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Biomedical subjects

Robert R Conley

Publications and source records attributed to Robert R Conley.

At least 37 records · Page 2Linked to original sources
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↗
PubMed2004

The effects of clozapine and high-dose olanzapine on brain function in treatment-resistant schizophrenia: a case study.

Although demonstrating superior efficacy in people with treatment-resistant schizophrenia, clozapine may cause serious side effects, requires blood monitoring and is costly to administer. Olanzapine is similar to clozapine in molecular structure and pharmacologic action but has not demonstrated as robust results as clozapine at routine doses (10-25 mg). Here we present a case study measuring blood flow by positron emission tomography (PET) imaging for a patient treated sequentially with a high dose of olanzapine (50 mg/day) followed by clozapine each for 8 weeks in a double-blind design. During a task, clozapine produced more brain activation patterns than during treatment with olanzapine or during the drug free condition (2 week washout). Clozapine resulted in recruitment of frontal, parietal and cingulate regions that did not appear to be active during olanzapine in this 44 year old right handed male. Additionally, a more robust decrease in symptoms was noted on the Brief Psychiatric Rating Scale (BPRS) score than with olanzapine treatment. These findings suggest that high doses of olanzapine do not produce similar brain activation patterns as clozapine in people with treatment-resistant schizophrenia.

Adult↗
PubMed2004

The Texas Medication Algorithm Project antipsychotic algorithm for schizophrenia: 2003 update.

BACKGROUND: The Texas Medication Algorithm Project (TMAP) has been a public-academic collaboration in which guidelines for medication treatment of schizophrenia, bipolar disorder, and major depressive disorder were used in selected public outpatient clinics in Texas. Subsequently, these algorithms were implemented throughout Texas and are being used in other states. Guidelines require updating when significant new evidence emerges; the antipsychotic algorithm for schizophrenia was last updated in 1999. This article reports the recommendations developed in 2002 and 2003 by a group of experts, clinicians, and administrators. METHOD: A conference in January 2002 began the update process. Before the conference, experts in the pharmacologic treatment of schizophrenia, clinicians, and administrators reviewed literature topics and prepared presentations. Topics included ziprasidone's inclusion in the algorithm, the number of antipsychotics tried before clozapine, and the role of first generation antipsychotics. Data were rated according to Agency for Healthcare Research and Quality criteria. After discussing the presentations, conference attendees arrived at consensus recommendations. Consideration of aripiprazole's inclusion was subsequently handled by electronic communications. RESULTS: The antipsychotic algorithm for schizophrenia was updated to include ziprasidone and aripiprazole among the first-line agents. Relative to the prior algorithm, the number of stages before clozapine was reduced. First generation antipsychotics were included but not as first-line choices. For patients refusing or not responding to clozapine and clozapine augmentation, preference was given to trying monotherapy with another antipsychotic before resorting to antipsychotic combinations. CONCLUSION: Consensus on algorithm revisions was achieved, but only further well-controlled research will answer many key questions about sequence and type of medication treatments of schizophrenia.

Algorithms↗
PubMed2003

Abnormal expression and functional characteristics of cyclic adenosine monophosphate response element binding protein in postmortem brain of suicide subjects.

BACKGROUND: Cyclic adenosine monophosphate response element binding protein (CREB) is a transcription factor that, on phosphorylation by protein kinases, is activated, and in response, regulates the transcription of many neuronally expressed genes. In view of the recent observations that catalytic properties and/or expression of many kinases that mediate their physiological responses through the activation of CREB are altered in the postmortem brain of subjects who commit suicide (hereafter referred to as suicide subjects), we examined the status of CREB in suicidal behavior. METHODS: These studies were performed in Brodmann area (BA) 9 and hippocampus obtained from 26 suicide subjects and 20 nonpsychiatric healthy control subjects. Messenger RNA levels of CREB and neuron-specific enolase were determined in total RNA by means of quantitative reverse transcriptase-polymerase chain reaction. Protein levels and the functional characteristics of CREB were determined in nuclear fractions by means of Western blot and cyclic adenosine monophosphate response element (CRE)-DNA binding activity, respectively. In the same nuclear fraction, we determined the catalytic activity of cyclic adenosine monophosphate-stimulated protein kinase A by means of enzymatic assay. RESULTS: We observed a significant reduction in messenger RNA and protein levels of CREB, CRE-DNA binding activity, and basal and cyclic adenosine monophosphate-stimulated protein kinase A activity in BA 9 and hippocampus of suicide subjects, without any change in messenger RNA levels of neuron-specific enolase in BA 9. Except for protein kinase A activity, changes in CREB expression and CRE-DNA binding activity were present in all suicide subjects, irrespective of diagnosis. These changes were unrelated to postmortem intervals, age, sex, or antidepressant treatment. CONCLUSIONS: Given the significance of CREB in mediating various physiological functions through gene transcription, our results of decreased expression and functional characteristics of CREB in postmortem brain of suicide subjects suggest that CREB may play an important role in suicidal behavior.

Adult↗
PubMed2003

Altered gene expression of brain-derived neurotrophic factor and receptor tyrosine kinase B in postmortem brain of suicide subjects.

BACKGROUND: Suicide is a major public health concern. Although authors of many studies have examined the neurobiological aspects of suicide, the molecular mechanisms associated with suicidal behavior remain unclear. Brain-derived neurotrophic factor (BDNF), one of the most important neurotrophins, after binding with and activating receptor tyrosine kinase B (trk B), is directly involved in many physiological functions in the brain, including cell survival and synaptic plasticity. The present study was performed to examine whether the expression of BDNF and/or trk B isoforms was altered in postmortem brain in subjects who commit suicide (hereafter referred to as suicide subjects) and whether these alterations were associated with specific psychopathologic conditions. METHODS: These studies were performed in prefrontal cortex in Brodmann area 9 and hippocampus obtained in 27 suicide subjects and 21 nonpsychiatric control subjects. Levels of messenger RNA and protein levels of BDNF and trk B were determined with competitive reverse transcriptase-polymerase chain reaction and Western blot technique, respectively. The level of neuron-specific enolase messenger RNA as a neuronal marker was also determined in these brain areas. RESULTS: Messenger RNA levels of BDNF and trk B were significantly reduced, independently and as a ratio to neuron-specific enolase, in both prefrontal cortex and hippocampus in suicide subjects, as compared with those in control subjects. These reductions were associated with significant decreases in the protein levels of BDNF and of full-length trk B but not trk B's truncated isoform. These changes were present in all suicide subjects regardless of psychiatric diagnosis and were unrelated to postmortem interval, age, sex, or pH of the brain. CONCLUSIONS: Given the importance of BDNF in mediating physiological functions, including cell survival and synaptic plasticity, our findings of reduced expression of BDNF and trk B in postmortem brain in suicide subjects suggest that these molecules may play an important role in the pathophysiological aspects of suicidal behavior.

Adult↗
PubMed2003

Rehospitalization risk with second-generation and depot antipsychotics.

Decreasing hospital admissions is important for improving outcomes for people with schizophrenia. Second-generation antipsychotics (SGAs) are better tolerated for long-term therapy than traditional medications and may contribute to a lower rehospitalization risk, but have not been compared to depot forms with regard to long-term outcomes. This study evaluates the risk of readmission in patients discharged from six State of Maryland inpatient mental health facilities between Jan. 1, 1997 and Dec. 31, 1997 on clozapine (N = 41), risperidone (N = 149), and olanzapine (N = 103). These patients were compared with those discharged from the two largest state facilities during the same time period on fluphenazine decanoate (N = 59) or haloperidol decanoate (N = 59). One-year readmission risk (measured by Kaplan-Meier survival analysis with Holm's adjustment for multiple comparison on Log Rank tests) were 10% for clozapine, 12% for risperidone, and 13% for olanzapine. These risks were not significantly lower than the readmission risk for fluphenazine decanoate (21%) but were significantly lower than haloperidol decanoate (35%) for all three SGAs. Demographic and clinical variables did not predict readmission for any of the medications. In patients with similar demographic and clinical characteristics, 1-year risk of readmission for patients treated with SGAs were at least comparable to the 1-year risk for patients receiving fluphenazine decanoate and lower than the risk for patients treated with haloperidol decanoate. SGAs may provide better long-term prognoses and outcomes for patients with schizophrenia.

Adult↗
PubMed2003

Perception of depot antipsychotics by mental health professionals.

OBJECTIVE: This study examines attitudes of mental health professionals about the use and usefulness of depot antipsychotic medications and determines similarities and differences in attitudes between professional groups. METHODS: Mental health professionals working with patients with severe mental illness completed a questionnaire designed to evaluate their opinions concerning rate of depot use, indications for use of depots, problems with use of depots, common side effects of depots, barriers to switching from depot to oral atypical antipsychotics, impact of staffing levels on drug choice, and relative confidence in various antipsychotics for the management of chronic psychosis. RESULTS: Overall, all professional groups perceived depot antipsychotics as a requirement for the treatment of those with serious mental illness who were poorly adherent. However, there were a number of professional differences in responses to certain items in the survey that probably reflected the degree of direct contact with patients. Medical staff were remarkably uniform in their opinions on the use and usefulness of depots. Mental health staff from all the professional groups surveyed considered extrapyramidal side effects (EPS) a major concern, while few rated cognitive side effects, sexual side effects, and weight gain as significant concerns, even though these problems are reported to be a principal concern of patients. Although all professional groups indicated an awareness of the potential toxicity of depot antipsychotics and there was an overall consensus that atypical antipsychotics are likely to be beneficial in chronic psychosis, limitations in resources were seen as a barrier to switching. CONCLUSIONS: Attitudes concerning the usefulness and rationale for use of depot antipsychotics differ by medical profession. Nursing and allied health workers are more likely than medical staff to note patient specific variables such as weight gain, injection site reactions, and patient preferences as problems with depots. The results also suggest that, in a community-based psychiatric care system, the use of newer and potentially better agents for the management of psychosis is impaired by resource limitations in service delivery as well as by educational disparities between the professions.

Journal Article↗