Conventional Antipsychotic Drugs Research Articles

Evaluating appropriateness of prescribing of long-acting risperidone for injection in acute care settings.

Long-acting risperidone for injection is a second-generation antipsychotic indicated for the treatment of schizophrenia and related psychotic disorders. It is a relatively new agent with pharmacokinetic and dosing properties unlike those of conventional long-acting antipsychotic drugs administered by injection. To determine the proportion of patients for whom long-acting risperidone for injection was prescribed appropriately in acute care settings in the Fraser Health Authority of British Columbia, according to the following 4 criteria: approved indication for therapy, 2-week dosing intervals, dose increases no sooner than every 4 weeks, and initial overlap supplementation with another antipsychotic for at least 3 weeks. A variety of other variables, including documented approval under special authority from the provincial drug coverage program, length of hospital stay, initial dose of risperidone, and total number of doses, were assessed as secondary outcomes. A chart review was conducted for all patients for whom therapy with long-acting risperidone for injection was prescribed during stays in 8 acute care hospitals between July 1, 2007, and July 22, 2008. The appropriateness of prescribing was assessed according to the 4 prespecified criteria. Long-acting risperidone for injection was prescribed for 116 patients during the study period, and 82 of these started therapy and were included in the evaluation. The primary outcome could not be assessed for 27 of these 82 patients, because they were discharged early, and data for some or all of the 4 criteria were not available. For 33 (60%) of the 55 remaining patients, long-acting risperidone for injection had been prescribed appropriately. In contrast, for 22 (40%) of the patients, prescription of risperidone was deemed inappropriate because of failure to meet at least 1 of the 4 criteria. Premature escalation of the dose and inadequate overlap with antipsychotic supplementation were the most common reasons for designation of the prescription as inappropriate. Opportunities exist to improve prescribing practices for long-acting risperidone for injection in acute care institutions in this health authority.

Association of Disrupted in Schizophrenia 1 (DISC1) missense variants with ultra-resistant schizophrenia

Three common missense variants of the Disrupted in Schizophrenia 1 (DISC1) gene, rs3738401 (Q264R), rs6675281 (L607F) and rs821616 (S704C), have been variably associated with the risk of schizophrenia. In a case-control study, we examine whether these gene variants are associated with schizophrenia and ultra-resistant schizophrenia (URS) in a population of French Caucasian patients. The URS phenotype is characterized according to stringent criteria as patients who experience no clinical, social and/or occupational remission in spite of treatment with clozapine and at least two periods of treatment with distinct conventional or atypical antipsychotic drugs. We find a significant association between DISC1 missense variants and URS. The association with rs3738401 remains significant after appropriate correction for multiple testing. These results suggest that the DISC1 rs3738401 missense variant is statistically linked with ultra-resistance to antipsychotic treatment.

A prospective study on the pattern of medication use for schizophrenia in the outpatient pharmacy department, Hospital Tengku Ampuan Rahimah, Selangor, Malaysia

Schizophrenia is a chronic psychiatric disorder and pharmacotherapy plays a major role in its management. The 1950s and early 1960s saw milestones in the introduction of psychotropic drugs in clinical practice. A review of drug prescriptions in different settings provides an insight into the pattern of drug use, identifies drug-related problems and may be used to compare recommended guidelines with actual practice. This effort led to the evaluation of the drug prescribing pattern of antipsychotics in patients attending the psychiatric clinic at a government hospital. The data from 371 antipsychotic medication prescriptions that included 200 prescriptions for schizophrenia were collected during one month (1rst-31rst August 2008) at the outpatient pharmacy department. The mean age of patients was 35.0 years (SD = 1.131), with a male to female ratio of 2:1. The most widely used oral antipsychotic was haloperidol (16.3%) while the most common depot preparation prescribed was zuclopenthixol decanoate (8.8%). The daily dose of the average antipsychotic prescribed in this clinic was 342.06 mg equivalent of chlorpromazine. There was no relation between the doses received and ethnicity of the patient (Malay, Chinese or Indian). However, there was a significant relationship between the prescribed dose and patient age (P < 0.042). Nearly 32% of the schizophrenia patients were prescribed with atypical antipsychotics such as olanzapine (10.8%), risperidone (10.0%), quetiapine (7.6%) and clozapine (3.2%). Monotherapy was given to 73.0% of the schizophrenia patients. The majority of patients also received antidepressants. To conclude, this study gave evidence that physicians had a strong preference for monotherapy with conventional antipsychotic drugs while the use of atypical drugs was less prevalent.

Effects of Olanzapine and Haloperidol on the Metabolic Status of Healthy Men

A large body of evidence suggests that antipsychotic drugs cause body weight gain and type 2 diabetes mellitus, and atypical (new generation) drugs appear to be most harmful. The aim of this study was to determine the effect of short-term olanzapine (atypical antipsychotic drug) and haloperidol (conventional antipsychotic drug) treatment on glucose and lipid metabolism. Healthy normal-weight men were treated with olanzapine (10 mg/d; n = 7) or haloperidol (3 mg/d, n = 7) for 8 d. Endogenous glucose production, whole body glucose disposal (by [6,6-(2)H(2)]glucose dilution), lipolysis (by [(2)H(5)]glycerol dilution), and substrate oxidation rates (by indirect calorimetry) were measured before and after intervention in basal and hyperinsulinemic condition. Olanzapine hampered insulin-mediated glucose disposal (by 1.3 mg x kg(-1) x min(-1)), whereas haloperidol did not have a significant effect. Endogenous glucose production was not affected by either drug. Also, the glycerol rate of appearance (a measure of lipolysis rate) was not affected by either drug. Olanzapine, but not haloperidol, blunted the insulin-induced decline of plasma free fatty acid and triglyceride concentrations. Fasting free fatty acid concentrations declined during olanzapine treatment, whereas they did not during treatment with haloperidol. Short-term treatment with olanzapine reduces fasting plasma free fatty acid concentrations and hampers insulin action on glucose disposal in healthy men, whereas haloperidol has less clear effects. Moreover, olanzapine, but not haloperidol, blunts the insulin-induced decline of plasma free fatty acids and triglyceride concentrations. Notably, these effects come about without a measurable change of body fat mass.

PO09-MO-05 Risk of death over six months in users of conventional and atypical antipsychotic drugs

PO09-MO-05 Risk of death over six months in users of conventional and atypical antipsychotic drugs

Handwriting movement analyses for monitoring drug-induced motor side effects in schizophrenia patients treated with risperidone

Epidemiologic studies indicate that nearly 60% of schizophrenia (SZ) patients treated with conventional antipsychotic drugs develop extrapyramidal side effects (EPS) such as parkinsonism and tardive dyskinesia. Although the prevalence of EPS has decreased due to the newer antipsychotics, EPS continue to limit the effectiveness of these medicines. Ongoing monitoring of EPS is likely to improve treatment outcome or compliance and reduce the frequency of re-hospitalization. A quantitative analysis of handwriting kinematics was used to evaluate effects of antipsychotic medication type and dose in schizophrenia patients. Twenty-seven schizophrenia patients treated with risperidone, six schizophrenia patients who received no antipsychotic medication and 47 healthy comparison participants were enrolled. Participants performed a 20-min handwriting task consisting of loops of various sizes and a sentence. Data were captured and analyzed using MovAlyzeR software. Results indicated that risperidone-treated participants exhibited significantly more dysfluent handwriting movements than either healthy or untreated SZ participants. Risperidone-treated participants exhibited lower movement velocities during production of simple loops compared to unmedicated patients. Handwriting dysfluency during sentence writing increased with dose. A 3-factor model consisting of kinematic variables derived from sentence writing accounted for 83% (r=.91) of the variability in medication dose. In contrast, we found no association between observer-based EPS severity ratings and medication dose. These findings support the importance of handwriting-based measures to monitor EPS in medicated schizophrenia patients.

Neurobiological and pharmacological aspects of atypical antipsychotic drugs

Atypical (second generation) antipsychotic drugs have radically changed and revolutionized the pharmacological treatment of schizophrenia and related disorders. The currently approved atypical antipsychotic drugs, which are available, are characterized by relatively weak affinities for D2-type dopamine receptors and relatively high affinities for 5-HT2A serotonin receptors, when compared with typical (conventional) antipsychotic drugs. The strong interaction with 5-HT2A receptors, with a relative sparing of D2-type dopamine receptors, is likely responsible for the optimal effects of atypical antipsychotic drugs on affective and cognitive symptoms in comparison with conventional antipsychotic drugs. In addition to these actions, several atypical antipsychotic drugs are characterized by a "fast dissociation" rate from D2-dopamine receptors. Mediating special signal transduction pathways, their activity on neuronal survival and plasticity might also contribute to their clinical advantage over typical neuroleptic drugs. By modulating chemical neurotransmission and the intracellular signal transduction systems, antipsychotic drugs may influence a variety of functions regulating neuronal resilience and viability and may have their potential for neuroprotection.

Clozapine in the treatment of tremor in Parkinson's disease

Tremor at rest is a classic symptom of Parkinson's disease that causes significant disability and distress for the patient and is generally only weakly responsive to conventional treatment, like anticholinergic and dopaminergic medication. This study describes the treatment with Clozapine in patients with Parkinson's disease, who despite optimal antiparkinson medical therapy still have a major disabling tremor at rest. Clozapine is an "atypical" neuroleptic agent, producing fewer extra pyramidal side effects common to conventional antipsychotic drugs. Clozapine, however, has as its most serious complication agranulocytosis, and hence all patients taking Clozapine must undergo blood tests at least several times a month. Under these frequent blood monitoring conditions, in this study Clozapine produced a substantial alleviation of parkinsonian tremor in 17 of 23 patients (73%). The beneficial response was reached with a relative low dose of Clozapine (18 mg./day), while previous antiparkinson medication was kept unchanged. The improvement of tremor at rest was noticeable generally within 2 weeks of beginning Clozapine therapy. No tolerance to the antitremor efficacy of Clozapine was seen during study-period of at least 6 months. Leucopenia developed in one patient, other major adverse events were hypersalivation and day-time drowsiness. These findings confirm the substantial antitremor efficacy of Clozapine in Parkinson's disease.

Clozapine versus typical neuroleptic medication for schizophrenia

Long-term drug treatment of schizophrenia with typical antipsychotics has limitations: 25 to 33% of patients have illnesses that are treatment-resistant. Clozapine is an antipsychotic drug, which is claimed to have superior efficacy and to cause fewer motor adverse effects than typical drugs for people with treatment-resistant illnesses. Clozapine carries a significant risk of serious blood disorders, which necessitates mandatory weekly blood monitoring at least during the first months of treatment. To evaluate the effects of clozapine compared with typical antipsychotic drugs in people with schizophrenia. For the current update of this review (March 2006) we searched the Cochrane Schizophrenia Group Trials Register. All relevant randomised clinical trials (RCTs). We extracted data independently. For dichotomous data we calculated relative risks (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis, based on a fixed-effect model. We calculated numbers needed to treat/harm (NNT/NNH) where appropriate. For continuous data, we calculated weighted mean differences (WMD) again based on a fixed-effect model. We have included 42 trials (3950 participants) in this review. Twenty-eight of the included studies are less than 13 weeks in duration, and, overall, trials were at significant risk of bias. We found no significant difference in the effects of clozapine and typical neuroleptic drugs for broad outcomes such as mortality, ability to work or suitability for discharge at the end of the study. Clinical improvements were seen more frequently in those taking clozapine (n=1119, 14 RCTs, RR 0.72 CI 0.7 to 0.8, NNT 6 CI 5 to 8). Also, participants given clozapine had fewer relapses than those on typical antipsychotic drugs (n=1303, RR 0.62 CI 0.5 to 0.8, NNT 21 CI 15 to 49). BPRS scores showed a greater reduction of symptoms in clozapine-treated patients, (n=1145, 16 RCTs, WMD -4.22 CI -5.4 to -3.1), although the data were heterogeneous (Chi(2) 0.0001, I(2) 66%). Short-term data from the SANS negative symptom scores favoured clozapine (n=196, 5 RCTs, WMD -5.92 CI -7.8 to -4.1). We found clozapine to be more acceptable in long-term treatment than conventional antipsychotic drugs (n=982, 16 RCTs, RR 0.60 CI 0.5 to 0.7, NNT 15 CI 12 to 20). Blood problems occurred more frequently in participants receiving clozapine (3.2%) compared with those given typical antipsychotics (0%) (n=1031, 13 RCTs, RR 7.09 CI 2.0 to 25.6). Clozapine participants experienced more drowsiness, hypersalivation, or temperature increase, than those given conventional neuroleptics. However, clozapine patients experienced fewer motor adverse effects (n=1433, 18 RCTs, RR 0.58 CI 0.5 to 0.7, NNT 5 CI 4 to 6).The clinical effects of clozapine were more pronounced in participants resistant to typical neuroleptics in terms of clinical improvement (n=370, 4 RCTs, RR 0.71 CI 0.6 to 0.8, NNT 4 CI 3 to 6) and symptom reduction. Thirty-four per cent of treatment-resistant participants had a clinical improvement with clozapine treatment. Clozapine may be more effective in reducing symptoms of schizophrenia, producing clinically meaningful improvements and postponing relapse, than typical antipsychotic drugs - but data are weak and prone to bias. Participants were more satisfied with clozapine treatment than with typical neuroleptic treatment. The clinical effect of clozapine, however, is, at least in the short term, not reflected in measures of global functioning such as ability to leave the hospital and maintain an occupation. The short-term benefits of clozapine have to be weighed against the risk of adverse effects. Within the context of trials, the potentially dangerous white blood cell decline seems to be more frequent in children and adolescents and in the elderly than in young adults or people of middle-age.The existing trials have largely neglected to assess the views of participants and their families on clozapine. More community-based long-term randomised trials are needed to evaluate the efficacy of clozapine on global and social functioning as trials in special groups such as people with learning disabilities.

P03-16 Do antipsychotic drugs lengthen QT interval?

Objectives:Prolongation of myocardial repolarization, i.e. lengthening of the QTc interval on surface electrocardiogram, with increased risk of cardiac arrhythmias, has been recognized as a side effect of many drugs. Most conventional and atypical antipsychotic drugs can cause dose-related prolongation of QTc, although there are important differences in the potency of individual agents. Antipsychotic polipharmacy increases the risk for sever cardiac side effects.Subjects and methods:In this prospective clinical investigation, we analyzed ECGs in 46 patients suffering from schizophrenic disorder who were treated with different antipsychotic drugs one week after the admission to the psychiatric hospital. Hearth rate, QT interval and QTc interval were assessed. the average daily dose of prescribed antipsychotic drugs was calculated and transformed to chlorpromazine units.Results:Average QTc interval in patients undergoing our clinical investigation was 417 msec, only 3 out of 46 (6,5%) patients had QTc over 450 msec and only one patient (2,2%) had QTc over 500 msec.We found no differences in QTc interval between patients who were treated either with conventional or atypical antipsychotic or with combination of both, and no gender differences for QTc interval were found.Conclusions:Our results raise the question of the clinical relevance of a single ECG for diagnostics of cardiac complications in schizophrenia patients and suggest the need to conduct ECG monitoring in patients with high risk for cardiac complications during antipsychotic treatment.

Staging intervention and meeting needs in early psychosis

Staging intervention and meeting needs in early psychosis

Coregulation of genes in the mouse brain following treatment with clozapine, haloperidol, or olanzapine implicates altered potassium channel subunit expression in the mechanism of antipsychotic drug action

Antipsychotic drugs are the most effective treatment for the psychotic symptoms of schizophrenia, yet their mechanism of action remains largely unknown. Earlier studies have shown gene expression changes in rodent brains after treatment with antipsychotic drugs. We aimed to further characterize these changes using whole-genome transcript profiling to explore coregulation of genes after multiple antipsychotic drug treatment studies. This study involved transcript profile analysis after 7-day treatment of inbred C57BL/6 mice with conventional (haloperidol) or atypical (clozapine or olanzapine) antipsychotic drugs. Microarray analysis was undertaken using whole-brain mRNA on Affymetrix 430v2 arrays, with quantitative reverse transcriptase-PCR used to confirm gene expression changes. Western blotting was also used to explore translation of gene dysregulation to protein changes and to explore anatomical specificity of such changes. Thirteen genes showed verified regulation by multiple antipsychotic drugs - three genes significantly upregulated and 10 genes significantly downregulated by treatment. These genes encode proteins that function in various biological processes including neurogenesis, cell adhesion, and four genes are involved in voltage-gated ion channels: neural precursor cell developmentally downregulated gene 4 (Nedd4), Kv channel interacting protein 3 (KChip3), potassium voltage-gated channel, shaker-related subfamily, alpha1 (Kcna1) encoding Kv1.1 protein and beta1 (Kcnab1) encoding Kvbeta1 protein. The translation of these gene expression changes to protein dysregulation for Kv1.1, KCHIP3, and NEDD4 was confirmed by western blot, with regional protein analyses undertaken for Kv1.1 and KCHIP3. These results suggest that transcriptional regulation of ion channels, crucial for neurotransmission, may play a role in mediating antipsychotic drug effects.

FDA: Antipsychotics Risky for Elderly

The US Food and Drug Administration (FDA) is warning physicians that using conventional antipsychotic drugs to treat elderly patients with dementia may increase the risk of death in these patients. In 2005, the agency warned of similar risks associated with newer atypical antipsychotic drugs.

Effect of regulatory warnings on antipsychotic prescription rates among elderly patients with dementia: a population-based time-series analysis

Three warnings of serious adverse events associated with the use of atypical antipsychotic drugs among elderly patients with dementia were sent to health care professionals in Canada. We assessed the impact of these warnings on prescription rates of antipsychotic drugs in this patient population. We used prescription drug claims data from Ontario to calculate prescription rates of atypical and conventional antipsychotic drugs among elderly patients with dementia from May 1, 2000, to Feb. 28, 2007. We performed a time-series analysis to estimate the effect of each warning on rates of antipsychotic drug use. Before the first warning, growth in the use of atypical antipsychotics was responsible for an increasing rate of overall antipsychotic use. Each warning was associated with a small relative decrease in the predicted growth in the use of atypical antipsychotic drugs: a 5.0% decrease after the first warning, 4.9% after the second and 3.2% after the third (each p < 0.05). The overall prescription rate of antipsychotic drugs among patients with dementia increased by 20%, from 1512 per 100 000 elderly patients in September 2002, the month before the first warning, to 1813 per 100 000 in February 2007, 20 months after the last warning. Although the warnings slowed the growth in the use of atypical antipsychotic drugs among patients with dementia, they did not reduce the overall prescription rate of these potentially dangerous drugs. More effective interventions are necessary to improve postmarket drug safety in vulnerable populations.

Antipsychotics Linked to Serious Adverse Events in Some Elderly

Antipsychotics Linked to Serious Adverse Events in Some Elderly

Atypical vs. Conventional antipsychotic drugs – effects on quality of life

Atypical vs. Conventional antipsychotic drugs – effects on quality of life

Chlorpromazine attenuates pancreatic β-cell function and mass through IRS2 degradation, while exercise partially reverses the attenuation

We investigated the effect and mechanism of exercise and chlorpromazine (CPZ), a conventional anti-psychotic drug, on beta-cell function and mass in 90% pancreatectomized (Px) male rats. The diabetic Px rats were divided into two groups, one of which was provided with exercise whereas the other was not. Both groups were subdivided into the three groups and administered with 0, 5 or 50 mg CPZ per kg body weight (control, low dosage of chlorpromazine (LCPZ), high dosage chlorpromazine (HCPZ)) for 8 weeks. LCPZ did not modulate glucose homeostasis. HCPZ impaired acute phase and second phase insulin secretion during hyperglycemic clamp. Apoptosis of pancreatic beta-cells increased in the HCPZ group, and proliferation decreased, contributing to reduced beta-cell mass. Exercise partially improved glucose-stimulated insulin secretion and beta-cell mass in HCPZ-treated rats. Interestingly, insulin receptor substrate-2 (IRS2) protein levels in islets decreased by increased degradation in the HCPZ group, whereas exercise partially reversed this trend by induction of IRS2 expression. In isolated islets, 50 microM CPZ decreased IRS2 expression by promoting ubiquitin-proteasome degradation, which had been prevented by proteasome inhibitors. Furthermore, similar to the effect of HCPZ treatment, a high dosage of rottlerin, a protein kinase C-delta inhibitor, reduced IRS2 levels in the islets. In conclusion, exercise partially recovered the diabetic symptoms exacerbated by HCPZ through enhancement of beta-cell function and mass in diabetic rats. This modulation by HCPZ and exercise was associated with increasing intracellular IRS2 protein levels in independent pathways.

Pulmonary Thromboembolism Associated with Olanzapine and Risperidone

Several studies and reports suggest an increased risk of venous thromboembolism (VTE) in patients treated with conventional antipsychotic drugs, as well as with clozapine. We report the case of a 25-year-old man with early-onset schizo-affective disorder, with no identified risk factor for thromboembolism, who developed pulmonary embolism on three occasions, once shortly after initiating treatment with olanzapine and twice with risperidone. This case indicates that VTE can be associated with the use of olanzapine and risperidone, two atypical agents having similar properties and the same 5HT2 receptors antagonism, possibly implicated in this adverse event. As suggested by this observation, patients who have had one episode of VTE with antipsychotics with an affinity for 5HT2 receptors should receive neuroleptics from other classes, such as amisulpride, which does not interact with 5HT2 receptors. They should also be closely monitored to ensure early detection and prompt treatment of VTE.

Neurocognitive effects of atypical and conventional antipsychotic drugs in schizophrenia: A naturalistic 6-month follow-up study

The present study aimed to assess the neurocognitive effects of atypical and conventional antipsychotic drugs on neurocognition under naturalistic treatment conditions. Eighty-two patients with schizophrenia underwent a comprehensive neuropsychological assessment both at baseline during inpatient treatment and 6 months after discharge from hospital (follow-up). From this sample, we selected two subgroups of patients, which had either a continuous atypical ( n = 33) or conventional ( n = 16) antipsychotic medication. Twenty-seven out of 40 healthy controls were also retested to control for practice effects. Both patient groups showed a moderate and significant improvement in global cognitive functioning. The repeated measurement ANOVAs revealed no differential treatment effects for all neuropsychological domains. These results remained after controlling for potential confounders between groups. Administering antipsychotic medications in an individually optimized manner seems to have the potential to improve some aspects of neurocognition in schizophrenia, regardless of the kind of antipsychotic medication.

Atypical Antipsychotic Drugs Directly Impair Insulin Action in Adipocytes: Effects on Glucose Transport, Lipogenesis, and Antilipolysis

Treatment with second-generation antipsychotics (SGAs) has been associated with weight gain and the development of diabetes mellitus, although the mechanisms are unknown. We tested the hypothesis that SGAs exert direct cellular effects on insulin action and substrate metabolism in adipocytes. We utilized two cultured cell models including 3T3-L1 adipocytes and primary cultured rat adipocytes, and tested for effects of SGAs risperidone (RISP), clozapine (CLZ), olanzapine (OLZ), and quetiapine (QUE), together with conventional antipsychotic drugs butyrophenone (BUTY), and trifluoperazine (TFP), over a wide concentration range from 1 to 500 microM. The effects of antipsychotic drugs on basal and insulin-stimulated rates of glucose transport were studied at 3 h, 15 h, and 3 days. Both CLZ and OLZ (but not RISP) at doses as low as 5 microM were able to significantly decrease the maximal insulin-stimulated glucose transport rate by approximately 40% in 3T3-L1 cells, whereas CLZ and RISP reduced insulin-stimulated glucose transport rates in primary cultured rat adipocytes by approximately 50-70%. Conventional drugs (BUTY and TFP) did not affect glucose transport rates. Regarding intracellular glucose metabolism, both SGAs (OLZ, QUE, RISP) and conventional drugs (BUTY and TFP) increased basal and/or insulin-stimulated glucose oxidation rates, whereas rates of lipogenesis were increased by CLZ, OLZ, QUE, and BUTY. Finally, rates of lipolysis in response to isoproterenol were reduced by the SGAs (CLZ, OLZ, QUE, RISP), but not by BUTY or TFP. These experiments demonstrate that antipsychotic drugs can differentially affect insulin action and metabolism through direct cellular effects in adipocytes. However, only SGAs were able to impair the insulin-responsive glucose transport system and to impair lipolysis in adipocytes. Thus, SGAs directly induce insulin resistance and alter lipogenesis and lipolysis in favor of progressive lipid accumulation and adipocyte enlargement. These effects of SGAs on adipocytes could explain, in part, the association of SGAs with weight gain and diabetes.