Long-term diagnostic stability, predictors of diagnostic change, and time until diagnostic change of first-episode psychosis: a 21-year follow-up study.

BACKGROUND: Although diagnostic instability in first-episode psychosis (FEP) is of major concern, little is known about its determinants. This very long-term follow-up study aimed to examine the diagnostic stability of FEP diagnoses, the baseline predictors of diagnostic change and the timing of diagnostic change. METHODS: This was a longitudinal and naturalistic study of 243 subjects with FEP who were assessed at baseline and reassessed after a mean follow-up of 21 years. The diagnostic stability of DSM-5 psychotic disorders was examined using prospective and retrospective consistencies, logistic regression was used to establish the predictors of diagnostic change, and survival analysis was used to compare time to diagnostic change across diagnostic categories. RESULTS: The overall diagnostic stability was 47.7%. Schizophrenia and bipolar disorder were the most stable diagnoses, with other categories having low stability. Predictors of diagnostic change to schizophrenia included a family history of schizophrenia, obstetric complications, developmental delay, poor premorbid functioning in several domains, long duration of untreated continuous psychosis, spontaneous dyskinesia, lack of psychosocial stressors, longer duration of index admission, and poor early treatment response. Most of these variables also predicted diagnostic change to bipolar disorder but in the opposite direction and with lesser effect sizes. There were no significant differences between specific diagnoses regarding time to diagnostic change. At 10-year follow-up, around 80% of the diagnoses had changed. CONCLUSIONS: FEP diagnoses other than schizophrenia or bipolar disorder should be considered as provisional. Considering baseline predictors of diagnostic change may help to enhance diagnostic accuracy and guide therapeutic interventions.

The association of adverse childhood experiences with long-term outcomes of psychosis: a 21-year prospective cohort study after a first episode of psychosis.

BACKGROUND: Evidence suggests a possible relationship between exposure to childhood adversity (CA) and functional impairment in psychosis. However, the impact of CA on long-term outcomes of psychotic disorders remains poorly understood. METHODS: Two hundred and forty-three patients were assessed at their first episode of psychosis for CA and re-assessed after a mean of 21 years of follow-up for several outcome domains, including symptoms, functioning, quality of life, cognitive performance, neurological dysfunction, and comorbidity. The unique predictive ability of CA exposure for outcomes was examined using linear regression analysis controlling for relevant confounders, including socioeconomic status, family risk of schizophrenia, and obstetric complications. RESULTS: There were 54% of the patients with a documented history of CA at mild or higher levels. CA experiences were more prevalent and severe in schizophrenia than in other psychotic disorders (p < 0.001). Large to very large effect sizes were observed for CA predicting most role functioning variables and negative symptoms (ΔR2 between 0.105 and 0.181). Moderate effect sizes were observed for positive symptoms, personal functioning, impaired social cognition, impaired immediate verbal learning, poor global cognition, internalized stigma, poor personal recovery, and drug abuse severity (ΔR2 between 0.040 and 0.066). A dose-response relationship was observed between levels of CA and severity of outcome domains. CONCLUSION: Our results suggest a strong and widespread link between early adversity exposure and outcomes of psychotic disorders. Awareness of the serious long-term consequences of CA should encourage better identification of those at risk and the development of effective interventions.

Social exclusion as a major outcome domain of psychotic disorders: early predictors, and associations with non-recovery and clinical staging 21 years after a first episode of psychosis.

PURPOSE: People with psychotic disorders have high levels of social exclusion; however, little is known about its early predictors. We present a long-term observational cohort study aimed at examining early risk factors for later social exclusion. METHODS: A total of 243 subjects were assessed at their first psychotic episode for early risk factors including sociodemographic variables, familial risk of major mental disorders, perinatal complications, childhood factors, and adolescent factors and re-assessed after a mean follow-up of 21 years for 12 social exclusion domains: leisure activities, housing, work, income, neighborhood deprivation, educational attainment, physical and mental health, family and social support, legal competence, and discrimination. The ability of risk factors to predict social exclusion was examined using hierarchical linear regression. RESULTS: Overall social exclusion was independently predicted by low parental socio-economic status, length of follow-up, familial risk of schizophrenia, obstetric complications, neurodevelopmental delay, poor childhood adjustment, childhood adversity, poor adolescent social networks, poor adolescent adjustment, and low premorbid IQ. The model explained 58.2% of the variance in total social exclusion score. Each social exclusion domain was predicted by a different set of variables, which explained between 17.8 and 57.0% of their variance, although low socio-economic status, familial risk of schizophrenia, obstetric complications, childhood adversity, and poor social networks predicted most of the social exclusion domains. CONCLUSION: Early risk factors strongly predicted later social exclusion. A multifaceted approach to preventing later social exclusion is crucial in people with a first episode of psychosis and early risk factors of social exclusion.

Link between cognitive polygenic risk scores and clinical progression after a first-psychotic episode.

BACKGROUND: Clinical intervention in early stages of psychotic disorders is crucial for the prevention of severe symptomatology trajectories and poor outcomes. Genetic variability is studied as a promising modulator of prognosis, thus novel approaches considering the polygenic nature of these complex phenotypes are required to unravel the mechanisms underlying the early progression of the disorder. METHODS: The sample comprised of 233 first-episode psychosis (FEP) subjects with clinical and cognitive data assessed periodically for a 2-year period and 150 matched controls. Polygenic risk scores (PRSs) for schizophrenia, bipolar disorder, depression, education attainment and cognitive performance were used to assess the genetic risk of FEP and to characterize their association with premorbid, baseline and progression of clinical and cognitive status. RESULTS: Schizophrenia, bipolar disorder and cognitive performance PRSs were associated with an increased risk of FEP [false discovery rate (FDR) ⩽ 0.027]. In FEP patients, increased cognitive PRSs were found for FEP patients with more cognitive reserve (FDR ⩽ 0.037). PRSs reflecting a genetic liability for improved cognition were associated with a better course of symptoms, functionality and working memory (FDR ⩽ 0.039). Moreover, the PRS of depression was associated with a worse trajectory of the executive function and the general cognitive status (FDR ⩽ 0.001). CONCLUSIONS: Our study provides novel evidence of the polygenic bases of psychosis and its clinical manifestation in its first stage. The consistent effect of cognitive PRSs on the early clinical progression suggests that the mechanisms underlying the psychotic episode and its severity could be partially independent.

Assessment of cognitive impairment in psychosis spectrum disorders through self-reported and interview-based measures.

Self-reported and interview-based measures can be considered coprimary measures of cognitive performance. We aimed to ascertain to what extent cognitive impairment in psychotic disorders, as assessed with a neuropsychological battery, is associated with subjective cognitive complaints compared to difficulties in daily activities caused by cognitive impairment. We assessed 114 patients who had a psychotic disorder with a set of neuropsychological tests and two additional measures: the Cognitive Assessment Interview-Spanish version (CAI-Sp) and the Frankfurt Complaint Questionnaire (FCQ). Patients also underwent a clinical assessment. The CAI-Sp correlated significantly with all the clinical dimensions, while the FCQ correlated only with positive and depressive symptoms. The CAI-Sp correlated significantly with all cognitive domains, except for verbal memory and social cognition. The FCQ was associated with attention, processing speed and working memory. The combination of manic and depressive symptoms and attention, processing speed, working memory and explained 38-46% of the variance in the patients' CAI-Sp. Education and negative symptoms, in combination with attention, processing speed, and executive functions, explained 54-59% of the CAI-Sp rater's variance. Only negative symptoms explained the variance in the CAI-Sp informant scores (37-42%). Depressive symptoms with attention and working memory explained 15% of the FCQ variance. The ability to detect cognitive impairment with the CAI-Sp and the FCQ opens the possibility to consider these instruments to approximate cognitive impairment in clinical settings due to their ease of application and because they are less time-consuming for clinicians.

A neuropsychological study on Leonhard's nosological system.

Phenotype validation of endogenous psychosis is a problem that remains to be solved. This study investigated the neuropsychological performance of endogenous psychosis subtypes according to Wernicke-Kleist-Leonhard's classification system (WKL). The participants included consecutive admissions of patients with schizophrenia spectrum disorder or mood disorder with psychotic symptoms (N = 98) and healthy comparison subjects (N = 50). The patients were assessed by means of semi-structured interviews and diagnosed through the WKL system into three groups: a manic-depressive illness and cycloid psychosis group (MDC), unsystematic schizophrenia (USch) and systematic schizophrenia (SSch). All the participants completed a comprehensive neuropsychological battery. The three Leonhard's psychosis subtypes showed a common neuropsychological profile with differences in the severity of impairment relative to healthy controls. MDC patients showed better performance on premorbid intelligence, verbal memory and global cognitive index than USch and SSch patients, and they showed better performance on processing speed, and working memory than SSch patients. USch patients outperformed SSch patients in verbal memory, working memory and global cognitive index. Neuropsychological performance showed a modest accuracy for classification into the WKL nosology. Our results suggest the existence of a common profile of cognitive impairment cutting across WKL subtypes of endogenous psychosis but with significant differences on a severity continuum. In addition, classification accuracy in the three WKL subtypes by means of neuropsychological performance was modest, ranging between 40 and 64% of correctly classified patients.

Motor abnormalities and basal ganglia in first-episode psychosis (FEP).

BACKGROUND: Motor abnormalities (MAs) are the primary manifestations of schizophrenia. However, the extent to which MAs are related to alterations of subcortical structures remains understudied. METHODS: We aimed to investigate the associations of MAs and basal ganglia abnormalities in first-episode psychosis (FEP) and healthy controls. Magnetic resonance imaging was performed on 48 right-handed FEP and 23 age-, gender-, handedness-, and educational attainment-matched controls, to obtain basal ganglia shape analysis, diffusion tensor imaging techniques (fractional anisotropy and mean diffusivity), and relaxometry (R2*) to estimate iron load. A comprehensive motor battery was applied including the assessment of parkinsonism, catatonic signs, and neurological soft signs (NSS). A fully automated model-based segmentation algorithm on 1.5T MRI anatomical images and accurate corregistration of diffusion and T2* volumes and R2* was used. RESULTS: FEP patients showed significant local atrophic changes in left globus pallidus nucleus regarding controls. Hypertrophic changes in left-side caudate were associated with higher scores in sensory integration, and in right accumbens with tremor subscale. FEP patients showed lower fractional anisotropy measures than controls but no significant differences regarding mean diffusivity and iron load of basal ganglia. However, iron load in left basal ganglia and right accumbens correlated significantly with higher extrapyramidal and motor coordination signs in FEP patients. CONCLUSIONS: Taken together, iron load in left basal ganglia may have a role in the emergence of extrapyramidal signs and NSS of FEP patients and in consequence in the pathophysiology of psychosis.

The longitudinal effect of antipsychotic burden on psychosocial functioning in first-episode psychosis patients: the role of verbal memory.

BACKGROUND: Previous literature supports antipsychotics' (AP) efficacy in acute first-episode psychosis (FEP) in terms of symptomatology and functioning but also a cognitive detrimental effect. However, regarding functional recovery in stabilised patients, these effects are not clear. Therefore, the main aim of this study is to investigate dopaminergic/anticholinergic burden of (AP) on psychosocial functioning in FEP. We also examined whether cognitive impairment may mediate these effects on functioning. METHODS: A total of 157 FEP participants were assessed at study entry, and at 2 months and 2 years after remission of the acute episode. The primary outcomes were social functioning as measured by the functioning assessment short test (FAST). Cognitive domains were assessed as potential mediators. Dopaminergic and anticholinergic AP burden on 2-year psychosocial functioning [measured with chlorpromazine (CPZ) and drug burden index] were independent variables. Secondary outcomes were clinical and socio-demographic variables. RESULTS: Mediation analysis found a statistical but not meaningful contribution of dopaminergic receptor blockade burden to worse functioning mediated by cognition (for every 600 CPZ equivalent points, 2-year FAST score increased 1.38 points). Regarding verbal memory and attention, there was an indirect effect of CPZ burden on FAST (b = 0.0045, 95% CI 0.0011-0.0091) and (b = 0.0026, 95% CI 0.0001-0.0006) respectively. However, only verbal memory post hoc analyses showed a significant indirect effect (b = 0.009, 95% CI 0.033-0.0151) adding premorbid IQ as covariate. We did not find significant results for anticholinergic burden. CONCLUSION: CPZ dose effect over functioning is mediated by verbal memory but this association appears barely relevant.

Cognitive, community functioning and clinical correlates of the Clinical Assessment Interview for Negative Symptoms (CAINS) in psychotic disorders.

Negative symptoms are a core dimension of schizophrenia and other psychoses that account for a large degree of the poor functional outcomes related to these disorders. Newer assessment scales for negative symptoms, such as the Clinical Assessment Interview for Negative Symptoms (CAINS), provide evidence for separate dimensions of motivational and pleasure (MAP) and expression (EXP) dimensions. This study was aimed at extending the analysis of the clinical, functional and cognitive correlates of CAINS dimensions in a sample of patients with psychotic disorders (n = 98) and 50 healthy controls.A psychopathological evaluation was conducted by using the Comprehensive Assessment of Symptoms and History (CASH). To assess the extrapyramidal signs, the UKU scale was used. Community functioning was evaluated by means of real-world and functional attainment measures. Additionally, a full neuropsychological test battery was administered. Pearson correlation and hierarchical multiple linear regression analyses were performed to identify the influencing and predictive factors associated with the CAINS dimensions.The MAP and EXP dimensions showed strong associations with the Scale for the Assessment of Negative Symptoms (SANS) items and were not significantly associated with extra-pyramidal or cognitive deficits. The MAP and EXP CAINS dimensions revealed good predictive validity for real-world functioning and functional attainment measures.These findings suggest that the CAINS scale endorses good convergent validity for the assessment of negative symptoms and is very useful in the prediction of psychosocial functioning. In addition, the CAINS dimensions might provide advantages over old assessment scales on disentangling the complex associations between negative symptoms and cognitive impairment.

Using the cognitive assessment interview to screen cognitive impairment in psychosis.

Cognitive impairment in psychosis is closely related to functional outcome, so research into psychotic disorders is focusing most effort on treatments for improving cognition. New treatments must show not only an improvement on neuropsychological tests but also in co-primary measures of cognition. The cognitive assessment interview (CAI) is an interview-based measure of cognition which assesses the impact of cognitive deficits in patients' daily lives. Information obtained from patients and their relatives is integrated into a rater composite score. This study examines the validity of the CAI (adapted to Spanish, CAI-Sp) as a screening instrument for cognitive impairment, compared to an objective test of cognitive functioning. The psychometric properties of the CAI-Sp and its association with clinical dimensions are also explored. Eighty-one patients with a psychotic disorder and 38 healthy controls were assessed using the CAI-Sp and the screen for cognitive impairment in psychiatry (SCIP-S). Patients also underwent a clinical assessment. Poorer cognitive functioning as assessed with the CAI-Sp was associated to illness severity, specifically positive, negative and disorganised syndromes. Binary logistic regression showed that the CAI-Sp was able to detect cognitive impairment in patients, when considering CAI-Sp patient and informant information and CAI-Sp rater scores. The CAI-Sp was found to be a valid and reliable scale to assess cognitive functioning in the context of its impact on daily living. Given its ease and speed of application, the CAI-Sp could prove useful in clinical practice, though not a substitute of objective cognitive testing.

A comparative study of the working memory multicomponent model in psychosis and healthy controls.

Working memory deficits are considered nuclear deficits in psychotic disorders. However, research has not found a generalized impairment in all of the components of working memory. We aimed to assess the components of the Baddeley and Hitch working memory model: the temporary systems-the phonological loop, the visuospatial sketchpad and the episodic buffer (introduced later by Baddeley)-and the central executive system, which includes four executive functions: divided attention, updating, shifting and inhibition. We assessed working memory performance in a sample of 21 patients with a psychotic disorder and 21 healthy controls. Patients also underwent a clinical assessment. Both univariate and repeated measures ANOVAs were applied to analyze performance in the working memory components between groups. Patients with a psychotic disorder underperformed compared to the controls in all of the working memory tasks, but after controlling for age and premorbid IQ, we only found a difference in performance in the N-Back task. Repeated measures ANCOVAs showed that patients also underperformed compared to the controls in the Digit span test and the TMT task. Not all of the components of working memory were impaired in the patients. Specifically, patients' performance was impaired in the tasks selected to assess the phonological loop and the shifting executive function. Patients' also showed worse performance than controls in the N-Back task, representative of the updating executive function. However, we did not find higher impairment in the patients' performance respect to controls when increasing the loading of the task.

20-Year trajectories of six psychopathological dimensions in patients with first-episode psychosis: Could they be predicted?

Patients with first-episode psychoses (FEP) exhibit heterogeneity in clinical manifestations and outcomes. This study investigated the long-term trajectories of six key psychopathological dimensions (reality-distortion, negative, disorganization, catatonia, mania and depression) in patients diagnosed with FEP. A total of 243 patients were followed up for 20 years and the trajectories of the dimensions were analysed using growth mixture modelling. These dimensions showed varied course patterns, ranging from two to five trajectories. Additionally, the study examined the predictive value of different factors in differentiating between the long-term trajectories. The exposome risk score showed that familial load, distal and intermediate risk factors, acute psychosocial stressors and acute onset were significant predictors for differentiating between long-term psychopathological trajectories. In contrast, polygenic risk score, duration of untreated psychosis and duration of untreated illness demonstrated little or no predictive value. The findings highlight the importance of conducting a multidimensional assessment not only at FEP but also during follow-up to customize the effectiveness of interventions. Furthermore, the results emphasize the relevance of assessing premorbid predictors from the onset of illness. This may enable the identification of FEP patients at high-risk of poor long-term outcomes who would benefit from targeted prevention programs on specific psychopathological dimensions.

The effect of anticholinergic burden of psychiatric medications on major outcome domains of psychotic disorders: A 21-year prospective cohort study.

BACKGROUND: Most medications used to treat psychotic disorders possess anticholinergic properties. This may result in a considerable anticholinergic burden (ACB), which may have deleterious effects on long-term outcomes. The extent to which cumulative ACB over years of treatment with psychotropic medications impacts different outcome domains remains unknown. METHODS: This was a naturalistic study of 243 subjects with first-episode psychosis aimed at examining the cumulative effect of ACB of psychotropic medications administered over the illness course (ACB-years exposure) on several outcome domains assessed after a mean 21-year follow-up. Associations between ACB and the outcomes were modelled accounting for relevant confounding factors by using hierarchical linear regression analysis. RESULTS: Over the study period, 81.9 % of the participants were dispensed at least one drug with strong anticholinergic effects for at least 1 year; at the follow-up visit, 60.5 % of the participants continued to take medications with strong ACB. ACB-years exposure was uniquely related to severity of negative symptoms (ß = 0.144, p = 0.004), poor psychosocial functioning (ß = 0.186, p < 0.001) and poor cognitive performance (ß = -0.273, p < 0.001). This association pattern was independent of a schizophrenia diagnosis. Most of the associations between ACB at the follow-up visit and the outcomes were accounted for ACB-years exposure. CONCLUSION: Lifetime ACB of psychotropic medications has deleterious effects on the outcome of psychotic disorders. Clinicians should avoid prescribing medications with strong ACB, since there are numerous alternatives within each psychotropic drug group for prescribing medications with low ACB.

Long-term trajectories of clinical staging in first-episode psychosis and their associated cognitive outcome: A 21-year follow-up study.

Cognitive deficits are already present before psychosis onset but are a key feature of first-episode psychosis (FEP). The objective of this study was to investigate the cognitive outcomes of a cohort of FEP patients who were diagnosed using the clinical staging approach and were followed for up to 21 years. We analyzed data from 173 participants with first-admission psychosis who were followed-up for a mean of 20.9 years. The clinical staging assessment was adapted from the clinical staging framework developed by McGorry et al.1 Cognitive assessment was performed using the MATRICS Consensus Cognitive Battery (MMCB) at the end of follow-up. FEP patients who were longitudinally diagnosed in the lowest clinical stages (stages 2A and 2B) showed better performance in attention, processing speed, and MCCB overall composite score than those in the highest clinical stages (stages 4A and 4B). There was a significant linear trend association between worsening of all MCCB cognitive functions and MCCB overall composite score and progression in clinical staging. Furthermore, the interval between two and five years of follow-up appears to be associated with deficits in processing speed as a cognitive marker. Our results support the validation of the clinical staging model over a long-term course of FEP based on neuropsychological performance. A decline in some cognitive functions, such as processing speed, may facilitate the transition of patients to an advanced stage during the critical period of first-episode psychosis.

Psychopathological networks in psychosis: Changes over time and clinical relevance. A long-term cohort study of first-episode psychosis.

BACKGROUND: First-episode psychosis is a critical period for early interventions to reduce the risk of poor outcomes and relapse as much as possible. However, uncertainties about the long-term outcomes of symptomatology remain to be ascertained. METHODS: The aim of the present study was to use network analysis to investigate first-episode and long-term stages of psychosis at three levels of analysis: micro, meso and macro. The sample was a cohort of 510 patients with first-episode psychoses from the SEGPEP study, who were reassessed at the long-term follow-up (n = 243). We used the Comprehensive Assessment of Symptoms and History for their assessments and lifetime outcome variables of clinical relevance. RESULTS: Our results showed a similar pattern of clustering between first episodes and long-term follow-up in seven psychopathological dimensions at the micro level, 3 and 4 dimensions at the meso level, and one at the macro level. They also revealed significant differences between first-episode and long-term network structure and centrality measures at the three levels, showing that disorganization symptoms have more influence in long-term stabilized patients. CONCLUSIONS: Our findings suggest a relative clustering invariance at all levels, with the presence of two domains of disorganization as the most notorious difference over time at micro level. The severity of disorganization at the follow-up was associated with a more severe course of the psychosis. Moreover, a relative stability in global strength of the interconnections was found, even though the network structure varied significantly in the long-term follow-up. The macro level was helpful in the integration of all dimensions into a common psychopathology factor, and in unveiling the strong relationships of psychopathological dimensions with lifetime outcomes, such as negative with poor functioning, disorganization with high antipsychotic dose-years, and delusions with poor adherence to treatment. These results add evidence to the hierarchical, dimensional and longitudinal structure of psychopathological symptoms and their clinical relevance in first-episode psychoses.

A clinical staging model of psychotic disorders based on a long-term follow-up of first-admission psychosis: A validation study.

We examined the empirical validity of a staging model of psychotic disorders primarily based on their long-term course. The model distinguished 6 consecutive stages (2A, 2B, 3A, 3B, 4A, 4B) based on symptom recurrence, persistence and progression, such as functional decline. We analyzed data from 243 participants with first-admission psychosis who were followed-up for a mean of 20.9 years and assessed for 22 baseline variables, 23 construct-related variables and 31 outcome variables. Later stages scored significantly poorer than early stages on most validators by showing generally medium to large effect sizes and a dose-response pattern, thus confirming the validity of the model. For each set of validators, differences between consecutive stages were especially evident for stages 2 and 3A, although many variables from each validation realm also differentiated between the consecutive stages 3A and above. Baseline predictors including familial load of schizophrenia, neurodevelopmental impairment, childhood adversity, treatment delay, negative symptoms, neurological impairment and poor early response to treatment, independently accounted for 49.9% of the variance of staging. A staging model of psychosis based primarily on its long-term course has sound construct, outcome and predictive validity, which may inform about stage indicators and predictors of clinical stages from psychosis onset.

Relapse, cognitive reserve, and their relationship with cognition in first episode schizophrenia: a 3-year follow-up study.

Schizophrenia is frequently characterized by the presence of multiple relapses. Cognitive impairments are core features of schizophrenia. Cognitive reserve (CR) is the ability of the brain to compensate for damage caused by pathologies such as psychotic illness. As cognition is related to CR, the study of the relationship between relapse, cognition and CR may broaden our understanding of the course of the disease. We aimed to determine whether relapse was associated with cognitive impairment, controlling for the effects of CR. Ninety-nine patients with a remitted first episode of schizophrenia or schizophreniform disorder were administered a set of neuropsychological tests to assess premorbid IQ, attention, processing speed, working memory, verbal and visual memory, executive functions and social cognition. They were followed up for 3 years (n=53) or until they relapsed (n=46). Personal and familial CR was estimated from a principal component analysis of the premorbid information gathered. Linear mixed-effects models were applied to analyse the effect of time and relapse on cognitive function, with CR as covariate. Patients who relapsed and had higher personal CR showed less deterioration in attention, whereas those with higher CR (personal and familial CR) who did not relapse showed better performance in processing speed and visual memory. Taken together, CR seems to ameliorate the negative effects of relapse on attention performance and shows a positive effect on processing speed and visual memory in those patients who did not relapse. Our results add evidence for the protective effect of CR over the course of the illness.

The polygenic basis of relapse after a first episode of schizophrenia.

Little is known about genetic predisposition to relapse. Previous studies have linked cognitive and psychopathological (mainly schizophrenia and bipolar disorder) polygenic risk scores (PRS) with clinical manifestations of the disease. This study aims to explore the potential role of PRS from major mental disorders and cognition on schizophrenia relapse. 114 patients recruited in the 2EPs Project were included (56 patients who had not experienced relapse after 3 years of enrollment and 58 patients who relapsed during the 3-year follow-up). PRS for schizophrenia (PRS-SZ), bipolar disorder (PRS-BD), education attainment (PRS-EA) and cognitive performance (PRS-CP) were used to assess the genetic risk of schizophrenia relapse.Patients with higher PRS-EA, showed both a lower risk (OR=0.29, 95% CI [0.11-0.73]) and a later onset of relapse (30.96± 1.74 vs. 23.12± 1.14 months, p=0.007. Our study provides evidence that the genetic burden of neurocognitive function is a potentially predictors of relapse that could be incorporated into future risk prediction models. Moreover, appropriate treatments for cognitive symptoms appear to be important for improving the long-term clinical outcome of relapse.

Characterization of spontaneous Parkinsonism in drug-naive patients with nonaffective psychotic disorders.

Spontaneous Parkinsonism (SP) in schizophrenia-related disorders is poorly characterized. The objective of this study was to examine the concordance and clinical validity of alternative definitions of SP in patients with nonaffective psychotic disorders. Two-hundred drug-naive patients with nonaffective psychotic disorders were examined for core parkinsonian signs, including bradykinesia, rigidity, and tremor, and diagnosed of SP according to the Simpson-Angus Scale (SAS) cutoff criterion, the UK Parkinson's disease brain bank (UKPDBB) criteria, the National Institute of Neurological Disorders and Stroke (NINDS) criteria, and criteria requiring the presence of all three core features (full syndrome criteria). Parkinsonian signs and criteria were examined in relation to a number of relevant clinical variables. The most frequent sign was rigidity (33.5%) followed by bradykinesia (16%) and tremor (12%). The prevalence rate of SP according to the SAS cutoff criterion, the UKPDBB criteria, the NINDS criteria for possible and probable SP, and the full syndrome criteria were 20.5, 13, 25.5, 18.5, and 4%, respectively. Bradykinesia was specifically related to negative symptoms, rigidity to neurological soft signs, and tremor to dyskinetic movements. The set of criteria showing more associations with clinical variables were the NINDS criteria for probable SP. Patients fulfilling these criteria had higher ratings for poor premorbid adjustment, negative symptoms, dyskinesia, neurological soft signs, and poor global treatment response than those without that diagnosis. The NINDS criteria for probable SP, i.e., presence of any two of the three core parkinsonian signs, seem to be the most suitable for clinical and research purposes.

Neuromotor dysfunction as a major outcome domain of psychotic disorders: A 21-year follow-up study.

BACKGROUND: The long-term stability of neuromotor domains assessed at the first episode of psychosis (FEP) and their ability for predicting a number of outcomes remains largely unknown, and this study addressed these issues. METHODS: This was a longitudinal study of 243 participants with FEP who were assessed at baseline for background variables and parkinsonism, dyskinesia, neurological soft signs (NSS) and catatonia, and reassessed 21 years later for the same neuromotor variables, psychopathology, functioning, personal recovery, cognitive performance and medical comorbidity. Stability of neuromotor ratings was assessed using the intraclass correlations coefficient and associations between the predictors and outcomes were examined using univariate and multivariate statistics. RESULTS: Baseline dyskinesia and NSS ratings showed excellent stability over time whereas that for parkinsonism and catatonia was relatively low. Neuromotor dysfunction at follow-up was independently predicted by a family history of schizophrenia, obstetric complications, neurodevelopmental delay, low premorbid IQ and baseline ratings of dyskinesia and NSS. Moreover, baseline dyskinesia and NSS ratings independently predicted more positive and negative symptoms, poor functioning and less personal recovery; catatonia predicted less personal recovery and more medical comorbidity. Baseline neuromotor ratings explained between 4% (for medical comorbidity) and 34% (for neuromotor dysfunction) of the variance in the outcomes. Lastly, neuromotor dysfunction at baseline highly predicted clinical staging at follow-up. CONCLUSION: Baseline neuromotor domains show variable stability over time and relate distinctively to very long-term outcomes. Both baseline dyskinesia and NSS are trait markers of the disease process and robust predictors of the outcomes.