie some of the behavioural and cardiovascular effects of caffeine. This was examined using a clonidine challenge paradigm. Twenty-four healthy volunteers were assigned to one of four conditions: (i) clonidine/caffeine; (ii) clonidine/placebo; (iii) placebo/caffeine: (iv) placebo/placebo. Baseline measurements of mood, cognitive performance, saccadic eye movements and cardiovascular function were recorded. Subsequently, volunteers were given either clonidine (200 microg) or placebo and consumed coffee containing caffeine (1.5 mg/kg) or placebo. The test battery was then repeated 30 min, 150 min and 270 min later. A second cup of coffee (with the same amount of caffeine as the first) was consumed 120 min after the first cup. The results showed that clonidine reduced alertness, impaired many aspects of performance and slowed saccadic eye movements; caffeine removed many of these impairments. Both clonidine and caffeine influenced blood pressure (clonidine reduced it, caffeine raised it) but the effects appeared to be independent, suggesting that separate mechanisms were involved. In addition, there were some behavioural effects of caffeine that were independent of the clonidine effect (e.g. effects on speed of encoding of new information) and these may reflect other neurotransmitter systems (e.g cholinergic effects). Overall, the results suggest that caffeine counteracts reductions in the turnover of central noradrenaline. This mechanism may underlie the beneficial effects of caffeine seen in low alertness states.

Adolescent↗
PubMed2003

Death and dependence: current controversies over the selective serotonin reuptake inhibitors.

Recent years have seen a considerable media interest in the adverse effects of the selective serotonin reuptake inhibitors (SSRIs). This has led to claims that these antidepressants may lead to suicide and homicide and that they cause dependence or even addiction. Such claims have caused great concerns to many patients and have confused doctors in both primary care and psychiatric practice. In this article I review the basis of these claims and show that many seem to emerge from the misinterpretation of evidence and the use of imprecise definitions. Although the SSRIs are not free of problems they compare very favourably with other antidepressants and other classes of psychotropic drugs. There is no evidence they are addictive in the formal sense of leading to a drug dependence syndrome. Some suggestions on the way these issues can be more precisely defined and studied in future are given.

Antidepressive Agents, Second-Generation↗
PubMed2002

Distribution of [(3)H]BU224, a selective imidazoline I(2) binding site ligand, in rat brain.

BU224 (2-(4,5-dihydroimidaz-2-yl)-quinoline) is a selective imidazoline I(2) binding site ligand characterised in both competition binding assays and functional studies. However, in some studies, BU224 has been reported to have a different functional effect from that seen with another selective imidazoline I(2) binding site ligand 2-BFI (2-(2-benzofuranyl)-2-imidazoline). This effect may reflect differing efficacies of the ligands or a difference in their brain distribution. The present study has investigated the distribution of the tritiated form of BU224 in rat brain and correlated this distribution with other imidazoline I(2) binding site ligands, [(3)H]idazoxan and [(3)H]2-BFI. Saturation studies revealed binding of [(3)H]BU224 was of high affinity and saturable. The central distribution of [(3)H]BU224 was similar to that previous reported for imidazoline I(2) binding site in rat brain. Autoradiography revealed that the highest levels of binding were in the arcuate nucleus, interpeduncular nucleus, area postrema, pineal gland and ependymal cell layer lining the ventricles. Correlation analysis of the binding distribution with our previous published studies revealed a highly significant correlation between [(3)H]BU224 and both [(3)H]idazoxan (r=0.94) and [(3)H]2-BFI (r=0.96). These data indicate [(3)H]BU224 labels the same population of imidazoline I(2) binding site in rat brain as seen with [(3)H]idazoxan and [(3)H]2-BFI. Therefore, the differences in functional effects observed with these compounds may reflect agonist and antagonist properties.

Animals↗
PubMed2002

Tolerability and safety aspects of mirtazapine.

The tolerability and safety profile of the noradrenergic and specific serotonergic antidepressant (NaSSA) mirtazapine reflects its unique pharmacological profile. The 5-HT(2) blocking effect contributes towards its anxiolytic effects and benefits on sleep, as well as preventing the sexual dysfunction that may occur with non-specific stimulation of the serotonin system by drugs such as the selective serotonin reuptake inhibitors (SSRIs). In addition, 5-HT(3) blockade by mirtazapine helps to prevent nausea and vomiting. Weight gain is the most commonly reported side-effect of mirtazapine, although there is evidence to suggest that this is not a significant problem during long-term treatment. In conclusion, mirtazapine has a good tolerability and safety profile that demonstrates several benefits over other antidepressants.

Adrenergic alpha-Antagonists↗
PubMed2002

Inhalation of 35% CO(2) results in activation of the HPA axis in healthy volunteers.

BACKGROUND: The hypothalamo-pituitary-adrenal (HPA) axis is a major stress responsive system in humans. Although there are numerous ways of testing responsiveness of the HPA in experimental animals, this is much more difficult in man. Hypercapnea is a very stressful stimulus for humans and has been used as an anxiogenic probe in psychiatric patients. We have now investigated whether the simple challenge of a single 35% inhalation of CO(2) activates the neuroendocrine system as evidenced by changes in HPA activity, as well as cardiovascular and subjective responses, in healthy volunteers. METHODS: Fourteen healthy male volunteers were recruited. They underwent single vital capacity inhalation of room air and 35% CO(2), in a single blind fashion. Neuroendocrine, cardiovascular and subjective fear measures were taken at regular intervals. RESULTS: CO(2) inhalation produced significant activation of the HPA axis in all subjects, as measured with plasma cortisol. Heart rate was decreased and systolic blood pressure was significantly increased shortly after the inhalation of CO(2). The subjects reported short-lived symptoms of fear with the experimental gas. CONCLUSIONS: Single vital capacity inhalation of 35% CO(2) activated the HPA axis in healthy volunteers. It also had a significant cardiovascular and psychological (anxiogenic) effect, as expected from previous published studies. The test is potentially useful in studying the responsivity of the HPA axis in health and disease.

Administration, Inhalation↗
PubMed2002

N1'-fluoroethyl-naltrindole (BU97001) and N1'-fluoroethyl-(14-formylamino)-naltrindole (BU97018) potential delta-opioid receptor PET ligands.

The properties of two prospective positron emission tomography (PET) ligands for the delta-opioid receptor, N1'-fluoroethyl-naltrindole (BU97001) and N1'-fluoroethyl-(14-formylamino)-naltrindole (BU97018) were investigated. Both were antagonists in the mouse vas deferens, and showed high affinity and selectivity, 1.81 nM and 3.09 nM respectively. [3H]BU97001 binding to rat whole brain was also of high affinity, K(D) of 0.42 nM of and B(MAX) of 59.95 fmol mg of protein(-1). In autoradiographic studies, it was found to bind to brain areas previously shown to be associated with the delta-opioid receptor and good correlations were found to exist with naltrindole and DPDPE. BU97018 and especially BU97001 appear to show good potential as delta-opioid receptor PET ligands with the incorporation of 18F.

Animals↗
PubMed2002

Generalized anxiety disorder: comorbidity, comparative biology and treatment.

Generalized anxiety disorder (GAD) is a severe and chronic anxiety disorder characterized by uncontrollable worrying and somatic anxiety (tension, insomnia and hypervigilance). It is a common condition, with lifetime prevalence rates for DSM-IV GAD in the general population of approx. 5-6% being reported. In addition, like other anxiety disorders, GAD also shows comorbidity with depression and most of the other anxiety disorders. This article reviews data on the prevalence of GAD, its comorbidity with depression, and its social and economic impact. Proposed neurobiological mechanisms for GAD are discussed, since an understanding of these may help in the development of future therapies. Finally, current pharmacological and non-pharmacological treatment options for GAD are reviewed, with particular attention being paid to published clinical-trial data.

Anti-Anxiety Agents↗
PubMed2002

Imaging the GABA-benzodiazepine receptor subtype containing the alpha5-subunit in vivo with [11C]Ro15 4513 positron emission tomography.

There is evidence of marked variation in the brain distribution of specific subtypes of the GABA-benzodiazepine receptor and that particular subtypes mediate different functions. The alpha5-containing subtype is highly expressed in the hippocampus, and selective alpha5 inverse agonists (which decrease tonic GABA inhibition) are being developed as potential memory-enhancing agents. Evidence for such receptor localization and specialization in humans in vivo is lacking because the widely used probes for imaging the GABA-benzodiazepine receptors, [11C]flumazenil and [123I]iomazenil, appear to reflect binding to the alpha1 subtype, based on its distribution and affinity of flumazenil for this subtype. The authors characterized for positron emission tomography (PET) a radioligand from Ro15 4513, the binding of which has a marked limbic distribution in the rat and human brain in vivo. Competition studies in vivo in the rat revealed that radiolabeled Ro15 4513 uptake was reduced to nonspecific levels only by drugs that have affinity for the alpha5 subtype (flunitrazepam, RY80, Ro15 4513, L655,708), but not by the alpha1 selective agonist, zolpidem. Quantification of [11C]Ro15 4513 PET was performed in humans using a metabolite-corrected plasma input function. [11C]Ro15 4513 uptake was relatively greater in limbic areas compared with [11C]flumazenil, but lower in the occipital cortex and cerebellum. The authors conclude that [11C]Ro15 4513 PET labels in vivo the GABA-benzodiazepine receptor containing the alpha5 subtype in limbic structures and can be used to further explore the functional role of this subtype in humans.

Animals↗
PubMed2002

The neuropharmacology of serotonin and noradrenaline in depression.

Several classes of antidepressant drug exist, divided into three broad families, the monoamine reuptake inhibitors, the monoamine oxidase inhibitors and the monoamine receptor antagonists. All these drugs have a common pharmacological effect, to raise the synaptic concentrations of noradrenaline and serotonin. Although different drugs have different relative selectivity for noradrenaline and serotonin systems, these two neurotransmitter pathways work in parallel and in a coherent manner to produce the same final antidepressant response. The lag-time in the onset of action of antidepressants can be explained by the activation of inhibitory autoreceptors on serotonergic and noradrenergic neurones which initially attenuate the effects of antidepressants on synaptic transmitter levels. Over time, these autoreceptors desensitize, allowing the emergence of an overt antidepressant response. This theory has led to the proposition that antagonists at these autoreceptors such as pindolol may be useful adjuncts to antidepressant treatment, in order to hasten the appearance of a clinical response. Evidence for the clinical validity of this idea remains equivocal, however. The use of central monoamine depletion studies has demonstrated that it is elevated synaptic monoamine levels themselves, rather than some downstream postsynaptic changes in, for example, receptor sensitivity, that are responsible for the therapeutic effect of antidepressant drugs. Taken together, the data collected over the last 40 years have allowed the emergence of a unified monoamine hypothesis of antidepressant drug action.

Adrenergic Uptake Inhibitors↗
PubMed2002

Does 5-HT restrain panic? A tryptophan depletion study in panic disorder patients recovered on paroxetine.

The neurobiological basis of panic disorder has not been clearly established, although a role for serotonin (5-HT) has been postulated. It is clear that drugs which increase 5-HT neurotransmission are effective in treating the condition but how they do so remains a point of debate. The aim of this study was to determine if lowering brain serotonin activity using the technique of tryptophan depletion provoked a short-term relapse of panic symptoms in patients with panic disorder who had responded to drug treatment. Fourteen patients with panic disorder who had responded to treatment with the selective serotonin reuptake inhibitor (SSRI) paroxetine received a tryptophan-free amino acid drink on one occasion and a control drink on the other in a double-blind crossover design. In addition, they received an infusion of flumazenil (used as a pharmacological challenge) and placebo on each day. The tryptophan depleted drink produced an 87% reduction in plasma tryptophan concentration. Flumazenil produced a panic attack (defined by changes in the panic inventory) in seven out of 14 patients when tryptophan depleted and one out of 14 on the control day (p < 0.02). Three patients also experienced temporary depressive symptoms when tryptophan depleted, with no mood changes being seen on the control days. We conclude that rapid lowering of brain serotonin function can allow the precipitation of panic symptoms in response to flumazenil in panic disorder patients who have responded to treatment with an SSRI. This implies that in panic disorder increased 5-HT availability is important in maintaining the response to SSRIs.

Adult↗