Effects Of Atypical Antipsychotic Drugs Research Articles

Effectiveness of Atypical Antipsychotic Drugs in Patients with Alzheimer's Disease

Second-generation (atypical) antipsychotic drugs are widely used to treat psychosis, aggression, and agitation in patients with Alzheimer's disease, but their benefits are uncertain and concerns about safety have emerged. We assessed the effectiveness of atypical antipsychotic drugs in outpatients with Alzheimer's disease. In this 42-site, double-blind, placebo-controlled trial, 421 outpatients with Alzheimer's disease and psychosis, aggression, or agitation were randomly assigned to receive olanzapine (mean dose, 5.5 mg per day), quetiapine (mean dose, 56.5 mg per day), risperidone (mean dose, 1.0 mg per day), or placebo. Doses were adjusted as needed, and patients were followed for up to 36 weeks. The main outcomes were the time from initial treatment to the discontinuation of treatment for any reason and the number of patients with at least minimal improvement on the Clinical Global Impression of Change (CGIC) scale at 12 weeks. There were no significant differences among treatments with regard to the time to the discontinuation of treatment for any reason: olanzapine (median, 8.1 weeks), quetiapine (median, 5.3 weeks), risperidone (median, 7.4 weeks), and placebo (median, 8.0 weeks) (P=0.52). The median time to the discontinuation of treatment due to a lack of efficacy favored olanzapine (22.1 weeks) and risperidone (26.7 weeks) as compared with quetiapine (9.1 weeks) and placebo (9.0 weeks) (P=0.002). The time to the discontinuation of treatment due to adverse events or intolerability favored placebo. Overall, 24% of patients who received olanzapine, 16% of patients who received quetiapine, 18% of patients who received risperidone, and 5% of patients who received placebo discontinued their assigned treatment owing to intolerability (P=0.009). No significant differences were noted among the groups with regard to improvement on the CGIC scale. Improvement was observed in 32% of patients assigned to olanzapine, 26% of patients assigned to quetiapine, 29% of patients assigned to risperidone, and 21% of patients assigned to placebo (P=0.22). Adverse effects offset advantages in the efficacy of atypical antipsychotic drugs for the treatment of psychosis, aggression, or agitation in patients with Alzheimer's disease. (ClinicalTrials.gov number, NCT00015548 [ClinicalTrials.gov].).

Noradrenergic Augmentation of Escitalopram Response by Risperidone: Electrophysiologic Studies in the Rat Brain

Atypical antipsychotic drugs have been used in depressed patients not responding adequately to the selective serotonin reuptake inhibitors (SSRIs). The aim of the current study was to investigate putative mechanisms of the beneficial effect of atypical antipsychotic drugs during their co-administration with SSRIs. In previous electrophysiological studies, it was found that SSRIs decrease, while atypical antipsychotics increase, norepinephrine neuronal firing. Thus, the resistance to SSRIs could be explained, at least in part, by the SSRI-induced decrease of norepinephrine neuronal firing activity, and the beneficial effect of atypical antipsychotic drugs could be explained by the reversal of the above-mentioned suppression of firing. Rats were administered the SSRI escitalopram and the atypical antipsychotic drug risperidone. Norepinephrine neuronal activity was determined using in vivo electrophysiology. Subacute and long-term escitalopram decreased, while risperidone co-administered with escitalopram increased, norepinephrine neuronal firing. Attempts at reversing the escitalopram-induced decrease of firing with various selective antagonists revealed that the serotonin-2A receptor antagonistic property of risperidone may mediate the pronoradrenergic action of atypical antipsychotics in the presence of serotonin reuptake inhibition. Risperidone reverses escitalopram-induced inhibition of norepinephrine neuronal activity by a mechanism involving serotonin-2A receptors. This reversal may explain the beneficial effect of atypical antipsychotics in treatment-resistant depression.

Neuroprotective effects of olanzapine in a rat model of neurodevelopmental injury

Recent clinical studies have suggested that treatment with atypical antipsychotic drugs, such as olanzapine, may slow progressive changes in brain structure in patients with schizophrenia. To investigate the possible neural basis of this effect, we sought to determine whether treatment with olanzapine would inhibit the loss of hippocampal neurons associated with the administration of the excitotoxin, kainic acid, in neonatal rats. At post-natal day 7 (P7), rats were exposed to kainic acid via intracerebroventricular administration. Neuronal loss within the CA2 and CA3 subfields of the hippocampus and neurogenesis within the dentate gyrus of the hippocampus were then assessed at P14 by Fluoro-Jade B and BrdU labeling, respectively. Daily doses of olanzapine (2, 6, or 12 mg/day), haloperidol (1.2 mg/kg), melatonin (10 mg/kg), or saline were administered between P7 and P14. Melatonin is an anti-oxidant drug and was included in this study as a positive control, since it has been observed to have neuroprotective effects in a variety of animal models. The highest dose of olanzapine and melatonin, but not haloperidol, ameliorated the hippocampal neuronal loss triggered by kainic acid administration. However, drug administration did not have a significant effect on the rate of neurogenesis. These results suggest that olanzapine has neuroprotective effects in a rat model of neurodevelopmental insult, and may be relevant to the observed effects of atypical antipsychotic drugs on brain structure in patients with schizophrenia.

Effectiveness of Atypical Antipsychotic Drugs in Patients with Alzheimer's Disease

Effectiveness of Atypical Antipsychotic Drugs in Patients with Alzheimer's Disease

Typical and atypical antipsychotic drug effects on locomotor hyperactivity and deficits in sensorimotor gating in a genetic model of NMDA receptor hypofunction

Typical and atypical antipsychotic drug effects on locomotor hyperactivity and deficits in sensorimotor gating in a genetic model of NMDA receptor hypofunction

Effects of Atypical Antipsychotic Drugs on Intralipid Intake and Cocaine-Induced Hyperactivity in Rats

Clozapine and olanzapine have been shown to acutely stimulate consumption of a fat emulsion (Intralipid) by male Lister hooded rats. We initially investigated the extent of any sex difference in Intralipid hyperphagia associated with olanzapine treatment. We then examined the degree of Intralipid hyperphagia produced by a range of atypical antipsychotic drugs having different associations with human weight gain, and also determined their effects on cocaine-stimulated locomotor activity as a measure of functional dopamine antagonism in vivo. Olanzapine (0.1-1 mg/kg) stimulated Intralipid intake to an equal extent in male and female rats. Quetiapine (10 mg/kg) also stimulated Intralipid intake whereas ziprasidone (0.3-10 mg/kg) or risperidone (0.03-0.3 mg/kg) did not have this effect. All of the compounds, except quetiapine, reduced cocaine-stimulated locomotor activity but the relationship to the degree of Intralipid hyperphagia was variable. Since there was a positive relationship between Intralipid hyperphagia and the reported extent of human body weight gain, we conclude that Intralipid hyperphagia may have predictive value for this drug-associated side effect and is not related to the dopamine antagonist properties of these agents.

A81 THE DISCRIMINATIVE STIMULUS PROPERTIES OF THE ATYPICAL ANTIPSYCHOTIC CLOZAPINE IN C57BL/6 MICE

Serotonin and a1 adrenergic receptor antagonism may contribute to atypical antipsychotic drug effects. Clozapine (2.5 mglkg) drug discrimination in C57BL16 mice may selectively screen atypical antipsychotic drugs. Previous data show that the atypical antipsychotics olanzapine, risperidone, ziprasidone but not the typical antipsychotic haloperidol fully substitutes for clozapine. The present study demonstrated that the atypical antipsychotics quetiapine, sertindole, zotepine, iloperidone, melperone fully substituted for clozapine but aripiprazole did not. The typical antipsychotics fluphenazine and perphenazine failed to fully substitute for clozapine but chlorpromazine and thioridazine fully substituted for clozapine. This model does not differentiate between atypical and typical antipsychotic drugs but it may be useful in the detection of antipsychotics with potent serotonin and a1 adrenergic receptor antagonist actions.

Treatment of sialorrhea with botulinum toxin: an overview

Hypersalivation (sialorrhea) is a common complaint of patients with neurodegenerative disorders such as Parkinson's disease or amyotrophic lateral sclerosis and a frequently disabling side effect of atypical antipsychotic drugs. Conventional treatment including oral anticholinergic or antihistamine medication is often limited by adverse effects and lack of efficacy. Over the past few years, several studies reported decreased drooling after injections of botulinum toxin into the salivary glands. This review describes the current state of treatment of sialorrhea with botulinum toxin.

A retrospective chart review of the clinical effects of atypical antipsychotic drugs on glycemic control in institutionalized patients with schizophrenia and comorbid diabetes mellitus

Background: The association between schizophrenia and onset of type 2 diabetes mellitus (DM) is well documented. It is unclear whether this association is due to inherent risk factors in individuals with schizophrenia or to treatment with antipsychotic drugs, particularly atypical antipsychotic agents. Objectives: The goals of this retrospective, observational study were the following: (1) to determine whether adequate glycemic control could be achieved in patients with schizophrenia and comorbid DM who were undergoing treatment with atypical antipsychotic drugs, (2) to identify inherent risk factors that may affect glycemic control in this patient population, and (3) to consider the possibility that combined medication and inherent risk factors may affect glycemic control. Methods: This was a retrospective, observationalchart review that evaluated institutionalized patients in a New Jersey mental institution with concurrent diagnoses of schizophrenia and type 1 or 2 DM who were being treated with atypical antipsychotic agents (ie, olanzapine, risperidone, clozapine, or quetiapine) and were referred by their hospital internists to a weekly, half-day, in-hospital DM clinic. All patients with initial and end-point data for the efficacy measure (ie, change in glycosylated hemoglobin [HbA 1c]) were included in the analysis. Mixed-effects linear and least-squares models were used to test whether a specific comorbidity had an effect on the change in HbA 1c adjusted for the duration of the observation. Results: A total of 72 patients met entry criteria.Among the 38 patients with baseline and end-point data (20 treated with olanzapine and 18 treated with risperidone), mean (SD) HbA 1c decreased from 8.21% (2.4%) to 7.62% (1.7%). The only baseline demographic characteristic or comorbidity that predicted significant worsening in the adjusted HbA 1c change was hepatitis ( P = 0.003). Conclusions: Using appropriate, aggressive antidiabetictherapy, glycemic control was achieved in this group of patients with schizophrenia and comorbid DM who were treated with atypical antipsychotic agents.

P.3.027 Fluoxetine in the treatment of combat relatedPTSD: A subanalysis of a placebo-controlled trial of Bosnian, Croatian and Serbian veterans of the war in the former Yugoslavia (1992–1995)

Atypical antipsychotic drugs commonly cause asymptomatic increase in the liver enzymes and serum bilirubin levels. However they rarely may induce a serious hepatic toxicity. In this article we aimed to evaluate the effect of atypical antipsychotic drugs namely olanzapine, risperidone and quetiapine on the hepatic enzymes and serum bilirubin levels in psychiatric patients.Chart reviews of 312 patient followed-up at Psychiatry Department of Zonguldak Karaelmas University Hospital were examined in detail. The patients whose baseline and follow-up liver function tests including alanine aminotransfeaminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), alkaline phosphotase (ALP) and serum bilirubin that were measured before and within the treatment period of first and sixth months were enrolled. Forty eight males and 62 females whose ages ranging from 12 to 65 years were eligible for this study (no pregnant case was present).The repartition according to treatment is as follows: olanzapine (n = 33), risperidone (n = 29), and quetiapine (n = 48). Two of the 110 patients (1.8%) presented with increased AST levels of up to 4 fold and ALT of thrice the basal level and needed to stop treatment (AST increase in one female with olanzapine 20 mg/day; ALT increase in one male with olanzapine 30 mg/day). Thirty of the 110 patients (27.2%) showed asymptomatic increases in ALT, AST, GGT and serum bilirubin levels in the first month of the study. After 6 months of the treatment, abnormalities in the liver function tests were observed in 25 patients (22.7%).These results were in accordance with previous studies that asymptomatic increase of liver enzymes are common but significant liver enzyme elevations are rare during atypical antipsychotic treatment. We suggest that obtaining baseline liver enzyme tests before atypical antipsychotic therapy and monitoring regularly specifically in patients with risk factors for liver damage during therapy.

Side effects of atypical antipsychotic drugs.

Recently there has been increased concern over the side effects of the atypical antipsychotic drugs, including diabetes, hyperlipidemia and obesity. The relationship between diabetes and antipsychotic drugs requires a careful analysis. Patients with schizophrenia are known to suffer from diabetes more often than the general population. In addition, a number of case reports indicate that the conventional antipsychotic as well as atypical antipsychotic drugs produce diabetes. Clozapine and olanzapine, in particular, have been implicated producing diabetes as well as diabetic ketoacidosis. Epidemiological surveys have supplemented the case reports, finding increased incidence of diabetes in patients treated with atypical antipsychotic agents, but these surveys have not yielded consistent results regarding the differential effects of the various atypical antipsychotic drugs. The mechanism by which antipsychotic agents produce diabetes is not elucidated. Weight gain and consequent alteration in triglycerides and cholesterol have been known to occur frequently with olanzapine and clozapine. The ensuing metabolic syndrome itself may cause insulin resistance and diabetes. In the absence of definitive scientific data on the differential effects of antipsychotic drugs in inducing diabetes, clinical prudence and careful monitoring of all patients on atypical antipsychotic drugs is necessary. Aripiprazole and ziprasidone have not been shown to increase weight or produce diabetes, but more information on the diabetogenic effects of ziprasidone and aripiprazole is needed. In order to assess the differential effects of atypical antipsychotic drugs in producing diabetes and the mechanisms by which they produce this reaction, further research is necessary.

P1-346 No effect of atypical antipsychotic drugs on weight gain and risk of developing type II diabetes or lipid abnormalities among nursing home elderly patients with Alzheimer's disease

P1-346 No effect of atypical antipsychotic drugs on weight gain and risk of developing type II diabetes or lipid abnormalities among nursing home elderly patients with Alzheimer's disease

Sedation.

AimThe aim of this article, the seventh in the care maps series, is to describe a care map that enables healthcare professionals, especially community mental health nurses, and patients to manage sedation, a side effect of atypical antipsychotic drugs. Atypical antipsychotics that have a high, medium, low or very low risk of sedation are identified. The care map expands and elaborates on the assessment and management options for sedation outlined in the flow chart. The evidence base that has informed the care map is also included.

Care map. 3: Atypical antipsychotics. Hyperlipidaemia/cardiovascular disease.

Aim The aim of this article, the fourth in the care maps series, is to describe a care map that enables healthcare professionals, especially community mental health nurses, and patients to manage hyperlipidaemia and cardiovascular disease, a side effect of atypical antipsychotic drugs. The relative risks of the atypical antipsychotics with respect to this side effect are identified. The care map expands and elaborates on the assessment and management options for hyperlipidaemia and cardiovascular disease outlined in the flow chart.

Care map. 1: Atypical antipsychotics. Weight gain.

AimThe aim of this article, the second in the care maps series, is to describe a care map that enables healthcare professionals, especially community mental health nurses, and patients to manage weight gain, a side effect of atypical antipsychotic drugs. Atypical antipsychotics that have a high, medium or low risk of weight gain are identified. This care map expands and elaborates on the assessment and management options for weight gain outlined in the flow chart.

The effects of systemic NT69L, a neurotensin agonist, on baseline and drug-disrupted prepulse inhibition

Centrally administered neurotensin (NT) produces behavioral and biochemical effects that are very similar to the effects of antipsychotic drugs. Therefore, there is much interest in the potential use of NT agonists as antipsychotic drugs. We have previously reported that PD149163, a NT(8–13) analogue, produced effects on prepulse inhibition (PPI) of startle after systemic administration that were suggestive of an atypical antipsychotic-like drug profile. To determine if these effects are shared by other peripherally administered NT agonists, we tested the effects of NT69L, a recently developed NT agonist that penetrates the CNS, on drug-induced PPI deficits. In the first experiment, rats received subcutaneous (s.c.) injections of NT69L (vehicle, 0.08, 0.25, and 1.0mg/kg) followed 30min later by subcutaneous saline or d-amphetamine (2.0mg/kg). In the second experiment, NT69L injections were followed by saline or the non-competitive NMDA antagonist dizocilpine (0.1mg/kg). Both d-amphetamine and dizocilpine significantly decreased PPI as expected. In the first experiment, NT69L significantly increased PPI levels at baseline and after d-amphetamine. In the second experiment, NT69L attenuated PPI deficits produced by dizocilpine, without increasing baseline PPI. In addition, NT69L had no effect on startle magnitude. The effects of NT69L in these studies were similar in some ways to the effects of PD149163 and were also consistent with the preclinical effects of atypical antipsychotic drugs. These data provide further support for the notion that NT agonists may have use as novel antipsychotic drugs. Furthermore, the ability of NT69L and PD149163 to attenuate dizocilpine-disrupted PPI, an antipsychotic drug effect not mediated by dopamine, suggests that NT agonists may produce some of their antipsychotic-like effects by modulating neurotransmitter systems other than dopamine, such as serotonin, noradrenaline or glutamate.

The effect of atypical antipsychotic drugs in patients with preexisting diabetes

The effect of atypical antipsychotic drugs in patients with preexisting diabetes

Clinical correlates of weight gain in first episode psychosis patients treated with olanzapine

Weight gain is increasingly recognized as an unwanted side effect of atypical antipsychotic drugs. To explore the mechanisms underlying this side effect, we examined the effects of olanzapine, an atypical antipsychotic drug, on cellular proliferation and differentiation in the adult mouse hypothalamus. A 6-week treatment with olanzapine resulted in a significant increase in body weight. The sizes and numbers of olanzapine-treated mouse adipocytes were significantly larger than those of control mice. No significant differences were observed in the levels of blood insulin, cholesterol, triglyceride, leptin, and ghrelin among olanzapine-, haloperidol-treated and control mice with an exception that adiponectin was significantly higher in olanzapine group than control group. Body temperature and the level of uncoupling protein 2 were also comparable between the olanzapine-treated and control groups. We found that the treatment increased BrdU-incorporating cell numbers in the hypothalamus, while the same regimen with haloperidol or control had little effect on cellular proliferation. Double-labeling immunohistochemistry revealed that the majority of the BrdU-positive cells were also Olig2- or APC-positive, indicating that oligodendrocyte-lineage cells were generated in response to olanzapine treatment. Enhancement of hypothalamic cellular proliferation after intracerebroventricular infusion of cytosine arabinoside coincided with elevated food intake and weight gain. These findings suggest a possible link between gliogenesis in the hypothalamus and weight gain following olanzapine treatment.

Acute effects of antipsychotic drugs on cardiovascular responses to stress

The effect of acute treatment with clozapine, risperidone and haloperidol on cardiovascular response to open field novelty stress was investigated in rats using radio-telemetry and video-tracking analysis. Pretreatment with clozapine dose-dependently inhibited the pressor response, tachycardia and increase in d P/d t and caused a marked reduction of exploratory locomotor activity. Similar effects were observed after risperidone treatment. Haloperidol treatment markedly reduced locomotor activity but its cardiovascular effects were limited to a more rapid return of heart rate towards baseline levels. These data suggest that particularly the atypical antipsychotic drugs, clozapine and risperidone, but not the typical antipsychotic, haloperidol, reduce cardiovascular stress responses, an effect that could reflect their anxiolytic action. Such anxiolytic effects could contribute to the beneficial clinical effects of atypical antipsychotic drugs in patients with schizophrenia.

Can antipsychotic drugs be classified by their effects on a particular group of dopamine neurons in the brain?

During the four decades that research has been carried out on antipsychotic drugs, a variety of methods have been used to study the effects of these compounds on dopamine neurotransmission. An important issue in this research was to find an explanation for the difference between “typical” and “atypical” antipsychotic drugs. The hypothesis that the beneficial properties and the motor side effects of antipsychotic drugs result from their effects on different groups of dopamine neurons has received considerable attention. Numerous researchers have tried to discover regiospecific actions of antipsychotic drugs in mesolimbic and in mesocortical dopamine neurons. An overview of these research attempts is presented here. Electrophysiological studies showed a selective action of atypical antipsychotic drugs on A10 dopamine neurons. It was found that chronic treatment with these compounds induced a preferential depolarisation block of the A10 neurons that project to the mesolimbic areas. The model represents certain clinical features of antipsychotic drug use and offers a possible explanation for the lack of extrapyramidal side effects of atypical antipsychotic drugs. Dopamine neurons projecting from A10 to the frontal cortex are also considered as a possible site of action of atypical antipsychotic drugs. Microdialysis studies have shown that certain atypical antipsychotic drugs selectively enhance the release of dopamine in the prefrontal cortex when compared with typical antipsychotic drugs. The finding that repeated treatment with antipsychotic drugs increased dopamine D 2 receptor binding in the frontal cortex confirms the significance of this brain area. These properties might indeed explain certain beneficial effects of atypical antipsychotic drugs such as improvement of cognitive dysfunction. However the effects of typical and atypical antipsychotic drugs in the frontal cortex could not be fully differentiated, which illustrates the difficulty of localising clinical effects of antipsychotic drugs in terms of regional dopamine neurons. Recently new insights into the mechanism of action of typical and atypical antipsychotic drugs have been published. Clinical positron emission tomography (PET) studies have indicated that a moderate dopamine D 2 receptor occupancy, probably combined with a high dissociation rate, might provide the optimal clinical conditions for an antipsychotic drug, without inducing extrapyramidal side effects. Moreover the efficacy of benzamides as atypical antipsychotic drugs suggests that low to moderate dopamine D 2 blockade is probably the most important—if not the only—criterion that determines “atypicality”. Interestingly these new insights are based on PET studies of the human basal ganglia and not on the comparison of different brain areas. Apparently, according to this concept an ideal antipsychotic drug need not to act on a particular type of dopamine neurons, as it is the moderate dopamine D 2 receptor occupancy that determines the desirable clinical effects. It is concluded that both beneficial actions and side effects, of antipsychotic drugs might be dose dependently localised in A9 as well as A10 dopamine neurons.