The selective 5-HT1B receptor inverse agonist 1'-methyl-5-[[2'-methyl-4'-(5-methyl-1,2, 4-oxadiazol-3-yl)biphenyl-4-yl]carbonyl]-2,3,6,7-tetrahydro- spiro[furo[2,3-f]indole-3,4'-piperidine] (SB-224289) potently blocks terminal 5-HT autoreceptor function both in vitro and in vivo.

5-HT1 receptors are members of the G-protein-coupled receptor superfamily and are negatively linked to adenylyl cyclase activity. The human 5-HT1B and 5-HT1D receptors (previously known as 5-HT1Dbeta and 5-HT1Dalpha, respectively), although encoded by two distinct genes, are structurally very similar. Pharmacologically, these two receptors have been differentiated using nonselective chemical tools such as ketanserin and ritanserin, but the absence of truly selective agents has meant that the precise function of the 5-HT1B and 5-HT1D receptors has not been defined. In this paper we describe how, using computational chemistry models as a guide, the nonselective 5-HT1B/5-HT1D receptor antagonist 4 was structurally modified to produce the selective 5-HT1B receptor inverse agonist 5, 1'-methyl-5-[[2'-methyl-4'-(5-methyl-1,2, 4-oxadiazol-3-yl)biphenyl-4-yl]carbonyl]-2,3,6, 7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (SB-224289). This compound is a potent antagonist of terminal 5-HT autoreceptor function both in vitro and in vivo.

The behavioural effects of corticotropin-releasing factor-related peptides in rats.

The present study determined the behavioural effects of the corticotropin releasing factor (CRF)-related peptides, human/rat CRF (h/rCRF), ovine CRF (oCRF), sauvagine (SAUV), urotensin I (UT) and the recently discovered neuropeptide, rat urocortin (rUCN). All of the peptides dose-dependently increased motor activity in a familiar environment and reduced feeding in hungry rats. There was no apparent relationship between potency/affinity at CRF2 receptors and effects in these two tests. In a comparison of h/rCRF and rUCN upon discrete spontaneous behaviours, both peptides (3.0 microg i.c.v.) increased activity and grooming, induced a fore-paw tremor and reduced the incidence of motionlessness. However, h/rCRF reduced motionlessness to a greater extent and was a more potent inducer of defaecation, weight loss, oral movements and fore-paw tremor than rUCN. In the elevated X maze, both h/rCRF and rUCN (1.0 microg i.c.v.) had anxiogenic-like effects upon behaviour. In contrast, h/rCRF (1.0 microg i.c.v.), but not rUCN (1.0-10 microg i.c.v.) increased the startle response to an acoustic stimulus. In summary, all the CRF-related peptides increased motor activity and reduced feeding in rats in a similar manner and both rUCN and h/rCRF induced anxiogenesis. However, there were some behavioural differences between rUCN and h/rCRF which require further study. Further pharmacological investigation of the role of CRF receptor subtypes requires the use of subtype selective antagonists.

A computer-controlled apparatus for measuring and analysing myoclonic jerk activity in guinea pigs.

Guinea pigs respond to 5-hydroxytryptophan (5-HTP) with a complex behavioural syndrome which includes distinctive whole-body jerks (myoclonic jerks). These are species-specific, involve all major muscle groups, are highly rhythmic and can occur with relatively high frequency (1-2/s). Current methods of quantifying the response, which rely on observer ratings are unsatisfactory. We report the development of a fully automated, PC-based system for detecting and analysing myoclonic jerks. Floor-mounted accelerometers generate a movement signal and detection is performed by an algorithm based on a detailed analysis of the topography of myoclonic jerk responses. The system can monitor the output from 10 purpose-built test enclosures and it provides for pseudorandom treatment allocation, flexible control of experimental parameters and automated data output to a spreadsheet which generates appropriate graphs, statistical summaries and data analysis. This robust response provides a useful means of exploring the role of novel 5-HT receptor subtypes in guinea-pig behaviour.

The role of 5-HT1D and 5-HT1A receptors in mediating 5-hydroxytryptophan induced myoclonic jerks in guinea pigs.

Systemic administration of 5-hydroxytryptophan (5-HTP) to guinea pigs causes species-specific, rhythmic, whole body jerks (myoclonic jerks), the frequency and amplitude of which were measured in an automated apparatus. The brain penetrant 5-HT1D receptor agonist 3-(2-dimethylaminoethyl)-4-chloro-5-propoxyindole hemifumarate (SKF 99101H) (3-30 mg/kg i.p.) and the selective 5-HT1A receptor agonist (+/-)8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (0.3-3 mg/kg s.c.) dose dependently potentiated the frequency and intensity of myoclonic jerks caused by 5-HTP (100 mg/kg). Cotreatment of guinea pigs with 8-OH-DPAT (3 mg/kg s.c.) and SKF 99101H (30 mg/kg i.p.), which were inactive when given alone, gave a marked myoclonic jerk response. Conversely, the myoclonic jerk response to higher doses of 5-HTP (150 mg/kg i.p.) was dose dependently blocked by the 5-HT1D receptor antagonist GR 127935 (N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-1 ,2,4-oxadiazol-3-yl)[1,1'-biphenyl]4-carboxamide oxalate) (ED50 0.32 mg/kg i.p.) and the selective 5-HT1A receptor antagonist WAY 100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride) (ED50 0.33 mg/kg i.p.). The response to 5-HTP (150 mg/kg i.p.) was also blocked by ritanserin (0.01-0.3 mg/kg i.p.). Our data therefore confirm previous reports concerning the effects of 5-HT2A/2C receptor blockade on 5-HTP induced myoclonic jerks and suggest that both 5-HT1D and 5-HT1A receptors play an important role in mediating this behavioural response.

Stimulation of 5-HT1B receptors causes hypothermia in the guinea pig.

The selective, brain penetrant, 5-HT(1B/D) (formerly 5-HT(1D beta/alpha)) receptor agonist SKF-99101H (3-(2-dimethylaminoethyl)-4-chloro-5-propoxyindole hemifumarate) (30 mg/kg i.p.) causes a dose related fall in rectal temperature in guinea pigs which previous studies have shown to be blocked by the non-selective 5-HT(1B/D) receptor antagonist GR-127935 (N-[4-methoxy-3-(4-methyl-1-piperazinyl) phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl) [1,1'biphenyl]-4-carboxamide oxalate). The present study shows that the hypothermic response to SKF-99101H is dose-dependently blocked by SB-224289G (1'-methyl-5-(2'-methyl-4'-[(5-methyl-1,2,4-oxadiazol-3-yl)bipheny l-4-yl]carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-pi peridone] hemioxalate) (0.3-10.0 mg/kg p.o.) (ED50 3.62 mg/kg), which is the first compound to be described which is more than 60 fold selective for the 5-HT1B receptor over the 5-HT1D receptor. SB-216641A (N-[3-(2-dimethylamino) ethoxy-4-methoxy-phenyl] 2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-(1,1'-biphenyl)-4-car boxamide hydrochloride) (0.6-20.0 mg/kg i.p.), which is somewhat less selective (30 fold) for the 5-HT1B receptor over the 5-HT1D receptor had a similar effect (ED50 4.43 mg/kg). The brain penetrant 5-HT1D selective receptor antagonist, BRL-15572 (4-(3-chlorophenyl)-alpha-(diphenylmethyl)-1-piperazineethanol+ ++ dihydrochloride) (0.3-100.0 mg/kg i.p.) was inactive. When administered alone neither BRL-15572 (0.1-10 mg/kg i.p.) nor SB-224289G (2.2-22 mg/kg p.o.) had an effect on body temperature. These data demonstrate that 5-HT1B (formerly 5-HT(1D beta)) and not 5-HT1D (formerly 5-HT(1D alpha)) receptors mediate the hypothermic response to SKF-99101H (30 mg/kg i.p.) in guinea pigs. The compounds described are useful pharmacological tools for distinguishing responses to 5-HT1B and 5-HT1D receptors.

Motivation to comply with infection control procedures.

This paper addresses the critical issue of motivating hospital staff to comply with standard infection control procedures. Previous psychological assessment of infection control knowledge, attitudes and behaviour has indicated that the reasons for non-compliance are very basic and reflect inter alia a low perception of the importance of the measures and a lack of motivation. It is argued that, although staff have a theoretical awareness of the value of complying with such procedures, in practice these seem to have a low priority. Compliance levels, therefore, are variable and generally of a low order. If recent advances in the fields of social psychology, behavioural psychology and clinical psychology could be imported to hospital medicine, they could have a dramatic impact in infection control. The Elaboration Likelihood Model, an effective theoretical approach to message-based persuasion, and the energizing effects of intrinsic and extrinsic motivational processes are defined. Finally, the implications of these concepts for persuasive intra-hospital communication in infection control are highlighted. They can provide a framework for developing effective infection prevention programmes.

5-HT 1D receptors mediate SKF 99101H-induced hypothermia in the guinea pig.

The selective, brain penetrant, 5-HT(1D) receptor agonist SKF 99101H (10-30 mg/kg i.p.) caused a dose-related fall in rectal temperature in guinea pigs which lasted longer than 2 h. Sumatriptan (1.0-100 mg/kg i.p.), a selective 5-HT(1D) agonist which does not penetrate the brain, did not produce hypothermia, suggesting that peripheral mechanisms are not critically involved in the response. The hypothermia induced by SKF 99101H (30 mg/kg i.p.) was dose-dependently blocked by the 5-HT(1D) receptor antagonists GR 127935 (0.01-1 mg/kg i.p.) and GR 125743 (0.01-3 mg/kg i.p.), confirming the role of 5-HT(1D) receptors. Mianserin (0.3-10.0 mg/kg i.p.) and granisetron (0.1-3.0 mg/kg i.p.) were inactive, suggesting that 5-HT(2A/2B/2C) or 5-HT( 3) receptors play no significant role in the generation of the hypothermic response. Nor was the hypothermia reversed by prazosin (0.03-1.0 mg/kg i.p.), idazoxan (0.03-1.0 mg/kg i.p.) or scopolamine (0.01-0.3 mg/kg i.p.), thereby excluding mediation by α(1)- and α(2)-adrenoceptors and muscarinic receptors. WAY 100635 (0.1-1.0 mg/kg) significantly potentiated the effect of SKF 99101H. The antagonists, when given alone, had no effect on body temperature, with the exception of prazosin (0.1 and 1.0 mg/kg). Three days of treatment with parachloroamphetamine (30 mg/kg i.p.) depleted forebrain 5-HT by ∼ 75% in frontal cortex, hypothalamus, hippocampus and striatum, but failed to alter the hypothermic response to SKF 99101H. The hypothermia is, therefore, unlikely to be mediated by 5-HT(1D) receptors located on 5-HT neurons. SKF 99101H-induced hypothermia in the guinea pig may serve as a useful model for investigation of centrally acting 5-HT( 1D) receptor antagonists.

Taking responsibility for cancer treatment.

One hundred and fourteen consecutive patients with early breast cancer were entered into a study on the psychological effects of involvement in treatment choice. All women were offered counselling throughout. One group of women (n = 34), were advised to undergo mastectomy, due to the nature or position of the tumour. These women fared less well psychologically when compared on a battery of measures, before and after surgery, with women who were involved in choosing their own treatment (n = 80). The latter group itself was randomly allocated into two groups for taking explicit responsibility for treatment choice, using a double-blind procedure. These were a Patient Decision Group (n = 41) and a Surgeon Decision Group (n = 39). Results support the hypothesis that over and above the benefits of receiving their preferred treatment, women can further benefit from taking explicit responsibility for their treatment choice.

An application of the fear avoidance model to three chronic pain problems.

The Fear Avoidance Model of Exaggerated Pain Perception was developed in an attempt to explain how, and why, some individuals develop a more substantial psychological overlay to their low back pain problem than do others. The present paper describes a study in which three chronic pain groups, consisting of Post-Herpetic neuralgia patients, Reflex Sympathetic Dystrophy patients and chronic low back pain patients were compared with three pain-free comparison groups using the Fear Avoidance Model of Exaggerated Pain Perception. The results show statistically significant differences between the chronic groups and the recovered comparison groups. These results demonstrate the usefulness of the Fear Avoidance Model as an explanation of psychological overlay in chronic pain conditions regardless of pathology.

The prediction of chronicity in patients with an acute attack of low back pain in a general practice setting.

STUDY DESIGN: Three hundred patients, attending their general practitioners with attacks of acute low back pain, formed the subject population for a study of fear avoidance and other variables in the prediction of chronicity. Follow-up was at 2 and 12 months. OBJECTIVE: The hypothesis to be tested was that evidence of psychological morbidity, particularly fear-avoidance behavior, would be manifest from the outset of the presenting attack in susceptible subjects. SUMMARY OF BACKGROUND DATA: While back pain is an almost universal human experience, only about 5% of sufferers seek medical advice. Most of these respond to conservative treatment. However, approximately 10% of those who experience an acute attack of low back pain go on to become chronic sufferers. METHODS: Psychosocial and physiological data (including fear-avoidance measures) were collected from a sample of 300 acute low back pain patients within 1 week of presentation and at 2 months, to try to predict 12 month outcome. RESULTS: Data analysis showed that subjects who had not recovered by 2 months were those who went on to become chronic low back pain patients (7.3%). Using multiple regression analyses, fear-avoidance variables were the most successful in predicting outcome. Using multiple discriminant function analyses, the results suggest that the outcome in terms of the future course of low back pain can be correctly classified in 66% from fear-avoidance variables alone and in 88% of patients from all variables. CONCLUSIONS: The results suggest that, at the earliest stage of low back pain, fear of pain should be identified by clinicians and, where this is severe, pain confrontation should arguably form part of the approach to treatment.

Chronic low back pain rehabilitation programs: a study of the optimum duration of treatment and a comparison of group and individual therapy.

STUDY DESIGN: Eighty-four patients with chronic low back pain were treated using cognitive behavioral principles on a pain management program. Outcome data were collected at four points: 10 weeks before treatment, immediately before and immediately after treatment, and 6 months after treatment. In part 1 of the study, patients were assigned randomly to group or individual treatment contexts. In part 2 of the study, patients were assigned randomly to programs of 15, 30, or 60 hours duration. OBJECTIVES: To identify the differences in outcome between programs that treated patients as part of a group and those that treated patients individually and the effects of duration of treatment on outcome. SUMMARY OF BACKGROUND DATA: Cognitive behavioral programs have been shown to be an effective means of managing chronic low back pain. The literature is concerned with group programs, however, the duration of which vary widely. METHOD: Psychological and functional variables were measured before and after treatment and at the 6-month follow-up visit. Changes in these variables were measured, and comparisons were made between group and individual programs and between 15-, 30-, and 60-hour programs. RESULTS: Data analysis showed a significant, beneficial effect of intervention in terms of the majority of variables; however, these changes were generally independent of whether patients were treated as part of a group or individually and whether patients completed a 15-, 30-, or 60-hour program. CONCLUSIONS: Cognitive behavioral rehabilitation programs have been demonstrated to be an effective means of reducing psychological distress, of changing cognition, and of improving the function of patients with chronic low back pain; however, the length of program and whether patients were treated individually or as part of a group did not affect outcome. This finding has clinical and economic implications.

Treatment and follow-up variables discriminating abstainers, controlled drinkers and relapsers.

A group of behaviorally treated abstainers, controlled drinkers and relapsers who had been followed up for a minimum of 1 year were compared on eight treatment and 11 posttreatment variables. Discriminating characteristics of abstainers were their goal of abstinence at discharge and length of attendance at aftercare facilities. Controlled drinkers had a goal of controlled drinking and were most likely to have had controlled drinking training during treatment. Relapsers were most likely to have been discharged from treatment prematurely, to receive further treatment and to use psychotropic medication. No controlled drinkers attended Alcoholics Anonymous or received residential care during follow-up in contrast to a small proportion of abstainers and relapsers who did. Some aspects of the drinking behavior of controlled drinkers and relapsers were also studied. Controlled drinkers were more likely to have a period of initial abstinence and for a longer period of time. Of the controlled drinkers, 66% drank at least once per week and 86% set themselves drinking limits; average consumption of alcohol was 48 and 32 g/day by men and women, respectively. The majority of controlled drinkers changed their preferred beverage and their social and physical drinking environment after treatment in accordance with therapeutic advice.

Predictors of outcome type in treated problem drinkers.

Fifty successful controlled drinkers, 45 abstainers and 44 relapsers who had been followed up intensively for a minimum of 1 year were compared on 32 pretreatment variables in an attempt to isolate those which would be predictors of outcome type. Treatment was behaviorally oriented, and all subjects except for those with liver damage were left to make their own choice of treatment goal. The results showed that the best predictors of abstinence were: previous contact with Alcoholics Anonymous (A.A.); medium period of previous abstinence; having been initiated to seek help by a specialist; having been a periodic drinker, and drinking exclusively alone or socially. Controlled drinkers were more likely to be continuous drinkers, were not likely to have attended A.A. or to have abstained for a significant period of time, were likely to have relatives with a drinking problem, to have been motivated to seek help by a friend or a relative and to be less discriminating about the social drinking environment. Relapsers were more likely to be unemployed, to have a history of A.A. attendance and to have had a short period of previous abstinence. They were most likely to have liver damage and therefore advised to abstain. The results were interpreted as suggesting that outcome is likely to be influenced by the subjects' cognitions, by past behavioral expectations and experience of abstinence, as well as having the freedom of a choice of goals for recovery.

A follow-up study of problem drinkers offered a goal choice option.

Patients (N = 100) who had been admitted to behaviorally oriented residential treatment for their drinking problems were followed up for 1 year. A treatment goal option of controlled drinking was explicitly catered for. Overall outcome, in which 27% of those available for follow-up were categorized as "successful," 35% as "equivocal" and 38% as "failure," does not appear to be markedly dissimilar to that reported from other agencies. The distribution of approximately equal abstinent and nonabstinent successful outcomes is similar to that found following treatment programs that promote a single goal. Sociodemographic variables were less influential in predicting outcome than were treatment variables--with frequency of aftercare attendance being particularly significant. Those who had received previous hospital treatment for their problem, those who habitually drank in company and those who had abnormal blood test results prior to entering treatment had poorer outcome.

Reality testing and auditory hallucinations: a signal detection analysis.

The hypothesis that hallucinators are deficient in the metacognitive skill of reality testing was tested using the methodology of signal detection theory. In Expt 1 undergraduate subjects scoring high or low on a scale measuring predisposition to hallucination were tested on an auditory signal detection task. High scorers on the scale were found to differ from low scorers on a measure of perceptual bias but not on a measure of sensitivity. In Expt 2 a similar methodology was used with hallucinating and non-hallucinating schizophrenic patients, with similar results. These results support the hypothesis that hallucinators or subjects highly disposed towards hallucination are deficient in reality testing and are therefore prone to identify imaginary events as real.

The multidimensional nature of schizotypal traits: a factor analytic study with normal subjects.

Fourteen published scales of psychotic traits or symptoms (measuring various delusional states, magical ideation, perceptual aberration, disposition towards hallucination, hypomanic personality, schizotypal personality, borderline personality and anhedonia) were combined with the Eysenck Personality Questionnaire to form a Combined Schizotypal Traits Questionnaire (CSTQ) which was administered to 180 normal subjects. Two factor analyses were carried out on the scale scores. The first analysis excluded symptom scores derived from the Delusions Symptoms States Inventory of Foulds and Bedford and yielded a three-factor solution which appeared to measure traits relating to (i) positive psychotic symptomatology; (ii) negative psychotic symptomatology; and (iii) aspects of schizotypy involving social anxiety and cognitive disorganization. The Foulds scales were included in the second analysis which yielded a four-factor solution. The first three factors were similar to those obtained from the first analysis; the fourth factor seemed to measure an asocial component of schizotypy. This last factor was mainly accounted for by the P scale from the EPQ. These results support previous findings suggesting that different schizotypy scales relate to different underlying aspects of schizophrenia. The findings also indicate that psychotic traits are distributed along at least three dimensions.

An experimental analysis of perfectionism and dissatisfaction.

The striving after perfection has been often mentioned in clinical literature; however, there have been few systematic analyses of the concept. In the present study, a questionnaire measure of Perfectionism and General Dissatisfaction (the SCANS) together with the Eysenck Personality Questionnaire and measures thought to gauge aspects of perfectionistic thinking, were administered to a mixed group of 148 subjects, including 25 eating disorder patients. Perfectionism was found to correlate negatively with Psychoticism (as measured by the EPQ) and positively with the Lie scale. Thus Perfectionism appears to be associated with a tendency to deny personally deviant behaviour and to present oneself in the best possible light. It is also associated with greater accuracy in a visual search task. General Dissatisfaction was correlated significantly with Neuroticism, Introversion and Psychoticism. It thus appears to be related to a combination of 'neurotic introversion' and 'personality deviance'. It is also associated with a tendency to be under-inclusive, that is to find difficulty in ruling out irrelevant stimuli when forming categories. Dissatisfaction was also associated with increased reaction time in the visual search task, perhaps also a reflection of an inability to ignore irrelevant stimuli. Only the EPQ N and P scales successfully differentiated neurotic or dissatisfied perfectionists from normal or satisfied perfectionists, although several measures derived from the visual search task produced results which were approaching significance.

Good and bad clinicians: supervisors' judgements of trainees' competence.

Experienced supervisors of trainee clinical psychologists used 24 scales to rate four concepts: 'your stereotype of a good trainee'; "a good trainee well known to you'; 'a bad trainee well known to you'; and 'your stereotype of a bad trainee'. Similar ratings were given for both the good trainee concepts, which were rated differently from both the bad concepts, which were also rated differently from each other. Factor analysis revealed that the supervisor's judgements fell across two interpretable dimensions.

The specific psychosocial effects of orthognathic surgery.

This study was to test the validity of patients' opinions and provide a more accurate method than previously reported of assessing the specific psycho-social effects of orthognathic surgery. Questionnaires were used preoperatively and postoperatively providing a longitudinal sample, while those patients who only completed questionnaires either before or after surgery provided cross-sectional samples. Different questionnaires were used to provide data on a 'Body Satisfaction Scale', 'Fear of Negative Evaluation', 'Social Avoidance and Distress', and a 'General Health Questionnaire'. The results indicate that surgery produced an improvement in body image, particularly in the evaluation of facial attractiveness.

A dual process model of perfectionism based on reinforcement theory.

This article begins with a brief review of the current literature on the structure and measurement of perfectionism. It is concluded from this review that two major types can be distinguished, a normal/healthy form and a pathological form. These two forms are then defined as positive and negative perfectionism and related directly to Skinnerian concepts of positive and negative reinforcement. The positive/negative distinction is then further elaborated on in terms of approach/avoidance behavior, goal differences, self-concept involvement, emotional correlates, and the promoting environment. Finally, some of the more obvious theoretical and practical implications are briefly explored.