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Background: Delirium is highly prevalent in the intensive care unit (ICU) and is associated with high morbidity and mortality. The antipsychotic haloperidol is the most frequently used agent to treat delirium although this is not supported by solid evidence. The agents intervening against delirium in the intensive care unit (AID-ICU) trial investigates the effects of haloperidol versus placebo for the treatment of delirium in adult ICU patients., Methods: This protocol describes the secondary, pre-planned Bayesian analyses of the primary and secondary outcomes up to day 90 of the AID-ICU trial. We will use Bayesian linear regression models for all count outcomes and Bayesian logistic regression models for all dichotomous outcomes. We will adjust for stratification variables (site and delirium subtype) and use weakly informative priors supplemented with sensitivity analyses using sceptical priors. We will present results as absolute differences (mean differences and risk differences) and relative differences (ratios of means and relative risks). Posteriors will be summarised using median values as point estimates and percentile-based 95% credibility intervals. Probabilities of any benefit/harm, clinically important benefit/harm and clinically unimportant differences will be presented for all outcomes., Discussion: The results of this secondary, pre-planned Bayesian analysis will complement the primary frequentist analysis of the AID-ICU trial and facilitate a nuanced and probabilistic interpretation of the trial results., (© 2022 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation.)

Background: The AID-ICU trial aims to assess the benefits and harms of haloperidol for the treatment of delirium in acutely admitted, adult intensive care unit (ICU) patients. This paper describes the detailed statistical analysis plan for the primary publication of results from the AID-ICU trial., Methods: The AID-ICU trial is an investigator-initiated, pragmatic, international, multicentre, randomized, blinded, parallel-group trial allocating 1000 adult ICU patients with manifest delirium 1:1 to haloperidol or placebo. The primary outcome measure is days alive and out of hospital within 90 days post-randomization. Secondary outcome measures are days alive without delirium or coma, serious adverse reactions (SARs) to haloperidol, use of escape medicine, days alive without mechanical ventilation, and mortality, health-related quality-of-life measures and cognitive function 1-year post-randomization. Statistical analysis will be conducted in accordance with the current pre-specified statistical analysis plan. One formal interim analysis will be performed. The primary outcome will be adjusted for stratification variables (site and delirium motor subtype) and compared between treatment groups using a likelihood ratio test described by Jensen et al A secondary analysis will be conducted with additional adjustment of the primary outcome for prognostic variables at baseline. The primary conclusion of the trial will be based on the intention-to-treat analysis of the primary outcome adjusted for stratification variables., Conclusion: The AID-ICU trial will provide important, high-quality data on the benefits and harms of treatment with haloperidol in acutely admitted, adult patients with manifest delirium in the ICU., (© 2020 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Background: Haloperidol is the most frequently used drug to treat delirium in the critically ill patients. Yet, no systematic review has focussed on the effects of haloperidol in critically ill patients with delirium., Methods: We conducted a systematic review with meta-analysis and Trial Sequential Analysis of randomized clinical trials (RCTs) assessing the effects of haloperidol vs any intervention on all-cause mortality, serious adverse reactions/events, days alive without delirium, health-related quality of life (HRQoL), cognitive function and delirium severity in critically ill patients with delirium. We also report on QTc prolongation, delirium resolution and extrapyramidal symptoms., Results: We included 8 RCTs with 11 comparisons (n = 951). We adjudicated one trial as having overall low risk of bias. Three trials used rescue haloperidol; excluding these, we did not find an effect of haloperidol vs control on all-cause mortality (RR 1.01; 95% CI 0.33-3.06; I 2  = 0%; 112 participants; 3 trials; 4 comparisons; very low certainty) or delirium severity (SMD -0.15; 95% CI -0.61-0.30; I 2  = 27%; 134 participants; 3 trials; 4 comparisons; very low certainty). No trials reported adequately on serious adverse reactions/events. Only one trial reported on days alive without delirium, cognitive function and QTc prolongation, and no trials reported on HRQoL. Sensitivity analyses, including trials using rescue haloperidol, did not change the results., Conclusions: The evidence for the use of haloperidol to treat critically ill patients with delirium is sparse, of low quality and inconclusive. We therefore have no certainty regarding any beneficial, harmful or neutral effects of haloperidol in these patients., (© 2019 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Background: Delirium among patients in the intensive care unit (ICU) is a common condition associated with increased morbidity and mortality. Haloperidol is the most frequently used pharmacologic intervention, but its use is not supported by firm evidence. Therefore, we are conducting Agents Intervening against Delirium in the Intensive Care Unit (AID-ICU) trial to assess the benefits and harms of haloperidol for the treatment of ICU-acquired delirium., Methods: AID-ICU is an investigator-initiated, pragmatic, international, randomised, blinded, parallel-group, trial allocating adult ICU patients with manifest delirium 1:1 to haloperidol or placebo. Trial participants will receive intravenous 2.5 mg haloperidol three times daily or matching placebo (isotonic saline 0.9%) if they are delirious. If needed, a maximum of 20 mg/daily haloperidol/placebo is given. An escape protocol, not including haloperidol, is part of the trial protocol. The primary outcome is days alive out of the hospital within 90 days post-randomisation. Secondary outcomes are number of days without delirium or coma, serious adverse reactions to haloperidol, usage of escape medication, number of days alive without mechanical ventilation; mortality, health-related quality-of-life and cognitive function at 1-year follow-up. A sample size of 1000 patients is required to detect a 7-day improvement or worsening of the mean days alive out of the hospital, type 1 error risk of 5% and power 90%., Perspective: The AID-ICU trial is based on gold standard methodology applied to a large sample of clinically representative patients and will provide pivotal high-quality data on the benefits and harms of haloperidol for the treatment ICU-acquired delirium., (© 2019 Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Aim: Early clinical response predicts symptomatic remission and recovery in the maintenance treatment phase of first-episode schizophrenia (FES). However, little is known about predictors of symptomatic remission during acute treatment of severely ill patients with FES. Here, we conducted a secondary analysis of our retrospective observational study, which examined response, remission and treatment-resistance rates in seriously ill patients with FES spectrum disorders involuntarily hospitalized and treated with algorithm-based pharmacotherapy., Methods: We performed a retrospective chart review of 131 involuntarily admitted patients with schizophrenia or schizoaffective disorder. Our algorithm aimed to delay olanzapine treatment, standardize medications and suggest initiation of clozapine after failure of third-line antipsychotic treatment. The duration of each adequate antipsychotic treatment at an optimal dosage was 4 weeks or more. Remission was defined using the symptom-severity component of consensus remission criteria. A logistic regression model was applied to identify significant predictors of remission at discharge., Results: Overall, 74 patients (56%) were in remission at discharge. Non-remitters were hampered from becoming remitters mainly by the presence of negative symptoms. There were no differences in first-line antipsychotics, dosage of antipsychotics at time of response and adherence rates to algorithm-based pharmacotherapy between remitters and non-remitters. Shorter duration of untreated psychosis, favourable early response and less negative symptoms at baseline were identified as independent predictors of remission at discharge., Conclusions: The importance of early intervention and specific and adequate treatments of negative symptoms is highlighted., (© 2017 John Wiley & Sons Australia, Ltd.)

Objective: To determine the impact of CYP1A2 genetic polymorphisms on the pharmacokinetics of CYP1A2-metabolized antipsychotic drugs in humans by means of systematic review and meta-analysis., Method: A systematic search was conducted in PubMed and Scopus databases as of June 26, 2018. Studies reporting the pharmacokinetic parameters of CYP1A2-metabolized antipsychotic drugs in individuals who were genotyped for CYP1A2 genetic polymorphisms were retrieved. Pharmacokinetic parameters of individuals who have mutant alleles of a CYP1A2 genetic polymorphism were compared with the wild-type individuals. Pooled-effect estimates, presented as standardized mean difference, were calculated by means of the fixed-effect or random-effects model, as appropriate., Results: Ten studies involving 872 clozapine users, seven studies involving 712 olanzapine users, and two studies involving 141 haloperidol users were included. All but one study reported no associations between any CYP1A2 genetic polymorphisms and the pharmacokinetics of CYP1A2-metabolized antipsychotic drugs. The pooled-effect estimates through meta-analyses of seven studies demonstrated no significant associations between the -163C>A or -2467delT polymorphism and clozapine or olanzapine concentrations in the blood., Conclusions: This study suggests that CYP1A2 genetic polymorphisms have no significant impact on the pharmacokinetics of CYP1A2-metabolized antipsychotic drugs. CYP1A2 genotyping may have no clinical implications for personalized dosing of CYP1A2-metabolized antipsychotic drugs., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: In the intensive care unit, the prevalence of delirium is high. Delirium has been associated with morbidity and mortality including more ventilator days, longer intensive care unit stay, increased long-term mortality, and cognitive impairment. Thus, the burden of delirium for patients, relatives, and societies is considerable. The objective of this systematic review was to critically access the evidence of randomised clinical trials on the effects of haloperidol vs. placebo or any other agents for delirium in critically ill patients., Methods: We will search for randomised clinical trials in the following databases: Cochrane Library, MEDLINE, EMBASE, Science Citation Index, BIOSIS, Cumulative Index to Nursing and Allied Health Literature, Latin American and Caribbean Health Sciences Literature, and Allied and Complementary Medicine Database. Two authors will independently screen and select references for inclusion using Covidence, extract data and assess the methodological quality of the included randomised clinical trials using the Cochrane risk of bias tool. Any disagreement will be resolved by consensus. We will analyse the extracted data using Review Manager, STATA 15, and Trial Sequential., Analysis: The aim of this study was to assess the quality of the evidence, we will create a 'Summary of Findings' table containing our primary and secondary outcomes using the GRADE assessment., Discussion: Our ambition with this systematic review is to provide reliable and powered evidence to better inform decision makers on the use of or future trials with haloperidol for the management of delirium in critically ill patients., (© 2018 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Group II metabotropic glutamate receptor agonists have been suggested as potential anti-psychotics, at least in part, based on the observation that the agonist LY354740 appeared to rescue the cognitive deficits caused by non-competitive N-methyl-d-aspartate receptor (NMDAR) antagonists, including spatial working memory deficits in rodents. Here, we tested the ability of LY354740 to rescue spatial working memory performance in mice that lack the GluA1 subunit of the AMPA glutamate receptor, encoded by Gria1, a gene recently implicated in schizophrenia by genome-wide association studies. We found that LY354740 failed to rescue the spatial working memory deficit in Gria1 -/- mice during rewarded alternation performance in the T-maze. In contrast, LY354740 did reduce the locomotor hyperactivity in these animals to a level that was similar to controls. A similar pattern was found with the dopamine receptor antagonist haloperidol, with no amelioration of the spatial working memory deficit in Gria1 -/- mice, even though the same dose of haloperidol reduced their locomotor hyperactivity. These results with LY354740 contrast with the rescue of spatial working memory in models of glutamatergic hypofunction using non-competitive NMDAR antagonists. Future studies should determine whether group II mGluR agonists can rescue spatial working memory deficits with other NMDAR manipulations, including genetic models and other pharmacological manipulations of NMDAR function., (© 2017 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Objective: To determine whether the prescription of aripiprazole, compared with olanzapine and haloperidol, was associated with a lower frequency of metabolic syndrome (MS) and treatment discontinuation at 1 year., Method: Patients were randomly assigned to be treated open-label and according to usual clinical practice with either aripiprazole, olanzapine, or haloperidol and followed up for 1 year., Results: Three hundred out-patients with persistent schizophrenia were recruited in 35 mental health services. The intention-to-treat (ITT) analysis found no significant differences in the rate of MS between aripiprazole (37%), olanzapine (47%), and haloperidol (42%). Treatment discontinuation for any cause was higher for aripiprazole (52%) than for olanzapine (33%; OR, 0.41; P = 0.004), or haloperidol (37%; OR, 0.51; P = 0.030). No significant difference was found between olanzapine and haloperidol. Time to discontinuation for any cause was longer for olanzapine than for aripiprazole (HR, 0.55; P < 0.001). No significant differences were found between haloperidol and aripiprazole, or between olanzapine and haloperidol., Conclusion: The prescription of aripiprazole did not significantly reduce the rates of MS, but its treatment retention was worse. Aripiprazole cannot be considered the safest and most effective drug for maintenance treatment of schizophrenia in routine care, although it may have a place in antipsychotic therapy., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Study Objectives: To measure concordance between different intensive care unit (ICU) clinicians and a consensus group of electrophysiology (EP) cardiologists for use of a common rate-corrected QT interval (QTc)-prolonging medication in cases containing different potential risk factor(s) for torsade de pointes (TdP)., Design: Prospective case-based evaluation., Setting: Academic medical center with 320 beds., Subjects: Medical house staff (MDs) and ICU nurses (RNs) from one center and select critical care pharmacists (PHs)., Intervention: Completion of a survey containing 10 hypothetical ICU cases in which patients had agitated delirium for which a psychiatrist recommended intravenous haloperidol 5 mg every 6 hours. Each case contained different potential risk factor(s) for TdP in specific combinations. A group of five EP cardiologists agreed that haloperidol use was safe in five cases and not safe in five cases., Measurements and Main Results: For each case, participants were asked to document whether they would administer haloperidol, to provide a rationale for their decision, and to state their level of confidence in that decision. Most clinicians (92 of 115 [80%]) invited to participate completed the cases. Among the five cases where EP cardiologists agreed that haloperidol was not safe, 29% of respondents felt that haloperidol was safe. Conversely, in the five cases where EP cardiologists felt haloperidol was safe, 21% of respondents believed that it was not safe. Overall respondent-EP cardiologist agreement for haloperidol use across the 10 cases was moderate (κ = 0.51). MDs and PHs were in agreement with the EP cardiologists more than RNs (p=0.03). Interprofessional variability existed for the TdP risk factors each best identified. Clinician confidence correlated with EP cardiologist concordance for MDs (p=0.002) and PHs (p=0.0002), but not for RNs (p=0.69)., Conclusion: When evaluating use of a QTc interval-prolonging medication, ICU clinicians often fail to identify the TdP risk factors that EP cardiologists feel should prevent its use. Clinician-EP cardiologist concordance varies by the specific risk factor(s) for TdP and the ICU professional conducting the assessment., (© 2013 Pharmacotherapy Publications, Inc.)

Objective: To evaluate the predictive validity of early response in first-episode schizophrenia within a 1-year follow-up trial and to compare the resulting cutoff to the currently proposed early response definition (20% improvement by week 2)., Method: Receiver operator characteristic (ROC) analyses were used to identify the predictive validity of the psychopathological improvement of treatment from week 1 to week 8, regarding the maintenance of response until week 52 as well as to define the most reasonable cutoff in 132 first-episode patients. The Youden Index (maximum of sensitivity and specificity) was used to compare the newly developed and the commonly used early response definition., Results: Starting with week 6, a reasonable validity to predict the maintenance of response was found (area under the curve = 0.721) with the best fitting cutoff being a 51.6% PANSS total score improvement. Using this cutoff 74 patients (56%) were correctly identified to become responder and maintain response during follow-up (sensitivity: 0.747). The Youden Index was higher applying the newly developed early response cutoff featuring higher specificity compared to the commonly used early response definition., Conclusion: Regarding long-term treatment, it seems more appropriate to base predictions of the patient's maintenance of response not before 6 weeks of treatment., (© 2012 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Instrumental conditioning has been implicated in persistence at slot machine gambling, but its specific role remains unclear. Dopamine (DA) mediates aspects of instrumental responding, and D2 antagonists reliably alter this process. This study investigated the effects of the preferential D2 antagonist, haloperidol (3 mg) on reward-related betting behavior in 20 subjects with pathological gambling (PG) and 18 healthy controls. Hierarchical regression assessed the prospective relationship between Payoff and Bet Size on consecutive trials, along with potential moderating effects of Cumulative Winnings and Phase of game (early/late) under drug and placebo. Payoff predicted Bet Size on the next trial regardless of other factors, consistent with an instrumental view of slot machine gambling. Under placebo, this correlation varied as a function of Winnings and Phase in PG subjects but was strong and invariant in Controls. Under haloperidol, the Payoff-Bet Size correlation in PG subjects resembled the invariant pattern of Controls under placebo. In contrast, the Payoff-Bet Size correlation rose then fell sharply over trials under haloperidol in controls. The correlation of Payoff with Bet Size is remarkable given that there is no actual contingency between winning and betting, and suggests that reward expectancies largely drive slot machine gambling. By blocking inhibitory D2 receptors, haloperidol may have reversed 'tolerance' to monetary reward mediated by increased tonic DA in PG subjects. Disturbance of the Payoff-Bet Size correlation in controls may reflect indiscriminate reward signaling under haloperidol in subjects with normal DA function. Indirect enhancement of DA transmission may reduce undue reward-related responding in PG subjects., (© 2010 The Authors. Journal compilation © 2010 Society for the Study of Addiction.)

Objective: Renewed insight into dose-related effects of sertindole and haloperidol was sought by re-analysing published data for antipsychotic effect, extrapyramidal effect, and patient wellbeing - i.e., the important pharmacopsychometric triangle domains., Method: Selected Positive and Negative Syndrome Scale (PANSS) subscales and the Simpson-Angus scale were tested for validity. Standardized effect sizes [last observation carried forward (LOCF)] at endpoint were calculated., Results: The scales were found to be valid instruments. The PANSS(11) psychotic subscale showed clinically significant effect sizes for all doses of sertindole (12, 20, and 24 mg) and haloperidol (4, 8, and 16 mg). Extrapyramidal effects were evident for all doses of haloperidol, but absent for the lower doses of sertindole. The PANSS(6) depression subscale, a proxy measure of quality of life, showed a clinically significant effect for sertindole 20 mg and no effect for haloperidol., Conclusion: This re-analysis confirmed the antipsychotic effect and absence of extrapyramidal effects for sertindole and, in addition, showed a clinically significant antidepressant effect. A profile for bipolar states emerged., (© 2010 John Wiley & Sons A/S.)

Tricyclic antidepressants decrease rapid eye movement (REM) sleep and may suppress sleep atonia. Reports indicate that these agents can induce visual hallucinations, sometimes characterized as hypnopompic or associated with a dissociated sleep-wakefulness state. In addition, disturbing dreams and confusional states were reported during clinical trials and in subsequent studies. To our knowledge, only two cases of nightmares associated with mirtazapine, a tetracyclic antidepressant, have been previously reported. We describe a 43-year-old Caucasian man with major depressive disorder who started mirtazapine 15 mg at bedtime because he had poor symptom control with other antidepressant drugs. Three days later, vivid dream activity was noted, evolving into realistic nightmares that the patient was not able to distinguish from reality on awakening. Acute paranoia was suspected, and haloperidol was started. The dream activity then ended, and within 3 days the patient was able to identify the dreams as unreality. Haloperidol was discontinued, but mirtazapine was continued, and the vivid dream activity persisted; however, reality testing when awake was intact. A short course of haloperidol restored the patient's reality testing, and mirtazapine was eventually replaced with bupropion. The unusual nocturnal activity resolved as a result. Clinicians should be aware of the possible transition from exceptionally vivid dreams to REM sleep behavior disorder and psychosis based on dream content as an adverse effect of mirtazapine.

Background: We evaluated the prophylactic effect of low-dose haloperidol (1 mg) on post-operative nausea and vomiting (PONV) in women undergoing ambulatory laparoscopic surgery. Droperidol (0.625 mg) and saline were controls., Methods: One hundred and fifty women undergoing ambulatory laparoscopic surgery under general anaesthesia were enrolled in this randomized, double-blind, and placebo-controlled study. After tracheal intubation, the haloperidol group (n=50) received intravenous haloperidol (1 mg), the droperidol group (n=50) received intravenous droperidol (0.625 mg), and the saline group (n=50) received intravenous saline., Results: Haloperidol- and droperidol-group patients reported a lower incidence of PONV [24% and 23% vs. 49% (saline group); P<0.05] and requested fewer doses of rescue antiemetics [13% and 16% vs. 38% (saline group); P<0.05] during the first four post-operative hours. During the 24-h post-operative period, haloperidol- and droperidol-group patients also reported a lower incidence of PONV [31% and 32% vs. 62% (saline group); P<0.01]. No differences were found between the haloperidol and droperidol groups., Conclusion: Like droperidol (0.625 mg), prophylactic intravenous haloperidol (1 mg) significantly reduced the incidence of PONV in women undergoing ambulatory laparoscopic surgery.

It is not known whether dexamethasone increases the effectiveness of anti-emetics when given to treat postoperative nausea and vomiting (PONV). In a randomised study, 242 patients who were experiencing PONV received dolasetron and placebo, haloperidol and placebo, dolasetron and dexamethasone, or haloperidol and dexamethasone. The results from 228 patients were suitable for analysis. PONV recurred significantly less frequently in patients treated with additional dexamethasone (33%) than in patients treated without additional dexamethasone (51%). The combination of dexamethasone with dolasetron or dexamethasone with haloperidol is superior to dolasetron or haloperidol alone for the treatment of PONV.

Purpose: To evaluate the cost-effectiveness of three antipsychotic medications (olanzapine, risperidone and haloperidol) in the treatment of schizophrenia using the Positive and Negative Symptom Scale., Study Design and Methods: A decision analysis model was created to evaluate the cost-effectiveness of two atypical antipsychotics (risperidone and olanzapine) and haloperidol. Outcome probabilities were determined from published clinical trials. The main dependent variable of interest was to compare the incremental cost-effectiveness ratios (ICER) of the atypical antipsychotic with haloperidol, and also to compare the ICER of olanzapine and risperidone. Sensitivity analyses were conducted for olanzapine and risperidone to determine the effects of altering drug cost, efficacy and re-hospitalization rate on total costs., Results: Risperidone and olanzapine were dominant strategies compared with haloperidol (less costly and more effective). Risperidone was also dominant when compared with olanzapine. A one-way sensitivity analysis for efficacy indicated that the efficacy of risperidone would need to decrease by approximately 3% from the base-case in order for olanzapine and risperidone to have equal total costs. In a two-way sensitivity analysis varying both the cost of olanzapine and risperidone, the difference in drug costs between them would have to increase from $2.12 per day to $4.12 per day in order to have equal total costs. In terms of varying re-hospitalization rates, the re-hospitalization rate for risperidone would have to increase from 3% to 33% greater than the re-hospitalization rate for olanzapine in order to have equal total direct costs., Conclusion: Based on this decision model, atypical antipsychotics were a dominant strategy over haloperidol primarily because of increased efficacy and lower re-hospitalizations. The ICER indicated that risperidone was dominant over olanzapine because of lower drug costs and increased number of responders, which leads to decreased total costs.

Delirium is common in acutely ill patients and can result in substantial morbidity if left untreated. Atypical antipsychotics have been postulated to be safer and more effective than haloperidol for treatment of this condition. To evaluate the role of atypical antipsychotics versus haloperidol for treatment of delirium in hospitalized acutely ill adults, we searched MEDLINE (1977-September 2006) and International Pharmaceutical Abstracts (1997-September 2006) for English-language publications of clinical trials that compared atypical antipsychotics and haloperidol. Four comparative studies were identified: one double-blind, randomized study (risperidone vs haloperidol), one single-blind, randomized study (olanzapine vs haloperidol), and two retrospective studies (olanzapine vs haloperidol and quetiapine vs haloperidol). These studies demonstrated that atypical antipsychotics are as efficacious as haloperidol. In addition, they appear to be associated with a lower frequency of extrapyramidal effects, and thus are safer than haloperidol. However, these conclusions are based on a limited number of studies; larger comparative trials are needed to elucidate the role of atypical antipsychotics for treating delirium in this population.

The contribution of immune system to schizophrenia has been an important area of focus in schizophrenia research. Several genetic variants in the cytokine system have been associated with the pathogenesis of schizophrenia. The purpose of this study was to determine whether a pharmacogenetic relationship exists between a variable number of tandem repeats (VNTR) polymorphism in the interleukin-1 receptor antagonist gene (IL-1RN) and clinical improvement during antipsychotic treatment in patients with a first non-affective psychotic episode. One hundred and fifty-four subjects presenting with a first non-affective psychotic episode were randomly assigned to treatment with haloperidol, risperidone, or olanzapine and rated with the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment of Negative Symptoms (SANS) and the Scale for the Assessment of Positive Symptoms (SAPS) both at baseline and after 6 weeks of treatment. A control sample of 336 blood bank donors was also included. No differences in genotype or allele distributions were found between patients and controls. However, after controlling for baseline SANS scores, the genotype in the VNTR polymorphism in the IL-1RN gene significantly predicted negative symptom improvement, accounting for approximately 7% of the variance (F = 5.23, df = 2, P = 0.006). The mean decrease in SANS scores was 58% for the IL-1RN* 2/2, 44% for the IL-1RN* 1/2, and 14% for the IL-1RN* 1/1 subjects, respectively. These results suggest that the VNTR polymorphism in the IL-1RN gene may be a useful predictor of negative symptom improvement in schizophrenic patients treated with antipsychotic drugs., ((c) 2006 Wiley-Liss, Inc.)

This retrospective study of patients treated in a ninety-day, inpatient, dual-diagnosis treatment program examined antipsychotic effectiveness in this population using length of stay in treatment and successful program completion as outcome measures. All patients with co-occurring substance dependence and schizophrenia or schizoaffective disorder treated with olanzapine, risperidone, ziprasidone, and typical depot neuroleptics from January 2001 to December 2003 (N = 55) are the subjects of this study. Patients stayed longer in treatment when taking risperidone (82 +/- 19 days) or ziprasidone (74 +/- 21 days) compared with olanzapine (44 +/- 30 days) or typicals (47 +/- 36 days). Eighty-eight percent of risperidone patients and 64% of ziprasidone patients successfully completed the program, while only 33% of olanzapine patients and 40% of patients on typicals successfully completed the program. Risperidone and ziprasidone were associated with significantly better program performance than olanzapine or depot typicals in this population. Possible reasons for this difference are discussed.

Study Objective: To standardize treatment of alcohol withdrawal syndrome (AWS) in internal medicine patients using an adult AWS practice guideline with a symptom-triggered management approach., Design: Prospective interventional (pilot group) and retrospective (control group)., Setting: University teaching hospital., Patients: Thirty-two internal medicine patients identified as being at risk for AWS and treated according to the AWS practice guideline who were compared with 49 internal medicine patients managed with nonstandardized approaches., Intervention: Patients in the pilot group were assessed using the AWS type indicator. They received lorazepam, clonidine, or haloperidol, based on AWS type indicator assessment and adult AWS practice guideline criteria., Measurements and Main Results: Data collected and analyzed were drugs administered to control AWS symptoms, use of sitters and physical restraints, length of hospital stay, and discharge from hospital receiving tapered drug therapy. Pilot patients received 46.6% less benzodiazepine (p=0.001), 20% more clonidine (p=0.01), and 18.2% more haloperidol (p=0.002) than control patients. No drug therapy was required in 19% of pilot patients compared with 2% of controls (p=0.01). Significantly more control (71.4%) than pilot patients (18.8%) were discharged with tapered benzodiazepine therapy (p

Objective: We describe a patient in whom improvement in negative symptoms contributed to early weight loss and subsequent long-term improvement in weight management., Method: Case report., Results: A 26-year-old woman with schizophrenia gained 7 kg over the course of 1 year after starting treatment with olanzapine. However, as negative symptoms gradually improved with treatment, she became motivated to diet and exercise regularly. She quickly lost 9 kg and subsequently maintained optimal weight (55 kg; body mass index, 24.1 kg/m(2) )., Conclusion: Important strategies for minimizing weight gain in patients taking antipsychotic agents include improving negative symptoms of avolition and apathy, regular monitoring of body weight and potential medical consequences of overweight and obesity, and educating the patient about the importance of diet and regular exercise.

Objective: To investigate the association between duration of untreated psychosis (DUP) and treatment outcome in a sample of subjects from a developing country., Method: Forty-eight subjects with a first episode of psychosis were evaluated prior to treatment and at 3-month intervals over a period of 24 months. We first examined correlations between DUP and symptom improvement as measured on the Positive and Negative Symptom Scale (PANSS), and then performed multivariate analysis to determine the validity of DUP as a predictor of outcome., Results: DUP was significantly correlated with improvement in PANSS total and negative subscale scores as well as the PANSS depression factor at 21 and 24 months. Multivariate analysis found DUP to be the only significant predictor of improvement in negative symptoms at 24 months., Conclusion: DUP was a significant predictor of outcome in a cohort form a developing country. This study provides support for early detection and intervention strategies., (Copyright (c) Blackwell Munksgaard 2004)

Objective: To investigate all published case reports of torsade de pointes (TdP) induced by psychotropic drugs (PDs) in order to examine the prevalence of risk factors for TdP prior to the drug initiation., Method: We found 45 reports on 70 patients with TdP induced by PDs. Each report was analyzed for the presence of risk factors for TdP: female gender, heart disease, hypokalemia, high doses of offending agent, concomitant use of a QT interval prolonging agent, and a history of long-QT syndrome., Results: Female gender was the most common risk factor for TdP (71.4%). The other studied risk factors were also frequently present (34.2-14.2%). Nearly all patients had at least one and 51 (73%) patients had >2 risk factors for TdP prior to PD initiation., Conclusion: We wish to raise the level of awareness of risk factors for TdP in the psychiatric community., (Copyright (c) Blackwell Munksgaard 2005)

The main study was designed primarily to compare the clinical effects of four antipsychotics in 157 patients with schizophrenia or schizoaffective disorder. The secondary genetic study, reported here, is based on a subset of 60 patients who consented to genotyping assays. Based on previous work with the catechol-O-methyltransferase (COMT) 158 polymorphism, we hypothesized that the Met-Met homozygotes would be more hostile than the heterozygotes and the Val-Val homozygotes. Hostility ratings at baseline were used to test this hypothesis. The Met-Met homozygotes (N = 7) were found to have significantly higher levels of hostility than the other patients (N = 53). The hypothesis was thus supported. The finding should be replicated in a larger sample., (Copyright 2003 Wiley-Liss, Inc.)

A 42-year-old woman who underwent single lung transplantation who received tacrolimus and a 58-year-old woman with pneumonia and multiple comorbidities who received haloperidol both experienced drug-induced prolongation of cardiac repolarization. The second woman also developed torsade de pointes. Critically ill patients are particularly susceptible to developing torsade de pointes due to various comorbidities, electrolyte disturbances, and receipt of numerous drugs. These two case reports illustrate the increased risk for drug-induced cardiotoxicity in the critically ill patient. They also indicate the need for current knowledge derived from basic research and retrospective case reports on drug-induced torsade de pointes to be integrated into the existing body of knowledge. Guidelines can then be developed to help prospectively reduce the frequency of adverse effects in intensive care patients. Research is necessary regarding identification of high-risk patients before drugs are administered, and clarification of the proper role of therapeutic QT monitoring in clinical practice.

Objective: Recent theoretical approaches emphasize a disorder of face processing in the pathogenesis of the Capgras syndrome. We report a patient with the Capgras syndrome developing in the physical absence of the person who is believed to be replaced and thus a limited role for a disorder of face processing., Method: The clinical phenomenology of a case of the Capgras syndrome is explored., Results: A disorder of face processing might not be a sufficient explanation of the course of the disorder in this patient., Conclusion: Face processing accounts, of the Capgras delusion, have to be supplemented by additional assumptions.

Aims: The cytochrome P-450 2D6 (CYP2D6) gene duplication/multiduplication producing an increase in enzyme activity, and the common Japanese mutation, CYP2D6*10A producing a decrease of enzyme activity were screened in a large number of Japanese psychiatric subjects (n = 111) in order to investigate whether these mutated alleles affected the plasma concentration of haloperidol., Methods: Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was performed to identify the CYP2D6*10A and CYP2D6*2 genotypes in subjects who had been taking haloperidol. For the screening of duplicated active CYP2D6 gene, allele-specific long PCR was performed. Plasma concentration of haloperidol was measured by the enzyme immunoassay, and expressed as "plasma concentration dose ratio" to normalize individual differences., Results: The plasma concentration-dose ratio showed large interindividual differences of approximately 18-fold. PCR-RFLP methods revealed that 29 (26.1%), 10 (9.0%), 39 (35.1%), 0 (0%), seven (6.3%) and 26 (23.4%) cases possessed the CYP2D6 genotypes *1/*1, *1/*2, *1/*10A, *2/*2, *2/*10A and *10 A/*10A, respectively. Six cases (5.4%) had duplicated CYP2D6 genes. There were no significant differences of plasma concentration-dose ratio between the groups classified by CYP2D6*10A and *2 genotypes (Kruskal-Wallis test; P = 0.37), even in those cases whose daily doses were lower than 20 mg (n = 90, P = 0.91). Subjects having duplicated genes (n = 6) did not show significant differences of plasma concentration-dose ratio by comparison with subjects who had no duplicated genes (Mann-Whitney U-test; P = 0.80)., Conclusions: Gene duplication, and the common Japanese mutation CYP2D6*10A on CYP2D6 gene are not likely to be the main modulatory factors of plasma concentration of haloperidol in Japanese psychiatric subjects.

Study Objective: To standardize treatment of alcohol withdrawal syndrome (AWS) in surgical patients using an AWS practice guideline with a symptom-triggered approach., Design: Prospective interventional (pilot group) and retrospective (comparison group)., Setting: University teaching hospital., Patients: Thirty-eight trauma, orthopedic, and general surgery patients identified at risk for AWS in the pilot group, and 34 patients who were managed using nonstandardized approaches., Interventions: At-risk patients in the pilot group were assessed using the AWS Type Indicator. They received lorazepam, clonidine, or haloperidol, based on AWS Type Indicator assessment and AWS practice guideline criteria., Measurements and Main Results: A standardized symptom-triggered approach to managing AWS was expected to decrease the use of benzodiazepines, avoid undertreatment of adrenergic hyperactivity and delirium, decrease the need for sitters and physical restraints, and reduce hospital length of stay. Pilot patients received a mean of 23 mg less benzodiazepine (p=0.01), 0.1 mg more clonidine (p=0.01), and 20 mg less haloperidol (p=0.06) than comparison patients. Pilot patients also required significantly fewer sitter hours (p=0.04) and hours of restraint use (p=0.09) than comparison patients. No significant differences were found between groups for length of stay (p=0.77)., Conclusions: This pilot project suggests that trauma, orthopedic, and general surgery patients at risk for AWS can be safely and effectively managed with a standardized, symptom-triggered approach. Moreover, this approach decreased the amounts of benzodiazepines and haloperidol administered to patients at risk for AWS.

Postoperative nausea and vomiting (PONV) are frequent and unpleasant symptoms. This prospective study aimed to assess the efficacy of a multimodal approach to prevent PONV, and patient satisfaction using the willingness-to-pay method. Two validated risk scores were applied to forecast the individual risk for PONV in 900 consecutive patients of whom 108 were identified as high-risk patients (predicted risk: 79-87%). High-risk patients received multimodal anti-emetic prophylaxis: total intravenous anaesthesia with propofol, high fractional inspired oxygen (80%), omission of nitrous oxide, dexamethasone 8 mg, haloperidol 10 microg.kg(-1), and tropisetron 2 mg. Of the remaining patients with low or moderate risk for PONV, a random sample of 71 females received balanced propofol-desflurane anaesthesia without prophylactic anti-emetics. All patients were interviewed 2 and 24 h after surgery for occurrence of nausea and vomiting. Patient satisfaction was measured using the willingness-to-pay method. The incidence of PONV (95%-confidence interval) in the control-group was 41% (29-51%), slightly lower than predicted by the risk scores (53-57%). The multimodal anti-emetic approach reduced the predicted risk (79-87%) in the high risk-group to 7% (3-14%). This was associated with a high willingness-to-pay median (25th/75th percentile) of 84 UK pounds (33-184 UK pounds) in the multimodal anti-emetic group compared to 14 UK pounds (4-30 UK pounds) in the control group. A multimodal anti-emetic approach can considerably reduce the incidence of PONV in high-risk patients and is associated with a high patient satisfaction as measured by the willingness-to-pay method.

Aims: This study was carried out to evaluate the influence of CYP2D6 genotype on the steady state plasma concentrations of haloperidol and reduced haloperidol in Korean schizophrenic patients., Methods: One hundred and twenty Korean schizophrenic patients treated with various, clinically determined, doses of haloperidol (range 3-60, median 20 mg day-1) during monotherapy were recruited. CYP2D6 genotypes were determined by analysis of the CYP2D6*10 allele using allele-specific PCR and the CYP2D6*5 allele by long-PCR. Steady state plasma concentrations of haloperidol and reduced haloperidol were analysed by h.p.l.c., Results: Twenty-three (19.2%), 60 (50.0%), 1 (0.8%), 33 (27.5%) and 3 patients (2.5%) possessed the CYP2D6 genotypes *1/*1, *1/*10, *1/*5, *10/*10 and *10/*5, respectively. The allele frequencies of CYP2D6*1, *10 and *5 were 44.6%, 53.8% and 1.7%, respectively. Significant relationships between dose and plasma concentrations of haloperidol (linear; r2 = 0.60, P < 0.0001) and reduced haloperidol (quadratic equation; r(2) = 0.67) were observed. Overall, the concentrations normalized for dose (C/D) of haloperidol were significantly different between the CYP2D6*1/*1, *1/*10 and *10/*10 genotype groups (one-way ANOVA; P = 0.028). No significant differences between the genotype groups were found with respect to the C/D of reduced haloperidol (P = 0.755). However, in patients with daily doses less than 20 mg, significant differences in the C/D of haloperidol (P = 0.003), but not of reduced haloperidol, were found between the three major genotype groups. In patients with doses higher than 20 mg, no differences were found between the genotype groups for either haloperidol or reduced haloperidol. 68 patients (57%) used benztropine, an antimuscarinic agent. All four patients with a *5 allele (one together with *1 and three with *10) were found to use benztropine. The patients homozygous for the *1 allele seemed to need less benztropine than the patients with one or two mutated alleles (Fisher's exact test; P = 0.036)., Conclusions: The dose-corrected steady state plasma concentrations of haloperidol, but not of reduced haloperidol, were significantly different between the CYP2D6*1/*1, *1/*10 and *10/*10 genotype groups when doses lower than 20 mg haloperidol were given. No differences were found at higher doses. These results suggest the involvement of CYP2D6 in the metabolism of haloperidol at low doses of haloperidol (< 20 mg daily), while another enzyme, probably CYP3A4, contributes at higher doses.

Objective: Typical antipsychotics have their indication in the ultra-short (first week) treatment of severe episodes of mania. In this setting the Bech-Rafaelsen Mania Scale (MAS) was psychometrically compared with the Clinical Global Impression scale (CGI) to assess its ability to measure response., Method: Ratings on patients with marked to severe mania (n = 80) who participated in the clinical trials to evaluate the ultra-short antimanic effect of zuclopenthixol acetate were assessed. The MAS was analysed for internal validity (total score a sufficient statistic) and for external validity., Results: The MAS was shown to have a high internal validity showing onset of action already after days of treatment. After 6 days of treatment 53% of the patients responded according to the MAS but only 30% according to the CGI. The difference was statistically significant., Conclusion: The MAS has been found to be a valid scale to measure early onset of action and response in the ultra-short antimanic treatment with typical antipsychotics.

Objective: To assess the efficacy of the new atypical antipsychotic drug, amisulpride., Method: Studies comparing the efficacy of amisulpride with that of haloperidol and risperidone, respectively, are reviewed. Outcome measures were Clinical Global Impression, Brief Psychiatric Rating Scale (BPRS), and Positive And Negative Symptom Scale (PANSS) scores., Results: Amisulpride was at least as effective as haloperidol and risperidone in the improvement of positive symptoms, and significantly more efficacious than haloperidol in reducing PANSS negative subscores (P=0.038) in patients with acute exacerbations. Amisulpride demonstrated a greater improvement in BPRS total scores (P<0.05) and PANSS negative subscores (P=0.0001) than haloperidol after 12 months of treatment in chronic schizophrenic patients with acute exacerbations., Conclusion: Amisulpride can thus be considered for use as first-line treatment of acute and chronic schizophrenia.

Objective: To assess the safety of the new atypical antipsychotic drug, amisulpride, in short- and long-term use., Method: Studies comparing the safety of amisulpride with that of haloperidol and risperidone, respectively, are reviewed. Safety was monitored by open adverse event reporting, the Simpson-Angus Scale, the Barnes Akathisia Scale and the Abnormal Involuntary Movement scale., Results: In short- and long-term studies, amisulpride induced significantly less EPS and akathisia than haloperidol. Safety ratings were similar to risperidone in short-term studies. In studies of chronic schizophrenia with predominant negative symptoms, amisulpride was similar to placebo. Endocrine effects were similar in amisulpride-, haloperidol- and risperidone-treated patients. Weight gain with amisulpride was significantly less than risperidone in a short-term study. No clinically important effects on haematological, hepatic or cardiac function were recorded. Data obtained in short- and long-term studies have been confirmed in extensive post-marketing surveillance data., Conclusion: Amisulpride has a broad spectrum of efficacy in schizophrenia without introducing the iatrogenic consequences associated with older therapies.

We report a 22-year-old girl presenting with acute onset left sided hemiballism-hemichorea (HH) and non-ketotic hyperglycemia (NKH). Initial brain CT revealed faint hyperdensities, sharply confined to the contralateral nucleus caudatus and putamen. Sequential MRI investigations yielded increasing hypersignal intensities on T1-weighted images and resolving hypodensities on T2-weighted images of the right striatum, leaving small sequelae in the head of the right caudate nucleus. NKH is an unusual cause of HH. The abnormalities seen in neuroimaging are rare, but seem to be quite specific to this syndrome. We give an update on current literature regarding the possible pathophysiological processes underlying this specific clinical entity.

In a 4-week study of 14 drug-free schizophrenic patients (according to DSM-III-R), free and conjugated fractions of plasma homovanillic acid (pHVA) were repeatedly measured. Free HVA levels decreased during the first 2 h of haloperidol intake (P < 0.03). Conjugated HVA levels slowly decreased during the following weeks (P < 0.05), while free HVA levels remained stable. After 4 weeks, free HVA levels remained unchanged 2 h after morning haloperidol intake, but conjugated HVA levels tended to increase. In haloperidol responders, at baseline the free/total HVA ratio was significantly higher than that in non-responders (P < 0.01). Tolerant patients, i.e. those whose post-treatment free HVA levels decreased below pre-treatment levels, were not found to respond better to haloperidol than non-tolerant patients. The balance between free and conjugated pHVA may be a better reflection of the action of haloperidol than free pHVA levels and it may be of prognostic value in terms of drug response.

Hemiballism and hemichorea following anesthesia-induced hypotension has rarely been described, but a recent case suggests an association. After experiencing marked hypotension during spinal anesthesia, a 70-year-old woman developed hemiballism and hemichorea. Involuntary ballistic movements with writhing, consisting of repetitive rotation and flexion-extension without apparent muscle weakness, affected her left limbs proximally. Low-amplitude, involuntary, choreiform movements involved the distal portions of these limbs. Magnetic resonance imaging demonstrated an area of high signal intensity in the contralateral subthalamic nucleus, suggestive of a focal ischemic lesion. Although such occurrences are rare, anesthesiologists should be aware of the risk of subthalamic nucleus ischemia following marked hypotension.

Study Objective: To compare the utility of intramuscular lorazepam (LZ) with the combination of intramuscular haloperidol (HDL) and LZ to control acutely agitated behavior., Design: Randomized double-blind comparison., Setting: Psychiatric emergency service of a large, university-affiliated, municipal hospital., Patients: Twenty subjects treated on the psychiatric emergency service., Interventions: Patients received an injection of either LZ 2 mg (11 patients) or HDL 5 mg plus LZ 2 mg (9 patients). The Overt Aggression Scale (OAS), visual analog scales reflecting agitation and hostility, and the Clinical Global Impressions (CGI) severity scale were administered at baseline and 30, 60, 120, and 180 minutes after the injection., Measurements and Main Results: Planned data comparisons included categoric assignment of patients as improved, as defined by decreases in outcome measures 60 minutes after the injection, as well as continuous variables up to 180 minutes after the injection. A significantly greater percentage of subjects receiving combined treatment improved on the specific measures 60 minutes after dosing (p<0.05). Kaplan-Meier survival analyses showed significant between-group differences in survival curves plotted for the entire study period (p<0.05). Repeated measures analyses of variance studying group differences showed that both groups improved over time, but between-group differences were not significant. The powers of these analyses were low due to the small sample. No serious adverse effects occurred in either treatment group., Conclusion: Our results suggest superior efficacy for HDL-LZ over LZ alone. Categoric tests of improvement at 60 minutes provided the strongest evidence of group differences.

Droperidol and haloperidol have demonstrated efficacy and safety in the treatment of acute delirium in critically ill patients. We conducted MEDLINE and manual searches of literature published from 1966-1996 to identify articles describing conduction disturbances associated with the drugs. The objectives were to describe the proposed mechanisms of acquired long QTc interval syndrome and torsades de pointes, and to recommend how critically ill patients receiving these agents should be monitored. We found 11 published reports of conduction disturbances associated with intravenous administration of droperidol or haloperidol. The majority of cases occurred in critically ill patients prescribed more than 50 mg/24 hours of either agent. Of the 18 patients described, 13 (72%) had a history of cardiovascular disease. Based on the small number of available case reports, it seems reasonable to suggest that the incidence of adverse cardiovascular effects due to droperidol and haloperidol is small. The mechanism of butyrophenone-induced QTc interval prolongation is not known, but is presumed to involve abnormal ventricular repolarization and the development of early after-depolarizations. Before initiating therapy with droperidol or haloperidol in critically ill patients, a baseline QTc interval and serum magnesium and potassium concentrations should be measured. If the baseline QTc interval is 440 msec or longer, and they are receiving other drugs that may prolong the QTc interval or they have electrolyte disturbances, a butyrophenone antipsychotic should be prescribed with caution. All critically ill patients receiving droperidol or haloperidol should undergo electrocardiogram monitoring and QTc interval measurement; special attention should be given to those receiving doses greater than 50 mg/24 hours, as these patients appear to be at greatest risk for development of conduction disturbances. Based on the currently available literature, in any critically ill patient receiving droperidol or haloperidol therapy whose QTc interval lengthens by 25% or more over baseline, therapy should be discontinued or the dosage reduced.

Schizophrenia is an illness with numerous neurobiologic features. It is hypothesized that patients may have a relative deficit of dopamine neurotransmission in the nigrostriatal and mesocortical tracts of the brain, as contrasted with an excess of dopamine neurotransmission in the mesolimbic area. The dopamine deficit may be related to the negative symptoms (blunted affect, anhedonia, asociality, inability to initiate and carry out complex tasks to completion) of schizophrenia, whereas the dopamine excess may be responsible for the positive symptoms (hallucinations, delusions, and thought disorder). Compared with healthy subjects, schizophrenic patients may also have increased levels of serotonin and decreased levels of norepinephrine in the brain. Conventional antipsychotic drugs nonselectively block dopamine D2 receptors throughout the central nervous system. This may help reduce positive symptoms, but has little or no effect on negative symptoms. Newer agents have more anatomically selective activity with respect to dopaminergic systems but are more complex with respect to their actions in other neurochemical systems, such as serotonin and norepinephrine, which presumably contributes to their apparent greater therapeutic efficacy.

Recently, our laboratory reported that the activity of dipeptidyl-peptidase IV (DPP IV) was significantly lower in the peripheral blood of major depressed patients than in normal controls. The present study examines plasma DPP IV activity in 43 major depressed and 13 schizophrenic subjects versus 21 normal controls and the effects of antidepressants and antipsychotic drugs on plasma DPP IV activity. DPP IV activity was significantly lower in major depressed subjects than in normal controls and schizophrenic subjects. There was a trend towards higher DPP IV activity in schizophrenic patients than in normal controls. There were no significant effects of antidepressants or neuroleptics on plasma DPP IV activity in depressed and schizophrenic patients, respectively. There were no significant relationships between plasma DPP IV activity and plasma cortisol or immune-inflammatory markers, such as serum interleukin-6 (IL-6) or soluble IL-2 receptor. A significant and positive correlation was found between plasma DPP IV and prolyl endopeptidase (PEP) enzyme activity in the study group as a whole and in schizophrenic subjects. The results support the hypothesis that lower and higher plasma DPP IV activities are trait markers of major depression and schizophrenia, respectively. It is concluded that alterations in the enzyme activity of peptidases, such as DPP IV and PEP, play a role in the pathophysiology of major depression and schizophrenia.

We determined the presence of antinuclear autoantibodies (ANA), antinative DNA and histone-reactive ANA in 3 groups of chronic schizophrenic patients (n=85): haloperidol-treated patients (for at least 3 months) (n=35), drug-free for at least 3 months (n=35) and neuroleptic-naive patients (n=15). The autoantibody titers were compared with those of healthy controls (n=37). A significantly higher frequency of positive ANA was found among chronic schizophrenic patients (approximately 20%) as compared with the controls (approximately 5%), irrespective of drug treatment, sex and age. No antinative ANA autoantibodies or histone reactive ANA were detected in either schizophrenic patients or controls. Further studies are needed to isolate and characterize in ANA-positive schizophrenic patients a putative specific ANA profile.

Rhabomyolysis with myoglobinuria has been added relatively recently to the neurologic complications associated with the increased use of cocaine and the introduction of its alkaloid form (crack). This retrospective study reports our experience with 14 patients who presented with rhabdomyolysis after cocaine use in a municipal hospital over a 3-year period. Seven patients used "crack", 2 intravenous and 3 nasal insufflation. All patients but one had hyperthermia, 11 altered mental status, 8 tachycardia, and 4 muscle rigidity. Nine developed renal failure; 3 of these patients died. Two other patients died of cardiorespiratory arrest. Cocaine-related rhabdomyolysis has a high mortality. The observed association with hyperthermia and other central neurologic features resembles the neuroleptic malignant syndrome. Since chronic cocaine use may alter the availability of dopamine either through transmitter depletion or decrease in the number of dopamine receptors, a common pathogenetic mechanism is possible. However, other mechanisms, which are not mutually exclusive but rather frequently overlapping, may play an important role. These include agitation, hyperthermia, adrenergic overstimulation leading to vasoconstriction and ischemia or calcium release from the sarcoplasmic reticulum resulting in increased entry into the muscle cell leading to cell death; in addition, cocaine has direct toxic effect on the muscles.

Many conflicts in the literature about negative symptoms arise because different authors use different definitions of negative symptoms. If narrow definitions are used, it appears that drugs have little effect against negative symptoms, although those who use broader definitions tend to conclude that negative symptoms do respond to drugs. Another complication is that negative symptoms may be secondary to other causes, such as psychotic symptoms, the side effects of drugs, depression and understimulation as a result of hospitalisation. Attempting to measure drug effects on negative symptoms can be complicated by such factors as different co-medication in the test and control groups and different pharmacological profiles of test and standard drugs, in particular in terms of extrapyramidal side effects or antidepressant effects. Several approaches to dissecting the direct effect of drugs from their indirect effects on negative symptoms have included analyses of covariance, regression analyses and path analyses. Applying path analysis to the data from the North American clinical trial of risperidone suggests that a significant component of the advantageous effect of risperidone on negative symptoms, compared with haloperidol, is due to a direct effect that cannot be accounted for by the effect of risperidone on positive symptoms and its superior side-effect profile. Although it is possible to analyse studies retrospectively in this way, the best approach is probably to design future clinical trials so that the effects of drugs on negative symptoms are more easily determined than has been the case in the past.

Ninety first-episode patients fulfilling ICD-9 criteria for schizophrenia were followed up prospectively for 10 years. Complete assessments were possible on 76. The pattern of illness was good in 67% of the cases, and the commonest patterns was one with recurrent episodes. Predictors of poor course and longer time spent in psychosis were identified. All positive and negative symptoms showed a steep decline at the end of 10 years. The results are discussed in the context of longitudinal research on the course of schizophrenia in developing countries.

To investigate whether the occurrence of extrapyramidal side effects was related to D2 dopamine receptor occupancy, iodobenzamide single positron emission computed tomography was carried out in 27 schizophrenic patients and 10 controls. Eighteen patients were treated with haloperidol; 9 patients were treated with clozapine. Our data suggest a relationship between D2 receptor occupancy and extrapyramidal side effects as well as the existence of a neuroleptic threshold of a striatal:frontal cortex ratio of 1.2, below which drug-induced exptrapyramidal side effects can be expected.

Pimozide, a dopamine receptor antagonist, dopamine uptake inhibitor and L-type calcium channel blocker, is used in children suffering from Tourette syndrome (TS), but its effect on frequently comorbid attention deficit hyperactivity disorder (ADHD) is unknown. We have characterized the cognitive effects of pimozide and haloperidol in TS in relation to comorbid ADHD. Sixty-six consecutive outpatients with TS (DSM-III-R), ages 7-16, were randomly assigned to pimozide, haloperidol or medication-free clinical treatment and evaluated cognitively after 6 weeks. Continuous performance task (CPT) and memory search efficiency were compared across treatments. Treatment, comorbid ADHD and their interaction were significant on the CPT task. Pimozide treatment was superior to haloperidol and improved memory search efficiently over the no-drug condition.

In studies by means of the Swedish version of the Positive and Negative Syndrome Scale, we have demonstrated a 5-factor model of schizophrenia, including positive, negative, excited, anxious/depressive and cognitive factors. In this study, the 5 factors were correlated with background factors in a series comprising 140 patients with schizophrenic syndromes. None of the 5 factors revealed any significant age or sex differences. The positive factor correlated positively with the number of previous hospitalizations and the negative factor correlated negatively. The excited factor correlated negatively with age at onset, age at first hospitalization and positively with the duration of the illness and the number of previous hospitalizations. The cognitive factor correlated negatively with age at onset and age at first hospitalization and positively with the duration of the illness. Age at onset was positively correlated with delusions, excitement, unusual thought content and poor impulse control and negatively with lack of spontaneity. The duration of illness correlated positively with excitement, difficulty in abstract thinking and mannerisms. The number of previous hospitalizations correlated positively with delusions, excitement, unusual thought content and poor impulse control and significant negative correlations were demonstrated as concerns blunted affect and lack of spontaneity.