David J. Nutt

Evaluation of Severe Insomnia In The General Population: Results of a European Multinational Survey:

The epidemiology of severe insomnia and its effect on quality of life and healthcare consumption was assessed in a survey of the general population of five northern European countries. Applying established consumer sampling techniques, insomnia sufferers were selected from the general population using a questionnaire, conducted by face-to-face interview, and severity of insomnia was ranked (severe, mild/moderate, no sleep complaint) using a specific algorithm. Population samples were matched according to case control methodology for age, gender and geographical region. A second questionnaire gathered information on sleep problems, quality of life (SF-36 scores) and healthcare consumption. The prevalence of severe insomnia ranged from 4% to 22%, was higher in females than in males, but did not increase significantly with age. Patients with severe insomnia had been experiencing sleeping problems for a median of 2–6 years. In all countries, insomnia had a negative impact on quality of life, and the degree of impairment in quality of life was directly related to the severity of insomnia. Individuals with severe insomnia also showed a higher level of healthcare consumption. Despite this, severe insomnia did not appear to feature prominently in the doctor-patient relationship.

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.

The neurobiology of social phobia.

Abstract Although Social Phobia has been recognised for centuries in comparison with other anxiety disorders, relatively little work has been done to understand its neural basis. The present review attempts to redress this balance by giving an overview of the current state of knowledge in this disorder. By putting together data from the treatment responses to specific agents, the effects of chemical challenges which have been used in other anxiety disorders and by reviewing data on central and peripheral neurotransmitter and endochrine abnormalities, it is possible to begin to generate some potentially testable therories of aetiology and mechanisms. Finally, we review the potential use of neuroimaging techniques to better detail the brain circuits and possibly neurotransmitters involved in social phobia, showing some of our preliminary work using 15O water blood flow PET activation studies to determine the brain circuits in which metabolism is changed during the experience of social anxiety.

Home cage presentation of complex discrimination tasks to marmosets and rhesus monkeys

The study reported here demonstrates the feasibility of presenting cognitive tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB) to either marmosets or rhesus monkeys in their home cages. This location of testing offers opportunities for the measurement of additional indices, for example spontaneous behaviour (Prowse et al. 1995) and electrophysiology (Pearce et al. 1998) as well as facilitating repeated test presentation. Results from 12 marmosets and 4 rhesus monkeys which have completed several sequences of an eight-stage discrimination task involving simple discriminations, compound discriminations and reversals are reported. The paradigm developed has application in long-term studies. Tests from CANTAB have been used extensively in normal humans (Robbins et al. 1994) as well as a range of patient groups (Owen et al. 1992, Elliott et al. 1995) and to assess drug effects (Coull et al. 1996). Additionally some of these tests have been presented to marmosets (Roberts et al. 1988) to examine neuropsychological functioning. This comparative approach facilitates meaningful cross species comparison, particularly in the study of the effects of pharmacological intervention.

Treatment of depression and concomitant anxiety

The prevalence of depression and concomitant anxiety is high in the community. Patients with depression and concomitant anxiety experience increased functional disability, increased disruption to social, work and family life, and frequently report more symptoms. Treatment needs to be primarily efficacious for depression and secondly for anxiety; both sets of symptoms require prompt and effective treatment. Although benzodiazepines are still prescribed for depression and associated anxiety, they are essentially ineffective in treating depression and therefore are inappropriate. The anxiolytic effect of tricyclic antidepressants (TCAs) takes longer to develop than their antidepressant effect and their adverse tolerability profile can hinder treatment compliance. Selective serotonin re-uptake inhibitors (SSRIs) are a newer class of antidepressants that are as effective as TCAs in treating depression and are well tolerated in the long term and have demonstrated efficacy in the treatment of anxiety. This paper will provide evidence to demonstrate the short- and long-term efficacy of SSRIs in the treatment of depression and comorbid anxiety, with most clinical evidence supporting the anxiolytic profile of the SSRI paroxetine.

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

Abstract 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.

Sleep and daytime sleepiness the next day following single night-time dose of fluvoxamine, dothiepin and placebo in normal volunteers

To explore the effects of sedating and non-sedating antidepressants, we conducted a placebo-controlled, double-blind cross-over study in 12 normal subjects of the effects of a single night-time dose of fluvoxamine 100 mg, dothiepin 100 mg or placebo on night-time sleep recorded at home, and sleepiness and performance the following day. Night-time sleep was altered significantly by both drugs, with main effects on rapid eye movement (REM) sleep and sleep continuity. Dothiepin increased total sleep time, REM latency and stage 2 sleep and decreased arousals, wake after sleep onset and stage 1, whereas fluvoxamine decreased total sleep time and REM time and increased wake after sleep onset. Sleep latencies in daytime naps were significantly shorter for dothiepin and longer for fluvoxamine, showing that subjects were more sleepy when taking dothiepin. Electroencephalograms (EEG) performed during performance tasks failed to distinguish significantly between drugs. There were no significant differences between groups on our measures of tracking performance or reaction time; however, these tasks were designed primarily to provide a standard setting in which to monitor continuous EEG, and were unsuitable to detect sleepiness effects themselves. Saccadic eye movement velocity, acceleration and deceleration showed small non-significant changes after both drugs. Mood self ratings showed no significant differences among the groups. Subjective measures of night-time sleep reflected the objective measures of sleep continuity, and the items for difficulty and speed of wakening in the morning were significantly higher (i.e. more difficulty and slower) in the dothiepin group. The home-recorded sleep findings after fluvoxamine in this study were very similar to sleep laboratory studies with other antidepressant drugs, thus providing more validation of the home recording method.

The processing of automatic thoughts of drug use and craving in opiate-dependent individuals.

This study investigated the processing of sentences describing craving and withdrawal in opiate-dependent individuals. Eighteen patients who attended a methadone maintenance clinic for obtaining methadone, 18 patients who were not treated with methadone, and 18 control family members performed on a computerized contextual priming task. The task was priming sentences (craving, withdrawal, or neutral) to words (addiction, neutral, or nonwords). The methadone group was slower to process all sentences compared with family members. They were also faster to process drug-related words following withdrawal-related sentences compared with neutral words following neutral sentences. Finally, they were slower to recognize neutral words following neutral sentences compared with the nonmethadone group. Results suggest that the processing of information describing withdrawal and craving for drugs plays an important role in opiate dependence.

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 CDSs 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 CDSs extracted from bovine tissues. These results support the notion of the existence of several CDSs.

New Directions in Anxiety: OCD Spectrum Disorders

This session was divided into two sections. The first explored the neurobiologic basis of stress and stress sensitivity and the second examined the issue of body dysmorphic disorder, a relatively underdiagnosed and poorly understood condition.