Stefano Barlati

Cognitive Functioning in Prodromal Psychosis: A Meta-analysis

CONTEXT A substantial proportion of people at clinical high risk (HR) of psychosis will develop a psychotic disorder over time. Cognitive deficits may predate the onset of psychosis and may be useful as markers of increased vulnerability to illness. OBJECTIVE To quantitatively examine the cognitive functioning in subjects at HR in the literature to date. DATA SOURCES Electronic databases were searched until January 2011. All studies reporting cognitive performance in HR subjects were retrieved. STUDY SELECTION Nineteen studies met the inclusion criteria, comprising a total of 1188 HR subjects and 1029 controls. DATA EXTRACTION Neurocognitive functioning and social cognition as well as demographic, clinical, and methodological variables were extracted from each publication or obtained directly from its authors. DATA SYNTHESIS Subjects at HR were impaired relative to controls on tests of general intelligence, executive function, verbal and visual memory, verbal fluency, attention and working memory, and social cognition. Processing speed domain was also affected, although the difference was not statistically significant. Later transition to psychosis was associated with even more marked deficits in the verbal fluency and memory domains. The studies included reported relatively homogeneous findings. There was no publication bias and a sensitivity analysis confirmed the robustness of the core results. CONCLUSIONS The HR state for psychosis is associated with significant and widespread impairments in neurocognitive functioning and social cognition. Subsequent transition to psychosis is particularly associated with deficits in verbal fluency and memory functioning.

Effectiveness of different modalities of cognitive remediation on symptomatological, neuropsychological, and functional outcome domains in schizophrenia: a prospective study in a real-world setting.

OBJECTIVES The efficacy of cognitive remediation interventions in schizophrenia has been demonstrated in several experimental studies. However, the effectiveness of such treatments in the usual setting of care of schizophrenia and a direct comparison of different modalities of interventions have not been systematically analyzed. The aim of the study was to assess the effectiveness of the cognitive subprograms of Integrated Psychological Therapy (IPT-cog) and of a computer-assisted cognitive remediation (CACR) method on symptomatological, neuropsychological and functional outcome measures in schizophrenia. METHODS Ninety patients with schizophrenia were assigned to IPT-cog, CACR or usual rehabilitative interventions (REHAB) in a naturalistic setting of care. Clinical, neuropsychological, and functional outcome variables were assessed at baseline and after 24 weeks of treatment. RESULTS Both the IPT-cog and CACR groups improved more than the comparison group with respect to all outcome variables. The more responsive cognitive domains were speed of processing and working memory. The effectiveness of the 2 remediation methods on the outcome dimensions considered was comparable. However, IPT-cog, but not CACR, was more effective than REHAB on speed of processing, and the CACR group had better outcome than both the REHAB and the IPT-cog groups when the Health of the Nation Outcome Scale was considered. Few correlations between neurocognitive and functional outcome changes were found. CONCLUSIONS The study demonstrates the effectiveness, although nongeneralized, of IPT-cog and CACR in schizophrenia when applied within a psychiatric and psychosocial treatment regimen representative of the usual setting and modality of care, with no evident superiority of any of the methods, and indicates that the changes in functional outcome during treatment are modestly mediated by improvement in specific cognitive domains.

Glutamate AMPA receptor subunit 1 gene (GRIA1) and DSM-IV-TR schizophrenia: A pilot case-control association study in an Italian sample

Glutamatergic dysfunction is one of the major hypotheses for the pathogenesis of schizophrenia. The GRIA1 gene encodes for one (GluR1) of the four (GluR1–4) ionotropic AMPA receptor subunits. GRIA1 is a good candidate gene for susceptibility to schizophrenia since it maps in 5q33, a region where the presence of susceptibility loci has been suggested by independent genome‐wide scans and because its expression has been found to be decreased in the brain of some schizophrenia patients. We present data from a case‐control association study on the Italian population with eight polymorphisms spanning the whole GRIA1 gene. Single‐locus analysis revealed a significantly different allele distribution in cases and in controls of two SNPs (rs707176, 0.41 vs. 0.31, P = 0.009; rs2963944, 0.41 vs. 0.30, P = 0.007), and one microsatellite (rs10631988, allele 9: 0.40 vs. 0.29, P = 0.004). Haplotype analysis showed an increased frequency of a specific haplotype for these markers (C09CC, 0.39 vs. 0.28, P = 0.009). Therefore our data indicate that GRIA1 may be involved in susceptibility to DSM‐IV‐TR schizophrenia.

Cognitive Remediation in Schizophrenia: Current Status and Future Perspectives

Objectives. This study is aimed to review the current scientific literature on cognitive remediation in schizophrenia. In particular, the main structured protocols of cognitive remediation developed for schizophrenia are presented and the main results reported in recent meta-analyses are summarized. Possible benefits of cognitive remediation in the early course of schizophrenia and in subjects at risk for psychosis are also discussed. Methods. Electronic search of the relevant studies which appeared in the PubMed database until April 2013 has been performed and all the meta-analyses and review articles on cognitive remediation in schizophrenia have been also taken into account. Results. Numerous intervention programs have been designed, applied, and evaluated, with the objective of improving cognition and social functioning in schizophrenia. Several quantitative reviews have established that cognitive remediation is effective in reducing cognitive deficits and in improving functional outcome of the disorder. Furthermore, the studies available support the usefulness of cognitive remediation when applied in the early course of schizophrenia and even in subjects at risk of the disease. Conclusions. Cognitive remediation is a promising approach to improve real-world functioning in schizophrenia and should be considered a key strategy for early intervention in the psychoses.

Study on GRIA2, GRIA3 and GRIA4 genes highlights a positive association between schizophrenia and GRIA3 in female patients†‡

Impairment of glutamatergic neurotransmission is one of the major hypotheses proposed to explain the neurobiology of schizophrenia. Therefore, the genes involved in the glutamate neurotransmitter system could be considered potential candidate genes for schizophrenia susceptibility. A systematic study on alpha‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole‐propionic acid (AMPA) receptor genes has been carried out and the results obtained from the analysis on GRIA2, GRIA3 and GRIA4 are reported. No evidence of association with schizophrenia was found for the GRIA2 and GRIA4 genes; strong evidence of association with schizophrenia was found for GRIA3. This X‐linked gene showed a different behavior in the two genders; a positive association with schizophrenia was observed among females but not in males. Female carriers of rs1034428 A allele were found to have a 2.19‐fold higher risk of developing schizophrenia compared to non‐carriers and 3.28‐fold higher risk for developing a non‐paranoid phenotype. The analysis at the haplotype level showed that susceptibility to schizophrenia was associated with the specific haplotype rs989638–rs1034428–rs2227098 CAC (P = 0.0008). We conclude that, of the three AMPA genes analyzed here, only GRIA3 seems to be involved in the pathogenesis of schizophrenia, but only in females.

Brain Structural Effects of Antidepressant Treatment in Major Depression.

Depressive disorder is a very frequent and heterogeneous syndrome. Structural imaging techniques offer a useful tool in the comprehension of neurobiological alterations that concern depressive disorder. Altered brain structures in depressive disorder have been particularly located in the prefrontal cortex (medial prefrontal cortex and orbitofrontal cortex, OFC) and medial temporal cortex areas (hippocampus). These brain areas belong to a structural and functional network related to cognitive and emotional processes putatively implicated in depressive symptoms. These volumetric alterations may also represent biological predictors of response to pharmacological treatment. In this context, major findings of magnetic resonance (MR) imaging, in relation to treatment response in depressive disorder, will here be presented and discussed.

Cognitive Remediation in the Early Course of Schizophrenia: A Critical Review

BACKGROUND The aim of cognitive remediation is to target the cognitive impairments of patients with psychosis, including attentional deficits, memory problems, and limitations in planning and problem solving. It is hoped that by addressing these deficits, patients will be more able to take advantage of other interventions and will be more able to function in social and other domains. Many results in controlled trials of cognitive remediation in adult patients affected by schizophrenia have demonstrated its effectiveness on different cognitive domains and on patients functioning. Some researchers speculate that deficits in cognition are more amenable to remediation during earlier phases of illness than when chronicity has developed. For these reasons cognitive rehabilitation should be a key component of early intervention programs, seeking to produce durable functional changes in the early course of schizophrenia. Although there is strong evidence that cognitive remediation is effective in adult schizophrenia, there is little evidence about its efficacy and long-term generalized effectiveness in the early course of the disease, and its possible application in the prodromal phase of the disease. PURPOSE OF REVIEW The aim of this paper is to review the available literature on cognitive remediation in the prodromal phase and in the early course of schizophrenia. This review summarizes especially findings of cognitive changes induced in the early course or in the prodromal phases of schizophrenia by different remediation methods. Controlled studies of cognitive training are discussed in more detail. CONCLUSION Few studies on the effects of cognitive training programs have been conducted in first episode or in early schizophrenia and only one study has been conducted in the prodromal phase of the disease. Although preliminary positive results have been achieved, more empirical research is needed to confirm the efficacy of cognitive remediation in the early course of schizophrenia, and future studies should address the issue of the usefulness of cognitive remediation in the prodromes of psychosis.

Mitochondrial DNA haplogroups and age at onset of schizophrenia

A number of studies support a possible link between mitochondrial dysfunction and schizophrenia. To test the hypothesis of a direct contribution of mitochondrial DNA (mt‐DNA) in susceptibility to DSM‐IV‐TR‐schizophrenia, we looked for differences in the frequency distribution of the major European haplogroups (hgs) in 142 patients and 190 controls both of Italian origin. A subgroup of patients (N = 37) and healthy counterparts (N = 41) was also analyzed for possible differences in the relative amount of mt‐DNA versus nuclear‐DNA in blood cells. Patients and controls were comparable for hg frequency distribution and the relative levels of mt‐DNA even after stratification by gender and schizophrenia subtype. However, patients harboring the hg J‐T showed an anticipated onset of the disorder. These results indicate that the J‐T hg of mt‐DNA may have a modulator effect on deeper determinants of schizophrenia.

Persistence of effectiveness of cognitive remediation interventions in schizophrenia: A 1-year follow-up study

OBJECTIVES Cognitive remediation interventions are effective in patients with schizophrenia, but the durability of their effects is still under debate. This study aimed to investigate the 1-year persistence of the effectiveness of cognitive remediation. METHODS Patients with schizophrenia treated with cognitive remediation or usual rehabilitation were reassessed with clinical, neuropsychological and functional measures 1year after cognitive remediation. RESULTS At the 1-year follow-up, the advantages of cognitive remediation remained significant for clinical variables and specific cognitive domains. Functional measures showed increasing improvement at follow-up. CONCLUSIONS The study suggests that the effectiveness of cognitive remediation in schizophrenia persists after 1year.

Adult Autism Subthreshold Spectrum (AdAS Spectrum): Validation of a questionnaire investigating subthreshold autism spectrum

AIM Increasing literature has shown the usefulness of a dimensional approach to autism. The present study aimed to determine the psychometric properties of the Adult Autism Subthreshold Spectrum (AdAS Spectrum), a new questionnaire specifically tailored to assess subthreshold forms of autism spectrum disorder (ASD) in adulthood. METHODS 102 adults endorsing at least one DSM-5 symptom criterion for ASD (ASDc), 143 adults diagnosed with a feeding and eating disorder (FED), and 160 subjects with no mental disorders (CTL), were recruited from 7 Italian University Departments of Psychiatry and administered the following: SCID-5, Autism-Spectrum Quotient (AQ), Ritvo Autism and Asperger Diagnostic Scale 14-item version (RAADS-14), and AdAS Spectrum. RESULTS The AdAS Spectrum demonstrated excellent internal consistency for the total score (Kuder-Richardsons coefficient=.964) as well as for five out of seven domains (all coefficients>.80) and sound test-retest reliability (ICC=.976). The total and domain AdAS Spectrum scores showed a moderate to strong (>.50) positive correlation with one another and with the AQ and RAADS-14 total scores. ASDc subjects reported significantly higher AdAS Spectrum total scores than both FED (p<.001) and CTL (p<.001), and significantly higher scores on the Childhood/adolescence, Verbal communication, Empathy, Inflexibility and adherence to routine, and Restricted interests and rumination domains (all p<.001) than FED, while on all domains compared to CTL. CTL displayed significantly lower total and domain scores than FED (all p<.001). A significant effect of gender emerged for the Hyper- and hyporeactivity to sensory input domain, with women showing higher scores than men (p=.003). A Diagnosis* Gender interaction was also found for the Verbal communication (p=.019) and Empathy (p=.023) domains. When splitting the ASDc in subjects with one symptom criterion (ASD1) and those with a ASD, and the FED in subjects with no ASD symptom criteria (FED0) and those with one ASD symptom criterion (FED1), a gradient of severity in AdAS Spectrum scores from CTL subjects to ASD patients, across FED0, ASD1, FED1 was shown. CONCLUSIONS The AdAS Spectrum showed excellent internal consistency and test-retest reliability and strong convergent validity with alternative dimensional measures of ASD. The questionnaire performed differently among the three diagnostic groups and enlightened some significant effects of gender in the expression of autistic traits.