Roberto Cavallaro

Standardized remission criteria in schizophrenia.

Objective:  Recent work has focussed on schizophrenia as a ‘deficit’ state but little attention has been paid to defining illness plasticity in terms of symptomatic remission.

Pharmacogenetics of Tardive Dyskinesia: Combined Analysis of 780 Patients Supports Association with Dopamine D3 Receptor Gene Ser9Gly Polymorphism

Variability among individuals in their therapeutic response to psychotropic drugs and in susceptibility to adverse effects is considerable. Pharmacogenetics addresses the contribution of genetic factors to this variability. An important focus of interest in pharmacogenetics has been on candidate genes that play a role in susceptibility to the antipsychotic drug-induced adverse effect, tardive dyskinesia (TD). Four published studies have reported an association between a serine (ser) to glycine (gly) polymorphism in exon 1 of the dopamine D3 receptor gene (DRD3) and TD; three failed to replicate this finding and one found an insignificant trend. We examined the association in a pooled sample of 780 patients (317 with TD and 463 without TD) drawn from 6 research centers, who were divided into 8 groups based on their population origin. The analysis employed stepwise logistic regression so as to allow confounding effects of group, age, and gender to be taken into account. TD was significantly associated with DRD3 gly allele carrier status (x2=4.46, df 1, p = .04) and with DRD3 genotype (x2=6.62, df 2, p = .04) over and above the effect of group. Similar positive effects were observed when controlling for age and gender (x2=5.02, df 1, p = .02 for gly allele carrier status; x2 = 7.51, df 2, p = .002 for genotype). Examining abnormal involuntary movement scores as a continuous variable, we found that patients homozygous for the gly allele had significantly higher scores than ser-gly heterozygotes (p = .006) or ser-ser homozygotes (p < .0001). We also performed a meta-analysis that included, besides the groups in the combined analysis, three other published studies on DRD3 and TD. The Mantel-Haenszel pooled odds ratio for DRD3 gly allele carrier status increasing susceptibility to TD was 1.33 (95% CI 1.04–1.70, p = .02); the cumulative pooled estimate showed an odds ratio of 1.52 (95% CI 1.08–1.68, p < .0001). These findings support a small but significant contribution of the DRD3 ser9gly polymorphism to TD susceptibility that is demonstrable over and above population effects and the effect of age and gender on the phenotype.

Basal-corticofrontal circuits in schizophrenia and obsessive-compulsive disorder: a controlled, double dissociation study

BACKGROUND Several lines of research suggest that prefrontal cortex dysfunctions observed in obsessive compulsive disorder (OCD) and schizophrenia (SKZ) are linked to two partially independent neuroanatomic systems: the ventromedial prefrontal cortex and the dorsolateral prefrontal cortex, with different neuroanatomic connections, including the striatum. The primary aim of this study was to test this hypothesis using a double dissociation study of neuropsychological tasks performance of the dorsolateral prefrontal cortex and ventromedial prefrontal cortex. METHODS We administered the Wisconsin Card Sorting Test, the Gambling Task, and the four-disk version of the Tower of Hanoi to 110 SKZ and 67 OCD patients and 56 control subjects. RESULTS A clear double dissociation of Wisconsin Card Sorting Test and Gambling Task performances was found, with SKZ patients performing the Wisconsin Card Sorting test significantly worse than OCD patients and control subjects and OCD patients performing the Gambling Task significantly worse than SKZ and control subjects. Both SKZ and OCD patients performed the Tower of Hanoi significantly worse than control subjects. CONCLUSIONS Results from our double dissociation study confirm the hypothesis of involvement of different frontal lobe subsystems within basal-corticofrontal circuits function in SKZ and OCD.

Functional and structural brain correlates of theory of mind and empathy deficits in schizophrenia

BACKGROUND Patients affected by schizophrenia show deficits in social cognition, with abnormal performance on tasks targeting theory of mind (ToM) and empathy (Emp). Brain imaging studies suggested that ToM and Emp depend on the activation of brain networks mainly localized at the superior temporal lobe and temporo-parietal junction. METHODS Participants included 24 schizophrenia patients and 20 control subjects. We used brain blood oxygen level dependent fMRI to study the neural responses to tasks targeting ToM and Emp. We then studied voxel-based morphometry of grey matter in areas where diagnosis influenced functional activation to both tasks. Outcomes were analyzed in the context of the general linear model, with global grey matter volume as nuisance covariate for structural MRI. RESULTS Patients showed worse performance on both tasks. We found significant effects of diagnosis on neural responses to the tasks in a wide cluster in right posterior superior temporal lobe (encompassing BA 22-42), in smaller clusters in left temporo-parietal junction and temporal pole (BA 38 and 39), and in a white matter region adjacent to medial prefrontal cortex (BA 10). A pattern of double dissociation of the effects of diagnosis and task on neural responses emerged. Among these areas, grey matter volume was found to be reduced in right superior temporal lobe regions of patients. CONCLUSIONS Functional and structural abnormalities were observed in areas affected by the schizophrenic process early in the illness course, and known to be crucial for social cognition, suggesting a biological basis for social cognition deficits in schizophrenia.

Combined analysis of 635 patients confirms an age-related association of the serotonin 2A receptor gene with tardive dyskinesia and specificity for the non-orofacial subtype

Tardive dyskinesia (TD) is an important limiting factor in the use of typical antipsychotic drugs. Genetic variability in the serotonin 2A (5-HT(2A)) receptor may influence risk for TD but the results of prior studies are not confirmatory. The objective of this study was to determine association of T102C and His452Tyr polymorphisms in the 5-HT(2A) receptor gene (HTR(2A)) with TD in a large, multicentre patient sample. The design employed case-control analysis controlling for possible confounders using pooled, original data from published and available unpublished samples and employing logistic regression, analysis of variance and meta-analysis. The study sample consisted of 635 patients with schizophrenia or schizoaffective disorder (256 with TD and 379 without TD) drawn from five research centres, divided into six groups based on population origin. The main outcome measure was association of a categorical diagnosis of TD based on the Research Diagnostic Criteria for TD with HTR(2A) T102C and His452Tyr genotypes and haplotypes. The findings indicate significant association of TD with HTR(2A) T102C genotype (p=0.002) over and above the effect of population group, also when controlling for age and gender (p=0.0008), but not with His452Tyr genotype. The T102C genotype was significantly associated with TD in older (>median age 47 yr, p=0.002) but not younger patients and in patients with non-orofacial (limb-truncal) (p=0.001) but not orofacial TD. By meta-analysis the Mantel-Haenszel (M-H) pooled odds ratio (OR) across all the available data was 1.64. A T102C-His452Tyr haplotype was significantly associated with TD (p=0.0008). These findings confirm that genetic variability in HTR(2A) contributes a small but significant degree of risk for the expression of TD, particularly in older patients and specifically for the non-orofacial (limb-truncal) type. Together with other genetic variants associated with TD the findings could be used to assess risk in patients who are candidates for treatment with typical antipsychotic medications.

The Brief Assessment of Cognition in Schizophrenia. Normative data for the Italian population

ObjectiveTo provide normative values for the Italian population for the Brief Assessment of Cognition in Schizophrenia (BACS), a recent brief neuropsychological instrument for the assessment of cognition in patients with schizophrenia.ParticipantsData were collected from 204 healthy adult Italian subjects, stratified by gender, education and age.Measurements and resultsTests included in the BACS are the following: list learning, digit sequencing, verbal fluency, token motor task, symbol-coding and Tower of London. Normative values were established using the Equivalent Scores method in order to enable comparison with other neuropsychological tasks commonly used in the assessment of the Italian population. Performance on the BACS was influenced by the commonest demographic variables such as age and education.ConclusionsThe availability of normative data for the Italian population will increase the usefulness of this test for both clinical and experimental purposes.SommarioNon esistono ad oggi batterie specifiche brevi e facilmente fruibili in lingua italiana per la valutazione del deficit cognitivo dei pazienti con schizofrenia. Lo scopo di questo studio è di tradurre e tarare sulla popolazione italiana la batteria BACS (Brief Assessement of Cognition in Schizophrenia), un breve strumento di screening creato per indagare in modo specifico gli ambiti cognitivi riconosciuti come quelli con le maggiori disfunzioni e correlati ai sintomi della schizofrenia (memoria verbale, velocità e coordinazione psico-motoria, attenzione, funzioni esecutive e fluenza verbale) e che ha mostrato nella validazione in lingua americana una buona correlazione con batterie neuropsicologiche standard e una buona affidabilità testretest. Il campione è costituito da 204 soggetti italiani stratificati per sesso, età e scolarità. I test inclusi nella BACS sono i seguenti: memoria di lista di parole, riordinamento di cifre, fluenza verbale, compito motorio dei gettoni, associazione simboli-numeri e Torre di Londra. I dati normativi sono stati calcolati con il metodo statistico dei Punteggi Equivalenti, con l’obiettivo di rendere possibile il confronto con altri test neuropsicologici usati comunemente in lingua italiana. Le prestazioni alla BACS sono risultate influenzate da variabili demografiche come età e scolarità, confermando i dati presenti in letteratura. La disponibilità di dati normativi per la popolazione italiana ha la potenzialità di aumentare l’utilità di questo test per scopi sia clinici che di ricerca.

Computer-aided neurocognitive remediation as an enhancing strategy for schizophrenia rehabilitation

Cognitive dysfunction is a chronically disabling feature of schizophrenia, associated with limits in obtaining rehabilitation improvements. The purpose of this study is to assess the effectiveness of intensive computer-aided cognitive remediation treatment (CRT) added to a standard rehabilitation treatment (SRT), in enhancing neuropsychological performances and daily functioning in patients with schizophrenia. A 12-week, randomized, controlled, single-blind trial of neurocognitive remediation was carried out on 86 patients with clinically stabilized DSM-IV schizophrenia. Patients were assessed on cognitive and daily functioning before and after either CRT or placebo training that had been added to their SRT. After 3 months the repeated measure ANOVA showed a significant time x treatment interaction for executive function and attention performances and in daily functioning assessment in favour of patients in the SRT+CRT treatment. Results confirmed that cognitive remediation added to the SRT of schizophrenia enhanced its neuropsychological effects and increased the effects of a long-term rehabilitation programme in terms of functional outcomes.

Influence of catechol-O-methyltransferase Val158Met polymorphism on neuropsychological and functional outcomes of classical rehabilitation and cognitive remediation in schizophrenia.

Neurocognitive deficits are recognized as core features of schizophrenia and have a great impact on functional outcome. Recent reports have suggested that a functional polymorphism, Val158Met, of the catechol-O-methyltransferase (COMT) gene, partially influences cognitive performances (mainly cognitive flexibility and working memory) both in schizophrenic patients and in healthy controls, probably by modulating prefrontal dopamine function. While previous studies focused on single evaluation of cognitive functioning, we aimed to analyse the additive effect of COMT genotype and cognitive exercise on dynamic modulation of cognitive performances. We analysed the COMT Val158Met polymorphism in 50 patients with chronic schizophrenia randomly allocated to two treatment conditions for 3 months: standard rehabilitation treatment (SRT) alone and SRT plus specific cognitive exercise of impaired functions. We then divided our sample in four subgroups on the basis of genotype (Val/Val versus Met carriers) and treatment (placebo versus active). We assessed patients with a neuropsychological battery, the Positive and Negative Symptoms Scale (PANSS) and the Quality of Life Scale (QLS) at enrolment, after 3 months of therapy and after further 3 months of follow-up. We found significantly greater improvement of cognitive flexibility performance and QLS total score for Met carriers on active treatment in comparison to Val/Val on placebo. The findings support the hypothesis that COMT polymorphism influences individual capacity to recover from cognitive deficit through rehabilitation therapy after a wider intervention also including deficit-specific cognitive exercise as a potentiating tool.

Obsessive compulsive disorder among idiopathic focal dystonia patients: an epidemiological and family study

BACKGROUND A disturbed function of striato-thalamo-cortical circuitry is hypothesized to underlie idiopathic focal dystonia (IFD) and obsessive compulsive disorder (OCD), two severe and disabling neurologic and psychiatric disorders. Previous studies on small samples showed either higher obsessionality scores or higher frequency of OCD in dystonic patients than in normal control subjects. The aim of this study was to evaluate the frequency and familial loading of OCD in a population of patients with IFD. METHODS We evaluated OCD diagnosis and family history in 76 patients affected by IFD. RESULTS Of our subjects 19.7% satisfied DSM-IV criteria for OCD diagnosis and had a family morbidity risk for OCD of 13.8%, significantly higher than that found in the general population. CONCLUSIONS Our results support the hypothesis of a common pathologic background for OCD and IFD, at least in a subgroup of IFD, indicating basal ganglia dysfunction.

Olanzapine-induced neutropenia after clozapine-induced neutropenia.

Olanzapine is a new antipsychotic drug, pharmacodynamically similar to clozapine, but putatively devoid of haematological iatrogenicity. We report a case of relapse of previously clozapine-induced neutropenia after olanzapine treatment.