Ana M. Sánchez-Torres

Characterization of the Deficit Syndrome in Drug-Naive Schizophrenia Patients: The Role of Spontaneous Movement Disorders and Neurological Soft Signs

This study aimed to characterize the deficit syndrome in drug-naive schizophrenia patients and to examine the relationship between deficit features and primary neurological abnormalities. Drug-naive schizophrenia patients (n = 102) were examined at baseline for demographics, premorbid functioning, duration of untreated illness (DUI), psychopathology, neurological signs, and deficit symptoms, and reassessed at 1-year follow-up. Neurological abnormalities were examined before inception of antipsychotic medication and included four domains of spontaneous movement disorders (SMD) and four domains of neurological soft signs (NSS). Patients fulfilling the deficit syndrome criteria at the two assessments (n = 20) were compared with nondeficit patients (n = 82) across demographic, clinical, and neurological variables. Deficit and nondeficit groups showed similar demographic characteristics and levels of psychotic, disorganization, and depressive symptoms. Compared with nondeficit patients, deficit patients showed poorer premorbid adjustment, higher premorbid deterioration, a lengthier DUI, and much poorer functional outcome. Relative to the nondeficit patients, those with the deficit syndrome showed higher levels of SMD--excepting akathisia--and NSS. This association pattern was also evident for deficit and neurological ratings in the whole sample of schizophrenia patients. Parkinsonism, motor sequencing, and release signs were all independently related to the deficit syndrome. These findings confirm that the deficit/nondeficit categorization is replicable and reliable in first-admission patients and raise the possibility that premorbid deterioration, deficit symptoms, and neurological abnormalities represent a triad of manifestations that share common underlying neurobiological mechanisms. More specifically, the data are consistent with a neurodevelopmental model of deficit symptoms involving basal ganglia dysfunction.

Risk factors, pre-morbid functioning and episode correlates of neurological soft signs in drug-naive patients with schizophrenia-spectrum disorders.

BACKGROUND There is a lack of consistent evidence regarding associations of neurological soft signs (NSS) with illness-related variables in schizophrenia. This study examined NSS in first-episode psychotic patients with respect to their factor structure and associations with risk factors, pre-morbid characteristics, psychopathology and spontaneous extrapyramidal syndromes. METHOD First-episode, drug-naive patients with schizophrenia-spectrum disorders (n=177) were assessed for NSS using the Neurological Evaluation Scale, and its 26 constituting items were factor analysed. The identified neurological dimensions were then entered into hierarchical regression models as outcome dependent variables of a set of predictors including risk factors (familial loading for schizophrenia, obstetric complications), pre-morbid characteristics (neurodevelopmental delay, symptoms of attention deficit-hyperactivity disorder, pre-morbid functioning), psychopathological domains (reality distortion, disorganization, negative symptoms, mania, depression, catatonia) and spontaneous extrapyramidal syndromes (parkinsonism, dyskinesia, akathisia). RESULTS Five neurological domains were identified: sequencing, release signs, sensory integration, abnormal movements and coordination. Multivariate analyses showed independent associations (p<0.01) of sequencing with familial liability to schizophrenia, deterioration of pre-morbid adjustment and parkinsonism; release signs with obstetric complications, catatonic symptoms and parkinsonism; sensory integration with familial liability to schizophrenia; abnormal movements with familial liability to schizophrenia, obstetric complications, parkinsonism and dyskinesia; and coordination with neurodevelopmental delay. The empirically derived factors explained additional variance over and above that explained by subscale scores across the examined variables. CONCLUSIONS Familial liability to schizophrenia, obstetric complications, neurodevelopmental delay, deterioration in pre-morbid functioning and observable motor disorders appear to contribute independently to domains of neurological dysfunction. The findings support a neurodevelopmental model of NSS in schizophrenia.

Duration of untreated negative and positive symptoms of psychosis and cognitive impairment in first episode psychosis

BACKGROUND Duration of untreated psychosis (DUP) has been significantly associated with poor clinical and social outcomes in First Episode Psychosis (FEP) patients, but an association with cognitive outcomes has not been clearly established. METHOD Seventy-seven consecutively admitted, drug-naïve patients with FEP were assessed at baseline and at 1month and 6months. Underlying dimensions of DUP (general prodrome and positive, negative and disorganisation symptoms) were assessed using the Symptom Onset in Schizophrenia (SOS) inventory (Perkins et al., 2000). To assess the effect of DUP on the neuropsychological status of the patients, a linear mixed-effect model was fitted to each neuropsychological dimension. These models included a dichotomised version of DUP (short versus long duration) as a fixed effect, several adjusting variables to account for patient differences, and a random effect to incorporate the longitudinal structure of the data. RESULTS Patients with a short duration of untreated negative symptoms (DUNS) or a short duration of untreated positive symptoms (DUPS) outperformed patients with a long duration of untreated symptoms on memory tasks and a pre-attentional visual task but not on measures of verbal fluency, attention, reaction time, visual processing and executive functions. CONCLUSIONS This study provides additional support for an early intervention to shorten DUP to facilitate a better outcome in memory and attentional domains of FEP patients.

The meaning of childhood attention-deficit hyperactivity symptoms in patients with a first-episode of schizophrenia-spectrum psychosis

OBJECTIVE To examine childhood ADHD symptoms in regard to their association with a number of illness-related variables including risk factors, early neurodevelopment, premorbid functioning and clinical characteristics in patients with schizophrenia-spectrum psychoses. METHODS One-hundred and twenty-two first-episode patients with DSM-IV schizophrenia-spectrum disorders were retrospectively assessed by means of their biological mothers for childhood ADHD symptoms. Using correlational analyses and hierarchical regression models, the severity of ADHD symptoms was examined in relation to familial liability to schizophrenia, obstetric complications, milestones attainment delay, premorbid functioning during childhood and adolescence, age at illness onset, episode psychopathology and response to treatment after one-month trial with antipsychotic medication. RESULTS Twenty-one patients (17%) met DSM-IV criteria for childhood ADHD. Univariate analyses showed that severity of childhood ADHD symptoms was related to male gender, obstetric complications, delayed milestones attainment, poor school functioning and an earlier age of onset of psychotic symptoms. Hierarchical regression analyses showed that severity of childhood ADHD symptoms was independently predicted by obstetric complications and neurodevelopmental delay, with no further variables entering in the regression models. Path analyses showed that obstetric complications had both direct and indirect effects, through neurodevelopmental delay, on ADHD symptoms. CONCLUSIONS These findings are consistent with a neurodevelopmental model of schizophrenia and with the hypothesis of shared environmental risk factors between ADHD and schizophrenia-spectrum disorders. Childhood ADHD symptoms in schizophrenia-spectrum disorders appear to be an epiphenomenon of obstetric complications and early neurodevelopment delay with no further influence on the clinical expression of the illness.

Spontaneous Parkinsonism Is Associated With Cognitive Impairment in Antipsychotic-Naive Patients With First-Episode Psychosis: A 6-Month Follow-up Study

There is now growing evidence that parkinsonism and other extrapyramidal signs are highly prevalent in patients with first-episode psychosis who have never been exposed to antipsychotic drugs. However, the neurocognitive correlates of parkinsonism in this population remained to be clarified. A sample comprising 100 consecutive drug-naive patients with first-episode psychosis were enrolled on the study and followed up for 6 months. Seventy-seven completed assessments at 3 time points (baseline, 1 mo, and 6 mo), involving clinical and cognitive examinations and a specific assessment of motor abnormalities. The Simpson-Angus Scale (SAS) was used for the assessment of extrapyramidal signs, and each motor domain was evaluated with a standard assessment scale. Linear mixed models were built to explore the longitudinal relationships between parkinsonism scores and cognitive impairment. Parkinsonism scores showed significant strong longitudinal associations with deficits in memory, executive functioning, and attention. Spontaneous parkinsonism (total SAS score and hypokinesia and rigidity subscores at baseline) showed high 6-month predictive values for cognitive impairment. In addition, they also had high predictive values for neurologic soft-sign abnormalities but not for dyskinesia, akathisia, and pure catatonic abnormalities. No predictive value was found for glabella-salivation or tremor subscores on the SAS scale. These results emphasize the relevance of the assessment of parkinsonism signs prior to starting to administer antipsychotic drugs, as core manifestations of psychotic illness with a high predictive value for cognitive impairment.

Executive functioning in schizophrenia spectrum disorder patients and their unaffected siblings: A ten-year follow-up study

Executive dysfunction represents a core deficit that is associated with schizophrenia spectrum disorders (SSDs). However, the longitudinal course of executive deficits in SSDs is still controversial. The aim of this study was to examine the executive performance of 34 SSD patients in relation to 34 of their unaffected siblings over a period of 10 years. Both groups completed psychopathological and executive assessments. Thirteen healthy controls were assessed using the same instruments. At baseline, the SSD patients differed significantly from siblings and controls in their performance on the Trail Making Test-B (TMT-B) and the number of categories in which they succeeded in the Wisconsin Card Sorting Test (WCST). They also differed significantly from the controls in the total number of errors in the WCST. The siblings did not differ in executive functioning from the controls over the follow-up. Longitudinally, the patients demonstrated significant improvement only for the TMT-B. However, only 14.71% of the patients showed reliable and clinically significant improvements for the TMT-B, and 8.82% made more errors on the WCST at the follow-up evaluation. Less than 3% of the patients showed either improved or worse results on the remaining measures of the WCST. A stabilisation pattern for the WCST was observed in the three groups. The patients performed worse than their siblings and controls on both executive tests. Some patients exhibited significant improvements in the TMT-B over time, but this improvement was reliable and clinically significant for less than 15% of the sample. Thus, we conclude that the patients exhibited stable impairments over time in the executive functions assessed.

Familiality of Psychotic Disorders: A Polynosologic Study in Multiplex Families.

INTRODUCTION Phenotype definition of psychotic disorders has a strong impact on the degree of familial aggregation. Nevertheless, the extent to which distinct classification systems affect familial aggregation (ie, familiality) remains an open question. This study was aimed at examining the familiality associated with 4 nosologic systems of psychotic disorders (DSM-IV, ICD-10, Leonhards classification and a data-driven approach) and their constituting diagnoses in a sample of multiplex families with psychotic disorders. METHODS Participants were probands with a psychotic disorder, their parents and at least one first-degree relative with a psychotic disorder. The sample was made of 441 families comprising 2703 individuals, of whom 1094 were affected and 1709 unaffected. RESULTS The Leonhard classification system had the highest familiality (h (2) = 0.64), followed by the empirical (h (2) = 0.55), DSM-IV (h (2) = 0.50), and ICD-10 (h (2) = 0.48). Familiality estimates for individual diagnoses varied considerably (h (2) = 0.25-0.79). Regarding schizophrenia diagnoses, Leonhards systematic schizophrenia (h (2) = 0.78) had the highest familiality, followed by latent class core schizophrenia (h (2) = 0.74), DSM-IV schizophrenia (h (2) = 0.48), and ICD-10 schizophrenia (h (2) = 0.41). Psychotic mood disorders showed substantial familiality across nosologic systems (h (2) = 0.60-0.77). Domains of psychopathology other than reality-distortion symptoms showed moderate familiality irrespective of diagnosis (h (2) = 0.22-0.52) with the deficit syndrome of schizophrenia showing the highest familiality (h (2) = 0.66). CONCLUSIONS While affective psychoses showed relatively high familiality estimates across classification schemes, those of nonaffective psychoses varied markedly as a function of the diagnostic scheme with a narrow schizophrenia phenotype maximizing its familial aggregation. Leonhards classification of psychotic disorders may be better suited for molecular genetic studies than the official diagnostic systems.

Controversies surrounding the diagnosis of schizophrenia and other psychoses

The diagnosis of schizophrenia and other psychotic disorders in current psychiatric classifications identifies individuals who are severely ill but who have few clinical characteristics in common. The usual picture of psychotic patients is a mixture of mood and psychotic symptoms. Fortunately, clinicians do not base their therapeutic strategies exclusively on diagnosis, but also on symptom predominance. Thus, clinicians’ treatments have been dimensional in nature for years, although, until recently, their psychiatric classifications had been mainly categorical. The main principle in psychosis classification has been the Kraepelinian dichotomy, despite its lack of enduring empirical validation. Without doubt, current psychiatric classifications have made great strides in reliability and clinical utility, although these advantages have not been enough to compensate for their shortcomings concerning validity. It has recently been suggested that the Kraepelinian dichotomy may be hindering progress in neurobiological research within psychosis. Mounting evidence is now fuelling a paradigm shift in the ongoing process of review of psychiatric classifications toward the introduction of complementary dimensional indicators of psychiatric categorical diagnoses. This new approach will allow us to understand psychosis as prototypical extremes of a severity continuum. The gradients of this continuum may begin with subtle expressions in the general population, continue with milder forms in relatives of psychotic patients and subclinical cases and finally reach the prototypical forms of psychosis at the other extreme. Future complementary dimensional indicators will require sound instruments capable of reflecting a multidimensional assessment of psychopathological symptoms, polydiagnostic interviews and the assessment of a wide range of nonsymptomatic domains. These new methods of assessment merging created by the shift toward a dimensional paradigm will be applied in the forthcoming new diagnostic criteria and may allow for a phenome-wide scanning for psychosis.

The course of negative symptoms in first-episode schizophrenia and its predictors: A prospective two-year follow-up study

AIMS This study aimed to investigate the course of negative symptoms and its stability over a two-year period following a first-episode schizophrenia (FES) and the possible predictors of higher severity in this symptomatology after this period. METHODS In this longitudinal two-year prospective follow-up study we included 268 patients with a FES, according to DSM-IV. Analysis of variance was conducted in patients who completed the full follow-up to study changes in negative symptoms over three visits. Regression analyses were conducted to show correlates and potential predictors of negative symptoms at two-year follow-up. RESULTS There was a significant effect for time in negative symptomatology, which was less severe at one-year follow-up after a FES and remained stable up to two years (Time 1>Time 2>Time 3); F(2,151)=20.45, p<0.001. Poorer premorbid adjustment (p=0.01) and higher negative symptoms at baseline (p<0.001) made a significant contribution to the changes in the negative symptoms severity at two-years after a FES (R2=0.21, p<0.001). CONCLUSIONS We found a reduction in the negative symptomatology at one-year after a FES. This change remained stable at two-year. Our results suggested that the presence of this symptomatology early in the course of the illness, together with a poorer premorbid adjustment, predict more severe negative symptoms at mid-term outcome.

Cannabis use, COMT, BDNF and age at first-episode psychosis

Although an interaction between COMT Val158Met and BDNF Val66Met polymorphisms with cannabis use has been proposed with respect to the risk of psychosis emergence, findings remain inconclusive. The aim of the present study was to evaluate the different possible associations between these polymorphisms and early cannabis use and the age at the first episode of psychosis. The relationship between age at psychosis onset and COMT Val158Met and BDNF Val66Met polymorphisms with early cannabis use as well as those factors associated with early cannabis use were investigated. Among 260 Caucasian first-episode psychosis patients, early cannabis use and the presence of the met-allele from the BDNF Val66Met polymorphism were significantly associated with age at psychosis onset. Furthermore, early cannabis use was significantly associated with male gender in the logistic regression analysis. These findings provide evidence of the important role of early cannabis use and the Val66Met BDNF polymorphism on age at psychosis onset and they point out to sex-specific differences in cannabis use patterns.