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Biomedical subjects

R R Conley

Publications and source records attributed to R R Conley.

At least 19 recordsLinked to original sources
PubMed2001

Management of treatment resistance in schizophrenia.

A systematic approach to the evaluation and characterization of treatment resistance in schizophrenia has become increasingly important since the introduction of the second-generation antipsychotics. The need for accurate evaluation will increase further as other new antipsychotic medications are developed. Patients with schizophrenia may manifest poor response to therapy because of intolerance to medication, poor adherence, inappropriate dosing, as well as true resistance of their illness to antipsychotic drug therapy. Criteria for treatment-resistance are presented to help in standardizing treatment and clinical trials. As clinicians face the decision of when to change or augment antipsychotic medications, a clear understanding of the appropriate length of a treatment trial and which target symptoms respond to antipsychotic therapy is critical for maximizing response in patients with treatment-resistant schizophrenia.

Adrenergic beta-Antagonists↗
PubMed2001

A comparison of symptom provocation procedures in psychiatry and other areas of medicine: implications for their ethical use in research.

BACKGROUND: Symptom provocation is used to study a wide variety of medical disorders. In contrast to other areas of medicine, the application of these procedures to the study of mental disease has generated significant scientific, political, and public debate. Purported differences include an overabundance of these procedures in psychiatry and a lack of diagnostic and therapeutic utility. Accurate appraisal of these research designs is needed to address scientific merit and ethical concerns. This article provides a general review of challenge studies in several areas of medical research, compares purposes and methods to those used in psychiatry, and ascertains whether fundamental differences exist. METHODS: In total, 655 challenge studies were identified using MEDLINE and PsychInfo Boolean key word searches. Information was collected from each study including the year of publication, whether subjects were healthy or patient volunteers, the disease being studied, and the study purpose (e.g., to study pathophysiology, test treatment efficacy, or diagnosis of a disorder). RESULTS: Differences in study design, purpose, and frequency of studies across time were similar for medical and psychiatric diseases. CONCLUSIONS: Given extensive similarity in purpose and procedures, why are psychiatric challenge studies being subjected to public criticism and special review and approval procedures? Several relevant issues are addressed including risk, scientific merit, and clinical application.

Ethics, Medical↗
PubMed2001

A randomized double-blind study of risperidone and olanzapine in the treatment of schizophrenia or schizoaffective disorder.

OBJECTIVE: The safety and efficacy of risperidone and olanzapine were compared in a double-blind trial that used doses widely accepted in clinical practice. METHOD: Subjects (N=377) who met DSM-IV criteria for schizophrenia or schizoaffective disorder were randomly assigned to receive 2-6 mg/day of risperidone (mean modal dose=4.8 mg/day) or 5-20 mg/day of olanzapine (mean modal dose=12.4 mg/day) for 8 weeks. RESULTS: The two study groups were similar at baseline except that the olanzapine group was slightly younger than the risperidone group. Seventy-five percent of the participants completed the trial, with no between-treatment differences in the proportion of dropouts. Similar proportions of the risperidone and olanzapine groups reported extrapyramidal symptoms (24% and 20%, respectively). Severity of extrapyramidal symptoms was low in both groups, with no between-group differences. Total Positive and Negative Syndrome Scale scores and scores on the five Positive and Negative Syndrome Scale factors were improved in both groups at week 8 (subjects who completed the study) and endpoint (all subjects, including dropouts). There were overall between-treatment differences in efficacy. Comparison of individual factors found no significant differences at endpoint; at week 8, however, improvements on Positive and Negative Syndrome Scale factors for positive symptoms and anxiety/depression were greater with risperidone than olanzapine. An increase in body weight of > or =7% was seen in 27% of olanzapine participants and 12% of risperidone participants. CONCLUSIONS: Both treatments were well tolerated and efficacious. The frequency and severity of extrapyramidal symptoms were similar in the two treatment groups. Greater reductions in severity of positive and affective symptoms were seen with risperidone than with olanzapine treatment among study completers. There was no measure on which olanzapine was superior. Greater weight gain was associated with olanzapine than with risperidone treatment.

Adult↗
PubMed2001

Comparison of discharge rates and drug costs for patients with schizophrenia treated with risperidone or olanzapine.

This study compared the discharge rates and drug costs of 789 patients with schizophrenia or schizoaffective disorder who began pharmacotherapy with olanzapine or risperidone between July 1997 and June 1998. Discharge rates 30 days after the start of treatment were 45 percent for the patients treated with risperidone and 32 percent for those treated with olanzapine (p=.001). Daily drug costs during the same period were $6.42 for risperidone and $12.29 for olanzapine (p<.001). For risperidone, lower dosages were associated with higher hospital discharge rates, whereas no significant association was observed for olanzapine. These data suggest that among inpatients with schizophrenia or schizoaffective disorder, use of risperidone results in a higher discharge rate and a lower drug cost than use of olanzapine.

Antipsychotic Agents↗
PubMed2001

Evaluating clinical trial data: outcome measures.

Schizophrenia is too often a severely disabling disease, and the discovery of interventions that can ease or eliminate symptoms without troubling side effects has long been the goal of schizophrenia research. In this endeavor, researchers, clinicians, and patients all desire an optimal outcome; outcome measures, which measure the relative success or failure of an intervention, are accordingly important. In addition, the costs of pharmacologic interventions-particularly of the atypical antipsychotics--in schizophrenia make the optimal measurement of treatment outcomes critical. Sometimes outcomes are focused on minimizing costly events, such as rehospitalization, rather than focusing on patient-oriented outcomes. This article discusses the outcome measures employed in 5 clinical trials comparing atypical antipsychotics, examining their usefulness and suggesting types of outcome measures that may be useful in the future.

Antipsychotic Agents↗
PubMed2000

Decisional capacity for informed consent in schizophrenia research.

BACKGROUND: The adequacy of subjects' informed consent to research is the focus of an important public and professional debate. The potential impairment of decisional capacity in persons with schizophrenia is central to the discussions. This study ascertains the decisional capacity for informed consent in schizophrenic research subjects, to determine if reduced capacity relates to specific aspects of psychopathologic features and to test the hypothesis that reduced capacity can be remediated with an educational informed consent process. METHODS: Decisional capacity was assessed for 30 research subjects with schizophrenia and 24 nonill (normal) comparison subjects. Measures of psychopathologic features and cognition were obtained for the subjects with schizophrenia. Subjects who performed poorly on the decisional capacity measure received an educational intervention designed to improve their ability to provide informed consent and were then retested. RESULTS: The patient group did not perform as well as the controls on initial decisional capacity assessment. Poor performance was modestly related to the extent of symptoms but robustly related to cognitive impairments. Following the educational intervention, the performance of subjects with schizophrenia was equal to that of the nonill comparison group. CONCLUSIONS: Many persons with schizophrenia may be challenged by the cognitive demands of an informed consent process for research participation. In many cases, their reduced capacity can be compensated by a more intensive educational intervention as part of the informed consent process.

Adult↗
PubMed2000

Ionotropic glutamate receptors and expression of N-methyl-D-aspartate receptor subunits in subregions of human hippocampus: effects of schizophrenia.

OBJECTIVE: Multiple quantifiable biologic abnormalities have been localized to the hippocampus in schizophrenia. Alterations in glutamate-mediated transmission at N-methyl-D-aspartic acid (NMDA)-sensitive receptors in hippocampus have been implicated in the pathophysiology of the illness. The authors tested the hypothesis that glutamatergic transmission within and efferent from hippocampus is altered in schizophrenia. METHOD: The authors analyzed postmortem hippocampal tissue from individuals with schizophrenia and from healthy individuals. The tissue samples had been collected by two brain tissue banks, one in Maryland and the other in Melbourne, Australia. lonotropic receptor binding for the NMDA, kainate, and (3)H-amino-3-hydroxy-5-methylisoxazol-4-propionate (AMPA) receptors was quantified by using usual radioligand techniques. In situ hybridization autoradiography was used to quantify mRNA for the NMDA receptor subunits NR1, NR2A, and NR2B. RESULTS: Ligand binding to the ionotropic glutamate receptors (NMDA, kainate, and AMPA) did not differ significantly overall or in any subregion between the schizophrenia tissue and the healthy comparison tissue. The only exception was AMPA receptor binding in hippocampal subregion CA2, which was slightly but significantly less in schizophrenia. However, the level of mRNA for the NMDA receptor subunits NR1 and NR2B was significantly different between groups; in several hippocampal subregions, the level of NR1 mRNA was lower and the level of NR2B mRNA higher in schizophrenia. CONCLUSIONS: Because the NR1 subunit of the NMDA receptor is critical to full receptor activity, a reduction of NR1 in hippocampus in schizophrenia suggests a functional impairment in glutamatergic transmission at the NMDA receptor, resulting in reduced glutamatergic transmission within and possibly efferent from the hippocampus in schizophrenia. This defect could underlie a hypoglutamatergic state in regions of limbic cortex, consistent with published results from other lines of research in schizophrenia.

Adult↗
PubMed2000

Risperidone side effects.

The overall effectiveness of traditional antipsychotics has been hindered by their extrapyramidal side effects, which contribute to noncompliance and relapse in patients with schizophrenia. The side effects associated with traditional antipsychotic treatment are generally minimal in patients who take risperidone, a combined 5-HT2/D2 antagonist, but the literature is sparse on adverse events among the newer atypical antipsychotics. Risperidone is associated with relatively few motor side effects compared with the traditional antipsychotics, and weight gain is less likely with risperidone than with either clozapine or olanzapine. While increased prolactin levels have been reported in patients taking risperidone, little correlation has been found between prolactin levels and adverse events. As antipsychotic treatment options expand to include the new agents, it is important for clinicians to anticipate side effects and to query patients about specific adverse events.

Antipsychotic Agents↗
PubMed2000

Adverse events related to olanzapine.

Olanzapine, a serotonin-dopamine receptor antagonist, is one of the novel atypical antipsychotics that is effective against the positive and negative symptoms of schizophrenia with significantly fewer treatment-emergent extrapyramidal symptoms and less akathisia associated with traditional antipsychotics. Compared with traditional agents, olanzapine shows only a few adverse events such as dry mouth, sedation, and increase in appetite. Compared with risperidone, olanzapine causes greater increases in weight gain and body mass index but less hyperprolactinemia. Transient, non-dose-dependent, asymptomatic elevations in liver enzymes have also been noted in olanzapine-treated patients. Because of the comparative efficacy and improved side effect profiles of the atypical antipsychotics, consideration should be given to using the newer agents as preferred treatment for schizophrenia and related psychoses.

Akathisia, Drug-Induced↗
PubMed1999

Differential olanzapine plasma concentrations by sex in a fixed-dose study.

This study examined plasma concentrations of olanzapine by sex (20 males and seven females) in an 8-week fixed-dose study. Dosing was 12.5 mg/day for the first week, then 25 mg/day. Trough plasma concentrations were drawn at weeks 1, 3, 5 and 8. Women volunteers were found to have significantly higher plasma concentrations than men. This difference was first evident at study week 5. Women have higher plasma concentrations of olanzapine, possibly due to differences in metabolism of the CYP450 isoenzyme system.

Adult↗
PubMed1999

Treatment-resistant schizophrenic patients respond to clozapine after olanzapine non-response.

BACKGROUND: Treatment-resistance in schizophrenia remains a public health problem. Clozapine has been shown to be effective in about one third of this population, but carries with it medical risks and weekly blood draws. As olanzapine is a drug with a very similar biochemical profile to clozapine, it is important to evaluate whether non-response to olanzapine predicts clozapine non-response. METHODS: Forty-four treatment-resistant patients received eight weeks of olanzapine, either in a double-blind trial or subsequent open treatment at a mean daily dose of 25 mg/day. Two of 44 patients (5%) responded to olanzapine treatment. Patients who did not respond could then receive clozapine. Twenty-seven subsequently received an 8-week open trial of clozapine. RESULTS: Patients who did and did not receive clozapine did not differ demographically or in psychopathology. Eleven of 27 (41%) met a priori response criteria during clozapine treatment (mean dose 693 mg/day) after failing to respond to olanzapine. CONCLUSIONS: This study demonstrates that failure to respond to olanzapine treatment does not predict failure to clozapine. Treatment-resistant patients who fail on olanzapine may benefit from a subsequent trial of clozapine.

Adult↗
PubMed1999

Sense and nonsense: an essay on schizophrenia research ethics.

In this essay, the authors select topics from the current debate on the ethics of schizophrenia research. Accepting competent and voluntary informed consent as essential for most projects, the authors discuss the relation of diagnosis to decisional capacity, the respective roles of psychosis and cognitive impairments in decisional capacity, and whether impairments in capacity can be remediated. The roles of investigator, external agent, patient subject, and family or surrogate in the informed consent process are reviewed. A lack of understanding of the treatment of persons with schizophrenia has distorted and inflamed public discussion of issues such as 'withholding treatment'. A standard, based in common sense, is proposed: for viewing protocols; for allowing autonomy and altruism despite diagnostic class; and, for a meaningful discussion of what is meant by and what should be done about 'risk without direct benefit' protocols.

Antipsychotic Agents↗
PubMed1999

Low phosphoinositide-specific phospholipase C activity and expression of phospholipase C beta1 protein in the prefrontal cortex of teenage suicide subjects.

OBJECTIVE: The enzyme phosphoinositide-specific phospholipase C (PI-PLC) is a component of the phosphoinositide signal transduction system. Other components of this system have been found to be abnormal in adults and adolescents who have committed suicide, and so the authors examined whether PI-PLC activity and protein expression of PLC isozymes are abnormal in postmortem brains of teenage suicide subjects. METHOD: PI-PLC activity and protein expression of the PLC beta1, delta1, and gamma1 isozymes were examined in Brodmann's areas 8 and 9 of postmortem brains obtained from 18 teenage suicide subjects and 18 matched comparison subjects. PI-PLC activity was determined by enzymatic assay, and protein expression of the PLC isozymes was determined by the Western blot technique. RESULTS: Compared with the normal subjects, the teenage suicide subjects had significantly lower PI-PLC activity and immunolabeling of the specific PLC beta1 isozyme in both membrane and cytosol fractions of Brodmann's areas 8 and 9 combined (prefrontal cortex). There was also a significant correlation between PI-PLC activity and protein levels of the PLC beta1 isozyme in the brains of the teenage suicide subjects. There was no significant difference in PI-PLC activity or level of PLC beta1 protein between the suicide subjects with a history of mental disorders and those with no history of mental disorders; however, both groups had significantly lower PI-PLC activity and expression of PLC beta1 protein than the normal subjects. CONCLUSIONS: Low PI-PLC activity and expressed levels of the PLC beta1 isozyme in postmortem brains of suicide subjects may have clinical relevance in the pathophysiology of suicidal behavior.

Adolescent↗
PubMed1999

Rehospitalization rates of patients recently discharged on a regimen of risperidone or clozapine.

OBJECTIVE: The purpose of this study was to examine rehospitalization rates of people receiving risperidone or clozapine who had been discharged from state psychiatric hospitals in Maryland. METHOD: Rehospitalization status was monitored for all patients discharged from state psychiatric facilities on a regimen of either risperidone or clozapine between March 14, 1994, and Dec. 31, 1995. Patients were followed up with respect to readmission until Dec. 31, 1996. Time to readmission was measured by the product-limit (Kaplan-Meier) formula. Risk factors associated with rehospitalization were examined. RESULTS: One hundred sixty patients were discharged on risperidone, 75 having the diagnosis of schizophrenia. The patients with schizophrenia were more likely to be readmitted than the 85 patients with other mental disorders. Recidivism rates for schizophrenic patients discharged on risperidone versus those discharged on clozapine were not significantly different over the 24-month study period. However, no patient who received clozapine and remained discharged for more than 10 months (N = 49) was readmitted, while the readmission rate for risperidone-treated patients appeared to be steady up to 24 months. At 24 months 87% of the clozapine-treated patients and 66% of the risperidone-treated patients remained in the community. No clinical or demographic variables were found to predict rehospitalization. CONCLUSIONS: This study demonstrates that the rehospitalization rates of patients taking the second-generation antipsychotics risperidone and clozapine are lower than those in previously published reports of conventional antipsychotic treatment.

Adult↗
PubMed1999

A dose-outcome analysis of risperidone.

BACKGROUND: Although the establishment of appropriate dosage ranges for antipsychotics has important ramifications for both short-term treatment and long-term therapeutic outcomes, difficulties in dosing persist. Evidence exists that initial dosing recommendations for the titration of risperidone to 6 mg/day in 3 days are excessive. This study examines dosage trends of risperidone and further examines the relationship between dose and outcome by determination of discharge rates among individuals receiving varying doses of the drug. METHOD: Records of individuals receiving risperidone in Maryland state psychiatric facilities from March 1994 through February 1997 (N = 1056) were examined. Discharge rates and time to discharge were measured by Kaplan-Meier survival curve analysis. RESULTS: As risperidone use has risen each year since its introduction, mean doses in both inpatients and discharged patients have steadily declined. Additionally, risperidone doses for discharged patients were significantly lower than those for patients remaining in the hospital. Furthermore, patients receiving 2 and 4 mg/day were significantly more likely to be discharged than those receiving 6 mg/day (log-rank chi2 = 13.54, df = 2, p = .0011). This difference was seen in patients with similar diagnoses, ages, and racial status. CONCLUSION: Patients treated with doses less than the 6-mg/day initial dosing recommendations have better outcomes in terms of discharge. This finding should encourage clinicians to utilize adequate trials of risperidone aimed at stabilizing patients on doses in the 2- to 4-mg/day range before proceeding to higher doses.

Adolescent↗
PubMed1998

Olanzapine response in treatment-refractory schizophrenic patients with a history of substance abuse.

As many as half of all schizophrenic patients have abused alcohol or illicit drugs. This study determines the extent of substance abuse in a treatment-resistant population and assesses the response of this population to olanzapine treatment. Sixty patients with a DSM-III-R diagnosis of schizophrenia were included in an open 7-week trial of up to 25 mg/day of olanzapine. A history of substance abuse was present in 23 (38%) of the patients. At baseline evaluation, patients with a history of substance abuse had lower CGI scores and less negative symptomatology while having a higher rate of tardive dyskinesia. The overall group improved significantly over time. There were no differences in response between the substance-abusing (SA) and non-substance-abusing (NSA) patients as measured by the total BPRS, GGI and SANS ratings. The NSA group had significantly greater improvement in negative symptoms as measured by the BPRS negative symptom factor. Sixty-nine per cent (16/23) of the SA group and 60% (22/37) of the NSA were considered olanzapine responders by a priori criteria (p = NS). Extrapyramidal symptoms declined significantly in the overall group, but did not significantly differ between the SA and NSA groups. Treatment-refractory patients with prior substance abuse had a comparable outcome on olanzapine therapy to those with no history of abuse, as well as no increase in adverse effects. This suggests that olanzapine may be of benefit to SA patients who have a greater tendency for antipsychotic side effects and tardive dyskinesia.

Adult↗