Anticholinergic use in hospitalised schizophrenic patients in Belgium

This naturalistic study aims to evaluate the influence of antipsychotic treatment on the use of anticholinergics. The observed use of anticholinergics will give an indication of the occurrence of extrapyramidal side effects (EPS) in the different antipsychotic treatment conditions. The medication use of 1215 hospitalised patients with DSM-IV 295.xx diagnosis is recorded. Four antipsychotic treatment conditions are distinguished: 1) only first generation antipsychotics (FGA): patients receive one or a combination of first generation antipsychotics, 2) a combination of high potency FGA and second generation antipsychotics (SGA), 3) a combination of low potency FGA and SGA, and 4) only SGA: patients receive one or a combination of SGA. Antipsychotic treatment significantly influences the use of anticholinergics. Anticholinergic use is highest in patients treated with high potency FGA (whether or not in combination with SGA) as compared with patients only treated with SGA and patients combining SGA with low potency FGA. The two latter groups do not significantly differ. However, there were no significant differences in the prevalence of EPS with the exception of akathisia between FGA and SGA. Thus, through the use of anticholinergics, EPS induced by FGA can be effectively reduced.     

Different serine and glycine metabolism in patients with schizophrenia receiving clozapine

Dysfunction of the N-methyl-d-aspartate receptor, which is modulated by excitatory amino acids (EAA), is involved in the pathophysiology of schizophrenia. The effects of antipsychotics on EAA metabolism are uncertain. Positive clinical effects of treatment with antipsychotics were not always associated with changes in EAA serum levels in patients with schizophrenia in clinical trials. To examine EAA serum levels in relation to the intensity of psychotic symptoms and the type of medication received we compared these variables among patients with schizophrenia (n = 49) treated with first (FGA) or second (SGA) generation antipsychotics or clozapine. Glutamate, aspartate, glycine, total serine and d-serine serum levels were measured by High Performance Liquid Chromatography. The Positive and Negative Syndrome Scale (PANSS) and the Scale for the Assessment of Negative Symptoms (SANS) were used to assess symptoms of schizophrenia. Lower average levels of glycine and total serine were found in the serum of patients receiving clozapine when compared to the groups of patients treated with FGA or SGA. There were no differences in serum glutamate, aspartate or d-serine levels or in the intensity of schizophrenic symptoms assessed by PANSS or SANS among the groups of patients treated with FGA or SGA or clozapine. Lower glycine and total serine serum levels could be caused by the particular characteristics of the population of patients receiving clozapine rather than as an effect of the clozapine. The results suggest selective deficiency of l-serine synthesis in the patients with resistance to non-clozapine treatment. It might be an unique biochemical and pathophysiological characteristic of the treatment-resistance in schizophrenia.     

Time to rehospitalization in patients with schizophrenia discharged on first generation antipsychotics, non-clozapine second generation antipsychotics, or clozapine

Rehospitalization is an important outcome of drug effectiveness in schizophrenia. In this study, the hypothesis that clozapine and some second generation antipsychotics (SGA) were superior to first generation antipsychotics (FGA) in preventing rehospitalization of patients with schizophrenia discharged from a university hospital in Brazil was tested. A retrospective observational study was conducted designed to evaluate time to rehospitalization of patients with schizophrenia discharged on a regimen of oral FGA, depot FGA, risperidone, olanzapine and amisulpride, other SGA, or clozapine, during a three-year follow-up period. Risk factors associated with rehospitalization were examined. Of the 464 patients with schizophrenia discharged from hospital, 242 met criteria for study entry. Higher rehospitalization rates were observed in patients treated with depot FGA (30%), risperidone (30%) and other SGA groups (28.5%), respectively. Clozapine was significantly associated with lower rehospitalization risk compared with risperidone. The risk of rehospitalization in patients on olanzapine and amisulpride, and oral FGA, was similar to that of patients in use of clozapine. These results however, are limited by the heterogeneity of illness severity across the groups.     

第二代抗精神病药对慢性精神分裂症患者的治疗作用

目的：探讨第1代抗精神病药（FGA）联合与未联合第2代抗精神病药（SGA）对慢性精神分裂症患者临床疗效、认知功能及社会功能的影响。方法：74例慢性精神分裂症患者被随机分为联合组和对照组,联合组为FGA联合SGA,对照组则为持续应用FGA,治疗至少12周。采用简明精神病量表（BPRS）分别于治疗前后评估患者临床疗效,以探究性眼动检测来评估患者的认知功能,采用个人和社会功能量表（PSP）评估社会功能。结果：探究性眼动检测治疗前凝视点数联合组显著低于对照组（P〈0.05）;尽管经过联合SGA治疗后两组间凝视点数虽不存在差异（P〉0.05）,但联合组治疗前后的凝视点数增加值却显著好于对照组（P〈0.001）;反应性探索（RSS）评分在疗前、疗后两组间均差异无显著性。所有联合SGA患者在治疗后PSP评分均显著优于未联合用药组（P〈0.05或P〈0.001）;LSD分析提示：尤以联合利培酮或阿立哌唑对患者PSP评分改善最为显著（P均〈0.001）。结论：联合SGA对慢性精神分裂症患者疗效显著,尤其对患者认知和社会功能改善明显。     

Acute effects of single‐dose aripiprazole and haloperidol on resting cerebral blood flow (rCBF) in the human brain

Antipsychotic drugs act on the dopaminergic system (first‐generation antipsychotics, FGA), but some also directly affect serotonergic function (second‐generation antipsychotics, SGA) in the brain. Short and long‐term effects of these drugs on brain physiology remain poorly understood. Moreover, it remains unclear whether any physiological effect in the brain may be different for FGAs and SGAs. Immediate (+3.30 h) and different effects of single‐dose FGA (haloperidol, 3 mg) and a SGA (aripiprazole, 10 mg) on resting cerebral blood flow (rCBF) were explored in the same 20 healthy volunteers using a pulsed continuous arterial spin labeling (pCASL) sequence (1.5T) in a placebo‐controlled, repeated measures design. Both antipsychotics increased striatal rCBF but the effect was greater after haloperidol. Both decreased frontal rCBF, and opposite effects of the drugs were observed in the temporal cortex (haloperidol decreased, aripiprazole increased rCBF) and in the posterior cingulate (haloperidol increased, aripiprazole decreased rCBF). Further increases were evident in the insula, hippocampus, and anterior cingulate after both antipsychotics, in the motor cortex following haloperidol and in the occipital lobe the claustrum and the cerebellum after aripiprazole. Further decreases were observed in the parietal and occipital cortices after aripiprazole. This study suggests that early and different rCBF changes are evident following a single‐dose of FGA and SGA. The effects occur in healthy volunteers, thus may be independent from any underlying pathology, and in the same regions identified as structurally and functionally altered in schizophrenia, suggesting a possible relationship between antipsychotic‐induced rCBF changes and brain alterations in schizophrenia. Hum Brain Mapp, 2013. © 2012 Wiley Periodicals, Inc.     

Antipsychotics and seizures: Higher risk with atypicals?

PurposeAlmost all antipsychotics have been associated with a risk of epileptic seizure provocation. Among the first-generation antipsychotics (FGA) chlorpromazine appears to be associated with the greatest risk of seizures among the second-generation antipsychotics (SGA) clozapine is thought to be most likely to cause convulsions. This information is largely based on studies that are not sufficiently controlled. Besides, information about the seizure risk associated with newer antipsychotics is scarce.MethodThe Pharmacovigilance Unit of the Basque Country (network of centers of the Spanish Pharmacovigilance System, SEFV) provided reporting data for adverse reactions (AR) from the whole SEFV to estimate the reporting odds ratio (ROR) for antipsychotics and seizures (“convulsions” as Single MedDra Query). Data was obtained from SEFV database from 1984 to the June 2011.ResultsThe total number of convulsions reported for SGA was 169 (total reported AR 3.204). The number of convulsions reported for FGA was 35 (total reported AR 2.051). 94 convulsions were reported in association with clozapine (total AR 1.052). The ROR for SGA versus FGA was 3.2 (CI 95%: 2.21–4.63). The ROR for SGA excluding clozapine versus FGA was 2.08 (CI 95%: 1.39–3.12).ConclusionOur results show that SGA may pose a higher risk of seizures than FGA, mainly, but not only due to clozapine. This is line with recent studies suggesting that some SGA carried a higher average risk of electroencephalographic abnormalities than many FGA. Nonetheless, It is well known that spontaneous reports do not allow strong inferences about adverse drug effects, because differences in reporting fractions by time, drug or type of event are difficult or even impossible to distinguish from differences in the occurrence rates of adverse events. Still, we consider that the possibility of SGA carrying a higher risk of seizure induction than FGA warrants further research.     

Pharmacological treatment of hospitalised schizophrenic patients in Belgium

Objective. The aim of the present study is two-fold: (1) evaluate to what degree antipsychotic prescribing patterns are in accordance with published treatment recommendations; (2) gain insight in factors determining guideline adherence or non-adherence. Method. The medication use at first assessment of 1215 psychotic in-patients, participating in a naturalistic prospective follow-up study, was registered. Results. In Belgium, use of novel antipsychotics is frequent (69.4%) in hospitalised schizophrenic patients. In the total sample 57.8% receive only one antipsychotic drug. The majority of patients are treated with drugs of only one antipsychotic drug group, either first-generation antipsychotics (FGA) (27.8%) or second-generation antipsychotics (SGA) (42.3%). Roughly one-quarter of patients combine different types of antipsychotic. Antipsychotic dosing is adequate for the majority of patients, but one-third receive a higher than recommended dose. The use of SGA is influenced by the patients’ age and duration of illness. Polypharmacy and the administration of high doses FGA are influenced by symptom severity and illness duration. No clear determinants of SGA overdosing were found. Conclusions. SGA are most frequently used for the treatment for schizophrenic psychosis. Polypharmacy and excessive dosing are still frequently observed and appear influenced by the patient's clinical condition and illness duration. Evidence-based guidelines have not been sufficiently implemented in daily clinical practice yet.     

Atypical Antipsychotic Use in the Treatment of Psychosis in Primary Care

Atypical antipsychotics are a class of novel agents increasingly employed for the treatment of psychotic disorders. The pharmacodynamic properties of the atypicals appear to impact a broader spectrum of psychotic symptoms than had been appreciated with older generation antipsychotics. In addition, the atypical agents appear to have a reduced risk of neurologic side effects compared with conventional antipsychotic use. Both of these features enhance the appeal of the atypical antipsychotics and may be associated with enhanced patient compliance. The atypical antipsychotics appear to be effective for schizophrenia as well as other psychotic disorders, including schizoaffective disorder and mood disorders with psychotic features. Consequently, atypical antipsychotics are now considered to be the first-line treatment for schizophrenia, with the exception of clozapine, which is considered a second-line agent because of risks associated with its use. This review will discuss the literature on atypical antipsychotic efficacy in psychotic disorders. Issues related to antipsychotic use, dosing, adverse effects, and drug interactions are also discussed.     

Drug treatments for schizophrenia: pragmatism in trial design shows lack of progress in drug design

Aims.The introduction of second generation antipsychotic (SGA) medication over a decade ago led to changes in prescribing practices; these drugs have eclipsed their predecessors as treatments for schizophrenia. However, the metabolic side effects of these newer antipsychotics have been marked and there are increasing concerns as to whether these novel drugs really are superior to their predecessors in terms of the balance between risks and benefits. In this article, we review the literature regarding comparisons between first generation antipsychotic (FGA) and SGA in terms of clinical effectiveness.Methods.Large (n > 150) randomized-controlled trials (RCTs) comparing the effectiveness (efficacy and side effects) of FGA and SGA medications other than clozapine were reviewed, as were meta-analyses that included smaller studies.Results.The superiority in efficacy and reduced extrapyramidal side effects (EPSE) of SGAs is modest, especially when compared with low-dose FGAs. However, the high risk of weight gain and other metabolic disturbances associated with certain SGAs such as olanzapine is markedly higher than the risk with FGAs at the doses used in the trials.Conclusions.The efficacy profiles of various FGAs and SGAs are relatively similar, but their side effects vary between and within classes. Overall, large pragmatic trials of clinical effectiveness indicate that the care used in prescribing and managing drug treatments to ensure tolerability may be more important than the class of drug used.Key words: antipsychotic drugs, clinical effectiveness, schizophrenia, randomized controlled trials     

Long-term outcomes in chronically hospitalized geriatric patients with schizophrenia: retrospective comparison of first generation and second generation antipsychotics

INTRODUCTION: Some groups have reported the longitudinal course of elderly poor outcome schizophrenic patients to be characterized by progressive decline in cognitive functions and functional capacity. Although many of these patients experience minimal reduction of psychotic symptoms, there may be beneficial effects of antipsychotic treatments on cognitive functions and functional capacity. METHODS: This naturalistic study compared the longitudinal course of psychotic symptoms, cognitive functions and functional impairment in geriatric schizophrenic patients treated with first generation (N=97) or second generation (N=78) antipsychotic medications. Mixed effects linear regression analyses were used to examine the effects of treatment (first generation vs. second generation antipsychotic), time and treatment x time. RESULTS: Cognitive functions (Mini Mental State Examination time effect estimate=-.41, p<.001; ADAS-L Cog time effect estimate=.64, p<.001) and self-care skills (ADAS-L Self-Care time effect estimate=.65, p<.001) declined over time for the subject group as a whole and this decline was not modified by treatment with second generation antipsychotics relative to first generation antipsychotics. Similarly, second generation antipsychotic treatment produced no effect on the progressive worsening of negative symptom over time. CONCLUSION: This long-term naturalistic study of poor outcome geriatric patients with schizophrenia did not find atypical antipsychotics to produce any differential protective effect relative to typical antipsychotics on the long-term manifestations of symptoms, cognition and self-care in poor outcome geriatric schizophrenic patients.     

Adjunctive quetiapine decreases symptoms of tardive dyskinesia in a patient taking risperidone

Tardive dyskinesia is a potentially permanent and disfiguring side effect associated with the use of conventional, or first generation, antipsychotics. Quetiapine is a second generation antipsychotic with transient dopamine receptor occupancy, a property shared with clozapine. Quetiapine was administered to a patient who had persistent choreoathetoid movements that developed during treatment with conventional antipsychotics and remained unimproved during longterm treatment with risperidone. During 10 weeks of monotherapy with quetiapine, his Abnormal Involuntary Movement Scale score fell from 11 to 3. He was subsequently switched back to risperidone and his movements returned. The addition of quetiapine to his risperidone regimen once again resulted in a decrease of his tardive dyskinesia symptoms. The mechanism by which quetiapine improved tardive dyskinesia symptoms in this patient is not known, but differential treatment effects between the novel antipsychotics may exist. Controlled trials of quetiapine in the treatment of tardive dyskinesia should be pursued.     

Evaluating the CANSAS self-report (CANSAS-P) as a screening instrument for care needs in people with psychotic and affective disorders

The metabolic profiles of Chinese patients treated with second-generation antipsychotic (SGA) medication and first-generation antipsychotic (FGA) medication were compared. The sample comprised 99 patients treated with SGA (risperidone, olanzapine and ziprasidone) and 99 with FGA (chlorpromazine, haloperidol and trifluoperazine) from the outpatient clinic of a teaching hospital in Hong Kong. The most frequent psychiatric diagnosis was schizophrenia, followed by affective disorder and other psychiatric diagnoses. Subjects were measured for body weight, body height, fasting lipid and glucose levels. SGA was associated with higher LDL-cholesterol level than FGA. Individual comparison of different antipsychotics showed that patients on olanzapine had the greatest increases in cholesterol and triglycerides among all antipsychotics. The finding suggested SGA, particularly olanzapine, were associated with more metabolic risk factors than first-generation antipsychotics.     

Differential effects of clozapine versus other antipsychotics on clinical outcome and dopamine release in the brain

The first atypical antipsychotic, clozapine (Clozaril), dramatically improved the outcome of treatment of patients with schizophrenia in two ways. First, it reduced psychotic symptoms without eliciting significant neurological side effects. Second, it was effective in approximately 30% of individuals who were previously refractory to treatment. Efforts to develop similar drugs have been partially successful in that newer antipsychotics are also less likely to produce neurological side effects. However, it has not yet been established that the newest antipsychotics are more effective than conventional agents in individuals who are refractory to treatment. In the first part of this review, the results of studies that evaluated the new antipsychotics and provided an outcome measure of response rate (regardless of how this index was defined) are summarized. Even with this broad criterion, the evidence suggests that the newer antipsychotics do not share the clinical advantages of clozapine. To explore the possible mechanisms for the clinical advantage of clozapine, evidence of antipsychotic-induced dopamine release in the brain is discussed in the second half of this article. This analysis indicates that acute clozapine administration induces the release of more dopamine in the cortex than in the striatum or limbic system. With conventional antipsychotics, this relationship is reversed. The newest antipsychotics do not show a preference among these sites. Moreover, after long-term treatment, tolerance develops to haloperidol, but not to clozapine, with regard to the amount of dopamine released in the brain. No data are available on the newest antipsychotics. Although more studies need to be done-especially studies of the effects of long-term administration of various conventional and atypical antipsychotics-this distinction might be relevant to the unique clinical advantage of clozapine.     

Cerebral cortical gray expansion associated with two second-generation antipsychotics.

BACKGROUND: Second-generation antipsychotics (SGAs) differ from first-generation antipsychotics (FGAs) with respect to induction of less extrapyramidal morbidity, partially reducing negative symptoms, and causing modest improvement in neurocognitive functioning in patients with schizophrenia. SGAs demonstrate 5-HT2a antagonism. Differential effects of SGAs and FGAs on cortical gray volumes are explored herein. METHODS: Cerebral cortical gray was examined volumetrically in 19 patients with schizophrenia before and following 28 days of treatment with two SGAs (risperidone and ziprasidone; n = 13) or a FGA (haloperidol; n = 6). Seven (untreated) control subjects were also assessed at a similar interval. RESULTS: During treatment with the SGAs risperidone and ziprasidone, cerebral cortical gray of 13 patients with schizophrenia expanded 20.6 +/- 11.4 cc (p < .0005). Six patients receiving the FGA haloperidol, as well as 7 control subjects, showed no change in cortical gray volumes (p = .983 and p = .932, respectively) at the time of reassessment. CONCLUSIONS: Volumetric increase of cerebral cortical gray occurred early in the course of treatment with the SGAs ziprasidone and risperidone, but not with the FGA haloperidol. Such cortical gray expansion may be relevant to the reported enhanced neurocognition and quality of life associated with SGA treatment.     

Psychosis among "healthy" siblings of schizophrenia patients

Background

Second generation antipsychotics (SGA) have demonstrated several advantages over first generation antipsychotics (FGA) in terms of positive, negative, cognitive, and affective symptoms and a lower propensity for extrapyramidal side effects. Despite these undeniable advantages, SGA have been associated with causing and exacerbating metabolic disorders, such as obesity, diabetes, and hyperlipidemia. This cross sectional study aimed to evaluate the metabolic risk factor profile associated with use of SGAs in comparison with non -treated control patients.

Methods

The study was carried out at a Community Mental Health Centre (CMHC) in Bologna. The study subjects were outpatients with serious mental disorders treated with SGA (clozapine, olanzapine, risperidone, quetiapine). A sample of adult men and women suffering from idiopathic hyperhydrosis, without psychiatric history or antipsychotic treatment, were randomly selected from outpatients of the Department of Neurology in Bologna as a reference group. We investigated differences among the treatment and reference groups for glycaemia, cholesterolaemia and triglyceridaemia levels.

Results

The study sample was composed of 76 patients, 38 males and 38 females. The reference group was composed of 36 subjects, 19 females and 17 males. All patients treated with SGAs had higher mean glycaemia and triglyceridaemia and a significantly higher risk of receiving a diagnosis of hyperglycaemia and hypertriglyceridaemia than the reference group. We did not find any differences in mean glycaemia or mean triglyceridaemia levels among treatment groups. Patients with clozapine had a significantly higher mean BMI value and rate of obesity than patients treated with other SGAs.

Conclusion

The rate of obesity and metabolic disorders observed in this study were higher than the prevalence in the control group and similar to that previously reported in psychiatric samples; these findings implyper se that more attention should be paid to the metabolic condition of psychiatric patients. In line with the International Consensus Conferences we recommend that monitoring of weight, fasting plasma glucose, cholesterol and triglyceride levels be obtained in routine clinical practice with all antipsychotics.     

Efficacy and tolerability of second-generation antipsychotics in children and adolescents with schizophrenia

Early-onset schizophrenia-spectrum (EOSS) disorders (onset of psychotic symptoms before 18 years of age) represent a severe variant associated with significant chronic functional impairment and poor response to antipsychotic treatment. All drugs with proven antipsychotic effects block dopamine D(2) receptors to some degree. The ongoing development of the dopamine and other neurotransmitter receptor systems during childhood and adolescence may affect clinical response and susceptibility to side effects in youth. A literature search was conducted of clinical trials of antipsychotics in children and adolescents with EOSS disorders between 1980 and 2007 from the Medline database, reference lists, and conference proceedings. Trials were limited to double-blind studies of duration of 4 or more weeks that included 15 or more patients. Ten clinical trials were identified. Antipsychotic medications were consistently found to reduce the severity of psychotic symptoms in children and adolescents when compared with placebo. The superiority of clozapine has been now demonstrated relative to haloperidol, standard-dose olanzapine, and "high-dose" olanzapine for EOSS disorders. However, limited comparative data are available regarding whether there are differences among the remaining second-generation antipsychotics (SGAs) in clinical effectiveness. The available data from short-term studies suggest that youth might be more sensitive than adults to developing antipsychotic-related adverse side effects (eg, extrapyramidal side effects, sedation, prolactin elevation, weight gain). In addition, preliminary data suggest that SGA use can lead to the development of diabetes in some youth, a disease which itself carries with it significant morbidity and mortality. Such a substantial risk points to the urgent need to develop therapeutic strategies to prevent and/or mitigate weight gain and diabetes early in the course of treatment in this population.     

Is it worth while changing clinically stable schizophrenic out-patients with mild to moderate residual symptoms and/or side effects from conventional to atypical antipsychotics? A prospective, randomised study with olanzapine

Fifty clinically stable, schizophrenic outpatients, suffering from residual schizophrenic symptoms and/or neurological side effects, were randomised to either continue their conventional neuroleptic(s) or change it to olanzapine. After 12 weeks patients on olanzapine exhibited significant improvement in neurological side effects and psychotic symptomatology as compared to patients on conventional antipsychotics.     

Dyskinésies tardives secondaires aux neuroleptiques et antipsychotiques : quelles perspectives thérapeutiques ?

If neuroleptics then antipsychotics are a therapeutic revolution in the treatment of psychosis and which have decreased the mortality, the latter are also a source of numerous adverse effects, the most significant being extrapyramidal symptoms and particularly tardive dyskinesia. Tardive dyskinesia causes involuntary movements of the tongue, jaw, the extremities and the trunk. It usually develops during a neuroleptic treatment prescribed for at least 3 months or by contrast within 4 weeks after stopping the treatment. However, the latter can, although rarely, occur rapidly and with low doses. In practice, it most probably develops after years of exposure to high doses. Patients suffering from dyskinesia have more positive and negative psychotic symptoms in comparison with controlled schizophrenic subjects. This dyskinesia is associated with a bad therapeutic prognosis of the schizophrenia. Furthermore and contrary to initial presuppositions, the risk of occurrence is probably similar regardless of the generation of therapeutics used. Tardive dyskinesia is very often resistant to therapies. When it occurs, it is recommended to exchange the incriminated antipsychotic for another antipsychotic, preferably atypical. Some of these atypical antipsychotics such as clozapine and quetiapine are preferentially used for this indication. A few clinical trials on tetrabenazine and vitamin E have been carried out. Other therapeutic prospects using cerebral electrostimulation techniques are being developed for this indication. We successively evoke electro-shock therapy, magnetic transcranial stimulation and deep cerebral stimulation. Finally, due to the low number of patients included in these studies up to now, no recommendation has come to the fore enabling a consensus on the best therapeutic strategy.