Metabolic abnormalities occur frequently in patients treated with antipsychotics and are of growing concern to clinicians. This study sought to determine whether antipsychotic-associated metabolic abnormalities identified through intensive monitoring can be reversed by switching to aripiprazole. Recent evidence suggests that aripiprazole may exhibit a favorable metabolic safety profile. The study population is a subset of a large (n > 500) ongoing prospective cohort. Thirty-one consecutive patients with schizophrenia who were started on aripiprazole were included in the study. All patients underwent an extensive metabolic evaluation, including an oral glucose tolerance test, at baseline, at 6 weeks, and at 3 months post switch. Metabolic abnormalities were defined as any of the following: new onset diabetes, impaired fasting glucose, impaired glucose tolerance, metabolic syndrome (MetS) according to various definitions, and dyslipidemia. After 3 months of treatment with aripiprazole (mean daily dose 16.3 mg), there was a significant decrease in body weight, body mass index, and waist circumference. There was a significant reduction in fasting glucose, fasting insulin, insulin resistance index, and serum lipids levels (cholesterol, triglycerides, low-density lipoprotein (LDL), LDL/HDL, Chol/HDL, and non-HDL cholesterol). There was also a significant reduction in prolactin levels. All 7 cases of recent onset diabetes were reversed at 3 months follow-up. The MetS was reversed in 50% of patients at 3 months follow-up. Our results support the reversibility of recent onset diabetes on antipsychotic medication when detected early and followed by a switch to aripiprazole.

Background: The relationship between negative symptoms, early visual information–processing deficits, and effortful processing resource allocation was investigated. Methods: Older patients with chronic schizophrenia (n = 58) and healthy controls (n = 71) participated. Pupillary responses were recorded during performance of the span of apprehension task (blocks of 3- and 10-letter arrays) as an index of resource allocation or mental effort during the task. Results: Patients and controls showed larger pupillary responses in higher relative to lower processing loads both during array processing and just prior to array onset (preparation). Both groups, therefore, invested more cognitive effort preparing for and then processing larger arrays. A subgroup of patients with abnormally small pupillary responses and impaired performance showed greater negative symptom severity relative to a subgroup of patients with normal pupillary responses. Smaller pupillary responses in the patients were also significantly correlated with greater negative symptom severity, independent of positive symptom severity. Patients with reduced effortful resource allocation, therefore, exhibited greater negative symptomatology. A subgroup of patients with normal pupillary responses still showed impaired detection accuracy relative to controls, suggesting that reduced cognitive effort or resource allocation problems cannot account for impairments in early visual information processing in this subgroup. Conclusions: The study illustrates important relationships between cognitive effort and performance that can impact conclusions about the nature of cognitive impairments and associations between negative symptoms and neurocognition in schizophrenia.

A convincing body of evidence now exists to indicate that the ubiquitous protozoan Toxoplasma gondii can cause permanent behavioral changes in its host, even as a consequence of adult-acquired latent infection. Such behavioral alterations appear to be the product of strong selective pressures for the parasite to enhance transmission from its intermediate host reservoir, primarily rodent, to its feline definitive host, wherein sexual reproduction can occur and the life cycle completed. This article reviews evidence of behavioral alterations in animal hosts and considers what these may elucidate about the potential mechanisms involved and what implications such alterations could have on animal and human health.

Although latent infection with Toxoplasma gondii is among the most prevalent of human infections, it has been generally assumed that, except for congenital transmission, it is asymptomatic. The demonstration that latent Toxoplasma infections can alter behavior in rodents has led to a reconsideration of this assumption. When infected human adults were compared with uninfected adults on personality questionnaires or on a panel of behavioral tests, several differences were found. Other studies have demonstrated reduced psychomotor performance in affected individuals. Possible mechanisms by which T. gondii may affect human behavior include its effect on dopamine and on testosterone.

In the last decade, there has been an increasing interest in cognitive alterations during the early course of schizophrenia. From a clinical perspective, a better understanding of cognitive functioning in putative at-risk states for schizophrenia is essential for developing optimal early intervention models. Two approaches have more recently been combined to assess the entire course of the initial schizophrenia prodrome: the predictive "basic symptom at-risk" (BS) and the ultra high-risk (UHR) criteria. Basic symptoms are considered to be present during the entire disease progression, including the initial prodrome, while the onset of symptoms captured by the UHR criteria expresses further disease progression toward frank psychosis. The present study investigated the cognitive functioning in 93 subjects who met either BS or UHR criteria and thus were assumed to be at different points on the putative trajectory to psychosis. We compared them with 43 patients with a first episode of psychosis and to 49 help-seeking patient controls. All groups performed significantly below normative values. Both at-risk groups performed at intermediate levels between the first-episode (FE) group and normative values. The UHR group demonstrated intermediate performance between the FE and BS groups. Overall, auditory working memory, verbal fluency/processing speed, and declarative verbal memory were impaired the most. Our results suggest that cognitive impairments may still be modest in the early stages of the initial schizophrenia prodrome and thus support current efforts to intervene in the early course of impending schizophrenia because early intervention may prevent or delay the onset of frank psychosis and thus prevent further cognitive damage.

Objective: This study evaluates longitudinal neuropsychological performance and its association with clinical symptomatology and psychosocial outcome in individuals identified as ultra high risk (UHR) for psychosis. Methods: Thirty-five UHR individuals completed neurocognitive, clinical, and social/role functioning assessments at baseline and, on average, 8.3 months later. Results: UHR subjects showed significant cognitive deficits at baseline and 2 distinct profiles of cognitive change over time. On average, 50% demonstrated improvement in social and role functioning over the follow-up period, while the other half showed either stability or decline in functioning. Functional improvement was associated with improved processing speed and visual memory, as well as improvement in clinical symptoms over the follow-up period. In contrast, patients who did not improve functionally showed stable clinical symptoms and cognitive performance over time. Conclusions: Although the degree of neurocognitive deficit at baseline in UHR patients does not predict psychosocial outcome, the course of neurocognitive change over the first 8 months of follow-up does differentiate patients with good and poor functional outcomes.

Toxoplasma gondii (TG) infection has been reported to be more frequent in schizophrenia. The interaction of the lifelong persisting parasite with the host's immune system involves T-cell/interferon-gamma–induced degradation of tryptophan and provides a challenge to the host well beyond a possible role in the etiology of schizophrenia. The hypothesis we tested in this study was that TG infection may be more frequent (serofrequency) and/or more intense (serointensity) in patients with schizophrenia or major depression compared with psychiatrically healthy controls. In addition, these measures are associated with the clinical course. We did a cross-sectional, prospective investigation of individuals with schizophrenia (n = 277) and major depression (n = 465) admitted to our department (2002–2005) and of healthy controls (n = 214), with all groups adjusted for age and geographic home region. Serofrequency was comparable between the groups, but serointensity was significantly higher in the patients. In individuals with schizophrenia, serointensity was significantly positively associated with C-reactive protein levels and leukocyte counts, and first-episode patients yielded significantly higher serotiters. Immunomodulatory medication was associated with decreased serotiters. In addition, the route of infection appears to differ between patients and controls. Thus, our results support increased host responses to TG infection in the patients, as well as increased titers in first-episode patients with schizophrenia; this may relate to the shifted T-helper 1/2 status described in these patients. Therefore, we suggest that TG infection, particularly in individuals with schizophrenia, is an important environmental factor in the interaction between psychiatric vulnerability, genetic background, immunomodulation, and the neurotransmitter systems.

Schizophrenia is a serious neuropsychiatric disease of uncertain etiology. We investigated the seropositivity rate for anti-Toxoplasma IgG and IgM antibodies by enzyme-linked immunosorbent assay (ELISA) in patients with schizophrenia to ascertain a possible relationship between Toxoplasma gondii and schizophrenia. We selected 100 patients with schizophrenia, 50 with depressive disorder, and 50 healthy volunteers to investigate the seropositivity rate of anti-Toxoplasma antibodies by ELISA. The seropositivity rate for anti-Toxoplasma IgG antibodies among schizophrenia patients (66%) was significantly higher than among patients with depressive disorder or healthy volunteers (P < .01). Thus, there might be a causal relationship between toxoplasmosis and the etiology of schizophrenia.

The objective of this study was to examine the predictive validity of the remission criteria proposed by Andreasen et al in first-episode patients responding to antipsychotics. Antipsychotic responsive patients with first-episode schizophrenia showing symptom remission (n = 60) were compared with patients who did not fulfill the proposed criteria (n = 65). Outcome in terms of symptom severity, social functioning, and quality of life was assessed after 18 months. Patients in the remission group showed a significantly better outcome during follow-up on all Positive and Negative Syndrome Scale subscale scores (positive, negative, and general symptom subscales) and a significantly higher level of social functioning. Quality of life did not differ between groups. The proposed multidimensional criteria for symptomatic remission convey significant information when applied to first-episode patients who responded to antipsychotics, predicting outcome on the domains of both psychopathology and social functioning. The criteria represent a practicable benchmark with clinical relevance. Their implementation should be promoted in research settings, clinical practice, and routine outcome assessment procedures.

Kynurenic acid (KYNA) is a tryptophan metabolite that is synthesized and released by astrocytes and acts as a competitive antagonist of the glycine site of N-methyl-D-aspartate receptors at high concentrations and as a noncompetitive antagonist of the 7-nicotinic acetylcholine receptor at low concentrations. The discovery of increased cortical KYNA levels in schizophrenia prompted the hypothesis that elevated KYNA concentration may underlie the working memory dysfunction observed in this population that has been attributed to altered glutamatergic and/or cholinergic transmission. The present study investigated the effect of elevated endogenous KYNA on spatial working memory function in rats. Increased KYNA levels were achieved with intraperitoneal administration of kynurenine (100 mg/kg), the precursor of KYNA synthesis. Rats were treated with either kynurenine or a vehicle solution prior to testing in a radial arm maze task at various delays. Elevations of endogenous KYNA resulted in increased errors in the radial arm maze. In separate experiments, assessment of locomotor activity in an open field and latency to retrieve food reward from one of the maze arms ruled out the possibility that deficits in the maze were attributable to altered locomotor activity or motivation to consume food. These results provide evidence that increased KYNA levels produce spatial working memory deficits and are among the first to demonstrate the influence of glia-derived molecules on cognitive function. The implications for psychopathological conditions such as schizophrenia are discussed.

People with schizophrenia frequently have significant problems in community functioning. Progress in developing effective interventions to ameliorate these problems has been slowed by the absence of reliable and valid measures that are suitable for use in clinical trials. The National Institute of Mental Health convened a workgroup in September 2005 to examine this issue and make recommendations to the field that would foster research in this area. This article reports on issues raised at the meeting. Many instruments have been developed to assess community functioning, but overall insufficient attention has been paid to psychometric issues and many instruments are not suitable for use in clinical trials. Consumer self-report, informant report, ratings by clinicians and trained raters, and behavioral assessment all can provide useful and valid information in some circumstances and may be practical for use in clinical trials. However, insufficient attention has been paid to when and how different forms of assessment and sources of information are useful or how to understand inconsistencies. A major limiting factor in development of reliable and valid instruments is failure to develop a suitable model of functioning and its primary mediators and moderators. Several examples that can guide thinking are presented. Finally, the field is limited by the absence of an objective gold standard of community functioning. Hence, outcomes must be evaluated in part by "clinical significance." This criterion is problematic because different observers and constituencies often have different opinions about what types of change are clinically important and how much change is significant.

There have been recent advances in the ability to identify people at high risk of developing psychosis. This has led to interest in the possibility of preventing the development of psychosis. A randomized controlled trial compared cognitive therapy (CT) over 6 months with monthly monitoring in 58 patients meeting criteria for ultrahigh risk of developing a first episode of psychosis. Participants were followed up over a 3-year period. Logistic regression demonstrated that CT significantly reduced likelihood of being prescribed antipsychotic medication over a 3-year period, but it did not affect transition to psychosis defined using the Positive and Negative Syndrome Scale (PANSS) or probable Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis. However, exploratory analyses revealed that CT significantly reduced the likelihood of making progression to psychosis as defined on the PANSS over 3 years after controlling for baseline cognitive factors. Follow-up rate at 3 years was 47%. There appear to be enduring benefits of CT over the long term, suggesting that it is an efficacious intervention for people at high risk of developing psychosis.

Introduction: Research on prediction and prevention of schizophrenia has increasingly focused on prodromal (prepsychosis) social and role dysfunction as developmentally early, stable, and treatment-resistant illness components. In this report, 2 new measures, Global Functioning: Social and Global Functioning: Role, are presented, along with preliminary findings about psychometric properties and course of social and role (academic/work) functioning in the prodromal phase of psychosis. Methods: Subjects included 69 participants from the Recognition and Prevention program and 52 from the Center for the Assessment and Prevention of Prodromal States. Ages ranged from 12 to 29 years, and all met criteria for Attenuated Positive Symptom syndrome. Retrospective (past year) and baseline data are reported for all 121 prodromal subjects and for 44 normal controls (NCs). Prospective follow-up data are reported for a subsample of patients reevaluated at both 6 and 12 months (N = 44). Results: For both scales, interrater reliability was high, and preliminary data supported construct validity. Relative to NCs, prodromal individuals displayed impaired social and role functioning at baseline. Analyses of change over time indicated that role functioning declined over the year before ascertainment and improved over 12-month follow-up, presumably with treatment. Social impairment, by contrast, was constant across time and predicted later psychosis (P = .002). Discussion: Using 2 new global measures, social functioning was found to be a stable trait, unchanged by treatment, with considerable potential to be a marker of schizophrenia. Role functioning, by contrast, may be a more direct barometer of clinical change and may be responsive to treatment and environmental change.

Objective: The presence and specificity of a bipolar prodrome remains questioned. We aimed to characterize the prodrome prior to a first psychotic and nonpsychotic mania and to examine the phenotypic proximity to the schizophrenia prodrome. Methods: Using a semi-structured interview, the Bipolar Prodrome Symptom Scale-Retrospective, information regarding the mania prodrome was collected from youth with a research diagnosis of bipolar I disorder and onset before 19 years of age, and/or their caregivers. Only newly emerging, at least moderately severe, symptoms were analyzed. Prodromal characteristics were compared between patients with and without subsequent psychotic mania and with published bipolar and schizophrenia prodrome data. Results: In 52 youth (age at first mania: 13.4 ± 3.3 years), the prodrome onset was predominantly "insidious" (>1 year, 51.9%) or "subacute" (1–12 months, 44.2%), while "acute" presentations (

The prodrome of psychosis has become a target for early identification and for treatments that address both symptoms and risk for future psychosis. Interest and activity in this realm is now worldwide. Clinical trials with rigorous methodology have only just begun, making treatment guidelines premature. Despite the sparse evidence base, treatments are currently applied to patients in the new prodromal clinics, usually treatments developed for established psychosis and modified for the prodromal phase. This communication will describe representative samplings of how treatment-seeking prodromal patients are currently recruited and treated in prodromal clinics worldwide. Recruitment includes how prodromal patients are sought, initially evaluated, apprised of their high-risk status, and informed of the risks and benefits of prodromal treatments and how their mental state is monitored over time. The treatment modalities offered (and described) include engagement, supportive therapy, case management, stress management, cognitive behavioral treatment, family-based treatment, antipsychotic pharmacotherapy, and non-antipsychotic pharmacotherapy. References for details are noted.