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Background: Neurocognitive impairment is a core feature of schizophrenia spectrum disorders (SSDs), and the relationship between cognition and symptoms in SSDs has been widely researched. Negative symptoms are related to a wide range of cognitive impairments; however, the aspects of negative symptoms that underpin this relationship have yet to be specified., Study Design: We used iterative Constrained Principal Component Analysis (iCPCA) to explore the relationship between 18 cognitive measures (including processing speed, attention, working, spatial and verbal memory and executive functions) and 46 symptoms in schizophrenia at the individual item level while minimizing the risk of Type I errors. ICPCA was conducted on a sample of SSD patients in the early stages of psychiatric treatment (n = 121) to determine the components of cognition overlapping with symptoms measured by the Scale for the Assessment of Negative Symptoms (SANS) and the Scale for the Assessment of Positive Symptoms (SAPS)., Results: We found that a verbal memory component was associated with items from SANS and SAPS related to impoverished and disorganized emotional communication, language, and thought. In contrast, a working memory component was associated with SANS items related to motor system impoverishment., Conclusions: The iCPCA allowed us to explore the associations between individual items, optimized to understand the overlap between symptoms and cognition. The specific symptoms linked to verbal and working memory impairments imply distinct brain networks, which further investigation may lead to our deeper understanding of the illness and the development of treatment methods., Competing Interests: Declaration of competing interest There are no financial or other conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Persistent negative symptoms (PNS) are an important factor of first episode of psychosis (FEP) that present early on in the course of illness and have a major impact on long-term functional outcome. Lack of clinical insight is consistently associated with negative symptoms during the course of schizophrenia, yet only a few studies have explored its evolution in FEP. We sought to explore clinical insight change over a 24-month time period in relation to PNS in a large sample of FEP patients. Clinical insight was assessed in 515 FEP patients using the Scale to assess Unawareness of Mental Disorder. Data on awareness of illness, belief in response to medication, and belief in need for medication were analyzed. Patients were divided into 3 groups based on the presence of negative symptoms: idiopathic (PNS; n = 135), secondary (sPNS; n = 98), or absence (non-PNS; n = 282). Secondary PNS were those with PNS but also had clinically relevant levels of positive, depressive, or extrapyramidal symptoms. Our results revealed that insight improved during the first 2 months for all groups. Patients with PNS and sPNS displayed poorer insight across the 24-month period compared to the non-PNS group, but these 2 groups did not significantly differ. This large longitudinal study supported the strong relationship known to exist between poor insight and negative symptoms early in the course of the disorder and probes into potential factors that transcend the distinction between idiopathic and secondary negative symptoms., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Cognitive difficulties are a core deficit for people with schizophrenia and are generally assessed with neuropsychological tests. Self-report assessments are also useful in understanding difficulties from the service user's perspective. This study aims to introduce and test the shorter version of the Subjective Scale to Investigate Cognition in Schizophrenia (SSTICS) to improve its acceptability and comprehensibility. Methods: In consultation with service users and clinicians, we identified items from the original 21-item SSTICS that were found difficult and these were excluded. The reduced scale was explored with Confirmatory Factor Analysis (CFA) in two independent samples in the UK and Canada. Convergent validity with symptoms and IQ was assessed and compared between the original and the reduced scale. Results: Six-hundred and seven people with schizophrenia and first-episode psychosis took part in this study. Seven items were removed to produce the SSTICS-Brief. This had good reliability and the CFA confirmed a unidimensional structure. Convergent validity with symptoms and IQ were optimal between the long and short versions. Conclusions: The SSTICS-B has better acceptability than its longer form and could be administered in less time. The resulting measure is likely to be a valuable short self-assessment of cognitive complaints for people with schizophrenia.

Aim: Duration of untreated psychosis (DUP) has been associated with negative symptoms in several studies; however, longitudinal findings have been inconsistent. No previous study has accounted for active psychosis after presentation, although this could impact on outcomes in a manner similar to DUP., Methods: We measured Scale for the Assessment of Positive Symptoms at frequent intervals during the 12 months after initial presentation to determine the active psychosis duration for 230 individuals with first-episode psychosis. This duration was added to DUP prior to presentation to create a new variable, duration of active psychosis (DAP). Negative symptoms were divided into expressivity and motivation/pleasure domains as measured by Scale for the Assessment of Negative Symptoms (SANS). The relationship of DUP and DAP with negative symptoms at 24-month follow up was determined and confounders controlled for using regression analysis., Results: When DUP and DAP were compared as binary variables with long and short groups, 25.2% of individuals had differing category membership. DAP had a significant uncorrected association with both expressivity domain and motivation/pleasure domains at 24 months; however, relationship with DUP was not significant. DAP remained a significant predictor of 24-month expressivity domain after controlling for potential confounders., Conclusions: Active psychosis after presentation is substantial, which is a limitation of DUP studies if active psychosis is considered as the key factor within DUP. DAP is a better predictor of negative symptoms than DUP at 2-year follow up, which suggests this concept requires further research., (© 2015 Wiley Publishing Asia Pty Ltd.)

In people with psychoses, Self-Reflectiveness may rely on the right ventrolateral prefrontal cortex (VLPFC). We used functional magnetic resonance imaging (fMRI) and a novel virtual reality paradigm to evaluate the role of the VLPFC for Self-Reflectiveness in 25 first-episode of schizophrenia (FES) participants and 24 controls. Participants first viewed 20 characters each paired with a unique object/location, and later completed source memory judgements during fMRI scanning. Self-Reflectiveness, measured with the Beck Cognitive Insight Scale, was significantly and positively correlated to activation in bilateral VLPFC in FES, but not in controls, providing further evidence that the VLPFC supports Self-Reflectiveness in FES., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objective: Functional recovery remains the primary goal following treatment of a psychotic disorder, especially after a first episode. Evidence regarding relative contributions of predictors of functional outcome, including symptoms and cognition, remains equivocal. The objective of the study was to determine the relative contribution of cognition, in particular verbal memory, and symptomatic remission to social and occupational functioning while controlling for established predictors of functioning in a large sample of patients presenting with a first episode of a schizophrenia spectrum or affective psychosis., Method: Patients (aged 14-35 years) met DSM-IV criteria for a first episode of a schizophrenia spectrum or affective psychosis and had been admitted to the Prevention and Early Intervention Program for Psychoses, Montreal, Quebec, Canada, between 2003 and 2009 for treatment and follow-up for 2 years. Established predictors (duration of untreated psychosis, medication adherence, age at onset, substance use, premorbid adjustment), verbal memory, and length of positive and negative symptom remission were regressed on functioning (using the Strauss Carpenter Scale) at 1 (n = 208) and 2 (n = 159) years. Regressions were conducted with established predictors in the first step, followed by verbal memory and consecutive months of combined positive and negative symptom remission in the third step. Regressions were then repeated with length of positive and negative symptom remission, respectively., Results: Length of combined positive and negative symptom remission explained the most variance in functioning at 1 (R² adjusted = 0.35, F₉,₁₂₉ = 9.33, P < .001) and 2 (R² adjusted = 0.38, F₉,₉₇ = 8.21, P < .001) years, and verbal memory contributed only slightly to such outcome. While length of remission of negative symptoms was a stronger predictor of functioning than remission of positive symptoms at 1 year, length of positive symptom remission also made a large contribution at 2 years., Conclusions: These results highlight the importance of achieving and maintaining remission of both negative and positive symptoms for longer periods in patients with a first episode of a psychotic disorder and the need for effective interventions to do so., (© Copyright 2014 Physicians Postgraduate Press, Inc.)

With the introduction of a clear definition of symptomatic remission from the Remission in Schizophrenia Working Group (RSWG), studies have sought to characterize cognitive functioning in remitted and non-remitted schizophrenia patients. However, most investigations of cognition and remission are cross-sectional or have studied samples of chronically ill patients. Therefore, the aim of this study was to compare cognitive performance between remitted and non-remitted first-episode psychosis (FEP) patients longitudinally. Seventy patients were categorized as remitted (n=17) or non-remitted (n=53) using the full RSWG criteria after being treated for approximately 15months, during which cognition was evaluated twice. Since our previous investigations in FEP have isolated verbal memory as a potential cognitive marker of symptomatic remission, analyses were limited to verbal, visual and working memory. We have found that non-remitted patients had a significantly worse verbal memory performance than remitted patients after 3months (F(1,68)=6.47, p=0.006) and 15months of treatment (F(1,68)=19.49, p<0.001). Visual memory was also significantly lower in non-remitted patients compared to those in remission but only at initial assessment (F(1,68)=8.21, p=0.003) while working memory performance was similar at both time points. Our findings suggest that verbal memory may be a specific and stable marker of clinical remission in FEP patients. This cognitive domain can easily be evaluated at treatment intake in the hope of identifying early on patients who are less likely to remit., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Objective: Our study examines the unique influence of social and family support on adherence to medication in a sample of patients treated for first-episode psychosis (FEP)., Method: Social and family support using the Multidimensional Scale of Perceived Social Support and medication adherence (consensus of subjective and objective data) were evaluated on a monthly basis during a 6-month period in a sample of 82 FEP patients. The relation between social support and adherence was evaluated using correlational and linear regression analyses, controlling for other relevant variables. A longitudinal analysis using hierarchical linear models was conducted to model change in adherence over time., Results: Monthly correlations between social support and adherence were significant at 4 of 7 time points during a 6-month period. There was a modest correlation between the percentage of months of good adherence and the average level of family support across the study period. The linear regression failed to demonstrate a significant relation between baseline social support and overall adherence during the entire study period. Change in social support over time was inversely associated with change in adherence., Conclusions: Our study emphasizes the concurrent influence of social (mostly family) support on adherence but this effect does not persist over time. Changes in the degree of social support may have a complex effect on changes in adherence.

Background: Although persistent negative symptoms (PNS) are known to contribute significantly to poor functional outcome, they remain poorly understood. We examined the heuristic value of various PNS definitions and their respective prevalence in patients with first episode psychosis (FEP). We also contrasted those definitions to the Proxy for the Deficit Syndrome (PDS) to identify deficit syndrome (DS) in the same FEP cohort., Methods: One hundred and fifty-eight FEP patients were separated into PNS and non-PNS groups based on ratings from the Scale for Assessment of Negative Symptoms (SANS). PNS was defined in the following ways: 1) having a score of 3 or greater on at least 1 global subscale of the SANS (PNS&#95;1); 2) having a score of 3 or more on at least 2 global subscales of the SANS (PNS&#95;2); and 3) having a score of 3 or more on a combination of specific SANS subscales and items (PNS&#95;H). For all three definitions, symptoms had to be present for a minimum of six consecutive months. Negative symptoms were measured upon entry to the program and subsequently at 1,2,3,6,9 and 12 months. Functional outcome was quantified at first assessment and month 12., Results: PNS prevalence: PNS&#95;1 (27%); PNS&#95;2 (13.2%); PNS&#95;H (13.2%). The prevalence of DS was found to be 3% when applying the PDS. Regardless of the definition being applied, when compared to non-PNS, patients in the PNS group were shown to have significantly worse functioning at month 12. All three PNS definitions showed similar associations with functional outcome at month 12., Conclusion: Persistent negative symptoms are present in about 27% of FEP patients with both affective and non-affective psychosis. Although there has previously been doubt as to whether PNS represents a separate subdomain of negative symptoms, the current study suggests that PNS may be more applicable to FEP when compared to DS. Although all three PNS definitions were comparable in predicting functional outcome, we suggest that the PNS definition employed is dependent on the clinical or research objective at hand.

One dimension of insight in psychosis is the ability to attribute correctly one's symptoms to a mental disorder. Recent work suggests that gray matter volumes of the orbitofrontal cortex (OFC) are correlated with aggregate symptom attribution scores in first-episode schizophrenia. Whether regions beyond the OFC are important for symptom attribution remains to be established. Further, whether common or separable neural systems underlie attribution of specific symptoms (e.g., delusions, asociality) has not been studied. In the current magnetic resonance imaging study, 52 people with a first-episode psychosis (FEP) were rated with the Scale for Assessment of Unawareness of Mental Disorder on attribution of hallucinations, delusions, flat affect and asociality. Attribution ratings were regressed on cortical thickness at 81,924 vertices. Mapping statistics revealed that delusion misattribution was associated with thickness in the OFC [Brodmann's area (BA) 11/47]. Delusion, flat affect and asociality misattribution were associated with cortical thinness in the dorsolateral prefrontal cortex (BA 9/46). Differential associations emerged between each attribution item and cortical thickness/thinness in a variety of frontal, temporal, parietal and occipital areas. The results imply a selective role for the OFC in delusion misattribution in FEP. Evidence for cortical thickness covariation in a variety of regions suggests partial independence in the neural architecture underlying attribution for different symptoms in FEP., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

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.

Objective: In psychotic disorders, impairments in cognition have been associated with both clinical and functional outcome, while deficits in social cognition have been associated with functional outcome. As an extension to a recent report on neurocognition and short-term clinical outcome in first-episode psychosis (FEP), the current study explored whether social cognitive deficits could also identify poor short-term clinical outcome among FEP patients., Methods: We defined the social-cognition domain based on the scores from the Hinting Task and the Four Factor Tests of Social Intelligence. Data were collected in 45 FEP patients and 26 healthy controls. The patients were divided into good- and poor-outcome groups based on clinical data at six months following initiation of treatment. Social cognition was compared among 27 poor-outcome, 18 good-outcome, and 26 healthy-control participants., Results: Outcome groups significantly differed in the social cognition domain (z-scores: poor outcome=-2.0 [SD=1.4]; good outcome=-1.0 [SD=1.0]; p=0.005), with both groups scoring significantly lower than the control group (p<0.003). Moreover, outcome groups differed significantly only on the Cartoon Predictions subtest (z-scores: poor outcome=-2.7 [SD=2.7]; good outcome=-0.7 [SD=1.8]; p=0.001) among the five subtests used., Conclusions: Overall, social cognition appears to be compromised in all FEP patients compared to healthy controls. More interestingly, significant differences in social cognitive impairments exist between good and poor short-term clinical outcome groups, with the largest effect found in the Cartoon Predictions subtest.

Alterations of the fornix in chronic patients with psychosis are well established, but its integrity in the early stage of schizophrenia remains unknown. Thirty-two patients experiencing first-episode schizophrenia (FES) and 25 matched controls completed a DTI scan. DTI-tractography was used to estimate fractional anisotropy (FA) in bilateral fornices. The analysis showed significant overall FA reductions in the fornix in FES patients relative to controls. No significant correlations were found between FA values and clinical and sociodemographic data in FES patients. These findings revealed slight alterations along the fornix in early stage of schizophrenia., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)

Background: Cognitive deficits in schizophrenia are well established and are known to be present during the first episode of a psychotic disorder. In addition, consistent heterogeneity within these impairments remains unexplained. One potential source of variability may be the level of pre-morbid adjustment prior to the onset of first-episode psychosis (FEP)., Method: Ninety-four FEP patients and 32 healthy controls were assessed at baseline on several neuropsychological tests comprising six cognitive domains (verbal memory, visual memory, working memory, processing speed, reasoning/problem-solving and attention) and an abbreviated version of the full IQ. A global neurocognitive domain was also computed. Pre-morbid adjustment patterns were divided into three distinct groups: stable-poor, stable-good and deteriorating course., Results: Based on a cut-off of 0.8 for effect size, the stable-poor pre-morbid adjustment group was significantly more impaired on most cognitive domains and full IQ compared to the deteriorating group, who were more severely impaired on all measures compared to the stable-good group. The type of cognitive deficit within each subgroup did not differ and the results indicate that a global neurocognition measure may reliably reflect the severity of cognitive impairment within each subgroup., Conclusions: Pre-morbid adjustment patterns prior to onset of psychosis are associated with severity but not type of cognitive impairment. Patients in the stable-poor group are generally more impaired compared to the deteriorating group, who are, in turn, more impaired than the stable-good group.

Aim: We first aimed to evaluate the progression of insight and psychopathology over the first year of treatment for a psychosis. We hypothesized that improvement in insight would associate with improvement in positive and negative symptoms, and depressive and anxious symptom exacerbation. Secondly, in an exploratory analysis, we aimed to identify quantitatively distinct insight trajectory groups, and to describe the impact of psychopathology over time on the different trajectory groups., Methods: One-hundred and sixty-five patients were administered a comprehensive clinical evaluation, and insight was rated on the Scale for Assessment for Unawareness of Mental Disorder, item 1 (awareness of mental disorder), at admission and after 1, 2, 3, 6, 9 and 12 months., Results: In a generalized estimating equation (GEE) model of change, insight improved concurrently with positive, negative and anxious symptoms between baseline and month 1 in the entire cohort. Latent group-based trajectory analysis revealed five insight groups: good, increasing, decreasing, moderate poor and very poor. GEE modelling revealed that the very poor and moderate poor insight groups displayed greater overall negative symptoms than patients with good and increasing insight trajectories. The good insight group showed significantly greater overall depressive symptoms than the diminished and very poor insight groups., Conclusions: The results suggest that specific longitudinal insight trajectories were driving the observed associations between insight and negative and depressive symptoms in the entire first-episode psychosis cohort. Persistently poor insight may be an important factor in negative symptom maintenance. Good or increasing course of insight may be early clinical indicators of a liability to depression.

Previous work on chronic psychosis patients has suggested that low self-reflectiveness and overconfidence in judgments may be associated with delusions. In the present study we evaluated whether this extends to a first-episode psychosis sample. Thirteen actively delusional and 53 non-delusional participants with a first-episode psychosis completed the Beck Cognitive Insight Scale. Relative to non-delusional participants, delusional participants endorsed greater self-reflectiveness, though their confidence in their judgments was the same as non-delusional participants. These results suggest that the capacity to self-reflect and refrain from overconfidence may interact with delusions differentially across multiple phases of psychosis. The cognitive system involved in self-reflectiveness may be important for delusional thinking during a first-episode psychosis.

Background: Outcome from psychotic disorders is heterogeneous with poorer outcomes frequently identified too late to be influenced. Symptomatic ratings at 1 or more years following initiation of treatment have been related to cognition in first-episode psychosis. However, the relationship between cognition and early outcome remains unclear., Aims: To determine whether specific cognitive domains could identify poor short-term outcome among individuals with first-episode psychosis., Method: One hundred and fifty-one individuals with first-episode psychosis were divided into two groups based on 6-month clinical data after the initiation of treatment. Six cognitive domains were compared among 78 participants with poor outcomes, 73 with good outcomes and 31 healthy controls., Results: Lower performance on verbal memory (z-scores: poor outcome=-1.3 (s.d.=1.1); good outcome=-0.8 (s.d.=0.9); P=0.001) and working memory (poor outcome=-1.0 (s.d.=1.2); good outcome=-0.4 (s.d.=0.9); P=0.003) identified individuals with first-episode psychosis with a poor outcome after 6 months of treatment., Conclusions: The early identification of those individuals with first-episode psychosis with a poor clinical outcome may encourage clinicians to pay special attention to them in the form of alternative pharmacological and psychological treatments for a more favourable outcome in the long term.

Context: Memory is one of the cognitive functions most affected in schizophrenia, with deficits observed from the first episode of psychosis (FEP). Previous studies have indicated that some memory processes may be more affected than others., Objective: To examine the neural correlates of 3 specific memory processes in FEP by means of functional magnetic resonance imaging (fMRI)., Design: Case-control study., Setting: Prevention and Early Intervention Program for Psychoses of the Douglas Hospital and Montreal Neurological Institute, McGill University. Subjects Twenty-six patients with FEP and 20 healthy controls., Main Outcome Measures: Behavioral performance and regional brain activity measured during memory encoding by fMRI. Our fMRI design included 3 within-subject contrasts (associative vs item-oriented encoding, encoding of arbitrary vs semantically related image pairs, and successful vs unsuccessful memory encoding) that were then used for group conjunctions and between-group analyses., Results: Patients with FEP showed normal activation of several brain regions, including the prefrontal cortex, hippocampus, and parahippocampal cortex, during successful memory encoding and associative encoding. In contrast, the hippocampus and surrounding medial temporal areas showed reduced activity during the encoding of arbitrary pairs. This selective dysfunction reflected by abnormal brain activation during encoding was accompanied by a greater deficit for subsequent recognition of arbitrary pairs relative to the semantically related pairs., Conclusions: This study demonstrated that, in the same group of patients with FEP, the hippocampus could show either normal or abnormal modulation of activation depending on the specific cognitive process that was examined. The normal modulation of hippocampal activation observed during successful memory encoding in FEP argues against a general inability to recruit this region. Instead, the dysfunction was specifically linked to semantic relatedness. This selective deficit seems to affect memory performance in FEP and denotes an important representational problem that may confer greater vulnerability to psychotic disorders and would thus be interesting to examine in high-risk populations.

Objective: The aim of this study was to examine the reliability, validity and factor structure of the Community Assessment of Psychic Experiences (CAPE), a 42-item self-report questionnaire. We analyzed the internal consistency of the CAPE to determine whether the 3-factor structure (positive, negative and depressive symptoms) found by the CAPE authors would also be found in our sample., Method: A sample of 2275 individuals from the general community in the Montreal area completed the questionnaire in either French or English., Results: The internal consistencies of the original three subscales were good and the confirmatory factor models had a good fit. The exploratory factor analysis suggested a 3-5-factor solution, without improving the alternative factor structures. The 4-factor solution separated positive symptoms into factors we called 'bizarre positive symptoms' and 'social delusions', and the 5-factor solution separated positive symptoms further and included a 'popular psychic beliefs' factor. Results suggest that the scalability might be improved by shortening the original questionnaire to 23 items with the same 3 original scales., Conclusion: We support the internal consistency of the CAPE. Although alternative scaling (4 and 5 factors) did not improve the model fit, researchers interested in distinguishing 3 factors of positive symptoms could find utility in these two new scales. Finally, reducing the number of CAPE items could be useful for shorter surveys. Future studies should test the implications of these suggestions.

The amplitude of the P300 event-related potential (ERP) has been reported to be reduced over left compared to right temporal sites in schizophrenia patients. This left temporal P300 reduction has been associated with positive symptom severity and gray matter reduction in the left superior temporal gyrus. We investigated a group of patients with a first episode of schizophrenia spectrum psychosis and a group of normal controls to verify if P300 amplitude asymmetry already exists around the time of presentation for treatment. Relative to normal control subjects, no P300 asymmetry was found in patients. Nevertheless, P300 asymmetry was correlated with the severity of positive symptoms and worse global functioning (GAF), a good predictor of poor outcome.

Objective: It is suggested that schizophrenic patients who respond to neuroleptic medication and those who do not might differ with respect to their pathogenesis. In particular, it has been proposed that genetic factors may contribute to treatment response and/or outcome. In order to test this hypothesis, we compared the pattern of familial aggregation of schizophrenia related disorders in schizophrenic patients who are either responders (R) or nonresponders (NR) to typical neuroleptics., Method: R (n=36) or NR (n=35) patients to typical neuroleptics and healthy controls (n=63) were recruited. At least one key informant relative of each proband was interviewed blind as to the status of the proband using the Family Interview for Genetic Studies. Morbid risk for schizophrenia and cluster A personality disorders and family loading score for schizophrenia were examined in first- and second-degree relatives of these probands., Results: First-degree relatives of NR patients were at a significantly higher risk for schizophrenia (MR=8.84), compared, respectively, to relatives of controls (MR=1.52) or relatives of R patients (MR=2.45). The same pattern was observed in second-degree relatives. Family loading score for schizophrenia in first- and second-degree relatives was significantly higher in NR compared to R patients., Conclusions: Schizophrenic patients who do not respond to typical neuroleptics may suffer from a more familial form of schizophrenia compared to patients who are responders.

Although clozapine (CLZ) is effective in resistant schizophrenia, it fails in some cases leading to a therapeutic problem. Authors report a case of schizophrenia which resists several neuroleptic trials (including haloperidol, chlorpromazine and thioproperazine) and responds to a sequence of CLZ and amisulpride. These two atypical neuroleptics have the same main target (mesolimbic system) but have different and complementary affinities to neuromediator receptors: CLZ has strong serotoninergic and anticholinergic action, noradrenergic alpha 1 affinity and moderately active dopaminergic antagonism; amisulpride has a high and specific dopaminergic D2 antagonism when used at high posology. This clinical improvement can be related to "second treatment effect", described by Goldman in 1966: his study included two groups of refractory schizophrenic patients who received successively during two 6 months periods, 2 neuroleptics (fluphenazine and trifluperazine). Without initial therapeutic response, he noted a significant improvement only after change of neuroleptic medication. Tricyclic antidepressants may turn to be effective, after an initial failure, when they are given after an uneffective ECT trial. The same model may be applied and the clozapine-amisulpride sequence is proposed as an alternative treatment in resistant schizophrenia: even if CLZ is uneffective, it may produce carryover effects which ease the action of amisulpride. The hypothesis of an action on 5HT2-D2 antagonism is advanced. It leads to the general question of the opportunity of neuroleptic sequential prescription in resistant schizophrenia as a therapeutic option.

Through a review of the literature, the average mortality in schizophrenia is twice higher than among the population. This over mortality is highest among the 20-40 years range of age and added risk tends to disappear after 60 years. All studies stress the unnatural causes of death, suicide or accidental deaths. However several studies found an over mortality caused by natural death. The pathologies most often involved are: infections, lung, gastrointestinal, urogenital and cardiovascular diseases. Cancer mortality in schizophrenic patients is still debated. Some studies point out a reduced mortality compared to the general population whereas other studies find similar or over mortality. Nevertheless mortality ratio is found to be near 1 in the majority of studies. So it can be admitted that schizophrenic patient do really not differ from the general population in regard to cancer mortality. Premature death is highly linked to suicide. The epidemiological indicators that enable us to estimate the importance of suicide mortality are: the rate of suicide per 105 patients per year varies between 150 and 500, the percentage of death by suicide range between 10 and 15 percent. Suicide risk factors are numerous. Some of them are accepted as valid and others are still discussed. The former are: male gender, young and medium age ten first years of the illness course, associated depressive symptoms, past history of suicide attempts, iterative relapses and post hospital discharge period. The latter are: social isolation, celibacy, unemployment, high level of instruction, delusional and hallucinatory activity and familiar rejection.