Antimanic potency of typical neuroleptic drugs and affinity for dopamine D2 and serotonin 5-HT2A receptors--a new analysis of data from the archives and implications for improved antimanic treatments.

Datasets of antimanic potency ratings and receptor-binding affinities [inhibition constants (K(i))] at dopamine D2 and serotonin 5-HT2A brain receptors were accessed from published literature for a large series (n = 24) of typical neuroleptic drugs, many of which are now obsolete and unobtainable. There was a strong positive association between antimanic potency and affinity for D2 receptors, in support of a 'dopamine-blockade hypothesis' of antimanic drug action. Taking the series of neuroleptics as a whole, there was no association between antimanic potency and affinity for 5-HT2A receptors. Despite this, within a subsample of typical neuroleptics with low affinity for D2 receptors resembling new generation atypical antipsychotics, a positive association between antimanic potency and affinity for 5-HT2A receptors emerged. This suggests that blockade of brain 5-HT2A receptors plays at least a subsidiary role in the antimanic effects of some typical neuroleptics. Other considerations also suggest that combining drugs to achieve high affinity for and blockade of both dopamine D2 receptors and serotonin 5-HT2A receptors, possibly with additional direct or indirect stimulation of postsynaptic 5-HT1A receptors, might maximize antimanic efficacy.

Heavy users of acute psychiatric beds: randomized controlled trial of enhanced community management in an outer London borough.

BACKGROUND: Heavy users of psychiatric services, often defined as the population that uses the most beds, consume a large part of the resources used by the whole service, despite being relatively small in number. Any intervention that reduces heavy use is therefore likely to lead to significant savings, and enhancement of standard care using a form of intensive case management akin to assertive community treatment was thought to be a pragmatic strategy for testing in this group. METHODS: The effectiveness of enhanced community management (ECM) was compared with standard care alone in heavy users, who represented the 10% of patients with the highest number of hospital admissions and occupied bed days over the previous 6.5 years in an outer London borough. One hundred and ninety-three patients were randomly assigned to ECM or standard care and their use of services was determined after 1 and 2 years, with assessments of costs, clinical symptoms, needs, and social function made before entry into the study and after 1 and 2 years. RESULTS: Despite a 24 fold increase in community contacts in the study group, there were no significant differences between the two groups in any of the main outcome measures. Small savings on in-patient and day-hospital service costs were counterbalanced by the increased costs of outpatient and community care for the subjects assigned to ECM. Clinical outcome data derived from interviews in two-thirds of the subjects were similar in both groups. CONCLUSIONS: Providing additional intensive community focused care to a group of heavy users of psychiatric in-patient services in an outer London borough does not lead to any important clinical gains or reduced costs of psychiatric care.

Costs and characteristics of heavy inpatient service users in outer London.

"Heavy users" is a new term often used to describe those who occupy a disproportionate number of psychiatric beds. In this study we identified the heaviest 10% (193) inpatient service users in one London borough over a 6 year period and compared these with a control group of 400 ordinary inpatient users. A weighting index was used to combine frequency of admission with duration. Heavy users were diagnostically and demographically similar to ordinary inpatient service users and only differed by their extensive use of services, about 3 times more than ordinary users in terms of health care costs, during the measured year. Their heavy use mainly depended on occupying hospital beds, and their use of outpatient, day patient and community services was relatively light.

A randomized controlled trial of community-oriented and hospital-oriented care for discharged psychiatric patients: influence of personality disorder on police contacts.

An important forensic psychiatric measure, contacts with police, was compared in a randomized, controlled trial of 155 patients with severe mental illness with a previous admission within the past two years. The patients, who also had their personality status addressed formally before randomization, were allocated to community multidisciplinary teams or to hospital-based care programs after discharge from in-patient care and were followed up for one year. A total of 138 patients (89%) had at least one post-baseline assessment and of these patients, 16 (12%) had at least one police contact in the year of the study, most of which were emergency assessments. The data showed significantly greater numbers of police contacts in patients with increasing severity of personality disturbance. Patients with such disturbance were six times more likely to have police contacts than those with no personality disorder. There were significantly more contacts in patients with borderline and antisocial (dissocial) personality disorder allocated to community-oriented care compared with hospital-oriented care. These findings have important implications for risk assessment in severe mental illness.

Randomised controlled trial of two models of care for discharged psychiatric patients.

OBJECTIVE: To compare the clinical outcome and costs of care of psychiatric patients allocated to community multidisciplinary teams or to hospital based care programmes after discharge from inpatient care. DESIGN: Randomised controlled trial. SETTING: Inner London (Paddington and North Kensington) and outer London (Brent) psychiatric services. SUBJECTS: 155 patients with severe mental illness with a previous admission within the past 2 years. MAIN OUTCOME MEASURES: Ratings of clinical psychopathology, depression, anxiety, and social functioning; comprehensive costs of health care. RESULTS: Clinical outcomes were available for 133 patients and cost data for 144 patients after 1 year. The clinical outcomes of the two models of care were essentially similar, but admission to hospital was more likely in the hospital based care group and the costs of health care were 14% greater per patient than in the community group. This difference, however, was dwarfed by a twofold difference in the costs of care in the outer London services compared with those in inner London. This was explained largely by greater inpatient care for outer London patients (58 median bed days v 18 for inner London patients), more of which was provided by extracontractual referrals to other psychiatric hospitals as Brent had only 0.28/1000 beds available for acute adult patients compared with 0.82/1000 in Paddington and North Kensington over the period of the study. CONCLUSION: Aftercare by community teams for psychiatric patients with severe mental illness has a similar outcome to hospital based aftercare but with fewer admissions to hospital. When psychiatric bed requirements are insufficient for a population, however, neither form of aftercare is effective as greater use of hospital beds elsewhere swamps any advantage of community care programmes, with disintegration and discontinuity of psychiatric services leading to escalating costs.

Facial and other non-verbal communicative behaviour in chronic schizophrenia.

Facial behaviour may be an important determinant in clinical ratings of psychopathology. A standardized objective technique was used to quantify measures of facial behaviour in 21 chronic schizophrenic subjects, in comparison with control groups of depressed, demented and Parkinsonian subjects. Facial behaviours were counted and timed from video recordings of each subjects' face during a clinical interview. Separate measurement of behaviours were obtained while subjects were speaking and silent. For most variables, the amount of facial behaviour was significantly less in schizophrenic subjects than in control groups. The groups differed significantly on a number of measures, but schizophrenics could not be reliably identified by a single facial behaviour variable. However, using a discriminant function analysis with measures for eye contact while speaking and silent, broad smiles and small smiles, discrimination between groups was good, with over 80% correctly classified as either schizophrenic, or not schizophrenic. These techniques may increase our understanding of psychopathological signs and the mechanisms that underly them.

Flumazenil-precipitated panic and dysphoria in patients dependent on benzodiazepines: a possible aid to abstinence.

Ten long-term users of benzodiazepines (average daily dose, 20 mg of diazepam or equivalent) who had experienced problems in withdrawing from the drugs were given an i.v. challenge with either the benzodiazepine antagonist flumazenil (1 mg injected over 30 s) or placebo (vehicle solution) in a randomized double-blind design. There were no 'pseudo withdrawal' responses to either single-blind or double-blind placebo injections, whereas flumazenil produced dramatic panic reactions in all four subjects tested, followed by characteristic benzodiazepine withdrawal symptoms. There were also small but significant rises in pulse rate and blood pressure, but no change in serum cortisol. Flumazenil-induced panic could not be entirely accounted for by a past or present diagnosis of panic disorder, and did not seem to be related to previous withdrawal problems, present benzodiazepine dosage, or to the severity of withdrawal symptoms precipitated by flumazenil in the same challenge test. Attempts to reduce benzodiazepine intake over the next 3 weeks tended to be more successful in the flumazenil group. The results are discussed with reference to possible changes in the GABA-benzodiazepine system in long-term benzodiazepine users.

A randomised controlled study of close monitoring of vulnerable psychiatric patients.

The care programme approach was introduced in mental health services in the UK in 1991. It was intended to improve the quality of care and prevent patients losing contact with care services and, by implication, to reduce psychiatric admissions. We did a study to find out if the approach worked. 400 patients from a London inner-city area who had been identified as psychiatrically vulnerable and included on a case register of patients with special needs were randomised into two groups of 200 each. One group received close supervision by nominated key-workers (as recommended in the care programme approach of the UK Department of Health), and the other received standard follow-up from psychiatric and social services. Outcome was recorded after eighteen months. Data on 393 patients was available for analysis. Of 197 patients allocated to standard care, 64 (32.5%) were lost to follow-up compared with 40 (20.4%) of 196 patients receiving close supervision (p = < 0.005). However, patients under close supervision had significantly more admissions (30% vs 18%, chi 2 = 7.61, p < 0.01) and spent 68% more days in hospital than the standard group. The findings of greater hospital-bed use, which differ from those of studies with community-based psychiatric teams, suggest that close supervision by a single key worker, as recommended in the care programme approach, will lead to greater success in maintaining contact with vulnerable patients, but is likely to lead to more psychiatric admissions.

L-dopa helps positive but not negative features of neuroleptic-insensitive chronic schizophrenia.

L-dopa (Sinemet-110 in a final dose equivalent to - 4 g per day) added to maintenance chlorpromazine, produced a small antipsychotic effect in a group of eight severely impaired male chronic schizophrenic in-patients. Negative symptoms were unaffected by L-dopa, although the improvement in psychotic behaviour and positive symptoms was restricted to the four patients with the most severe negative symptoms measured during the control treatment period. These L-dopa responders also tended to improve slightly when the dose of chlorpromazine was halved, an indication of their poor, or even counter-therapeutic response to conventional neuroleptic medication given in relatively high dosage. Signs of increased dopaminergic activity (raised eye blink rate and reduced plasma prolactin) were not observed in subjects showing an antipsychotic response to L-dopa. This raises the possibility that L-dopa may exert an antipsychotic effect in neuroleptic-insensitive subjects by altering noradrenergic activity in the brain.

Imipramine normalizes naturally-occurring and drug-induced differences in the exploratory activity of rats.

1 Exploratory activity of female hooded rats was measured in a Y maze on two occasions, 1 week apart. Locomotion (maze arm entries), rearing, and head-dipping into pots were scored for 5 min at each trial. 2 In control rats, differences between individuals in the amount of locomotion and rearing were consistent, as shown by significant test-retest correlations (r = +0.55, and +0.83 respectively). There was no correlation between head-dipping scores obtained in the two tests. 3 Imipramine (Imip) pretreatment before the second trial (10 mg/kg i.p on the 3 preceding days, and 2.5 mg/kg 1 h before) abolished these correlations. The scatter of the scores about the mean was also reduced by Imip, but there was no significant change in mean scores. Thus Imip appeared to have a 'normalizing' effect on locomotion and rears: after pretreatment, scores tended to be more uniform, and no longer reflected naturally-occurring individual differences. 4 Imip abolished the changes in exploratory activity produced by drugs which alter brain 5-hydroxytryptamine metabolism: p-chlorophenylalanine (100 mg/kg 24 h before testing) increased and DL-5-hydroxytryptophan (12.5 mg/kg 1 h before testing) decreased the fall in activity over the trial in saline-treated rats but not that in Imip-treated rats. In this case, Imip also produced an overall reduction in activity scores. 5 The normalizing effects of Imip on rat behaviour may be analogous to its therapeutic effects in human depressive disorders.

Evoked potential correlates of stable inter-individual differences in rat behaviour.

Individual differences in rats' exploratory behaviour are stable over time, suggesting inherent differences in brain mechanisms for handling sensory information. These differences may have a neurophysiological basis since a negative correlation was found between individual variation in exploratory behaviour and recovery functions of cortical visual evoked potentials. Recovery functions were an expression of the extent to which the visual system recovered its responsiveness following initial stimulation. They were obtained by using pairs of flash stimuli separated by 3 interstimulus intervals (ISIs): 100, 200 and 300 msec. Recovery was defined as the amplitude of the response to the second flash expressed as a proportion of the response to the first flash. Only short latency components of the evoked responses were considered. The mean value for recovery averaged over the three ISIs constituted the recovery function. Only responses recorded when rats were quiet but alert were used for analysis. Evoked potential recovery functions appear to reflect a neurophysiological mechanism underlying the different capacities of individual rats for responding to novelty.