The effects of risperidone on the five dimensions of schizophrenia derived by factor analysis: combined results of the North American trials

BACKGROUND: In two double-blind trials conducted in North America, 513 patients with chronic schizophrenia received risperidone, haloperidol, or placebo. In the present study, combined data from the two trials were analyzed. METHOD: Patients were randomly assigned to receive placebo, fixed doses of risperidone (2, 6, 10, and 16 mg/day) or 20 mg/day of haloperidol for 8 weeks. Factor analysis of scores on the Positive and Negative Syndrome Scale (PANSS) produced five dimensions (negative symptoms, positive symptoms, disorganized thought, uncontrolled hostility/excitement, and anxiety/depression), similar to the five dimensions of previous factor-analytic studies of PANSS data. RESULTS: Mean changes (symptom reductions) in PANSS factor scores from baseline to treatment Weeks 6 and 8 were significantly greater in patients receiving 6-16 mg/day of risperidone than in patients receiving placebo or haloperidol. The advantages of risperidone were greatest for negative symptoms, uncontrolled hostility/excitement, and anxiety/depression. Even at the lowest dose, 2 mg/day, risperidone was significantly (p < or = .05) superior to haloperidol in reducing negative symptoms. The differences in outcomes between risperidone and haloperidol on PANSS scores were not related to extrapyramidal symptoms. CONCLUSION: Risperidone produced significantly (p < or = .05) greater improvements than haloperidol on all five dimensions. The large between-group differences on negative symptoms, hostility/excitement, and anxiety/depression suggest that risperidone and other serotonin/dopamine antagonists have qualitatively different effects from those of conventional antipsychotic agents.     

Iodine-123-iodobenzamide SPECT assessment of dopamine D2 receptor occupancy in riperidone-treated schizophrenic patients

The recently introduced neuroleptic, risperidone, was expected to block fewer dopamine D2 receptors than typical neuroleptics (e.g., haloperidol), but at comparable potency. The aim of this study was to evaluate the degree of dopamine D2 receptor occupancy in relation to the neuroleptic dosage and to correlate the findings with the presence of extrapyramidal symptoms (EPS). Additionally, the data were compared to previous iodobenzamide (IBZM) SPECT findings in patients treated with other neuroleptics, haloperidol and clozapine. METHODS: In 20 patients with schizophrenia [Diagnostic and Statistical Manual of Mental Disorders (Third Edition-Revised)] treated with mean daily doses of risperidone ranging from 0.029 to 0.128 mg/kg body weight, SPECT was performed 2 hr after intravenous injection of 185 MBq 123I-IBZM, a selective dopamine D2 receptor ligand. Striatal IBZM binding was assessed by calculating a striatal/frontal cortex ratio, expressed as a percentage of the control value. RESULTS: Selective dopamine D2 receptor binding of the ligand was reduced in all treated patients, with binding values ranging from 7% to 68%. The degree of occupancy displayed an exponential dose-response relationship (r = -0.86; p < 0.0001). The slope of the curve was between those of haloperidol and clozapine but was closer and more similar in shape to the curve of haloperidol. Extrapyramidal symptoms were observed in 8 of 20 patients with binding values between 7% and 47%. However, there was no clear relationship between the degree of receptor occupancy and the presence of EPS. CONCLUSION: The findings suggest an exponential dose-response relationship between the daily dosage of risperidone and the dopamine D2 receptor occupancy. The blockade of specific striatal IBZM binding found under therapy with risperidone is between those of haloperidol and clozapine. The dose-response curve for risperidone, however, shows greater similarity to that of haloperidol.     

Blind, controlled, long-term study of the comparative incidence of treatment-emergent tardive dyskinesia with olanzapine or haloperidol

OBJECTIVE: Tardive dyskinesia is a serious and common complication of neuroleptic treatment. Olanzapine is a novel antipsychotic agent exhibiting regional mesolimbic dopaminergic selectivity and a broad-based pharmacology encompassing serotonin, dopamine, muscarinic, and adrenergic receptor binding affinities. The authors' goal was to compare the incidence of tardive dyskinesia among patients receiving olanzapine and those receiving the conventional dopamine 2 antagonist haloperidol. METHOD: Data were analyzed from three actively controlled and blind long-term responder studies of subjects meeting DSM-III-R criteria for schizophrenia, schizophreniform disorder, or schizoaffective disorder treated with olanzapine (N = 707, up to 20 mg/day, 237 median days of exposure) or haloperidol (N = 197, up to 20 mg/day, 203 median days of exposure) who did not have evidence of tardive dyskinesia at baseline. All of the subjects had a chronic disease course (mean greater than 10 years), and there were no significant between-treatment group differences in demographic or disease characteristics. The Abnormal Involuntary Movement Scale and research diagnostic criteria for tardive dyskinesia were used to define the comparative incidence rates of long-term treatment-emergent tardive dyskinesia. RESULTS: The incidence of newly emergent tardive dyskinesia at any visit after baseline, at the final visit, and at the final two clinical assessments was statistically significantly lower among olanzapine-treated patients than among haloperidol-treated patients. CONCLUSIONS: These findings support an atypical extrapyramidal symptom profile and the potential of a significantly lower risk of tardive dyskinesia with olanzapine than with haloperidol among patients requiring maintenance antipsychotic treatment.     

Intravenous flumazenil following acute and repeated exposure to lorazepam in healthy volunteers: antagonism and precipitated withdrawal

The effects of i.v. administered flumazenil (3.0 mg) were studied in healthy male subjects who received pretreatment with p.o. placebo or lorazepam. The duration of placebo or lorazepam (3.0 mg single p.o. daily dose) pretreatment before a flumazenil or placebo injection was 1, 3, 7 or 14 days in four sequential groups of subjects. Initial administration of lorazepam produced a classic sedative profile of effects on various psychomotor/behavioral performance, observer-rated and subject-rated measures. Tolerance to repeated daily administration of lorazepam was suggested by a progressive diminution of performance disrupting effects. In subjects pretreated with placebo, flumazenil increased subject-ratings of dizziness over preinjection ratings. Flumazenil produced an immediate reversal of lorazepam effects in subjects who were not tolerant to lorazepam (1- and 3-day pretreatment groups). Flumazenil did not precipitate withdrawal symptoms in subjects who received a single administration of lorazepam. Precipitated withdrawal symptoms were evident after 3 and 7 days of lorazepam pretreatment, and there was a tendency toward precipitated withdrawal symptoms (that included one panic attack) after 14 days of lorazepam pretreatment. Precipitated withdrawal was characterized by an elevation in subject-rated symptoms including dizziness, tenseness, tachycardia, perceptual disturbance and sweating. Symptoms were maximal immediately after injection, usually mild in severity and usually resolved within 1 hr. There was no evidence of precipitated withdrawal on psychomotor/behavioral performance or observer ratings. The present study provides the strongest human experimental evidence to date that flumazenil can precipitate withdrawal symptoms after a history of repeated benzodiazepine exposure.     

Outcomes after stereotactically guided pallidotomy for advanced Parkinson's disease

OBJECT: Parkinson's disease (PD) is a prevalent neurodegenerative disorder that becomes refractory to medication as the disease progresses. Although in the past 5 years increasing numbers of patients have undergone stereotactically guided posteroventral pallidotomy for advanced PD, the safety and efficacy of surgery remains to be documented. The goal in this study was to determine the potential operative morbidity and types of functional outcomes by using validated PD rating scales and a patient survey. METHODS: In a prospective analysis of a consecutive surgical series the authors evaluated 58 patients with advanced PD who ranged in age from 40 to 79 years (mean 67 years) and who had undergone surgery between 1994 and 1997. They used a patient survey and the Unified Parkinson's Disease Rating Scale (UPDRS) to study patients during periods of medication administration ("on") and withdrawal ("off"; mean off score before surgery = 96). Temporary surgical morbidity was found in four patients (6.9%), three of whom developed transient dysarthria and one of whom exhibited transient confusion (1.7%). One patient had persistent dysarthria (1.7%). No patient developed a visual field deficit or sustained a brain hemorrhage. All patients were discharged from the hospital within 24 hours. Significant postsurgical improvements were noted in the UPDRS off-period total and motor scores, as well as in tremor, rigidity, bradykinesia, and contralateral dyskinesia (p < 0.005). Improvements persisted in dyskinesia and tremor for the 21 patients who were evaluated past 1 year. The authors found no improvement in any on-period symptoms except dyskinesia. Thirty-one (61 %) of 51 patients surveyed reported functional gains and/or dramatic improvement in symptoms, 17 (33%) reported symptomatic improvement without functional gains, and three (6%) had minimal or no change in symptoms. No change in the mini mental state examination score was noted during follow up. There were no significant postoperative changes in the use of medication. CONCLUSIONS: In advanced PD associated with either a medically refractory state with significant off periods or levodopa-induced dyskinesias, magnetic resonance imaging-guided pallidotomy with macrostimulation was associated with minimal morbidity and yet significantly reduced dyskinesia and off-period disability. These improvements were of value to the patient and persisted beyond the 1st year.     

Risperidone vs. haloperidol on reaction time, manual dexterity, and motor learning in treatment-resistant schizophrenia patients

BACKGROUND: The present study compared the effects of risperidone vs. haloperidol on reaction time, manual dexterity, and two types of motor learning in a sample of treatment-resistant schizophrenia patients. METHODS: Fifty-six DSM-III-R diagnosed schizophrenia inpatients participated in a randomized, double-blind comparison of risperidone vs. haloperidol. Measures of reaction time, manual dexterity, motor sequence learning, and gross motor learning were administered at baseline, after 4 weeks of fixed-dose medication, and after 4 weeks of flexible-dose medication. RESULTS: The results indicated that patients receiving risperidone showed greater improvement in reaction time and manual dexterity than patients receiving haloperidol. After covarying symptom changes and movement disorder ratings, the results remained significant. The two treatment groups did not differ on either measure of motor learning. CONCLUSIONS: The differences in performance in reaction time and manual dexterity may be due to a specific beneficial effect of risperidone, as opposed to a general reduction in extrapyramidal symptom liability, compared to haloperidol.     

Risperidone treatment of children and adolescents with pervasive developmental disorders: a prospective open-label study

OBJECTIVE: To investigate the short-term safety and efficacy of risperidone in the treatment of children and adolescents with pervasive developmental disorders. METHOD: This was a 12-week, prospective, systematic, open-label trial that included 18 subjects (15 boys and 3 girls) with a mean age of 10.2 +/- 3.7 years. The sample included 11 subjects with autistic disorder, 3 with Asperger's disorder, 1 with childhood disintegrative disorder, and 3 with pervasive developmental disorder not otherwise specified. Fourteen subjects had comorbid mental retardation. Behavioral ratings were obtained during two baseline visits and again after 12 weeks of risperidone treatment. RESULTS: The optimal dose of risperidone for the 18 subjects was 1.8 +/- 1.0 mg/day. On the basis of the global improvement item of the Clinical Global Impression Scale, 12 of 18 subjects were considered responders. Significant improvement was seen in measures of interfering repetitive behavior, aggression and impulsivity, and some elements of impaired social relatedness. The most common side effect was weight gain (range 10 to 35 lb). CONCLUSIONS: These preliminary results suggest that risperidone may be effective for improving interfering behavioral symptoms in some children and adolescents with pervasive developmental disorders. Double-blind, placebo-controlled studies are needed before definitive statements of safety and efficacy can be made.     

Acute withdrawal syndrome related to the administration of analgesic and sedative medications in adult intensive care unit patients

OBJECTIVES: To estimate the frequency of acute withdrawal syndrome related to the administration of analgesic and sedative medications in mechanically ventilated adult intensive care unit (ICU) patients; to identify associated clinical factors. DESIGN: Retrospective review of medical records. SETTING: An adult trauma/surgical ICU in an urban Level I trauma center. PATIENTS: Twenty-eight mechanically ventilated adult trauma/ surgical ICU patients requiring >7 days of ICU care. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Daily doses of all opioid, sedative, hypnotic, and major tranquilizer drugs administered to each patient were measured, as was duration of ICU stay, duration of mechanical ventilation, and duration of the administration of analgesic, sedative, and neuromuscular blocking agents (NMBAs) for each patient. All opioids and benzodiazepines were converted to their respective fentanyl and lorazepam equivalent units based on potency and bioavailability. Calculation of the weaning rate for each patient during tapering from opioid and benzodiazepine medications was performed. The presence or absence of acute withdrawal syndrome was identified for each patient. Nine (32.1%) patients developed acute withdrawal syndrome potentially related to the administration of analgesic or sedative medications. Patients in the withdrawal group received significantly higher mean daily (p = .049) and peak (p = .032) doses of fentanyl equivalents, as well as higher mean daily lorazepam equivalents (p = .049) compared with patients not experiencing withdrawal. Patients in the withdrawal group were also significantly more likely to have received neuromuscular blocking agents (p = .004) or propofol (p =.026) for >1 day during ICU admission compared with patients not experiencing withdrawal. Duration of mechanical ventilation (p = .049), benzodiazepine therapy (p = .048), and propofol therapy (p = .049) was also significantly longer in the group experiencing withdrawal. Withdrawal patients received a significantly lower mean daily dose of haloperidol (p = .026). There was a significant association between the development of withdrawal syndrome and the presence of ARDS (p = .017). Finally, the slopes of the lines representing opioid and benzodiazepine drug weaning were more steep for the withdrawal group, although these results did not achieve statistical significance. CONCLUSIONS: These results suggest that mechanically ventilated adult patients with extended ICU care (> or =7 days) who receive large doses of analgesic and sedative medications are at risk for acute withdrawal syndromes during drug weaning. The association between ARDS and withdrawal syndrome, combined with the observation that withdrawal syndromes were also associated with the use of neuromuscular blocking agents and prolonged mechanical ventilation, suggests that patients with ARDS may be more likely to receive high doses of analgesic and sedative medications, and are therefore at increased risk for withdrawal syndrome.     

Environmental ways forward in a postmodern (nursing) world

Anticholinergic treatment of neuroleptic extrapyramidal movement disorders (EPS) has been associated with induction of tardive dyskinesia. Also an increasing abuse of anticholinergics by schizophrenic patients is noted. Since as early as 1976, positive effects of amantadine (AMA) on neuroleptic EPS have been described, therefore a controlled study of these reports seemed worthwhile. Forty-two schizophrenic patients (of which 7 were dropouts) of three centers entered the study and were treated for EPS in a double-blind design: 18 (11 m, 7 f) with AMA and 17 (8 m, 9 f) with biperiden (BIP). Identical preparations of AMA 100 mg, tid) and BIP (2 mg, tid) were used in treatment of haloperidol-induced EPS (AMA, mean 22.4 mg haloperidol; BIP, mean 19.6 mg haloperidol). Effects of treatment and possible side effects were rated: EPS for the intensity of EPS, BPRS for quantification of psychotic symptoms, FSUCL for rating the side effects and KUSTA to document patients' mood. Ratings were recorded on days 0, 3, 7, 14, 28 and at discontinuation, respectively. All patients were treated with haloperidol and levomepromazine (for tranquilization/sleep induction) and the respective antiparkinsonian agent for 14 days. Patient characteristics did not differ significantly in either groups. In the AMA treatment group, 2 patients dropped out for noncompliance, in the BIP group, 5 (3 no effect, 1 noncompliance, 1 agitation). All results as recorded with the different rating instruments showed a significant (p < 0.01) overall improvement, whereas no significant differences between treatment groups could be determined, notably the treatment effect of both drugs on EPS was similar. Thus, the application of AMA in cases of neuroleptic EPS seems justified and is a useful alternative of anticholinergic drugs. Certain advantageous aspects of AMA treatment of EPS with regard to the glutamate hypothesis of schizophrenia and tardive dyskinesia are discussed.     

Oral Dyskinesias and striatal lesions in rats after long-term co-treatment with haloperidol and 3-nitropropionic acid

The pathophysiologic basis of tardive dyskinesia remains unclear. It has been proposed that tardive dyskinesia may be a result of excitotoxic neurodegeneration in the striatum caused by a neuroleptic-induced increase in striatal glutamate release and impaired energy metabolism. To investigate this hypothesis, haloperidol decanoate (38 mg/kg/four weeks intramuscularly) and the succinate dehydrogenase inhibitor 3-nitropropionic acid (8 mg/kg/day via subcutaneous osmotic mini-pumps), were administered alone or together for 16 weeks to four-months-old rats. Control rats received sesame oil intramuscularly and had empty plastic tubes subcutaneously. Vacuous chewing movements, a putative analogue to human tardive dyskinesia, were recorded during and after drug treatment. Haloperidol alone, 3-nitropropionic acid alone, and 3-nitropropionic acid+haloperidol treatments induced an increase in vacuous chewing movements. However, vacuous chewing movements were more pronounced and appeared earlier in rats treated with 3-nitropropionic acid+haloperidol. After drug withdrawal, increases in vacuous chewing movements persisted for 16 weeks in the haloperidol alone and 3-nitropropionic acid+haloperidol group and for four weeks in the 3-nitropropionic acid alone group. Brains from each group were analysed for histopathological alterations. Bilateral striatal lesions were present only in rats with high levels of vacuous chewing movements in the 3-nitropropionic acid+haloperidol-treated rats. Nerve cell depletion and astrogliosis were prominent histopathologic features. There was selective neuronal sparing of both large- and medium-sized aspiny striatal neurons. These results suggest that mild mitochondrial impairment in combination with neuroleptics results in striatal excitotoxic neurodegeneration which may underlie the development of persistent vacuous chewing movements in rats and possibly irreversible tardive dyskinesia in humans.     

Self-Efficacy and Compliance With Benzodiazepine Taper in Older Adults With Chronic Insomnia.

Better understanding of compliance with BZD taper is warranted. Compliance with a taper program and perceived self-efficacy (SE) in being able to comply with hypnotic reduction goals was monitored weekly in 52 older adults (mean age: 63.0 years) with chronic insomnia (average duration: 21.9 years) who underwent a 10-week physician-supervised medication tapering. One group received cognitive- behavior therapy for insomnia during discontinuation, whereas the other did not. Compliant patients showed higher SE ratings at Weeks 6, 8, 9, and 10. Medication-free patients at the end of the treatment also reported higher mean SE ratings at those 4 weeks. Differences remained significant when withdrawal symptoms and sleep efficiency were controlled for. These results have important clinical implications because SE may indicate key time points when patients are experiencing more difficulty during discontinuation. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Primary structure of apolipophorin-III from the greater wax moth, Galleria mellonella

BACKGROUND: Neurobiological research has implicated the dopamine and serotonin systems in the pathogenesis of autism. Open-label reports suggest that the serotonin2A-dopamine D2 antagonist risperidone may be safe and effective in reducing the interfering symptoms of patients with autism. METHODS: Thirty-one adults (age [mean+/-SD], 28.1+/-7.3 years) with autistic disorder (n=17) or pervasive developmental disorder not otherwise specified (n=14) participated in a 12-week double-blind, placebo-controlled trial of risperidone. Patients treated with placebo subsequently received a 12-week open-label trial of risperidone. RESULTS: For persons completing the study, 8 (57%) of 14 patients treated with risperidone were categorized as responders (daily dose [mean+/-SD], 2.9+/-1.4 mg) compared with none of 16 in the placebo group (P<.002). Risperidone was superior to placebo in reducing repetitive behavior (P<.001), aggression (P<.001), anxiety or nervousness (P<.02), depression (P<.03), irritability (P<.01), and the overall behavioral symptoms of autism (P<.02). Objective, measurable change in social behavior and language did not occur. Nine (60%) of 15 patients who received treatment with open-label risperidone following the double-blind placebo phase responded. Other than mild, transient sedation, risperidone was well tolerated, with no evidence of extrapyramidal effects, cardiac events, or seizures. CONCLUSION: Risperidone is more effective than placebo in the short-term treatment of symptoms of autism in adults.     

An association between increased serum-soluble interleukin-2 receptors and a disturbance in muscle force in schizophrenic patients

1. Serum-soluble interleukin-2 receptors (SIL-2Rs), a sign of immune activation, are increased in approximately 30% of schizophrenic subjects. 2. In a recent publication the authors found that SIL-2Rs were particularly elevated in schizophrenic subjects with tardive dyskinesia (TD). 3. This paper investigates the relationship between muscle force instability and SIL-2Rs in 32 schizophrenic patients, 10 of whom were neuroleptic-naive. 4. The authors hypothesized that there would be a positive correlation between increased levels of SIL-2Rs and muscle force instability. 5. Serum SIL-2Rs and muscle force instability were positively correlated (r = 0.54, p < .001) in the schizophrenic patients, and this correlation held even for the subset of neuroleptic-naive patients (r = .73, df 8, p = .016). 6. These findings suggest that there is an important correlation between immune activation and muscle force instability in schizophrenic patients.     

Health-related quality of life outcomes of omeprazole versus ranitidine in poorly responsive symptomatic gastroesophageal reflux disease

OBJECTIVE: This study evaluated changes in health-related quality of life (HRQL) outcomes of once-daily omeprazole compared with ranitidine for the short-term treatment of patients with poorly responsive symptomatic gastroesophageal reflux disease (GERD). METHODS: A double-blind, randomized clinical trial, compared omeprazole versus ranitidine for the treatment of poorly responsive GERD. Eligible patients had a history of predominant heartburn symptoms with symptomatic heartburn after 6 weeks of ranitidine treatment. Patients were randomized to omeprazole 20 mg once daily (n = 156) or ranitidine 150 mg twice daily (n = 161) and followed for 8 weeks. Assessments were completed at baseline and after 8 weeks with physician-rated symptoms: Gastrointestinal Symptom Rating Scale (GSRS); Psychological General Well-Being (PGWB) Index; Sleep Scale; Impact on Daily Activities Scale, and Overall Treatment Effect. Primary HRQL endpoints were the GSRS reflux scale and PGWB total score. RESULTS: No differences between the 2 treatment groups were observed in baseline demographic, clinical or HRQL measures. After 8 weeks, omeprazole-treated patients had greater improvement in GSRS reflux scale scores (p<0.0001) and PGWB total scores (p = 0. 019) compared with ranitidine-treated patients. Significant between group differences favoring omeprazole were also observed in GSRS total scores (p<0.0001), abdominal pain scale scores (p = 0.003), and indigestion scale scores (p = 0.003), Impact on Daily Activities (p = 0.001), PGWB positive well-being (p = 0.015), anxiety (p = 0. 030), and general health scale scores (p = 0.010). Patient ratings of overall treatment effect demonstrated the significantly (p<0. 0001) greater benefits of omeprazole (mean = 5.26) compared with ranitidine treatment (mean = 3.83). CONCLUSIONS: Omeprazole treatment significantly reduced persistent reflux-related symptoms and normalized psychological well-being compared with ranitidine in poorly responsive symptomatic patients with GERD.     

Repeated dosing with oral cocaine in humans: Assessment of direct effects, withdrawal, and pharmacokinetics.

Cocaine withdrawal symptoms are thought to play a role in relapse; studies characterizing the symptomatology have yielded mixed findings. This study sought to examine the pharmacodynamic/pharmacokinetic profile of repeated high dose exposure to oral cocaine and characterize acute and protracted withdrawal in cocaine abusers. This study employed a repeated-dosing, single-blind design in which subjects (n = 9), resided for 40 days on a closed ward. They were maintained for two 4-day cocaine exposure periods (Days 1–4 & Days 9–12, cocaine 175 mg, p.o.; 5 hourly doses; 875 mg/day) separated by a 4-day matched placebo exposure period (Days 5–8). After these 12 days, an additional period of 28 days of placebo maintenance followed (Days 13–40). Test sessions were conducted during each phase; measures of mood, drug effects, sleep, pharmacokinetics, and prolactin were collected throughout the study. The dosing regimen produced cocaine plasma concentrations (Cmax of 680 ng/mL) two to threefold higher than typically seen in acute dose studies. Prototypic psychostimulant effects, including subjective ratings of euphoric effects (liking, high, good effects) and significant cardiopressor effects, were sustained during the active dosing periods, corresponding to the rise and fall of plasma cocaine. Withdrawal-like symptoms (i.e., disruptions of sleep, increased ratings of anxiety, irritability, crashing) were observed within 24-hr after cessation of dosing. Cocaine reduced prolactin acutely, but no sustained alterations were observed for this measure or for other signs or symptoms during the 28-day abstinence period. These findings indicate that exposure to controlled high doses of cocaine produces modest symptoms consistent with cocaine withdrawal within hours of cessation of dosing but provide no evidence of symptoms persisting beyond 24 hours. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Use of the stages of change in exercise adherence model among older adults with a cardiac diagnosis

Open-label buspirone was studied in 25 prepubertal psychiatric inpatients (age 8.0 +/- 1.8 years, 76% boys) presenting with anxiety symptoms and moderately aggressive behavior. Patients with severe aggression, requiring rapid treatment with mood stabilizers or neuroleptics, were excluded. A 3-week titration (maximum 50 mg daily) preceded a 6-week maintenance phase at optimal dose. Buspirone was discontinued in 6 children (25%): 4 developed increased aggression and agitation, and 2 developed euphoric mania. For the 19 patients who completed the study, mean optimal dose was 28 mg daily. Among completers, depressive symptoms were reduced 52% by Week 6 on Children's Depression Inventory (p < or = 0.001). Decreased aggressivity was reflected in a 29% reduction on Measure of Aggression, Violence, and Rage in Children [MAVRIC] ratings (p < or = 0.02) and in 86% less time in seclusion or physical restraints (p < or = 0.02). Clinical Global Assessment scores improved (CGAS 41 vs. 54, p < or = 0.01). Only 3 children improved sufficiently to continue buspirone after the study. Residual aggressivity and global functioning remained problematic. Buspirone may pose behavioral risks in treating moderate aggressivity in 24% of children with anxiety; in the others, the therapeutic effects on aggression, anxiety, and depression were limited but significant.     

Drug utilization patterns and outcomes associated with in-hospital treatment with risperidone or olanzapine

This study compared the drug-utilization costs and indicators of clinical outcomes associated with the use of risperidone and olanzapine in a hospital setting. We conducted a nonrandomized, retrospective chart review of consecutive patients identified as presenting with psychotic symptoms on inpatient wards at Riverview Hospital in British Columbia and given either risperidone or olanzapine as their first new drug after reassessment (n = 30 per treatment group). Data were collected for up to 120 days. No significant differences were observed between groups in terms of sex, age, duration of illness, or diagnosis. The mean dosage of risperidone for responders was 4.89 +/- 2.56 mg/d, whereas that for olanzapine was 17.19 +/- 3.88 mg/d. The associated daily drug-acquisition costs were significantly different, at CA$4.69 for risperidone and CA$11.52 for olanzapine. Notes in patient charts indicated that a significantly greater proportion of risperidone-treated patients (60.0%) than olanzapine-treated patients (26.7%) responded to therapy, as indicated by improvement in at least one target symptom (P < 0.01). Forty percent of patients initially treated with risperidone were discharged on their original therapy, compared with 13.3% of patients treated with olanzapine (P < 0.05). These results were not substantially affected by correction for markers of illness severity or treatment resistance. Overall, no significant differences in side effects were recorded in the patient records of the two groups. Within this cohort of patients, risperidone treatment was associated with lower drug-acquisition cost and better treatment outcomes than olanzapine.     

Clozapine and risperidone in chronic schizophrenia: effects on symptoms, parkinsonian side effects, and neuroendocrine response

OBJECTIVE: Clozapine and risperidone were the first two "second-generation" antipsychotic drugs approved for schizophrenia. There is currently little information about their comparative efficacy from head-to-head clinical trials. The purpose of this study was to examine the comparative efficacy of clozapine and risperidone for positive and negative symptoms, depression, parkinsonian side effects, and indexes of neuroendocrine function in schizophrenic patients who met a priori criteria for partial response to traditional neuroleptic agents. METHOD: After a baseline fluphenazine treatment period, 29 patients participated in a 6-week, double-blind, parallel-group comparison of the effects of these agents. RESULTS: Clozapine was superior to risperidone for positive symptoms and parkinsonian side effects, but there were no significant differences between the drugs on two measures of negative symptoms, Brief Psychiatric Rating Scale total scores, and depression scores. The clozapine patients, but not the risperidone patients, demonstrated significant reductions from the fluphenazine baseline in positive symptoms, total symptoms, and depression. In addition, clozapine produced fewer effects on plasma prolactin than risperidone or fluphenazine. The mean daily doses during week 6 of the trial were 403.6 mg of clozapine and 5.9 mg of risperidone. CONCLUSIONS: The findings from this study indicate that these drugs have both important differences and similarities in their comparative efficacy in chronically ill, partially responsive patients with schizophrenia. Further research on second-generation antipsychotic drugs in this patient population that addresses key methodological issues, such as optimal dose and treatment duration, are needed.     

Geographic distribution and genetic variability of hepatitis delta virus genotype I

OBJECTIVES: We sought to determine the prevalence, intensity and evolving changes of myocardial damage detected by myocardial uptake of antimyosin antibodies in patients with alcohol-induced dilated cardiomyopathy, alcohol addicts attending a detoxification unit and healthy subjects with short-term alcohol consumption. BACKGROUND: Evidence of alcohol-induced myocardial damage may be provided by myocardial uptake of indium-111-labeled monoclonal antimyosin antibodies. The spectrum of such damage in patients who are heavy drinkers (> 100 g for > 10 years), with or without cardiomyopathy, and the impact of short-term alcohol ingestion on antimyosin antibody uptake have not been adequately explored. METHODS: One hundred twenty antimyosin studies were performed in 56 patients with dilated cardiomyopathy (group I), 15 alcohol addicts attending a detoxification unit (group II) and 6 volunteers for short-term alcohol ingestion (group III). Estimation of antibody uptake was calculated through a heart/lung ratio (HLR) (normal < 1.55). RESULTS: The 56 patients in group I (54 men, 2 women; mean [+/-SD] age 46 +/- 11 years) had consumed 123 +/- 60 g/day of alcohol for 21 +/- 9 years, for a cumulative intake of 914 +/- 478 kg. Mean duration of symptoms was 46 +/- 49 months. Mean left ventricular end-diastolic diameter was 71 +/- 10 mm, and mean ejection fraction was 28 +/- 12%. No differences in New York Heart Association functional class, ventricular size or ejection fraction were noted between 28 active and 28 past consumers, except for the prevalence and intensity of antibody uptake (75% vs. 32%, p < 0.001) and HLR (1.75 +/- 0.26 vs. 1.49 +/- 0.17, p = 0.0001). In 19 patients in the active group restudied after alcohol withdrawal, antibody uptake decreased (from 1.76 +/- 0.17 to 1.55 +/- 0.19, p < 0.001), and ejection fraction improved (from 30 +/- 12% to 43 +/- 16%, (p < 0.001). No changes occurred in the 15 past consumers restudied. The 15 male patients in group II (mean age 36 +/- 4 years) had consumed 156 +/- 59 g/day for 17 +/- 5 years, for a cumulative alcohol intake of 978 +/- 537 kg, an amount similar to that in patients in group I, but antimyosin antibody uptake was detected in only 3 (20%) of 15 patients. None of six group III subjects developed antibody uptake after short-term ethanol ingestion. Despite the small sample size, the power to detect clinically relevant differences in most variables that did not reach statistical significance was amply sufficient. CONCLUSIONS: In alcohol-induced dilated cardiomyopathy, alcohol withdrawal is associated with the reduction or disappearance of myocardial damage and improvement of function. The difference in prevalence of antimyosin antibody uptake in patients with and without cardiac disease who consume similar amounts of alcohol suggests the presence of those with different myocardial susceptibilities to alcohol. Short-term ethanol ingestion in healthy subjects does not induce detectable uptake of antimyosin antibodies.     

Risperidone versus haloperidol: II. Cost-effectiveness

Australia and Canada are currently the only Western nations with government guidelines for analyzing the cost-effectiveness of drugs. We used guidelines issued by the Australian Pharmaceutical Benefits Advisory Committee to construct a model for comparing the cost-effectiveness of risperidone and haloperidol over a 2-year period in patients with chronic schizophrenia. Use of clozapine was also included in the analysis as an alternative treatment given to patients who proved unresponsive to therapy with haloperidol or risperidone. Results are expressed in Australian dollars. Cost-effectiveness was determined by using decision-analytic modeling to compare clinical outcomes and costs. The analytic model contained a decision tree for each of the compared agents that tracked the distribution of patients between treatment outcome pathways (i.e., scenarios). Distributions were based on probabilities derived from our meta-analysis results reported elsewhere and from other sources. Each scenario had an associated monetary cost that included all significant direct costs (i.e., hospital costs; outpatient costs; and the cost of drugs, the services of health care professionals, and government-subsidized hostel accommodation). The cost for a given outcome was the sum of costs for all scenarios leading to that outcome. Cost-effectiveness was expressed as the total cost per favorable outcome. The definition of a favorable outcome was one in which the patient was in a response phase at the end of the 2-year period. The probability of a patient experiencing a favorable outcome at the end of 2 years was 78.9% for risperidone versus 58.9% for haloperidol. The total cost of treatment for 2 years was $15,549.00 for risperidone versus $18,332.00 for haloperidol. The expected cost per favorable outcome was $19,709.00 for risperidone and $31,104.00 for haloperidol. Risperidone was more cost-effective than haloperidol and therefore was "dominant" in pharmacoeconomic terms because it produced a higher proportion of favorable outcomes at lower cost. Sensitivity analysis showed that the difference in clinical response rate was a key determinant of cost-effectiveness.