In addition to clozapine, other atypical antipsychotic drugs pharmacologically similar to clozapine, for example, olanzapine, risperidone, and melperone, are also effective in a similar proportion of ...treatment-resistant schizophrenia (TRS) patients, ~40%. The major goal of this study was to compare 2 doses of lurasidone, another atypical antipsychotic drug, and time to improvement in psychopathology and cognition during a 6-month trial in TRS patients.
The diagnosis of TRS was based on clinical history and lack of improvement in psychopathology during a 6-week open trial of lurasidone 80 mg/d (phase 1). This was followed by a randomized, double-blind, 24-week trial of lurasidone, comparing 80- and 240-mg/d doses (phase 2).
Significant non-dose-related improvement in the Positive and Negative Syndrome Scale-Total and subscales and in 2 of 7 cognitive domains, speed of processing and executive function, were noted. Twenty-eight (41.8%) of 67 patients in the combined sample improved ≥20% in the Positive and Negative Syndrome Scale-Total. Of the 28 responders, 19 (67.9%) first reached ≥20% improvement between weeks 6 and 24 during phase 2, including some who had previously failed to respond to clozapine.
Improvement with lurasidone is comparable with those previously reported for clozapine, melperone, olanzapine, and risperidone in TRS patients. In addition, this study demonstrated that 80 mg/d lurasidone, an effective and tolerable dose for non-TRS patients, was also effective in TRS patients but required longer duration of treatment. Direct comparison of lurasidone with clozapine in TRS patients is indicated.
Abstract In previous studies, we demonstrated that tandospirone, a serotonin-5-HT1A partial agonist, added to ongoing treatment with small to moderate doses of typical antipsychotic drugs, improved ...executive function and verbal learning and memory. However, tandospirone is not available in most countries, and atypical antipsychotic drugs (AAPDs) have largely replaced typical antipsychotic drugs as the primary treatment for schizophrenia. Therefore, the goal of this randomly assigned placebo-controlled double-blind study was to determine if the addition of buspirone, a widely available 5-HT1A partial agonist, would enhance cognitive function, in subjects with schizophrenia treated with AAPDs. Seventy-three patients with schizophrenia, who had been treated with an AAPD for at least three months, were randomly assigned to receive either buspirone, 30 mg/day, or matching placebo. All other medications remained unchanged. Attention, verbal fluency, verbal learning and memory, verbal working memory, and executive function, as well as psychopathology, were assessed at baseline, and 6 weeks, and 3 and 6 months after baseline. A significant Time × Group interaction effect was noted on the Digit Symbol Substitution Test, a measure of attention/speeded motor performance, due to better performance of the buspirone group compared to the placebo group at 3 months. No significant interaction effects were noted for other domains of cognition. Scores on the Brief Psychiatric Rating Scale (Total, Positive) were improved during treatment with buspirone but not placebo, but the effects did not reach statistical significance. The results of this study showed a possible benefit of buspirone augmentation of AAPDs to enhance attention. However, we did not replicate the results of the previous study with tandospirone, which may be due to the differences between tandospirone and buspirone, between typical antipsychotics and AAPDs, or a combination of the above. Further study to determine the usefulness of 5-HT1A agonist treatment in schizophrenia is indicated.
Since 2009, earlier initiation of highly active antiretroviral therapy (HAART) after an opportunistic infection (OI) has been recommended based on lower risks of death and AIDS-related progression ...found in clinical trials. Delay in HAART initiation after OIs may be an important barrier for successful outcomes in patients with advanced disease. Timing of HAART initiation after an OI in "real life" settings in Latin America has not been evaluated.
Patients in the Caribbean, Central and South America network for HIV Epidemiology (CCASAnet) ≥18 years of age at enrolment, from 2001-2012 who had an OI before HAART initiation were included. Patients were divided in an early HAART (EH) group (those initiating within 4 weeks of an OI) and a delayed HAART (DH) group (those initiating more than 4 weeks after an OI). All patients with an AIDS-defining OI were included. In patients with more than one OI the first event reported was considered. Calendar trends in the proportion of patients in the EH group (before and after 2009) were estimated by site and for the whole cohort. Factors associated with EH were estimated using multivariable logistic regression models.
A total of 1457 patients had an OI before HAART initiation and were included in the analysis: 213 from Argentina, 686 from Brazil, 283 from Chile, 119 from Honduras and 156 from Mexico. Most prevalent OI were Tuberculosis (31%), followed by Pneumocystis pneumonia (24%), Invasive Candidiasis (16%) and Toxoplasmosis (9%). Median time from OI to HAART initiation decreased significantly from 5.7 (interquartile range IQR 2.8-12.1) weeks before 2009 to 4.3 (IQR 2.0-7.1) after 2009 (p<0.01). Factors associated with starting HAART within 4 weeks of OI diagnosis were lower CD4 count at enrolment (p-<0.001), having a non-tuberculosis OI (p<0.001), study site (p<0.001), and more recent years of OI diagnosis (p<0.001).
The time from diagnosis of an OI to HAART initiation has decreased in Latin America coinciding with the publication of evidence of its benefit. We found important heterogeneity between sites which may reflect differences in clinical practices, local guidelines, and access to HAART. The impact of the timing of HAART initiation after OI on patient survival in this "real life" context needs further evaluation.
The goal of this study was to evaluate the effects of the addition of tandospirone, a serotonin-1A (5-HT(1A)) agonist, to ongoing treatment with typical antipsychotic drugs, on two cognitive domains ...that are relevant to functional outcome in patients with schizophrenia.
Twenty-six patients with schizophrenia who were receiving stable doses of typical antipsychotics were randomly assigned to adjunctive treatment with 30 mg/day of tandospirone or placebo for 6 weeks. Executive function and verbal memory as well as psychopathology were assessed at baseline and after 6 weeks.
Both cognitive measures improved significantly in the patients who received tandospirone; subjects who did not receive tandospirone showed no change. There was no significant change in psychopathology ratings in either group.
The results suggest the usefulness of 5-HT(1A) agonists for enhancing some types of cognitive performance and possibly social and work function in patients with schizophrenia.
This study aimed to evaluate trends and predictors of survival after cancer diagnosis in persons living with HIV in the Caribbean, Central, and South America network for HIV epidemiology cohort.
...Demographic, cancer, and HIV-related data from HIV-positive adults diagnosed with cancer ≤ 1 year before or any time after HIV diagnosis from January 1, 2000-June 30, 2015 were retrospectively collected. Cancer cases were classified as AIDS-defining cancers (ADC) and non-AIDS-defining cancers (NADC). The association of mortality with cancer- and HIV-related factors was assessed using Kaplan-Meier curves and Cox proportional hazards models stratified by clinic site and cancer type.
Among 15,869 patients, 783 had an eligible cancer diagnosis; 82% were male and median age at cancer diagnosis was 39 years (interquartile range IQR: 32-47). Patients were from Brazil (36.5%), Argentina (19.9%), Chile (19.7%), Mexico (19.3%), and Honduras (4.6%). A total of 564 ADC and 219 NADC were diagnosed. Patients with NADC had similar survival probabilities as those with ADC at one year (81% vs. 79%) but lower survival at five years (60% vs. 69%). In the adjusted analysis, risk of mortality increased with detectable viral load (adjusted hazard ratio aHR = 1.63,
= 0.02), age (aHR = 1.02 per year,
= 0.002) and time between HIV and cancer diagnoses (aHR = 1.03 per year,
= 0.01).
ADC remain the most frequent cancers in the region. Overall mortality was related to detectable viral load and age. Longer-term survival was lower after diagnosis of NADC than for ADC, which may be due to factors unrelated to HIV.
Previous studies have suggested decreased N-methyl-D-aspartate (NMDA)-type glutamate receptor function may contribute to increased negative symptoms in patients with schizophrenia. Consistent with ...this hypothesis, glycine, a co-agonist at NMDA receptors, has been reported to improve negative symptoms associated with the illness. This study was performed to determine if plasma levels of glycine or its ratio to serine, a precursor of glycine, are decreased in patients with schizophrenia compared to normal control subjects or patients with major depression. We also tested the hypothesis that these amino acids were correlated with negative symptoms in subjects with schizophrenia. Plasma levels of glycine, serine, and their ratio, were compared in 144 patients with schizophrenia, 44 patients with major depression, and 49 normal control subjects. All subjects were medication-free. Psychopathology was evaluated using the Brief Psychiatric Rating Scale (BPRS). Plasma glycine levels and glycine/serine ratios were decreased in patients with schizophrenia relative to control subjects and patients with major depression. By contrast, serine levels were increased in patients with schizophrenia compared to normal subjects but not compared to major depression. Patients with major depression also had increased plasma serine levels and decreased glycine/serine ratios compared to normal controls, but glycine levels were not different from those of normal controls. In subjects with schizophrenia, glycine levels predicted the Withdrawal–Retardation score (BPRS), whereas no such correlation was found in subjects with major depression. These results provide additional evidence that decreased availability of glycine may be related to the pathophysiology of negative symptoms. The decreases in plasma glycine levels support the evidence for an abnormality in the glutamatergic system in schizophrenia, and provide additional support for efforts to improve negative symptoms by augmentation of antipsychotic drugs with agonists at the glycine site of the NMDA receptor.
The favorable effect of clozapine on psychotic symptoms in patients with treatment-resistant (TR) schizophrenia (SCZ) in short-term studies is well established. However, prospective studies of the ...long-term outcome of clozapine treatment on psychopathology, cognition, quality of life, and functional outcome in TR-SCZ are limited.
Here, we have examined the long-term (mean duration of follow-up 14 years) effects of clozapine on those outcomes in a prospective, open label study in 54 TR-SCZ patients. Assessments were performed at baseline, 6 weeks, 6 months, and at the last follow-up.
Brief Psychiatric Rating Scale (BPRS) total, positive symptoms, and anxiety/depression at the last follow-up improved significantly from baseline, as well as from the 6-month evaluation ( P < 0.0001), with a 70.5% responder rate (≥20% improvement at the last follow-up from baseline). Quality of Life Scale (QLS) total improved by 72% at the last follow-up, with 24% of patients rated as having "good" functioning compared with 0% at baseline. Suicidal thoughts/behavior was significantly reduced at the last follow-up from the baseline. No significant change in negative symptoms was found at the last follow-up in the total sample. Short-term memory function declined at the last follow-up from baseline, but there was no significant change in processing speed. The QLS total showed a significant negative correlation with BPRS positive symptoms but not with cognitive measures, or negative symptoms, at the last follow-up.
For patients with TR-SCZ, improving psychotic symptoms with clozapine seems to have a more significant impact than negative symptoms or cognition on improving psychosocial function.
Melperone, a butyrophenone, has been shown to possess atypical antipsychotic properties, i.e. ability to produce an antipsychotic effect in man at doses that cause minimal extrapyramidal side ...effects. In addition, melperone shares the following with other atypical antipsychotic drugs: (1) effectiveness for ameliorating negative symptoms; (2) no prolactin elevation; and (3) effectiveness in the treatment of some patients with neuroleptic-resistant schizophrenia. Other atypical antipsychotic drugs have been reported to improve cognitive function. This study was performed to investigate the effect of melperone on cognitive function. Nineteen patients with schizophrenia or schizoaffective disorder, including 11 neuroleptic-resistant patients, were treated with melperone for 6 weeks. A comprehensive neurocognitive test battery and psychopathological ratings (Brief Psychiatric Rating Scale, BPRS) were administered at baseline and after 6 weeks of melperone treatment. Treatment with melperone was associated with improvement in executive function, as measured by the Wisconsin Card Sorting Test (WCST)-Categories and WCST-Percent Perseveration. On the other hand, visuospatial manipulation, as measured by the Wechsler Intelligent Scale for Children-Revised (WISC-R) Maze, worsened during melperone treatment. There were no significant changes in other domains of cognition, i.e. verbal learning and memory, verbal working memory, verbal fluency and sustained attention. Scores of WCST-Categories and Perseveration at 6 weeks were predicted from the relevant cognitive test scores at baseline and the change in BPRS Total and Positive scores. These results suggest the usefulness of melperone for facilitating work and social function in patients with schizophrenia. The differences in the cognition-enhancing abilities between melperone and clozapine are discussed.
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•Harmonizing observational data is challenging in global research consortia.•Use of R/Shiny web application improved data quality (61% average decrease in errors).•Structured ...testing/training protocol engages users in development, improves adoption.•Generalized design via REDCap simplifies maintenance and adaptation to other domains.
We describe the design, implementation, and impact of a data harmonization, data quality checking, and dynamic report generation application in an international observational HIV research network. The IeDEA Harmonist Data Toolkit is a web-based application written in the open source programming language R, employs the R/Shiny and RMarkdown packages, and leverages the REDCap data collection platform for data model definition and user authentication. The Toolkit performs data quality checks on uploaded datasets, checks for conformance with the network’s common data model, displays the results both interactively and in downloadable reports, and stores approved datasets in secure cloud storage for retrieval by the requesting investigator. Including stakeholders and users in the design process was key to the successful adoption of the application. A survey of regional data managers as well as initial usage metrics indicate that the Toolkit saves time and results in improved data quality, with a 61% mean reduction in the number of error records in a dataset. The generalized application design allows the Toolkit to be easily adapted to other research networks.
Abstract Preliminary evidence suggests that a single nucleotide polymorphism (SNP), the val108/158met SNP, within the gene that codes for catechol- O -methyltransferase (COMT), a key enzyme involved ...in regulating dopamine (DA) transmission within the prefrontal cortex (PFC), is related to cognitive function in schizophrenia and cognitive improvement with atypical antipsychotic drugs (APDs). Specifically, several studies have identified an association between working memory and executive functions, and COMT val108/158met genotype in schizophrenia; although there have been several negative findings that are likely related to small sample sizes and, possibly, medication status of patients at the time of testing. The association between COMT val108/158met genotype, cognitive function, and cognitive improvement with clozapine was investigated in a relatively large prospective sample of patients with schizophrenia, most of whom were unmedicated at baseline. Patients were genotyped for the COMT val108/158met SNP after completing a cognitive battery consisting of tests of attention, working memory, verbal learning and memory, executive function, and verbal fluency at baseline and after 6 weeks and 6 months of treatment with clozapine. Consistent with several previous studies, an association between COMT genotype and tests of executive function and working memory was identified at baseline. In addition, a novel interaction between genotype and improvement on tests of attention and verbal fluency was identified. Specifically, met homozygous and val/met heterozygous patients demonstrated significantly greater improvement than val homozygous patients following 6 months of treatment with clozapine. The results are discussed in relation to previous cross-sectional studies and prospective investigations of the associations between COMT genotype, cognition, and cognitive improvement with atypical APDs in schizophrenia.
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