Browsing by Subject "Antipsychotic Agents"
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Item Antipsychotic drugs: comparison in animal models of efficacy, neurotransmitter regulation, and neuroprotection(American Society for Pharmacology & Experimental Therapeutics, 2008-09) LIEBERMAN, JEFFREY A.; BYMASTER, FRANK P.; MELTZER, HERBERT Y.; DEUTCH, ARIEL Y.; DUNCAN, GARY E.; MARX, CHRISTINE E.; APRILLE, JUNE R.; DWYER, DONARD S.; LI, XIN-MIN; MAHADIK, SAHEBARAO P.; DUMAN, RONALD S.; PORTER, JOSEPH H.; MODICA-NAPOLITANO, JOSEPHINE S.; NEWTON, SAMUEL S.; CSERNANSKY, JOHN G.; Department of Psychiatry, IU School of MedicineVarious lines of evidence indicate the presence of progressive pathophysiological processes occurring within the brains of patients with schizophrenia. By modulating chemical neurotransmission, antipsychotic drugs may influence a variety of functions regulating neuronal resilience and viability and have the potential for neuroprotection. This article reviews the current literature describing preclinical and clinical studies that evaluate the efficacy of antipsychotic drugs, their mechanism of action and the potential of first- and second-generation antipsychotic drugs to exert effects on cellular processes that may be neuroprotective in schizophrenia. The evidence to date suggests that although all antipsychotic drugs have the ability to reduce psychotic symptoms via D(2) receptor antagonism, some antipsychotics may differ in other pharmacological properties and their capacities to mitigate and possibly reverse cellular processes that may underlie the pathophysiology of schizophrenia.Item Haloperidol and Ziprasidone for Treatment of Delirium in Critical Illness(Massachusetts Medical Society., 2018-12-27) Girard, T.D.; Exline, M.C.; Carson, S.S.; Hough, C.L.; Rock, P.; Gong, M.N.; Douglas, I.S.; Malhotra, A.; Owens, R.L.; Feinstein, D.J.; Khan, B.; Pisani, M.A.; Hyzy, R.C.; Schmidt, G.A.; Schweickert, W.D.; Hite, R.D.; Bowton, D.L.; Masica, A.L.; Thompson, J.L.; Chandrasekhar, R.; Pun, B.T.; Strength, C.; Boehm, L.M.; Jackson, J.C.; Pandharipande, P.P.; Brummel, N.E.; Hughes, C.G.; Patel, M.B.; Stollings, J.L.; Bernard, G.R.; Dittus, R.S.; Ely, E.W.; Medicine, School of MedicineBACKGROUND: There are conflicting data on the effects of antipsychotic medications on delirium in patients in the intensive care unit (ICU). METHODS: In a randomized, double-blind, placebo-controlled trial, we assigned patients with acute respiratory failure or shock and hypoactive or hyperactive delirium to receive intravenous boluses of haloperidol (maximum dose, 20 mg daily), ziprasidone (maximum dose, 40 mg daily), or placebo. The volume and dose of a trial drug or placebo was halved or doubled at 12-hour intervals on the basis of the presence or absence of delirium, as detected with the use of the Confusion Assessment Method for the ICU, and of side effects of the intervention. The primary end point was the number of days alive without delirium or coma during the 14-day intervention period. Secondary end points included 30-day and 90-day survival, time to freedom from mechanical ventilation, and time to ICU and hospital discharge. Safety end points included extrapyramidal symptoms and excessive sedation. RESULTS: Written informed consent was obtained from 1183 patients or their authorized representatives. Delirium developed in 566 patients (48%), of whom 89% had hypoactive delirium and 11% had hyperactive delirium. Of the 566 patients, 184 were randomly assigned to receive placebo, 192 to receive haloperidol, and 190 to receive ziprasidone. The median duration of exposure to a trial drug or placebo was 4 days (interquartile range, 3 to 7). The median number of days alive without delirium or coma was 8.5 (95% confidence interval [CI], 5.6 to 9.9) in the placebo group, 7.9 (95% CI, 4.4 to 9.6) in the haloperidol group, and 8.7 (95% CI, 5.9 to 10.0) in the ziprasidone group (P=0.26 for overall effect across trial groups). The use of haloperidol or ziprasidone, as compared with placebo, had no significant effect on the primary end point (odds ratios, 0.88 [95% CI, 0.64 to 1.21] and 1.04 [95% CI, 0.73 to 1.48], respectively). There were no significant between-group differences with respect to the secondary end points or the frequency of extrapyramidal symptoms. CONCLUSIONS: The use of haloperidol or ziprasidone, as compared with placebo, in patients with acute respiratory failure or shock and hypoactive or hyperactive delirium in the ICU did not significantly alter the duration of delirium. (Funded by the National Institutes of Health and the VA Geriatric Research Education and Clinical Center; MIND-USA ClinicalTrials.gov number, NCT01211522 .).Item Relationships between auditory event-related potentials and mood state, medication, and comorbid psychiatric illness in patients with bipolar disorder(Wiley Blackwell (Blackwell Publishing), 2009-12) Fridberg, Daniel J.; Hetrick, William P.; Brenner, Colleen A.; Shekhar, Anantha; Steffen, Ashley N.; Malloy, Frederick W.; O'Donnell, Brian F.; Department of Psychiatry, IU School of MedicineBACKGROUND: Patients with bipolar disorder (BD) exhibit aberrations in auditory event-related potentials (ERPs), although the relationships between these measures and mood state at testing, comorbid psychiatric illness, presence of psychotic features, and medication usage are unclear. The purpose of this study was to investigate the relationships between these factors and auditory ERP measures in BD patients. METHODS: An auditory 'oddball' discrimination task was used to elicit ERPs from 69 patients with type I BD and 52 healthy controls. Patients were placed into subgroups based upon their mood state at testing (euthymic or symptomatic), and ANOVA was used to compare amplitude and peak latency measures from the N100, P200, N200, and P300 ERP components across subgroups. Multiple regression was used to investigate relationships between ERP measures and comorbid psychiatric diagnosis, history of psychotic features, and medication status. RESULTS: Relative to healthy control participants, euthymic and symptomatic BD patients exhibited reduced P300 and P200 amplitude, but ERP measures did not differ among BD patients on the basis of mood status. A history of a comorbid anxiety disorder was associated with reduced N200 peak latency, but prolonged P300 peak latency among BD patients. No other relationships between clinical variables and ERP measures were significant. CONCLUSIONS: The results suggest that disrupted auditory attention may be observed in BD patients regardless of their mood state at testing, medication status, or history of psychosis. These results extend previous findings, and provide further evidence for aberrations in the P300 ERP as an endophenotype for BD.Item Selective Effects of D- and L-Govadine in Preclinical Tests of Positive, Negative, and Cognitive Symptoms of Schizophrenia(Nature Publishing Group, 2014-06) Lapish, Christopher C; Ahn, Kee-Chan; Chambers, R Andrew; Ashby, Donovan M; Ahn, Soyon; Phillips, Anthony G; Department of Psychology, School of ScienceThere is a critical need to develop novel pharmacotherapeutics capable of addressing the positive, negative, and cognitive symptoms of schizophrenia. Building on recent studies with a racemic mixture of the synthetic tetrahydroprotoberberine, D,L-Govadine, we isolated the D- and L-stereoisomers and employed a battery of behavioral, neurochemical, and electrophysiological procedures to assess their individual therapeutic potential. Rodent models predictive of antipsychotic efficacy and those that model positive symptoms were employed and we found that L-Govadine, but not D-Govadine, improved these measures. Pretreatment with either stereoisomer during CS pre-exposure prevented the disruption of latent inhibition by amphetamine. Moreover, pretreatment with either stereoisomer also improved deficits in social interaction in the neonatal ventral hippocampal lesioned rat. Improved cognitive performance in two different prefrontal cortex-dependent tasks was observed with D-, but not L-Govadine, which strongly suggests that the D-steroisomer may be an effective cognitive enhancer. Alterations in dopamine efflux were also assessed and L-Govadine increased dopamine efflux in both the prefrontal cortex and nucleus accumbens. However, D-Govadine only increased dopamine efflux in the prefrontal cortex and not in the nucleus accumbens. Electrophysiological studies confirmed that L-Govadine is a DA-D2 antagonist, whereas D-Govadine shows no appreciable physiological effects at this receptor. Collectively these data show that L-Govadine performs well on measures predictive of antipsychotic efficacy and rodent models of positive symptoms through antagonism of DA-D2 receptors, whereas D-Govadine improves impairments in compromised memory function in delayed response tasks possibly through selective increases in DA efflux in the frontal cortex.Item Tardive Dyskinesia in Relation to Estimated Dopamine D2 Receptor Occupancy in Patients with Schizophrenia: Analysis of the CATIE data(Elsevier, 2014-03) Yoshida, Kazunari; Bies, Robert R.; Suzuki, Takefumi; Remington, Gary; Pollock, Bruce G.; Mizuno, Yuya; Mimura, Masaru; Uchida, Hiroyuki; Department of Medicine, Division of Clinical Pharmacology, IU School of MedicineObjective The objective of this study was to evaluate the relationship between antipsychotic-induced tardive dyskinesia (TD) and estimated dopamine D2 receptor occupancy levels in patients with schizophrenia, using the dataset from the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE). Methods The dataset from 218 subjects (risperidone, N=78; olanzapine, N=100; ziprasidone, N=40) who presented with a score of zero on the Abnormal Involuntary Movement Scale (AIMS) at baseline in Phase 1 of the CATIE study, and remained for ≥6 months, was used. Peak and trough dopamine D2 receptor occupancy levels on the day of the AIMS assessment at the endpoint were estimated from plasma antipsychotic concentrations, using population pharmacokinetic analysis and our D2 prediction model. The estimated dopamine D2 receptor occupancy levels were compared between patients who presented an AIMS score of ≥2 at endpoint and those with a score of zero, using the Mann-Whitney U test. Results Estimated dopamine D2 receptor occupancy levels at trough were significantly higher in subjects who developed involuntary movements (N=23) than those who did not (N=195) (71.7±14.4% vs. 64.3±19.3%, p<0.05) while no significant difference was found in the estimated peak D2 receptor occupancy between them (75.4±8.7% vs. 72.1±9.9%, p=0.07). When the analyses were separately conducted for the three drugs, there were no significant differences in estimated peak or trough D2 occupancy although the values were consistently numerically higher among those developing involuntary movements. Conclusion Greater dopamine D2 receptor blockade with antipsychotics at trough might increase the risk of tardive involuntary movements although this finding needs to be replicated in larger trials.Item Tolerability, Safety, and Benefits of Risperidone in Children and Adolescents with Autism: 21-Month Follow-up After 8-Week Placebo-Controlled Trial(Mary Ann Liebert, Inc., 2015-08-01) Aman, Michael; Rettiganti, Mallikarjuna; Nagaraja, Haikady N.; Hollway, Jill A.; McCracken, James; McDougle, Christopher J.; Tierney, Elaine; Scahill, Lawrence; Arnold, L. Eugene; Hellings, Jessica; Posey, David J.; Swiezy, Naomi B.; Guhman, Jaswinder; Grados, Marco; Shah, Bhavik; Vitiello, Benedetto; Department of Psychiatry, IU School of MedicineOBJECTIVE: Risperidone has demonstrated efficacy for acute (8 week) and intermediate length (6 month) management of severe irritability and aggression in children and adolescents with autism. Less is known about the long-term effects of risperidone exposure in this population. We examined the tolerability, safety, and therapeutic benefit of risperidone exposure over a 1-2 year follow-up period. METHODS: In a naturalistic study, 84 children and adolescents 5-17 years of age (from an original sample of 101) were assessed an average of 21.4 months after initial entry into a placebo-controlled 8 week trial of risperidone for children and adolescents with autism and severe irritability. They were assessed at baseline and at follow-up on safety and tolerability measures (blood, urinalysis, electrocardiogram [ECG], medical history, vital signs, neurological symptoms, other adverse events), developmental measures (adaptive behavior, intelligence quotient [IQ]), and standardized rating instruments. Treatment over the follow-up period, after completion of protocol participation, was uncontrolled. Statistical analyses assessed outcome over time with or without prolonged risperidone therapy. RESULTS: Two-thirds of the 84 subjects continued to receive risperidone (mean 2.47 mg/day, S.D. 1.29 mg). At follow-up, risperidone was associated with more enuresis, more excessive appetite, and more weight gain, but not more adverse neurological effects. No clinically significant events were noted on blood counts, chemistries, urinalysis, ECG, or interim medical history. Regardless of drug condition at follow-up, there was considerable improvement in maladaptive behavior compared with baseline, including core symptoms associated with autism. Height and weight gains were elevated with risperidone. Social skills on Vineland Adaptive Behavior Scale (VABS) improved with risperidone. Parent-rated Aberrant Behavior Checklist (ABC) Irritability subscale scores were reduced in those taking risperidone at follow-up. Several other measures of maladaptive behavior (some related to socialization) also showed improved functioning in association with risperidone on the ABC or on the Modified Real Life Rating Scale. CONCLUSIONS: Increased appetite, weight gain, and enuresis are risks associated with long-term risperidone. Our data suggest that these risks were balanced by longer-term behavioral and social benefits for many children over 1.8 years of ongoing treatment.