Trends in use of antipsychotics in elderly patients with dementia: Impact of national safety warnings

Based on evidence of an increased risk of death, drug agencies issued safety warnings about the use of second generation antipsychotics (SGAs) in the elderly with dementia. The French agency issued a warning in 2004. which was extended to all antipsychotics in 2008. Little is known about the impact of these warnings on use. We conducted a quasi-experimental study (interrupted time-series) in France, for 2003–2011, including subjects aged ≥65 with dementia and subjects aged ≥65 without dementia in the EGB database (1/97th representative random sample of claims from the main Health Insurance scheme). Outcomes were monthly rates of use of antipsychotics (by class and agent) and of five comparison drug classes (antidepressants, benzodiazepines, dermatologicals, antidiabetics, antiasthmatics). Trends were analyzed by joinpoint regression, impact of warnings by linear segmented regression. In patients with dementia (n=7169), there was a 40% reduction in antipsychotic use from 14.2% in 2003 to 10.2% in 2011. The reduction began before 2004 and was unaffected by the warnings. Use of first generation antipsychotics declined over the period, while use of SGAs increased and leveled off from 2007. Use of the five comparison drug classes increased on the period. In subjects without dementia (n=91,942), rates of overall antipsychotic use decreased from 2.3% in 2003 to 1.8% in 2011 with no effect of the warnings. Meanwhile, use of SGAs continuously increased from 0.37% to 0.64%. Antipsychotic use decreased in the elderly between 2003 and 2011, especially in dementia. The timing of the decrease, however, did not coincide with safety warnings.     

Behavioral changes in the rat after low doses of cholinesterase inhibitors

In rats the acute effects of low doses of five cholinesterase (ChE) inhibitors were investigated in six behavioral tests. Considerable differences were found between the inhibitors studied. TEPP and sarin at doses up to 30% LD50 were without effects. In contrast, soman, physostigmine, and pyridostigmine caused effects at dose levels which did not produce overt symptoms and did not affect running speed and simple coordinated locomotion. Soman (≤3% LD50), physostigmine (≤4.5% LD50), and pyridostigmine (≤10% LD50) interfered with two-way shuttlebox avoidance learning, open field behavior, and complex coordinated movements (hurdle-stepping task). Tests of retention in a passive avoidance learning test appeared less sensitive. It is concluded that paradigms that involve higher CNS structures and require motor activity are sensitive to some ChE inhibitors at doses far below those that cause overt symptoms. The individual characteristics of ChE inhibitors play an important role. In contrast to TEPP and sarin, soman has a predominantly central effect. Further, the finding that pyridostigmine was also effective at unexpectedly low dose levels suggests that this compound may have more central actions than hitherto accepted.     

Options for pharmacological management of obesity in patients treated with atypical antipsychotics

Obesity is associated with considerable morbidity and decreased life expectancy. Weight gain is a commonly encountered problem associated with antipsychotic treatment. We reviewed the literature regarding the mechanisms of weight gain in response to these agents and eight substances implicated as potential obesity prevention or treatment: orlistat, sibutramine, fluoxetine, topiramate, amantadine, nizatidine and cimetidine, and metformin. Weight gain in response to antipsychotic treatment may be mediated through serotonergic, dopaminergic, adrenergic, cholinergic, histaminergic and glutaminergic receptors. Sex hormone dysregulation and altered insulin sensitivity have also been implicated. Two compounds, orlistat and sibutramine, have been shown to help prevent weight gain following a hypocaloric diet, but orlistat requires compliance with a fat-reduced diet, and sibutramine is unsuitable for patients taking serotonergic agents. The weight reducing effect of fluoxetine, even in conjunction with a hypocaloric diet, is only transient. Topiramate, amantadine and metformin may have adverse side-effects potentially outweighing the weight reducing potential. The effectiveness of cimetidine and nizatedine remains unclear. The hazards of these agents in a psychiatric population are discussed. It is concluded that the current evidence does not support the general use of pharmacological interventions for overweight patients treated with antipsychotic medication, although individually selected patients may benefit.     

Effects of an educational intervention on weight gain in patients treated with antipsychotics

BACKGROUND: Increasing numbers of reports have raised concerns about significant increases in weight and adiposity over both short- and long-term treatment in patients treated with antipsychotics (APs). The management of overweight and obesity in patients treated with APs has included pharmacological interventions, dietary suggestions, and behavioral strategies. Nevertheless, current evidence does not support the use of pharmacological management of this specific type of obesity, and only a limited number of studies have been published regarding prevention and treatment of weight gain with other strategies. OBJECTIVE: The aim of this study was to evaluate the effectiveness of an educational intervention (EI) that combines low-calorie diet with increased physical activity to prevent and treat weight gain in patients treated with APs. METHOD: Data were from 53 subjects whose body mass index (BMI) had increased by more than 7% after starting an AP therapy and who consented to participate in a 12-week educational intervention study aimed at preventing further weight gain and, when possible, at inducing a weight loss. Weight and BMI were measured at baseline (at each of the monthly follow-up visits) and at study completion 12 weeks from entry in the study. RESULTS: Twenty-six patients completed the 12-week program. Completers showed a significant mean body weight decrease of 3.15 kg, with a mean BMI reduction of 1.2 (kg/m) at the end of the 3-month period. CONCLUSIONS: Educational intervention can be an important tool for the management of weight increase in patients treated with APs. A larger prospective and controlled study is now needed to confirm our findings.     

The effect of clozapine on caudate nucleus volume in schizophrenic patients previously treated with typical antipsychotics.

Typical antipsychotics have been reported to enlarge the caudate nucleus in schizophrenic patients. The atypical antipsychotic, clozapine, is associated with a decrease in caudate size in patients previously treated with typical antipsychotics. The present study investigates whether a change in caudate volume after switching from treatment with typical antipsychotics to treatment with clozapine is related to improvement in symptoms or tardive dyskinesia (TD). Twenty-six schizophrenic patients participated in this open study. Caudate nucleus volume and TD were assessed before discontinuing typical antipsychotics and after 24 weeks of treatment with clozapine. After discontinuing typical antipsychotics, symptoms were assessed in a 3 days drug-free period and subsequently once a month. Treatment with clozapine resulted in a decrease in caudate volume, improvement in symptoms and amelioration of TD. However, no difference in caudate volume changes was found between responders and non-responders to clozapine and no correlations were found between caudate volume changes and reduction of TD. In conclusion, this study replicates earlier findings that clozapine decreases caudate volume in patients previously treated with typical antipsychotics and suggests that this effect is unrelated to treatment response or to amelioration of TD.     

Drug persistency of cholinesterase inhibitors for patients with dementia of Alzheimer type in Korea

Archives of Pharmacal Research - This study examined 1-year persistency with cholinesterase inhibitors (ChEIs) for the treatment of elderly Alzheimer’s dementia (AD) patients in Korea. Korean...     

Changes of cholinesterase activities in the rat blood and brain after sarin intoxication pretreated with butyrylcholinesterase

After sarin inhalation exposure of rats pretreated with equine serum butyrylcholinesterase (EqBuChE), cholinesterase activities of the whole blood, acetylcholinesterase (AChE) in erythrocytes, pontomedullar area, frontal cortex, and striatum of the brain, and plasma butyrylcholinesterase (BuChE) were determined. Using different doses of EqBuChE as a pretreatment (intraperitoneal injection), dose-dependent increases in plasma BuChE activity and no changes in the erythrocyte and brain AChE activities were demonstrated. Decreases in plasma BuChE activity and red blood cells (RBC) and brain AChE activities were observed in control rats after sarin inhalation exposure without EqBuChE pretreatment. In rats pretreated with EqBuChE, this inhibition was lower compared with control animals not only in the blood but also in the brain structures studied. These results demonstrate protective effects of EqBuChE pretreatment in rats intoxicated with sublethal concentrations of sarin by inhalation.     

Possible induction of cholinesterase in epileptic patients treated with anticonvulsant drugs: relationship with lipoprotein levels

The effect of enzyme-inducing anticonvulsant drugs on the serum concentrations of lipoproteins has been widely studied. However, there is little agreement between the results with regard to the possible development of a lipoprotein profile related to an increased or decreased cardiovascular risk. It has been suggested that cholinesterase (ChE) could be induced by these drugs, something of undeniable interest as ChE appears to have a relation to the metabolism of lipoproteins. The serum activity of ChE was determined in a group of 90 adult epileptic patients (56 male and 34 female) treated with phenobarbital, phenytoin, and carbamazepine. The liver enzyme induction produced by these drugs was then evaluated by determining serum gamma-glutamyltranspherase activity and urinary excretion of D-glucaric acid. A significant increase of serum ChE (p < 0.005) was found in the group of patients compared to a control group (n = 49) with a similar distribution for age and sex. A significant correlation was found for both male and female patients between ChE and concentrations of triglycerides, phospholipids, cholesterol, low-density lipoprotein (LDL) phospholipids, LDL-cholesterol, and apolipoprotein B (p < 0.01). Similarly, in female patients, ChE had a significant correlation with the total cholesterol/high-density lipoprotein (HDL) cholesterol and LDL-cholesterol/HDL-cholesterol ratios (p < 0.01). The ChE/HDL-cholesterol relationship, which has been proposed as a marker for cardiovascular risk, presented significant correlations with the total cholesterol/HDL-cholesterol and LDL-cholesterol/HDL-cholesterol ratios in patients of both sexes (p < 0.001). In the case of epileptic patients treated with enzyme-inducing anticonvulsant drugs, there may be an association between the possible induction of ChE and the metabolism of lipoproteins containing apolipoprotein B.     

托吡酯减轻第2代抗精神病药物所致精神分裂症患者体质量增加的Meta分析

目的 探讨托吡酯减轻第2代抗精神病药物(SGA)所致精神分裂症患者体质量增加的疗效.方法 检索PubMed、EBSCO、EMbase、Ovid、Cochrane Library、中国期刊全文数据库(CNKI)、万方数据库和维普中文科技期刊数据库(VIP),纳入关于托吡酯减轻SGA所致体质量增加的随机对照研究,检索时限从各数据库建库起至2014年1月.由2位研究者独立进行文献筛检、资料提取和方法学质量评价后,采用Cochrane协作网Rev-Man 5.1软件按体质、生化指标、临床疗效、不良反应等方面进行Meta分析.结果 最终纳入7篇随机对照研究(RCT),共444例患者(托吡酯组223例,对照组221例).Meta分析结果显示,托吡酯组干预体质量、体重指数、臀围、腰围和腰臀比的效果优于对照组,差异均有统计学意义[均数差(MD):-3.67～-0.12,95％置信区间(CI):-4.78 ～-0.03,P＜0.05];托吡酯组干预空腹血糖、总胆固醇、低密度脂蛋白胆固醇和高密度脂蛋白胆固醇的效果与对照组比较,差异均无统计学意义(MD:-13.58 ～-4.58,95％CI:-22.44 ～-1.32,P＞0.05);托吡酯组干预三酰甘油的效果优于对照组,差异有统计学意义(MD:-0.57,95％CI:-1.12～-0.01,P＜0.05).托吡酯组的临床疗效改善优于对照组,差异均有统计学意义(MD:-2.12,95％ CI:-3.16～-1.17,P＜0.05).托吡酯组常见不良反应有嗜睡36例(30.8％)、运动减少22例(18.8％)和做梦增多18例(15.4％)等.托吡酯组出现的体质量增加、食欲增加和头晕不良反应发生率低于对照组,差异有统计学意义[相对危险度(RR):0.17～0.41;95％ CI:0.08～0.91,P＜0.05];对照组出现的注意力集中困难和运动减少不良反应发生率低于托吡酯组,差异有统计学意义(RR:2.04 ～8.97;95％ CI:1.17 ～68.62,P ＜0.05);其他不良反应及脱落情况比较,2组差异均无统计学意义(P＞0.05).结论 托吡酯不仅能有效地减轻SGA所致的精神分裂症患者体质量增高,而且能明显地提高临床疗效.     

Brain volume changes after withdrawal of atypical antipsychotics in patients with first-episode schizophrenia

The influence of antipsychotic medication on brain morphology in schizophrenia may confound interpretation of brain changes over time. We aimed to assess the effect of discontinuation of atypical antipsychotic medication on change in brain volume in patients. Sixteen remitted, stable patients with first-episode schizophrenia, schizoaffective or schizophreniform disorder and 20 healthy controls were included. Two magnetic resonance imaging brain scans were obtained from all subjects with a 1-year interval. The patients either discontinued (n = 8) their atypical antipsychotic medication (olanzapine, risperidone, or quetiapine) or did not (n = 8) discontinue during the follow-up period. Intracranial volume and volumes of total brain, cerebral gray and white matter, cerebellum, third and lateral ventricle, nucleus caudatus, nucleus accumbens, and putamen were obtained. Multiple linear regression analyses were used to assess main effects for group (patient-control) and discontinuation (yes-no) for brain volume (change) while correcting for age, sex, and intracranial volume. Decrease in cerebral gray matter and caudate nucleus volume over time was significantly more pronounced in patients relative to controls. Our data suggest decreases in the nucleus accumbens and putamen volumes during the interval in patients who discontinued antipsychotic medication, whereas increases were found in patients who continued their antipsychotics. We confirmed earlier findings of excessive gray matter volume decrements in patients with schizophrenia compared with normal controls. We found evidence suggestive of decreasing volumes of the putamen and nucleus accumbens over time after discontinuation of medication. This might suggest that discontinuation reverses effects of atypical medication.     

A fMRI investigation of startle gating deficits in schizophrenia patients treated with typical or atypical antipsychotics

A key feature of schizophrenia is the inability to screen out irrelevant sensory input. Prepulse inhibition (PPI) of the startle response, a cross-species measure of sensorimotor gating, provides a valuable opportunity to study this feature. PPI is reliably impaired in schizophrenia. Animal models of disrupted PPI have proved valuable for the evaluation of antipsychotic substances. The cortico-striato-pallido-thalamic circuitry is primarily responsible for modulation of PPI in animals. We examined PPI and its brain correlates, using functional magnetic resonance imaging (fMRI), in men with schizophrenia treated with typical or atypical antipsychotics. Thirty men with schizophrenia on stable doses of typical antipsychotics (n=10), risperidone (n=10) or olanzapine (n=10; 9 with usable fMRI data) and 12 healthy men underwent psychophysiological testing and fMRI during a tactile PPI paradigm. The results showed reduced PPI of the eye-blink startle response in patients compared with healthy controls. Within the patient group, those on typical antipsychotics showed significantly impaired PPI but risperidone- or olanzapine-treated patients showed a milder (non-significant) deficit. Increased activity in the striatum, thalamus, insula, hippocampal, temporal, inferior frontal and inferior parietal regions occurred in association with PPI in controls. Patients treated with risperidone or olanzapine, but not with typical antipsychotics, showed significant activation in PPI-relevant regions. Our findings provide preliminary evidence that atypical antipsychotics positively influence PPI and partially restore associated brain functions in schizophrenia. Imaging data buttress the validity of PPI as a useful animal model of schizophrenia.     

Aspirin-triggered lipoxin in patients treated with aspirin and selective vs. nonselective COX-2 inhibitors

AIMS

Cyclooxygenase (COX)-2 inhibition has been reported to suppress the biosynthesis of the gastroprotective lipoxygenase metabolite 15(R)-epi-lipoxin A₄, also termed ‘aspirin-triggered lipoxin’ (ATL). We tested the hypothesis that the co-administration of aspirin with either the selective COX-2 inhibitor celecoxib or the nonselective COX inhibitor ibuprofen reduces ATL biosynthesis.

METHODS

We measured the urinary excretion of ATL in 24 patients with both ischaemic heart disease and osteoarthritis, chronically treated with aspirin and co-administered celecoxib 200 mg b.i.d., ibuprofen 600 mg t.i.d., or placebo for 7 days.

RESULTS

Baseline ATL was comparable in the three groups. On days 1 and 7, 4 h after co-administration of celecoxib or ibuprofen, ATL levels did not show significant variations (day 1: 0.24 ± 0.33, 0.26 ± 0.21 and 0.37 ± 0.22 ng mg⁻¹ creatinine, respectively; day 7: 0.21 ± 0.13, 0.35 ± 0.15 and 0.23 ± 0.18 ng mg⁻¹ creatinine, respectively).

CONCLUSIONS

Neither selective nor nonselective COX-2 inhibition appreciably interferes with ATL biosynthesis, suggesting that this mediator is not involved in exacerbating gastrotoxicity by the association of aspirin with COX-2 inhibitors.     

Characterization of the serotonin transporter in lymphocytes and platelets of schizophrenia patients treated with atypical or typical antipsychotics compared to healthy individuals.

A rapidly growing body of data suggests that abnormalities in serotonergic function might be involved in the pathophysiology of schizophrenia and that serotonergic mechanisms play a role in the therapeutic effects of antipsychotics. The activity of the serotonin transporter (5-HTT), as determined by [(3)H]5-HT uptake to blood lymphocytes, was measured in 38 medicated schizophrenia patients (15 of them treated with typical antipsychotics and 23 treated with atypical antipsychotics) and 15 healthy control subjects. In addition, the pharmacodynamic characteristics of platelet 5-HTT were assessed by [(3)H]citalopram binding. There were no significant differences in the density (B(max)) of platelet [(3)H]citalopram binding sites between the three groups. Similarly, the dissociation constant (K(d)) values were indistinguishable. There were no significant differences in the maximal uptake velocity (V(max)) of [(3)H]5-HT to fresh lymphocytes between the three groups. The affinity (K(m)) values of 5-HT to the 5-HTT were significantly higher in schizophrenia patients treated with typical antipsychotics compared with control subjects. The K(m) values in schizophrenia patients treated with atypical antipsychotics were significantly lower compared with those observed in the group of schizophrenia patients treated with typical antipsychotics; however, they were comparable to values in the control group. The high values of K(m) associated with typical antipsychotic treatment may be relevant to the high risk of developing extrapyramidal side effects (EPS). The role of the various components of the serotonergic system in the etiopathology of schizophrenia and the mechanisms by which antipsychotics achieve their therapeutic effects need to be further evaluated.     

免疫抑制剂和抗胆碱酯酶联合治疗眼肌型重症肌无力的疗效观察（附59例分析）

目的观察免疫抑制荆和抗胆碱酯酶联合治疗眼肌型包括上睑下垂和眼外肌麻痹而不伴全身症状重症肌无力患者的治疗结果。方法回顾性分析1996年6月至2005年10月在我科就诊的59例眼肌型重症肌无力患者的临床资料。治疗前均行胸腺CT或MRI检查,56例患者予糖皮质激素和抗胆碱酯酶治疗,3例糖皮质激素疗效欠佳或不能用糖皮质激素治疗而改用硫唑嘌呤。随访时间3～5年,平均3．8年。结果痊愈36例（61.02％）,基本痊愈22例（37．29％）,显效1例（1．69％）。2年后有2例发展为全身型重症肌无力。未见免疫抑制剂严重并发症。结论免疫抑制剂和抗胆碱酯酶联合治疗眼肌型重症肌无力疗效佳,并发症少且轻。     

Effect of buspirone on sexual dysfunction in depressed patients treated with selective serotonin reuptake inhibitors.

To evaluate the possible influence of buspirone on sexual dysfunction in depressed patients treated with a selective serotonin reuptake inhibitor (SSRI), we analyzed data from a placebo-controlled trial designed to explore the efficacy of buspirone as add-on treatment for patients not responding to an SSRI alone. At baseline, all patients met the criteria for a major depressive episode according to DSM-IV and had received citalopram or paroxetine during a minimum of 4 weeks without responding to the treatment. Buspirone (flexible dosage, 20-60 mg/day) or placebo was added to the SSRI for 4 weeks; the mean daily dose of buspirone at endpoint was 48.5 mg (SD = 1.0). Sexual dysfunction was evaluated using a structured interview. Before starting medication with buspirone or placebo, 40% (47 of 117) reported at least one kind of sexual dysfunction (decreased libido, ejaculatory dysfunction, orgasmic dysfunction). During the 4 weeks of treatment, approximately 58% of subjects treated with buspirone reported an improvement with respect to sexual function; in the placebo group, the response rate was 30%. The difference between placebo and active drug treatment was more pronounced in women than in men. The response was obvious during the first week, with no further improvement during the course of the study. It is suggested that the effect of buspirone on sexual dysfunction is a result of a reversal of SSRI-induced sexual side effects rather than of an antidepressant effect of the drug.     

Frequency of thrombocytopenia in psoriasis patients treated with tumor necrosis factor-a inhibitors

Tumor necrosis factor-? (TNF-?) inhibitors are biologic agents that are currently in wide use for the treatment of psoriasis as well as other inflammatory diseases. Following reports of thrombocytopenia as a potential adverse effect of anti-TNF-? therapy, we performed a retrospective study to determine the frequency of thrombocytopenia, defined as a platelet count <50x109 cells/L, in a cohort of 187 psoriatic patients treated with anti-TNF-? agents over a nine-year period. Although none of our patients met serologic criteria for thrombocytopenia or displayed clinical manifestations of thrombocytopenia, two patients developed platelet counts below 100×109 cells/L. Thrombocytopenia induced by anti-TNF-? agents is a potential adverse effect, it is a rare occurrence that will require further investigation in large, placebo-controlled, double-blind, prospective studies.