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Background In a previous open-label study of hydroxyurea therapy, the synthesis of fetal hemoglobin increased in most patients with sickle cell anemia, with only mild myelotoxicity. By inhibiting sickling, increased levels of fetal hemoglobin might decrease the frequency of painful crises. Methods In a double-blind, randomized clinical trial, we tested the efficacy of hydroxyurea in reducing the frequency of painful crises in adults with a history of three or more such crises per year. The trial was stopped after a mean follow-up of 21 months. Results Among 148 men and 151 women studied at 21 clinics, the 152 patients assigned to hydroxyurea treatment had lower annual rates of crises than the 147 patients given placebo (median, 2.5 vs. 4.5 crises per year, P

Chronic users of cannabis often report withdrawal symptoms after abstinence from use, but little is known about cannabis withdrawal in people with schizophrenia.Cannabis use patterns and withdrawal symptoms in adults with schizophrenia who had at least weekly cannabis use before attempting to quit without formal treatment were assessed with the Marijuana Quit Questionnaire (MJQQ), a 176-item, semi-structured questionnaire.120 participants, predominantly African-American (62.5%) and male (76.7%), met inclusion criteria. 20.1% reported that their first regular cannabis use (median age 15 years [range 8-48]) preceded their age at first psychotic symptoms (20 [4-50] years). Twenty (16.7%) participants met lifetime criteria for cannabis abuse; 98 (81.7%) met surrogate criteria for lifetime cannabis dependence. Withdrawal symptoms were reported by 113 (94.2%) participants, with 74.2% reporting ≥4 symptoms. The most frequently reported withdrawal symptoms were craving for cannabis (59.2%), feeling anxious (52.57%), feeling bored (47.5%), feeling sad or depressed (45.8%), feeling irritable or jumpy (45.0%), feeling restless (43.3%), and trouble failing asleep (33.3%). One hundred-and-four (92.0%) participants took some action to relieve at least one of their withdrawal symptoms during their index-quit attempt, including 26 (23.0%) participants who reported resuming cannabis use.Cannabis withdrawal is a clinically significant feature of cannabis use among people with schizophrenia, may serve as a negative reinforcer for relapse, and deserves greater attention in treatment and research. Clinical Trials registration NCT00679016.

article i nfo Background: Deficits in olfactory identification have been widely reported in patients with schizophrenia (SZ) and are associated with negative symptomatology. Adjunctive oxytocin delivered intranasally has been shown to improve some aspects of social cognition as well as positive and negative symptoms in patients with schizophrenia. Given the intranasal delivery route of oxytocin to olfactory pathways and that olfactory abnormalities are a potential endophenotype in SZ, we investigated the effect of intranasal oxytocin on olfac- tory identification as well as positive and negative symptoms in people with schizophrenia. Methods: Individuals with schizophrenia or schizoaffective disorder (n=28; 16 outpatients, 12 inpatients) were randomized to receive adjunctive intranasal oxytocin 20 IU BID or placebo for 3 weeks. Results: All 28 participants completed the clinical trial. Odor identification performance significantly im- proved on the University of Pennsylvania Smell Identification Test (UPSIT) total score and subscore for pleas- ant smells. UPSIT score (F=5.20, df=1,23, p=0.032) and subscore for pleasant smells (F=4.56, df=1,23, p=0.044), in patients treated with oxytocin were compared to placebo from baseline to endpoint. Global symptomatology as well as positive and negative symptoms were not improved by intranasal oxytocin. In fact, global symptoms, not positive or negative symptoms, improved in the placebo group. Secondary analysis shows that intranasal oxytocin improved negative symptoms in the small group of inpatients. Intranasal oxy- tocin was well tolerated during the three week trial. Conclusion: Adjunctive intranasal oxytocin may improve olfactory identification, particularly in items of pos- itive valence. Larger studies are needed to determine the effects of oxytocin on negative symptoms in SZ. (NCT00884897; http://www.clinicaltrials.gov). Published by Elsevier B.V.

Oral cannabinoids are taken for medicinal or recreational purposes, yet little is known about tolerance to their effects after high-dose extended exposure. The development of tolerance to effects of around-the-clock oral synthetic Δ9-tetrahydrocannabinol (THC) (20 mg every 3.5-6 h) was evaluated in 13 healthy male daily cannabis smokers residing on a secure research unit: 40 mg on Day 1; 100 mg on Days 2-4; 120 mg on Days 5-6. Systolic and diastolic blood pressure (BP), heart rate, and symptoms of subjective intoxication (100 mm visual-analogue scales, VAS) were assessed the morning of Day 1 (before any oral THC), and on Days 2, 4 and 6, every 30 min for 3 h after the first morning THC dose. Morning subjective intoxication ratings increased from Days 1 to 2, and then declined on Days 4 and 6. The morning THC dose increased intoxication ratings on Day 2, but had less effect on Days 4 and 6, a pattern consistent with tolerance. THC lowered BP and increased heart rate over the six days. Plasma THC and 11-OH-THC concentrations increased significantly over the first five days of dosing. Six days of around-the-clock, oral THC produced tolerance to subjective intoxication, but not to cardiovascular effects.

The current study examined the factor structure of the Brief Negative Symptom Scale (BNSS), a next-generation negative symptom rating instrument developed in response to the NIMH-sponsored Consensus Development Conference on Negative Symptoms. Participants included 146 individuals with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder. Principal axis factoring indicated two distinct factors explaining 68.7% of the variance. Similar to previous findings, the factors reflected motivation and pleasure and emotional expressivity. These findings provide further support for the construct validity of the BNSS, and for the existence of these two negative symptom factors.

The prevalence of cigarette smoking among people with schizophrenia is greater than that of the general population. Because smoking and use of other drugs covary, we examined illicit drug use in current smokers not trying to quit or reduce their tobacco use. We recruited outpatient participants who had a DSM-IV diagnosis of schizophrenia or schizoaffective disorder (schizophrenia, n=70) and a control group who had no Axis I psychiatric disorders (control, n=97). During a 2-3-hour session, participants completed demographic and research questionnaires, including the Drug Use Survey (DUS).Participants with schizophrenia were older than controls (p0.001) and smoked more cigarettes per day (p=0.01), but did not differ in degree of nicotine dependence. Ever using a drug was similar between the groups, except that significantly more participants with schizophrenia reported ever using hallucinogens (p0.001) and inhalants (p=0.001). For alcohol, cocaine, and marijuana, fewer participants with schizophrenia were current users, but more participants with schizophrenia were past users (ps0.0001). Heavy smokers from the general population continued to use illicit drugs throughout their lives, while schizophrenia participants had the highest period of illicit drug use in their 20s.These data suggest that illicit drug use tends to be high in heavy cigarette smokers, regardless of a schizophrenia diagnosis. However, while illicit drug use is high across the lifespan of heavy smokers in the general population, heavy smokers with schizophrenia use illicit drugs mostly in the first decade of their illness.

Up to 50-90% of persons with schizophrenia smoke cigarettes. Limited data and theories suggest persons with schizophrenia may smoke for different reasons than persons without schizophrenia, making smoking cessation interventions particularly challenging in this population. Although health consequences of smoking are widely known, less information is available regarding characteristics of different amounts of smoking exposure in this population. This study was performed to investigate differences between heavy (≥ 1 pack per day) and non-heavy (

The purpose of this study was to analyze angiographic findings, clinical course, and follow-up data on 1,752 patients who underwent protocol cardiac catheterization 18 to 48 hours after enrollment in the Thrombolysis in Myocardial Infarction (TIMI) II pilot and randomized trial: 244 patients (14.0%) had or = 60% in diameter with TIMI grade 2 or 3 flow, and 259 patients (15%) had TIMI grade 0 or 1 flow (total occlusion). Patients with 55% (p or = 60% and TIMI grade 2 or 3 flow (p = 0.05) and 7.0% for patients with total occlusion (p = 0.004). Patients with stenosis < 60% in the infarct-related artery 18 to 48 hours after thrombolytic therapy have a good prognosis. Infarct artery status predicts predischarge ejection fraction and 1-year mortality.

In many chronic diseases, therapy aims to prevent or reduce the frequency of episodes of a disease manifestation, for example cardiac ischaemic episodes or epileptic seizures. Entry criteria for clinical trials typically include a minimum number of episodes within a baseline period, and regression to the mean should be anticipated. The distribution of the number of episodes at follow-up, the statistical power for treatment comparisons, and the difficulty of recruitment will depend on the entry criterion chosen. A gamma-Poisson mixture model is employed to describe the regression to the mean when the entry criterion and outcome measure are counts of discrete events. Sample size formulae which take account of the entry criterion are derived for comparison of mean number of events at follow-up and the proportion of patients with zero events at follow-up. Application of these formulae to screening data from the Aymptomatic Cardiac Ischemia Pilot (ACIP) Study is presented as an example.

The aim of this study is to examine the effects of treatment with varenicline, a partial agonist at the α4β2 and full agonist at the α7 nicotine acetylcholine receptor, on cognitive impairments in people with schizophrenia. In all, 120 clinically stable people with schizophrenia participated in randomized, double-blind, placebo-controlled 8-week trial. Antipsychotic and concomitant medication doses remained fixed throughout the study. Varenicline was titrated up to 1 mg twice daily for weeks 2–8. Neuropsychological, clinical, and safety assessments were administered at baseline and weeks 1, 2, 4, and 8. In the primary analyses of neurocognitive differences at week 8, no varenicline–placebo differences were significant. In secondary longitudinal analyses, varenicline improved compared with placebo on the Digital Symbol Substitution Test (p=0.013) and the Wisconsin Card Sorting Test non-perseverative errors (p=0.043). Some treatment effects were different between smokers and non-smokers. In smokers, Continuous Performance Test hit reaction time (p=0.008) and Stroop Interference (p=0.004) were reduced for varenicline compared with placebo, while there were no treatment differences in non-smokers. No significant treatment main effects or interactions were noted for total scores on the Positive and Negative Syndrome Scale or the Scale for the Assessment for Negative Symptoms. Our findings suggest beneficial effects of adjunctive varenicline treatment with antipsychotics for some cognitive impairments in people with schizophrenia. In some cases, effects of treatment varied between smokers and non-smokers. Further study is required to assess the functional significance of these changes.

Cannabinoid CB1 receptor antagonists have potential therapeutic benefits, but antagonist-elicited cannabis withdrawal has not been reported in humans. Ten male daily cannabis smokers received 8 days of increasingly frequent 20-mg oral Δ⁹-tetrahydrocannabinol (THC) dosages (40-120 mg/d) around-the-clock to standardize cannabis dependence while residing on a closed research unit. On the ninth day, double-blind placebo or 20- (suggested therapeutic dose) or 40-mg oral rimonabant, a CB1-cannabinoid receptor antagonist, was administered. Cannabis withdrawal signs and symptoms were assessed before and for 23.5 hours after rimonabant. Rimonabant, THC, and 11-hydroxy-THC plasma concentrations were quantified by mass spectrometry. The first 6 subjects received 20-mg rimonabant (1 placebo); the remaining 4 subjects received 40-mg rimonabant (1 placebo). Fourteen subjects enrolled; 10 completed before premature termination because of withdrawal of rimonabant from clinical development. Three of 5 subjects in the 20-mg group, 1 of 3 in the 40-mg group, and none of 2 in the placebo group met the prespecified withdrawal criterion of 150% increase or higher in at least 3 visual analog scales for cannabis withdrawal symptoms within 3 hours of rimonabant dosing. There were no significant associations between visual analog scale, heart rate, or blood pressure changes and peak rimonabant plasma concentration, area-under-the-rimonabant-concentration-by-time curve (0-8 hours), or peak rimonabant/THC or rimonabant/(THC + 11-hydroxy-THC) plasma concentration ratios. In summary, prespecified criteria for antagonist-elicited cannabis withdrawal were not observed at the 20- or 40-mg rimonabant doses. These data do not preclude antagonist-elicited withdrawal at higher rimonabant doses.

The purpose of this study was to examine the cognitive and clinical correlates of the MATRICS Consensus Cognitive Battery (MCCB) which was originally developed to be an endpoint for cognitive enhancement clinical trials. In a sample of 117 people with schizophrenia and 77 healthy control participants we found the following: a) the MCCB was highly sensitive to the type and level of impairment typically observed in schizophrenia, b) the MCCB composite score was highly correlated with WASI Estimated Full Scale IQ score, c) that the MCCB domain scores were generally moderately-highly intercorrelated, d) that MCCB performance was minimally related to clinical symptom type and severity, and e) the MCCB is sensitive to employment status with better performance in employed vs. unemployed patients. These data support the validity of the MCCB as a sensitive measure of cognitive impairment in schizophrenia and suggest that MCCB performance is relevant for functional outcome. The data also suggest that the MCCB domain scores may offer limited resolution on discrete cognitive functions.

SummaryMethods and results from the quality assurance program of the Atherosclerosis Risk in Communities (ARIC) Study regarding hemostasis variables are presented, following up previous reports in this journal on standardized procedures for blood collection and processing (7) and an organized plan for the performance of those procedures (8). Efforts were made to control for and assess all sources of variability, from venipuncture to laboratory analysis, including also local field center processing and sample shipping. The quality control program included (a) a standardized protocol for blood collection and processing; (b) training, certification, and annual recertification of field center personnel for blood collection and processing; (c) monitoring of fasting times, phlebotomy times, processing times, and shipping problems; (d) hemostatic laboratory internal quality control; (e) a replicate blood sample program; (f) an intraindividual variability study; and (g) continual monitoring of quality control and study participants’ data. This paper focused on items (c), (d), and (e). Measures of Variation, generally Standard deviations and coefficients of Variation, are estimated for replicate blood sampling and internal quality control data, for activated partial thromboplastin time, fibrinogen, factor VII and VIII activity, von Willebrand factor, antithrombin-III, and protein C. The results demonstrate that it is possible to reliably measure these hemostatic variables in a large multicenter study.

Weight gain is a major adverse effect of several second-generation antipsychotic medications. Rimonabant is a cannabinoid-1 receptor antagonist that promotes weight loss in the general population. We conducted a 16-week, double-blind, placebo-controlled study of rimonabant (20 mg/d) in people with schizophrenia or schizoaffective disorder, based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria, who were clinically stable on second-generation antipsychotics. Participants had a body mass index of 27 kg/m2 or higher with hyperlipidemia or body mass index of 30 kg/m2 or higher, and no current substance abuse/dependence (except nicotine), more than weekly cannabis use, or recent depressive symptoms/suicidality. An exercise and dietary counseling group was offered weekly. Target enrollment was 60; the trial was terminated early because of withdrawal of rimonabant from the European market. Fifteen participants were randomized (7 rimonabant, 8 placebo); 5 completed in each group. Rimonabant was associated with a greater reduction in Brief Psychiatric Rating Scale total score versus placebo (mean ± SE difference, −1.9 ± 0.8, P = 0.02), driven by differences in the Brief Psychiatric Rating Scale anxiety/depression (−1.4 ± 0.35, P = 0.0004) and hostility (−0.7 ± 0.3, P = 0.02) factors. Group differences were not significant for the Calgary Depression Scale total score (P = 0.24), Scale for the Assessment of Negative Symptoms total score (P = 0.13), weight, blood pressure, or fasting lipids or glucose. Rimonabant was well tolerated with no significant adverse events. No significant weight loss, metabolic effects, or adverse psychiatric effects were associated with the cannabinoid-1 receptor antagonist rimonabant in this small sample of people with schizophrenia. The endocannabinoid system remains a promising target for pharmacotherapy of schizophrenia and obesity.

People with schizophrenia have a higher prevalence of obesity than the general population. Many people with this illness struggle with weight gain, due, in part, to medications and other factors that act as obstacles to exercise and healthy eating. Several studies have shown the benefits of behavioral weight loss programs targeting eating and/or exercise in people with schizophrenia. Fewer studies have used competitive events as a goal for an exercise program. The current study tested the feasibility of preparing, using an exercise program, for a 5-kilometer (5K) event in people with schizophrenia. The exercise program was a 10-week training program consisting of three supervised walking/jogging sessions per week and a weekly educational meeting on healthy behaviors. Almost 65% (11/17) of the subjects participated in all of the training sessions, and 82% (14/17) participated in the 5K event. Participants did not gain a significant amount of weight during the exercise program (median weight change = 0.7 kg; 25th percentile 0.5, 75th percentile 3.9, p = .10). This study suggests that using an achievable goal, such as a 5K event, promotes adherence to an exercise program and is feasible in a population of people with chronic schizophrenia.

Objective: We examined perceived consequences/benefits of cigarette smoking and motivation for quitting in nontreatment-seekingsmokerswhohadschizophreniaorschizoaffective disorder (N 5 100) or had no Axis I psychiatric disorder (normals, N 5 100). Methods: Participants completed questionnaires and provided a breath carbon monoxide (CO) sample 10–15 minutes after smoking 1 preferredbrand cigarette. Primary assessments included the Smoking Consequences Questionnaire-Adult, the Reasons for Quitting Scale, and the Stages of Change. Results: There were no differences between the schizophrenia and control group in mean age of smoking onset (16.2 5.4 vs 15.6 5.5 y, P 5 .44), number of cigarettes daily (17.9 11.6 vs 17.0 7.9, P 50.51),orinbreathCO(28.0 14.5vs22.9 8.0ppm,P 5 .61).Comparedwithnormals,peoplewithschizophreniareportgreater stimulation/state enhancement (P

The levels of kynurenic acid (KYNA), an astrocyte-derived metabolite of the branched kynurenine pathway (KP) of tryptophan degradation and antagonist of α7 nicotinic acetylcholine and N-methyl-D-aspartate receptors, are elevated in the prefrontal cortex (PFC) of individuals with schizophrenia (SZ). Because endogenous KYNA modulates extracellular glutamate and acetylcholine levels in the PFC, these increases may be pathophysiologically significant. Using brain tissue from SZ patients and matched controls, we now measured the activity of several KP enzymes (kynurenine 3-monooxygenase [KMO], kynureninase, 3-hydroxyanthranilic acid dioxygenase [3-HAO], quinolinic acid phosphoribosyltransferase [QPRT], and kynurenine aminotransferase II [KAT II]) in the PFC, ie, Brodmann areas (BA) 9 and 10. Compared with controls, the activities of KMO (in BA 9 and 10) and 3-HAO (in BA 9) were significantly reduced in SZ, though there were no significant differences between patients and controls in kynureninase, QPRT, and KAT II. In the same samples, we also confirmed the increase in the tissue levels of KYNA in SZ. As examined in rats treated chronically with the antipsychotic drug risperidone, the observed biochemical changes were not secondary to medication. A persistent reduction in KMO activity may have a particular bearing on pathology because it may signify a shift of KP metabolism toward enhanced KYNA synthesis. The present results further support the hypothesis that the normalization of cortical KP metabolism may constitute an effective new treatment strategy in SZ.

We examined tobacco craving and dependence in current smokers (18–65 years) with schizophrenia (N=100) and those without a psychiatric disorder (normal controls, N=100). During the 2–3 hour visit participants completed demographic and smoking related questionnaires and provided a breath CO sample. The Tobacco Craving Questionnaire-Short Form (TCQ-SF) was administered. Immediately after smoking one cigarette, no difference in TCQ-SF total score was noted (46.7 ± 19.5 schizophrenia, 42.8 ± 18.2 controls, p=0.15); however, after 15 min TCQ-SF total score was significantly higher in people with schizophrenia (50.0 ± 19.6) than in controls (38.6 ± 19.4) (p =0.0014). TCQ-SF factors of emotionality (p=0.0015), compulsivity (p=0.0003) and purposefulness (p=0.0174) were significantly greater in the schizophrenia group than the control group. FTND scores (5.5 ± 2.0 vs 5.3 ± 2.0, p=0.62) number of cigarettes smoked daily (17.9 ± 11.6 vs. 17.0 ± 7.9), expired breath CO (28.0 ± 14.5 ppm vs. 22.0 ± 8.0 ppm) and age at smoking initiation (16.2 ± 5.4 vs. 15.6 ± 5.5 years, p=0.44) did not differ in the schizophrenia and control groups respectively. In conclusion, tobacco craving as measured by the TCQ-SF was significantly greater in people with schizophrenia than controls 15 min post-smoking, despite similar scores in dependence and similar smoking histories and current smoking patterns.

Review of the 1-year prevalence of screening for osteoporosis and of osteoporosis or idiopathic fracture in Maryland Medicaid administrative records found that screening rates did not differ among women in the control population, women with psychosis, and women with major mood disorders, but were reduced compared to controls in women with substance use disorder, with or without psychosis. Prevalence of osteoporosis was increased compared to controls in women with major mood disorders or women over 55 dually diagnosed with psychosis and substance use disorder. Osteoporosis is a major public health concern. Substance abuse and psychosis may be risk factors, however, frequency of screening and disease risk in women with psychotic disorders and substance use disorder (SUD) remains unknown. This study examined rates (FY 2005) of osteoporosis screening and disease risk in Medicaid enrolled women aged 50 to 64 (N = 18,953). Four diagnostic groups were characterized: (1) psychosis, (2) SUD, (3) major mood disorder, and (4) controls. The interaction of psychosis and SUD on screening and disease prevalence of osteoporosis was tested. The prevalence of osteoporosis across the entire population was 6.7%. Four percent of those without an osteoporosis diagnosis received osteoporosis screening with no notable differences between psychosis and controls. Those with SUD, however, had a significant reduction in screening compared to controls (OR = 0.61, 95% CI = 0.40–0.91, p = 0.016). Women with a major mood disorder were more likely to have osteoporosis in their administrative record (OR = 1.32, 95% CI = 1.03–1.70, p = 0.028) compared to controls. Those who were dually diagnosed (SUD and psychosis) in the oldest ages (55–64 years) had a markedly higher prevalence of osteoporosis compared to controls (OR = 6.4 CI = 1.51–27.6, p = 0.012), whereas this interaction (SUD and psychosis) was not significant in the entire population over age 49. Osteoporosis screening in the Medicaid population is significantly lower for women with SUD, after adjusting for age, race, and Medicaid enrollment category. The prevalence of osteoporosis appears markedly elevated in those with major mood disorders and those over age 55 dually diagnosed with schizophrenia and SUD.

Background In a previous pilot study, MK-0777—a γ-aminobutyric acid (GABA) A α2/α3 partial agonist—was reported to improve delayed memory and cognitive measures of prefrontal cortical function in people with schizophrenia. The current study was designed to further examine the efficacy and safety of MK-0777 for the treatment of cognitive impairments in schizophrenia. Methods Sixty people with DSM-IV schizophrenia entered a 4-week, multi-center, double-blind, placebo-controlled, randomized clinical trial. Participants were randomized to: MK-0777 3 mg b.i.d. ( n = 18); MK-0777 8 mg b.i.d. ( n = 21); or placebo ( n = 21). Participants were clinically stable. The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery, AX-Continuous Performance Test, and N-Back were used to assess cognition. The University of California San Diego (UCSD) Performance Based Skills Assessment-2 and the Schizophrenia Cognition Rating Scale assessed functional capacity and served as functional outcome coprimary measures. Results There were no significant group differences on the primary outcome measure, the MATRICS Consensus Cognitive Battery composite score. Secondary analyses suggested that participants randomized to placebo performed significantly better on visual memory and reasoning/problem-solving tests than participants assigned to either MK-0777 dose. There were no significant group differences on the AX-Continuous Performance Test or N-Back d prime scores or UCSD Performance-Based Skills Assessment–2 and Schizophrenia Cognition Rating Scale total scores. In general, MK-0777 was well-tolerated with minimal side effects. Conclusions The study results suggest that MK-0777 has little benefit for cognitive impairments in people with schizophrenia. The GABA A receptor remains a promising target, but a more potent partial agonist with greater intrinsic activity at the GABA A α2 site might be needed for cognitive enhancement in schizophrenia.

Much epidemiologic research is based on estimation of an association between a putative risk factor and a health outcome--for example, plasma concentration of lipoproteins and ischemic heart disease. Since the repeatability of a risk factor measurement determines, in part, the ability to ascertain its association in populations, the Atherosclerosis Risk in Communities (ARIC) Intraindividual Variability Study was conducted to estimate various components of variation in analyte data and to estimate the repeatability of these measurements. A total of 40 subjects (17 males and 23 females) from Forsyth County, North Carolina, Minneapolis, Minnesota, Jackson, Mississippi, and Washington County, Maryland, were studied in 1988. Fasting blood was collected three times from each subject, with a 1- to 2-week interval between each visit. The contributions of between-person variability, within-person variability, and processing and assay variability were estimated. From these components, the reliability coefficient, R, the correlation between measures made at repeat visits, was estimated. R was above 0.85 for total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol, triglycerides, and lipoprotein(a). Low repeatability was obtained for apolipoprotein A-I (R = 0.60). High density lipoprotein subfractions 2 and 3 were intermediate in repeatability. Reliability coefficients from the ARIC Intraindividual Variability Study are generally higher than those found in other studies, and this is related to relative variability in populations studied, to the time between measurements, and to differences in laboratory variability. Only for apolipoprotein A-I would the findings strongly suggest the need to adjust for measurement variability in estimation using one of these analytes as an independent variable.

Recent epidemiologic studies found that there is a strong association of hemostatic factors with ischemic heart disease. The Atherosclerosis Risk in Communities (ARIC) Intraindividual Variability (IIV) Study was conducted to estimate the various components of variation in hemostasis factors measured in the ARIC Study and to estimate the measures of repeatability of these factors. A total of 39 subjects (16 men, 23 women) were studied. Each had blood collected three times, with a 1- to 2-week interval between each visit. The contributions of between-person variability, within-person (biologic) variability, and processing and assay variability were estimated. Then the reliability coefficient R was estimated as the proportion of total variance accounted for by between-person variance. The reliability coefficient can be interpreted as the correlation between measures made at repeat visits. Among the various analytes, the reliability coefficients were quite high for activated partial thromboplastin time and plasma factor VIII (R = 0. 92, 0.86, respectively). Low repeatability was obtained for antithrombin III activity and protein C (R = 0.42, 0.56, respectively). The lack of repeatability for these variables derives mostly from the processing (field center and laboratory) variation. Other analytes-fibrinogen, plasma factor VII, and von Willebrand factor— were intermediate in repeatability. In comparing the analyte-specific high-level to low-level groups, no substantial difference of within-person plus method coefficient of variation between the two groups was found for any analyte except for factor VIII, whereas the corresponding variance components for most analytes were higher for the higher analyte level. Reliability coefficients from this ARIC IIV Study are generally higher than those found in other studies, and this is related to the relative variations in populations studied and to the time between measurements.

Mechanisms of death among patients who died within 18 h of enrollment in the Thrombolysis in Myocardial Infarction Phase II (TIMI II) study were analyzed. Of 3,339 patients enrolled, 32 died within the 1st 4 h and 31 died within the subsequent 14 h. Thirteen of the 63 patients had shock at enrollment; 22 had advanced hemodynamic compromise without shock and 28 initially had minimal to no compromise.Prior infarction was present in 16 patients (25%). Pump failure was responsible for 39 early deaths (62%), ventricular rupture for 10 (16%), arrhythmia for 8 (13%) and complications of therapy for 6 (10%). Nine of 720 patients randomized to immediate intravenous beta-adrenergic blocking agent therapy had an early death compared with 6 of 714 assigned to deferred beta-blocker therapy.Thus, mortality is highest in the early hours after myocardial infarction, even in patients treated with thrombolytic therapy and is most frequently due to pump failure. These results imply that efforts to reduce mortality during this critical time period should be directed at prevention, limitation or palliation of early pump failure.

Objectives Galantamine is an acetylcholinesterase inhibitor and an allosteric modulator of the alpha4beta2 and alpha7 nicotinic receptors. There are several case reports describing the potential benefits of galantamine for negative symptoms associated with schizophrenia. This secondary analysis describes the effects of galantamine on psychopathology in people with schizophrenia. Methods Subjects with clinically stable chronic schizophrenia were randomized to adjunctive galantamine (24 mg/d) or placebo in a 12-week double-blind trial. Symptomatology was assessed with the Brief Psychiatric Rating Scale (BPRS) and the Clinical Global Impression Scale. The Scale for the Assessment of Negative Symptoms (SANS) was used to measure negative symptoms. Results Eighty-six patients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis of schizophrenia or schizoaffective disorder taking a stable dose of antipsychotic medications were randomized to adjunctive treatment with study drug (galantamine, n = 42; placebo, n = 44); 73 subjects completed the study (galantamine, n = 35; placebo, n = 38). No significant differences were found on BPRS total score (P = 0.585) or BPRS subfactor scores. Scale for the Assessment of Negative Symptoms total scores also did not decrease significantly (P = 0.106) in either group; however, galantamine treatment was associated with a greater benefit in the SANS subfactor, alogia (P = 0.007). Conclusions The lack of robust significant effects of galantamine on negative, and other symptom domains, may be due to the relatively low baseline level of these symptoms in the tested population. Galantamine may have some benefit on certain negative symptoms, particularly alogia. Studies specifically designed to address the issue of the efficacy of galantamine for negative symptoms are needed to confirm this observation.

Studies have found that motion perception is impaired in patients with schizophrenia and that higher motion perception thresholds are significantly correlated with poor eye tracking or smooth pursuit eye movement (SPEM) (1-4). These findings are generally interpreted as evidence of a motion-processing deficit causing the SPEM abnormality in schizophrenia. Many studies (3,5-10), including those from our own (11), have shown abnormal smooth pursuit onset in schizophrenia. Because response to initial target motion is a response to retinal motion before eye movement feedback occurs (12-14), abnormal initiation response suggests a motion perception impairment. However, this conflicts with studies that report normal or even faster onset latencies as well as accurate saccades and SPEMs in response to initial target motion in schizophrenia patients (10,14-18). Using unexpected target changes during smooth pursuit, we found that patients made more accurate response to unexpected target direction changes than healthy subjects, suggesting unimpaired motion processing during SPEM in schizophrenia patients (19). One possible explanation for the inconsistent findings on initiation responses could be the role of anticipation. We recently examined the effect of anticipation on pursuit initiation and found that when anticipation of pursuit onset was removed, schizophrenia patients and healthy subjects showed similar pursuit initiation; when anticipation was introduced, schizophrenia patients showed impaired pursuit onset (18). Based on these data, we hypothesize that motion processing per se is unimpaired and not the cause of eye-tracking abnormality observed in schizophrenia. If true, then how does one explain the findings of impaired speed discrimination in schizophrenia patients? Eye movements are known to closely interact with motion perception (20,21). A critical methodological weakness of previous motion perception studies in schizophrenia was that no attempts were made to monitor eye movements. One cannot rule out the possibility that the observed motion perception problem in schizophrenia may be a consequence rather than the source of the patients’ known SPEM difficulty. Smooth pursuit eye movements occur frequently in motion perception tasks because humans have difficulty holding their eyes still when presented with moving images (22). Smooth pursuit eye movement is initiated in response to retinal motion, a moving image across the retina. The motor command to move the eye is considered a source of extraretinal motion information (21,23). The extraretinal motion signal is critical for normal motion perception (20,21). Data suggest that retinal motion and reafferent stimuli, i.e., the motion of the target image resulting from the eye movement, interact with the motor command to form an accurate motion perception (24,25). Traditional speed discrimination studies use motion of objects that are presented for a duration of 200 msec or longer, which is sufficient time to initiate SPEM and to generate a motor command that can be incorporated into the motion perception. Schizophrenia patients have specific problems in processing extraretinal motion information (26-28). Their poor motion perception could be derived from deficits in extraretinal rather than retinal motion processing, if the normal process of integrating the oculomotor command into motion perception (29) is impaired. This hypothesis can be studied by simultaneously examining motion perception and eye movements. A behavioral study that pinpoints whether the primary deficit is motion perception or SPEM has important implications for understanding the pathophysiology of schizophrenia, since these two visual functions are distinct in many brain areas. Motion perception involves the early visual pathway from lateral geniculate nucleus to primary visual cortex to middle temporal (MT) cortex, while SPEM pathway involves signals from this early visual pathway and also medio-superior temporal (MST), frontal, parietal, and cerebellar mechanisms (30-32). In this study, we hypothesized that speed discrimination deficit in schizophrenia patients described in previous studies may be affected by their eye-tracking difficulties. This hypothesis was tested in two contrasting experiments. In experiment 1, motion stimulus was presented for 150 msec duration, so the stimulus ended before the SPEM initiation, which generally occurs within 150 msec to 180 msec of target motion onset. Thus, the 150 msec condition should limit the influence of feedback information from eye movement during motion perception testing by minimizing the induction of eye movements (20). In consequence, we expected speed discrimination thresholds would not differ between schizophrenia patients and control subjects. In experiment 2, the motion stimulus was presented for 300 msec, intended to replicate the previous finding of speed discrimination deficit in schizophrenia patients. Eye movements were monitored in both experiments to determine whether or not individuals maintained fixation during motion perception testing and if they did not, to what extent eye movements contributed to the speed discrimination thresholds. A third experiment was performed to examine regular smooth pursuit and to determine whether subjects’ eye movements during speed discrimination are related to their capacity to pursue a moving target when they were instructed to do so.

Context The auditory sensory gating deficit has been considered a leading endophenotype in schizophrenia. However, the commonly used index of sensory gating, P50, has low heritability in families of people with schizophrenia, raising questions about its utility in genetic studies. We hypothesized that the sensory gating deficit may occur in a specific neuronal oscillatory frequency that reflects the underlying biological process of sensory gating. Frequency-specific sensory gating may be less complex than the P50 response, and therefore closer to the direct genetic effects, and thus a more valid endophenotype. Objectives To compare the gating of frequency-specific oscillatory responses with the gating of P50 and to compare their heritabilities. Design We explored single trial–based oscillatory gating responses in people with schizophrenia, their relatives, and control participants from the community. Setting Outpatient clinics. Participants Persons with schizophrenia (n = 102), their first-degree relatives (n = 74), and control participants from the community (n = 70). Main Outcome Measures Gating of frequency-specific oscillatory responses, gating of the P50 wave, and their heritability estimates. Results Gating of the θ-α–band responses of the control participants were significantly different from those with schizophrenia ( P P = .04 to .009). The heritability of θ-α–band gating was estimated to be between 0.49 and 0.83 and was at least 4-fold higher than the P50 heritability estimate. Conclusions Gating of the θ-α–frequency oscillatory signal in the paired-click paradigm is more strongly associated with schizophrenia and has significantly higher heritability compared with the traditional P50 gating. This measure may be better suited for genetic studies of the gating deficit in schizophrenia.

Impairments of executive functioning, such as set-shifting ability, are seen as core deficits of schizophrenia and are of interest as candidate intermediate phenotype markers. The Intradimensional/Extradimensional (ID/ED) shift task offers a differentiated assessment of shifting from previously reinforced stimuli as well as shifting from previously reinforced features and has proven to be sensitive to the impairment seen in patients with schizophrenia.We examined ID/ED performance in 147 patients with schizophrenia, 131 of their healthy siblings, and 303 healthy control subjects. Participants were recruited from local and national sources as volunteers for the Clinical Brain Disorders Branch/National Institute of Mental Health "sibling study".Nearly all control subjects (87%) finished the task successfully, as did 80% of siblings. In contrast only 54% of patients with schizophrenia were able to complete the task. Despite the apparent similarity of performance across the sibling and healthy comparison group, the two groups differed significantly in terms of the number of stages until failure. This difference, however, was not present at any particular stage or any other measure of performance.Patients demonstrated robust ID/ED deficits. However, their siblings were minimally impaired, and this impairment did not seem to run in families. These results suggest that impairments on attentional set shifting assessed by ID/ED task are strongly associated with clinical illness, but these impairments are not a promising intermediate phenotype.

Abstract The concepts of partial recovery and remission have become increasingly important for the evaluation of the effectiveness of schizophrenia therapeutics. The relationship of baseline symptoms and changes in symptoms to remission of psychosis was evaluated. Fifty-six outpatients with residual schizophrenia completed a double-blind trial of olanzapine versus haloperidol and were then enrolled into a one-year open-label trial of olanzapine. Out of these 56 subjects, 13 (23%) met remission criteria at the beginning of the open-label treatment and were excluded. During the one-year study, 7/43 (16%) subjects met remission criteria. These subjects had significantly lower baseline ratings for tardive dyskinesia (TD) than subjects who did not achieve remission (1.8 ± 1.5 vs. 4.2 ± 4.6, P = 0.03). As expected, remitted subjects had significantly greater improvements in Brief Psychiatric Rating Scale total scores, positive subscale scores and scale for the Assessment of Negative Symptoms total scores. Remitted subjects also experienced a significantly greater improvement in depressive symptoms ( P = 0.001), activation ( P = 0.005), and Clinical Global Impressions scores ( P

The second-generation antipsychotics are effective for treating psychotic disorders and incur fewer motor side effects than are commonly experienced with the use of first-generation antipsychotics. However, their use is commonly associated with weight gain and metabolic disturbances. This study examined weight and metabolic changes with two widely used antipsychotics, risperidone and olanzapine; addressing the issue of early monitoring for metabolic side effects.This 8-week double blind randomized trial included patients with schizophrenia or schizoaffective disorder (N = 377) randomly assigned to risperidone (2-6 mg/day) or olanzapine (5-20 mg/day). Weight, BMI, HbA1C, total cholesterol (TC), LDL-C, HDL-C and triglycerides (TG) were monitored.Mean BMI increases were higher in the olanzapine group as compared to risperidone (1.3 kg/m(2)(SD = 0.13) vs. 0.7 kg/m(2) (SD = 0.13)(p0.001). Increases in mean TC (13.5 mg/dl (SD 2.4), LDL-C (11.0 mg/dl (SD 2.2)) and TG (14.8 mg/dl (SD = 7.6)) occurred in the olanzapine group while significant changes in TC (-3.9 mg/dl (SD = 2.5)) and TG (-32.8 mg/dl (SD = 7.8)) were noted in the risperidone group. Men (not women) on olanzapine had higher than expected increases in lipids given the amount of weight gain. Baseline values and prior therapy did not contribute to the significant differences, however BMI increases (p = 0.0002) were linked to study discontinuation in both drug groups.The fact that significant metabolic changes occurred (both positive and negative) in eight weeks is important to clinical care. Monitoring for metabolic changes may be important within the first eight weeks of treatment, as changes can be determined very early in antipsychotic treatment.

Cigarette smoking is in schizophrenia is prevalent and may be due to self-medicating attempts to improve cognitive deficits related to α7 and α4β2 nicotinic receptor dysregulation. Galantamine is an acetylcholinesterase inhibitor that acts as a positive allosteric modulator of nicotine acetylcholine receptors including both the α4β2 and α7 subunits. In a double-blind randomized clinical trial galantamine was compared to placebo for its effects on cognitive functioning in people with schizophrenia. This manuscript reports findings for galantamine's effect on smoking behavior in people from this 12-week trial who were smokers (18 galantamine, 25 placebo). Expired CO was measured every 2 weeks and the Fagerstrom Test for Nicotine Dependence (FTND) was administered at baseline and endpoint. Expired CO measures in galantamine subjects were 23.0±9.7 ppm and 21.1±10.3 ppm at baseline and Week 12, respectively, compared to 20.1±8.5 ppm and 21.0±10.3 ppm at baseline and Week 12 in placebo subjects. The mean tau-b correlation between expired CO level and visit was −0.05±0.41 in the galantamine group and 0.13±0.42 in the placebo group (F =0.73, df=1,38, p=0.40), suggesting that there were no trends toward increased or decreased smoking in either group. Mean FTND scores in the galantamine group were 4.9±2.5 at baseline and 5.2±2.2 at Week 12, compared to 4.1±2.6 at baseline and 3.7±2.6 at Week 12 in the placebo group (Mantel–Haenszel χ 2 =5.53, df=1,p=0.019), for an effect size of 0.4. These results suggest that galantamine has no effect on cigarette smoking and that during galantamine treatment nicotine dependency scores worsen. © 2008 Elsevier B.V. All rights reserved.

This study compares patient characteristics and treatment response between inpatients treated with clozapine in a research setting as compared to those initiated on clozapine during routine inpatient treatment.Subjects on clozapine, in clinical trials, were compared with clozapine inpatients receiving routine clinical care.At baseline, patients in routine clinical practice had more negative symptoms (P0.001), activation (P0.001) and greater total Brief Psychiatric Rating Scale (BPRS) scores (P = 0.022) than those in the research setting. Routine clinical practice subjects had larger decreases in BPRS total scores (P = 0.042) and positive item scores (P = 0.0005) compared to research subjects. Response to clozapine was observed in 15/85 (18%) research subjects as compared to 60/223 (27%) patients in routine care (P = 0.09).Patients treated in routine clinical practice have more severe baseline symptoms, but experience significantly greater improvements in psychiatric symptoms.

Use of placebo-controlled trials in medical and psychiatric research has been controversial, although a consensus is emerging about conditions under which placebo-controlled trials are ethical. In schizophrenia research, the paradigm of slow onset of antipsychotic effects has led to a model in which placebo-controlled trials of 6-8 weeks duration have been used to demonstrate efficacy. Recent evidence that the largest symptom reductions are typically seen in the first weeks of treatment suggests that shorter placebo-controlled studies to demonstrate antipsychotic efficacy are possible. In a pilot study of the feasibility of shortening placebo-controlled studies, we reanalyzed data from placebo-controlled registry trials of olanzapine and risperidone and found that trials as short as 4 weeks could have similar power to longer term 6-8 week studies, given the estimated time course of treatment effects. Although fuller evaluation is required, the results suggest future antipsychotic trials could be shortened from 6-8 weeks to 3-4 weeks with a relatively low increase in sample size requirements. Shortening placebo-controlled trials would reduce patient burden and ethical objections to prolonged administration of placebo and reduce potential bias due to high dropout rates in longer clinical trials.

Background To utilize fully a schizophrenia endophenotype in gene search and subsequent neurobiological studies, it is critical that the precise underlying physiologic deficit is identified. Abnormality in smooth pursuit eye movements is one of the endophenotypes of schizophrenia. The precise nature of the abnormality is unknown. Previous work has shown a reduced predictive pursuit response to a briefly masked (i.e., invisible) moving object in schizophrenia. However, the overt awareness of target removal can confound the measurement. Methods This study employed a novel method that covertly stabilized the moving target image onto the fovea. The foveal stabilization was implemented after the target on a monitor had oscillated at least for one cycle and near the change of direction when the eye velocity momentarily reached zero. Thus, the subsequent pursuit eye movements were completely predictive and internally driven. Eye velocity during this foveally stabilized smooth pursuit was compared among schizophrenia patients (n = 45), their unaffected first-degree relatives (n = 42), and healthy comparison subjects (n = 22). Results Schizophrenia patients and their unaffected relatives performed similarly and both had substantially reduced predictive pursuit acceleration and velocity under the foveally stabilized condition. Conclusions These findings show that inability to maintain internal representation of the target motion or integration of such information into a predictive response may be the specific brain deficit indexed by the smooth pursuit endophenotype in schizophrenia. Similar performance between patients and unaffected relatives suggests that the refined predictive pursuit measure may index a less complex genetic origin of the eye-tracking deficits in schizophrenia families.

Background. It is well known that individuals with schizophrenia have dopaminergic abnormalities as well as memory-related difficulties, both of which are associated with impulsive decision making. We used a delay discounting measure to test the degree to which patients make future-oriented decisions. Methods. 42 patients with schizophrenia and 29 healthy participants completed a delay discounting measure along with tests of cognitive function and, in patients, symptom ratings. Results. Patients discounted more steeply than did comparison participants. Discounting among patients related to memory capacity and tended to relate inversely to negative symptoms. Conclusions. The impulsive decision making evidenced by patients suggests that they may be prone to choosing immediate over long-term rewards, even when their interests are better served by choosing the latter. Improving cognitive function may enhance their ability to make future-oriented decisions.

This study reports evidence that individuals with schizophrenia (SC) demonstrate intact attentional selection for visual working memory (WM) storage. A group of 62 participants with SC and 55 control participants without SC were studied in a series of 5 experiments that examined the ability to use top-down and bottom-up cues to guide WM encoding, as well as the ability to spontaneously select a subset of representations for storage. Participants with SC exhibited a consistent and robust ability to use selective attention in the control of WM in all 5 experiments, demonstrating a remarkable island of preserved functioning given the broad spectrum of impairments of attention and WM that have been widely reported in those with SC. These findings indicate that attention is not globally impaired in SC and make it possible to delineate more precisely the nature of the specific impairment of attention in this disorder.

Recent evidence suggests that schizophrenia reflects a neurodegenerative process. The studies have not compared brain change patterns in male and female patients with schizophrenia or examined the relation of these patterns to patient subgroups defined by specific symptom domains. Maximum Total Brain Volume (TBVmax), total cranial (TCV), total brain (TBV), sulcal CSF (sCSF), and ventricular (VV) volumes were measured in 66 normal controls (32 females, 34 males), and 85 patients with schizophrenia (21 females, 64 males). Sixty-six patients were categorized as nondeficit and 19 as deficit patients. Patients had smaller TBV and larger VV than normal controls. Patients also showed significant excessive brain volume loss after, but not before, TBVmax was achieved compared with normal controls. Although male patients had larger brain volume loss compared with male normal controls than female patients had compared with female normal controls, there were no significant gender × diagnosis interactions. Male patients with the deficit syndrome, but not those without the deficit syndrome, had significantly larger ventricles than normal controls. There were no other significant deficit/nondeficit differences. The present study suggests that brain volume loss in schizophrenia occurs after TBVmax and that male and female patients and deficit and nondeficit patients with schizophrenia do not demonstrate any differences in the time course of their brain volume reductions.

To investigate attentional impairment in schizophrenia, the authors examined the performance of 22 patients with schizophrenia and 16 healthy control subjects in 4 visual search tasks that varied in perceptual requirements and in the need for precise attentional control. The rate of search was slowed in the patients in all tasks. However, the degree of slowing was largest in tasks requiring precise attentional control and smallest in tasks that were perceptually difficult but required less attentional control. This pattern of results indicates that the primary impairment of attention in schizophrenia lies in the control of attention and not in the selection processes that operate once attention has been directed to an object.

Research suggests that first-degree relatives and individuals with schizophrenia spectrum personality disorders (SSPD) may represent nonpenetrant carriers of the genetic diathesis for schizophrenia. This study examined visuospatial working memory (SWM) as a cognitive endophenotype of schizophrenia by expanding the concept of risk for pathophysiological dysfunction beyond overt psychosis. Risk was thus defined by familial status and the presence or absence of SSPD. SWM was assessed in the following groups, in order of decreasing likelihood of genetic vulnerability: 23 patients with schizophrenia, 17 SSPD relatives of patients with schizophrenia, 23 non-SSPD relatives of patients with schizophrenia, 14 SSPD community members with no family history of psychosis, and 36 non-SSPD community members. SWM performance during a computer task was quantified by A-Prime. Relative risk ratios for SWM deficits were compared among the groups. Compared with community non-SSPD volunteers, relative risk (RR) of SWM deficits was significantly elevated in patients with schizophrenia (RR = 3.76, p = .002) and SSPD family members (RR = 2.97, p = .027), but not in the family non-SSPD (RR = 1.88, p = .241) or community SSPD (RR = 1.03, p = .971) groups. The pattern of SWM performance deficits reflected the proposed model of latent genetic liability, upholding SWM as a viable cognitive endophenotype. The results underscore the importance of including both familial liability and the schizophrenia spectrum when considering risk for schizophrenia and schizophrenia-related traits. This is particularly relevant for research efforts to identify pathophysiological components of the disease.

Background Abnormal smooth pursuit eye movements (SPEMs) are some of the most reproducible biological changes associated with the susceptibility for schizophrenia. Recent studies have suggested that deficit in predictive pursuit, a specific component of the SPEMs, marks schizophrenia susceptibility. Objective To test whether predictive pursuit contains less extraneous noise and may be under more direct genetic control than the traditional measure of overall pursuit performance using maintenance pursuit gain. Design Familial aggregation estimation of the predictive pursuit measure and the traditional maintenance pursuit measure in sibling pairs from families of schizophrenic patients. Setting Outpatient clinics. Participants Patients with schizophrenia and their full siblings were recruited, provided that at least 1 sibling pair could be formed per family. Ninety-two siblings were recruited into the study. They formed 70 sibling pairs. Ninety healthy control subjects were also recruited using targeted local community advertisements based on patients' county of residence, aiming to capture the basic demographics of the regions from which the patients were recruited. Main Outcome Measures Familial correlations and heritability estimates of 2 SPEM measures: maintenance pursuit gain and predictive pursuit gain. Results The sibling intraclass correlation coefficient of the predictive pursuit gain ( r = 0.45-0.48) was significantly higher than that of maintenance pursuit gain ( r = 0.02-0.20) ( P = .005-.007). Variance component analysis suggested a high genetic loading for predictive pursuit (heritability = 0.90, SE = 0.22; P P = .08). Conclusion These results suggest that predictive pursuit may index stronger genetic effect and may be better suited for genetic studies than the traditional SPEM measure of maintenance pursuit gain.

People with schizophrenia who have current substance use disorder (SUD) are generally excluded from clinical trials for the following reasons: safety/side effect risk, concern about adherence to the study protocol (Kreyenbuhl et al., 2011) and avoidance of confounds to efficacy evaluations (Buchanan et al., 2010). Patients with a past history of SUD are generally not excluded, but may represent a population with similar potentially unfavorable characteristics. To evaluate the possible consequences of this differential exclusion practice, we examined baseline symptoms of participants with substantial lifetime substance use and compared to participants with no substantial lifetime substance use in a sample of 15 outpatients with schizophrenia or schizoaffective disorder (DSM-IV criteria) enrolled in a controlled clinical trial of an adjunct weight loss medication (Kelly et al., 2011; Boggs et al., 2012). This analysis includes the full sample of patients enrolled in the clinical trial, which was prematurely terminated because of withdrawal of the experimental compound; thus, within-study sample bias did not influence our findings. Participants were 18–55 years old, with stable psychiatric symptoms, treated with a second generation antipsychotic for ≥eight weeks (same dose for ≥four weeks), overweight or obese, with a Calgary Depression Scale (Addington et al., 1992) total score ≤7, no history of hospitalization for depression or suicidal thoughts or behavior in the prior six months, and no substance dependence (DSM-IV criteria) within the prior six months other than caffeine or nicotine and no substance abuse within the prior month. Current drug use status was confirmed by urine and blood tests and self-report. SUD history was evaluated using the Structured Clinical Interview for DSM-IV Disorders, with more detailed information on alcohol, heroin, methadone, barbiturates, cocaine, amphetamines, cannabis, hallucinogens, inhalants, and nicotine use from the modified Addiction Severity Index (ASI) interview (McLellan et al., 1980). The ASI collects information on use in the prior 30 days and number of years of lifetime use. Substantial lifetime substance use was defined as ≥5 years of past use ≥4 times per week or with binging or problematic use in which normal activities are compromised. Current schizophrenia symptoms were assessed with the Brief Psychiatric Rating Scale and Scale for the Assessment of Negative Symptoms. There were no significant differences in participants’ socio-demographic characteristics. Both patient groups were comparable in demographic characteristics and cigarette smoking. The ten participants with substantial lifetime substance use had more severe current positive symptoms and less severe negative symptoms than the five participants without a substantial history of substance use (Table 1). Table 1 Psychiatric characteristics of 15 people with schizophrenia without current substance use disorder and with or without substantial lifetime substance use. This study has several limitations, including very small sample size, which precluded any statistical control for potential confounding factors, and substance use based on retrospective self-report without objective corroboration. Future studies are warranted with larger sample sizes, objective assessments of substance use, and clear distinctions between substance use groups to validate our findings. These findings suggest that more attention be given to past history of substance use in people without a current SUD who enroll in clinical trials. Persisting effects from prior substance use may adversely affect response to treatment, leading clinicians to add or change medications, when a more appropriate action might be evaluation of prior substance use. In addition, prior substance use is a risk factor for relapse to present substance use or abuse, with potential adverse effects on current treatment response. Therefore, all clinicians should pay attention to lifetime, not just current, co-occurring SUDs. Future research should consider the inclusion of participants with lifetime substance use, even if substantial, in order to improve the external validity of their studies, and account for lifetime substance use in their analysis plan.

We report on the correlations between whole brain rCBF and the positive and negative symptoms of schizophrenia in two cohorts of patients who were scanned while free of antipsychotic medication. We hypothesized that positive symptoms would correlate with rCBF in limbic and paralimbic regions, and that negative symptoms would correlate with rCBF in frontal and parietal regions. Both cohorts of patients with schizophrenia (Cohort 1: n=32; Cohort 2: n=23) were scanned using PET with H(2)(15)O while free of antipsychotic medication for an average of 21 and 15 days, respectively. Both groups were scanned during a resting state. Using SPM99, we conducted pixel by pixel linear regression analyses between BPRS scores and whole brain rCBF. As hypothesized, positive symptoms correlated with rCBF in the anterior cingulate cortex (ACC) in a positive direction and with the hippocampus/parahippocampus in a negative direction in both patient groups. When the positive symptoms were further divided into disorganization and hallucination/delusion scores, similar positive correlations with ACC and negative correlations with hippocampus rCBF were found. In both cohorts, the disorganization scores correlated positively with rCBF in Broca's area. As expected, negative symptoms correlated inversely with rCBF in frontal and parietal regions. This study provides evidence that limbic dysfunction may underlie the production of positive symptoms. It suggests that abnormal function of Broca's area may add a specific language-related dimension to positive symptoms. This study also provides further support for an independent neurobiological substrate of negative symptoms distinct from positive symptoms. The involvement of both frontal and parietal regions is implicated in the pathophysiology of negative symptoms.

Smooth pursuit eye movement (SPEM) abnormalities are some of the most consistently observed neurophysiological deficits associated with genetic risk for schizophrenia. SPEM has been traditionally assessed by infrared or video oculography using laboratory-based fixed-display systems. With growing interest in using SPEM measures to define phenotypes in large-scale genetic studies, there is a need for measurement instruments that can be used in the field. Here we test the reliability of a portable, head-mounted display (HMD) eye movement recording system and compare it with a fixed-display system. We observed comparable, modest calibration changes across trials between the two systems. The between-methods reliability for the most often used measure of pursuit performance, maintenance pursuit gain, was high (ICC = 0.96). This result suggests that the portable device is comparable with a lab-based system, which makes possible the collection of eye movement data in community-based and multicenter familial studies of schizophrenia.

Depressive symptoms have been associated with increased cardiac morbidity and mortality rates, but the pathophysiologic mechanism linking depressive symptoms to cardiovascular outcome has yet to be fully understood. Lower heart rate variability has also been associated with increased risk of cardiac events in healthy individuals and in patients with coronary artery disease. Findings regarding a relationship between depressive symptoms and heart rate variability that could explain increased cardiovascular risk have been inconsistent across studies.As an ancillary study to the Women's Health Initiative Observational Study, 3372 postmenopausal women aged 50 to 83 years were enrolled for further evaluation using 24-hour ambulatory electrocardiographic monitoring. A shortened version of the Center for Epidemiological Studies Depression Scale and the Diagnostic Interview Schedule were administered. Women with adequate electrocardiographic data and depressive symptom information and without coronary artery disease were analyzed (n = 2627).Two hundred sixty-nine women (10.2%) had depressive symptoms as measured using the 2 instruments. Women with depressive symptoms had a higher mean +/- SD heart rate (77.4 +/- 9.6 vs 75.5 +/- 8.5 beats/min) and lower heart rate variability than women without depressive symptoms. All differences remained significant after adjusting for age (P.01).Women with depressive symptoms had significant reductions in heart rate variability and higher heart rates, suggestive of increased sympathetic tone. These findings may contribute to the increased cardiac morbidity and mortality rates associated with depression in other studies.

This study reports evidence that patients with schizophrenia demonstrate a slowing of working memory (WM) consolidation, which is the process of transforming transient perceptual representations into durable WM representations. Sixteen schizophrenia patients and 16 healthy control participants performed a task measuring the visual WM consolidation rate in a change-detection paradigm. A target display containing 3 colored squares was followed by a variable delay of 17-483 ms, a pattern mask, and then a test stimulus. This pattern mask does not interfere with perception but disrupts WM consolidation. Control participants reached no-mask performance by 250 ms, indicating completed WM consolidation, whereas patients failed to reach no-mask performance by 483 ms. Slowed consolidation may play an important and largely unrecognized role in schizophrenia.

Olanzapine has been hypothesized to have superior efficacy in patients with treatment-resistant schizophrenia. The authors examined the comparative efficacy and safety of olanzapine and haloperidol in outpatients with partially responsive schizophrenia.Sixty-three outpatients with schizophrenia who met retrospective and prospective criteria for either residual positive or residual negative symptoms entered a 16-week double-blind, parallel-groups comparison of olanzapine and haloperidol.There were no significant differences between the two drugs in their effect on positive or negative symptoms. There were no significant differences between the two treatment groups on measures of social and functional outcome. Olanzapine-treated patients had a significant reduction in extrapyramidal symptoms and subjective measures of stiffness and dry mouth, but the increases in systolic blood pressure and weight in olanzapine-treated patients were significantly greater than they were in haloperidol-treated patients.Olanzapine has limited differential benefit for either positive or negative symptoms in patients with treatment-resistant schizophrenia. Although olanzapine is associated with fewer extrapyramidal symptoms, other side effects may offset this benefit.

This study evaluated body mass index, body surface area, subcutaneous fat tissue, and coronary atherosclerosis by autopsy reports for people with schizophrenia who were deceased to evaluate the presence of cardiac atherosclerosis and its association with body weight. Included in the study were autopsy reports for 134 people with schizophrenia and 134 matched normal subjects who had died between January 1990 and December 2000 and whose family had donated brain tissue to Maryland Brain Collection. Cause of death due to cardiovascular disease was observed for 45.7% of people with schizophrenia and 42.3% of the control group (P = NS). Body weight, body mass index, body surface area, and subcutaneous fat were not significantly different between the 2 groups; however, a larger proportion of the schizophrenia group had high (33.3%) and low (20.9%) percentile body weight compared with controls (27.7% vs 10.0%). People with schizophrenia who were underweight had higher rates of cardiac death than the controls (37.7% vs 13%) (chi(2) = 5.79, P = .01); however, no difference was noted in the number of coronary arteries occluded. Twenty-three (48.9%) of 47 of the controls with abnormally high subcutaneous fat showed cardiac atherosclerosis, whereas only 15 (33.3%) of 45 of the schizophrenia group with abnormally high subcutaneous fat had atherosclerosis (P = NS). Overall, the percentage of deaths due to cardiovascular disease was not higher in people with schizophrenia; however, in normal controls, cardiovascular disease appears to be related more to weight than in people with schizophrenia. This may be related to intrinsic metabolic differences associated with schizophrenia, lifestyle differences, or effects of antipsychotic medications. Nonetheless, our study suggests that efforts for the prevention of coronary atherosclerosis in schizophrenia patients should go beyond weight control to target multiple risk factors such as smoking, dyslipidemia, and cardiac side effect of antipsychotic medications.