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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

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↗
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↗
PubMed2005

First-episode schizophrenia: a focus on pharmacological treatment and safety considerations.

Schizophrenia is a debilitating disorder, which is usually chronic, and is one of the most devastating medical illnesses. Early and appropriate treatment with antipsychotics is an important strategy for patients with first-episode schizophrenia. However, there are many possible safety issues for patients with schizophrenia that should be considered and properly addressed. Depressive symptoms and suicidal behaviour commonly occur in first-episode schizophrenic patients, and every effort should be made to treat and minimise these symptoms. There are also important issues and considerations in young and first-episode patients that should also be considered in the emergency treatment setting and for minimising medication nonadherence in this population. Most importantly, adverse effects should be considered, minimised and addressed. While first- and second-generation antipsychotics (SGAs) both appear to offer similar efficacy for amelioration of positive symptoms in first-episode patients, SGAs may offer better tolerability, specifically regarding extrapyramidal symptoms (EPS) and tardive dyskinesia risk, and some prolactin-sparing benefits. However, these medications do cause a host of adverse effects, including weight gain, metabolic disturbances, corrected QT interval prolongation and prolactin-related adverse effects, which are important considerations relating to both the short- and long-term safety of patients with schizophrenia being treated with SGAs. Clozapine and olanzapine are most likely to cause weight gain and metabolic effects, while risperidone is more likely to cause EPS and prolactin elevations. Most antipsychotics should be used in low doses to minimise adverse effects and each medication should be optimised in a highly individualised way to maximise adherence and treatment outcomes and minimise tolerability and safety concerns. At some point in their lives, these patients will most probably experience periods of depression, suicidal behaviours, adverse effects and nonadherence, and every effort should be made to minimise or prevent these from occurring. Thus, safety concerns in this group of young patients, in the beginning of their first psychotic episode, are a major issue as they are starting a journey of antipsychotic treatment that is likely to last for the remainder of their lives.

Age of Onset↗
PubMed2005

Thyroid function in treatment-resistant schizophrenia patients treated with quetiapine, risperidone, or fluphenazine.

BACKGROUND: Thyroid dysfunction is relatively common in patients with schizophrenia, possibly related to a genetic linkage of the disorders and to antipsychotic treatment. Quetiapine has been implicated as causing some degree of thyroid function changes, yet it remains unclear as to what extent or why these changes may occur. Furthermore, the need for thyroid function monitoring in patients taking this medication is not definitive. METHOD: Thyroid function was assessed in 38 adult DSM-IV-diagnosed schizophrenia patients after 6 weeks of prospective, double-blind, randomized treatment with quetiapine (400 mg/day), risperidone (4 mg/day), or fluphenazine (12.5 mg/day). Data were collected from 1997 to 2002. RESULTS: At baseline, the percentages of randomized patients with abnormal values were 18% (4/22) for serum T(3) resin uptake, 13% (4/30) for thyroid-stimulating hormone (TSH), and 9% (2/22) for total serum thyroxine (TT(4)), representing fairly widespread thyroid abnormalities independent of treatment group. Little change was noted in thyroid function during the 6 weeks of treatment, except for a significant decrease in TT(4) values for those taking quetiapine (p = .01). Clinically, however, no patients demonstrated any signs or symptoms of hypothyroidism during the study, nor were any significant changes in the free thyroxine index or TSH levels noted. CONCLUSIONS: It is expected that TT(4) levels will decrease during quetiapine treatment, and this may possibly be related to competitive metabolism of thyroid hormones and quetiapine by UDP-glucuronosyltransferase. Routine monitoring of thyroid function in quetiapine-treated patients without a history of thyroid disease is not recommended.

Adult↗
PubMed2005

Second-generation antipsychotics for schizophrenia: a review of clinical pharmacology and medication-associated side effects.

Second-generation antipsychotics (SGAs) are replacing traditional antipsychotics as first line therapy for the treatment of schizophrenia. While recent evidence suggests similar efficacy with low dose conventional antipsychotics, much of the advantage favoring SGAs comes from the fact that there are fewer extrapyramidal side effects (EPS) at effective doses with these drugs. As a medication class and with the exception of clozapine, the SGAs overall are very similar with regard to efficacy yet are heterogeneous with regard to receptor binding and structure-activity as well as their side effect liabilities. This paper will review the clinical psychopharmacology of the SGAs as well as adverse events associated with these drugs. Because certain side effects may be associated with nonadherence with treatment, more detailed data for each of the SGA with regards to EPS, weight gain and metabolic abnormalities and sexual dysfunction are presented.

Antipsychotic Agents↗
PubMed2004

The heterogeneity of schizophrenia in disease states.

PREVIOUS PRESENTATION: Some of the contents of this paper have been previously presented at the 16th Annual Meeting of the International Society for Technology Assessment in Health Care June 20, 2000 in the Hague, Netherlands and at the 21st Annual Meeting of the Society for Medical Decision Making as a poster on October 3, 1999 in Reno, NV. BACKGROUND: Studies of schizophrenia treatment often oversimplify the array of health outcomes among patients. Our objective was to derive a set of disease states for schizophrenia using the Positive and Negative Symptom Assessment Scale (PANSS) that captured the heterogeneity of symptom responses. METHODS: Using data from a 1-year clinical trial that collected PANSS scores and costs on schizophrenic patients (N=663), we conducted a k-means cluster analyses on PANSS scores for items in five factor domains. Results of the cluster analysis were compared with a conceptual framework of disease states developed by an expert panel. Final disease states were defined by combining our conceptual framework with the empirical results. We tested its utility by examining the influence of disease state on treatment costs and prognosis. RESULTS: Analyses led to an eight-state framework with varying levels of positive, negative, and cognitive impairment. The extent of hostile/aggressive symptoms and mood disorders correlated with severity of disease states. Direct treatment costs for schizophrenia vary significantly across disease states (F=27.47, df=7, p<0.0001), and disease state at baseline was among the most important predictors of treatment outcomes. CONCLUSION: The disease states we describe offer a useful paradigm for understanding the links between symptom profiles and outcomes.

Adolescent↗
PubMed2004

Protein kinase A in postmortem brain of depressed suicide victims: altered expression of specific regulatory and catalytic subunits.

BACKGROUND: We recently reported reduced [3H]cyclic adenosine monophosphate binding and catalytic activity of protein kinase A in prefrontal cortex of depressed suicide victims. Here we examined the molecular basis of these alterations and whether these findings can be replicated in another cohort. METHODS: Prefrontal cortex from depressed suicide victims and nonpsychiatric controls were obtained from the Lenhossek Human Brain Program, Budapest and the Maryland Brain Collection Program. [3H]cyclic adenosine monophosphate binding and protein kinase A activity were determined by radioligand binding and enzymatic assay, respectively. Expression of catalytic and regulatory subunits was determined by quantitative reverse transcription polymerase chain reaction and Western blot, respectively. RESULTS: [3H]cyclic adenosine monophosphate binding and total and endogenous protein kinase A activity were significantly decreased in membrane and cytosol fractions of prefrontal cortex of depressed suicide victims from the Budapest cohort, with a similar magnitude (33%-40% reduction) as reported for the Maryland cohort. In both cohorts, selective reduction (36%-41%) in mRNA and protein expression of the regulatory RIIbeta and the catalytic Cbeta was observed. CONCLUSIONS: Our results suggest abnormalities in [3H]cyclic adenosine monophosphate binding and catalytic activity kinase A in brain of depressed suicide victims, which could be due to reduced expression of RIIbeta and Cbeta. These abnormalities in PKA may be critical in the pathophysiology of depression.

Adult↗
PubMed2004

Decreased catalytic activity and expression of protein kinase C isozymes in teenage suicide victims: a postmortem brain study.

BACKGROUND: Teenage suicide is a major public health concern. Although there is some understanding of the psychosocial factors associated with teenage suicide, little is known about the neurobiologic factors of teenage suicide. Protein kinase C (PKC) is a critical phosphorylating enzyme in the phosphoinositide signaling pathway (which is involved in many physiologic functions in the brain and has been implicated in the pathogenesis of mood disorders) and is also a target for the therapeutic action of mood-stabilizing drugs. OBJECTIVE: To examine whether the pathogenesis of teenage suicide is associated with changes in PKC. DESIGN: Postmortem brain study. PARTICIPANTS: Seventeen teenage suicide victims and 17 nonpsychiatric control subjects. MAIN OUTCOME MEASURES: Catalytic activity of PKC and protein and messenger RNA levels of various PKC isozymes, such as PKC alpha, beta, and gamma, were determined in the prefrontal cortex and hippocampus of both groups. RESULTS: Protein kinase C activity was statistically significantly decreased in membrane and cytosol fractions of the prefrontal cortex and hippocampus of teenage suicide victims compared with control subjects. Statistically significant decreases in protein levels of PKC alpha, beta I, beta II, and gamma isozymes were also observed in both of these fractions. These decreases were associated with decreases in levels of their respective messenger RNAs. CONCLUSION: Because many physiologic functions are mediated through phosphorylation by PKC and because PKC is a target for the therapeutic action of psychoactive drugs, our findings indicate that the pathogenesis of teenage suicide may be associated with abnormalities in PKC and that PKC may be a target for therapeutic intervention in patients with suicidal behavior.

Adolescent↗
PubMed2004

Atypical antipsychotic use in a state hospital inpatient adolescent population.

Atypical antipsychotics are now the most commonly prescribed antipsychotics in young patients. These drugs are increasingly being used because of better tolerance and safety as seen in the adult populations. Youth with more severe psychopathology who are treated in the inpatient setting have been overlooked in much of the published research, and the extent of use and rationale in this population is unknown. This naturalistic retrospective study examined a population of adolescents in an inpatient state hospital setting with regard to their use of atypical antipsychotics. All patients who received an inpatient prescription for atypical antipsychotics between January 1, 1997 and June 1, 2000 and were ages 18 or younger at the time of medication initiation were included in the study. Twenty-three percent (88/380) of patients received an atypical antipsychotic: 68% (60/88) risperidone, 27% (24/88) olanzapine, and 5% (4/88) quetiapine. Psychotic disorders were considered as the primary diagnosis in only 17% of patients treated with atypical antipsychotics, and no particular diagnosis was predictive of monotherapy with an atypical antipsychotic. In the adolescent populations, atypical antipsychotics are being used for a wide variety of diagnoses and are commonly used adjunctively (more than 80%) with many concomitant psychotropic medications. More research is needed to develop useful and specific practice guidelines in children and adolescents for these commonly used medications.

Adolescent↗
PubMed2004

Sexuality and schizophrenia: a review.

Sexual functioning has received little attention as an important aspect of patient care for those suffering from severe mental disorders such as schizophrenia. Yet, it has been implicated as one of the major factors contributing to noncompliance with antipsychotic medications and is documented by people with schizophrenia to be one of the areas of treatment with the most unmet needs. A stronger focus on sexuality and preventing sexual dysfunction in schizophrenia would likely be a major benefit for improving treatment. This review will describe possible mechanisms for sexual dysfunction, describe sexual disturbances that have been documented in the literature of people who have schizophrenia, and summarize and discuss assessment measures available. Moreover, a focus on second-generation antipsychotics (SGA) and their association with sexual functioning is described. Each SGA (clozapine, risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole) will be described for its prolactin effects, documented sexual disturbances associated with use, and product labeling regarding sexual function. Treatment options and psychosocial issues pertaining to sexuality also are presented.

Amenorrhea↗