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Stephen R Marder

Publications and source records attributed to Stephen R Marder.

At least 19 recordsLinked to original sources
PubMed2006

Social cognition in schizophrenia: relationships with neurocognition and negative symptoms.

Despite the growing importance of social cognition in schizophrenia, fundamental issues concerning the nature of social cognition in schizophrenia remain unanswered. One issue concerns the strength of the relationships between social cognition and key features of the disorder such as neurocognitive deficits and negative symptoms. The current study employed structural equation modeling to examine three key questions regarding the nature of social cognition in schizophrenia: 1) Are social cognition and neurocognition in schizophrenia better modeled as one or two separate constructs? 2) Are social cognition and negative symptoms in schizophrenia better modeled as one or two separate constructs?, and 3) When social cognition, neurocognition, and negative symptoms are included in a single model, is social cognition more closely related to neurocognition or to negative symptoms? In this cross sectional study, one hundred outpatients with schizophrenia or schizoaffective disorder were administered measures of social cognition, neurocognition, and negative symptoms. A two-factor model that represented social cognition and neurocognition as separate constructs fit the data significantly better than a one-factor model, suggesting that social cognition and neurocognition are distinct, yet highly related, constructs. Likewise, a two-factor model that represented social cognition and negative symptoms as separate constructs fit the data significantly better than a one-factor model, suggesting that social cognition and negative symptoms are distinct constructs. A three-factor model revealed that the relationship between social cognition and neurocognition was stronger than the relationship between social cognition and negative symptoms. The current findings start to provide insights into the structure of social cognition, neurocognition, and negative symptoms in schizophrenia.

Adult↗
PubMed2006

Determination of ziprasidone in human plasma by liquid chromatography-electrospray tandem mass spectrometry and its application to plasma level determination in schizophrenia patients.

An accurate, rapid and simple liquid chromatography-tandem mass spectrometry (LC-MS-MS) assay method was developed for the determination of ziprasidone (ZIP) in the plasma of schizophrenia patients. A simple one step liquid-liquid extraction with 20% methylene dichloride in pentane was used to isolate ZIP and the internal standard from the plasma matrix. The compounds were separated on a C-18 column by an isocratic elution and the eluted compounds were analyzed by a triple quadrupole mass spectrometer with a TurboIon spray interface using the positive ion atmospheric pressure electrospray ionization method and detected using multiple reaction monitoring mode. The ZIP standard calibration curve was linear over the range of 0.25-500ng/ml when 0.5ml of plasma was used for the analysis (r(2)>0.998). The intra-assay (within-day) and inter-assay (between-day) variations were less than 12% for the spiked standard curve and quality control samples. The absolute extraction efficiency was 82% for ZIP and 68% for INS-RSP. The analysis time for each sample was less than 3min and useful for high turnaround plasma level determinations. This LC-MS-MS assay method for ZIP is highly specific, sensitive, accurate and rapid and is currently being used for the plasma level determination of ZIP in schizophrenia patients treated with various daily oral doses of ZIP. The data showed large inter-individual variations.

Adult↗
PubMed2006

Treatment of schizophrenia negative symptoms: future prospects.

New findings from neuroscience, genetics, and experimental psychology have emerged that provide alternative explanations of many negative symptoms. We review the continuing limitations in treatment and discuss possible sources of heterogeneity among negative symptoms. We also anticipate conceptual uncertainties that may arise with forthcoming treatment developments.

Antipsychotic Agents↗
PubMed2006

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Antipsychotic Agents↗
PubMed2006

Initiatives to promote the discovery of drugs to improve cognitive function in severe mental illness.

Current pharmacotherapy for treating schizophrenia is limited because treatments focus on positive symptom control rather than improving social and vocational function and few new treatments have been developed in the past 50 years. To better facilitate the development of treatments for the cognitive impairments in schizophrenia and for improving functional outcome in schizophrenia, the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) program was established. The MATRICS program has developed a way of measuring outcome in trials of cognition-enhancing drugs, provided guidelines for doing studies of cognition-enhancing drugs, and looked at the most promising molecular targets for improving cognition using different kinds of pharmacologic agents. By focusing on cognitive impairments and negative symptoms, the functional outcomes of patients with schizophrenia may be improved.

Clinical Trials as Topic↗
PubMed2006

The NIMH-MATRICS project for developing cognition-enhancing agents for schizophrenia.

The US National Institute of Mental Health supported an initiative to facilitate the development of pharmacological agents for enhancing neurocognition in patients with schizophrenia. This has been accomplished through a consensus-building process that has included representatives from academia, the pharmaceutical industry, and government. The group has addressed obstacles to drug development that include (i) the lack of a well-accepted instrument for measuring neurocognition in clinical trials; (ii) the lack of a consensus on the best molecular target or targets for drug development; (iii) the lack of a consensus regarding the optimal trial design for either comedication that improves cognition when added to an antipsychotic or a broad spectrum agent that improves cognition and treats psychosis; and (iv) the approaches of regulatory agencies such as the US Food and Drug Administration to approving and labeling a new agent.

Antipsychotic Agents↗
PubMed2006

Drug initiatives to improve cognitive function.

Unlike for other chronic illnesses, the development of new medications for the treatment of schizophrenia has been relatively dormant since the 1950s. Recently, the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) program was established by the National Institute of Mental Health (NIMH) in order to facilitate the development of treatments for cognitive impairment and functional outcome in schizophrenia. Although effective medications for managing the positive symptoms of schizophrenia have permitted many patients to live in the community, these medications often fail to improve social and vocational function. As a result, some experts believe that research into new treatments should focus instead on the functional outcomes of patients by improving cognitive abilities and social competence. The MATRICS program brought together scientists from academia, government, and industry to discuss ways of promoting the development of new treatments for schizophrenia and gain consensus on treatment targets. The initiatives that have come out of the MATRICS program include focusing on adjunct medications, addressing regulatory issues with the U.S. Food and Drug Administration, determining the best way to measure functional outcomes, classifying symptoms, developing a battery of cognitive tests for assessing outcomes in clinical trials, and ranking promising targets for new treatment development.

Antipsychotic Agents↗
PubMed2006

A review of agitation in mental illness: treatment guidelines and current therapies.

BACKGROUND: Agitation is an important therapeutic target in the acute and/or emergent setting, as well as for longer-term care of patients with psychiatric illness. METHOD: Select reviews and guidelines published (from 2000 to 2006) on the treatment of agitation in various psychiatric disorders were evaluated. RESULTS: After maximizing the safety of all individuals in the presence of an acutely agitated patient, initial therapy generally involves verbal deescalation. Pharmacologic management of acute agitation relies on typical antipsychotics, particularly haloperidol; benzodiazepines; and atypical antipsychotics. The selection of a specific agent (or combination of agents) should be guided by etiologic considerations, efficacy of the drug(s), side effects, potential drug interactions, and drug formulation. Seclusion or restraints are treatments of last resort due to safety issues. CONCLUSION: Compared with conventional antipsychotics (e.g., haloperidol), preliminary evidence indicates that atypical antipsychotics effectively reduce agitation, are better tolerated, and have fewer side effects. After an acute episode, atypical agents also help ease the transition from intramuscular to oral medication to promote ongoing treatment.

Aggression↗
PubMed2005

Low-dose fluvoxamine as an adjunct to reduce olanzapine therapeutic dose requirements: a prospective dose-adjusted drug interaction strategy.

Despite the advances in antipsychotic pharmacotherapy over the past decade, many atypical antipsychotic agents are not readily accessible by patients with major psychosis or in developing countries where the acquisition costs may be prohibitive. Olanzapine is an efficacious and widely prescribed atypical antipsychotic agent. In theory, olanzapine therapeutic dose requirement may be reduced during concurrent treatment with inhibitors of drug metabolism. In vitro studies suggest that smoking-inducible cytochrome P450 (CYP) 1A2 contributes to formation of the metabolite 4'-N-desmethylolanzapine. The present prospective study tested the hypothesis that olanzapine steady-state doses can be significantly decreased by coadministration of a low subclinical dose of fluvoxamine, a potent inhibitor of cytochrome P450 1A2. The study design followed a targeted "at-risk" population approach with a focus on smokers who were likely to exhibit increased cytochrome P450 1A2 expression. Patients with stable psychotic illness (N = 10 men, all smokers) and receiving chronic olanzapine treatment were evaluated for steady-state plasma concentrations of olanzapine and 4'-N-desmethylolanzapine. Subsequently, olanzapine dose was reduced from 17.5 +/- 4.2 mg/d (mean +/- SD) to 13.0 +/- 3.3 mg/d, and a nontherapeutic dose of fluvoxamine (25 mg/d, PO) was added to regimen. Patients were reevaluated at 2, 4, and 6 weeks during olanzapine-fluvoxamine cotreatment. There was no significant change in olanzapine plasma concentration, antipsychotic response, or metabolic indices (eg, serum glucose and lipids) after dose reduction in the presence of fluvoxamine (P > 0.05). 4'-N-desmethylolanzapine/olanzapine metabolic ratio decreased from 0.45 +/- 0.20 at baseline to 0.25 +/- 0.11 at week 6, suggesting inhibition of the cytochrome P450 1A2-mediated olanzapine 4'-N-demethylation by fluvoxamine (P < 0.05). In conclusion, this prospective pilot study suggests that a 26% reduction in olanzapine therapeutic dose requirement may be achieved by coadministration of a nontherapeutic oral dose of fluvoxamine.

Benzodiazepines↗
PubMed2005

Remission in schizophrenia: proposed criteria and rationale for consensus.

New advances in the understanding of schizophrenia etiology, course, and treatment have increased interest on the part of patients, families, advocates, and professionals in the development of consensus-defined standards for clinical status and improvement, including illness remission and recovery. As demonstrated in the area of mood disorders, such standards provide greater clarity around treatment goals, as well as an improved framework for the design and comparison of investigational trials and the subsequent evaluation of the effectiveness of interventions. Unlike the approach to mood disorders, however, the novel application of the concept of standard outcome criteria to schizophrenia must reflect the wide heterogeneity of its long-term course and outcome, as well as the variable effects of different treatments on schizophrenia symptoms. As an initial step in developing operational criteria, an expert working group reviewed available definitions and assessment instruments to provide a conceptual framework for symptomatic, functional, and cognitive domains in schizophrenia as they relate to remission of illness. The first consensus-based operational criteria for symptomatic remission in schizophrenia are based on distinct thresholds for reaching and maintaining improvement, as opposed to change criteria, allowing for alignment with traditional concepts of remission in both psychiatric and nonpsychiatric illness. This innovative approach for standardizing the definition for outcome in schizophrenia will require further examination of its validity and utility, as well as future refinement, particularly in relation to psychosocial and cognitive function and dysfunction. These criteria should facilitate research and support a positive, longer-term approach to studying outcome in patients with schizophrenia.

Brief Psychiatric Rating Scale↗
PubMed2005

The effects of clozapine and risperidone on spatial working memory in schizophrenia.

OBJECTIVE: The purpose of this investigation was to evaluate the effects of clozapine and risperidone on spatial working memory in patients with schizophrenia. METHOD: Spatial working memory performance was evaluated at baseline and after 17 and 29 weeks in 97 patients with schizophrenia participating in a multisite trial. RESULTS: Compared with baseline performance while receiving conventional antipsychotic medication, risperidone improved, and clozapine worsened, spatial working memory performance. CONCLUSIONS: The differential effects of these medications on spatial working memory may be due to the anticholinergic effects of clozapine and prefrontal dopamine-enhancing effects of risperidone.

Adult↗
PubMed2005

Long-term maintenance therapy with quetiapine versus haloperidol decanoate in patients with schizophrenia or schizoaffective disorder.

OBJECTIVE: To compare the long-term efficacy and tolerability of oral quetiapine with those of intramuscular haloperidol. METHOD: Patients with DSM-IV-diagnosed schizophrenia or schizoaffective disorder requiring long-term antipsychotic treatment were randomly assigned to open-label oral quetiapine or intramuscular haloperidol decanoate for 48 weeks. Clinicians were instructed to target dosing at 500 mg/day of quetiapine or 200 mg of haloperidol decanoate every 4 weeks. The Positive and Negative Syndrome Scale was used to assess efficacy; the Simpson-Angus Scale and the Barnes Akathisia Scale were used to assess safety and tolerability. For statistical analyses, a general linear mixed-model repeated-measures analysis of covariance was used, with change scores for dependent variables computed with the baseline score as covariate. Data were collected from 1998 to 2001. RESULTS: Thirty-five patients were enrolled, but 6 did not participate after being informed of their treatment assignment; 4 of the 6 withdrawals were assigned to haloperidol decanoate. Mean doses at week 48 were 493 mg/day of quetiapine (N = 16) and 170 mg/28 days of haloperidol decanoate (N = 9). Survival analysis showed no between-group differences in estimates of the number of patients remaining exacerbation-free over time. Both drugs were efficacious, but quetiapine was significantly better than haloperidol decanoate in controlling negative symptoms (p < .05). The incidence of extrapyramidal symptoms was low in both groups; patients receiving quetiapine showed significantly greater improvement in rigidity and akathisia (p < .05). CONCLUSION: Oral quetiapine was as efficacious as intramuscular haloperidol in preventing symptom exacerbation over 48 weeks in patients with schizophrenia or schizoaffective disorder, with fewer extrapyramidal symptoms, especially rigidity and akathisia. Quetiapine was more efficacious than haloperidol decanoate in treating negative symptoms.

Administration, Oral↗
PubMed2005

Clinical utility of magnetic resonance imaging radiographs for suspected organic syndromes in adult psychiatry.

OBJECTIVE: In psychiatric practice, adult patients are most commonly referred for magnetic resonance imaging (MRI) to screen for suspected organic medical diseases of the central nervous system that can mimic psychiatric syndromes. We identified the most common signs and symptoms prompting MRIs to establish the predictive value of these signs and symptoms for clinically pertinent organic syndromes. METHOD: This study was a retrospective chart review of psychiatric patients at the Veterans Affairs Greater Los Angeles Health Care Center (Los Angeles, Calif.) who were referred for MRI of the brain between 1996 and 2002. Patients referred for evaluation of dementia were excluded. The specific indications leading clinicians to obtain MRI were identified and grouped. In order to offset the uncertain significance of many MRI findings, for this study, the predictive value of each indication was calculated based on the percentage of patients in whom clinical management changed in response to MRI findings rather than on the percentage with any abnormal MRI results. RESULTS: Of 253 patients who had MRIs, 38 (15%) incurred some degree of treatment modification as a result of MRI findings, including 6 patients in whom MRI identified a medical condition that became the focus of treatment. Six indications appeared most likely to prompt clinicians to obtain MRIs. Because pertinent results were associated with each of these indications, statistical evaluation did not reveal significant differences in their predictive values (chi(2) = 4.32, df = 5, p = .505). CONCLUSIONS: Unlike prior studies showing no value to screening radioimaging, this study shows MRI can be a useful screening test among patients suspected of having organic psychiatric disorders and that the common indications for MRI employed at one institution were predictive.

Adult↗
PubMed2004

Anterior cingulate dysfunction during choice anticipation in schizophrenia.

The anterior cingulate cortex (ACGC) participates in selective attention, working memory (WM), anticipation, and behavioral monitoring. Subjects with schizophrenia exhibit deficits in these mechanisms during selective attention and WM tasks. However, ACGC dysfunctions have not been specifically investigated during behavioral anticipation, whose deficits may relate to salient schizophrenic features such as foresight abnormalities and impaired social functioning and behavior. We thus studied ACGC function in relation to two aspects of WM, remembering information and anticipating responses, in control and schizophrenic subjects. We measured brain activation in eight subjects with schizophrenia and eight healthy volunteers using functional magnetic resonance imaging. All subjects performed stimulus-response delay tasks with color dots or facial expression diagrams as cues and either 50% or 100% response predictability, which emphasized demands on remembering the cues or anticipating the response for correct performance, respectively. We found a double dissociation of ACGC activation between subject groups and task type. In controls, the ACGC became intensely activated during response anticipation (more extensively and bilaterally when the cues were colors than when they were facial diagrams) but remained at resting activity levels during remembering. In schizophrenic patients, significant ACGC activation was seen only when remembering a percept (more extensively and bilaterally when it was a facial diagram than when it was a color) but not when anticipating a response. These results reveal an ACGC dysfunction during choice anticipation in schizophrenia and suggest that it might underlie the foresight deficits seen in schizophrenic patients.

Adult↗
PubMed2004

Measurement and Treatment Research to Improve Cognition in Schizophrenia: NIMH MATRICS initiative to support the development of agents for improving cognition in schizophrenia.

The impairments in social and vocational outcome that are common in schizophrenia are strongly related to the severity of impaired neurocognition. This observation led to the initiation of The NIMH's Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative, which supports the development of pharmacological agents to improve cognition in schizophrenia. MATRICS addresses barriers to drug development through a number of activities, including the development of a consensus battery for measuring cognition in schizophrenia; the development of a consensus regarding the most promising molecular targets that should be the focus of drug development; the use of a joint meeting with representatives from the industry, academia, NIMH, and the U.S. Food and Drug Administration (FDA) to clarify guidelines for the design of clinical trials for cognition enhancing agents; and finally, to assist NIMH in developing its research agenda in this area.

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

Approaching a consensus cognitive battery for clinical trials in schizophrenia: the NIMH-MATRICS conference to select cognitive domains and test criteria.

To stimulate the development of new drugs for the cognitive deficits of schizophrenia, the National Institute of Mental Health (NIMH) established the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative. This article presents an overview of decisions from the first MATRICS consensus conference. The goals of the meeting were to 1) identify the cognitive domains that should be represented in a consensus cognitive battery and 2) prioritize key criteria for selection of tests for the battery. Seven cognitive domains were selected based on a review of the literature and input from experts: working memory, attention/vigilance, verbal learning and memory, visual learning and memory, reasoning and problem solving, speed of processing, and social cognition. Based on discussions at this meeting, five criteria were considered essential for test selection: good test-retest reliability, high utility as a repeated measure, relationship to functional outcome, potential response to pharmacologic agents, and practicality/tolerability. The results from this meeting constitute the initial steps for reaching a consensus cognitive battery for clinical trials in schizophrenia.

Clinical Trials as Topic↗