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Schizophrenia has a heritability of 60-80% 1 , much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Reasons for using antipsychotic polypharmacy (APP) in routine clinical practice, despite a potentially unfavorable risk-benefit ratio, are poorly understood. This research aimed to determine (1) if severe courses of schizophrenia were associated with APP and (2) if a schizophrenia-related acute event would predict a switch to APP in the short term. Observational prospective data (at baseline and 6months) were drawn from a French nationwide cohort ("Cohorte Générale Schizophrénie"), which included 1859 inpatients and outpatients with schizophrenia. APP was defined as the prescription of ≥2 antipsychotic drugs (there being different active substances). Early-onset schizophrenia, legal guardianship, higher lifetime maximal severity of illness and comorbid antisocial personality were used as proxies for severe courses of schizophrenia. Schizophrenia-related acute events included hospitalization and recent suicide attempts. Logistic regression models were used to determine (1) whether the use of APP at baseline (vs. monotherapy) was associated with a severe course of schizophrenia or not, independent of acute events, and (2) if a switch to APP at 6months (vs. remaining on monotherapy) was associated with acute events, independent of severe courses of schizophrenia. Increased odds of APP use at baseline were independently associated with legal guardianship (OR=1.6; 95%CI=1.3, 2.0) and higher lifetime maximum severity of illness (OR=1.3; 95%CI=1.2, 1.5). A switch to APP at 6months was predicted by a hospitalization occurring since baseline (OR=6.1; 95%CI=3.9, 9.4). In routine clinical practice, APP is more likely prescribed to patients with severe courses of illness, possibly indicating the difficulty to manage these patients., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objectives: Schizophrenia is a severe psychiatric disease affecting about 1% of the general population. The relative contribution of genetic factors has been estimated to be up to 80%. The mode of inheritance is complex, non-Mendelian, and in most cases involving the combined action of large numbers of genes., Methods: This review summarises recent efforts to identify genetic variants associated with schizophrenia detected, e.g., through genome-wide association studies, studies on copy-number variants or next-generation sequencing., Results: A large, new body of evidence on genetics of schizophrenia has accumulated over recent years. Many new robustly associated genetic loci have been detected. Furthermore, there is consensus that at least a dozen microdeletions and microduplications contribute to the disease. Genetic overlap between schizophrenia, other psychiatric disorders, and neurodevelopmental syndromes raised new questions regarding the current classification of psychiatric and neurodevelopmental diseases., Conclusions: Future studies will address especially the functional characterisation of genetic variants. This will hopefully open the doors to our understanding of the pathophysiology of schizophrenia and other related diseases. Complementary, integrated systems biology approaches to genomics, transcriptomics, proteomics and metabolomics may also play crucial roles in enabling a precision medicine approach to the treatment of individual patients.

Objectives: Despite progress in identifying molecular pathophysiological processes in schizophrenia, valid biomarkers are lacking for both the disease and treatment response., Methods: This comprehensive review summarises recent efforts to identify molecular mechanisms on the level of protein and gene expression and epigenetics, including DNA methylation, histone modifications and micro RNA expression. Furthermore, it summarises recent findings of alterations in lipid mediators and highlights inflammatory processes. The potential that this research will identify biomarkers of schizophrenia is discussed., Results: Recent studies have not identified clear biomarkers for schizophrenia. Although several molecular pathways have emerged as potential candidates for future research, a complete understanding of these metabolic pathways is required to reveal better treatment modalities for this disabling condition., Conclusions: Large longitudinal cohort studies are essential that pair a thorough phenotypic and clinical evaluation for example with gene expression and proteome analysis in blood at multiple time points. This approach might identify biomarkers that allow patients to be stratified according to treatment response and ideally also allow treatment response to be predicted. Improved knowledge of molecular pathways and epigenetic mechanisms, including their potential association with environmental influences, will facilitate the discovery of biomarkers that could ultimately be effective tools in clinical practice.

Objective: Schizophrenia is a severe mental disorder and many patients are treated in primary care settings. Apart from the pharmacological management of disease-associated symptoms, the detection and treatment of side effects is of the utmost importance in clinical practice. The purpose of this publication is to offer relevant evidence-based recommendations for the biological treatment of schizophrenia in primary care., Methods: This publication is a short and practice-oriented summary of Parts I-III of the World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Schizophrenia. The recommendations were developed by the authors and consented by a task force of international experts. Guideline recommendations are based on randomized-controlled trials and supplemented with non-randomized trials and meta-analyses where necessary., Results: Antipsychotics of different chemical classes are the first-line pharmacological treatments for schizophrenia. Specific circumstances (e.g., suicidality, depression, substance dependence) may need additional treatment options. The pharmacological and non-pharmacological management of side effects is of crucial importance for the long-term treatment in all settings of the healthcare system., Conclusions: This summary of the three available evidence-based guidelines has the potential to support clinical decisions and can improve treatment of schizophrenia in primary care settings.

Three electrophysiological endophenotypes are routinely studied in schizophrenia (SCZ): smooth pursuit eye movement (SPEM) dysfunction, deficits in P50 auditory-evoked potential inhibition, and saccadic inhibition deficits. The current study aimed to investigate the relationship between the COMT val158met polymorphism and these three endophenotypes. One hundred four SCZ patients (DSM-IV-R criteria) and 89 healthy controls were included in this study. P50 auditory-evoked potential inhibition, antisaccade paradigm and SPEM were analyzed. All individuals were genotyped for the COMT val158met. SCZ patients showed a higher rate of deficits measured by the SPEM, antisaccade and P50 inhibition paradigms without association with COMT val158met. However, in our control group, we have found an association between the Val polymorphism and the smoking status. More importantly, we have found a higher accuracy of saccades during the predictive pursuit task associated to the Met polymorphism in controls but not in SCZ patients who were receiving antidopaminergic medications. This result is in line with the hypothesis of the relationship between the Met polymorphism of the COMT gene, a higher level of dopamine in the prefrontal cortex and the role of the fronto-cerebellar loop in smooth predictive pursuit., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objectives: Schizophrenia is a group of severe psychiatric disorders with high heritability but only low odds ratios of risk genes. Despite progress in the identification of pathophysiological processes, valid biomarkers of the disease are still lacking., Methods: This comprehensive review summarises recent efforts to identify genetic underpinnings, clinical and cognitive endophenotypes and symptom dimensions of schizophrenia and presents findings from neuroimaging studies with structural, functional and spectroscopy magnetic resonance imaging and positron emission tomography. The potential of findings to be biomarkers of schizophrenia is discussed., Results: Recent findings have not resulted in clear biomarkers for schizophrenia. However, we identified several biomarkers that are potential candidates for future research. Among them, copy number variations and links between genetic polymorphisms derived from genome-wide analysis studies, clinical or cognitive phenotypes, multimodal neuroimaging findings including positron emission tomography and magnetic resonance imaging, and the application of multivariate pattern analyses are promising., Conclusions: Future studies should address the effects of treatment and stage of the disease more precisely and apply combinations of biomarker candidates. Although biomarkers for schizophrenia await validation, knowledge on candidate genomic and neuroimaging biomarkers is growing rapidly and research on this topic has the potential to identify psychiatric endophenotypes and in the future increase insight on individual treatment response in schizophrenia.

These updated guidelines are based on the first edition of the World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of schizophrenia published in the years 2005 and 2006. For this 2015 revision, all available publications pertaining to the biological treatment of schizophrenia were reviewed systematically to allow for an evidence-based update. These guidelines provide evidence-based practice recommendations which are clinically and scientifically relevant. They are intended to be used by all physicians diagnosing and treating patients with schizophrenia. Based on the first version of these guidelines a systematic review, as well as a data extraction from national guidelines have been performed for this update. The identified literature was evaluated with respect to the strength of evidence for its efficacy and subsequently categorised into six levels of evidence (A-F) and five levels of recommendation (1-5). This third part of the updated guidelines covers the management of the following specific treatment circumstances: comorbid depression, suicidality, various comorbid substance use disorders (legal and illegal drugs), and pregnancy and lactation. These guidelines are primarily concerned with the biological treatment (including antipsychotic medication and other pharmacological treatment options) of patients with schizophrenia.

The neurophysiological components that have been proposed as biomarkers or as endophenotypes for schizophrenia can be measured through electroencephalography (EEG) and magnetoencephalography (MEG), transcranial magnetic stimulation (TMS), polysomnography (PSG), registration of event-related potentials (ERPs), assessment of smooth pursuit eye movements (SPEM) and antisaccade paradigms. Most of them demonstrate deficits in schizophrenia, show at least moderate stability over time and do not depend on clinical status, which means that they fulfil the criteria as valid endophenotypes for genetic studies. Deficits in cortical inhibition and plasticity measured using non-invasive brain stimulation techniques seem promising markers of outcome and prognosis. However the utility of these markers as biomarkers for predicting conversion to psychosis, response to treatments, or for tracking disease progression needs to be further studied.

Current data and perspectives for schizophrenia research were reviewed in this paper. Increased incidence of schizophrenia is correlated to perinatal environmental factors, recent immigration, urban life and cannabis. Determining endophenotypes seems to be a promising strategy in the field of molecular genetics. Side effects and efficacy of treatments for schizophrenia could, now, be better predicted by the use of pharmacogenetic studies. Functional neuroimaging studies have described hypoactivations of certain brain areas supporting the hypothesis of a dysfunction of inner speech during auditory and verbal hallucinations. Dopaminergic and glutamatergic systems are disturbed in schizophrenia. These data contribute to a better understanding of the disease and may help to decrease the stigma that surrounds schizophrenia.

Abstract These updated guidelines are based on a first edition of the World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of schizophrenia published in 2006. For this 2012 revision, all available publications pertaining to the biological treatment of schizophrenia were reviewed systematically to allow for an evidence-based update. These guidelines provide evidence-based practice recommendations that are clinically and scientifically meaningful. They are intended to be used by all physicians diagnosing and treating people suffering from schizophrenia. Based on the first version of these guidelines, a systematic review of the MEDLINE/PUBMED database and the Cochrane Library, in addition to data extraction from national treatment guidelines, has been performed for this update. The identified literature was evaluated with respect to the strength of evidence for its efficacy and then categorised into six levels of evidence (A-F) and five levels of recommendation (1-5) ( Bandelow et al. 2008a ,b, World J Biol Psychiatry 9:242, see Table 1 ). This second part of the updated guidelines covers long-term treatment as well as the management of relevant side effects. These guidelines are primarily concerned with the biological treatment (including antipsychotic medication and other pharmacological treatment options) of adults suffering from schizophrenia.

These updated guidelines are based on a first edition of the World Federation of Societies of Biological Psychiatry Guidelines for Biological Treatment of Schizophrenia published in 2005. For this 2012 revision, all available publications pertaining to the biological treatment of schizophrenia were reviewed systematically to allow for an evidence-based update. These guidelines provide evidence-based practice recommendations that are clinically and scientifically meaningful and these guidelines are intended to be used by all physicians diagnosing and treating people suffering from schizophrenia. Based on the first version of these guidelines, a systematic review of the MEDLINE/PUBMED database and the Cochrane Library, in addition to data extraction from national treatment guidelines, has been performed for this update. The identified literature was evaluated with respect to the strength of evidence for its efficacy and then categorised into six levels of evidence (A-F; Bandelow et al. 2008b, World J Biol Psychiatry 9:242). This first part of the updated guidelines covers the general descriptions of antipsychotics and their side effects, the biological treatment of acute schizophrenia and the management of treatment-resistant schizophrenia.

Objective: The primary aim of this study was to compare the impact of risperidone long-acting injectable (R-LAI) to other antipsychotics on rates of hospitalisation in real-life settings., Method: The Cohort for the General study of Schizophrenia (CGS) followed 1859 patients diagnosed with schizophrenia (DSM-IV) from 177 psychiatric wards of public and private hospitals across France over a mean period of 12months. These patients were ambulatory or had been hospitalised for less than 93days at study entry. Recruitment was stratified for long-acting second-generation antipsychotic use. A multivariate Poisson regression adjusted for confounding with propensity scores and allowing for autocorrelation was used for the calculation of relative rates of hospitalisation with 95% confidence intervals., Results: The mean age of participants was 37.65years, 68.3% were male and 36.7% were hospitalised for less than 93days at study entry. Altogether, participants accumulated 796 hospital stays (53.4 per 100 person-years). R-LAI patients were slightly younger and had been hospitalised more often in the past 12months compared to non-R-LAI users. The adjusted Poisson regression analysis showed R-LAI use to be associated with a lower rate of future hospitalisation: 0.66 [0.46-0.96] compared to non-R-LAI use, and 0.53 [0.32-0.88] compared to use of other LAIs., Conclusion: Use of R-LAI was associated with lower rates of hospitalisation compared to non-use of R-LAI., (Copyright © 2011. Published by Elsevier B.V.)

Background: Oculomotor abnormality is one of the endophenotypes in schizophrenia. The predictive component of smooth pursuit can be studied by comparing the gain, i.e., the ratio of smooth eye position to target position, during predictable (pure sinusoidal) and unpredictable (pseudorandom) target motions. The aim of this experiment was to study predictive and nonpredictive components of smooth pursuit in two groups of schizophrenia patients compared with control subjects., Methods: Fifty-one schizophrenia patients (40 nondeficit and 11 deficit) and 21 control subjects were studied. During a predictable task, subjects were asked to track a sinusoidal target (.4 Hz). For the unpredictable task, the pseudorandom target motion consisted of five superimposed sinusoidal waveforms (.1, .2, .4, .6, and .8 Hz). The smooth eye position (eye position without saccades), gain, and phase were calculated for each frequency in each participant and for both tasks., Results: The mean sinusoidal smooth eye position gain was significantly lower in patients than in control subjects with no significant difference between deficit and nondeficit patients. During the pseudorandom task, all groups had a similar gain at .4 Hz., Conclusions: Our study reveals that patients have a normal nonpredictive component of smooth pursuit, regardless of their level of negative symptoms. In contrast, the predictive mechanisms involved in eye pursuit were impaired in schizophrenia patients. These results indicate that poor pursuit performance during smooth pursuit is primarily a consequence of a predictive problem and is not related to the ability to generate an accurate pursuit maintenance response., (Copyright 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Introduction: In animal studies, long-term prenatal nicotinic exposure alters the development of dopaminergic neurons. To determine whether prenatal smoking exposure was associated with schizophrenia, using a retrospective design study, we compared the prevalence of tobacco use during pregnancy in mothers of subjects with and without schizophrenia., Methods: One hundred patients with schizophrenia, 100 nonschizophrenic-matched subjects, and their respective mothers were interviewed. The prevalence of smoking was measured in these individuals as well as in their respective mothers during the pregnancy., Results: Patients with schizophrenia smoked more often compared with controls (73% vs 57%). In contrast, the prevalence of smoking during pregnancy did not differ between the groups of mothers. Indeed, the amount of tobacco used was significantly lower in mothers of patients with schizophrenia vs mothers of nonpsychotic subjects., Conclusion: This study did not show any association between prenatal tobacco exposure and further development of schizophrenia., (Copyright 2010 Elsevier Inc. All rights reserved.)

Background: The aim of this study was to examine impaired decision making in patients with schizophrenia and in patients with orbitofrontal cortex lesions., Methods: Schizophrenia patients (N=21), healthy controls (N=20) and an independent group of orbitofrontal patients (N=10) underwent a computerized version of the "Regret Gambling Task". Participants chose between two gambles, each having different probabilities and different expected monetary outcomes, and rated their emotional states after seeing the obtained outcome. Regret was induced by providing information about the outcome of the unchosen gamble., Results: Healthy controls reported emotional responses consistent with counterfactual reasoning between obtained and unobtained outcomes; they chose minimizing future regret and were able to learn from their emotional experience. In contrast, orbitofrontal patients and schizophrenia patients with prominent positive symptoms did not report any regret and did not anticipate any negative consequences of their choices. Our results demonstrate first the presence of very different behavioural deficits within the spectrum of schizophrenia patients which may have contributed to the discrepancies observed in previous studies. Second, the results suggest that a subgroup of schizophrenia patients might have an orbitofrontal dysfunction, in fact, schizophrenia patients with positive symptoms have a behavioural dysfunction analogous to that of the orbitofrontal patients., Conclusion: Schizophrenia patients with prominent positive symptoms were unable to integrate cognitive and emotional components of decision making which may contribute to their inability to generate adaptive behaviours in social and individual environments., (2009 Elsevier B.V. All rights reserved.)

Schizophrenia is a complex disease. Although family, twin and adoption studies have consistently suggested that genetic factors play an important etiologic role in schizophrenia, very little is known about the nature and number of these genetic factors. The familial transmission of this disorder cannot be explained by simple Mendelian models of inheritance, and non-genetic factors are also likely to play a substantial role in its aetiology. The current hypothesis is that genes with small interacting genetic effects, in conjunction with environmental factors, affect the risk for schizophrenia. But the relationship between observed genetic factors and specific DNA variants or protein alterations has not so far been identified. Classical methods, such as linkage or association studies, have led to inconsistent results. Other options such as the endophenotype strategy or the use of chromosomal aberrations associated with psychotic symptoms are probably more promising to identify candidate genes.

Background: The main objective of the study was to determine whether patients with schizophrenia are deficient relative to controls in the processing of faces at different levels of familiarity and types of emotion and the stage where such differences may occur., Methods: ERPs based on 18 patients with schizophrenia and 18 controls were compared in a face identification task at three levels of familiarity (unknown, familiar, subject's own) and for three types of emotion (disgust, smiling, neutral)., Results: The schizophrenic group was less accurate than controls in the face processing, especially for unknown faces and those expressing negative emotions such as disgust. P1 and N170 amplitudes were lower and P1, N170, P250 amplitudes were of slower onset in patients with schizophrenia. N170 and P250 amplitudes were modulated by familiarity and face expression in a different manner in patients than controls., Conclusions: Schizophrenia is associated with a genelarized defect of face processing, both in terms of familiarity and emotional expression, attributable to deficient processing at sensory (P1) and perceptual (N170) stages. These patients appear to have difficulty in encoding the structure of a face and thereby do not evaluate correctly familiarity and emotion.

The brain-derived neurotrophic factor (BDNF) belongs to the neurotrophins family and has a role in proliferation, differentiation of neurons but also as a neurotransmitter. This neurotrophin has received much attention during the last year in regard of the pathophysiology of schizophrenia. Results of genetic studies conducted in schizophrenia support a role for BDNF in schizophrenia and in brain function associated with the disorder. The changes of BDNF observed in the brain and in the plasma of patients with schizophrenia have generated results that can be interpreted either as a hallmark of the disease or a consequence of antipsychotic drugs. Antipsychotic drugs act by blocking the dopamine transmission at the dopamine D2-like receptors. BDNF controls the expression of one of these D2-like receptors, the dopamine D3 receptor. This raises the hypothesis of a link between cortical area, via BDNF, and the dopamine neurotransmission pathway in schizophrenia and its treatment.

In a previous report [Jacquet et al., 2005] we have shown that mild to moderate hyperprolinemia resulting from several alterations (either a complete deletion or missense mutations) of the proline dehydrogenase (PRODH) gene located on chromosome 22q11 is a risk factor for schizoaffective disorder but not for DSM3 R schizophrenia or bipolar disorder. We now report that hyperprolinemia is not associated with childhood onset schizophrenia (COS).

Abnormal sensory gating in schizophrenia has frequently been reported. The strength of central inhibitory pathways was measured using the P50 component of the auditory evoked potential in a conditioning-testing paradigm. The relationships between a relative decrease in P50 amplitude to repeated auditory stimuli and clinical symptoms remain controversial. Using the Positive and Negative Syndrome Scale, we studied the P50 auditory conditioning-testing paradigm in 81 schizophrenic subjects, categorized into subgroups with and without prominent negative symptoms, in comparison with 88 control subjects. We found increased ratios of testing stimuli to conditioning stimuli in both schizophrenic subgroups relative to findings in the control group. In addition, we found significantly increased mean latencies of the P50 responses to conditioning (C) and testing (T) stimuli and significantly increased T/C ratios in the subgroup with negative symptoms compared with the subgroup with non-negative symptoms.

Objective: The authors evaluated concordance rates among three electrophysiological measures in patients with schizophrenia, nonschizophrenic first-degree relatives of schizophrenia patients, and healthy comparison subjects. The purpose of the study was to provide data for defining a common endophenotype for genetic studies of schizophrenia and for improving the criteria for diagnosis., Method: P50 event-related potential inhibition, antisaccade, and smooth pursuit eye tracking paradigms were measured. Data for all three paradigms were available for 81 patients with schizophrenia, 25 parents of patients with schizophrenia, and 60 healthy comparison subjects., Results: The schizophrenia patients and the patients' parents showed a high rate of inhibitory deficits measured by the P50 inhibition and antisaccade paradigms. Both groups had a high prevalence of eye tracking dysfunction. Smooth pursuit gain and the error rate in the antisaccade paradigm were significantly correlated in the schizophrenia patients and the parents, whereas P50 inhibition showed no correlation with smooth pursuit gain or antisaccade paradigm measurements., Conclusions: Despite superficial similarities, two paradigms designed to measure central inhibition processes (antisaccade and P50 inhibition) do not appear to reflect the same neurobiological substrates. In contrast, the convergence in performance data for the antisaccade and eye tracking paradigms suggests that the neural circuitry underlying these tasks may overlap. P50 inhibition and antisaccade errors were the optimal paradigms for discrimination between comparison subjects, patients with schizophrenia, and the parents of patients with schizophrenia.

Background: Cognitive impairment has always been regarded as an important characteristic of schizophrenia. Many domains of cognition are disrupted with varying degrees of deficit: attention, executive functions, verbal and visuospatial working memory, learning, and memory. However, it is only recently that cognitive dysfunction has been recognized as a primary and enduring core deficit in schizophrenia (rather than the previous focus on positive and negative symptoms)., Objective: This article discusses cognitive impairment and the therapeutic effects of newer antipsychotic agents on cognitive functioning in patients with schizophrenia., Conclusions: Cognitive dysfunction occurs before the first psychotic episode and persists throughout the course of the illness. It involves every aspect of cognitive functioning and has an important impact on long-term social and occupational outcomes. Improvement of cognitive functioning by antipsychotic treatment can be due indirectly to the improvement of therapeutic profiles of the newer antipsychotic agents (eg, higher efficacy on positive and negative symptoms, fewer side effects, less anticholinergic effects) or directly to effects on cerebral functioning (eg, by restoring dopamine prefrontal activity). However, further research is needed regarding the therapeutic effects of the newer antipsychotic drugs on cognitive functioning and their impact on psychosocial outcome. Although newer medications may improve cognitive functioning, they do not normalize neurocognitive deficits in schizophrenia. In addition, various nonpharmacologic, psychological interventions have been used in the rehabilitation of patients with cognitive deficits.

The increased prevalence of schizophrenia among patients with the 22q11 interstitial deletion associated with DiGeorge syndrome has suggested the existence of a susceptibility gene for schizophrenia within the DiGeorge syndrome chromosomal region (DGCR) on 22q11. Screening for genomic rearrangements of 23 genes within or at the boundaries of the DGCR in 63 unrelated schizophrenic patients and 68 unaffected controls, using quantitative multiplex PCR of short fluorescent fragments (QMPSF), led us to identify, in a family including two schizophrenic subjects, a heterozygous deletion of the entire PRODH gene encoding proline dehydrogenase. This deletion was associated with hyperprolinemia in the schizophrenic patients. In addition, two heterozygous PRODH missense mutations (L441P and L289M), detected in 3 of 63 schizophrenic patients but in none among 68 controls, were also associated with increased plasma proline levels. Segregation analysis within the two families harboring respectively the PRODH deletion and the L441P mutation showed that the presence of a second PRODH nucleotide variation resulted in higher levels of prolinemia. In two unrelated patients suffering from severe type I hyperprolinemia with neurological manifestations, we identified a homozygous L441P PRODH mutation, associated with a heterozygous R453C substitution in one patient. These observations demonstrate that type I hyperprolinemia is present in a subset of schizophrenic patients, and suggest that the genetic determinism of type I hyperprolinemia is complex, the severity of hyperprolinemia depending on the nature and number of hits affecting the PRODH locus.

Efficacy of neuroleptic treatment is well recognized in the treatment of schizophrenia. Both "Practice Guideline of Paris" (1994) and "the Practice Guideline of the APA" (1997) could advise psychiatrists in the choice of therapeutic strategies. The early recognition and management of a first episode of schizophrenia and the maintenance of antipsychotic medication at lower doses (for at least one year after a first episode, and five years after two or more relapses) seem to influence positively the long-term outcome of the disease. Despite the advantages of atypical neuroleptics with regard to extrapyramidal symptoms and their clinical efficacy in the short term treatment of schizophrenia, these treatments induce other side effects (cardiovascular or metabolic) that need to be further investigated; in addition, their long-term efficacy has not been adequately studied.

Single voxel proton magnetic resonance spectroscopy (1H MRS) was used to study the metabolites N-acetylaspartate (NAA), choline (CHO), and myo-inositol (ml) in order to test a neurodegenerative hypothesis in schizophrenia (decrease of NAA, increase of CHO, and increase of ml) and a cerebral asymmetry of these metabolites. 1H MRS was performed in 17 schizophrenia patients and 14 healthy subjects in three cerebral areas highly involved in the pathophysiology of schizophrenia (the prefrontal cortex, the thalamus, and the hippocampus). The ratio amplitudes between metabolites and creatine plus phosphocreatine (Cr) were determined. No difference in the metabolites existed between patients and healthy subjects. However, relationships were noted between NAA/Cr and age in the thalami of the schizophrenia patients (r = -0.37; p = 0.14) and healthy subjects (r = -0.52; p = 0.05). A significant correlation was observed between NAA/Cr and age of onset of illness in the hippocampi of schizophrenia patients (r = -0.59; p < 0.05). Moreover, NAA/Cr was lower in the right than in the left prefrontal cortex in both schizophrenia patients and healthy subjects. There was no relationship between the metabolites and duration of illness or dose of antipsychotics. These findings might suggest a neurodegenerative process in the hippocampi of schizophrenia patients with late onset of illness, and the NAA/Cr ratio could be a marker of aging in the thalami.

Objective: The authors evaluated concordance rates among three electrophysiological measures in patients with schizophrenia, nonschizophrenic first-degree relatives of schizophrenia patients, and healthy comparison subjects. The purpose of the study was to provide data for defining a common endophenotype for genetic studies of schizophrenia and for improving the criteria for diagnosis. Method: P50 event-related potential inhibition, antisaccade, and smooth pursuit eye tracking paradigms were measured. Data for all three paradigms were avail- able for 81 patients with schizophrenia, 25 parents of patients with schizophrenia, and 60 healthy comparison subjects. Results: The schizophrenia patients and the patients' parents showed a high rate of inhibitory deficits measured by the P50 inhibition and antisaccade paradigms. Both groups had a high prevalence of eye tracking dysfunction. Smooth pursuit gain and the error rate in the antisaccade paradigm were significantly correlated in the schizophrenia patients and the parents, whereas P50 inhibition showed no correlation with smooth pursuit gain or anti- saccade paradigm measurements. Conclusions: Despite superficial similarities, two paradigms designed to measure central inhibition processes (antisaccade and P50 inhibition) do not appear to reflect the same neurobiological substrates. in contrast, the convergence in performance data for the antisaccade and eye tracking paradigms suggests that the neu- ral circuitry underlying these tasks may overlap. P50 inhibition and antisaccade errors were the optimal paradigms for discrimination between comparison subjects, patients with schizophrenia, and the parents of patients with schizophrenia. [ABSTRACT FROM AUTHOR]

Explores the evidence of a cohort effect for age at onset of schizophrenia. Incorporation of birth cohort effect for age at onset of schizophrenia into genetic models in psychiatry; Variations in the characteristics of an illness; Influence of secular trends in schizophrenia.