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It is unknown whether interim analyses portend final study results. Fatigue, pressure to complete trials and recruitment differences may mitigate against this. We examined the similarity of efficacy results of the first and second half of recruited patients to complete trials and explore possible intervening variables. Using data from the NewMeds repository of patient level data from placebo-controlled randomized trials of antipsychotics (AP) (22 studies, n =7056) and antidepressants (AD) (39 studies, n =12,217) we compared treatment effect size (placebo vs. active treatment) of the first and second half of patients recruited in completed trials. We found that in AP studies median difference in treatment effect between cohorts was −0.03, indicating that overall first and second cohorts yielded similar results. In AD studies, median difference between cohorts was 0.04, indicating that overall the second cohort had slightly larger active-placebo-difference. Overall, on average there were minimal differences in effect size between the first and the second cohorts, and in 30 of 39 trials interim results were a good estimate of the results on the 2nd cohort. In AD trials first and second cohort results were more similar when the proportion of patients per study centre and recruitment time of the two cohorts was similar. Results suggest that interim analyses in AD and AP studies may reliably serve to estimate ultimate effects and, at least in AD trials, are more accurate when the same sites are used to a similar extent and recruitment time of the two consequent cohorts is similar. [ABSTRACT FROM AUTHOR]

Background: Trajectory studies highlight heterogeneity in treatment response, although they are yet to systematically differentiate between antipsychotic medications.Aims: To compare treatment response trajectories across antipsychotic medication groups.Method: Data were analyzed from Phase 1 of CATIE, an 18-month double-blind randomized controlled trial of chronic schizophrenia. Change on recurrent Positive and Negative Syndrome Scale (PANSS) administrations for 1124 patients was used to index treatment response trajectories up to 18 months. Trajectory groups were identified with mixed-mode latent class regression modeling. Groups were derived for all participants, and separately for completers, dropouts, and each antipsychotic medication (olanzapine, perphenazine, quetiapine, risperidone, ziprasidone) and then characterized.Results: Trajectory analysis of the entire sample identified that 18.9% of participants belonged to a group of responders. This figure increased to 31.5% for completers, and fell to 14.5% for dropouts. Olanzapine treated patients were significantly more likely than other treatment groups to belong to the trajectory of responders (n=69, 32.55%; Chi=20.13, df=2, p<.01). Separate trajectory analyses of each medication group showed that all medication groups showed two trajectories except olanzapine that had three trajectories and the only trajectory that attained a 20% PANSS reduction by endpoint.Conclusions: Trajectories of treatment response differ between antipsychotic medications and demonstrate substantial heterogeneity in chronic schizophrenia. [ABSTRACT FROM AUTHOR]

The article describes metabolomic technologies suitable to identify enzymes that are potential targets for disease treatment and focuses on liquid chromatography-mass spectrometry (LC-MS) to discuss methods for quantitating known metabolites and identifying new ones. It presents methods for flux measurement emphasizing on enzymes that catalyze up-regulated fluxes. It shows the utility of the methods for drug target discovery using examples from viral infections.

Background: The associations of insight into illness and clinical and socio-demographic variables in schizophrenia have been examined, yet little attention has been given to premorbid functioning, insight change and outcomes.Objectives: We examined these associations in a large cohort of recent onset schizophrenia spectrum disorder patients.Methods: This was a prospective 6-month, open-label, multicentre, phase IV trial in 303 subjects with recent onset (Results: Insight was positively associated with better premorbid functioning, more education and schizoaffective disorder versus schizophrenia. Insight improved modestly, but significantly throughout treatment, particularly illness beliefs. Baseline insight was negatively correlated with quality of life and positive symptoms and positively correlated with anxiety/depression. It was not significantly associated with change in symptom severity or time in trial, but was positively associated with age.Conclusions: Insight, at least in this stable, comparatively high-insight sample, improved during treatment but this is not closely related to improvement in psychotic symptoms. Insight appears to have trait-like qualities demonstrated by association with premorbid factors. While insight is generally a favorable attribute and is associated with fewer psychotic symptoms, it is also associated with increased depression and lower perceived quality of life. Some components of insight are more amenable to improvement; particularly the ability to adopt less fixed illness attributions. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The goals of this study were to determine 1) the occurrence of various dissociative phenomena in patients with somatization disorder, 2) the occurrence of six different types of childhood interpersonal trauma in these patients, and 3) the nature of these patients' early family environment. METHOD: Twenty-two patients with somatization disorder and 19 medical comparison subjects completed the Structured Clinical Interview for DSM-IV Dissociative Disorders, the Childhood Trauma Interview, and the Family Functioning Scale. RESULTS: The somatization disorder patients reported significantly higher level of dissociative amnesia than the comparison subjects. The two groups reported similar levels of depersonalization, derealization, identity confusion, and identity alteration. Somatization disorder patients reported significantly greater childhood emotional abuse and more severe forms of physical abuse, relative to the comparison subjects, with chronic emotional abuse being the best predictor of unexplained symptoms. Childhood sexual abuse, separation/loss, and witnessing violence were equally common in the two groups. The somatization disorder group reported significantly more family conflict and less family cohesion. CONCLUSIONS: Only some types of dissociation are more severe in patients with somatization disorder, relative to medical comparison subjects. Many patients with somatization disorder are raised in an emotionally cold, distant, and unsupportive family environment characterized by chronic emotional and physical abuse. Sexual abuse is not a necessary prerequisite for the disorder. [ABSTRACT FROM AUTHOR]

Background: This study examined prevalence of perceived need for mental health assistance, characteristics of people with a perceived need, and how persons with a need who sought help were different from those who did not.Methods: A national random phone survey (n = 1,394) was conducted in Israel, which included questions about (1) perceived need for mental health assistance and (2) help seeking.Results: Prevalence of life-time and recent perceived need for males was 21% and 10.7%, and for females 31% and 15.1%. Of those with a perceived need, 31.4% of males and 41.6% of females had gone for help. Based on logistic regression models, the variables associated with need were being female, divorced, having a chronic physical disease, and low income (for males only), while predictors of help seeking were living in a big city and not being a recent immigrant. The major sources of help in descending order were: mental health professionals (46%), family physician (25%), family or friends (19%), and other (10%).Conclusions: A majority of people who feel that they need help for mental health problems do not get help. [ABSTRACT FROM AUTHOR]

This study explores the extent to which primary care physicians serve as gatekeepers for the treatment of psychosocial problems and the extent to which they have contact with social workers. We also attempted to identify physician variables related to gatekeeping and amount of contact with social workers. Data from a national study of the role of primary care physicians in Israel were used. About one-third of the physicians had regular contact with social workers, one-quarter had contact less often, and about one-third almost never had contact. Variables associated with gatekeeping for psychosocial problems included having a large caseload, specializing in family medicine, practicing in a rural location, and being under age 55. Variables associated with social work contact were affiliation with the largest health maintenance organization and specialization in family medicine. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Rational choice theory was applied to explain women's use of amniocentesis. Variables included knowledge about prenatal diagnostics, attitudes, and emotional preferences. METHODS: Using structured instruments at 9 to 14 and at 29 to 34 weeks' gestation, we interviewed 232 Israeli women who had low-risk pregnancies. RESULTS: Women who had elective amniocentesis (n = 39) were more knowledgeable about prenatal diagnostics, risks of invasive procedures, and probability of fetal abnormality in high maternal age; had fewer children; and had less favorable attitudes toward parenthood than those who had medically indicated amniocentesis (n = 57) and those who did not have amniocentesis (n = 136). CONCLUSIONS: The use and possible overuse of amniocentesis were associated with having more information about prenatal diagnostics and definite emotional preferences. [ABSTRACT FROM AUTHOR]

Gene Therapy 2002 9, 1413–1414. doi:10.1038/sj.gt.3301884 [ABSTRACT FROM AUTHOR]

Objectives: This non-interventional study (RIS-SCH-4023) examined tolerability and effectiveness of risperidone long-acting injectable (RLAI) versus oral second generation antipsychotics (oSGA: amisulpride, aripiprazole, olanzapine, quetiapine, risperidone or ziprasidone) in schizophrenia under daily routine. Methods: Outpatients receiving RLAI (n=177) or oSGA (n=257) were followed-up for 2 years (m/f 42%/58%; mean age 34.6 years; duration of disease 2.6 years). Outcome measures included PANSS, CGI, relapse rates, treatment adherence and tolerability. Post-hoc analyses focused on baseline between-group differences. Results: Multivariable analysis using recursive partitioning showed that upon study entry RLAI patients were 3.7 times (CI=2.48-5.59) more likely than oSGA patients to have switched to study medication due to non-compliance and/or to be substance abusers (RLAI= 59.9%, n=106/177 vs. oSGA=28.6%, n=73/255). Despite these differences, both groups demonstrated significant improvements in efficacy measures with no between-group differences. There were no significant differences in discontinuation of study medication over the two years (RLAI 41.2% vs. oSGA 36.6%) or in yearly relapse rate before change of the initial therapy (RLAI 0.48±1.48 vs. oSGA 0.71±2.63). In patients with high adherence (≥75%) to previous treatment (physicians’ estimates, 4-point Likert scale) RLAI vs. oSGA patients had significantly better retention rates (RLAI 57.4% vs. oSGA 35.1%) and times (527.0±32.6 vs. 424.1±22.3 days). Most frequently reported treatment-related adverse events were weight increase (13.0% vs. 9.7%), EPS (7.9% vs. 5.5%), hyperkinesia (6.2% vs. 3.5%), fatigue (5.7% vs. 9.7%). Conclusions: Results suggest that factors associated with poor outcomes such as poor compliance and substance abuse may be attenuated by treatment with RLAI. [Copyright &y& Elsevier]

Background: Information on premorbid functioning is often based on patients recalling their past. Premorbid functioning is relevant as it is associated with treatment response and other outcomes. The extent to which memory impairments of persons with schizophrenia may bias such reporting has not been investigated. The purpose of the current study was to assess the extent to which persons with schizophrenia might exhibit biased reporting relative to controls. Methods: Seventy males with schizophrenia or schizoaffective disorder and 51 males with no psychiatric symptoms participated in the study. Contemporaneous and retrospective reports from a behavioral functioning assessment conducted as part of the Israeli Draft Board were compared. This assessment routinely administered to all 17 years old males in the country assesses social functioning, individual autonomy, organizational ability, physical activity and functioning in structured environments. We compared the groups on the Draft Board behavioral measures at age 17 and at re-assessment. We also examined the relationship between symptom severity, neuropsychological performance and differences between age 17 and current behavioral assessment scores. Results: In a repeated measures MANCOVA of the five measures there was no overall significant difference in accuracy of reporting between persons with schizophrenia and those without. Both groups showed a slight tendency to glorify their past. Consistency of reporting was not significantly correlated with neuropsychological performance or levels of psychotic symptoms. Conclusions: We found that when reporting on personal and social functioning during teen age years persons with schizophrenia report with the same level of consistency as persons without schizophrenia. This suggests that self-report of premorbid functioning of persons with schizophrenia can be trusted as being reasonably accurate. [ABSTRACT FROM AUTHOR]

Research indicates that persons with learning disorders often suffer from psychopathology. We assessed current and future psychopathology in male adolescents with discrete impairments in reading comprehension (IRC) or arithmetic abilities (IAA) but with average or above-average general intellectual abilities. Subjects were a population-based cohort of 174,994 male adolescents screened by the Israeli Draft Board with average or above-average intellectual abilities but with low scores (8.6th and 10th lowest percentile respectively) on reading or arithmetic tests. They were compared with adolescents who scored in the 10th percentile and above on these tests (comparison group). Relative to the comparison group, male adolescents with IRC, IAA, or IRC and IAA (0.69%), had poorer scores on most behavioral assessments and higher prevalence of current psychopathology: 4.2% (comparison group), 8.0% (IRC), 7.0% (IAA), and 9.8% (IRC and IAA). Adolescents with IRC were also at increased risk for later hospitalization for schizophrenia (hazard ratios = 1.8, 95% confidence interval: 1.3-2.6). Male adolescents with average and above-average general intellectual abilities but with IRC or IAA are more likely to have current and future psychopathology. Impairments in intellectual functioning and abnormal behaviors leading to mental illnesses may share common neurobiological substrates. The results support screening male adolescents with learning disorders for psychopathology. [ABSTRACT FROM AUTHOR]

Weiser M, Reichenberg A, Rabinowitz J, Knobler HY, Lubin G, Yazvitzky R, Nahon D, Gur RC, Davidson M. Cognitive performance of male adolescents is lower than controls across psychiatric disorders: a population-based study.Acta Psychiatr Scand 2004: 1–5.© Blackwell Munksgaard 2004.Psychiatric patients, as well as humans or experimental animals with brain lesions, often concurrently manifest behavioral deviations and subtle cognitive impairments. This study tested the hypothesis that as a group, adolescents suffering from psychiatric disorders score worse on cognitive tests compared with controls.As part of the assessment for eligibility to serve in the military, the entire, unselected population of 16–17-year old male Israelis undergo cognitive testing and screening for psychopathology by the Draft Board. We retrieved the cognitive test scores of 19 075 adolescents who were assigned any psychiatric diagnosis, and compared them with the scores of 243 507 adolescents without psychiatric diagnoses.Mean test scores of cases were significantly poorer then controls for all diagnostic groups, except for eating disorders. Effect sizes ranged from 0.3 to 1.6.As group, adolescent males with psychiatric disorders manifest at least subtle impairments in cognitive functioning. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to compare the rehospitalization rates of patients discharged from the hospital while being treated with risperidone, olanzapine, or conventional antipsychotics.Method: By using Israel's National Psychiatric Hospitalization Case Registry, rehospitalization status was monitored for all patients with schizophrenia who were discharged from any inpatient psychiatric facility in Israel while taking risperidone (N=268) or olanzapine (N=313) between Jan. 1, 1998, and Dec. 31, 1998, and a group of patients discharged during that time who were treated with conventional antipsychotics (N=458). Time to readmission over the course of 2 years was measured by the product-limit (Kaplan-Meier) formula.Results: The readmission rate for patients discharged while taking conventional antipsychotics was higher than the rates for patients treated with either risperidone or olanzapine. At 24 months, 67% of the risperidone-treated patients and 69% of the olanzapine-treated patients remained in the community, as compared to 52% of the patients treated with conventional antipsychotics.Conclusions: This study suggests that the rehospitalization rates of patients taking the novel antipsychotics risperidone and olanzapine are not different from each other and are considerably lower than the rate for patients treated with conventional antipsychotics. The results confirm findings of previous studies suggesting that the levels of overall effectiveness of risperidone and olanzapine are not very different and offers evidence that these drugs are more effective in preventing rehospitalization than conventional antipsychotic drugs. [ABSTRACT FROM AUTHOR]

We use a novel technique that allows for closed recirculation of vector genomes in the cardiac circulation using cardiopulmonary bypass, referred to here as molecular cardiac surgery with recirculating delivery (MCARD). We demonstrate that this platform technology is highly efficient in isolating the heart from the systemic circulation in vivo. Using MCARD, we compare the relative efficacy of single-stranded (ss) adeno-associated virus (AAV)6, ssAAV9 and self-complimentary (sc)AAV6-encoding enhanced green fluorescent protein, driven by the constitutive cytomegalovirus promoter to transduce the ovine myocardium in situ. MCARD allows for the unprecedented delivery of up to 48 green fluorescent protein genome copies per cell globally in the sheep left ventricular (LV) myocardium. We demonstrate that scAAV6-mediated MCARD delivery results in global, cardiac-specific LV gene expression in the ovine heart and provides for considerably more robust and cardiac-specific gene delivery than other available delivery techniques such as intramuscular injection or intracoronary injection; thus, representing a potential, clinically translatable platform for heart failure gene therapy. [ABSTRACT FROM AUTHOR]

Abstract: Background : Social and intellectual premorbid functioning are generally estimated retrospectively, and related to clinical or hospitalization outcomes in schizophrenia. Yet the relationship between premorbid functioning assessed prior to psychiatric hospitalization and postmorbid functional outcomes has not been examined. Objectives : To test competing models of the relationship between (a) functional outcomes with (b) premorbid functioning assessed on nationally administered tests prior to psychiatric hospitalization, postmorbid intellectual functioning and symptomatology using a historical prospective design. Methods : Ninety one inpatient and outpatient males with schizophrenia or schizoaffective disorder, aged 19 to 35, were examined using the Positive and Negative Syndrome Scale, the WAIS-III and Strauss and Carpenter social and occupational functional outcome scale. Premorbid intelligence and social functioning data were obtained from national standardized tests administered during high school prior to first hospitalization for schizophrenia. Results : Path modeling showed that premorbid intelligence and behavioral functioning directly predicted postmorbid IQ and negative symptoms, and indirectly predicted postmorbid social and occupational functioning via negative symptoms. Item level analysis indicated that better social and occupational outcomes occurred in a group with few negative symptoms. Conclusions : Premorbid functioning, postmorbid IQ and negative symptoms are related, yet the relationship between premorbid functioning and postmorbid functional outcomes appears to be mediated by postmorbid negative symptoms. [Copyright &y& Elsevier]

We studied the effects of escalating doses of recombinant human IL-1β in patients receiving high-dose chemotherapy and ABMT for metastatic breast cancer or malignant melanoma. Sixteen patients received IL-1β, 4 to 32 ng/kg/day administered subcutaneously for 7 days beginning 3 h after bone marrow infusion. Three patients at the highest dose level also received G-CSF following completion of IL-1β. All patients completed the 7 days of therapy. The majority of patients experienced chills and fever following one or more injections, and seven had severe pain at the injection site. There was one episode of hypotension and one episode of transient confusion at the highest dose level; other significant toxicity was not identified. Recovery of neutrophils to >0.5 × 109/l and platelet transfusion independence occurred at a median of 23 and 22 days, respectively, which was comparable to historical controls. The mean number of bone marrow colony-forming unit granulocyte–macrophage (CFU-GM) per 105 mononuclear cells on day +21 post-ABMT was more than twice that of control patients or patients receiving G-CSF or GM-CSF. A linear correlation was found between the dose of IL-1β and endogenous concentrations of several cytokines. These patients also displayed significantly higher concentrations of endogenous G-CSF compared to historical controls receiving GM-CSF. While IL-1β was moderately toxic and had no effect on recovery of peripheral blood counts after ABMT, the increased number of bone marrow CFU-GM suggests that the addition of G- or GM-CSF to a short course of IL-1β may accelerate hematologic recovery. [ABSTRACT FROM AUTHOR]

The intracellular signaling molecule cyclic-di-GMP (c-di-GMP) has been shown to influence surface-associated behaviors of Pseudomonas aeruginosa, including biofilm formation and swarming motility. Previously, we reported a role for the bifA gene in the inverse regulation of biofilm formation and swarming motility. The bifA gene encodes a c-di-GMP-degrading phosphodiesterase (PDE), and the Δ bifA mutant exhibits increased cellular pools of c-di-GMP, forms hyperbiofilms, and is unable to swarm. In this study, we isolated suppressors of the Δ bifA swarming defect. Strains with mutations in the pilY1 gene, but not in the pilin subunit pilA gene, show robust suppression of the swarming defect of the Δ bifA mutant, as well as its hyperbiofilm phenotype. Despite the ability of the pilY1 mutation to suppress all the c-di-GMP-related phenotypes, the global pools of c-di-GMP are not detectably altered in the Δ bifA Δ pilY1 mutant relative to the Δ bifA single mutant. We also show that enhanced expression of the pilY1 gene inhibits swarming motility, and we identify residues in the putative VWA domain of PilY1 that are important for this phenotype. Furthermore, swarming repression by PilY1 specifically requires the diguanylate cyclase (DGC) SadC, and epistasis analysis indicates that PilY1 functions upstream of SadC. Our data indicate that PilY1 participates in multiple surface behaviors of P. aeruginosa, and we propose that PilY1 may act via regulation of SadC DGC activity but independently of altering global c-di-GMP levels. [ABSTRACT FROM AUTHOR]