Evaluation of a multifaceted intervention to limit excessive antipsychotic co-prescribing in schizophrenia out-patients.

OBJECTIVE: To evaluate the effect of a multifaceted educational intervention on the frequency of antipsychotic co-prescribing in adult schizophrenia out-patients. METHOD: Controlled quasi-experimental study performed in two Danish municipalities matched for baseline prevalence of antipsychotic polypharmacy, socioeconomic status and functional level of patients. The intervention was aimed at psychiatric healthcare providers and consisted of 1 day of didactic lectures, six 3-h educational outreach visits and an electronic reminder during drug prescribing. RESULTS: Between-group use of antipsychotic polypharmacy was compared at baseline (intervention group, N = 232/control group, N = 351) and after 1 year of intervention (intervention group, N = 216/control group, N = 386). The prevalence of antipsychotic polypharmacy at follow-up was not significantly different between treatment settings when adjusting for differences in case-mix (P = 0.07). CONCLUSION: This multifaceted educational intervention failed to reduce the frequency of antipsychotic co-prescribing, but it suggested that future efforts to improve prescribing practice should address organizational barriers to implementation.

Use of 360-degree assessment of residents in internal medicine in a Danish setting: a feasibility study.

BACKGROUND: The aim of the study was to explore the feasibility of 360 degree assessment in early specialist training in a Danish setting. Present Danish postgraduate training requires assessment of specific learning objectives. Residency in Internal Medicine was chosen for the study. It has 65 learning objectives to be assessed. We considered 22 of these suitable for assessment by 360-degrees assessment. METHODS: Medical departments of six hospitals contributed 42 interns to the study. Each resident was assessed by ten persons of whom one was a secretary, four were nurses and five senior doctors. The assessors spent 14.5 minutes (median) to fill in the forms. RESULTS: Of the 22 chosen objectives, 15 could reliably be assessed by doctors, 7 by nurses and none by secretaries. CONCLUSIONS: The method was practical in busy clinical departments and was well accepted by the assessors. Reliability of the method was acceptable. It discrimintated satisfactorily between the good and not so good performers.

Validation of the Bech-Rafaelsen Melancholia Scale and the Hamilton Depression Scale in patients with major depression; is the total score a valid measure of illness severity?

OBJECTIVE: Evaluation of antidepressant drug efficacy requires adequate rating scales for measuring the severity of depression. However, to measure the illness severity by such a total score, the scale needs to fulfil criteria of unidimensionality. On this background, we aimed at comparing the unidimensionality of the Bech-Rafaelsen Melancholia Scale (MES) and the 17-item Hamilton Depression Rating Scale (HAM-D(17)). METHOD: A total of 1629 patients aged between 18 and 65 years with a major depressive episode were treated openly with sertraline at a fixed oral dose of 50 mg daily during 4 weeks. The HAM-D(17) and the MES were applied at baseline and at weeks 2 and 4. Unidimensionality was tested with Mokken and Rasch analysis. RESULTS: Unidimensionality of the HAM-D(17) could not be confirmed. However, the 6-item Hamilton Depression Subscale (HAM-D(6)), was accepted by the Rasch analysis both at baseline and after 2 and 4 weeks of therapy. For the MES (as well as for the HAM-D(6)), a Loevinger coefficient of homogeneity above 0.40 (suggesting acceptance) was found at week 4. CONCLUSION: The HAM-D(6) and the MES did fulfil criteria for unidimensionality while the HAM-D(17) did not. Therefore, the extended use of the HAM-D(17) in drug trials may be questioned.

Irreversibility of kindled alcohol-withdrawal behaviour in rats.

In order to investigate whether alcohol-withdrawal kindling is an irreversible process, male Wistar rats were exposed to 12 episodes, each consisting of 2 days of severe alcohol intoxication and 5 days of alcohol withdrawal. Spontaneous withdrawal seizures were found in 15% of the animals during episodes 10-12. After an alcohol-free period of 26 days, the animals were subjected to three more episodes of alcohol dependence (i.e. episodes 13-15) in which 12% of the animals developed spontaneous withdrawal seizures. Based on several statistical tests, we concluded that there was no true difference between the seizure activity in episodes 10-12 and episodes 13-15, indicating that alcohol-withdrawal kindling is a long-lasting and perhaps irreversible process. In a second experiment, an alcohol-withdrawal kindled group was first exposed to seven episodes of alcohol dependence. A diazepam group went through the same alcohol regimen, but each withdrawal reaction was blocked by diazepam treatment. Finally, a single episode group was included which was fed isocalorically with the kindled animals. After an alcohol-free period of 11 days, all three groups were subjected to 4 days of severe alcohol intoxication. During the subsequent withdrawal reaction seizures were observed in 22-26% of the animals with no significant differences across the groups. These results call for a modification of the kindling hypothesis of alcohol withdrawal and suggest that kindling-induced alterations may be overlooked if convulsive behaviour is tested during a relatively strong withdrawal reaction.

Glutamate and benzodiazepine receptor autoradiography in rat brain after repetition of alcohol dependence.

During repeated alcohol withdrawal, convulsive withdrawal behavior has been shown to be increased in a kindling-like manner in both clinical and experimental studies. In the present experiment, quantitative autoradiography was used to investigate binding of tritiated ligands to glutamate receptor subtypes and the benzodiazepine/GABA (BZ/GABA) receptor complex in rats exposed to 14 episodes of alcohol withdrawal. Seizures were detected in 25% of the animals during withdrawal episode 10-13. Repeated alcohol withdrawal resulted in a decrease in the number of [3H]-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ([3H]-AMPA) binding sites in striatum and sub-regions of the entorhinal cortex, the cerebellum and the hippocampus, while the [3H]-flunitrazepam binding was down-regulated in the frontal cortex. There was no differences between the controls and the multiple withdrawal animals regarding the [3H]-dizocilpine ([3H]-MK801) binding and the [3H]-kainic acid binding. However, within the latter group, those animals in which withdrawal seizures were observed had increased [3H]-MK801 binding sites in focal regions of entorhinal cortex and hippocampus, compared to those in which seizures were not observed. The decreased AMPA binding suggested impaired glutamate neurotransmission. As such, this receptor probably did not contribute to alcohol withdrawal kindling, but rather was involved in seizure protective mechanisms during this process.

Diazepam prevents progression of kindled alcohol withdrawal behaviour.

The purpose of the present experiment was to study the "kindling" hypothesis of alcohol withdrawal stating that exposure to repeated episodes of alcohol withdrawal results in an increased severity of subsequent withdrawal reactions. Two groups of male Wistar rats were subjected to 13 episodes of 2 days severe alcohol intoxication and 5 days alcohol withdrawal. Animals in the control group (n = 80) developed clinical withdrawal signs following each intoxication episode. In the diazepam group (n = 80) the withdrawal reactions during episodes 1-9 were blocked by intraperitoneal diazepam administration (0-30 mg/kg) 8, 11 and 15 h into withdrawal. During episode 10-13 diazepam treatment was terminated and convulsive withdrawal behaviour was observed 9-15 h after last alcohol dose. The probability of seizure activity during these four withdrawal episodes was calculated as 0.239 and 0.066 in the control and the diazepam groups, respectively. Based on Monte Carlo simulation techniques, this difference was found to be statistically significant (P < 0.05). No differences in the non-convulsive alcohol withdrawal symptoms tremor, hyperactivity and rigidity were detected between controls and diazepam animals after diazepam treatment. It was concluded that the increased convulsive behaviour in the control group was caused by cumulated kindling-like cerebral alterations during the previous repeated alcohol withdrawal phases.

Electrical kindling of rats treated discontinuously or continuously with haloperidol.

Intermittent as opposed to continuous treatment of rats with haloperidol resulted in a long-lasting potentiation of oral activity. To examine if this behavioural sensitization to discontinuous neuroleptic treatment facilitates seizure development in electrical kindling, rats treated either intermittently or continuously with haloperidol for 15 weeks were kindled in the nucleus amygdala. Development of kindled seizures was significantly faster in the intermittently treated group (P < 0.01) than in controls or continuously treated rats. Furthermore, discontinuously treated animals displayed electroencephalographic afterdischarges in the substantia nigra from the beginning of treatment. The findings of cross-sensitivity between electrical amygdala kindling and pharmacological sensitization and of early appearance of epileptiform nigral activity have implications for the pathogenesis of both conditions. We suggest that depressed gamma-aminobutyric acid activity in substantia nigra could be a common mechanism.

Treatment of generalized anxiety disorder: comparison of a new beta-blocking drug (CGP 361 A), low-dose neuroleptic (flupenthixol), and placebo.

In an attempt to evaluate an alternative drug treatment to benzodiazepines in generalized anxiety disorders, a placebo controlled trial was carried out with a new beta-adrenergic blocker (CPG 361 A). A low-dosage neuroleptic (flupenthixol) was included as a reference drug. Depending on the clinical assessment scales the placebo treatment resulted in moderate to excellent improvement in 36% to 56% of the patients after four weeks of treatment. The active drugs generally had a higher improvement range (from 31% to 80%). The global improvement scale was found to be better than the other scales in discriminating between placebo (50% improvement) and the active drugs (CGP 361 A brought about 78% improvement and flupenthixol brought about 80% improvement). However, only for flupenthixol was the difference of statistical significance.

The Hamilton scales and the Hopkins Symptom Checklist (SCL-90). A cross-national validity study in patients with panic disorders.

The HRSD, HRSA, SCL-90 scales were psychometrically investigated in a cross-national sample of patients with varieties of non-psychotic symptoms of anxiety and depression. Across the cultural backgrounds the scores obtained from the original versions of these scales are not sufficient statistics. However, latent structure analysis has identified homogeneous subscales for depression (the HRSD) and for discomfort (an SCL subscale). High concurrent validity was found between the subscales of depression, anxiety and discomfort. In international research, inhomogeneity among scale items can be confounded with group differences which are usually ascribed to drug differences.

The Panic-Associated Symptom Scale: measuring the severity of panic disorder.

The Panic-Associated Symptom Scale (PASS) is presented as a new measurement of the severity of the core symptoms of panic disorder. This first description addresses the rationale for its design and its scoring, score distributions, test-retest reliability, correlations within the PASS and with other scales, principal component structure, and response to drug therapy. Data are presented from a large study group of patients with panic disorder (n = 1168). Problems in measuring panic disorder are discussed.

Intermittent versus continuous neuroleptic treatment in a rat model.

The treatment schedule for neuroleptic therapy is of relevance when evaluating the development of side-effects. Seventy-five rats were treated discontinuously or continuously with the predominantly dopamine D2 receptor blocker haloperidol or the combined dopamine D1/D2 receptor blocker zuclopenthixol for 15 weeks. During and after treatment, a broad spectrum of behavioural parameters including vacuous chewing movements and tongue protrusions were observed. Discontinuous neuroleptic treatment as opposed to continuous neuroleptic treatment produced a significant long-lasting increase in oral activity. The changes were most pronounced in haloperidol-treated rats. The differences observed may have methodological implications for animal models of neuroleptic-induced movement disorders. Our findings are consistent with the hypothesis that pharmacological sensitization to the dyskinetic side-effects of neuroleptics develops when the drug effect is allowed to wear off between repeated administrations.

Personality characteristics and epilepsy.

Patients with a long history of temporal lobe epilepsy or primary generalized epilepsy entered a questionnaire study of personality characteristics, based on a modification of the Bear-Fedio inventory for temporal lobe behavioural syndrome. Psoriasis patients and healthy volunteers served as controls. Four clinical meaningful dimensions of included personality traits were identified: ixoide, ideational, obsessive-compulsive and affective features. Analyses based on the Rasch model approved of all dimensions except for affective features. The epilepsy group obtained the highest scores on all 3 dimensions, healthy volunteers the lowest, while the psoriasis group repeatedly held an intermediate position in all sets of assessment (subjects, interviewers and relatives). A logistic regression analysis showed ixoide features being most important when the entire epilepsy group was compared with other study groups, while the dimension ideational features was significant when the temporal lobe epilepsy group was entered as target group and opposed to primary generalized epilepsy. The intermediate position of the psoriasis group, however, suggests that in addition to the presence of a cerebral dysfunction in the epilepsy group, the mere presence of a chronic disorder with potential social stigmatization influences personality.

The Brief Psychiatric Rating Scale. Dimension of schizophrenia--reliability and construct validity.

This study has focussed on a 10-item Brief Psychiatric Rating Scale (BPRS) subscale for the quantification of schizophrenic states. Seven psychiatrists interviewed jointly patients who all fulfilled the DSM-III criteria of schizophrenia, and in a subsequent pencil-and-paper procedure a judgment analysis was performed. The reliability analysis showed that less experienced BPRS raters made less consistent judgments implying the cautionary statement that the proper use of a scale for schizophrenia requires specialized training with the scale. The validity analysis showed that the BPRS items had an additive relationship implying that the sum of these items is a sufficient statistic for the measurement of severity of schizophrenic states. Finally, the results seem to indicate, that the underlying dimension defined by the 10-items BPRS subscale includes hierarchically the negative and positive symptoms of schizophrenia.

The Diagnostic Melancholia Scale (DMS): dimensions of endogenous and reactive depression with relationship to the Newcastle Scales.

The two diagnostic Newcastle Scales for depression have been evaluated in a drug trial with antidepressants. By use of latent structure analysis (Rasch models) it was found that two dimensions are necessary for describing the diagnosis of depression, one for endogenous features and one for reactive features. Of the depressed patients 50% had a pure endogenous depression, 14% had a pure reactive depression, 32% had mixed endogenous and reactive depression, and 4% had uncertain diagnosis. In the pure endogenous depression group 77% had a monotonically non-decreasing improvement curve during treatment whereas in the other diagnostic categories around 50% had such an improvement.

Assessment of symptom change from improvement curves on the Hamilton depression scale in trials with antidepressants.

A total of 97 patients, who participated in two studies on the relationship between the clinical effect and plasma levels of imipramine and clomipramine, were examined for improvement curves by use of weekly ratings on the Hamilton Depression Scale (HDS). Although we confirmed that our six-item HDS subscale, in contrast to the total 17-item HDS, was a one-dimensional measure of depression, the Rasch analysis showed that the weekly improvement in subscale scores only applied to the individual patient, i.e. an average improvement curve for a group of depressed patients is an abstraction to which the individual curves cannot be transferred. Our results indicate, however, that when the subscale scores are transformed into three clinical categories of depression: no, mild (minor), moderate/-severe (major) they could be described by a common improvement curve for all patients. This is illustrated by the percentage of patients who, week to week, changed from major to minor or no depression, or from minor to no depression. We found no specific improvement pattern for imipramine or clomipramine which could be used diagnostically. There is reason to assume that patients completing a controlled trial necessarily will follow a monotonic improvement curve, and the improvement pattern of all patients fulfilling the entry criteria should, therefore, always be reported. The present study thus indicates that calculation of average improvement curves is neither clinically nor statistically meaningful, and should be replaced by measures of changes in number of patients in different main severity categories, or by the final rating score. No difference in outcome between imipramine and clomipramine was shown neither on the subscale nor on the 17-item HDS.

The Hamilton depression scale. Evaluation of objectivity using logistic models.

The consistency of the Hamilton Depression Scale (HDS) as a measure of the severity of depressive states has been examined when the scale was used weekly during a trial when imipramine. By use of logistic models (Rasch) the consistency of the HDS has been considered across patient-variables as age, sex, plasma levels of imipramine, and diagnosis. The results showed that the original 17-item HDS was without adequate consistency, i.e. the total score of the sample of items was no one-dimensional measure of depressive states. However, a melancholia subscale of the HDS contained items the total of which can be used to compare patients quantitatively, although in some part of the analysis one of these items showed ceiling effect. It was concluded that the melancholia subscale (containing the items depressed mood, guilt, work and interests, retardation, psychic anxiety, and general somatic symptoms) can form the basis for further improvements in the field of quantitative rating scales for depressive states.

The Marke-Nyman temperament scale. Evaluation of transferability using the Rasch item analysis.

The purpose of this study was to test the transferability of the Marke-Nymann Temperament Scale (MNTS) using the Rasch item analysis. The results showed that the three Sjöbring personality dimensions Validity, Stability, and Solidity measured by the MNTS were without transferability. However, the item analysis demonstrated a subscale for each of the three Sjöbring dimensions having adequate transferability, i.e. the subscales continued to test the same dimension in different groups of patients. These subscales still cover much of the range of the original descriptions by Sjöbring.