Schizophrenia Research - Articles in Press

Case-control study of the relationship of depressive symptoms to suicide in a community-based sample of individuals with schizophrenia in China - Corrected Proof

John Kasckow, Nancy Liu, Grechen Haas, Michael R. Phillips — 2010-03-15

Abstract: Backgound: Suicide is the leading cause of premature death among people with schizophrenia. Most studies on suicide and schizophrenia report an associated depression history, but they are based on clinical samples from mostly western countries.Methods: We conducted a secondary analysis of 74 suicides (cases) and 24 accidental deaths (controls) among persons with schizophrenia identified in a national psychological autopsy study in mainland China using the Chinese version of the Structured Clinical Interview for DSM-IV. A ‘depression symptom severity score’ based on number, severity, and persistence of depressive symptoms 2weeks before death was derived from psychiatric interviews with 2 informants; determination of a ‘dysfunction due to depressive symptoms score’ was based on informants' reports about effects of depressive symptoms on decedents' functioning in the month before death. In addition, the mean number of negative life events was determined along with the effect of the events on the decedent. Comparison of the measures made for cases and controls were made by univariate analysis followed by adjustments using the False Discovery Rate.Results: Compared to persons with schizophrenia who died by accident, those who died by suicide were more likely to have a recent DSM IV diagnosis of major depression, the symptom of depressed mood, thoughts of death and a prior suicide attempt. In addition, those who died by suicide were more likely to have a higher overall depression severity score and greater dysfunction due to depressive symptoms.Discussion: This community-based study of individuals with DSM-IV schizophrenia who died by suicide in a non-western culture extends findings from clinical studies in western cultures providing data on the importance of depressive symptoms as risk factors for suicide in schizophrenia in a low income rural setting. These findings underline the importance of routine screening for depressive symptoms among patients with schizophrenia.

Effect of antipsychotic treatment on Insulin-like Growth Factor-1 and cortisol in schizophrenia: A longitudinal study - Corrected Proof

2010-03-12

Abstract: Neurodevelopmental pathogenesis of schizophrenia might be mediated by abnormalities in Insulin-like Growth Factor-1 (IGF-1). Developmental disturbances like obstetric complications, by themselves, as well as through the resultant hypercortisolemia due to hypothalamic–pituitary–adrenal (HPA) axis hyperactivity, can lead to deficient IGF-1 level. The relevance of IGF-1–Cortisol interactions in schizophrenia, especially in the context of antipsychotic treatment, is yet to be explored. In this study, thirty-three antipsychotic-naïve schizophrenia patients (13-men) were examined for serum IGF-1 and cortisol levels at baseline and after 3months of antipsychotic treatment. For baseline analyses, the patients were compared with 33 healthy controls matched for age, sex, socio-economic status, and physical activity. Symptoms were assessed using Scale for Assessment of Positive Symptoms (SAPS) and Scale for Assessment of Negative Symptoms (SANS). At baseline, schizophrenia patients had significantly lower levels of IGF-1 [t=4.6; p<0.0001] and higher levels of cortisol [t=3.9; p=0.0002] in comparison with healthy controls. Following treatment, IGF-1 level increased significantly [t=4.5; p<0.0001] whereas cortisol decreased significantly [t=2.5; p=0.02] in patients. There was a significant positive correlation between magnitude of increase in IGF-1 level and the magnitude of reduction in cortisol level [r=0.52; p=0.002]. Also, the greater the increase in IGF-1 the greater was the reduction in SAPS score [r=0.39; p=0.02]. Our study findings demonstrate that antipsychotic treatment can result in significant elevation of serum IGF-1 possibly mediated by reduction in cortisol levels. These observations suggest a possible link between HPA axis abnormalities and IGF-1 deficits in the neurodevelopmental pathogenesis of schizophrenia.

Intact associative learning in patients with schizophrenia: Evidence from a Go/NoGo paradigm - Corrected Proof

2010-03-12

Abstract: Objective: Schizophrenia is associated with deficits in executive control and associative learning. In the present study, we investigated the effect of associative learning during a Go/NoGo task in healthy controls subjects and patients with schizophrenia.Methods: Thirty patients with schizophrenia and 30 age-and-gender matched healthy control subjects performed 15 blocks of training and 3 blocks of test trials. The trials consisted of responding to words denoting either living or non-living objects. In the training condition, subjects were instructed to respond by pressing the space bar (Go-task) to one of the word types (living or non-living objects), but not the other. In the test phase, the Go/NoGo mapping was reversed. Subjects were instructed to respond as quickly and as accurately as possible. Reaction times (RT) and accuracy were recorded for each trial and all subjects were debriefed upon completion of the test trials.Results: Patients with schizophrenia had significantly longer Go RTs when compared to the control group, during both training and test trials. However, the two groups did not differ on any measure of associative learning.Conclusions: Our findings suggest that associative learning is intact in schizophrenia patients during the performance of a relational Go/NoGo paradigm.

Healthy lifestyle habits and 10-year cardiovascular risk in schizophrenia spectrum disorders: An analysis of the impact of smoking tobacco in the CLAMORS schizophrenia cohort - Corrected Proof

Julio Bobes, Celso Arango, Margarida Garcia-Garcia, Javier Rejas — 2010-03-11

Abstract: Aim: We analysed the impact of tobacco smoking over several healthy lifestyle habits along with the impact on 10-years cardiovascular event (CVE) risk in the CLAMORS schizophrenia cohort.Methods: This analysis was performed within the scope of the CLAMORS study which included consecutive outpatients meeting DSM-IV criteria for schizophrenia spectrum disorder. Beside smoking history, data on usual healthy lifestyle habits included current exercise, saturated fat sparing diet, low-caloric diet, and daily dietary fibre, salt, caffeine and alcohol consumption were recorded. The 10-year CVE risk was calculated with Framingham function.Results: 1704 patients (61.1% male), 18 to 74years were examined. Prevalence of smoking was 54.54% (95% CI: 52.16%–56.90%) significantly higher than in age and sex matched general population subjects, 31.51% (31.49%–31.52%); OR=2.61 (2.37–2.87, p<0.0001). After controlling by confounders smokers showed a 10-year CVE risk excess versus non-smokers of 2.63 (2.16–3.09), p<0.001. Smoking cessation would reduce the likely of high/very high 10-year CVE risk (above 10%) by near 90% [OR=0.10 (0.06–0.18), p<0.0001]. Also, smokers were more likely to consume alcohol daily [4.13 (3.07–5.54), p<0.0001] and caffeine [3.39 (2.72–4.23), p<0.0001] than non-smoker patients with schizophrenia, and less likely to avoid daily consumption of salt [0.58 (0.43–0.78), p<0.0001], saturated fat [0.71 (0.56–0.91), p=0.006], high fibre diet [0.67 (0.53–0.84), p=0.001], or to follow a low-caloric diet [0.63 (0.48–0.81), p<0.0001]. Smokers also were less likely to do exercise habitually [0.62 (0.48–0.82, p=0.001].Conclusion: Compared with the general population, patients with schizophrenia showed significant higher prevalence of smoking. Smokers who stop smoking would benefit by a near 90% reduction in the likely of 10-year cardiovascular event risk above 10%.

Religiosity and gender differences among Brazilian schizophrenic patients - Corrected Proof

2010-03-10

Spirituality and religion are often central issues among patients with chronic diseases, including mental illnesses such as affective disorders and schizophrenia (). Differences between male and female subjects without mental disorders regarding religious involvement have been previously demonstrated (), but it is unclear if these differences are found among schizophrenic patients as well. We describe here a study focused on gender differences and religiosity among patients diagnosed with schizophrenia.

Topiramate for prevention of olanzapine associated weight gain and metabolic dysfunction in schizophrenia: A double-blind, placebo-controlled trial - Corrected Proof

Preeta Kaur Narula, H.S. Rehan, K.E.S. Unni, Neeraj Gupta — 2010-03-08

Abstract: Background: Olanzapine associated weight gain (WG) is a major concern in patients with schizophrenia. The purpose of this study was to assess the efficacy of topiramate to prevent olanzapine induced WG in these cases. We also studied various metabolic parameters.Methods: In this 12-week, double-blind, parallel group study, seventy-two drug-naïve, first-episode schizophrenia patients were randomized to receive olanzapine+placebo (olanzapine group) or olanzapine+topiramate (100mg/day) (topiramate group). Weight, body mass index, fasting glucose, insulin, insulin resistance (IR), leptin, lipids and blood pressure were assessed at baseline and at 12weeks. The patients were clinically evaluated using Positive and Negative Syndrome Scale (PANSS) and were monitored for adverse effects.Results: Topiramate resulted in a weight loss of 1.27±2.28kg (p<0.01), decrease in leptin (p<0.001), glucose, cholesterol, triglyceride levels and systolic and diastolic blood pressure. In the olanzapine group, there was a significant WG, hyperglycemia, hyperinsulinemia, increased IR, hyperleptinemia, hypercholesterolemia and hypertriglyceridemia (p<0.001).There was a greater clinical improvement (PANSS scores) (p<0.001) in the topiramate group. The adverse effects were well tolerated.Conclusions: Topiramate could prevent olanzapine induced weight gain and adverse metabolic effects. It also results in a greater clinical improvement when used with olanzapine in schizophrenia.

Rate and predictors of service disengagement in an epidemiological first-episode psychosis cohort - Corrected Proof

2010-03-08

Abstract: Objectives: To assess the prevalence and predictors of service disengagement in a treated epidemiological cohort of first-episode psychosis (FEP) patients.Methods: The Early Psychosis Prevention and Intervention Centre (EPPIC) in Australia admitted 786 FEP patients from January 1998 to December 2000. Treatment at EPPIC is scheduled for 18months. Data were collected from patients' files using a standardized questionnaire. Seven hundred four files were available; 44 were excluded, because of a non-psychotic diagnosis at endpoint (n=43) or missing data on service disengagement (n=1). Rate of service disengagement was the outcome of interest, as well as pre-treatment, baseline, and treatment predictors of service disengagement, which were examined via Cox proportional hazards models.Results: 154 patients (23.3%) disengaged from service. A past forensic history (Hazard ratio [HR]=1.69; 95%CI 1.17–2.45), lower severity of illness at baseline (HR=0.59; 95%CI 0.48–0.72), living without family at discharge (HR=1.75; 95%CI 1.22–2.50) and persistence of substance use disorder during treatment (HR=2.30; 95%CI 1.45–3.66) were significant predictors of disengagement from service.Conclusions: While engagement strategies are a core element in the treatment of first-episode psychosis, particular attention should be paid to these factors associated with disengagement. Involvement of the family in the treatment process, and focusing on reduction of substance use, need to be pursued in early intervention services.

Is perseveration uniquely characteristic of schizophrenia? - Corrected Proof

Rachel N. Waford, Richard Lewine — 2010-03-04

Abstract: Evidence for the existence of categorically distinct disorders such as schizophrenia, bipolar disorder, and major depression is mixed: neuropsychological impairments may be similar in schizophrenia and bipolar disorder; schizophrenia and major depression show similar neuropsychological and frontal lobe disturbances; and overlap in biochemical anomalies among the disorders has also been reported. Interestingly, there are very few studies that directly compare all diagnoses. The present study compares cognitive perseveration in these three diagnostic groups using the Wisconsin Card Sorting Task (WCST) to examine performance across patients with schizophrenia (n=143), bipolar disorder (n=25) and major depression (n=21). Individuals used in this sample were 18–45years old at time of testing to eliminate confounds of aging. Sex ratios within each diagnostic group are comparable to those of the national population. Univariate analyses examining diagnostic group and percent perseverative error revealed no significant differences in WCST performance across the diagnostic groups. Examination of clinical variables in the sample of individuals with schizophrenia revealed that perseveration is related to negative symptoms and depressive symptoms in young adults.

Switching schizophrenia patients from typical neuroleptics to aripiprazole: Effects on working memory dependent functional activation - Corrected Proof

2010-03-02

Abstract: Background: Deficits in working memory (WM) are a core symptom of schizophrenia patients and have been linked to dysfunctional prefrontal activation, which might be caused by a mesocortical hypodopaminergic state. Aripiprazole – a partial dopamine antagonist – is a novel antipsychotic, which increases frontal dopamine concentrations in preclinical studies. However, little is known about specific medication effects on the modulation of frontal activation during WM performance.Methods: We measured BOLD-response during a WM task in a longitudinal fMRI-study in eleven schizophrenia patients first when they received conventional antipsychotics (T1) and a second time after they had been switched to aripiprazole (T2). A healthy control group matched for age, handedness and gender was investigated at two corresponding time points. Data was analyzed with SPM5 in a 2×2×2 design (group×session×task).Results: Schizophrenia patients showed fewer correct responses compared to healthy controls at T1 and a trend-wise normalization at T2. The task activated the fronto-parietal network during the contrast 2-back>0-back in all participants. At T1 patients revealed a hypoactivation in the dorsal anterior cingulate cortex (ACC), which normalized after switch to aripiprazole and correlated with improved task performance. This was due to a significant increase in the patients group while the control group did not change, as corroborated by a significant group×time interaction in this region.Conclusions: This study showed for the first time that the partial dopamine antagonist aripiprazole increases BOLD-signal during a WM task in the cognitive part of the ACC in schizophrenia patients, which may reflect its beneficial effect on cognitive deficits.

Failure to find an association between myosin heavy chain 9, non-muscle (MYH9) and schizophrenia: A three-stage case–control association study - Corrected Proof

2010-03-02

Abstract: Several genome-wide linkage studies have suggested linkage between markers on the long arm of chromosome 22 and schizophrenia. It has also been reported that 22q11.2 deletions increase the risk of schizophrenia. Therefore, 22q is a candidate region for schizophrenia. To search for genetic susceptibility loci for schizophrenia on 22q, we conducted a three-stage case–control association study in Japanese individuals. In the first stage, we examined 13 microsatellite markers on 22q in 766 individuals (340 patients with schizophrenia and 426 control individuals) and found a potential association of AFM262VH5 (D22S283) with schizophrenia. In the second stage, we performed fine mapping of the myosin heavy chain 9, non-muscle (MYH9) gene, where AFM262VH5 is located, using 25 tagging single nucleotide polymorphisms (SNPs). We obtained potential associations between three SNPs in MYH9 and schizophrenia in 1193 individuals (595 patients and 598 controls), which included the individuals analyzed in the first stage. In the third stage, however, we could not replicate these associations in 4694 independent individuals (2288 patients and 2406 controls). Our results suggest that MYH9 does not confer increased susceptibility to schizophrenia in the Japanese population, although we could not exclude possible contributions of other genes on 22q to the pathogenesis of schizophrenia.

Introduction - Corrected Proof

Lynn E. DeLisi, Henry A. Nasrallah — 2010-03-02

Since its inception 22years ago as an international, peer-reviewed journal, Schizophrenia Research has not only published the latest cutting-edge data articles in the field of schizophrenia, but it established a tradition for publishing the abstracts presented at relevant international meetings. When the two of us co-founded the Schizophrenia International Research Society [SIRS] in 2005, we continued this tradition for the 1st SIRS conference [June 2008, Venice]. The abstract book was referred to by the attendees at the conference itself and also accessed by the international community of schizophrenia investigators and clinicians world-wide who could not attend the SIRS conference but were eager to see the highlights of the science presented there.

Body image in individuals with schizophrenia: Examination of the B-WISE® questionnaire - Corrected Proof

Kelly P. Arbour-Nicitopoulos, Guy E. Faulkner, Tony A. Cohn — 2010-03-02

Medications commonly used to treat severe mental illness (SMI) are often associated with weight gain (), which may lead to body dissatisfaction, and inevitably, negative body image. Body image is a multidimensional construct, reflecting how we see, think, feel, and act towards our bodies (). Negative body image perceptions may spiral into other psychosocial maladjustments, such as social isolation and negative affect. As such, more research into the measurement of body image in persons with SMI is warranted.

Frequency of schizoaffective disorder in an International patient population with psychotic disorders using the Mini-International Neuropsychiatric Interview - Corrected Proof

Carla M. Canuso, Colette Kosik-Gonzalez, John Sheehan, Lian Mao, Amir H. Kalali — 2010-03-02

Limited epidemiologic data suggest schizoaffective disorder is up to one third as common as schizophrenia in western cultures (e.g., the United States [US], Europe, and Australia) (); however, the frequency in other regions (e.g., Asia) and the global prevalence rate is essentially unknown. In this feasibility assessment performed prior to initiating a global registration program, the frequency of schizoaffective disorder was evaluated in 4 globally diverse regions: Asia Pacific (i.e., Malaysia, the Philippines, and South Korea), Eastern Europe (Russia and Ukraine), India, and the US. This evaluation assessed the diagnosis of schizoaffective disorder using The Mini-International Neuropsychiatric Interview (MINI) for Schizophrenia and Psychotic Disorder Studies structured interview. The MINI has been translated into 43 languages and has been validated against the Structured Clinical Interview for DSM-IV (SCID-P) () and the ICD-10, with good to excellent concordance ().

Higher white blood cell counts are associated with an increased risk for metabolic syndrome and more severe psychopathology in non-diabetic patients with schizophrenia - Corrected Proof

2010-03-02

Abstract: Background: Unequivocal evidence has emerged linking inflammation to the risk of metabolic problems. Previous research also has suggested a relationship between inflammation and schizophrenia. The present study examined whether white blood cell count (WBC), a marker of systemic inflammation, is associated with metabolic syndrome and psychiatric symptoms in non-diabetic patients with schizophrenia.Methods: Outpatients 19 to 75years old diagnosed with schizophrenia or schizoaffective disorder participated in a multi-center, cross-sectional study. Vital signs and anthropometric measures were obtained. Fasting blood samples were collected to determine levels of glucose, lipids and WBC. Psychiatric symptoms were assessed using the Brief Psychiatric Rating Scale (BPRS).Results: In the sample of 199 patients, multiple logistic regression showed that WBC (log transformed) strongly predicted the condition of metabolic syndrome after potential confounding variables including age, gender, race, age of illness onset, family history of diabetes, smoking status and antipsychotic agent used were taken into consideration (odds ratio 47.2, 95% CI 3.4–658.7, p=0.004). On the other hand, significant correlations were found between WBC (log transformed) and BPRS-total score (r=0.18, p=0.014), negative symptom score (r=0.15, p=0.039) as well as anxious depression factor score (r=0.21, p=0.004) after potential confounding variables were taken into consideration.Conclusion: This study suggested that WBC, a simple, readily available and inexpensive measure, may potentially be a useful marker to predict an increased risk for metabolic syndrome and more severe psychiatric symptoms in non-diabetic patients with schizophrenia.

Deconstructing processing speed deficits in schizophrenia: Application of a parametric digit symbol coding test - Corrected Proof

2010-03-02

Abstract: Cognitive processing inefficiency, often measured using digit symbol coding tasks, is a putative vulnerability marker for schizophrenia and a reliable indicator of illness severity and functional outcome. Indeed, performance on the digit symbol coding task may be the most severe neuropsychological deficit patients with schizophrenia display at the group level. Yet, little is known about the contributions of simpler cognitive processes to coding performance in schizophrenia (e.g. decision making, visual scanning, relational memory, motor ability). We developed an experimental behavioral task, based on a computerized digit symbol coding task, which allows the manipulation of demands placed on visual scanning efficiency and relational memory while holding decisional and motor requirements constant. Although patients (n=85) were impaired on all aspects of the task when compared to demographically matched healthy comparison subjects (n=30), they showed a particularly striking failure to benefit from the presence of predictable target information. These findings are consistent with predicted impairments in cognitive processing speed due to schizophrenia patients' well-known memory impairment, suggesting that this mnemonic deficit may have consequences for critical aspects of information processing that are traditionally considered quite separate from the memory domain. Future investigation into the mechanisms underlying the wide-ranging consequences of mnemonic deficits in schizophrenia should provide additional insight.

The Health and Recovery Peer (HARP) Program: A peer-led intervention to improve medical self-management for persons with serious mental illness - Corrected Proof

2010-02-26

Abstract: Objectives: Persons with serious mental illnesses (SMI) have elevated rates of comorbid medical conditions, but may also face challenges in effectively managing those conditions.Methods: The study team developed and pilot-tested the Health and Recovery Program (HARP), an adaptation of the Chronic Disease Self-Management Program (CDSMP) for mental health consumers. A manualized, six-session intervention, delivered by mental health peer leaders, helps participants become more effective managers of their chronic illnesses. A pilot trial randomized 80 consumers with one or more chronic medical illness to either the HARP program or usual care.Results: At six month follow-up, participants in the HARP program had a significantly greater improvement in patient activation than those in usual care (7.7% relative improvement vs. 5.7% decline, p=0.03 for group∗time interaction), and in rates of having one or more primary care visit (68.4% vs. 51.9% with one or more visit, p=0.046 for group∗time interaction). Intervention advantages were observed for physical health related quality of life (HRQOL), physical activity, medication adherence, and, and though not statistically significant, had similar effect sizes as those seen for the CDSMP in general medical populations. Improvements in HRQOL were largest among medically and socially vulnerable subpopulations.Conclusions: This peer-led, medical self-management program was feasible and showed promise for improving a range of health outcomes among mental health consumers with chronic medical comorbidities. The HARP intervention may provide a vehicle for the mental health peer workforce to actively engage in efforts to reduce morbidity and mortality among mental health consumers.

Altered activation and functional connectivity of neural systems supporting cognitive control of emotion in psychosis proneness - Corrected Proof

Gemma Modinos, Johan Ormel, André Aleman — 2010-02-26

Abstract: Emotion regulation processes, such as reappraisal, are thought to operate through interactions between prefrontal emotion-control regions and subcortical emotion-generation regions such as the amygdala. Impairments in emotional processing and regulation have been reported in schizophrenia and at-risk populations. Psychometric measures may be used to detect vulnerability to schizophrenia in non-clinical samples, or psychosis proneness (PP). It has been shown that individuals with PP have a more than tenfold increased risk of developing a schizophrenia-spectrum disorder. In the present study, we used fMRI to examine the neural dynamics underlying reappraisal in such a sample. 600 undergraduate students completed the Community Assessment of Psychic Experiences Questionnaire (CAPE), positive subscale. Two groups were subsequently formed from the extremes of the distribution (total N=34). Blood-oxygenated-level-dependent activity elicited with a task involving 3 conditions was analyzed: viewing neutral pictures, viewing negative pictures, and reappraising negative pictures. Subjects reported the strength of experienced negative affect after each trial. Functional connectivity between prefrontal control regions and amygdala was investigated. At the behavioral level, both groups reported successful diminishment of experienced negative emotion. However, high psychosis-prone subjects showed stronger activation than low subjects in a number of prefrontal regions during reappraisal, relative to attending to negative pictures. The amygdala response to negative stimuli was decreased through reappraisal only in the low group. Functional connectivity analysis revealed less prefrontal-amygdala coupling in high psychosis-prone subjects. Thus, reduced cognitive control of emotion at a neural level appeared to be associated with PP. These findings extend the hypothesis of emotion dysregulation in schizophrenia to PP, and suggest that emotion regulation difficulties may be at the core of a vulnerability to psychosis.

Impaired facial affect labeling and discrimination in patients with deficit syndrome schizophrenia - Corrected Proof

2010-02-25

Abstract: Social and affective disturbances have long been thought to be core to schizophrenia. Deficits in accurately identifying and discriminating facial displays of emotion may be central components of the functional and social abnormalities seen in schizophrenia; however, their relationship with negative symptoms is less clear. The current study examined facial affect labeling and discrimination performance in a sample of 15 patients meeting criteria for deficit syndrome schizophrenia, 26 schizophrenia patients who do not meet criteria for the deficit syndrome, and 22 healthy controls. Results indicated that deficit schizophrenia patients displayed significantly greater facial affect labeling and discrimination difficulties than non-deficit patients and controls, as well as poorer performance on a basic visuoperceptual face processing task, suggesting that problems with facial affect processing may be mediated by a more general impairment in visuoperceptual processing. However, within this more generalized pattern of impairment, deficit syndrome patients were uniquely characterized by processing positive faces less accurately than negative faces. These findings suggest that abnormalities in processing facial emotion are associated with the negative symptoms of schizophrenia, with a unique deficit in the processing of positive emotions that stand out in the broader context of generalized impairment.

Time course of antipsychotic treatment response in schizophrenia: Results from a naturalistic study in 280 patients - Corrected Proof

2010-02-25

Abstract: Objective: To describe the course of positive and negative symptoms during inpatient treatment and examine remission and response rates under routine clinical care conditions.Methods: Two hundred and eighty inpatients with schizophrenia (DSM-IV criteria) were assessed with the Positive and Negative Syndrome Scale (PANSS) at admission and at biweekly intervals until discharge from hospital. Remission was defined according to the symptom–severity component of the consensus criteria (Remission in Schizophrenia Working Group) as a rating of three or less in the relevant PANSS items at discharge, and response as a reduction of at least 20% in the PANSS total score from admission to discharge.Results: The mean duration of inpatient treatment was 54.8days. Of the total sample, 78.5% achieved the criteria for response and 44.6% those for remission. Mean PANSS total scores decreased from 72.4 at admission to 52.5 at discharge (p<0.001). A reduction in PANSS total scores was found from visit to visit, up to week 8. The most pronounced decline was observed within the first two weeks of treatment.Conclusion: Response rates were comparable to those found in efficacy studies, and remission rates were slightly higher. This may be explained by differences in the selection and the treatment of patients. Nevertheless, the findings might indicate that a complex naturalistic treatment approach is beneficial in terms of effectiveness.

Varenicline induced polydipsia and hyponatremia in a patient with schizophrenia - Corrected Proof

Zahinoor Ismail, Jonathan Syms, Daniel Blumberger, Tony P. George — 2010-02-24

We report a case of polydipsia and hyponatremia in a patient with schizophrenia who was started on varenicline for smoking cessation. A 62-year old Caucasian man with a 32-year history of schizophrenia and COPD, smoking 15 cigarettes per day (25 pack years), was hospitalized for exacerbation of psychotic symptoms in the context of medication non-adherence. During a lengthy admission of 4months, he was stabilized back to his pre-hospitalization baseline on depot risperidone 25mg IM every two weeks with initial oral risperidone supplementation. When stabilized at the 3-month mark, he expressed an interest in quitting smoking and thus varenicline was prescribed and titrated up to 1mg bid. On varenicline, he significantly reduced his smoking to 2 cigarettes daily, and his self-reported cravings vanished. However, he developed increasing paranoia, delusions of reference, nihilism, disorganization and irritability. Despite no past history of polydipsia, hyponatremia or Syndrome of Inappropriate Antidiuretic Hormone (as per the patient and his old records), and a baseline sodium of 144mmol/L, he developed polydipsia after 18days of varenicline, when nursing staff initially detected a significant increase in his water intake. On day 20, varenicline was discontinued when his treating physicians detected hyponatremia (125mmol/L). Urinalysis that day confirmed diluted urine as per a specific gravity of <1.005. Serum glucose monitoring was normal, ruling out new onset diabetes. After an inability to enforce fluid restriction, the patient was given a normal saline bolus and a normal saline infusion on day 23. His sodium normalized as did his mental status: on day 25 his psychotic symptoms and polydipsia had resolved—he demonstrated a resolution of the paranoid, referential and nihilistic delusions and his thoughts became organized once more. His antipsychotic regime had remained unchanged over this time period. He was discharged 3days later. In subsequent visits post-discharge up to 5weeks, he remained stable on the same medications with no evidence of polydipsia or hyponatremia and no return of psychotic symptoms. He had, however, resumed smoking at this time.

No association between DAO and schizophrenia in a Japanese patient population: A multicenter replication study - Corrected Proof

2010-02-24

Dear Editors d-serine, a co-agonist that enhances N-methyl-d-aspartate (NMDA) glutamate receptors, is hypothesized to be involved in the pathophysiology of schizophrenia because treatment with d-serine improves some schizophrenic symptoms (). Thus, genes that are related to d-serine metabolism have arisen as candidate genes that may play a role in schizophrenia. Genomic case-control studies of one such candidate gene, d-amino acid-oxidase (DAO; 12q24), have shown relatively consistent positive results in which DAO is a susceptibility locus for patients with schizophrenia (). A previous well-explained report about the role of DAO in schizophrenia () and two representative meta-analyses showed an association between DAO and schizophrenia, specifically with the SNP, rs4623951 (). Previously, we performed stage 1 genomic case-control studies (340 schizophrenia patients, 340 healthy controls) for genes (PHGDH, SHMT1, SRR, DAO) related to d-serine synthesis/degradation. Our results from a haplotype case-control analysis showed that only three SNPs (rs3825251, rs3918347, and rs4964770) in DAO which are in strong linkage disequilibrium (LD) and show an association with schizophrenia, even after correction for multiple testing (). Some negative results have also been reported regarding a possible association between DAO and schizophrenia (). Thus, we performed a stage 2 replication study to clarify the conclusions of a possible role for DAO in schizophrenia. We reinvestigated the association between the above DAO haplotype (rs3825251–rs3918347–rs4964770) and schizophrenia using adequate statistical power.

Early developmental milestones and risk of schizophrenia: A 45-year follow-up of the Copenhagen Perinatal Cohort - Corrected Proof

2010-02-24

Abstract: The aim of the present study was to investigate the relationship between age of neuromotor milestone attainment and risk of adult schizophrenia. 5765 mothers of the Copenhagen Perinatal Cohort recorded 12 developmental milestones during the child's first year of life. Cohort members were followed until they were 46–48years old through record linkage with the Danish Psychiatric Central Research Register. The age at which milestones were met in the 92 individuals who later developed schizophrenia was compared with milestone attainment in the 691 individuals who developed other psychiatric disorders and in the 4982 cohort controls who were never admitted to a psychiatric department. Group comparisons were adjusted for gender, mother's age, father's age, parental social status, breadwinner's education, single mother status and parity. Individuals who developed schizophrenia reached all developmental milestones later than controls and differed significantly from the controls with respect to the mean age of reaching the 12 milestones. Five developmental milestones in particular (smiling, lifting head, sitting, crawling, and walking) differed significantly. Individuals who later developed psychiatric disorders other than schizophrenia reached most developmental milestones earlier than those who developed schizophrenia, but later than the controls. The two psychiatric groups only differed significantly with respect to age of walking without support. The findings corroborate and methodologically extend previous research from prospective longitudinal cohort studies suggesting developmental delays observable as early as within the first year of life. These early developmental delays may not only characterize schizophrenia, but may be associated with a range of psychiatric disorders.

Predicting the longitudinal effects of the family environment on prodromal symptoms and functioning in patients at-risk for psychosis - Corrected Proof

2010-02-22

Abstract: The current study examined the relationship between the family environment and symptoms and functioning over time in a group of adolescents and young adults at clinical high risk for psychosis (N=63). The current study compared the ability of interview-based versus self-report ratings of the family environment to predict the severity of prodromal symptoms and functioning over time. The family environmental factors were measured by interviewer ratings of the Camberwell Family Interview (CFI), self-report questionnaires surveying the patient's perceptions of criticism and warmth, and parent reported perceptions of their own level of criticism and warmth. Patients living in a critical family environment, as measured by the CFI at baseline, exhibited significantly worse positive symptoms at a 6-month follow-up, relative to patients living in a low-key family environment. In terms of protective effects, warmth and an optimal level of family involvement interacted such that the two jointly predicted improved functioning at the 6-month follow-up. Overall, both interview-based and self-report ratings of the family environment were predictive of symptoms and functioning at follow-up; however patient's self-report ratings of criticism had stronger predictive power. These results suggest that the family environment should be a specific target of treatment for individuals at risk for psychosis.

Do inter-regional gray-matter volumetric correlations reflect altered functional connectivity in high-risk offspring of schizophrenia patients? - Corrected Proof

2010-02-22

Abstract: Background: Schizophrenia patients and their relatives show aberrant functional connectivity in default network regions (DRs) such as the medial prefrontal, lateral temporal, cingulate and inferior parietal cortices and executive regions such as the dorsolateral prefrontal cortex (DLPFC). Gray-matter volumetric alterations may be related to these functional connectivity deficits. Also, gray-matter volume inter-regional correlations may reflect altered inter-regional functional connectivity.Aims: To examine our prediction of alterations of gray-matter volumes and inter-regional volume correlations for DRs and the DLPFC in offspring of schizophrenia patients (OS).Methods: We assessed 64 adolescent and young adult OS and 80 healthy controls (HC) using T1-MRI. Regional gray-matter volumes and inter-regional volume correlations between the DRs and between the DLPFC and DRs on each side were compared across groups.Results: Compared to HC, OS had reductions in several DRs and the DLPFC after controlling age, gender, and intra-cranial volume, and correcting for multiple comparisons. OS had stronger (more positive) gray-matter volume inter-correlations between DRs and between DRs and the DLPFC.Conclusions: Volumetric deficits in the default network and in the DLPFC may be related to familial diathesis in schizophrenia and to functional connectivity abnormalities in those at familial risk. Increased inter-correlations between DRs and between DR and DLPFC gray-matter volumes may serve as surrogate indices of abnormal functional connectivity.

Psychometric evaluation of the Medication Satisfaction Questionnaire (MSQ) to assess satisfaction with antipsychotic medication among schizophrenia patients - Corrected Proof

2010-02-22

Abstract: The Medication Satisfaction Questionnaire (MSQ) is a single-item questionnaire which evaluates satisfaction with antipsychotic medication in schizophrenia patients. This study evaluated the reliability and validity for its use in research and clinical settings. Data pooled across treatment groups (control vs. Paliperidone ER) from a randomized 6-week study were used to conduct four psychometric assessments of the MSQ: (1) test–retest reliability, (2) convergent validity, (3) known-groups validity, and (4) minimally important difference (MID). This analysis included 191 randomized subjects. Test–retest reliability was evaluated for patients with no change in satisfaction from weeks 2 to 4 and weeks 4 to 6 (ICC=0.80; 0.83, respectively). Convergent validity was demonstrated through large correlations with Treatment Satisfaction Questionnaire for Medication (TSQM) global score (r=0.72–0.77), and through small correlations with variables measuring clinical symptoms and functioning (e.g., Positive and Negative Syndrome Scale (PANSS) total score [r=−0.30 to −0.17], CGI-S [r=−0.35 to −0.27], SF-36 Physical Functioning Score [r=0.18] and side effects and extrapiramidal measures (including UKU, ESRS-A, SAS). Mean MSQ scores were significantly different between those who completed and discontinued the study, and between different satisfaction groups based on TSQM, demonstrating good known-groups validity. MID estimates for the MSQ ranged from 0.47 (standard error of measurement) to 0.58 (anchor-based method). Results suggest that the MSQ has acceptable reliability and validity, making this single-item questionnaire appropriate and easy to use in clinical research and potentially in clinical practice. A 1-point change on the MSQ may be considered clinically meaningful.

Formal thought disorder in non-clinical individuals with auditory verbal hallucinations - Corrected Proof

2010-02-22

Abstract: Background: Auditory verbal hallucinations (AVH) and formal thought disorder (FTD) may originate from the same aberration in the language system. The hypothesis of a shared neurobiological basis would be strengthened by the presence of FTD in individuals who frequently experience AVH, but do not meet DSM-IV criteria for a psychotic disorder.Methods: In this study, FTD was quantified in 40 non-clinical subjects with AVH, in 50 healthy subjects without AVH and in 40 schizophrenia patients with AVH. Recorded speech samples were analysed by one rater who was blind to the presence/absence of AVH and to diagnosis, using the Thought and Language Index.Results: Negative FTD was barely present in non-clinical subjects with AVH and in healthy controls without AVH. Positive FTD, however, was significantly higher in both groups experiencing AVH than in controls without AVH. Severity of positive FTD did not differ significantly between non-clinical subjects with AVH and schizophrenia patients with AVH.Conclusion: Negative FTD (alogia) appears not to be associated with AVH. However, the fact that positive FTD (disorganised speech) in schizophrenia patients with AVH is equally high in non-clinical subjects with AVH indicates that these two symptoms tend to co-occur, which may be suggestive of a shared neurobiological substrate.

Attribution bias in ultra-high risk for psychosis and first-episode schizophrenia - Corrected Proof

Suk Kyoon An, Jee In Kang, Jin Young Park, Kyung Ran Kim, Su Young Lee, Eun Lee — 2010-02-22

Abstract: Background: Attribution style bias, such as a greater tendency to perceive hostility, has been reported to be associated with paranoia in multi-episode, chronic schizophrenia patients. The aim of this study was to investigate whether young, first-episode schizophrenia patients exhibited a perceived hostility bias and if this bias was correlated with persecutory symptoms. This study also explored whether this attribution bias, associated with paranoid tendencies, also emerged in participants at ultra-high risk (UHR) for psychosis.Methods: Thirty-nine normal controls, 24 UHR participants, and 20 young, first-episode schizophrenia patients were asked to complete the Ambiguous Intentions Hostility Questionnaire (AIHQ) and other psychosocial measures. The AIHQ, specifically developed for paranoia, is a self-report questionnaire about negative outcomes that varied intentionality (i.e., intentional, accidental, and ambiguous intentions). The perceived hostility, composite blame, and aggression bias scores were calculated, in this study, from the ambiguous situations.Results: First-episode patients with schizophrenia were found to have a perceived hostility bias, which was associated with persecutory symptoms. The UHR participants also showed an attribution bias for perceiving hostility and blaming others, and this attribution bias was linked to the paranoia process.Conclusions: These findings suggest that a biased attribution style linked with paranoid symptoms may not only be present in first-episode psychotic patients but may already have evolved prior to the onset of frank psychotic symptoms. A biased attribution style may play a pivotal role in the persecutory process during the prodromal phase as well as a patient's first schizophrenic episode.

Elevated serum S100B protein in first-episode drug-naïve Chinese patients with schizophrenia - Corrected Proof

2010-02-18

Abstract: Mounting evidence suggest that astrocytes might be involved in the pathogenesis of schizophrenia. Of particular interest is S100B, a protein produced primarily by astrocytes that plays a critical role in the maintenance of functional neuronal and astroglial activation. Abnormalities in S100B levels have been associated with schizophrenia. In this study, we examined serum S100B protein levels and the relationship between S100B levels and psychopathological symptoms in first-episode, drug-naïve patients with schizophrenia (SCZ). Sixty-four patients with schizophrenia were compared with 66 age- and sex-matched healthy controls (HCs). Psychopathology in the SCZ group was assessed by the Positive and Negative Syndrome Scale (PANSS). Serum S100B protein levels were measured by sandwich enzyme-linked immunosorbent assay (ELISA). The results showed that S100B protein-like immunoreactivity was significantly higher in the SCZ group than the HC group. S100B-like immunoreactivity was correlated with age, duration of illness, and PANSS subscale scores for negative and general psychopathology and total scores. In the SCZ group, serum S100B levels in residual subtypes were significantly higher than in the paranoid and disorganized subtypes. Our findings suggest an upregulation of a marker for astrocyte activity, i.e., S100B, in first-episode medication-free patients with schizophrenia, and thus support the involvement of astrocytes in the pathogenesis of schizophrenia.

Paternal age and mortality in nonaffective psychosis - Corrected Proof

2010-02-18

Abstract: Introduction: Advanced paternal age (APA) is associated with an increased mortality in the general population, and is a risk factor for schizophrenia. We aimed to test if APA is associated with increased mortality in people with nonaffective psychosis.Methods: Subjects with nonaffective psychosis who were born in Helsinki, Finland, between 1951 and 1960 (n=529) were followed until June 2006 (age 46 to 55). Hazard ratios were calculated, adjusting for subject age, age of the other parent, and gender.Results: In females but not males, there was a significant increase in all-causes mortality (HR=7.04, 95% CI 1.60–31.04, p=0.01) and natural deaths (HR=7.64, 95% CI 1.20–48.66, p=0.03) in offspring of fathers age ≥40, after adjustment for potential confounders. In males but not females, there was a significant decrease in suicides (HR=0.89, 95% CI 0.81–0.97, p=0.01) with increasing maternal age (as a continuous variable). In the entire sample, there was also a trend for decreased all-cause mortality (HR=0.96, 95% CI 0.92–1.01, p=0.08) with increasing maternal age (as a continuous variable).Discussion: Both paternal and maternal age may affect mortality risk in offspring with psychosis. The specific disorders and pathway(s) associated with the increase in natural cause mortality remain to be determined.

Neuroanatomic and cognitive abnormalities related to herpes simplex virus type 1 in schizophrenia - Corrected Proof

2010-02-15

Abstract: Herpes simplex virus 1 (HSV-1) tends to replicate in the temporal cortex and can damage the limbic system. The presence of serum antibodies to HSV-1 is associated with cognitive impairment in adults with schizophrenia, suggesting that cerebral gray matter abnormalities might distinguish patient subgroups defined by HSV-1 exposure. We assessed 43 adult outpatients with schizophrenia. The assessment included clinical interviews, neurocognitive testing, anatomic brain magnetic resonance imaging and measures of serum IgG antibodies specific to herpes simplex viruses 1 and 2. We then compared 25 patients who tested positive for antibodies to HSV-1 with 15 who were seronegative for both HSV-1 and HSV-2. The seropositive patients performed significantly worse than the seronegative patients on four neuropsychological measures of psychomotor speed, executive functioning, and explicit verbal memory. Voxel-based morphometric analyses revealed that the same patients showed reduced gray matter volume in the anterior cingulate and areas of the cerebellum. Finally, performance on the test of psychomotor speed and executive functioning that showed the largest between- group effect size correlated with reduced gray matter volume in some of the same brain regions (cingulate and cerebellum) that distinguished the two HSV-1 subgroups. In these outpatients with schizophrenia, HSV-1 seropositivity and performance on a cognitive test that is highly sensitive to it co-localize to closely overlapping brain regions.

Cognitive decline in schizophrenia from childhood to midlife: A 33-year longitudinal birth cohort study - Corrected Proof

2010-02-15

Abstract: Background: We examined cognitive deficits before and after onset of schizophrenia in a longitudinal study that: 1) covers a long time interval; 2) minimizes test unreliability by including the identical measure at both childhood and post-onset cognitive assessments; and 3) minimizes bias by utilizing a population-based sample in which participants were selected neither for signs of illness in childhood nor for being at risk for schizophrenia.Methods: Participants in the present study, Developmental Insult and Brain Anomaly in Schizophrenia (DIBS), were ascertained from an earlier epidemiologic study conducted in Oakland, CA. The original version of the Peabody Picture Vocabulary Test (PPVT), a test of receptive vocabulary, was administered at age 5 or 9 and repeated as part of the DIBS study at an average age of 40. There were 10 DIBS cases with DSM-IV schizophrenia or schizoaffective disorder and 15 demographically similar DIBS controls with both child and adult PPVT scores.Results: Cases scored significantly lower than controls in childhood (d=0.95) and adulthood (d=1.67). Residualized scores indicating the number of SDs above or below one's predicted adult score revealed a mean case–control difference of −1.51SDs, consistent with significant relative decline over time among the cases (p<0.0013).Conclusions: In this prospective study, individuals who developed adult schizophrenia manifested impaired receptive vocabulary during childhood and further relative deterioration (or lack of expected improvement) between childhood and midlife. Limitations should also be acknowledged, including the small sample size and the fact that we cannot be certain when the continued deterioration took place.

P50 gating in deficit and nondeficit schizophrenia - Corrected Proof

2010-02-15

Abstract: Dysfunctional auditory sensory processing has generally been found in schizophrenia and it has been suggested that these deficits might be related to clinical and psychosocial variables. The present study included P50 recordings using a simple-paired click auditory evoked potential paradigm in sixty patients with deficit schizophrenia (DS), sixty patients with nondeficit schizophrenia (NDS), and sixty comparison subjects. The Schedule for the Deficit Syndrome was used to categorize patients as DS or NDS. The two patient groups did not differ in clinical variables, except for higher negative dimension and lower community outcome scores in DS than in NDS patients. There were no differences in P50 ratios between deficit and nondeficit subgroups; compared with normal subjects both groups of schizophrenia patients showed impaired P50 ratios (p<0.0001). This ratio appears to be independent of positive and negative symptoms. However, impairment in P50 gating correlated with poorer community outcome. The data document the existence of early auditory sensory processing abnormalities in DS and NDS, and might suggest that common neuronal network abnormalities underlie both forms of schizophrenia. Deficient P50 gating may be associated with impaired functional outcome in schizophrenia.

Time-to-pregnancy and risk of schizophrenia - Corrected Proof

2010-02-15

Abstract: Schizophrenia has been linked to advanced paternal age, but the explanation is unknown. We questioned whether the incidence of schizophrenia would be related to male reproductive capacity, as reflected in the time taken to conceive. We measured the incidence of schizophrenia in relation to time to conception in a sub-group of 12,269 in the Jerusalem cohort whose mothers, interviewed post-partum, reported that the pregnancy had been intended. Compared with those conceived in less than 3months, the unadjusted relative risks (RR) of schizophrenia associated with conception-waits of 3–5, 6–11 and 12+ months were 1.10 (95% confidence interval, 0.62–1.94), 1.41 (0.79–2.52) and 1.88 (1.05–3.37) with p for trend=0.035. This trend was attenuated somewhat by adjusting for paternal age, and was observed more strongly in offspring of fathers aged 30+ (p=.010). These findings suggest that factors associated with fecundability, either male or female, may contribute to the risk of schizophrenia.

Genetic association study of KREMEN1 and DKK1 and schizophrenia in a Japanese population - Corrected Proof

2010-02-15

Abstract: The aim of the current study was to examine the association of KREMEN1 and DKK1, two wnt pathway-related genes with schizophrenia in Japanese subjects. We genotyped 16 common genetic variants within the aforementioned genes and examined their associations with schizophrenia. Results demonstrated that a common variant in the promoter region of KREMEN1 might modulate the risk of schizophrenia in the Japanese. However, further replication will be needed for conclusive interpretation of the effect of this locus on the pathogenesis of schizophrenia.

Functional magnetic resonance imaging of choice reaction time in chronic schizophrenia and first-degree relatives - Corrected Proof

David P. McAllindon, Alan H. Wilman, Scot E. Purdon, Philip G. Tibbo — 2010-02-15

Reaction time (RT) deficits are well documented in schizophrenia (). The deficits have been associated with anomalies in the anterior cingulate cortex (ACC) by investigation of event-related potentials () and functional MRI (). Our goal was to confirm the lower activity in ACC in chronic schizophrenia, and extend the investigation to include a group of first-degree relatives, presumed to have a genetic vulnerability to schizophrenia but without the confounds of medication or symptoms.

Co-occurrence of neurodevelopmental genes in etiopathogenesis of autism and schizophrenia - Corrected Proof

S. Hossein Fatemi — 2010-02-15

Neurodevelopmental disorders schizophrenia and autism are set apart by their respective behavioral manifestations and course of development of pathology. Recently, a number of published reports indicate a potential involvement of certain brain genes in the etiology of both schizophrenia and autism (see ).

Psychopathology, social adjustment and personality correlates of schizotypy clusters in a large nonclinical sample - Corrected Proof

Neus Barrantes-Vidal, Kathryn E. Lewandowski, Thomas R. Kwapil — 2010-02-08

Abstract: Introduction: Correlational methods, unlike cluster analyses, cannot take into account the possibility that individuals score highly on more than one symptom dimension simultaneously. This may account for some of the inconsistency found in the literature of correlates of schizotypy dimensions. This study explored the clustering of positive and negative schizotypy dimensions in nonclinical subjects and whether schizotypy clusters have meaningful patterns of adjustment in terms of psychopathology, social functioning, and personality.Methods: Positive and negative schizotypy dimensional scores were derived from the Chapman Psychosis-Proneness Scales for 6137 college students and submitted to cluster analysis. Of these, 780 completed the NEO-PI-R and Social Adjustment Scale-self report version, and a further 430 were interviewed for schizophrenia-spectrum, mood, and substance use psychopathology.Results: Four clusters were obtained: low (nonschizotypic), high positive, high negative, and mixed (high positive and negative) schizotypy. The positive schizotypy cluster presented high rates of psychotic-like experiences, schizotypal and paranoid symptoms, had affective and substance abuse pathology, and was open to experience and extraverted. The negative schizotypy cluster had high rates of negative and schizoid symptoms, impaired social adjustment, high conscientiousness and low agreeableness. The mixed cluster was the most deviant on almost all aspects.Conclusions: Our cluster solution is consistent with the limited cluster analytic studies reported in schizotypy and schizophrenia, indicating that meaningful profiles of schizotypy features can be detected in nonclinical populations. The clusters identified displayed a distinct and meaningful pattern of correlates in different domains, thus providing construct validity to the schizotypy types defined.

Grey matter changes associated with host genetic variation and exposure to Herpes Simplex Virus 1 (HSV1) in first episode schizophrenia - Corrected Proof

2010-02-08

Abstract: Background: We previously reported reduced prefrontal cortex (PFC) grey matter volume among first episode, antipsychotic-naïve schizophrenia subjects (SZ) exposed to HSV1 but not among healthy subjects (HS) (Prasad et al., 2007). Independently, rs1051788, an exonic polymorphism of the MHC Class I polypeptide-related sequence B (MICB) gene was associated with HSV1 seropositivity, as well as SZ risk. In this study, we examined whether PFC grey matter changes associated with HSV1 exposure varied against the background of MICB genotypes.Methods: We examined Caucasian individuals from the sample we studied in our previous report (Prasad et al., 2007) (SZ, n=21 and HS, n=19). Whole brain voxelwise analysis of structural MRI scans was conducted using Statistical Parametric Mapping, ver 5 (SPM5). The impact of rs1051788 variation and HSV1 seropositivity on grey matter volumes was examined using regression models on the combined sample of cases and controls, and then within each diagnostic group.Results: In the combined sample of cases and controls, we observed the main effects of HSV1 seropositivity and genotypes, and a significant joint effect of HSV1 seropositivity and genotype mainly in the PFC. The joint effect was more prominent among cases than among controls.Discussion: Our observations suggest that rs1051788 and HSV1 seropositivity are associated individually and jointly with reduced PFC grey matter volume. The patterns of these associations differ by diagnostic status, and these factors explain only a “small” portion of the variance in the grey matter volume reductions.

Processing of facial configuration in individuals at ultra-high risk for schizophrenia - Corrected Proof

2010-02-05

Abstract: Background: Discrepancies in the ability to recognize faces constitute an important aspect of the impaired social cognitive abilities of patients with schizophrenia. Previous studies have suggested that specific problems with the processing of facial configuration affect the face-recognition deficit in patients with schizophrenia. However, little is known about whether these deficits in face recognition are present before the onset of schizophrenia.Method: This study compared performances on a face processing task among three groups: individuals at ultra-high risk for schizophrenia (n=20), patients with schizophrenia (n=18), and normal controls (n=20) using a face-discrimination task involving pairs of photographs depicting upright and inverted images with changing features and configurations. Chair stimuli were used as the control task.Results: The individuals at ultra-high risk for schizophrenia performed more poorly than did normal controls with regard to the processing of facial configuration but not the facial feature and did not differ significantly from the patients with schizophrenia with regard to the processing of facial configuration and upright facial features.Conclusion: This study suggests that a specific dysfunction in the processing of facial configuration, which has an impact on face recognition, might be present before and deteriorate in patients with schizophrenia. Deficits in face recognition among individuals at risk for psychosis might contribute significantly to the social dysfunction associated with schizophrenia.

Quality assessment and comparison of evidence for electroconvulsive therapy and repetitive transcranial magnetic stimulation for schizophrenia: A systematic meta-review - Corrected Proof

S.L. Matheson, M.J. Green, C. Loo, V.J. Carr — 2010-02-01

Abstract: Background: Randomized studies directly comparing the effects of electroconvulsive therapy (ECT) and repetitive transcranial magnetic stimulation (rTMS) for depression generally favour ECT. ECT and rTMS have also been investigated for chronic symptoms of schizophrenia although there are no direct comparisons available.Aims: We sought to determine the relative benefits and adverse outcomes of ECT and rTMS by comparing effect sizes reported in systematic reviews and to quality assess this evidence using GRADE and QUOROM guidelines.Method: Included are systematic reviews with meta-analysis published since 2000, reporting results for people with a diagnosis of schizophrenia, schizoaffective disorder, schizophreniform disorder or first episode schizophrenia. Medline, Embase, CINAHL, Current Contents, PsycINFO and the Cochrane library were searched and hand searching was conducted. Data extraction and quality assessment were completed by two independent reviewers.Results: Fifty-three of 58 reviews were excluded as they did not meet inclusion criteria. The remaining five have a low probability of reporting bias and show that high quality evidence suggests a short-term, medium to large treatment effect of rTMS for auditory hallucinations (d=0.88) but not other symptoms, for people treated with concurrent antipsychotics. For ECT, high quality evidence suggests a short-term small, significant effect for improvement in global symptoms, for people with or without concurrent antipsychotics (RR=0.76). There is no evidence for longer-term therapeutic or adverse effects of either treatment.Conclusions: It is worthwhile considering rTMS in cases where auditory hallucinations have not responded to antipsychotic medications and ECT where overall symptoms have not responded to antipsychotic medications.

Prenatal tobacco exposure in first-episode psychosis - Corrected Proof

2010-01-29

Recent research findings leave no reasonable doubt that prenatal tobacco exposure (PTE) impairs fetal brain development (). Smoking also impairs placental functioning and leads to fetal undernourishment and a dose-dependent restriction in growth (). Maternal smoking also results in fetal glucocorticoid over-activity and elevated stress hormones in newborns (). Finally, maternal smoking compromises fetal immune-system development and results in long-term suppression of the immune response (). The negative consequences of PTE for health, cognition and behavior during childhood and beyond are well documented (). Recent findings suggest that PTE may also increase the risk for psychosis (). Despite strong evidence for the neuroteratogenic effects of nicotine, few studies have assessed the risks associated with PTE in psychiatric patients.

Has an important test been overlooked? Closure flexibility in schizophrenia - Corrected Proof

Pamela D. Butler, Isaac Schechter, Nadine Revheim, Gail Silipo, Daniel C. Javitt — 2010-01-28

Abstract: Deficits in visual processing are now recognized as a core feature of schizophrenia. In the 1940s, Louis Thurstone developed a series of tests designed to evaluate specific aspects of visual perceptual processing including the Closure Flexibility Test (CFT), which was designed to measure “the ability to hold a configuration in mind despite distraction.” The present study evaluated patients' performance on this task and its relationship to other tests of neuropsychological function, particularly to a measure of sustained visual attention. Thirty-nine patients with schizophrenia or schizoaffective disorder and 40 controls participated. The CFT was administered both in its original form (10min) and also in a briefer form (3min) in which only a portion of stimuli were given. Patients showed highly significant large effect-size deficits on both the original (d=1.6) and brief (d=1.2) CFT. Between-group deficits in performance survived co-variation for IQ. In addition, the CFT score was significantly related to performance on the MATRICS measure of attention/vigilance, the Continuous Performance Test—Identical Pairs version (CPT-IP). This correlation remained significant even after controlling for non-specific intercorrelations among neurocognitive measures. Results confirm the severity of early visual processing deficits in schizophrenia. In addition, the CFT is a brief, easy to administer alphabet-independent, paper-and-pencil test with established psychometric properties that may be useful as an index of the sustained visual attention construct in schizophrenia.

Severe injuries in adolescence predict psychosis: A nested case control study of the Northern Finland 1966 Birth Cohort - Corrected Proof

Suvi Luoma, Helinä Hakko, Mauri Marttunen, Anja Taanila, Sari Lindeman — 2010-01-25

Abstract: Adolescents who later develop schizophrenia are likely to have problems with motor coordination and many adolescents with schizophrenia have self-injurious behaviour before treatment of first psychosis but association between injuries in adolescence and onset of psychotic disorder is unknown. The aim of this study was to describe what type of injuries psychotic individuals had during adolescence and in which age these injuries occurred. The study population consists of 155 members of the Northern Finland 1966 Birth Cohort with diagnosis of schizophrenia spectrum disease and 620 matched controls. All injuries which had occurred before onset of psychosis were extracted from Finnish Hospital Discharge Register. Individuals with psychotic disorder were more likely to have a history of severe injury. During the age 12–19, 11% of psychotic subjects and 5.3% of healthy controls had an injury (z=2.38; P=0.017) and the most common type of injury was fractures. Our findings suggest that severe injury in adolescence may be a predictor of psychosis.

Reduced white matter integrity as a neural correlate of social cognition deficits in schizophrenia - Corrected Proof

2010-01-25

Abstract: Background: The pathology of schizophrenia is thought to involve multiple gray and white matter regions. A number of studies have revealed impaired social cognition in schizophrenia. Some evidence suggests an association of this social cognition deficit with gray matter reductions in ‘social brain’ areas. However, no study has yet revealed the association between social cognition abilities and white matter abnormalities in schizophrenia patients.Methods: Twenty-six schizophrenia patients and 27 healthy controls underwent the Perception of Affect Task (PAT), which consisted of four subtasks measuring different aspects of emotion attribution. Voxelwise group comparison of white matter fractional anisotropy (FA) was performed using tract-based spatial statistics (TBSS). The relation between impaired social cognition ability and FA reduction was examined in patients for each subtask, using simple regression analysis within brain areas that showed a significant FA reduction in patients compared with controls. The same correlational analysis was also performed for healthy controls in the whole brain.Results: Schizophrenia patients showed reduced emotion attribution ability compared with controls in all four subtasks. The facial emotion perception subtask showed a significant correlation with FA reductions in the left occipital white matter region and left posterior callosal region. The correlational analyses in healthy controls revealed no significant correlation of FA with any of the PAT subtasks.Conclusions: Our voxelwise correlational analysis of white matter provided a potential neural basis for the social cognition impairments in schizophrenia, in support of the disconnection hypothesis.

Antipsychotic drug use is correlated with CRP40/mortalin mRNA expression in the dorsolateral prefrontal cortex of human postmortem brain specimens - Corrected Proof

2010-01-25

Abstract: Heat shock proteins act as intracellular chaperones by assisting with proper protein folding in response to various cellular stresses. In doing so, these proteins protect the cell from unwanted protein aggregation, which in turn, plays an important role in the pathogenesis of numerous disorders. Previous reports from our laboratory have described a 40kDa catecholamine regulated heat shock-like protein (CRP40), an alternate gene product of the 70kDa mitochondrial heat shock protein, mortalin. CRP40 shares an intimate association with dopaminergic activity, specifically as it pertains to dopamine dysregulation in schizophrenia. This study investigates human CRP40/mortalin mRNA expression within dorsolateral prefrontal cortex postmortem specimens from normal control, schizophrenic and bipolar patients obtained from the Stanley Medical Research Institute. Real-time polymerase chain reaction was carried out for all patient samples (n=105; n=35 per group) in a blinded manner. No significant alterations in CRP40/mortalin mRNA expression levels were observed between control, bipolar and schizophrenic patients. However, multiple regression demonstrated a distinct positive correlation between CRP40/mortalin mRNA expression and lifetime use of antipsychotic drugs within the schizophrenic patient profile, after controlling for important confounding factors. Thus, the data suggest that human CRP40/mortalin is modulated by dopaminergic activity and may act to protect neurons from excess catecholamine activity in regions of the brain associated with psychosis.

Subcortical alignment precision in patients with schizophrenia - Corrected Proof

2010-01-25

Abstract: Previous work has demonstrated less accurate alignment of cortical structures for patients with schizophrenia than for matched control subjects when using affine registration techniques. Such a mismatch presents a potential confound for functional neuroimaging studies conducting between-group comparisons. Critically, the same issues may be present for subcortical structures. However, to date no study has explicitly investigated alignment precision for major subcortical structures in patients with schizophrenia. Thus, to address this question we used methods previously validated for assessment of cortical alignment precision to examine alignment precision of subcortical structures. In contrasts to our results with cortex, we found that major subcortical structures (i.e. amygdala, caudate, hippocampus, pallidum, putamen and thalamus) showed similar alignment precision for schizophrenia (N=48) and control subjects (N=45) regardless of the template used (other individuals with schizophrenia or healthy controls). Taken together, the present results show that, unlike cortex, alignment for six major subcortical structures is not compromised in patients with schizophrenia and as such is unlikely to confound between-group functional neuroimaging investigations.

Decreased BDNF in patients with antipsychotic naïve first episode schizophrenia - Corrected Proof

2010-01-22

Abstract: Objective: Brain-derived neurotrophic factor (BDNF) is a key factor known to mediate neuronal proliferation, differentiation, survival and response to stress. Decreases in BDNF levels have been reported in schizophrenia, but studies in treatment naïve patients are few. Herein we report on serum BDNF levels in a series of patients with first-episode treatment naïve psychoses in comparison to age matched healthy controls.Method: Fasting serum BDNF levels were measured in 41 patients with treatment naive first episode psychosis (24 with schizophrenia, schizoaffective disorder or schizophreniform disorder, and 17 with non-schizophrenia psychotic disorders) and 41 age-matched healthy controls.Results: A three group analyses of covariance (ANCOVA) showed a diagnosis effect (p=.038) in which patients with schizophrenia had lesser serum BDNF levels than patient with non-schizophrenia psychosis, who in turn had lesser BDNF levels than matched healthy controls. Planned two-group ANCOVAs suggested that patients with schizophrenia had lower serum BDNF level than matched controls (p=.016), whereas patients with non-schizophrenia psychosis did not differ from controls. There were no age effects on BDNF, but there was a trend (p=.08) for a gender by group interaction with greater reductions in female patients with schizophrenia. The BDNF levels did not correlate with magnitude of smoking, body mass index, severity of positive and negative symptoms or overall functioning.Conclusions: Serum BDNF may be reduced at the onset of psychosis but its role in the pathogenesis of schizophrenia remains unclear. Elucidating the role of BDNF in schizophrenia and related psychotic disorders may provide an important therapeutic target. Further studies are also needed to examine if patients with schizophrenia have more pronounced reductions in BDNF than those with affective psychosis.

Schizophrenia patients with polydipsia and water intoxication are characterized by greater severity of psychotic illness and a more frequent history of alcohol abuse - Corrected Proof

2010-01-22

Abstract: Polydipsia and water intoxication (PWI) are relatively frequent among schizophrenic subjects, particularly in institutional settings and may lead to severe complications. However, little is known on their association with other characteristics of psychosis. Hence, we took advantage of a cohort of 114 subjects extensively assessed on natural history and clinical variables to examine the correlates of PWI in chronic schizophrenia.We randomly sampled DSM-IV schizophrenic subjects from: i) a lower functioning subgroup, i.e., long-term psychiatric wards or highly structured group housing facilities; and ii) a higher functioning subgroup, i.e., patients living in the community without supervision. Subjects were assessed from multiple sources for lifetime severity of positive, disorganisation, negative and depressive symptoms, premorbid adjustment, age of onset, level of functioning, comorbid diagnoses of substance abuse and lifetime history of PWI.Twelve subjects (10.5%) met our PWI criteria. We observed more severe psychotic symptoms, earlier onset, poorer current adjustment and more frequent prior alcohol use disorder in PWI subjects. When restricting comparisons to patients living in institutional setting, differences on clinical and natural history variables vanished but the association between PWI and prior alcohol abuse persisted (72.7% in PWI vs. 21.4% in non-PWI subjects, p<0.01). Onset of alcohol abuse predated the onset of PWI by a mean of 12.8years.PWI schizophrenic subjects are characterized by a non-specific greater severity on a broad array of clinical and natural history variables and by a specific association with prior alcohol abuse. Thus, our data suggest that a greater severity of illness and a prior history of alcohol use disorders interact in increasing the risk of developing PWI in chronic schizophrenic patients.

Memory profiles in schizophrenia: Categorization validity and stability - Corrected Proof

Morris D. Bell, Jason K. Johannesen, Tamasine C. Greig, Bruce E. Wexler — 2010-01-20

Abstract: Background: Memory profiles corresponding to nearly normal (NN), Subcortical impairment (Sub) and Cortical impairment (Cort) have been identified in schizophrenia by several investigators using cluster analytic techniques. Specific aims of the current study were to (1) perform a K means cluster analysis using Hopkins Verbal Learning Test-R scores (2) create classification rules based upon cluster distributions and expected memory profiles and to determine their concordance with cluster analysis; (3) explore differences among classified groups on demographic, neurocognitive and social cognitive domains; and (4) determine the stability of the classifications 12months later.Methods: Clinical and neuropsychological assessments were obtained at intake and 12months from 151 outpatients with schizophrenia or schizoaffective disorder from an urban community mental health center.Results: Clusters corresponded to those of the three expected subgroups. Using simple decision rules, rationally-derived groups were created and had 90% classification agreement with cluster groups. Groups did not differ on illness characteristics. Groups differed significantly in neurocognitive and social cognitive domains with NN>Cort and NN>Sub in all domains except visual/motor speed. Sub>Cort in verbal working memory. NN>Cort in social cognition. Rationally derived groupings showed fair stability at 12month follow-up with 65% classification agreement. Specificity was good for NN (82.4%).Discussion: Results support validity of memory profiles and offer some support for their stability at 12months. The simple rules for classification can be used by other investigators for neuroimaging and other studies. Findings support the hypothesis that verbal memory may be an important source of heterogeneity in schizophrenia.

Challenging the assumption that improvement in functional outcomes is delayed relative to improvement in symptoms in the treatment of schizophrenia - Corrected Proof

2010-01-18

Abstract: Objectives: Functional improvement is generally thought to be distal to improvement in psychiatric symptoms in patients with schizophrenia. In this study, we assessed the effects of early response/non-response to an atypical antipsychotic across multiple outcome measures.Methods: This was a randomized, double-blind, flexible-dose, 12-week study that enrolled chronically-ill patients (n=628) diagnosed with schizophrenia or schizoaffective disorder who were experiencing acute symptom exacerbation. Patients were initially assigned to risperidone drug therapy (2–6mg/day), and their response status at 2weeks was determined. Early responders (ERs) continued with risperidone therapy, whereas early non-responders (ENRs) were randomized (1:1) in a double-blind manner to either continue on risperidone or switch to another atypical antipsychotic for 10 additional weeks of therapy. Subsequent treatment outcomes were measured by the Quality of Life Scale (QLS), Schizophrenia Objective Functioning Instrument (SOFI), and Subjective Well-being under Neuroleptics (SWN-K) scale.Results: Compared to ENRs, ERs to risperidone showed significantly more improvement from baseline to endpoint on the QLS total score and all 4 categories (p<.01), the SOFI overall global score and all 4 domains (p<.001), and the SWN-K total score and all 5 subscales (p<.05). Among ERs, the majority of improvement had already been attained by Week 2. There was concordance among clinician- and patient-rated scales across outcomes.Conclusion: Improvement across multiple outcome dimensions was not delayed relative to improvement in psychiatric symptoms. Rather, patients who showed an early response to antipsychotic treatment as defined by improvement in psychiatric symptoms also showed early and consistent improvement in functioning, quality of life, and subjective well-being.