Schizophrenia Bulletin - Advance Access

Predictors of Outcome in Brief Cognitive Behavior Therapy for Schizophrenia

Brabban, A., Tai, S., Turkington, D. — 2009-07-01

Antipsychotic medications, while effective, often leave patients with ongoing positive and negative symptoms of schizophrenia. Guidelines recommend using cognitive behavior therapy (CBT) with this group. Clearly, mental health professionals require training and supervision to deliver CBT-based interventions. This study tested which antipsychotic-resistant patients were most likely to respond to brief CBT delivered by psychiatric nurses. Staff were trained over 10 consecutive days with ongoing weekly supervision. Training for carers in the basic principles of CBT was also provided. This article represents the secondary analyses of completer data from a previously published randomized controlled trial (Turkington D, Kingdon D, Turner T. Effectiveness of a brief cognitive-behavioural therapy intervention in the treatment of schizophrenia. Br J Psychiatry. 2002;180:523–527) (n = 354) to determine whether a number of a priori variables were predictive of a good outcome with CBT and treatment as usual. Logistic regression was employed to determine whether any of these variables were able to predict a 25% or greater improvement in overall symptoms and insight. In the CBT group only, female gender was found to strongly predict a reduction in overall symptoms (P = .004, odds ratio [OR] = 2.39, 95% confidence interval [CI] = 1.33, 4.30) and increase in insight (P = .04, OR = 1.84, 95% CI = 1.03, 3.29). In addition, for individuals with delusions, a lower level of conviction in these beliefs was associated with a good response to brief CBT (P = .02, OR = 0.70, 95% CI = 0.51, 0.95). Women with schizophrenia and patients with a low level of conviction in their delusions are most likely to respond to brief CBT and should be offered this routinely alongside antipsychotic medications and other psychosocial interventions.

Selective Emotional Processing Deficits to Social Vignettes in Schizophrenia: An ERP Study

Kuperberg, G. R., Kreher, D. A., Swain, A., Goff, D. C., Holt, D. J. — 2009-06-29

Schizophrenia is associated with abnormalities in emotional processing and social cognition. However, it remains unclear whether patients show abnormal neurophysiological responses during fast, online appraisals of the emotional meaning of social information. To examine this question, event-related potentials (ERPs) were collected while 18 schizophrenia patients and 18 demographically matched controls evaluated 2-sentence vignettes describing negative, positive, or neutral social situations. ERPs were time locked to a critical word (CW) in the second sentence that conferred emotional valence. A late positivity effect to emotional (vs neutral) CWs was seen in both groups (in controls, to negative and positive CWs; in patients, to negative CWs only). However, the controls showed a greater late positivity effect to the negative and positive (vs neutral) CWs than the schizophrenia patients at mid-posterior (negative vs neutral) and at right posterior peripheral (positive vs neutral) sites. These between-group differences arose from reduced amplitudes of the late positivity to the negative and positive CWs in the patients relative to the controls; there was no difference between the 2 groups in the amplitude of the late positivity to the neutral CWs. These findings suggest that schizophrenia is associated with a specific neural deficit during the online evaluation of emotionally valent, socially relevant information.

The Spectrum of Sanity and Insanity

Reina, A. — 2009-06-26

Gray Matter Deficits, Mismatch Negativity, and Outcomes in Schizophrenia

2009-06-26

Reduced mismatch negativity (MMN) in response to auditory change is a well-established finding in schizophrenia and has been shown to be correlated with impaired daily functioning, rather than with hallmark signs and symptoms of the disorder. In this study, we investigated (1) whether the relationship between reduced MMN and impaired daily functioning is mediated by cortical volume loss in temporal and frontal brain regions in schizophrenia and (2) whether this relationship varies with the type of auditory deviant generating MMN. MMN in response to duration, frequency, and intensity deviants was recorded from 18 schizophrenia subjects and 18 pairwise age- and gender-matched healthy subjects. Patients’ levels of global functioning were rated on the Social and Occupational Functioning Assessment Scale. High-resolution structural magnetic resonance scans were acquired to generate average cerebral cortex and temporal lobe models using cortical pattern matching. This technique allows accurate statistical comparison and averaging of cortical measures across subjects, despite wide variations in gyral patterns. MMN amplitude was reduced in schizophrenia patients and correlated with their impaired day-to-day function level. Only in patients, bilateral gray matter reduction in Heschl's gyrus, as well as motor and executive regions of the frontal cortex, correlated with reduced MMN amplitude in response to frequency deviants, while reduced gray matter in right Heschl's gyrus also correlated with reduced MMN to duration deviants. Our findings further support the importance of MMN reduction in schizophrenia by linking frontotemporal cerebral gray matter pathology to an automatically generated event-related potential index of daily functioning.

The Relationship Among Neuregulin 1-Stimulated Phosphorylation of AKT, Psychosis Proneness, and Habituation of Arousal in Nonclinical Individuals

Keri, S., Seres, I., Kelemen, O., Benedek, G. — 2009-06-23

Background: Previous studies reported an association between weak habituation of skin conductance orienting response and psychosis proneness. The aim of this study was to investigate the relationship among neuregulin 1 (NRG1)–stimulated AKT phosphorylation (a putative marker of psychosis), orienting response habituation, delusional ideas, anxiety, and depression in nonclinical individuals. Methods: One hundred twenty individuals participated in the skin conductance measurements. Weak and strong habituators were compared on measures of NRG1-stimulated AKT phosphorylation in B lymphoblasts, delusional ideas, anxiety, and depression. The predictors of delusional ideas were determined by multiple regression analysis. Results: Weak habituators displayed higher levels of delusional ideas/anxiety and a lower ratio of phosphorylated AKT as compared with strong habituators. There were 3 significant predictors of delusional ideas: decreased habituation, NRG1-induced AKT phosphorylation, and anxiety. Age, gender, education, IQ, and depression did not predict delusional ideas. Conclusions: These results suggest that decreased habituation of arousal, NRG1-induced AKT phosphorylation, and anxiety are related to delusional ideation in the general population.

Hippocampi, Thalami, and Accumbens Microstructural Damage in Schizophrenia: A Volumetry, Diffusivity, and Neuropsychological Study

2009-06-19

Volumetric abnormalities in the subcortical structures have been described in schizophrenia. However, it still has to be clarified if subtle microstructural damage is also present. Thus, we aimed to detect subcortical volume and mean diffusivity (MD) alterations in 45 patients with diagnosis of schizophrenia compared with 45 age-, gender-, and educational attainment–matched healthy comparison (HC) participants, by using a combined volumetry and diffusion tensor imaging (DTI) method. A secondary aim was to identify the neuropsychological correlates of subcortical abnormalities in the schizophrenic group. We found thalami and hippocampi bilaterally and left accumbens to show MD increase in the schizophrenic group. No volumetric decrease was found. Moreover, significant correlations between the MD values in subcortical structures (right thalamus and hippocampus and left accumbens) and working memory performance were found. Thus, subcortical microstructural alterations are present in schizophrenia even in absence of volumetric abnormalities. Furthermore, microstructural damage in subcortical areas is linked to working memory, suggesting the presence of a subtle microstructural subcortical dysfunction in the pathoetiological mechanism underlying high cognitive load performances in schizophrenia. Finally, our findings indicate that MD is a more sensitive marker of brain tissue deficits than signal intensity variations measured in T1-weighted imaging data, consistently with previous reports. Thus, DTI appears to be an invaluable tool to investigate subcortical pathology in schizophrenia, greatly enhancing the ability to detect subtle brain changes in this complex disorder.

Are Screening Instruments Valid for Psychotic-Like Experiences? A Validation Study of Screening Questions for Psychotic-Like Experiences Using In-Depth Clinical Interview

Kelleher, I., Harley, M., Murtagh, A., Cannon, M. — 2009-06-19

Individuals who report psychotic-like experiences are at increased risk of future clinical psychotic disorder. They constitute a unique "high-risk" group for studying the developmental trajectory to schizophrenia and related illnesses. Previous research has used screening instruments to identify this high-risk group, but the validity of these instruments has not yet been established. We administered a screening questionnaire with 7 items designed to assess psychotic-like experiences to 334 adolescents aged 11–13 years. Detailed clinical interviews were subsequently carried out with a sample of these adolescents. We calculated sensitivity and specificity and positive predictive value (PPV) and negative predictive value (NPV) for each screening question for the specific symptom it enquired about and also in relation to any psychotic-like experience. The predictive power varied substantially between items, with the question on auditory hallucinations ("Have you ever heard voices or sounds that no one else can hear?") providing the best predictive power. For interview-verified auditory hallucinations specifically, this question had a PPV of 71.4% and an NPV of 90.4%. When assessed for its predictive power for any psychotic-like experience (including, but not limited to, auditory hallucinations), it provided a PPV of 100% and an NPV of 88.4%. Two further questions—relating to visual hallucinations and paranoid thoughts—also demonstrated good predictive power for psychotic-like experiences. Our results suggest that it may be possible to screen the general adolescent population for psychotic-like experiences with a high degree of accuracy using a short self-report questionnaire.

Ziprasidone Vs Olanzapine in Recent-Onset Schizophrenia and Schizoaffective Disorder: Results of an 8-Week Double-Blind Randomized Controlled Trial

2009-06-19

Introduction: Head-to-head comparisons of antipsychotics have predominantly included patients with chronic conditions. The aim of the present study was to compare the efficacy and tolerability of ziprasidone and olanzapine in patients with recent-onset schizophrenia. Methods: The study was an 8-week, double-blind, parallel-group, randomized, controlled multicenter trial (NCT00145444). Seventy-six patients with schizophreniform disorder, schizophrenia or schizoaffective disorder (diagnosis < 5 y), and a maximum lifetime antipsychotic treatment <16 weeks participated in the study. Efficacy of ziprasidone (80–160 mg/d) and olanzapine 10–20 mg was measured using the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression (CGI) Scale, the Calgary Depression Scale for Schizophrenia (CDSS), and the Heinrich Quality of Life Scale (HQLS); tolerability assessments included laboratory assessments, body weight, and electroencephalogram. Results: Olanzapine (n = 34) and ziprasidone (n = 39) showed equal efficacy as measured by the PANSS, CDSS, CGI, and HQLS. However, mean weight gain was significantly higher in the olanzapine group (6.8 vs 0.1 kg, P < .001). Ziprasidone was associated with decreasing levels of triglycerides, cholesterol, and transaminases, while these parameters increased in the olanzapine group (all P values < .05). There were no significant differences in fasting glucose and prolactin levels or in cardiac or sexual side effects. Patients on ziprasidone used biperiden for extrapyramidal side effects more frequently (P < .05). Discussion: The results of this study indicate that ziprasidone and olanzapine have comparable therapeutic efficacy but differ in their side effect profile. However, there is a risk of a type II error with this sample size. Clinically significant weight gain and laboratory abnormalities appear early after initiating treatment and are more prominent with olanzapine, while more patients on ziprasidone received anticholinergic drugs to treat extrapyramidal symptoms.

Trimethoprim as Adjuvant Treatment in Schizophrenia: A Double-Blind, Randomized, Placebo-Controlled Clinical Trial

2009-06-16

Various infectious agents, such as Toxoplasma gondii, have been hypothesized to be potentially relevant etiological factors in the onset of some cases of schizophrenia. We conducted a randomized, double-blind, placebo-controlled treatment trial in an attempt to explore the hypothesis that the symptoms of schizophrenia may be related to infection of the central nervous system with toxoplasma gondii. Systematically selected patients with ongoing and at least moderately severe schizophrenia from Butajira, in rural Ethiopia, were randomly allocated to trimethoprim or placebo, which were added on to participants' regular antipsychotic treatments. Trial treatments were given for 6 months. The Positive and Negative Syndrome Scale (PANSS) was used to assess outcome. Ninety-one patients were included in the study, with 80 cases (87.9%) positive for T. gondii immunoglobulin G antibody. Seventy-nine subjects (87.0%) completed the trial. The mean age of subjects was 35.3 (SD = 8.0) years, with a mean duration of illness of 13.2 (SD = 6.7) years. Both treatment groups showed significant reduction in the overall PANSS score with no significant between-group difference. In this sample of patients with chronic schizophrenia, trimethoprim used as adjuvant treatment is not superior to placebo. However, it is not possible to draw firm conclusion regarding the etiological role of toxoplasmosis on schizophrenia based on this study because the timing and the postulated mechanisms through which toxoplasmosis produces schizophrenia are variable.

Looking at the Schizophrenia Spectrum Through the Prism of Self-disorders: An Empirical Study

Raballo, A., Saebye, D., Parnas, J. — 2009-06-15

Nonpsychotic anomalies of subjective experience were emphasized in both classic literature and phenomenological psychiatry as essential clinical features of schizophrenia. However, only in recent years, their topicality with respect to the construct validity of the concept of the schizophrenia spectrum has been explicitly acknowledged, mainly as a consequence of the increasing focus on early detection and prevention of psychosis. The current study tested the hypothesis of a specific aggregation of self-disorders (SDs, various anomalies of self-awareness) in schizophrenia-spectrum conditions, comparing different diagnostic groups; 305 subjects, previously assessed in the Copenhagen Schizophrenia Linkage Study, were grouped into 4 experimental samples, according to their Diagnostic and Statistical Manual of Mental Disorders (Third Edition Revised) main diagnosis: schizophrenia, (n = 29), schizotypal personality disorder (n = 61), other mental illness not belonging to the schizophrenia spectrum (n = 112), and no mental illness (n = 103). The effect of diagnostic grouping on the level of SDs was explored via general linear model and logistic regression. The diagnosis of schizophrenia and schizotypy predicted higher levels of SDs, and SDs scores were significantly different between spectrum and nonspectrum samples; the likelihood of experiencing SDs increased as well with the diagnostic severity. The findings support the assumption that SDs are a discriminant psychopathological feature of the schizophrenia spectrum and suggest their incorporation to strengthen its construct validity, with potential benefit for both early detection and pathogenetic research.

Validating Measures of Real-World Outcome: The Results of the VALERO Expert Survey and RAND Panel

Leifker, F. R., Patterson, T. L., Heaton, R. K., Harvey, P. D. — 2009-06-12

Background: People with schizophrenia demonstrate considerable discrepancy between self-reported functioning and informant reports. It is not clear whether these discrepancies originate from the instruments used or from the perspectives of different informants. The goal of the Validation of Everyday Real-World Outcomes (VALERO) Study is to enhance the measurement of real-world (RW) outcomes in the social, residential, and vocational domains through selection of optimal scales and informants using a multistep process similar to the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative. Methods: Forty-eight experts provided their opinion regarding the best scales measuring RW outcomes. Fifty-nine measures were nominated. The investigators selected the 11 scales that were the most highly nominated, had the most published validity data, and best represented the domains of interest. Information was provided to other experts who served as RAND panelists. Panelists rated each measure for its suitability across multiple a priori domains. Discrepant ratings were discussed until consensus was reached. Results: Following the RAND Panel, the 2 scales that scored highest across the various criteria for each of the classes of scales (hybrid, social functioning, and everyday living skills) were selected for use in the first substudy of VALERO. The scales selected were the Quality-of-Life Scale, Specific Levels of Functioning Scale, Social Behavior Schedule, Social Functioning Scale, Independent Living Skills Schedule, and Life Skills Profile. Discussion: The results show that although there are significant limitations with current scales used for the assessment of RW outcome in schizophrenia, a consensus is possible. Further, several existing instruments were rated as useful for measuring social, residential, and vocational outcomes.

Presynaptic Regulation of Dopamine Transmission in Schizophrenia

2009-06-12

A role for dopamine (DA) release in the hallucinations and other positive symptoms associated with schizophrenia has long been inferred from the antipsychotic response to D2 DA receptor antagonists and because the DA releaser amphetamine can be psychotogenic. Recent studies suggest that patients with schizophrenia, including those never exposed to antipsychotic drugs, maintain high presynaptic DA accumulation in the striatum. New laboratory approaches are elucidating mechanisms that control the level of presynaptic DA stores, thus contributing to fundamental understanding of the basic pathophysiologic mechanism in schizophrenia.

A Randomized Experimental Investigation of Reasoning Training for People With Delusions

Ross, K., Freeman, D., Dunn, G., Garety, P. — 2009-06-11

The present study aimed to investigate whether a brief reasoning training module changes the "jumping to conclusions" data gathering bias in people with delusions. A secondary aim was to examine whether improvements in reasoning would lead to greater flexibility in thinking about delusions. It was found that people with delusions and a diagnosis of schizophrenia (n = 34) requested less information on a reasoning task compared with a nonclinical control group (n = 34). The clinical group was then randomly allocated to a session of reasoning training or to an attention control condition. Following training, participants showed a significant increase in data gathering, and a small number reported more flexibility and less conviction in their delusions, although this finding was not significant. The presence at baseline of an extreme reasoning bias moderated the effect of training. The study provides further confirmation of the jumping to conclusions bias and shows that data gathering can be improved, though the severest form of the bias is resistant to change. It is recommended that lengthier, delusion-related reasoning packages be developed and evaluated.

Powerful Choices: Peer Support and Individualized Medication Self-Determination

West, C. — 2009-06-10

Peer support is unique in the mental health field because peer specialists provide a role model of recovery to both staff and people in recovery. Peer support as an evidence-based practice is reviewed. A personal recovery story and the experience of working as a certified peer specialist are shared to show the power peer supporters have in transforming the mental health system. Research supporting a more selective role for medication is reviewed along with the role of peer supporters in helping individuals to maximize their own unique medication needs with self-advocacy and negotiation skills. The importance of making choices is explained as a key motivating factor to keep both staff and people in recovery from giving up. Two main science-to-service gaps in real-world schizophrenia treatment are discussed: the lack of available peer support and the need for medication self-determination.

Is Early Intervention in Psychosis Cost-Effective Over the Long Term?

Mihalopoulos, C., Harris, M., Henry, L., Harrigan, S., McGorry, P. — 2009-06-09

Objective: This study assesses the long-term cost-effectiveness of a comprehensive model of mental health care for first-episode psychosis. The study is an extension of a previous economic evaluation of the Early Psychosis Prevention and Intervention Centre (EPPIC) that assessed the first-year costs and outcomes of treatment. Method: The current study used a matched, historical control group design with a follow-up of approximately 8 years. Complete follow-up data were available for 65 of the original 102 participants. Direct public mental health service costs incurred subsequent to the first year of treatment and symptomatic and functional outcomes of 32 participants initially treated for up to 2 years at EPPIC were compared with a matched cohort of 33 participants initially treated by generic mental health services. Treatment-related resource use was measured and valued using Australian published prices. Results: Almost 8 years after initial treatment, EPPIC subjects displayed lower levels of positive psychotic symptoms (P = .007), were more likely to be in remission (P = .008), and had a more favorable course of illness (P = .011) than the controls. Fifty-six percent of the EPPIC cohort were in paid employment over the last 2 years compared with 33% of controls (P = .083). Each EPPIC patient costs on average A$3445 per annum to treat compared with controls, who each costs A$9503 per annum. Conclusions: Specialized early psychosis programs can deliver a higher recovery rate at one-third the cost of standard public mental health services. Residual methodological limitations and limited sample size indicate that further research is required to verify this finding.

Prevalence of Celiac Disease and Gluten Sensitivity in the United States Clinical Antipsychotic Trials of Intervention Effectiveness Study Population

2009-06-03

Celiac disease (CD) and schizophrenia have approximately the same prevalence, but epidemiologic data show higher prevalence of CD among schizophrenia patients. The reason for this higher co-occurrence is not known, but the clinical knowledge about the presence of immunologic markers for CD or gluten intolerance in schizophrenia patients may have implications for treatment. Our goal was to evaluate antibody prevalence to gliadin (AGA), transglutaminase (tTG), and endomysium (EMA) in a group of individuals with schizophrenia and a comparison group. AGA, tTG, and EMA antibodies were assayed in 1401 schizophrenia patients who were part of the Clinical Antipsychotic Trials of Intervention Effectiveness study and 900 controls. Psychopathology in schizophrenia patients was assessed using the Positive and Negative Symptoms Scale (PANSS). Logistic regression was used to assess the difference in the frequency of AGA, immunoglobulin A (IgA), and tTG antibodies, adjusting for age, sex, and race. Linear regression was used to predict PANSS scores from AGA and tTG antibodies adjusting for age, gender, and race. Among schizophrenia patients, 23.1% had moderate to high levels of IgA-AGA compared with 3.1% of the comparison group (² = 1885, df = 2, P < .001.) Moderate to high levels of tTG antibodies were present in 5.4% of schizophrenia patients vs 0.80% of the comparison group (² = 392.0, df = 2, P < .001). Adjustments for sex, age, and race had trivial effects on the differences. Regression analyses failed to predict PANSS scores from AGA and tTG antibodies. Persons with schizophrenia have higher than expected titers of antibodies related to CD and gluten sensitivity.

Coronavirus Immunoreactivity in Individuals With a Recent Onset of Psychotic Symptoms

2009-06-02

Prenatal influenza exposure increases the risk for schizophrenia and brings to question how other respiratory viruses may contribute to neuropsychiatric disease etiopathology. Human coronaviruses cause respiratory infections that range in seriousness from common colds to severe acute respiratory syndrome. Like influenza, coronaviruses can be neurotropic. To test for associations between coronaviruses and serious mental disorders, we utilized a recently developed assay and measured immunoglobulin G (IgG) response against 4 human coronavirus strains (229E, HKU1, NL63, and OC43) in 106 patients with a recent onset of psychotic symptoms and 196 nonpsychiatric controls. We expressed results quantitatively as antibody levels and qualitatively as seroprevalence relative to a defined seropositivity cutoff value. Patient IgG levels were higher than controls for HKU1, NL63, and OC43, with HKU1 and NL63 both showing highly significant patient-to-control differences (HKU1, P ≤ .002; NL63, P ≤ .00001). All 4 coronaviruses were more seroprevalent in patients vs controls, with greatest intergroup differences observed for HKU1 (93% vs 77%, P ≤ .0001). HKU1 and NL63 associations with the patient group were further supported by multivariate analyses that controlled for age, gender, race, socioeconomic status, and smoking status (HKU1, odds ratio [OR] = 1.32, 95% confidence interval [CI] = 1.03–1.67, P ≤ .027; NL63, OR = 2.42, 95% CI = 1.25–4.66, P ≤ .008). Among patients, NL63 was associated with schizophrenia-spectrum (OR = 3.10, 95% CI = 1.27–7.58, P ≤ .013) but not mood disorders. HKU1 and NL63 coronavirus exposures may represent comorbid risk factors in neuropsychiatric disease. Future studies should explore links between the timing of coronavirus infections and subsequent development of schizophrenia and other disorders with psychotic symptoms.

Stigma Resistance in Patients With Schizophrenia

Sibitz, I., Unger, A., Woppmann, A., Zidek, T., Amering, M. — 2009-06-01

Background: An individual's capacity to counteract the stigma of mental illness, stigma resistance (SR), is considered as playing a crucial role in fighting stigma. However, little is known about SR and its correlates in patients with schizophrenia or schizoaffective disorder. Aim: Exploring SR in patients with schizophrenia or schizoaffective disorder. Method: One hundred fifty-seven participants completed the "Internalized Stigma of Mental Illness" (ISMI) Scale including its subscale on SR. Measures of perceived devaluation and discrimination, depression, self-esteem, empowerment, quality of life, and demographic and clinical variables were obtained. Results: Two-thirds of all patients showed high SR. SR correlated positively with self-esteem, empowerment, and quality of life and negatively with stigma measures and depression. A social network with a sufficient number of friends, being single or married, in contrast to being separated, as well as receiving outpatient treatment, was associated with higher SR. Conclusions: SR is a new and promising concept. The development of stigma-resisting beliefs might help individuals in their hope of finding a fulfilling life and in their recovery from mental illness.

Silencing the Self: Schizophrenia as a Self-disturbance

Kean, C. — 2009-05-28

Recovery as Discovery

Scotti, P. — 2009-05-25

This first person account describes recovery as discovery of new meanings and opportunities in life. It travels through a journey from illness to wellness, from darkness and despair to light and hope, from futility to fruitfulness, as well as, from a state of death and loss to new life.

Reinforcement Ambiguity and Novelty Do Not Account for Transitive Inference Deficits in Schizophrenia

2009-05-21

The capacity for transitive inference (TI), a form of relational memory organization, is impaired in schizophrenia patients. In order to disambiguate deficits in TI from the effects of ambiguous reinforcement history and novelty, 28 schizophrenia and 20 nonpsychiatric control subjects were tested on newly developed TI and non-TI tasks that were matched on these 2 variables. Schizophrenia patients performed significantly worse than controls on the TI task but were able to make equivalently difficult nontransitive judgments as well as controls. Neither novelty nor reinforcement ambiguity accounted for the selective deficit of the patients on the TI task. These findings implicate a disturbance in relational memory organization, likely subserved by hippocampal dysfunction, in the pathophysiology of schizophrenia.

Evidence That Onset of Clinical Psychosis Is an Outcome of Progressively More Persistent Subclinical Psychotic Experiences: An 8-Year Cohort Study

Dominguez, M.-d.-G., Wichers, M., Lieb, R., Wittchen, H.-U., van Os, J. — 2009-05-21

This study examined the hypothesis that developmental expression of psychometric risk in the form of subclinical psychotic experiences in the general population is usually transitory but in some instances may become abnormally persistent and progress to a clinical psychotic state. A prospective cohort study was conducted in a general population sample of 845 adolescents, aged 14–17 years, in Munich, Germany (Early Developmental Stages of Psychopathology Study). Expression of psychosis was assessed 4 times (T0–T3) over a period of 8.4 years. Transition from subclinical psychosis at T0–T2 to clinical psychosis in terms of impairment at T3 was examined as a function of the level of prior persistence of subclinical psychosis (present never, once, twice, or thrice). The more the subclinical psychosis persisted over the period T0–T2, the greater the risk of transition to clinical psychosis at T3 in a dose-response fashion (subclinical psychosis expression once over T0–T2: odds ratio [OR] = 1.5 [95% confidence interval {CI} = 0.6–3.7], posttest probability [PP] = 5%; twice: OR = 5.0 [95% CI = 1.6–15.9], PP = 16%; at all 3 measurements: OR = 9.9 [95% CI = 2.5–39.8], PP = 27%). Of all clinical psychosis at T3, more than a third (38.3%) was preceded by subclinical psychotic experiences at least once and a fifth (19.6%) at least twice. Consequently, a significant proportion of psychotic disorder may be conceptualized as the rare poor outcome of a common developmental phenotype characterized by persistence of psychometrically detectable subclinical psychotic experiences. This may be summarized descriptively as a psychosis proneness-persistence-impairment model of psychotic disorder.

Facial Emotion Processing in Schizophrenia: A Meta-analysis of Functional Neuroimaging Data

Li, H., Chan, R. C.K., McAlonan, G. M., Gong, Q.-y. — 2009-05-20

Background: People with schizophrenia have difficulty with emotion perception. Functional imaging studies indicate regional brain activation abnormalities in patients with schizophrenia when processing facial emotion. However, findings have not been entirely consistent across different studies. Methods: Activation likelihood estimation (ALE) meta-analyses were conducted to examine brain activation during facial emotion processing in patients with schizophrenia, controls, and patients compared with controls. Secondary meta-analyses were performed to assess the contribution of task design and illness chronicity to the results reported. Results: When processing facial expressions of emotions, both patients with schizophrenia and healthy controls activated the bilateral amygdala and right fusiform gyri. However, the extent of activation in these regions was generally much more limited in the schizophrenia samples. When directly compared with controls, the extent of activation in bilateral amygdala, parahippocampal gyrus and fusiform gyrus, right superior frontal gyrus, and lentiform nucleus was significantly less in patients. Patients with schizophrenia, but not controls, activated the left insula. A relative failure to recruit the amygdala in patients occurred regardless of whether the task design was explicit or implicit, while differences in fusiform activation were evident in explicit, not implicit, tasks. Restricting the analysis to patients with chronic illness did not substantially change the results. Conclusions: A marked underrecruitment of the amygdala, accompanied by a substantial limitation in activation throughout a ventral temporal-basal ganglia-prefrontal cortex "social brain" system may be central to the difficulties patients experience when processing facial emotion.

Neurocognitive Dysfunction in Bipolar and Schizophrenia Spectrum Disorders Depends on History of Psychosis Rather Than Diagnostic Group

2009-05-14

Objectives: Neurocognitive dysfunction is milder in bipolar disorders than in schizophrenia spectrum disorders, supporting a dimensional approach to severe mental disorders. The aim of this study was to investigate the role of lifetime history of psychosis for neurocognitive functioning across these disorders. We asked whether neurocognitive dysfunction in bipolar and schizophrenia spectrum disorders depends more on history of psychosis than diagnostic category or subtype. Methods: A sample of individuals with schizophrenia (n = 102), schizoaffective disorder (n = 27), and bipolar disorder (I or II) with history of psychosis (n = 75) and without history of psychosis (n = 61) and healthy controls (n = 280), from a large ongoing study on severe mental disorder, were included. Neurocognitive function was measured with a comprehensive neuropsychological test battery. Results: Compared with controls, all 3 groups with a history of psychosis performed poorer across neurocognitive measures, while the bipolar group without a history of psychosis was only impaired on a measure of processing speed. The groups with a history of psychosis did not differ from each other but performed poorer than the group without a history of psychosis on a number of neurocognitive measures. These neurocognitive group differences were of a magnitude expected to have clinical significance. In the bipolar sample, history of psychosis explained more of the neurocognitive variance than bipolar diagnostic subtype. Conclusions: Our findings suggest that neurocognitive dysfunction in bipolar and schizophrenia spectrum disorders is determined more by history of psychosis than by Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) diagnostic category or subtype, supporting a more dimensional approach in future diagnostic systems.

Oculomotor and Pupillometric Indices of Pro- and Antisaccade Performance in Youth-Onset Psychosis and Attention Deficit/Hyperactivity Disorder

Karatekin, C., Bingham, C., White, T. — 2009-05-08

The goals of the study were to examine inhibitory deficits on the antisaccade task in 8- to 20-year olds with youth-onset psychosis or attention deficit/hyperactivity disorder (ADHD) and healthy controls and to examine if age-related changes in performance differed across groups. In addition to the conventional measures of performance, pupillary dilations were used to obtain estimates of phasic and tonic level of arousal. Results showed that the psychosis, but not the ADHD, group had elevated antisaccade error rates; however, variability of error rates was high in all groups. These inhibitory failures were accompanied by a lower level of momentary cognitive effort (as indexed by pupillary dilations). The largest differences between the control and clinical groups were found not in the expected indices of inhibition but in the probability of correcting inhibitory errors and in variability of antisaccade response times, which were correlated with each other. These findings did not appear to be attributable to a deficit in maintaining task instructions in mind in either disorder or lack of motivation in ADHD. Instead, results point to impairments in both clinical groups in sustaining attention on a trial-by-trial basis, resulting in deficits in self-monitoring. Thus, results show inhibitory deficits in the context of more general attentional impairments in both disorders.

Fibroblast Growth Factors in Schizophrenia

Terwisscha van Scheltinga, A. F., Bakker, S. C., Kahn, R. S. — 2009-05-08

A large association study by O'Donovan et al recently suggested that genetic variation in fibroblast growth factor receptor (FGFR) 2 increases the risk for developing schizophrenia. Fibroblast growth factors (FGFs) are part of the family of glial growth factors; they control the growth and patterning of specific brain structures and regulate the maintenance and repair of neuronal tissues. In addition, a direct interaction was recently found between FGFRs and adenosine A_2A receptors, leading to corticostriatal plasticity and antagonizing the signaling pathway of dopamine D₂ receptors. These findings make FGFs plausible candidate genes for schizophrenia. Here, we review the role of FGFs in schizophrenia and combine evidence from studies on variations in FGF genes, RNA expression, protein levels, and FGF administration, as well as the effects of medication and environmental risk factors for schizophrenia. These data suggest that changes in the FGF system contribute to schizophrenia and possibly to a wider range of psychiatric disorders. The role of FGFs in schizophrenia and related disorders needs to be studied in more detail.

Ethnic Identity and the Risk of Schizophrenia in Ethnic Minorities: A Case-Control Study

Veling, W., Hoek, H. W., Wiersma, D., Mackenbach, J. P. — 2009-05-08

Objectives: The high incidence of schizophrenia in immigrant ethnic groups in Western Europe may be explained by social stress associated with ethnic minority status. Positive identification with one's own ethnic group is a strong predictor of mental health in immigrants. We investigated whether negative ethnic identity is related to schizophrenia risk in non-Western immigrants. Methods: Matched case-control study of first-episode schizophrenia, including 100 non-Western immigrant cases, general hospital controls (n = 100), and siblings (n = 63). Conditional logistic regression analyses were used to investigate associations between schizophrenia and ethnic group identity. Results: Cases had a negative ethnic identity more often than general hospital controls (64% and 35%, respectively, P < .001). After adjustment for marital status, level of education, unemployment, self-esteem, social support, and cannabis use, negative ethnic identity was associated with schizophrenia: odds ratio = 3.29; 95% confidence interval = 1.36–7.92. Cases significantly more often had an assimilated or a marginalized identity and less often had a separated identity. Comparisons between cases and siblings largely confirmed these findings. Conclusions: Negative identification with the own ethnic group may be a risk factor for schizophrenia in immigrants living in a context of social adversity.

The Effect of State Anxiety on Paranoid Ideation and Jumping to Conclusions. An Experimental Investigation

Lincoln, T. M., Lange, J., Burau, J., Exner, C., Moritz, S. — 2009-05-08

Theoretical models of persecutory delusions have emphasized the impact of reasoning biases and negative emotion at the early stages of symptom formation. However, the causal mechanisms remain unclear. This study tests the hypothesis that state anxiety will increase paranoid ideation and that this increase will be moderated by the level of individual vulnerability and mediated by the tendency to jump to conclusions. Healthy participants (n = 90) with varying levels of vulnerability (psychosis symptoms assessed by the Community Assessment of Psychic Experiences) were randomly assigned to either an anxiety or a nonanxiety condition. Anxiety was induced by pictures from the International Affective Picture System and by in sensu exposure to individual anxiety-provoking situations. During each condition, symptoms of paranoia were assessed by a state-adapted version of the Paranoia Checklist. Jumping to conclusions (JTC) was assessed using a modified version of the beads task. Overall, participants in the anxiety condition reported significantly more paranoid thoughts and showed more JTC than participants in the neutral condition. Participants with higher baseline vulnerability were more likely to show an increase in paranoia as reaction to the anxiety manipulation. Moreover, the association of anxiety and paranoia was mediated by the increased tendency to jump to conclusions in the beads task. The results are in line with a threat anticipation conceptualization of paranoia and provide evidence for an interaction of anxiety and reasoning biases in the development of paranoid beliefs. A combination of meta-cognitive training directed at reasoning biases and promoting emotion regulation skills might prove beneficial in preventing symptoms.

Concurrent Measurement of "Real-World" Stress and Arousal in Individuals With Psychosis: Assessing the Feasibility and Validity of a Novel Methodology

2009-05-08

Background: Psychosis has been repeatedly suggested to be affected by increases in stress and arousal. However, there is a dearth of evidence supporting the temporal link between stress, arousal, and psychosis during "real-world" functioning. This paucity of evidence may stem from limitations of current research methodologies. Our aim is to the test the feasibility and validity of a novel methodology designed to measure concurrent stress and arousal in individuals with psychosis during "real-world" daily functioning. Method: Twenty patients with psychosis completed a 36-hour ambulatory assessment of stress and arousal. We used experience sampling method with palm computers to assess stress (10 times per day, 10 AM -> 10 PM) along with concurrent ambulatory measurement of cardiac autonomic regulation using a Holter monitor. The clocks of the palm computer and Holter monitor were synchronized, allowing the temporal linking of the stress and arousal data. We used power spectral analysis to determine the parasympathetic contributions to autonomic regulation and sympathovagal balance during 5 minutes before and after each experience sample. Results: Patients completed 79% of the experience samples (75% with a valid concurrent arousal data). Momentary increases in stress had inverse correlation with concurrent parasympathetic activity ( = –.27, P < .0001) and positive correlation with sympathovagal balance ( = .19, P = .0008). Stress and heart rate were not significantly related ( = –.05, P = .3875). Conclusion: The findings support the feasibility and validity of our methodology in individuals with psychosis. The methodology offers a novel way to study in high time resolution the concurrent, "real-world" interactions between stress, arousal, and psychosis. The authors discuss the methodology's potential applications and future research directions.

Rate of Cannabis Use Disorders in Clinical Samples of Patients With Schizophrenia: A Meta-analysis

Koskinen, J., Lohonen, J., Koponen, H., Isohanni, M., Miettunen, J. — 2009-04-22

Objective: Our aim was to review recent studies and estimate the rate of cannabis use disorders (CUDs) in schizophrenia, as well as to examine the factors affecting this rate. Methods: We conducted an electronic search of 3 literature databases and a manual search of articles from 1996 to 2008. The key words used were "schizophreni*," "psychos*s," "psychotic," "cannabis abuse," "cannabis dependence," "cannabis use disorder," "substance use disorder," "substance abuse," "substance dependence," and "dual diagnosis." Articles that reported diagnoses according to the Diagnostic and Statistical Manual of Mental Disorders or International Classification of Diseases were included. Regression analysis was used to examine how estimated rates of CUDs are affected by various study characteristics such as the classification system, inpatient vs outpatient status, study location, proportion of males, age of the sample, or duration of illness. Results: Thirty-five studies met our search criteria. The median current rate of CUDs was 16.0% (interquartile range [IQR] = 8.6–28.6, 10 studies), and the median lifetime rate was 27.1% (IQR = 12.2–38.5, 28 studies). The median rate of CUDs was markedly higher in first-episode vs long-term patients (current 28.6%/22.0%, lifetime 44.4%/12.2%, respectively) and in studies where more than two-thirds of the participants were males than in the other studies (33.8%/13.2%). CUDs were also more common in younger samples than in the others (current 38.5%/16.0%, lifetime 45.0%/17.9%). Conclusions: Approximately every fourth schizophrenia patient in our sample of studies had a diagnosis of CUDs. CUDs were especially common in younger and first-episode patient samples as well as in samples with a high proportion of males.

Intrinsic Motivation Inventory: An Adapted Measure for Schizophrenia Research

Choi, J., Mogami, T., Medalia, A. — 2009-04-21

This article describes the psychometric validation of a scale designed to measure intrinsic motivation (IM) in schizophrenia. Recent studies have highlighted the relationship between motivation and functional outcome in schizophrenia and identified IM as an important mediating factor between neurocognition and psychosocial outcome. It therefore becomes imperative to have validated measures of IM for empirical use. To that end, we validated a self-report IM scale that gauges the central motivational structures identified by Self-determinism Theory as pertinent to cognitive task engagement, skill acquisition, treatment compliance, and remediation outcome. Participants were schizophrenia outpatients involved in a cognitive remediation study (n = 58), a convenience subsample of clinically stable schizophrenia outpatients (n = 15), and a group of healthy normals (n = 22). The Intrinsic Motivation Inventory for Schizophrenia Research (IMI-SR) is a concise instrument, possessing good internal consistency ( = .92) and test-retest reliability (intraclass correlation = .77). Data were analyzed to abridge the original 54 items into a final 21-item questionnaire comprised of 3 domains relevant to motivation for treatments (interest/enjoyment, perceived choice, value/usefulness). The scale was highly associated with germane constructs of motivation for health-related behaviors, including perceived competency for attempting challenging tasks and autonomous treatment engagement. Importantly, the scale was able to distinguish improvers and nonimprovers on a cognitive task and actual learning exercises, delineate high vs low treatment attendance, and demonstrate sensitivity to motivational changes due to intervention variation. The IMI-SR is a viable instrument to measure IM in schizophrenia as part of a cognitive remediation protocol or psychosocial rehabilitation program.

Validity of the Prodromal Risk Syndrome for First Psychosis: Findings From the North American Prodrome Longitudinal Study

2009-04-21

Treatment and prevention studies over the past decade have enrolled patients believed to be at risk for future psychosis. These patients were considered at risk for psychosis by virtue of meeting research criteria derived from retrospective accounts of the psychosis prodrome. This study evaluated the diagnostic validity of the prospective "prodromal risk syndrome" construct. Patients assessed by the Structured Interview for Prodromal Syndromes as meeting criteria of prodromal syndromes (n = 377) from the North American Prodrome Longitudinal Study were compared with normal comparison (NC, n = 196), help-seeking comparison (HSC, n = 198), familial high-risk (FHR, n = 40), and schizotypal personality disorder (SPD, n = 49) groups. Comparisons were made on variables from cross-sectional demographic, symptom, functional, comorbid diagnostic, and family history domains of assessment as well as on follow-up outcome. Prodromal risk syndrome patients as a group were robustly distinguished from NC subjects across all domains and distinguished from HSC subjects and from FHR subjects on most measures in many of these domains. Adolescent and young adult SPD patients, while distinct from prodromal patients on definitional grounds, were similar to prodromals on multiple measures, consistent with SPD in young patients possibly being an independent risk syndrome for psychosis. The strong evidence of diagnostic validity for the prodromal risk syndrome for first psychosis raises the question of its evaluation for inclusion in Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition).

Pretreatment and Outcome Correlates of Sexual and Physical Trauma in an Epidemiological Cohort of First-Episode Psychosis Patients

Conus, P., Cotton, S., Schimmelmann, B. G., McGorry, P. D., Lambert, M. — 2009-04-21

Objectives: High prevalence of trauma has been reported in psychosis. While role of trauma as a risk factor for developing psychosis is still debated, its negative impact on outcome has been described. Few studies have explored this issue in first-episode psychosis (FEP) patients. We assessed rate of stressful events, as well as premorbid and outcome correlates of past sexual and/or physical abuse (SPA) in an epidemiological FEP patients cohort. Methods: The Early Psychosis Prevention and Intervention Centre admitted 786 FEP patients between 1998 and 2000. Data were collected from patients' files using a standardized questionnaire. A total of 704 files were available, 43 excluded because of a nonpsychotic diagnosis at end point and 3 due to missing data regarding past stressful events; 658 patients were analyzed. Results: A total of 83% patients had been exposed to at least one stressful event and 34% to SPA. SPA patients were more likely to have presented other psychiatric disorders before psychosis onset (posttraumatic stress disorder, substance use disorder), to have made suicide attempts in the past, and to have had poorer premorbid functional levels. Additionally, SPA patients had higher rate of comorbid diagnosis at program entry and were more likely to attempt suicide during treatment. Conclusions: SPA prevalence is high in FEP patients and must be explored by clinicians considering its durable impact on psychological balance and link with long-lasting suicidal risk. More research is warranted to better understand mechanisms involved between trauma and its potential consequences, as well as to develop psychological interventions adapted to this very sensitive and complex issue.

Neurological Soft Signs in Schizophrenia: A Meta-analysis

Chan, R. C. K., Xu, T., Heinrichs, R. W., Yu, Y., Wang, Y. — 2009-04-17

Background: Neurological soft signs (NSS) are hypothesized as candidate endophenotypes for schizophrenia, but their prevalence and relations with clinical and demographic data are unknown. The authors undertook a quantification (meta-analysis) of the published literature on NSS in patients with schizophrenia and healthy controls. A systematic search was conducted for published articles reporting NSS and related data using standard measures in schizophrenia and healthy comparison groups. Method: A systematic search was conducted for published articles reporting data on the prevalence of NSS in schizophrenia using standard clinical rating scales and healthy comparison groups. Meta-analyses were performed using the Comprehensive Meta-analysis software package. Effect sizes (Cohen d) indexing the difference between schizophrenic patients and the healthy controls were calculated on the basis of reported statistics. Potential moderator variables evaluated included age of patient samples, level of education, sample sex proportions, medication doses, and negative and positive symptoms. Results: A total of 33 articles met inclusion criteria for the meta-analysis. A large and reliable group difference (Cohen d) indicated that, on average, a majority of patients (73%) perform outside the range of healthy subjects on aggregate NSS measures. Cognitive performance and positive and negative symptoms share 2%–10% of their variance with NSS. Conclusions: NSS occur in a majority of the schizophrenia patient population and are largely distinct from symptomatic and cognitive features of the illness.

Amygdalofrontal Functional Disconnectivity and Aggression in Schizophrenia

2009-04-16

A significant proportion of patients with schizophrenia demonstrate abnormalities in dorsal prefrontal regions including the dorsolateral prefrontal and dorsal anterior cingulate cortices. However, it is less clear to what extent abnormalities are exhibited in ventral prefrontal and limbic regions, despite their involvement in social cognitive dysfunction and aggression, which represent problem domains for patients with schizophrenia. Previously, we found that reduced white matter integrity in right inferior frontal regions was associated with higher levels of aggression. Here, we used resting-state functional magnetic resonance imaging to examine amygdala/ventral prefrontal cortex (vPFC) functional connectivity (FC) and its relation to aggression in schizophrenia. Twenty-one healthy controls and 25 patients with schizophrenia or schizoaffective disorder participated. Aggression was measured using the Buss Perry Aggression Questionnaire. Regions of interest were placed in the amygdala based on previously published work. A voxelwise FC analysis was performed in which the mean time series across voxels for this bilateral amygdala seed was entered as a predictor in a multiple regression model with motion parameters and global, cerebrospinal fluid, and white matter signals as covariates. Patients showed significant reductions in FC between amygdala and vPFC regions. Moreover, in patients, the strength of this connection showed a significant inverse relationship with aggression, such that lower FC was associated with higher levels of self-rated aggression. Similar results were obtained for 2 other measures—Life History of Aggression and total arrests. These results suggest that amygdala/vPFC FC is compromised in schizophrenia and that this compromise is associated with aggression.

Social Cognition Deficits Among Individuals at Familial High Risk for Schizophrenia

2009-04-14

Social cognition in young relatives of schizophrenia probands (N = 70) and healthy controls (N = 63) was assessed using the Penn Emotion Recognition Test-40 to examine the presence of social cognitive deficits in individuals at risk for the disorder. Measures of neurocognitive function and prodromal psychopathology were collected to assess the cognitive and clinical correlates of social cognitive impairments in at-risk relatives. Results indicated that when compared with healthy controls, individuals at familial high risk for schizophrenia were significantly more likely to overattribute emotions to neutral faces, with such individuals frequently misinterpreting neutral faces as negative. In addition, at-risk individuals had significantly greater reaction times when completing emotion recognition tasks, regardless of valence. Impairments in neurocognition were largely independent of social cognitive performance, and emotion recognition impairments persisted after adjusting deficits in neurocognitive function. Further, social cognitive impairments in the interpretation of neutral faces were significantly associated with greater positive and general prodromal psychopathology, whereas neurocognitive impairments were only associated with disorganization. These results suggest that impairments in social cognition may be unique endophenotypes for schizophrenia.

Autonomic Dysfunction in Unaffected First-Degree Relatives of Patients Suffering From Schizophrenia

2009-04-14

Recent studies revealed cardiac autonomic dysfunction in patients with acute schizophrenia, which appears to be mainly related to reduced vagal and increased sympathetic modulation. To understand the significance of cardiac autonomic function in patients with schizophrenia, we extended these studies to relatives of patients. In this study, we assessed cardiac autonomic modulation in healthy first-degree relatives of patients with schizophrenia (n = 36) to investigate a putative genetic influence. Data were compared with control subjects matched for age, gender, and physical activity as well as to patients suffering from schizophrenia. First-degree relatives showed an attenuated, yet identical pattern in autonomic dysfunction as patients with decreased vagal modulation of heart rate, decreased baroreflex sensitivity, but no difference in blood pressure variability could be detected. The patients' relatives also showed a similar pattern in regards to QT variability. In addition, the subgroup comparison of offspring vs. siblings showed a significant difference in heart rate variability suggesting a higher degree of heritability in offspring. In conclusion, the pattern of autonomic dysfunction seen in patients and relatives might indicate underlying disease-inherent genetic vulnerability, especially because autonomic parameters are heritable. In addition, these findings may be of value to identify the high-risk group of patients' relatives in regards to serious cardiovascular events so that early preventive measures can be taken.

Toward a Model of Cognitive Insight in First-Episode Psychosis: Verbal Memory and Hippocampal Structure

2009-04-03

Our previous work has linked verbal learning and memory with cognitive insight, but not clinical insight, in individuals with a first-episode psychosis (FEP). The current study reassessed the neurocognitive basis of cognitive and clinical insight and explored their neural basis in 61 FEP patients. Cognitive insight was measured with the Beck Cognitive Insight Scale (BCIS) and clinical insight with the Scale to assess Unawareness of Mental Disorder (SUMD). Global measures for 7 domains of cognition were examined. Hippocampi were manually segmented in to 3 parts: the body, head, and tail. Verbal learning and memory significantly correlated with the BCIS composite index. Composite index scores were significantly associated with total left hippocampal (HC) volume; partial correlations, however, revealed that this relationship was attributable largely to verbal memory performance. The BCIS self-certainty subscale significantly and inversely correlated with bilateral HC volumes, and these associations were independent of verbal learning and memory performance. The BCIS self-reflectiveness subscale significantly correlated with verbal learning and memory but not with HC volume. No significant correlations emerged between the SUMD and verbal memory or HC volume. These results strengthen our previous assertion that in individuals with an FEP cognitive insight may rely on memory whereby current experiences are appraised based on previous ones. The HC may be a viable location among others for the brain system that underlies aspects of cognitive insight in individuals with an FEP.

Facial Emotion Perception in Schizophrenia: A Meta-analytic Review

Kohler, C. G., Walker, J. B., Martin, E. A., Healey, K. M., Moberg, P. J. — 2009-03-27

Objectives: A considerable body of literature has reported on emotion perception deficits and the relevance to clinical symptoms and social functioning in schizophrenia. Studies published between 1970–2007 were examined regarding emotion perception abilities between patient and control groups and potential methodological, demographic, and clinical moderators. Data Sources and Review: Eighty-six studies were identified through a computerized literature search of the MEDLINE, PsychINFO, and PubMed databases. A quality of reporting of meta-analysis standard was followed in the extraction of relevant studies and data. Data on emotion perception, methodology, demographic and clinical characteristics, and antipsychotic medication status were compiled and analyzed using Comprehensive Meta-analysis Version 2.0 (Borenstein M, Hedges L, Higgins J and Rothstein H. Comprehensive Meta-analysis. 2. Englewood, NJ: Biostat; 2005). Results: The meta-analysis revealed a large deficit in emotion perception in schizophrenia, irrespective of task type, and several factors that moderated the observed impairment. Illness-related factors included current hospitalization and—in part—clinical symptoms and antipsychotic treatment. Demographic factors included patient age and gender in controls but not race. Conclusion: Emotion perception impairment in schizophrenia represents a robust finding in schizophrenia that appears to be moderated by certain clinical and demographic factors. Future directions for research on emotion perception are discussed.

Testing Definitions of Symptom Remission in First-Episode Psychosis for Prediction of Functional Outcome at 2 Years

Cassidy, C. M., Norman, R., Manchanda, R., Schmitz, N., Malla, A. — 2009-03-25

Background: To determine the clinical relevance of different definitions of symptom remission for prediction of functional outcome in first-episode psychosis (FEP). Methods: One hundred forty-one individuals receiving treatment for an FEP at a specialized early intervention service had positive and negative symptoms and functional status rated every month over the first 2 years of treatment using the Scale for the Assessment of Positive Symptoms, Scale for the Assessment of Negative Symptoms, and Social and Occupational Functioning Assessment Scale. Subjects were classified according to 4 definitions of remission varying the criteria for severity (negative symptom inclusion/exclusion) and duration (3/6 mo sustained). Results: Positive symptom remission was achieved by 94% and 84% of subjects for 3 and 6 months, respectively, compared with 70% and 56% for positive and negative symptom remission, respectively. Linear regression analyses showed that only definitions of remission containing both positive and negative symptoms independently predicted functional outcome. This was confirmed by receiver operating characteristic analyses where remission based on positive and negative symptoms was marginally better than positive symptoms alone (difference in area under the curve; z = 1.94, P = .052). There was little difference between a time criterion of remission of positive and negative symptoms of 3 (sensitivity = 100%, specificity = 42%) or 6 (sensitivity = 90%, specificity = 57%) months. Discussion: Consistent with the consensus definition of remission in schizophrenia, severity of both positive and negative symptoms in defining remission in FEP is necessary although a 3-month criterion had equal predictive validity to the 6-month criterion.

Reductions in the N1 and P2 Auditory Event-Related Potentials in First-Hospitalized and Chronic Schizophrenia

Salisbury, D. F., Collins, K.C., McCarley, R. W. — 2009-03-12

The N1 auditory event-related potential (ERP) is reduced in chronic schizophrenia, as is the P2 to attended tones. N1 reduction may be endophenotypic for schizophrenia, being reduced in twins of schizophrenic patients and showing heritability. Results in family members, however, are equivocal, with abnormally small N1 (consistent with an endophenotype) and abnormally large N1 (inconsistent with an endophenotype) reported. P2 has been little studied in schizophrenia or family members. One crucial step in establishing endophenotypes is to rule out causal chronicity factors. We examined schizophrenia patients within 1 year of first hospitalization (most within 2 wk), chronically ill patients, and matched controls to examine N1 and P2 reductions and disease stage. Two active target detection oddball tasks were used, one with 97-dB tones against 70-dB white masking noise, the second with 97-dB tones without noise. Results from 8 samples are reported: first-hospitalized patients and matched controls and chronic patients and matched controls for the 2 tasks. N1 and P2 were measured from the standard stimuli. N1 and P2 were significantly reduced in chronic patients, as expected, and reduced in first-hospitalized patients. Because N1 and P2 are reduced even at the first hospitalization for schizophrenia, they may serve as viable electrophysiological endophenotypes for the disorder. However, deficit early in the disease is necessary but not sufficient to establish these ERPs as endophenotypes. Deficits must next be demonstrated in at least a subset of unaffected family members, a crucial criterion for an endophenotype.

RGS4 Polymorphisms Associated With Variability of Cognitive Performance in a Family-Based Schizophrenia Sample

2009-03-12

Polymorphisms of the gene encoding the regulator of G protein signaling, subtype 4 (RGS4), may be associated with schizophrenia. Among first-episode schizophrenia patients, they are also associated with dorsolateral prefrontal cortex (DLPFC) volume. The DLPFC is a key region that regulates heritable cognitive functions implicated in schizophrenia pathogenesis. To further understand the relationship of RGS4 variants to schizophrenia, we examined their associations with cognitive functions among schizophrenia patients and their relatives. We analyzed 31 multiplex, multigenerational Caucasian families with schizophrenia recruited on the basis of 2 affected first-degree relatives. All participants underwent a computerized neurocognitive battery that evaluates accuracy and speed (response time) of performance on abstraction/mental flexibility; attention; verbal, spatial, and face memory; and spatial ability. "Tag" single-nucleotide polymorphisms (SNPs) representing common polymorphisms were genotyped. Measured genotype analyses accounting for family relationships were performed using Sequential Oligogenic Linkage Analysis Routines. SNPs rs10917670 ("SNP1") and rs951439 ("SNP7") were associated with face memory speed (P = .0003) at a significance level that survived Bonferroni correction (P = .039). The same SNPs have earlier been reported to be associated with schizophrenia. There also were uncorrected associations with rs10917670 ("SNP1") and rs951439 ("SNP7") on face memory efficiency (P = .03) and verbal memory efficiency (P = 0.02), rs28757217 on abstraction/mental flexibility speed (P = .02) and verbal memory efficiency (P = .03), SNP18 (rs2661319) on spatial memory accuracy (P = 0.02) and face memory speed (P = .03). RGS4 polymorphisms are associated with variations in cognitive functions and contribute a small but statistically significant proportion of variance in a family-based sample.

Functional Analysis of Upstream Common Polymorphisms of the Dopamine Transporter Gene

Bamne, M. N., Talkowski, M. E., Chowdari, K. V., Nimgaonkar, V. L. — 2009-03-09

The human dopamine transporter (DAT, SLC6A3) has been extensively investigated because of its potential involvement in neuropsychiatric disorders. The core elements responsible for its transcription have been identified. A regulatory role for certain genomic variants upstream to the core promoter is known. Recently, other single-nucleotide polymorphisms (SNPs) have been identified in this region and are thought to be associated with schizophrenia and bipolar I disorder. Hence, we have investigated the impact of common SNPs in a 2.8-kilobase region flanking the core promoter region (–2.7 to +63 base pair) in the neuroblastoma cell line SH-SY5Y. Haplotypes generated by site-directed mutagenesis revealed varying impact of individual SNPs on promoter activity using dual luciferase assays. In silico analyses also predicted allele-specific binding of transcription factors for some of these SNPs. Though electrophoretic mobility shift assays indicated several factors that appeared to bind to specific sites within this region, allele-specific binding was not detected for any SNP apart from rs3756450. We have thus identified novel putative regulatory domains flanking the core promoter of DAT that merit further investigation.

Antecedents and Patterns of Suicide Behavior in First-Admission Psychosis

Bakst, S., Rabinowitz, J., Bromet, E. J. — 2009-03-09

Background: Persons with psychotic illnesses have an increased risk for suicide, especially early in the illness. Sufficient knowledge allowing for early recognition is lacking. Objectives: To describe suicide behaviors before and during the 4 years following first psychiatric hospitalization, examine associations of demographic and psychiatric risk factors, and develop a suicide risk index. Method: Data came from the Suffolk County Mental Health Project, a first-admission cohort (n = 529). Cox regression was used to study associations of risk factors to suicide behaviors; a summary suicide behavior risk index was also tested. Results: Prior to first admission, 28.0% (n = 148) of the cohort had attempted suicide. During the 4-year follow-up, 13.6% (n = 72) of the cohort attempted suicide (29.7% of those with previous attempts and 7.3% making their first attempt) and 3 respondents died of suicide. The significant predictors at index admission of subsequent attempts were prior attempts or ideation, severity of depressive symptoms and thought disorder, lifetime substance abuse, and younger age. Suicide ideation was predicted by the same variables with the addition of insight into illness and with the exception of age at admission. A 3-category risk index was created; 61.1% of those who made a suicide attempt were in the highest risk group (n = 44/72). Conclusion: The current study confirms and extends previous research showing that risk factors early in the course of illness are predictive of subsequent ideation and attempts. The risk index may be a useful adjunct in identifying individuals likely to benefit from preventive interventions.

Neuroplasticity-Based Cognitive Training in Schizophrenia: An Interim Report on the Effects 6 Months Later

Fisher, M., Holland, C., Subramaniam, K., Vinogradov, S. — 2009-03-05

Background: New cognitive treatments for schizophrenia are needed that drive persistent gains in cognition and functioning. Using an innovative neuroplasticity-based cognitive training approach, we report our interim findings on the effects on cognition and functional outcome at 6 months after treatment. Methods: Thirty-two clinically stable schizophrenia subjects were randomly assigned to either targeted cognitive training (TCT, N = 22) or a computer games (CGs) control condition (N = 10). Twelve TCT subjects completed 50 hours of auditory based training; 10 TCT subjects completed an additional 50 hours of training targeting visual and cognitive control processes. Subjects were assessed on neurocognition and functional outcome after training and at 6-month follow-up. Results: Both TCT subject groups showed significant durable gains at 6 months on measures of verbal learning/memory and cognitive control. Only TCT subjects who completed 100 hours of training showed durable gains on processing speed and global cognition, with nonsignificant improvement in functional outcome. Improved cognition was significantly associated with improved functional outcome at 6 months for TCT subjects. Conclusions: A total of 50 hours of neuroplasticity-based computerized cognitive training appears sufficient to drive improvements in verbal learning/memory and cognitive control that endure 6 months beyond the intervention, but a higher "dose" and more "broad-spectrum" training may be necessary to drive enduring gains in processing speed and global cognition. Training-induced cognitive improvement is related to enhanced functioning at 6 months. These data suggest that (1) higher and "broader" doses of cognitive training may confer the most benefits for schizophrenia patients; (2) the posttraining period opens a critical window for aggressive adjunctive psychosocial rehabilitation.

Olfactory Hedonic Judgment in Patients With Deficit Syndrome Schizophrenia

Strauss, G. P., Allen, D. N., Ross, S. A., Duke, L. A., Schwartz, J. — 2009-02-17

Olfactory perception was examined in deficit syndrome (DS) and nondeficit syndrome (ND) schizophrenia patients. Participants included 22 controls (CN) and 41 patients with schizophrenia who were divided into DS (n = 15) and ND (n = 26) subtypes using the Schedule for the Deficit Syndrome (SDS). Olfactory perception for pleasant and unpleasant odors was assessed using the Brief Smell Identification Test. Participants were instructed to identifying each smell as well as provide hedonic judgment ratings of each smell on a 7-point scale (1 = extremely pleasant, 4 = neutral, and 7 = extremely unpleasant). Results indicated that when compared with the ND patients, the DS patients rated pleasant smells as being significantly less pleasant, although no difference between the groups was present for unpleasant smells, and both ND and DS groups significantly differed from CN on rating and identifying pleasant and unpleasant items. Additionally, lower smell identification accuracy was negatively correlated with SDS symptom severity, and valence ratings for pleasant odors were positively correlated with SDS diminished emotional range. Findings suggest that the DS is characterized by a unique pattern of olfactory valence judgment that is characterized by abnormalities in processing positively valenced stimuli.

Neuropsychological Profile in Early-Onset Schizophrenia-Spectrum Disorders: Measured With the MATRICS Battery

Holmen, A., Juuhl-Langseth, M., Thormodsen, R., Melle, I., Rund, B. R. — 2009-02-17

Objective: Neurocognitive impairments have been documented in adolescents with early-onset schizophrenia (EOS). There is still inconsistency regarding an average profile, which could be due to the fact that each study uses different tests. The purpose of this study was to examine whether the "Measurement and Treatment Research to Improve Cognition in Schizophrenia" (MATRICS) battery is useful in detecting differences between the patient group and the healthy controls, and to describe the neuropsychological pattern in the EOS group. Method: Neuropsychological functioning was examined in 31 adolescents with schizophrenia spectrum disorders and 67 healthy controls, using the MATRICS battery. Results: There were significant differences between the patients and the controls on every domain except for social cognition. Patients showed a generalized neurocognitive deficit of 0.8–1.8 SDs compared with controls, with verbal learning, working memory, and visual learning being the most affected areas. Conclusions: The MATRICS battery is sensitive in detecting differences between patients and controls in the adolescent population. However, we question the use of Mayer-Salovey-Caruso Emotional Intelligence Test in this age group. Results document a significant generalized deficit in adolescents with EOS.

"Excessive Thinking" as Explanatory Model for Schizophrenia: Impacts on Stigma and "Moral" Status in Mainland China

Yang, L. H., Phillips, M. R., Lo, G., Chou, Y., Zhang, X., Hopper, K. — 2009-02-04

Although psychiatric stigma in China is particularly pervasive and damaging, rates of high expressed emotion ("EE" or family members' emotional attitudes that predict relapse) are generally lower than rates found in Western countries. In light of this seemingly incongruous juxtaposition and because Chinese comprise approximately one-fifth of the world's mentally ill, we examine how one of the most widely held causal beliefs of schizophrenia—excessive thinking (xiang tai duo)—may powerfully shape how those exhibiting psychotic symptoms pass from "normal" status to stigmatized "other." Using a framework by which stigma threatens an actor's capacity to participate in core everyday engagements, we examine how expressions of excessive thinking intersect with psychotic symptoms and how this idiom reduces stigma by preserving essential moral standing. Four focus groups with family members (n = 34 total) of schizophrenia outpatients, who had participated in psychoeducation, were conducted in Beijing. Open coding was conducted by 2 bilingual coders achieving high interrater agreement. Common expressions of excessive thinking—taking things too hard that is perceived as a causal factor and unwarranted suspicion that is used to benignly interpret paranoid symptoms encapsulated disruptive behaviors that closely overlapped with psychotic symptoms. Because excessive thinking is understood to occur universally, this idiom encourages socially accommodating behavior that signifies acceptance of these individuals as full-status community members. In contrast, due to beliefs implying moral contamination, those labeled mentally ill are threatened with both subtle and outright social exclusion. We discuss implications of this idiom for EE and the detection of schizophrenia "prodrome" in China.

Delusions Are Associated With Poor Cognitive Insight in Schizophrenia

2009-01-27

The purpose of the study was to investigate the relationship between the symptoms delusions and hallucinations measured by the Positive and Negative Syndrome Scale and cognitive insight as assessed with the Beck Cognitive Insight Scale (BCIS) in patients with schizophrenia. The BCIS is based on 2 subscales, self-reflectiveness and self-certainty, measuring objectivity, reflectiveness and openness to feedback, and mental flexibility. Overall cognitive insight was defined as the difference between self-reflectiveness and self-certainty. This cross-sectional study of 143 patients showed that the occurrence of delusions is associated with low self-reflectiveness and high self-certainty, reflecting low cognitive insight. Hallucinations in the absence of delusions were associated with high self-reflectiveness and low self-certainty, possibly reflecting more open-mindedness and higher cognitive insight. The present findings suggest that delusions are associated with low cognitive insight, whereas solitary hallucinations may be associated with high cognitive insight.

Seeking Verisimilitude in a Class: A Systematic Review of Evidence That the Criterial Clinical Symptoms of Schizophrenia Are Taxonic

Linscott, R. J., Allardyce, J., van Os, J. — 2009-01-27

This review examines whether there is evidence that the criterion symptoms of Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) (DSM-IV) schizophrenia are taxonic—that schizophrenia is not part of a single distribution of normality. Two taxometric methods, coherent cut kinetics (CCK) and latent variable modeling (LVM), are demonstrated to be sensitive to latent classes and, therefore, were regarded as providing relevant statistical evidence. A systematic literature search identified 24 articles describing analyses of 28 participant cohorts in which CCK or LVM methods were used with one or more criterion symptoms of schizophrenia. Virtually all analyses yielded results that, on first impression, favored taxonic over dimensional interpretations of the latent structure of schizophrenia. However, threats to the internal and external validity of these studies—including biased or inadequate analyses, violation of statistical assumptions, inadequate indicator screening, and the introduction of systematic error through recruitment and sampling—critically undermine this body of work. Uncertainties about the potential effects of perceptual biases, unimodal assessment, and item parceling are also identified, as are limitations in seeking to validate classes with single or double dissociations of outcomes. We conclude that there is no reason to seriously doubt a single-distribution model of schizophrenia because there is no evidence that provides a serious test of this null hypothesis. A second fundamental question remains outstanding: is schizophrenia truly a group of schizophrenias, with taxonic divisions separating its types? We make design and analysis suggestions for future research addressing these questions.

Influence of Emotional Expression on Memory Recognition Bias in Schizophrenia as Revealed by fMRI

Sergerie, K., Armony, J. L., Menear, M., Sutton, H., Lepage, M. — 2009-01-27

We recently showed that, in healthy individuals, emotional expression influences memory for faces both in terms of accuracy and, critically, in memory response bias (tendency to classify stimuli as previously seen or not, regardless of whether this was the case). Although schizophrenia has been shown to be associated with deficit in episodic memory and emotional processing, the relation between these processes in this population remains unclear. Here, we used our previously validated paradigm to directly investigate the modulation of emotion on memory recognition. Twenty patients with schizophrenia and matched healthy controls completed functional magnetic resonance imaging (fMRI) study of recognition memory of happy, sad, and neutral faces. Brain activity associated with the response bias was obtained by correlating this measure with the contrast subjective old (ie, hits and false alarms) minus subjective new (misses and correct rejections) for sad and happy expressions. Although patients exhibited an overall lower memory performance than controls, they showed the same effects of emotion on memory, both in terms of accuracy and bias. For sad faces, the similar behavioral pattern between groups was mirrored by a largely overlapping neural network, mostly involved in familiarity-based judgments (eg, parahippocampal gyrus). In contrast, controls activated a much larger set of regions for happy faces, including areas thought to underlie recollection-based memory retrieval (eg, superior frontal gyrus and hippocampus) and in novelty detection (eg, amygdala). This study demonstrates that, despite an overall lower memory accuracy, emotional memory is intact in schizophrenia, although emotion-specific differences in brain activation exist, possibly reflecting different strategies.

Periods of Recovery in Deficit Syndrome Schizophrenia: A 20-Year Multi-follow-up Longitudinal Study

Strauss, G. P., Harrow, M., Grossman, L. S., Rosen, C. — 2008-12-18

Periods of recovery were examined in patients with and without deficit syndrome schizophrenia. Fifty-six patients with schizophrenia were studied, 39 of whom were divided into deficit and nondeficit syndrome schizophrenia subtypes using a proxy method. We also studied 39 nonpsychotic depressive comparison patients. Patients were evaluated as part of the Chicago Follow-up Study, which prospectively examined patients at regular intervals over a 20-year period. Using standardized instruments, patients were evaluated for the deficit syndrome, global recovery, rehospitalization, social dysfunction, occupational disability, and symptom presentation. Recovery was examined at 6 time points measured at 2-, 4.5-, 7.5-, 10-, 15-, and 20-year postindex hospitalization. Cumulatively, over the 20-year period, 13% of patients classified as meeting criteria for the deficit syndrome showed 1 or more 1-year periods of global recovery, in comparison to 63% of nondeficit schizophrenia patients and 77% of depressed patient controls. Results indicate that the deficit syndrome represents a persistently impaired subsample of schizophrenia patients, with continuous social, occupational, and symptom impairment. In contrast, nondeficit syndrome schizophrenia patients showed at least some periods of remission or recovery, with the likelihood of these periods increasing as they became older. Findings provide further support for the validity of the deficit syndrome concept and suggest that deficit status is characterized by a more persistently impaired course of illness and particularly poor long-term prognosis.

Tract-based Analysis of Magnetization Transfer Ratio and Diffusion Tensor Imaging of the Frontal and Frontotemporal Connections in Schizophrenia

2008-11-27

Background: In the pathophysiology of schizophrenia, aberrant connectivity between brain regions may be a central feature. Diffusion tensor imaging (DTI) studies have shown altered fractional anisotropy (FA) in white brain matter in schizophrenia. Focal reductions in myelin have been suggested in patients using magnetization transfer ratio (MTR) imaging but to what extent schizophrenia may be related to changes in MTR measured along entire fiber bundles is still unknown. Methods: DTI and MTR images were acquired with a 1.5-T scanner in 40 schizophrenia patients and compared with those of 40 healthy participants. The mean FA and mean MTR were measured along the genu of the corpus callosum and the left and right uncinate fasciculus. Results: A higher mean MTR of 1% was found in the right uncinate fasciculus in patients compared with healthy participants. A significant negative correlation between age and mean FA in the left uncinate fasciculus was found in schizophrenia patients but not in healthy participants. Conclusions: Decreased FA in the left uncinate fasciculus may be more prominent in patients with longer illness duration. The increased mean MTR in the right uncinate fasciculus could reflect a compensatory role for myelin in these fibers or possibly represent aberrant frontotemporal connectivity.

Morphometric Brain Abnormalities in Schizophrenia in a Population-Based Sample: Relationship to Duration of Illness

2008-11-17

Biased recruitment and sample selection may cause variability in neuroimaging studies. Epidemiologically principled population-based magnetic resonance imaging (MRI) studies of schizophrenia are very rare. We gathered structural MRI data on 154 subjects from the Northern Finland 1966 Birth Cohort, aged 33–35 (100 controls, 54 schizophrenia patients). Regional differences in density of gray matter, white matter, and cerebrospinal fluid (CSF) were identified between groups using nonparametric statistical analysis, and the relationship of the regional differences to duration of illness was explored. Gray matter reductions were found bilaterally in the cerebellum, thalamus, basal ganglia, middle frontal gyrus, inferior frontal gyrus, precentral gyrus, insula, superior temporal gyrus, fusiform gyrus, parahippocampal gyrus, cuneus, and lingual gyrus; in the left posterior cingulate, superior frontal gyrus, transverse temporal gyrus, and precuneus; and in the right postcentral gyrus. Gray matter excesses were observed bilaterally in the basal ganglia, anterior cingulate, and medial orbitofrontal cortices. There were white matter deficits in an extensive network including inter- and intrahemispheric tracts bilaterally in the frontal, temporal, parietal, and occipital lobes, subcortical structures, cerebellum, and brain stem. CSF excesses were found bilaterally in the lateral ventricles, third ventricle, interhemispheric, and left Sylvian fissure. We replicated the previous findings of structural brain abnormalities in schizophrenia on a general population level. Gray and white matter deficits were associated with duration of illness suggesting either that developmental brain deficits relate to an earlier age of onset or that brain abnormalities in schizophrenia are progressive in nature.

Supportive evidence for reduced expression of GNB1L in schizophrenia

2008-11-14

Background: Chromosome 22q11 deletion syndrome (22q11DS) increases the risk of development of schizophrenia more than 10 times compared with that of the general population, indicating that haploinsufficiency of a subset of the more than 20 genes contained in the 22q11DS region could increase the risk of schizophrenia. In the present study, we screened for genes located in the 22q11DS region that are expressed at lower levels in postmortem prefrontal cortex of patients with schizophrenia than in those of controls. Methods: Gene expression was screened by Illumina Human-6 Expression BeadChip arrays and confirmed by real-time reverse transcription-polymerase chain reaction assays and Western blot analysis. Results: Expression of GNB1L was lower in patients with schizophrenia than in control subjects in both Australian (10 schizophrenia cases and 10 controls) and Japanese (43 schizophrenia cases and 11 controls) brain samples. TBX1 could not be evaluated due to its low expression levels. Expression levels of the other genes were not significantly lower in patients with schizophrenia than in control subjects. Association analysis of tag single-nucleotide polymorphisms in the GNB1L gene region did not confirm excess homozygosity in 1918 Japanese schizophrenia cases and 1909 Japanese controls. Haloperidol treatment for 50 weeks increased Gnb1l gene expression in prefrontal cortex of mice. Conclusions: Taken together with the impaired prepulse inhibition observed in heterozygous Gnb1l knockout mice reported by the previous study, the present findings support assertions that GNB1L is one of the genes in the 22q11DS region responsible for increasing the risk of schizophrenia.

Functional MRI of Verbal Self-monitoring in Schizophrenia: Performance and Illness-Specific Effects

2008-11-07

Previous small-sample studies have shown altered frontotemporal activity in schizophrenia patients with auditory hallucinations and impaired monitoring of self-generated speech. We examined a large cohort of patients with schizophrenia (n = 63) and a representative group of healthy controls (n = 20) to disentangle performance, illness, and symptom-related effects in functional magnetic resonance imaging–detected brain abnormalities during monitoring of self- and externally generated speech in schizophrenia. Our results revealed activation of the thalamus (medial geniculate nucleus, MGN) and frontotemporal regions with accurate monitoring across all participants. Less activation of the thalamus (MGN, pulvinar) and superior-middle temporal and inferior frontal gyri occurred in poorly performing patients (1 standard deviation below controls’ mean; n = 36), relative to the combined group of controls and well-performing patients. In patients, (1) greater deactivation of the ventral striatum and hypothalamus to own voice, combined with nonsignificant activation of the same regions to others’ voice, associated positively with negative symptoms (blunted affect, emotional withdrawal, poor rapport, passive social avoidance) regardless of performance and (2) exaggerated activation of the right superior-middle temporal gyrus during undistorted, relative to distorted, feedback associated with both positive symptoms (hallucinations, persecution) and poor performance. A further thalamic abnormality characterized schizophrenia patients regardless of performance and symptoms. We conclude that hypoactivation of a neural network comprised of the thalamus and frontotemporal regions underlies impaired speech monitoring in schizophrenia. Positive symptoms and poor monitoring share a common activation abnormality in the right superior temporal gyrus during processing of degraded speech. Altered striatal and hypothalamic modulation to own and others’ voice characterizes emotionally withdrawn and socially avoidant patients.

The Appropriateness of Routine Medication Treatment for Schizophrenia

Young, A. S., Niv, N., Cohen, A. N., Kessler, C., McNagny, K. — 2008-11-07

Objective: Although national guidelines specify appropriate strategies for the treatment of schizophrenia, this disorder presents challenges to clinicians and health-care organizations. To improve care, it is useful to understand how often patients receive appropriate treatment. Most research evaluating treatment was performed when first-generation antipsychotic medications were the modal treatment. Given that most prescriptions are now for second-generation medications, this study describes current clinical problems and the appropriateness of treatment in routine practice. Method: Between 2002 and 2004, a random sample of patients (n = 398) were interviewed at baseline and 1 year at 3 Department of Veterans Affairs mental health clinics. Symptoms and side effects were assessed. Analyses examined whether prescribing were consistent with guidelines in patients with significant psychosis, depression, parkinsonism, akathisia, tardive dyskinesia, or elevated weight. Results: Few patients met criteria for depression, parkinsonism, or akathisia. A total of 44% of patients had significant psychosis, 11% had tardive dyskinesia, and 46% were overweight. Medication was appropriate in 27% of patients with psychosis, 25% of patients with tardive dyskinesia, and 2% of patients with elevated weight. Management of elevated weight improved modestly over time. Treatment was more likely to improve for patients whose psychiatrists had more than 12 patients with schizophrenia in their caseload. Conclusion: Compared with the 1990s, outpatients are more likely to have significant psychosis. The rate of appropriate treatment of psychosis is unchanged. Weight gain has become a prevalent side effect, yet treatment is rarely changed in response to weight. There is a need for interventions that improve management of psychosis and weight.

Dyskinesia and Parkinsonism in Antipsychotic-Naive Patients With Schizophrenia, First-Degree Relatives and Healthy Controls: A Meta-analysis

2008-11-05

Background:Several studies have reported the presence of dyskinesia and parkinsonism in antipsychotic-naive patients with schizophrenia as well as in their first-degree relatives. These movement disorders may therefore form an integral part of the illness and its (genetic) liability. Method: A systematic search was conducted in the Medline, EMBASE, and PsychINFO databases to identify studies reporting on dyskinesia and parkinsonism assessed in antipsychotic-naive patients with schizophrenia (n = 213) and controls (n = 242) and separately in nonill first-degree relatives (n = 395) and controls (n = 379). Effect sizes were pooled using random-effect models to calculate odds ratios (ORs) to compare the risk of these movement disorders among patients and healthy relatives each with matched controls. Results: Antipsychotic-naive schizophrenia was found to be strongly associated with dyskinesia (OR: 3.59, 95% confidence interval [CI]: 1.53–8.41) and parkinsonism (OR: 5.32, 95% CI: 1.75–16.23) compared with controls. Dyskinesia and parkinsonism were also significantly more prevalent in healthy first-degree relatives of patients with schizophrenia as compared with healthy controls (OR: 1.38, 95% CI: 1.06–1.81, and OR: 1.37, 95% CI: 1.05–1.79, respectively).Conclusion: The results suggest that movement disorders, and by inference abnormalities in the nigrostriatal pathway, are not only associated with schizophrenia itself but may also be related to the (genetic) risk of developing the disease.

Low-Frequency BOLD Fluctuations Demonstrate Altered Thalamocortical Connectivity in Schizophrenia

Welsh, R. C., Chen, A. C., Taylor, S. F. — 2008-11-05

The thalamus plays a central and dynamic role in information transmission and processing in the brain. Multiple studies reveal increasing association between schizophrenia and dysfunction of the thalamus, in particular the medial dorsal nucleus (MDN), and its projection targets. The medial dorsal thalamic connections to the prefrontal cortex are of particular interest, and explicit in vivo evidence of this connection in healthy humans is sparse. Additionally, recent neuroimaging evidence has demonstrated disconnection among a variety of cortical regions in schizophrenia, though the MDN thalamic prefrontal cortex network has not been extensively probed in schizophrenia. To this end, we have examined thalamo-anterior cingulate cortex connectivity using detection of low-frequency blood oxygen level dependence fluctuations (LFBF) during a resting-state paradigm. Eleven schizophrenic patients and 12 healthy control participants were enrolled in a study of brain thalamocortical connectivity. Resting-state data were collected, and seed-based connectivity analysis was performed to identify the thalamocortical network. First, we have shown there is MDN thalamocortical connectivity in healthy controls, thus demonstrating that LFBF analysis is a manner to probe the thalamocortical network. Additionally, we have found there is statistically significantly reduced thalamocortical connectivity in schizophrenics compared with matched healthy controls. We did not observe any significant difference in motor networks between groups. We have shown that the thalamocortical network is observable using resting-state connectivity in healthy controls and that this network is altered in schizophrenia. These data support a disruption model of the thalamocortical network and are consistent with a disconnection hypothesis of schizophrenia.

Rates of Homicide During the First Episode of Psychosis and After Treatment: A Systematic Review and Meta-analysis

Nielssen, O., Large, M. — 2008-11-05

The observation that almost half of the homicides committed by people with a psychotic illness occur before initial treatment suggests an increased risk of homicide during the first episode of psychosis. The aim of this study was to estimate the rates of homicide during the first episode of psychosis and after treatment. A systematic search located 10 studies that reported details of all the homicide offenders with a psychotic illness within a known population during a specified period and reported the number of people who had received treatment prior to the offense. Meta-analysis of these studies showed that 38.5% (95% confidence interval [CI] = 31.1%–46.5%) of homicides occurred during the first episode of psychosis, prior to initial treatment. Homicides during first-episode psychosis occurred at a rate of 1.59 homicides per 1000 (95% CI = 1.06–2.40), equivalent to 1 in 629 presentations. The annual rate of homicide after treatment for psychosis was 0.11 homicides per 1000 patients (95% CI = 0.07–0.16), equivalent to 1 homicide in 9090 patients with schizophrenia per year. The rate ratio of homicide in the first episode of psychosis in these studies was 15.5 (95% CI = 11.0–21.7) times the annual rate of homicide after treatment for psychosis. Hence, the rate of homicide in the first episode of psychosis appears to be higher than previously recognized, whereas the annual rate of homicide by patients with schizophrenia after treatment is lower than previous estimates. Earlier treatment of first-episode psychosis might prevent some homicides.

Ethnic Diversity and Pathways to Care for a First Episode of Psychosis in Ontario

Archie, S., Akhtar-Danesh, N., Norman, R., Malla, A., Roy, P., Zipursky, R. B. — 2008-11-05

Objective: To examine ethnic variations in the pathways to care for persons accessing early intervention (EI) services in Ontario. Method: The pathways to care and the duration of untreated psychosis were assessed for first-episode psychosis patients who entered specialized EI services in Ontario. The sample was assigned to the following ethnic classifications: the White (Caucasian), Black (African descent), and Asian (ancestry from the continent) groups, plus all the "other ethnicities" group. Results: There were 200 participants: 78% were male; 61% from the White, 15% Black, 13% Asian, and 11% were from the other ethnicities group. At the first point of contact, more participants used nonmedical contacts (12%), such as clergy and naturopathic healers, than psychologists (8%) or psychiatrists (7%). There were no ethnic differences for duration of untreated psychosis (median 22 weeks) or for initiation of help seeking by family/friends (53%), police (15%), or self (33%). After adjusting for relevant clinical and demographic factors, the Asian and other ethnicities groups were 4 and 3 times (respectively) more likely than the White or Black groups (P = .017) to use emergency room services as the first point of contact in the pathways to care. Participants from the Asian group experienced less involuntary hospitalizations (P = .023) than all the other groups. Yet overall, there were many more similarities than significant differences in the pathways to care. Conclusion: EI services should monitor the pathways to care for young people of diverse ethnic backgrounds to address any disparities in accessing care.

Symptom Correlates of Static and Dynamic Facial Affect Processing in Schizophrenia: Evidence of a Double Dissociation?

2008-10-26

Schizophrenia patients have been shown to be compromised in their ability to recognize facial emotion. This deficit has been shown to be related to negative symptoms severity. However, to date, most studies have used static rather than dynamic depictions of faces. Nineteen patients with schizophrenia were compared with seventeen controls on 2 tasks; the first involving the discrimination of facial identity, emotion, and butterfly wings; the second testing emotion recognition using both static and dynamic stimuli. In the first task, the patients performed more poorly than controls for emotion discrimination only, confirming a specific deficit in facial emotion recognition. In the second task, patients performed more poorly in both static and dynamic facial emotion processing. An interesting pattern of associations suggestive of a possible double dissociation emerged in relation to correlations with symptom ratings: high negative symptom ratings were associated with poorer recognition of static displays of emotion, whereas high positive symptom ratings were associated with poorer recognition of dynamic displays of emotion. However, while the strength of associations between negative symptom ratings and accuracy during static and dynamic facial emotion processing was significantly different, those between positive symptom ratings and task performance were not. The results confirm a facial emotion-processing deficit in schizophrenia using more ecologically valid dynamic expressions of emotion. The pattern of findings may reflect differential patterns of cortical dysfunction associated with negative and positive symptoms of schizophrenia in the context of differential neural mechanisms for the processing of static and dynamic displays of facial emotion.

Functional Deficits in the Extrastriate Body Area During Observation of Sports-Related Actions in Schizophrenia

2008-10-16

Exercise and sports are increasingly being implemented in the management of schizophrenia. The process of action perception is as important as that of motor execution for learning and acquiring new skills. Recent studies have suggested that body-selective extrastriate body area (EBA) in the posterior temporal-occipital cortex is involved not only in static visual perception of body parts but also in the planning, imagination, and execution of actions. However, functional abnormality of the EBA in schizophrenia has yet to be investigated. Using functional magnetic resonance imaging (fMRI) with a task designed to activate the EBA by sports-related actions, we aimed to elucidate functional abnormality of the EBA during observation of sports-related actions in patients with schizophrenia. Twelve schizophrenia patients and 12 age-sex–matched control participants participated in the study. Using sports-related motions as visual stimuli, we examined brain activations during observation of context-congruent actions relative to context-incongruent actions by fMRI. Compared with controls, the patients with schizophrenia demonstrated diminished activation in the EBA during observation of sports-related context-congruent actions. Furthermore, the EBA activation in patients was negatively correlated with the severity of negative and general psychopathology symptoms measured by the Positive and Negative Syndrome Scale. Dysfunction of the EBA might reflect a difficulty in representing dynamic aspects of human actions and possibly lead to impairments of simulation, learning, and execution of actions in schizophrenia.

Healthy Individuals With Auditory Verbal Hallucinations; Who Are They? Psychiatric Assessments of a Selected Sample of 103 Subjects

2008-10-09

Epidemiological studies suggest that auditory verbal hallucinations (AVH) occur in approximately 10%–15% of the general population, of whom only a small proportion has a clinically relevant psychotic disorder. It is unclear whether these hallucinations occur as an isolated phenomenon or if AVH in nonclinical individuals are part of a more general susceptibility to schizophrenia. For this study, 103 healthy individuals with frequent AVH were compared with 60 controls matched for sex, age, and education. All participants were examined by a psychiatrist using standardized diagnostic interviews and questionnaires. The individuals with AVH did not have clinically defined delusions, disorganization, or negative or catatonic symptoms, nor did they meet criteria for cluster A personality disorder. However, their global level of functioning was lower than in the controls and there was a pronounced increase on all subclusters of the Schizotypal Personality Questionnaire (SPQ) and the Peters Delusion Inventory, indicating a general increased schizotypal and delusional tendency in the hallucinating subjects. History of childhood trauma and family history of axis I disorders were also more prevalent in these individuals. We showed that higher SPQ scores, lower education, and higher family loading for psychiatric disorders, but not presence of AVH, were associated with lower global functioning. Our data suggest that AVH in otherwise healthy individuals are not an isolated phenomenon but part of a general vulnerability for schizophrenia.

Trajectories and Antecedents of Treatment Response Over Time in Early-Episode Psychosis

Levine, S. Z., Rabinowitz, J. — 2008-10-09

Background: Little is known about the extent of heterogeneity of symptomatology in treated early-onset psychosis. The current study aims to quantify the extent of heterogeneity in trajectories of treated symptom severity in early-episode psychosis and their antecedents. Methods: Data were from 491 persons with early-episode psychosis from a clinical trial of haloperidol and risperidone. Positive and Negative Syndrome Scale (PANSS) administrations were used to measure symptom severity trajectories for (a) rapid treatment response scores over 4 weeks and (b) medium-term course over 24 weeks. Baseline antecedents included sex, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis, age of onset, the Premorbid Adjustment Scale, and a cognitive test battery. Symptom severity trajectories were calculated with mixed mode latent class regression modeling from which groups were derived. Results: Five groups based on PANSS scores over time were identified. Over 4 weeks, 3 groups with varied baseline PANSS scores (54–105) did not surpass 30% PANSS improvement. Another group improved and then was stable (n = 76,15.3%), and another showed marked improvement (n = 94,18.9%). Logistic regression showed that membership in the best response trajectory was associated with not having a diagnosis of schizophrenia, good premorbid functioning, and higher cognitive functioning, whereas membership in the poor response trajectory was associated with earlier age of onset and poorer cognitive functioning. Conclusion: Amelioration generally characterizes treated symptom severity. Age of onset, diagnosis, cognitive functioning, and premorbid functioning have prognostic value in predicting treatment response trajectories.

Evaluating Early Preventive Antipsychotic and Antidepressant Drug Treatment in an Infection-Based Neurodevelopmental Mouse Model of Schizophrenia

Meyer, U., Spoerri, E., Yee, B. K., Schwarz, M. J., Feldon, J. — 2008-10-08

Current pharmacotherapy of schizophrenia remains unsatisfactory with little hope for complete functional restoration in patients once the disease has developed. A preventive approach based on intervention in the prodromal stage of the disease aiming to preserve functional integrity by halting the progress of the disease is therefore extremely attractive. Here, we investigated the effects of preventive antipsychotic or antidepressant drug treatment in a well-established neurodevelopmental mouse model of multiple schizophrenia-related abnormalities. Pregnant mice on gestation day 9 were exposed to the viral mimic polyriboinosinic-polyribocytidylic acid (2 mg/kg, intravenously) or corresponding vehicle treatment, and the resulting offspring from both prenatal treatment conditions were subjected to chronic antipsychotic (haloperidol or clozapine), antidepressant (fluoxetine), or placebo treatment during the periadolescent stage of development. The effects of the preventive pharmacotherapy on behavioral and pharmacological functions were then investigated in adulthood using paradigms relevant to schizophrenia, namely prepulse inhibition, latent inhibition, and sensitivity to psychostimulant drugs. We show that periadolescent treatment with the reference antipsychotic and antidepressant drugs can successfully block the emergence of multiple psychosis-related behavioral and pharmacological abnormalities in subjects predisposed to adult brain pathology by exposure to prenatal immune challenge. At the same time, however, our study reveals numerous negative influences of the early pharmacological intervention on normal behavioral development in control subjects. Hence, even though preventive pharmacotherapy may be beneficial in individuals with predisposition to psychosis-related brain dysfunctions, chronic antipsychotic or antidepressant drug treatment in false-positive subjects is associated with substantial risk for long-term behavioral disturbances in adulthood.

Impaired Modulation of Attention and Emotion in Schizophrenia

Dichter, G. S., Bellion, C., Casp, M., Belger, A. — 2008-10-08

Objective: Fronto-limbic interactions facilitate the generation of task-relevant responses while inhibiting interference from emotionally distracting information. Schizophrenia is associated with deficits in both executive attention and affective regulation. This study aims to elucidate the neural correlates of emotion-attention regulation and shifting in schizophrenia. Method: We employed functional magnetic resonance imaging to probe the fronto-limbic regions in 16 adults with schizophrenia and 13 matched adults with no history of psychiatric illness. Subjects performed a forced-choice visual oddball task where they detected infrequent target circles embedded in a series of infrequent nontarget aversive and neutral pictures and frequent squares. Results: In control participants, target events activated a dorsal frontoparietal network, whereas these regions were deactivated by aversive stimuli. Conversely, ventral frontolimbic brain regions were activated by aversive stimuli and deactivated by target events. In the patient group, regional hemodynamic timecourses revealed not only reduced activation to target and aversive events in dorsal executive and ventral limbic regions, respectively, but also reduced deactivation to target and aversive stimuli in ventral and dorsal regions, respectively, relative to the control group. Patients further showed reduced spatial extent of activation in the right inferior frontal gyrus during the target and aversive conditions. Activation of the anterior cingulate to aversive images was inversely related to severity of avolition and anhedonia symptoms in the schizophrenia group. Conclusions: These results suggest both frontal and limbic dysfunction in schizophrenia as well as aberrant reciprocal inhibitions between these regions during attention-emotion modulation in this disorder.

Schizophrenia Patients Show Task Switching Deficits Consistent With N-Methyl-D-Aspartate System Dysfunction But Not Global Executive Deficits: Implications for Pathophysiology of Executive Dysfunction in Schizophrenia

Wylie, G. R., Clark, E.A, Butler, P.D., Javitt, D.C. — 2008-10-03

Schizophrenia is associated with cognitive processing deficits, including deficits in executive processing, that represent a core component of the disorder. In the Task Switching Test, subjects view ambiguous stimuli and must alternate between competing rules to generate correct responses. Subjects show worse performance (prolonged response time and/or increased error rates) on the first response after a switch than on subsequent responses ("switch costs"), as well as performing worse when stimuli are incongruent as opposed to congruent ("congruence costs"). Finally, subjects show worse performance in the dual vs single task condition ("mixing costs"). In monkeys, the N-methyl-D-aspartate (NMDA) antagonist ketamine has been shown to increase congruence but not switch costs. Here, subjects viewed colored letters and had to respond alternately based upon letter (X vs O) or color (red vs blue). Switch, congruence and mixing costs were calculated. Patients with schizophrenia (n = 16) and controls (n = 17) showed similar switch costs, consistent with prior literature. Patients nevertheless showed increased congruence and mixing costs. In addition, relative to controls, patients showed worse performance across conditions in the letter vs color tasks, suggesting deficits in form vs color processing. Overall, while confirming executive dysfunction in schizophrenia, this study indicates that not all aspects of executive control are impaired and that the task switching paradigm may be useful for evaluating neurochemical vs neuroanatomic hypotheses of schizophrenia.

The Cognitive Neuropsychology of Auditory Hallucinations: A Parallel Auditory Pathways Framework

Badcock, J. C. — 2008-10-02

Auditory hallucinations are generally defined as false perceptions. Recent developments in auditory neuroscience have rapidly increased our understanding of normal auditory perception revealing (partially) separate pathways for the identification ("what") and localization ("where") of auditory objects. The current review offers a reexamination of the nature of auditory hallucinations in schizophrenia using this object-based framework. First, the structural and functional organization of auditory what and where pathways is briefly described. Then, using recent functional neuroimaging data from healthy subjects and patients with schizophrenia, key phenomenological features of hallucinations are linked to abnormal processing both within and between these pathways. Finally, current cognitive explanations of hallucinations, based on intrusive cognitions and impaired source memory, are briefly outlined and set within this framework to provide an integrated cognitive neuropsychological model of auditory hallucinations.

Do We Need Multiple Models of Auditory Verbal Hallucinations? Examining the Phenomenological Fit of Cognitive and Neurological Models

Jones, S. R. — 2008-09-26

The causes of auditory verbal hallucinations (AVHs) are still unclear. The evidence for 2 prominent cognitive models of AVHs, one based on inner speech, the other on intrusions from memory, is briefly reviewed. The fit of these models, as well as neurological models, to the phenomenology of AVHs is then critically examined. It is argued that only a minority of AVHs, such as those with content clearly relating to verbalizations experienced surrounding previous trauma, are consistent with cognitive AVHs-as-memories models. Similarly, it is argued that current neurological models are only phenomenologically consistent with a limited subset of AVHs. In contrast, the phenomenology of the majority of AVHs, which involve voices attempting to regulate the ongoing actions of the voice hearer, are argued to be more consistent with inner speech–based models. It is concluded that subcategorizations of AVHs may be necessary, with each underpinned by different neurocognitive mechanisms. The need to study what is termed the dynamic developmental progression of AVHs is also highlighted. Future empirical research is suggested in this area.

Getting the Cue: Sensory Contributions to Auditory Emotion Recognition Impairments in Schizophrenia

2008-09-23

Individuals with schizophrenia show reliable deficits in the ability to recognize emotions from vocal expressions. Here, we examined emotion recognition ability in 23 schizophrenia patients relative to 17 healthy controls using a stimulus battery with well-characterized acoustic features. We further evaluated performance deficits relative to ancillary assessments of underlying pitch perception abilities. As predicted, patients showed reduced emotion recognition ability across a range of emotions, which correlated with impaired basic tone matching abilities. Emotion identification deficits were strongly related to pitch-based acoustic cues such as mean and variability of fundamental frequency. Whereas healthy subjects’ performance varied as a function of the relative presence or absence of these cues, with higher cue levels leading to enhanced performance, schizophrenia patients showed significantly less variation in performance as a function of cue level. In contrast to pitch-based cues, both groups showed equivalent variation in performance as a function of intensity-based cues. Finally, patients were less able than controls to differentiate between expressions with high and low emotion intensity, and this deficit was also correlated with impaired tone matching ability. Both emotion identification and intensity rating deficits were unrelated to valence of intended emotions. Deficits in both auditory emotion identification and more basic perceptual abilities correlated with impaired functional outcome. Overall, these findings support the concept that auditory emotion identification deficits in schizophrenia reflect, at least in part, a relative inability to process critical acoustic characteristics of prosodic stimuli and that such deficits contribute to poor global outcome.

Neurocognitive Decline in Early-Onset Schizophrenia Compared With ADHD and Normal Controls: Evidence From a 13-Year Follow-up Study

Oie, M., Sundet, K., Rund, B. R. — 2008-09-18

The issue of neurodegeneration in schizophrenia is controversial. Although most studies indicate that neurocognitive deficits are relatively stable over the course of the illness, conclusions are limited by relatively short follow-up periods and absence of age-matched control groups. Furthermore, nearly all studies deal with adult-onset schizophrenia, and few studies have considered the possible effect of age of onset. The current study represents the first attempt to compare groups of adolescents with schizophrenia, attention deficit/hyperactivity disorder (ADHD), and normal controls on a comprehensive neurocognitive test battery in a longitudinal design over 13 years. In the baseline study, adolescents with schizophrenia were examined with a broad battery of neurocognitive tests. The comparison groups consisted of adolescents with ADHD and adolescents without a psychiatric diagnosis, between 12 and 18 years of age. In the follow-up study, the schizophrenia group consisted of 15 of the initial 19 individuals, the ADHD group of 19 of the 20 individuals, and the normal comparison group of all 30 individuals. They were reevaluated with the neurocognitive test battery and clinical measures. Subjects with schizophrenia showed a significant decline or arrest in neurocognitive functioning compared with the other 2 groups, particularly in verbal memory, attention, and processing speed. The impairments may be specific to early-onset schizophrenia due to interaction between ongoing brain maturation during adolescence and disease-related mechanisms and/or secondary to neuroleptic treatment in young age and/or social isolation.

Antipsychotic Therapy During Early and Late Pregnancy. A Systematic Review

Gentile, S. — 2008-09-11

Objective: Both first- (FGAs) and second-generation antipsychotics (SGAs) are routinely used in treating severe and persistent psychiatric disorders. However, until now no articles have analyzed systematically the safety of both classes of psychotropics during pregnancy. Data sources and search strategy: Medical literature information published in any language since 1950 was identified using MEDLINE/PubMed, TOXNET, EMBASE, and The Cochrane Library. Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from companies developing drugs. Search terms were pregnancy, psychotropic drugs, (a)typical-first-second-generation antipsychotics, and neuroleptics. A separate search was also conducted to complete the safety profile of each reviewed medication. Searches were last updated on July 2008. Data selection: All articles reporting primary data on the outcome of pregnancies exposed to antipsychotics were acquired, without methodological limitations. Conclusions: Reviewed information was too limited to draw definite conclusions on structural teratogenicity of FGAs and SGAs. Both classes of drugs seem to be associated with an increased risk of neonatal complications. However, most SGAs appear to increase risk of gestational metabolic complications and babies large for gestational age and with mean birth weight significantly heavier as compared with those exposed to FGAs. These risks have been reported rarely with FGAs. Hence, the choice of the less harmful option in pregnancy should be limited to FGAs in drug-naive patients. When pregnancy occurs during antipsychotic treatment, the choice to continue the previous therapy should be preferred.

Schizophrenia and Alterations in Self-experience: A Comparison of 6 Perspectives

Lysaker, P. H., Lysaker, J. T. — 2008-09-11

Contemporary researchers have tended to examine dysfunction among the lives of persons with schizophrenia as a matter of the impact of biological and social forces. While this has greatly advanced the knowledge base, any account of schizophrenia without a full consideration of the illness's first-person dimensions risks missing that schizophrenia is a disorder that interrupts the lives of people who must continue to struggle to find and create security and meaning. While literature from a range of sources has explored self-experience in schizophrenia, one barrier to the creation of a larger synthesis and application of this work is that it remains unclear whether, and to what degree, these differing views of self-experience are comparable with one another. To address this issue, this article reviews 6 different accounts of self-experience, a fundamental, first-person dimension of schizophrenia. The 6 are early psychiatry, existential psychiatry, psychoanalysis, phenomenology, psychosocial rehabilitation, and dialogical psychology. After comparing and contrasting the 6, we conclude that there is a wide-ranging, if general consensus, which suggests that many suffering from schizophrenia experience themselves as diminished relative to their former selves, ie, after onset they experience themselves as less able to engage the world effectively, which intensifies their anxieties in the face of everyday interactions. However, within this broad consensus, significant disagreements exist around issues such as whether these difficulties meaningfully predate the illness, how recovery is possible, and if so, under what conditions. In closing, we suggest a program of research to address these disagreements.

First-Rank Symptoms in Schizophrenia: Reexamining Mechanisms of Self-recognition

Waters, F. A.V., Badcock, J. C. — 2008-08-27

Disturbances of self are a common feature of schizophrenic psychopathology, with patients reporting that their thoughts and actions are controlled by external forces, as shown in first-rank symptoms (FRS). One widely accepted explanatory model of FRS suggests a deficiency in the internal forward model system. Recent studies in the field of cognitive sciences, however, have generated new insights into how complex sensory and motor systems contribute to the sense of self-recognition, and it is becoming clear that the forward model conceptualization does not have unique access to representations about the self. We briefly evaluate the forward model explanation of FRS, reassess the distinction made between the sense of agency and body ownership, and outline recent developments in 4 domains of sensory-motor control that have supplemented our understanding of the processes underlying the sense of self-recognition. The application of these findings to FRS will open up new research directions into the processes underlying these symptoms.

What Is Causing the Reduced Drug-Placebo Difference in Recent Schizophrenia Clinical Trials and What Can be Done About It?

2008-08-22

On September 18, 2007, a collaborative session between the International Society for CNS Clinical Trials and Methodology and the International Society for CNS Drug Development was held in Brussels, Belgium. Both groups, with membership from industry, academia, and governmental and nongovernmental agencies, have been formed to address scientific, clinical, regulatory, and methodological challenges in the development of central nervous system therapeutic agents. The focus of this joint session was the apparent diminution of drug-placebo differences in recent multicenter trials of antipsychotic medications for schizophrenia. To characterize the nature of the problem, some presenters reported data from several recent trials that indicated higher rates of placebo response and lower rates of drug response (even to previously established, comparator drugs), when compared with earlier trials. As a means to identify the possible causes of the problem, discussions covered a range of methodological factors such as participant characteristics, trial designs, site characteristics, clinical setting (inpatient vs outpatient), inclusion/exclusion criteria, and diagnostic specificity. Finally, possible solutions were discussed, such as improving precision of participant selection criteria, improving assessment instruments and/or assessment methodology to increase reliability of outcome measures, innovative methods to encourage greater subject adherence and investigator involvement, improved rater training and accountability metrics at clinical sites to increase quality assurance, and advanced methods of pharmacokinetic/pharmacodynamic modeling to optimize dosing prior to initiating large phase 3 trials. The session closed with a roundtable discussion and recommendations for data sharing to further explore potential causes and viable solutions to be applied in future trials.

Does Adherence to Medications for Type 2 Diabetes Differ Between Individuals With Vs Without Schizophrenia?

2008-08-20

Individuals with schizophrenia are at increased risk for poor health outcomes and mortality. This may be due to inadequate self-management of co-occurring conditions, such as type 2 diabetes. We compared adherence to oral hypoglycemic medications for diabetes patients with vs without comorbid schizophrenia. Using Veterans Affairs (VA) health system administrative data, we identified all patients with both schizophrenia and type 2 diabetes and with at least one oral hypoglycemic prescription fill in fiscal year 2002 (N = 11 454) and a comparison group of patients with diabetes who were not diagnosed with schizophrenia (N = 10 560). Nonadherence was operationalized as having a medication possession ratio indicating receipt of less than 80% of needed hypoglycemic medications. Poor adherence was less prevalent among diabetes patients with (43%) than without schizophrenia (52%, P < .001). In multivariable analyses, having schizophrenia was associated with a 25% lower likelihood of poor adherence compared with not having schizophrenia (adjusted odds ratio: 0.75, 95% confidence interval: 0.70–0.80). Poorer adherence was associated with black race, homelessness, depression, substance use disorder, and medical comorbidity. Having more outpatient visits, a higher proportion of prescriptions delivered by mail, lower prescription copayments, and more complex medication regimens were each associated with increased adherence. Among veterans with diabetes receiving ongoing VA care, overall hypoglycemic medication adherence was low, but individuals with comorbid schizophrenia were more likely to be adherent to these medications. Future studies should investigate whether factors such as comanagement of a chronic psychiatric illness or regular contact with mental health providers bestow benefits for diabetes self-management in persons with schizophrenia.

A Randomized Controlled Trial of Cognitive Remediation in Schizophrenia

2008-08-20

Individuals with schizophrenia have consistently been found to exhibit cognitive deficits, which have been identified as critical mediators of psychosocial functional outcomes. Recent reviews of cognitive remediation (CRT) have concluded that these deficits respond to training. This multi-site community study examined 40 individuals with schizophrenia who underwent cognitive remediation using the Neuropsychological Educational Approach to Remediation¹ (NEAR). Assessments using the same neuropsychological tests and measures of psychosocial outcome were made at four time points: baseline, before start of active intervention, end of active intervention and 4 months after end of active intervention. Dose of antipsychotic medication remained constant throughout the study period. After participating in NEAR, individuals showed significant improvements in verbal and visual memory, sustained attention and executive functioning. This effect persisted 4 months after the treatment ceased. The average effect size was mild to moderate. Social and occupational outcomes also improved from baseline to post-treatment, which persisted 4 months later. Our findings replicate those of previous studies that suggest that NEAR is effective in improving cognition in individuals with schizophrenia in a naturalistic and ecologically valid setting. Further it extends such findings to show a generalisation of effects to social/occupational outcomes and persistence of effects in the short term.

Differential Effects of Various Typical and Atypical Antipsychotics on Plasma Glucose and Insulin Levels in the Mouse: Evidence for the Involvement of Sympathetic Regulation

2008-08-14

Atypical antipsychotic treatment has been associated with serious metabolic adverse events, such as glucose dysregulation and development of type 2 diabetes. As part of our studies on possible underlying mechanisms, we investigated the acute effects of various typical and atypical antipsychotics on plasma glucose and insulin in FVB/N mice, a strain that showed a more pronounced hyperglycemic response to clozapine than C57BL/6 and CD-1 mice. Acute administration of high doses of clozapine, olanzapine, quetiapine, perphenazine, or chlorpromazine significantly increased plasma glucose by 100%–140% above basal levels without significant effects on insulin levels. In contrast, risperidone reduced plasma glucose (–30%) and markedly enhanced plasma insulin levels. Doses of ziprasidone that gave 50-fold higher free plasma concentrations than therapeutic plasma levels, as well as high doses of aripiprazole and haloperidol, did not significantly alter either glucose or insulin levels. Clozapine- and olanzapine-induced hyperglycemia occurred at free plasma concentrations that were within, or one order of magnitude above, the range of therapeutic plasma levels. Pretreatment with either the ganglionic blocker hexamethonium, or the ₂ adrenergic receptor antagonist yohimbine, blocked the clozapine- and chlorpromazine-induced increase in glucose levels. Taken together, these results suggest that typical and atypical antipsychotics with known metabolic liability produce acute hyperglycemia in mice and that this effect is likely driven by activation of the sympathetic autonomic nervous system via a central mechanism.

The Relationship Between IQ, Memory, Executive Function, and Processing Speed in Recent-Onset Psychosis: 1-Year Stability and Clinical Outcome

2008-08-04

Studies commonly report poor performance in psychotic patients compared with controls on tasks testing a range of cognitive functions, but, because current IQ is often not matched between these groups, it is difficult to determine whether this represents a generalized deficit or specific abnormalities. Fifty-three first-episode psychosis patients and 53 healthy controls, one-to-one matched for sex, age, and full-scale current IQ, were compared on Wechsler Adult Intelligence Scale (WAIS) subtests representing indices of perceptual organization, verbal comprehension, processing speed, and working memory as well as other tests of executive function and episodic memory. The groups showed an equivalent pattern of performance on all WAIS subtests except digit symbol processing speed, on which the patients were significantly worse. Patients were also worse on measures where performance correlated with digit symbol score, namely working and verbal memory tasks. Standardized residual scores for each subtest were calculated for each patient using the difference between their actual subtest score and a predicted subtest score based on their full-scale IQ and the performance of controls. Scaled scores and residual scores were examined for relationships with clinical measures. Digit symbol–scaled score was significantly correlated with concurrent negative syndrome score at baseline, and digit symbol residual score significantly predicted residual negative symptoms at 1-year follow-up. In summary, our comparison of patients and controls precisely matched for IQ revealed that processing speed was attenuated in recent-onset schizophrenia, contributed significantly to working and episodic memory deficits, and was a prognostic factor for poor outcome at 1 year.

Relating Schizotypy and Personality to the Phenomenology of Creativity

Nelson, B., Rawlings, D. — 2008-08-04

Introduction: Although a considerable amount of research has addressed psychopathological and personality correlates of creativity, the relationship between these characteristics and the phenomenology of creativity has been neglected. Relating these characteristics to the phenomenology of creativity may assist in clarifying the precise nature of the relationship between psychopathology and creativity. The current article reports on an empirical study of the relationship between the phenomenology of the creative process and psychopathological and personality characteristics in a sample of artists. Method: A total of 100 artists (43 males, 57 females, mean age = 34.69 years) from a range of disciplines completed the Experience of Creativity Questionnaire and measures of "positive" schizotypy, affective disturbance, mental boundaries, and normal personality. Results: The sample of artists was found to be elevated on "positive" schizotypy, unipolar affective disturbance, thin boundaries, and the personality dimensions of Openness to Experience and Neuroticism, compared with norm data. Schizotypy was found to be the strongest predictor of a range of creative experience scales (Distinct Experience, Anxiety, Absorption, Power/Pleasure), suggesting a strong overlap of schizotypal and creative experience. Discussion: These findings indicate that "positive" schizotypy is associated with central features of "flow"-type experience, including distinct shift in phenomenological experience, deep absorption, focus on present experience, and sense of pleasure. The neurologically based construct of latent inhibition may be a mechanism that facilitates entry into flow-type states for schizotypal individuals. This may occur by reduced latent inhibition providing a "fresh" awareness and therefore a greater absorption in present experience, thus leading to flow-type states.

Cognitive Performance and Functional Competence as Predictors of Community Independence in Schizophrenia

Heinrichs, R. W., Ammari, N., Miles, A. A., McDermid Vaz, S. — 2008-07-30

Measures of functional competence have been introduced to supplement standard cognitive and neuropsychological evaluations in schizophrenia research and practice. Functional competence comprises skills and abilities that are more relevant to daily life and community adjustment. However, it is unclear whether relevance translates into significantly enhanced prediction of real-world outcomes. The aim of this study was to assess the specific contribution of functional competence in predicting a key aspect of real-world outcome in schizophrenia: community independence. Demographic, clinical, cognitive, and functional competence data were obtained from 127 patients with schizophrenia or schizoaffective disorder and used to predict community independence concurrently and longitudinally after 10 months. Hierarchical regression analyses indicated that demographic, clinical, and cognitive predictors accounted jointly for 35%–38% of the variance in community independence across assessment points. Functional competence data failed to add significantly to this validity. Considered separately from demographic and clinical predictors, cognitive and functional competence data accounted for significant amounts of outcome variance. However, the addition of functional competence to standard cognitive test data yielded a significant increase in validity only for concurrent and not for longitudinal prediction of community independence. The specific real-world validity of functional competence is modest, yielding information that is largely redundant with standard cognitive performance.

Assessing Social-Cognitive Deficits in Schizophrenia With the Mayer-Salovey-Caruso Emotional Intelligence Test

2008-07-22

The emotion management subscale of the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT) has recently been recommended by the National Institute of Mental Health Measurement and Treatment Research to Improve Cognition in Schizophrenia committee as the sole measure of social cognition for trials of cognitive enhancement in schizophrenia, yet the psychometric properties of this subscale and the larger instrument in schizophrenia patients have not been thoroughly examined. This research presents a psychometric investigation of the MSCEIT in a sample of 64 early course outpatients with schizophrenia, schizoaffective, or schizophreniform disorder. Results demonstrated that the MSCEIT possesses adequate internal consistency reliability among its branch and total scales and that patients’ branch and overall test performance was significantly below normative levels. Estimates of discriminant and concurrent validity indicated that the MSCEIT diverged from measures of neurocognitive functioning and psychopathology, but was only modestly related with objective measures of functional outcome. Convergent validity estimates suggested that, contrary to expectations, the MSCEIT did not correlate with a behavioral measure of social cognition. Finally, exploratory factor analyses suggested the possibility of a shift in the latent structure of emotional intelligence in schizophrenia, compared with studies with healthy individuals. These findings support the use of the MSCEIT as a reliable and potentially valid method of assessing the emotional components of social cognition in schizophrenia, but also point to a need for additional measurement development efforts to assess broader social-cognitive domains that may exhibit stronger relations with functional outcome. Further investigation is warranted to examine the instrument's latent factor structure and convergence with other measures of social cognition.

Negative Symptoms in Schizophrenia: Avolition and Occam's Razor

Foussias, G., Remington, G. — 2008-07-21

The identification of schizophrenia's negative symptoms dates back to the earliest descriptions of Kraepelin and Bleuler, who each highlighted the central role of avolition in the phenomenology and course of this illness. Since, there have been numerous advances in our understanding of schizophrenia, and the present review tracks the changes that have taken place in our understanding of negative symptoms, their description and measurement. That these symptoms represent a distinct domain of the illness is discussed in the context of their ties to other symptoms and functional outcome. The underlying structure of the negative symptom construct is explored, including several lines of investigation that point towards diminished expression and amotivation as key underlying subdomains. We also discuss findings of intact emotional experience and consummatory pleasure in individuals with schizophrenia, calling into question the presence of anhedonia in this illness. We conclude with a reconceptualization of the negative symptoms, suggesting amotivation (ie, avolition) represents the critical component, particularly in regard to functional outcome. Further exploration and clarification of this core deficit will ultimately enhance our neurobiological understanding of schizophrenia, as well as strategies that may improve outcome.

Sex Differences in Wisconsin Schizotypy Scales--A Meta-analysis

Miettunen, J., Jaaskelainen, E. — 2008-07-21

Previous single studies have found inconsistent results on sex differences in positive schizotypy, women scoring mainly higher than men, whereas in negative schizotypy studies have often found that men score higher than women. However, information on the overall effect is unknown. In this study, meta-analytic methods were used to estimate sex differences in Wisconsin Schizotypy Scales developed to measure schizotypal traits and psychosis proneness. We also studied the effect of the sample characteristics on possible differences. Studies on healthy populations were extensively collected; the required minimum sample size was 50. According to the results, men scored higher on the scales of negative schizotypy, ie, in the Physical Anhedonia Scale (n = 23 studies, effect size, Cohen d = 0.59, z test P < .001) and Social Anhedonia Scale (n = 14, d = 0.44, P < .001). Differences were virtually nonexistent in the measurements of the positive schizotypy, ie, the Magical Ideation Scale (n = 29, d = –0.01, P = .74) and Perceptual Aberration Scale (n = 22, d = –0.08, P = .05). The sex difference was larger in studies with nonstudent and older samples on the Perceptual Aberration Scale (d = –0.19 vs d = –0.03, P < .05). This study was the first one to pool studies on sex differences in these scales. The gender differences in social anhedonia both in nonclinical samples and in schizophrenia may relate to a broader aspect of social and interpersonal deficits. The results should be taken into account in studies using these instruments.

Sensorimotor Gating of Schizophrenia Patients Depends on Catechol O-Methyltransferase Val158Met Polymorphism

Quednow, B. B., Wagner, M., Mossner, R., Maier, W., Kuhn, K.-U. — 2008-07-17

It has been recently shown that Catechol O-methyltransferase (COMT) Val¹⁵⁸Met polymorphism strongly influences prepulse inhibition (PPI) of the acoustic startle response (ASR) in healthy human volunteers. Given that schizophrenia patients exhibit impairment in PPI and that COMT is a putative susceptibility gene for schizophrenia, we investigated the impact of the COMT Val¹⁵⁸Met polymorphisms on PPI in schizophrenic inpatients. We analyzed COMT Val¹⁵⁸Met polymorphisms and assessed startle reactivity, habituation, and PPI of ASR in 68 Caucasian schizophrenia inpatients. Clinical symptoms were measured with the Positive and Negative Syndrome Scale (PANSS). Patients carrying the Val¹⁵⁸Met Met/Met allele showed elevated PPI levels whereas startle reactivity and habituation did not differ from the other two genotypes. These preliminary results imply that PPI is influenced by COMT Val¹⁵⁸Met genotype in schizophrenia as well. In concert with other findings, our data suggest that PPI is a polygenic trait.

Reasoning Anomalies Associated With Delusions in Schizophrenia

Langdon, R., Ward, P. B., Coltheart, M. — 2008-07-11

Deluded people differ from nondeluded controls on attributional style questionnaires and probabilistic-reasoning and theory-of-mind (ToM) tasks. No study to date has examined the relations between these 3 reasoning anomalies in the same individuals so as to evaluate their functional independence and potentially inform theories of delusion formation. We did so in 35 schizophrenic patients with a history of delusions, 30 of whom were currently deluded, and 34 healthy controls. Compared with healthy controls, patients showed (a) a jumping-to-conclusions bias and a bias to overadjust when confronted with a change of evidence on probabilistic-reasoning tasks, (b) an excessive externalizing attributional bias, and (c) performance deficits on 3 ToM tasks. Probabilistic-reasoning and ToM measures correlated, while attributional-bias scores were independent of other task measures. A general proneness to delusional ideation correlated with probabilistic-reasoning and ToM measures, while externalizing bias was unrelated to the study measures of delusional ideation. Personalizing bias associated specifically with paranoia across the clinical and nonclinical participants. Findings are consistent with a common underlying mechanism in schizophrenia which contributes to the anomalies on probabilistic-reasoning and ToM tasks associated with delusions. We speculate that this mechanism is impairment of the normal capacity to inhibit "perceived reality" (the evidence of our senses), a capacity that evolved as part of the "social brain" to facilitate intersubjective communication within a shared reality.

How Frequent is Chronic Multiyear Delusional Activity and Recovery in Schizophrenia: A 20-Year Multi-follow-up

Harrow, M., Jobe, T. H. — 2008-07-09

To determine how frequent chronic multiyear delusional activity is in modern-day schizophrenia, we studied 200 patients over a 20-year period. We also studied the relation of delusions to hallucinations and thought disorder-disorganization, to work disability, and to later periods of global recovery and assessed several protective factors against delusional activity. The sample was assessed 6 times over 20 years and includes 43 patients with schizophrenia. Participants were evaluated at each follow-up for delusions, hallucinations, thought disorder-disorganization, work disability, and global recovery. Possible protective factors were assessed prospectively at index hospitalization. Twenty-six percent of the patients with schizophrenia were delusional at all follow-ups over the 20 years. Overall, 57% had frequently recurring or persistent delusions. A subgroup of over 25% of the schizophrenia patients had no delusional activity at any of the 6 follow-ups over 20 years. Schizophrenia patients with posthospital delusional activity had increased work disability (P < .05). Delusions that persisted after the acute phase in schizophrenia patients predicted a lower likelihood of future global recovery (P < .01). In conclusion, slightly over half of modern-day schizophrenia patients are vulnerable to frequent or "chronic" delusional activity after the acute phase. Schizophreniform patients and other types of psychotic disorders are vulnerable to posthospital delusional activity, but less frequently, less severely, and more episodically. Delusional activity is associated with work disability. Internal factors such as good premorbid developmental achievements and favorable prognostic factors are protective factors that reduce the probability of chronic multiyear, delusional activity in schizophrenia (P < .01).

Basic Symptoms and Ultrahigh Risk Criteria: Symptom Development in the Initial Prodromal State

Schultze-Lutter, F., Ruhrmann, S., Berning, J., Maier, W., Klosterkotter, J. — 2008-06-25

Symptom development during the prodromal phase of psychosis was explored retrospectively in first-episode psychosis patients with special emphasis on the assumed time-related syndromic sequence of "unspecific symptoms (UN)–predictive basic symptoms (BS)–attenuated psychotic symptoms (APS)–(transient) psychotic symptoms (PS)." Onset of syndromes was defined by first occurrence of any of their respective symptoms. Group means were inspected for time differences between syndromes and influence of sociodemographic and clinical characteristics on the recalled sequence. The sequence of "UN–BS/APS–PS" was clearly supported, and both BS and, though slightly less, APS were highly sensitive. However, onset of BS and APS did not show significant time difference in the whole sample (N = 126; 90% schizophrenia), although when each symptom is considered independently, APS tended to occur later than first predictive BS. On descriptive level, about one-third each recalled an earlier, equal and later onset of BS compared with APS. Level of education showed the greatest impact on the recall of the hypothesized sequence. Thereby, those with a higher school–leaving certificate supported the assumed sequence, whereas those of low educational background retrospectively dated APS before BS. These findings rather point out recognition and recall bias inherent to the retrospective design than true group characteristics. Future long-term prospective studies will have to explore this conclusively. However, as regards the criteria, the results support the notion of BS as at least a complementary approach to the ultrahigh risk criteria, which may also allow for an earlier detection of psychosis.

Smoking in Schizophrenia: Diagnostic Specificity, Symptom Correlates, and Illness Severity

Kotov, R., Guey, L. T., Bromet, E. J., Schwartz, J. E. — 2008-06-17

Background: Cigarette smoking was consistently found to be more prevalent in individuals with schizophrenia than in other psychiatric groups and the general population. These findings have been interpreted as evidence of a specific association between schizophrenia and smoking. However, the supporting data come primarily from cross-sectional studies, which are susceptible to confounding. Our aim was to test specificity of this link longitudinally in an epidemiologic sample. Methods: A cohort of 542 inpatients with psychosis was followed for 10 years after first hospitalization, completing 5 face-to-face interviews. Assessments included ratings of specific symptoms (psychotic, negative, disorganized, and depressive), Global Assessment of Functioning, and a categorical measure of cigarette consumption. All participants were assigned longitudinal consensus diagnoses by study psychiatrists, and 229 were diagnosed with schizophrenia spectrum disorders (SZ). Results: At baseline, 52.4% of participants were current smokers and 69.3% were lifetime smokers. Smoking rates did not differ among the diagnostic groups (schizophrenia spectrum, major depressive, bipolar, or other psychotic disorder) at any assessment point. Smokers were more severely ill than nonsmokers but did not differ in specific symptoms either cross-sectionally or longitudinally. Among smokers, changes in cigarette consumption were linked only with changes in depression (β = .16, P < .001). Conclusions: Rates of smoking were elevated in subjects with schizophrenia but were just as high with other psychotic disorders. Smoking was not associated with psychotic symptoms, but cigarette consumption covaried with depression over time. Given the devastating health consequences of cigarette use, smoking cessation interventions are urgently needed in this population and should specifically address depression.

Antiviral Therapy Completion and Response Rates Among Hepatitis C Patients With and Without Schizophrenia

Huckans, M., Mitchell, A., Ruimy, S., Loftis, J., Hauser, P. — 2008-06-17

Background: Despite disproportionately high rates of hepatitis C (HCV) among patients with severe mental illness, to date, there is scant empirical data available regarding antiviral therapy outcomes within this population. Objective: To compare antiviral therapy completion and response rates between HCV patients with vs those without schizophrenia (SCHZ). Methods: A regional Veterans Healthcare Administration database was used to identify veterans meeting criteria for this retrospective chart review. All patients confirmed to have SCHZ and to have received antiviral therapy between 1998 and 2006 (n = 30) were compared with a control group of demographically matched (HCV genotype, age, race, gender) patients with no history of SCHZ (n = 30). Results: For HCV patients with genotype 1, antiviral completion, end of treatment response (ETR), and sustained viral response (SVR) rates did not significantly differ between groups. For those with genotypes 2 and 3 combined, antiviral therapy completion rates did not significantly differ between groups; however, the SCHZ group was significantly (P < 0.050) more likely to achieve an ETR and an SVR. For all genotypes combined, the SCHZ patients were no more likely than controls to discontinue therapy early for psychiatric symptoms, medical complications, or other adverse events, and groups did not significantly differ in terms of hospitalization rates during antiviral therapy. Conclusion: Our retrospective chart review suggests that patients with SCHZ complete and respond to antiviral therapy for HCV at rates comparable with those without SCHZ. Based on these data, SCHZ should not be considered a contraindication to antiviral therapy for HCV.

Catechol-O-Methyltransferase Val158Met Polymorphism and Antisaccade Eye Movements in Schizophrenia

2008-06-17

The catechol-O-methyltransferase (COMT) enzyme catabolizes dopamine. The val¹⁵⁸met single nucleotide polymorphism (rs4680) in the COMT gene has received considerable attention as a candidate gene for schizophrenia as well as for frontally mediated cognitive functions. Antisaccade performance is a good measure of frontal lobe integrity. Deficits on the task are considered a trait marker for schizophrenia. The aim of this study was to investigate the association of COMT val¹⁵⁸met polymorphism with antisaccade eye movements in schizophrenia patients and healthy controls. Schizophrenia patients (N = 105) and healthy controls (N = 95) underwent infrared oculographic assessment of antisaccades. Subjects were genotyped for COMT val¹⁵⁸met and divided into 3 groups according to genotype (val/val, val/met, and met/met). Patients displayed significantly more reflexive errors, longer and more variable latency, and lower amplitude gain than controls (all P < 0.02). A greater number of val¹⁵⁸ alleles was associated with shorter (P = 0.045) and less variable (P = 0.028) antisaccade latency and, nonsignificantly, with lower reflexive error rate (P = 0.056). None of these variables showed a group-by-genotype interaction (P > 0.1). There were no significant associations of genotype with measures of amplitude gain or spatial error (P > 0.2). The results suggest that COMT val¹⁵⁸ carrier status is associated with better performance on the antisaccade task. Possible explanations of this finding are discussed.

Semantic Expectations Can Induce False Perceptions in Hallucination-Prone Individuals

Vercammen, A., Aleman, A. — 2008-06-17

Recently, it has been proposed that exaggerated top-down processing may generate spontaneous perceptual output, and that this may constitute a cognitive predisposition toward hallucinations. In this experiment, we investigated whether hallucination proneness would be associated with increased auditory-verbal perceptual expectations, and at which processing level this occurs. From 351 undergraduate students screened for hallucination proneness, using the Launay-Slade Hallucination Scale (LSHS), 42 subjects were recruited for participation. Two word recognition tasks were administered, in which top-down influences on perception were manipulated through sentence context (semantic task) or auditory imagery (phonological task). Results revealed that LSHS scores were correlated with the number of semantically primed errors. Subjects with higher levels of hallucination proneness were more likely to report hearing a word that fits the sentence context, when it was not actually presented. This effect remained significant after controlling for general performance on the task. In contrast, hallucination proneness was not associated with phonologically primed errors. We conclude that aberrant top-down processing, particularly in the form of strong semantic expectations, may contribute to the experience of auditory-verbal hallucinations.

Emotional Experience in Patients With Schizophrenia Revisited: Meta-analysis of Laboratory Studies

Cohen, A. S., Minor, K. S. — 2008-06-17

Our understanding of the emotion deficits in schizophrenia is limited. Findings from studies employing trait emotion instruments suggest that patients have attenuated levels of positive emotion (ie, anhedonia) and increased levels of negative emotion. Conversely, patients and controls have not statistically differed in their subjective reactions to positive or negative valenced stimuli in most laboratory studies to date. Further obfuscating this issue is the fact that many of these laboratory studies are underpowered and a handful of emotion induction studies have found evidence of anhedonia. We conducted a meta-analysis of 26 published studies employing laboratory emotion induction procedures in patients with schizophrenia and healthy controls. Patients did not differ from controls when strictly rating their subjective hedonic reactions to the stimuli. However, they reported experiencing relatively strong aversion to both positive and neutral stimuli (Hedges D = .72 and .64, respectively). These findings were not the result of demonstrable sample or methodological differences across studies. Patients’ ability to experience hedonic emotion is preserved, although they also show relatively strong, simultaneously occurring aversive emotion when processing laboratory stimuli considered by others to be pleasant or neutral.

Passive and Active Schizophrenia: Toward a New Descriptive Micropsychopathology

Moscarelli, M. — 2008-06-17

The "experiences" reported by individuals affected by schizophrenia are fundamental components of the descriptive approach adopted by current diagnostic systems for mental disorders and by clinical diagnostic interviews and rating scales for the assessment of the symptoms of schizophrenia. However, the technical literature does not rely on a specific definition of experiences in schizophrenia. This article introduces a specific, restrictive, operationalized definition of the "experiential substrate" of schizophrenia, defined by the "self-giving" "passive experiences" of the disorder that break into the consciousness of the affected individual, and are distinguished from the "active" acts of judgment formulation and conviction/belief attainment. The experiential substrate of schizophrenia may be considered similar to the experiential substrate of pain. The operationalization of the definition of passive experiences can enable the experiential substrate of schizophrenia to be acknowledged as an independent domain with a specific role in the assessment of the disorder, a role that is substantially omitted or ignored by current research and practice. The term "descriptive micropsychopathology" is proposed for this new method aimed to describe passive experiences and active judgments as independent domains to enhance the reformulation of criteria for symptom assessment and, consequently, reformulation of the criteria for the assessment of the efficacy and effectiveness of interventions aimed at prevention, care, and rehabilitation in schizophrenia. A new measure focusing on the evaluation of the passive experiences of schizophrenia and on the disturbance they cause to patients is also described.

Schizophrenia Susceptibility Genes Directly Implicated in the Life Cycles of Pathogens: Cytomegalovirus, Influenza, Herpes simplex, Rubella, and Toxoplasma gondii

Carter, C.J. — 2008-06-13

Many genes implicated in schizophrenia can be related to glutamatergic transmission and neuroplasticity, oligodendrocyte function, and other families clearly related to neurobiology and schizophrenia phenotypes. Others appear rather to be involved in the life cycles of the pathogens implicated in the disease. For example, aspartylglucosaminidase (AGA), PLA2, SIAT8B, GALNT7, or B3GAT1 metabolize chemical ligands to which the influenza virus, herpes simplex, cytomegalovirus (CMV), rubella, or Toxoplasma gondii bind. The epidermal growth factor receptor (EGR/EGFR) is used by the CMV to gain entry to cells, and a CMV gene codes for an interleukin (IL-10) mimic that binds the host cognate receptor, IL10R. The fibroblast growth factor receptor (FGFR1) is used by herpes simplex. KPNA3 and RANBP5 control the nuclear import of the influenza virus. Disrupted in schizophrenia 1 (DISC1) controls the microtubule network that is used by viruses as a route to the nucleus, while DTNBP1, MUTED, and BLOC1S3 regulate endosomal to lysosomal routing that is also important in viral traffic. Neuregulin 1 activates ERBB receptors releasing a factor, EBP1, known to inhibit the influenza virus transcriptase. Other viral or bacterial components bind to genes or proteins encoded by CALR, FEZ1, FYN, HSPA1B, IL2, HTR2A, KPNA3, MED12, MED15, MICB, NQO2, PAX6, PIK3C3, RANBP5, or TP53, while the cerebral infectivity of the herpes simplex virus is modified by Apolipoprotein E (APOE). Genes encoding for proteins related to the innate immune response, including cytokine related (CCR5, CSF2RA, CSF2RB, IL1B, IL1RN, IL2, IL3, IL3RA, IL4, IL10, IL10RA, IL18RAP, lymphotoxin-alpha, tumor necrosis factor alpha [TNF]), human leukocyte antigen (HLA) antigens (HLA-A10, HLA-B, HLA-DRB1), and genes involved in antigen processing (angiotensin-converting enzyme and tripeptidyl peptidase 2) are all concerned with defense against invading pathogens. Human microRNAs (Hsa-mir-198 and Hsa-mir-206) are predicted to bind to influenza, rubella, or poliovirus genes. Certain genes associated with schizophrenia, including those also concerned with neurophysiology, are intimately related to the life cycles of the pathogens implicated in the disease. Several genes may affect pathogen virulence, while the pathogens in turn may affect genes and processes relevant to the neurophysiology of schizophrenia. For such genes, the strength of association in genetic studies is likely to be conditioned by the presence of the pathogen, which varies in different populations at different times, a factor that may explain the heterogeneity that plagues such studies. This scenario also suggests that drugs or vaccines designed to eliminate the pathogens that so clearly interact with schizophrenia susceptibility genes could have a dramatic effect on the incidence of the disease.

Imaging Genetic Liability to Schizophrenia: Systematic Review of fMRI Studies of Patients' Nonpsychotic Relatives

MacDonald, A. W., Thermenos, H. W., Barch, D. M., Seidman, L. J — 2008-06-12

There is a growing literature on brain activity in the nonpsychotic first-degree relatives of patients with schizophrenia as measured using functional imaging. This systematic review examined 20 studies in 4 domains of cognition, including cognitive control (7 samples), working memory (5 samples), long-term memory (4 samples), and language (4 samples). While the literature was widely divergent, these studies did consistently find activation differences between patients’ relatives and controls. The most consistent increases in activation within hemisphere were found in right ventral prefrontal cortex (PFC) and right parietal cortex. Abnormal activity, defined as significant increases or decreases in activation relative to controls irrespective of hemisphere, was found in about two-thirds of contrasts in the cerebellum, dorsal prefrontal, lateral temporal, and parietal cortices, and thalamus, with basal ganglia and ventral PFC showing abnormalities in approximately half of those contrasts. Anterior cingulate was generally spared in patients’ relatives. The diversity of findings in studies of patients’ relatives may derive from differences between the cognitive demands across studies. We identify avenues for building a more accurate and cumulative literature, including symmetrical inclusion criteria for relatives and controls, recording in-scanner responses, using both a priori and whole-brain tests, explicitly reporting threshold values, reporting main effects of task, reporting effect sizes, and quantifying the risk of false negatives. While functional imaging in the relatives of schizophrenia patients remains a promising methodology for understanding the impact of the unexpressed genetic liability to schizophrenia, no single region or mechanism of abnormalities has yet emerged.

Shared Neurocognitive Dysfunctions in Young Offspring at Extreme Risk for Schizophrenia or Bipolar Disorder in Eastern Quebec Multigenerational Families

2008-06-11

Background: Adult patients having schizophrenia (SZ) or bipolar disorder (BP) may have in common neurocognitive deficits. Former evidence suggests impairments in several neuropsychological functions in young offspring at genetic risk for SZ or BP. Moreover, a dose-response relation may exist between the degree of familial loading and cognitive impairments. This study examines the cognitive functioning of high-risk (HR) offspring of parents having schizophrenia (HRSZ) and high-risk offspring of parents having bipolar disorder (HRBP) descending from densely affected kindreds. Methods: The sample consisted of 45 young offspring (mean age of 17.3 years) born to a parent having SZ or BP descending from large multigenerational families of Eastern Québec that are densely affected by SZ or BP and followed up since 1989. The offspring were administered a lifetime best-estimate diagnostic procedure (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV]) and an extensive standard neuropsychological battery. Raw scores were compared with age- and gender-matched controls. Results: The offspring displayed differences in memory and executive functions when compared with controls. Moderate to large effect sizes (Cohen d) ranging from 0.65 to 1.25 (for IQ and memory) were observed. Several of the cognitive dysfunctions were present in both HRSZ and HRBP, even when considering DSM-IV clinical status. Conclusions: HRSZ and HRBP shared several aspects of their cognitive impairment. Our data suggest that the extremely high genetic and familial loading of these HRs may have contributed to a quantitatively increased magnitude of the cognitive impairments in both HR subgroups, especially in memory. These offspring at heightened risk present difficulties in processing information that warrant preventive research.

Taking the Perspective of the Other Contributes to Awareness of Illness in Schizophrenia

Langdon, R., Ward, P. — 2008-05-30

Two approaches dominate research on the lack of awareness of illness that characterizes schizophrenia. The "deficit" approach uses standardized neuropsychological batteries to identify the neural underpinnings of intact insight; the "nondeficit" approach investigates the psychological defense mechanisms that motivate denial of illness. We adopt, instead, a cognitive neuropsychological approach to model the cognitive processes which underpin insight and which might be either damaged (because of neuropathology) or not used (because of motivational forces). We conceive of these processes in terms of a metacognitive capacity "to see ourselves as others see us." We predict that a general difficulty with adopting other mental perspectives (with "seeing the world as others do"), indexed by performance deficits on theory of mind (ToM) tasks, will impair insight in schizophrenia. Thirty schizophrenic patients (also assessed for insight) and 26 healthy controls completed a battery of ToM tasks which varied presentation modality, response mode and instruction type (picture sequencing, joke appreciation and story comprehension tasks). While patients performed more poorly than controls on all ToM tasks, impairment in patients was not concordant across tasks. ToM scores from the picture sequencing and joke appreciation tasks, and not the story comprehension task, intercorrelated significantly in patients and predicted insight. Findings support the view that insight relies upon a cognitive capacity to adopt the other perspective, which, if intact, contributes to the metacognitive capacity to reflect upon "one's own" mental health from the other perspective. Findings also suggest that the nature of perspective-taking difficulty which disrupts insight in schizophrenia is best revealed using ToM tasks with "indirect" instructions.

Neuropsychological Function and Dysfunction in Schizophrenia and Psychotic Affective Disorders

2008-05-20

Background: Mounting evidence suggests that compromised neurocognitive function is a central feature of schizophrenia. There are, however, schizophrenia patients with a normal neuropsychological (NP) performance, but estimates of the proportion of NP normal patients vary considerably between studies. Neurocognitive dysfunction is also a characteristic of other psychotic disorders, yet there are inconsistencies in the literature regarding the similarity to impairments in schizophrenia. NP normality in psychotic affective disorders has not been systematically studied.

Methods: Data came from the Suffolk County Mental Health Project, an epidemiological study of first-admission patients with psychotic disorders. Respondents with a diagnosis of schizophrenia (N = 94) or schizoaffective disorder (N = 15), bipolar disorder (N = 78), and major depressive disorder (N = 48) were administered a battery of NP tests assessing 8 cognitive domains 2 years after index admission. Patients’ performance profile was compared, and their NP status was classified based on 3 previously published criteria that vary in their stringency.

Results: The 4 diagnostic groups had comparable NP performance profile patterns. All groups demonstrated impairments in memory, executive functions, and attention and processing speed. However, schizophrenia patients were more impaired than the other groups on all cognitive domains. Results were not attenuated when IQ was controlled. Prevalence of NP normality ranged between 16% and 45% in schizophrenia, 20% and 33% in schizoaffective disorder, 42% and 64% in bipolar disorder, and 42% and 77% in depression, depending on the criterion employed.

Conclusions: Evidence suggests that differences in NP performance between schizophrenia and psychotic affective disorders are largely quantitative. NP impairment is also common in psychotic affective disorders. A significant minority of schizophrenia patients are NP normal.

Major Self-mutilation in the First Episode of Psychosis

Large, M., Babidge, N., Andrews, D., Storey, P., Nielssen, O. — 2008-05-20

Major self-mutilation (MSM) is a rare but catastrophic complication of severe mental illness. Most people who inflict MSM have a psychotic disorder, usually a schizophrenia spectrum psychosis. It is not known when in the course of psychotic illness, MSM is most likely to occur. In this study, the proportion of patients in first episode of psychosis (FEP) was assessed using the results of a systematic review of published case reports. Histories of patients who had removed an eye or a testicle, severed their penis, or amputated a portion of a limb and were diagnosed with a schizophrenia spectrum psychosis were included. A psychotic illness was documented in 143 of 189 cases (75.6%) of MSM, of whom 119 of 143 (83.2%) were diagnosed with a schizophrenia spectrum psychosis. The treatment status of a schizophrenia spectrum psychosis could be ascertained in 101 of the case reports, of which 54 were in the FEP (53.5%, 95% confidence interval = 43.7%–63.2%). Patients who inflict MSM in FEP exhibited similar symptoms to those who inflict MSM later in their illness. Acute psychosis, in particular first-episode schizophrenia, appears to be the major cause of MSM. Although MSM is extremely uncommon, earlier treatment of psychotic illness may reduce the incidence of MSM.

Attributional Style in Delusional Patients: A Comparison of Remitted Paranoid, Remitted Nonparanoid, and Current Paranoid Patients With Nonpsychiatric Controls

Aakre, J. M., Seghers, J. P., St-Hilaire, A., Docherty, N. — 2008-05-20

Many studies have found that people experiencing persecutory delusions have a marked tendency to use external-personal attributions when establishing the causes of negative events. Although nonclinical populations also tend to attribute negative events to external causes, those causes are typically believed to be universal in nature, rather than personal. The central goal of the present study was to investigate whether individuals with remitted persecutory delusions would display this external-personal bias regarding negative events, in comparison to remitted patients whose delusions were not paranoid in nature and to nonpsychiatric controls. Results indicate that currently paranoid patients were significantly more likely than all other groups, including the remitted paranoid group, to use external-personal attributions in negative events. Interestingly, all patient groups also were found to be significantly more likely than the controls to use internal-personal and internal-universal attributions when explaining negative events.

Anatomical Abnormalities of the Anterior Cingulate Cortex in Schizophrenia: Bridging the Gap Between Neuroimaging and Neuropathology

Fornito, A., Yucel, M., Dean, B., Wood, S. J., Pantelis, C. — 2008-04-23

The anterior cingulate cortex (ACC) is a functionally heterogeneous region involved in diverse cognitive and emotional processes that support goal-directed behaviour. Structural magnetic resonance imaging (MRI) and neuropathological findings over the past two decades have converged to suggest abnormalities in the region may represent a neurobiological basis for many of the clinical manifestations of schizophrenia. However, while each approach offers complimentary information that can provide clues regarding underlying patholophysiological processes, the findings from these 2 fields are seldom integrated. In this article, we review structural neuroimaging and neuropathological studies of the ACC, focusing on the unique information they provide. The available imaging data suggest grey matter reductions in the ACC precede psychosis onset in some categories of high-risk individuals, show sub-regional specificity, and may progress with illness duration. The available post-mortem findings indicate these imaging-related changes are accompanied by reductions in neuronal, synaptic, and dendritic density, as well as increased afferent input, suggesting the grey matter differences observed with MRI arise from alterations in both neuronal and non-neuronal tissue compartments. We discuss the potential mechanisms that might facilitate integration of these findings and consider strategies for future research.

The Impact of Supported Employment and Working on Clinical and Social Functioning: Results of an International Study of Individual Placement and Support

2008-04-21

Background: Concerns are frequently expressed that working might worsen the mental health of people with severe mental illness (SMI). Several studies of Individual Placement and Support (IPS), however, have found associations between working and better nonvocational outcomes. IPS has been found to double the return to work of people with SMI in 6 European countries. Aims: To explore separately associations between IPS, returning to work, and clinical and social outcomes. Methods: Patients (n = 312) in a randomized controlled trial of IPS in 6 European centers were followed up for 18 months. Results: There were no differences in clinical and social functioning between IPS and control patients at 18 months. Those who worked had better global functioning, fewer symptoms, and less social disability at final follow-up; greater job tenure was associated with better functioning. Working was associated with concurrently better clinical and social functioning, but this contrast was stronger in the control group, suggesting that IPS was better than the control service at helping more unwell patients into work. Working was associated with having been in remission and out of hospital for the previous 6 months. It was also associated with a slight decrease in depression and with being in remission over the subsequent 6 months. Conclusions: Concerns among clinicians about possible detrimental effects of working and supported employment have been misplaced. Although some of the associations found may have been selection effects, there is sufficient evidence of work having beneficial effects on clinical and social functioning to merit further exploration.

A Review of the Fetal Brain Cytokine Imbalance Hypothesis of Schizophrenia

Meyer, U., Feldon, J., Yee, B. K. — 2008-04-11

Maternal infection during pregnancy increases the risk of schizophrenia and other brain disorders of neurodevelopmental origin in the offspring. A multitude of infectious agents seem to be involved in this association. Therefore, it has been proposed that factors common to the immune response to a wide variety of bacterial and viral pathogens may be the critical link between prenatal infection and postnatal brain and behavioral pathology. More specifically, it has been suggested that the maternal induction of pro-inflammatory cytokines may mediate the neurodevelopmental effects of maternal infections. Here, we review recent findings from in vitro and in vivo investigations supporting this hypothesis and further emphasize the influence of enhanced anti-inflammatory cytokine signaling on early brain development. Disruption of the fetal brain balance between pro- and anti-inflammatory cytokine signaling may thus represent a key mechanism involved in the precipitation of schizophrenia-related pathology following prenatal maternal infection and innate immune imbalances.

Secondary Effects of Antipsychotics: Women at Greater Risk Than Men

Seeman, M. V. — 2008-04-09

Context: The health burden of antipsychotic medication is well known, but the disproportionate effect on women as compared with men is underappreciated. Objective: The goal of this article is preventive—to better inform clinicians so that the risks to women and to their offspring can be diminished. Method: All PubMed sources in which the search term gender (or sex) was linked to a side effect of antipsychotic medication were reviewed. Result: There is general agreement in the literature on women's increased susceptibility to weight gain, diabetes, and specific cardiovascular risks of antipsychotics, with less consensus on malignancy risks and risks to the fetus. Cardiovascular death, to which men are more susceptible than women, is disproportionately increased in women by the use of antipsychotics. Sedating antipsychotics raise the risk of embolic phenomena during pregnancy, and postpartum. Prolactin-elevating drugs suppress gonadal hormone secretion and may enhance autoimmune proclivity. Conclusions: Clinicians need to be aware of the differential harm that women (and their offspring) can incur from the side effects of antipsychotics.

Principles of Antipsychotic Prescribing for Policy Makers, Circa 2008. Translating Knowledge to Promote Individualized Treatment

2008-04-02

Findings from 2 pivotal government-funded studies of comparative antipsychotic effectiveness undermine assumptions about the marked superiority of the more expensive second-generation "atypical" medications in comparison to the less expensive first-generation "typical" drugs. Because this assumption was the basis for the almost universal recommendation that these newer antipsychotics be used preferentially resulting in a 10-fold increase in state governmental expenditures on this class of medications over the past decade, a reassessment of policy is called for. To address the issue, the Medical Directors Council of the National Association of State Mental Health Program Directors critically reviewed findings of these studies in the context of other data and considered policy implications in the light of the obligations of state government to make available best possible and individually optimized treatment that is cost-effective. The Medical Directors Council unanimously adopted a set of recommendations to promote appropriate access, efficient utilization, and best practice use. We present our policy statement, in which we provide a succinct background, articulate general principles, and describe a set of 4 broad recommendations. We then summarize our understanding of the current state of knowledge about comparative antipsychotic effectiveness, best antipsychotic practice, and considerations for state policy that represent the basis of our position statement.