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Biomedical subjects

Robert R Conley

Publications and source records attributed to Robert R Conley.

At least 19 recordsLinked to original sources
PubMed2006

Clozapine underutilization and discontinuation in African Americans due to leucopenia.

Clozapine use has been notably lower in African American patients than in Caucasians. It has been suggested that lower normal ranges for white blood cell (WBC) counts in African Americans, known as benign ethnic neutropenia, may account partially for the disparity. We examined the rates of leucopenia and agranulocytosis as reasons for discontinuation of clozapine in a sample of 1875 patients with schizophrenia treated in the State of Maryland. Between 1989 and 1999, 5.3% (31/588) of African Americans and 2.4% (31/1287) of Caucasians discontinued clozapine treatment due to leucopenia (chi square = 10.35, df = 1, P = 0.001). No African American patients developed agranulocytosis while 8 Caucasian patients (0.62%) developed this blood dyscrasia. Discontinuations due to leucopenia occurred throughout treatment. Discontinuations due to agranulocytosis occurred primarily in the first 18 weeks (7/8; 87.5% patients with agranulocytosis). It is likely that African Americans had clozapine discontinued unnecessarily due to benign ethnic neutropenia. We concur with recent recommendations to acknowledge differences in WBC values in African Americans and to modify prescribing guidelines or formally acknowledge benign ethnic leucopenia like in other countries in order to facilitate greater use of clozapine in these patients.

Black or African American↗
PubMed2006

The burden of depressive symptoms in the long-term treatment of patients with schizophrenia.

OBJECTIVE: To prospectively measure the link between depressive symptoms and functional outcomes in the long-term treatment of people with schizophrenia. METHODS: Data were drawn from a large, multi-site, 3-year, prospective, naturalistic, observational study, in which subjects with schizophrenia were assessed at enrollment and at 12-month intervals thereafter. Individuals who were "Depressed" (defined as a total score > or =16 on the Montgomery-Asberg Depression Rating Scale) at enrollment were compared to those "Non-depressed" on functional outcomes, using self-report measures, clinicians' ratings, and information from medical records. Statistical analyses included Generalized Estimation Equation and mixed regression analyses adjusted for individual characteristics. Longitudinal group comparisons across the 3-year study were augmented with a cross-sectional group comparison at enrollment. RESULTS: At enrollment, 39.4% (877/2228) of the participants were deemed Depressed. Across the 3-year study, the depressed cohort was significantly more likely than the Non-depressed to use relapse-related mental health services (emergency psychiatric services, sessions with psychiatrists); to be a safety concern (violent, arrested, victimized, suicidal); to have greater substance-related problems; and to report poorer life satisfaction, quality of life, mental functioning, family relationships, and medication adherence. Furthermore, changes in depressed status were associated with changes in functional outcomes. CONCLUSIONS: People with schizophrenia and concurrent depressive symptoms have poorer long-term functional outcomes compared to the Non-depressed. Their poorer quality of life, greater use of mental health services, and higher risk of involvement with law enforcement agencies underscore a need for special treatment interventions. Treatment of the non-psychotic dimensions of schizophrenia is a critical part of recovery.

Activities of Daily Living↗
PubMed2006

Cyclic AMP response element-binding protein in post-mortem brain of teenage suicide victims: specific decrease in the prefrontal cortex but not the hippocampus.

Abnormalities in both adenylyl cyclase (AC) and phosphoinositide (PI) signalling systems have been observed in the post-mortem brain of suicide victims. Cyclic AMP response element-binding protein (CREB) is a transcription factor that is activated by phosphorylating enzymes such as protein kinase A (PKA) and protein kinase C (PKC), which suggests that both AC and PI signalling systems converge at the level of CREB. CREB is involved in the transcription of many neuronally expressed genes that have been implicated in the pathophysiology of depression and suicide. Since we observed abnormalities of both PKA and PKC in the post-mortem brain of teenage suicide victims, we examined if these abnormalities are also associated with abnormalities of CREB, which is activated by these phosphorylating enzymes. We determined CRE-DNA binding using the gel shift assay, as well as protein expression of CREB using the Western blot technique, and the mRNA expression of CREB using a quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) technique in the prefrontal cortex (PFC), and hippocampus obtained from 17 teenage suicide victims and 17 matched normal control subjects. We observed that the CRE-DNA binding and the protein expression of CREB were significantly decreased in the PFC of teenage suicide victims compared with controls. There was also a significant decrease in mRNA expression of CREB in the PFC of teenage suicide victims compared with control subjects. However, there were no significant differences in CRE-DNA binding or the protein and mRNA expression of CREB in the hippocampus of teenage suicide victims compared with control subjects. These results suggest that the abnormalities of PKA, and of PKC, observed in teenage suicide victims are also associated with abnormalities of the transcription factor CREB, and that this may also cause alterations of important neuronally expressed genes, and provide further support of the signal transduction of abnormalities in suicide.

Adolescent↗
PubMed2006

Differential and brain region-specific regulation of Rap-1 and Epac in depressed suicide victims.

CONTEXT: Depression is a major public health problem. Despite many years of research, the molecular mechanisms associated with depression remain unclear. Rap-1, activated in response to many extracellular stimuli, is one of the major substrates of protein kinase A, which participates in myriad physiologic functions in the brain, including cell survival and synaptic plasticity. Rap-1 is also activated directly by cyclic adenosine monophosphate through Epac, and thus participates in mediating physiologic functions independent of protein kinase A. OBJECTIVE: To examine whether the pathogenesis of depression is associated with altered activation and expression of Rap-1, as well as expression of Epac, in depressed suicide victims. DESIGN: Postmortem study. SETTING: Tissues were obtained from the Lenhossek Human Brain Program, Semmelweis University, Budapest, Hungary, and the Brain Collection Program of the Maryland Psychiatric Research Center, Baltimore. PARTICIPANTS: Postmortem brains of 28 depressed suicide victims and 28 nonpsychiatric control subjects. INTERVENTION: Examination of brain tissues. MAIN OUTCOME MEASURES: Rap-1 activation as well as messenger RNA and protein levels of Rap-1 and Epac in prefrontal cortex, hippocampus, and cerebellum. RESULTS: Rap-1 activation was significantly reduced (P<.001) in prefrontal cortex and hippocampus in the suicide group. This was associated with significant reductions in Rap-1 messenger RNA and protein levels (P<.001). In contrast, protein level of only Epac-2 (P<.001) but not Epac-1 (P = .89) was significantly increased in prefrontal cortex and hippocampus of these subjects. These changes were present whether the 2 cohorts were analyzed together or separately. None of the measures showed any significant change in cerebellum in the suicide group. CONCLUSION: Given the importance of Rap-1 in neuroprotection and synaptic plasticity, our findings of differential regulation of Rap-1 and Epac between brain regions suggest the relevance of these molecules in the pathophysiology of depression.

Acetylcysteine↗
PubMed2006

Plasma concentrations of high-dose olanzapine in a double-blind crossover study.

Olanzapine is structurally similar to clozapine but has not been shown at routine doses to share the superiority of clozapine to traditional antipsychotics in treatment-resistant patients. Olanzapine, however, has been increasingly used in higher doses as clinicians attempt to find a more tolerable therapy for those refractory to conventional agents. This study examined the relationship of high-dose olanzapine plasma concentrations to symptoms, adverse effects, smoking, and gender. Thirteen patients participated in a double blind 16-week crossover study (8 weeks each arm) of olanzapine (50 mg/day) compared to clozapine (450 mg/day). Women had significantly higher plasma olanzapine levels than men at each time point in each arm (weeks 4, 6, and 8). At 8 weeks women had a steady-state olanzapine level of 278 +/- 62 ng/ml while men had a steady-state level of 127 +/- 47 ng/ml (p = 0.005). At week 4, olanzapine levels tended to be higher in those who had been on clozapine previously (205 ng/ml) compared to those who received olanzapine in the first arm (105 ng/ml). Cigarette intake was negatively correlated to olanzapine plasma concentrations (week 8: r = -0.86, p < 0.05). Plasma levels were significantly higher in those experiencing constipation (176 vs. 82 ng/ml; p = 0.022). Plasma levels of olanzapine were not associated with symptom response and anticholinergic effects were seen at greater frequency with higher olanzapine concentrations. In conclusion, this study reports plasma olanzapine levels at high fixed doses of olanzapine (50 mg/day) in relation to side effects, symptoms, smoking, and gender.

Adult↗
PubMed2006

Adjunct divalproex or lithium to clozapine in treatment-resistant schizophrenia.

This retrospective study examined adjunct divalproex (N = 15) or lithium (N = 9) in treatment-resistant schizophrenia patients added to clozapine and compared to clozapine monotherapy (N = 25). Six month total BPRS scores were similarly improved in all treatment groups, however significantly greater improvements occurred in the first month for those on divalproex (-9) or lithium (-8) vs. clozapine alone (-4.5) (F = 3.32, df = 10.43, p = 0.0003). Rates of sedation, tachycardia, orthostasis, GI disturbances, confusion and dizziness were similar among groups. Mean weight gain was 8.7 pounds for clozapine monotherapy, 3.0 pounds in the adjunct divalproex group and 13.3 pounds in the adjunct lithium group (P = NS). A trend was noted for greater increases in blood glucose levels for those treated with adjunct lithium (F = 2.62, df = 2.28, p = 0.09). The addition of divalproex was significantly more effective in reducing global symptoms (driven by hostility and anxiety) in the first month of adjunct treatment as compared to clozapine monotherapy and to previous clozapine treatment.

Adult↗
PubMed2006

Are we treating schizophrenia effectively? Understanding the primary outcomes of the CATIE study.

The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study for schizophrenia was designed to independently evaluate the effectiveness of antipsychotic treatment in "real-world" patients. To assess the effectiveness of the conventional antipsychotics compared to the atypicals as well as the differences among the atypicals, patients were randomized to one of four atypical antipsychotics (olanzapine, quetiapine, risperidone, ziprasidone) or a representative conventional antipsychotic (perphenazine). Effectiveness was defined by time to discontinuation and duration of successful treatment. Time to "all-cause" discontinuation reflects both efficacy (ability of a drug to reduce symptoms) and safety/tolerability. Phase I revealed discontinuation rates ranging from 64% for olanzapine to 82% for quetiapine. Differences among the medications may be important in the selection of a drug for a particular patient. Physicians should involve the patient in choosing their medication by inquiring about the patient's past experience with medications and side effects, educating the patient on the risk-benefit ratio, and considering the patient's preference. To demonstrate how results of the CATIE study can contribute to the knowledge of practicing clinicians, this monograph presents a representative clinical case patient and illustrates how the CATIE safety and efficacy data has important implications for the patient.

Antipsychotic Agents↗
PubMed2006

Prevalence of bone mineral density loss in Korean patients with schizophrenia: a cross-sectional study.

OBJECTIVE: This study investigates bone mineral density (BMD) and the association between BMD and hormonal changes in Korean patients with schizophrenia. METHOD: This cross-sectional study was conducted from January 2005 to June 2005; 195 inpatients with schizophrenia (DSM-IV) were screened. Among them, 51 patients aged 18 to 45 years who had taken haloperidol monotherapy for at least 2 years participated in this study. The control group consisted of normal healthy volunteers who were of similar ages (N = 57). Bone mineral density was determined by a GE Lunar 4500 scanner. Hormone levels were measured by using commercial kits. The Student t test, the Pearson chi2 test, the Wilcoxon rank sum test, and logistic regression analysis were used for data analysis. RESULTS: Female patients, but not male patients, showed significantly lower BMD than the normal controls as seen in all bone regions studied. Among 18 female patients with BMD loss, 17 patients showed hyperprolactinemia, and 7 showed combined hypoestrogenemia. Prolactin levels were significantly higher in the female patients with BMD loss compared to those with normal bone density; however, other hormone levels were not different between the 2 groups. There was no significant difference in hormonal levels between bone loss and normal bone density groups. CONCLUSIONS: Bone mineral density loss in patients with schizophrenia tended to differ by gender. Decreased BMD compared to normal controls was seen in female patients; however, this was not observed in men.

Absorptiometry, Photon↗
PubMed2006

Clozapine utilization and outcomes by race in a public mental health system: 1994-2000.

OBJECTIVE: This study aimed to assess racial differences in clozapine prescribing, dosing, symptom presentation and response, and hospitalization status. This study extends previous studies of clozapine by examining patient- and treatment-related factors that may help explain or eliminate reasons for differential prescribing. METHOD: Clozapine records for 373 white and African American patients with schizophrenia or schizoaffective disorder treated between March 1, 1994, and December 31, 2000, in inpatient mental health facilities in the state of Maryland were examined. Records for this study were derived from 3 state of Maryland databases: the Clozapine Authorization and Monitoring Program, the State of Maryland Antipsychotic Database, and the Health Maintenance Information System Database. RESULTS: A total of 10.3% of African Americans (150/1458) with schizophrenia received clozapine treatment compared with 15.3% of whites (223/1453) (chi2 = 16.74, df = 1, p < .001) during inpatient treatment in the public mental health system in Maryland. Clozapine doses were lower in African Americans relative to whites (385.3 +/- 200.6 vs. 447.3 +/- 230.3 mg/day) (t = -2.66, df = 366, p = .008). At the time of clozapine initiation, whites had more activating symptoms as measured by the Brief Psychiatric Rating Scale (BPRS) (t = -3.98, df = 301, p < .0001); however, African Americans had significantly greater improvements in BPRS total symptoms (F = 4.80, df = 301, p = .03) and in anxiety/ depressive symptoms during 1 year of treatment with clozapine (F = 10.04, df = 303, p = .002). The estimated rate of hospital discharge was not significantly different for African Americans compared to whites prescribed clozapine (log-rank chi2 = 0.523, df = 1, p = .470); however, African Americans were more likely than whites to discontinue clozapine during hospitalization (log-rank chi2 = 4.19, df = 1, p = .041). CONCLUSION: Our data suggest underutilization of clozapine in African American populations. This racial disparity in clozapine treatment is of special concern because of the favorable outcomes associated with clozapine in treatment-resistant schizophrenia and in the specific benefits observed in African American patients. More research is needed to determine why disparities with clozapine treatment occur and why African Americans may be discontinued from clozapine at a higher rate, despite potential indicators of equal or greater effectiveness among African Americans compared with whites.

Black or African American↗
PubMed2005

A randomized double-blind 12-week study of quetiapine, risperidone or fluphenazine on sexual functioning in people with schizophrenia.

Sexual dysfunction is common in people suffering from schizophrenia and is reported by patients to be a significant reason for medication nonadherence. This report contains data for 27 people with schizophrenia who participated in a randomized double-blind 12-week trial of risperidone (4 mg/day), quetiapine (400 mg/day) or fluphenazine (12.5 mg/day). At baseline and endpoint, subjects were rated on the Changes in Sexual Function Questionnaire (CSFQ), the Prolactin-Related Adverse Event Questionnaire (PRAEQ) and had prolactin levels drawn. Endpoint prolactin levels were 50.6 +/- 40.4, 24.4 +/- 18.5, and 8.2 +/- 4.4 mg/dl for risperidone (N = 12), fluphenazine (N = 9) and quetiapine (N=6), respectively (F = 7.5,df = 2, p = 0.005, controlling for sex). Orgasm quality/ability improved significantly for quetiapine as compared to fluphenazine and risperidone (F = 4.41, df = 2, p = 0.033). Seventy-eight percent of patients on fluphenazine reported sexual dysfunction whereas did only 42 and 50% of those on risperidone and quetiapine. Forty percent of quetiapine patients reported they felt better about their sexuality as compared to previous treatment, as did 55% on risperidone. Conversely, only 13% of fluphenazine subjects reported any improvement. Hormonal problems (menstrual problems, gynecomastia, galactorrhea) were predominately observed in risperidone-treated subjects. Overall, quetiapine was associated with a normalization of prolactin levels and had the greatest benefits among these drugs regarding sexual functioning.

Adult↗
PubMed2005

Suicide brain is associated with decreased expression of neurotrophins.

BACKGROUND: Neurotrophins mediate diverse biological responses, including maintenance and growth of neurons and synaptic plasticity in adult brain. This study examined whether suicide brain is associated with changes in the expression of neurotrophins. METHODS: Messenger ribonucleic acid (mRNA) levels of nerve growth factor (NGF), neurotrophin (NT)-3, NT-4/5, and of cyclophilin and neuron-specific enolase (NSE) were measured by quantitative reverse transcriptase polymerase chain reaction, whereas protein levels of neurotrophins were determined by enzyme-linked immunosorbent assay, in prefrontal cortex (PFC) and hippocampus from 28 suicide victims and 21 control subjects. RESULTS: In hippocampus of suicide subjects compared with control subjects mRNA levels of NGF (p < .001), NT-3 (p < .001), and NT-4/5 (p < .001) were decreased, whether or not they were expressed as a ratio to cyclophilin or NSE. This was accompanied by a decrease in their respective protein levels (NGF [p < .001], NT-3 [p < .001], and NT-4/5 [p < .001]). In PFC, however, mRNA (p = .001) and protein (p < .001) levels of NT-4/5 and only protein level of NGF (p < .001) were decreased; NT-3 levels were unchanged. CONCLUSIONS: Given the role of neurotrophins in synaptic plasticity and maintenance of adult neurons, our findings of altered expression of neurotrophins in postmortem brain of suicide victims suggest that these molecules might play a vital role in the pathophysiology of suicide.

Adult↗
PubMed2005

Synaptic differences in the postmortem striatum of subjects with schizophrenia: a stereological ultrastructural analysis.

The striatum processes motor, cognitive, and limbic function, all of which are perturbed in schizophrenia. The present study examined the synaptic organization of the caudate and putamen in schizophrenia. Postmortem striatum was obtained from 10 normal controls (NC) and 17 subjects with schizophrenia (SZ), prepared for electron microscopy, and analyzed using stereological principles. The densities of total synapses, asymmetric synapses (characteristic of excitatory inputs), and asymmetric axospinous synapses (characteristic of cortical input) were higher in the caudate of the SZs vs. NCs. These changes were most profound in the off-drug SZ cases and were also elevated in subjects on antipsychotic drugs (APDs). In comparison to NCs, there were no significant differences in the putamen of the SZ cohort as a whole group; however, there were more asymmetric axospinous synapses in the off-drug subgroup. The increase in density of synapses in the SZs does not appear to be caused by antipsychotic medication and may represent failure of normal synaptic pruning or abnormal sprouting. Higher density of cortical-type synapses in SZs vs. NCs may reflect adaptation of corticostriatal circuitry or hyperstimulation of striatal projection neurons. The abnormal synaptic organization could have several important and different downstream effects depending on the precise circuitry involved and may be related to limbic or cognitive dysfunction in schizophrenia.

Adult↗
PubMed2005

More powerful two-sample tests for differences in repeated measures of adverse effects in psychiatric trials when only some patients may be at risk.

Common adverse effect measures in psychiatric trials are typically analysed with repeated measures ANOVA, despite having distributions which violate key assumptions of that method; moreover, some adverse effects may be concentrated in vulnerable subgroups of participants. For testing treatment differences in adverse effects, we propose use of Kendall's taub as a summary measure of within-participant trends in adverse events, in conjunction with a weighted modification of a rank test proposed by Conover and Salsburg. Data on extrapyramidal side effects from a controlled clinical trial conducted in persons with treatment resistant schizophrenia was used to compare the proposed analysis to repeated measures ANOVA using mixed models and alternate tests for treatment differences in taub trend scores.

Antipsychotic Agents↗
PubMed2005

Synaptic differences in the patch matrix compartments of subjects with schizophrenia: a postmortem ultrastructural study of the striatum.

The striatum processes motor, cognitive, and limbic circuitry. Striatal patch and matrix compartments are organized differently in many aspects including connectivity. Abnormalities in either compartment could have different functional consequences. The present study compares the synaptic organization in the patches and matrix in subjects with schizophrenia (SZ, n = 14) versus normal controls (NC, n = 8). Postmortem striatal tissue was processed for calbindin immunocytochemistry to identify the patch versus matrix compartments, prepared for electron microscopy, and analyzed using stereology. Several synaptic changes were observed in the SZ subjects vs. NCs including a higher density of cortical-type synapses in the putamen patch (44% higher) and in the caudate matrix (36% higher) in SZ cases on typical antipsychotic drugs. These changes appeared to be normalized rather than caused by treatment. The abnormal connectivity may represent a failure of normal synaptic pruning and may play a role in limbic or cognitive dysfunction in schizophrenia.

Calbindins↗
PubMed2005

Brain region specific alterations in the protein and mRNA levels of protein kinase A subunits in the post-mortem brain of teenage suicide victims.

Protein kinase A (PKA), a critical component of the adenylyl cyclase signaling system, phosphorylates crucial proteins and has been implicated in the pathophysiology of depression and suicide. The objective of the study was to examine if changes in PKA activity or in the protein and messenger RNA (mRNA) expression of any of its subunits are related to the pathophysiology of teenage suicide. We determined PKA activity and the protein and mRNA expression of different subunits of PKA in cytosol and membrane fractions obtained from the prefrontal cortex, (PFC) hippocampus, and nucleus accumbens (NA) of post-mortem brain from 17 teenage suicide victims and 17 nonpsychiatric control subjects. PKA activity was significantly decreased in the PFC but not the hippocampus of teenage suicide victims as compared with controls. However, the protein and mRNA expression of only two PKA subunits, that is, PKA RIalpha and PKA RIbeta, but not any other subunits were significantly decreased in both membrane and cytosol fractions of the PFC and protein expression of RIalpha and RIbeta in the NA of teenage suicide victims as compared to controls. A decrease in protein and mRNA expression of two specific PKA subunits may be associated with the pathogenesis of teenage suicide, and this decrease may be brain region specific, which may be related to the specific behavioral functions associated with these brain areas. Whether these changes in PKA subunits are related to suicidal behavior or are a result of suicide or are specific to suicide is not clear at this point.

Adolescent↗
PubMed2005

Comparison of clozapine use in Maryland and in Victoria, Australia.

OBJECTIVE: Studies of how differences in systems of care, including cultural differences, affect prescribing practice and patient outcomes are important and can help answer questions such as the effectiveness of clozapine in routine practice. This study examined the use of clozapine in Maryland and in Victoria, Australia. METHODS: This study used medical record data to examine the use of clozapine in January 2000 for people with schizophrenia in two different countries. Data were gathered from all six public inpatient facilities in Maryland and from the two main community outpatient centers in Victoria. Outpatients were studied in Victoria because Australia's inpatient mental health facilities have closed and people with treatment-resistant schizophrenia are managed exclusively as outpatients. RESULTS: In Maryland 591 inpatients with schizophrenia were given a prescription for second-generation antipsychotics; in Victoria 356 outpatients with schizophrenia were given such a prescription. Among second-generation antipsychotics, clozapine was used significantly more frequently in Australia than in Maryland for the treatment of schizophrenia (173 prescriptions, or 49 percent, compared with 144 prescriptions, or 19 percent). Both systems used clozapine mostly for the treatment of schizophrenia (94 percent in Victoria compared with 88 percent in Maryland). The mean clozapine dosages that were used for the treatment of schizophrenia were significantly higher in Maryland than in Australia (522 mg per day compared with 431 mg per day). CONCLUSIONS: Significant differences in use and dosages of clozapine were found in two populations that were similar in diagnoses and demographic characteristics.

Adult↗
PubMed2005

Tardive dyskinesia predicts prolactin response to buspirone challenge in people with schizophrenia.

Prolactin response to buspirone was evaluated in patients with schizophrenia, with and without tardive dyskinesia (TD). Prolactin response in patients with schizophrenia without TD was significantly decreased, compared to healthy comparison subjects (F = 6.36, df = 5, p < 0.0001). Furthermore, prolactin levels after administration of buspirone were not significantly increased from baseline. In contrast, there was no prolactin response difference between patients with schizophrenia and TD and healthy subjects. This finding suggests that decreased dopamine (D(2)) receptor sensitivity may result in lower risk of developing TD and may lead to a fuller understanding of the variable expression of D(2)-receptor mediated side effects.

Adult↗