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1.  Lithium and GSK3-β Promoter Gene Variants Influence White Matter Microstructure in Bipolar Disorder 
Neuropsychopharmacology  2012;38(2):313-327.
Lithium is the mainstay for the treatment of bipolar disorder (BD) and inhibits glycogen synthase kinase 3-β (GSK3-β). The less active GSK3-β promoter gene variants have been associated with less detrimental clinical features of BD. GSK3-β gene variants and lithium can influence brain gray matter structure in psychiatric conditions. Diffusion tensor imaging (DTI) measures of white matter (WM) integrity showed widespred disruption of WM structure in BD. In a sample of 70 patients affected by a major depressive episode in course of BD, we investigated the effect of ongoing long-term lithium treatment and GSK3-β promoter rs334558 polymorphism on WM microstructure, using DTI and tract-based spatial statistics with threshold-free cluster enhancement. We report that the less active GSK3-β rs334558*C gene-promoter variants, and the long-term administration of the GSK3-β inhibitor lithium, were associated with increases of DTI measures of axial diffusivity (AD) in several WM fiber tracts, including corpus callosum, forceps major, anterior and posterior cingulum bundle (bilaterally including its hippocampal part), left superior and inferior longitudinal fasciculus, left inferior fronto-occipital fasciculus, left posterior thalamic radiation, bilateral superior and posterior corona radiata, and bilateral corticospinal tract. AD reflects the integrity of axons and myelin sheaths. We suggest that GSK3-β inhibition and lithium could counteract the detrimental influences of BD on WM structure, with specific benefits resulting from effects on specific WM tracts contributing to the functional integrity of the brain and involving interhemispheric, limbic, and large frontal, parietal, and fronto-occipital connections.
PMCID: PMC3527112  PMID: 22990942
GSK3-β; lithium; bipolar disorder; white matter; cingulum bundle; Depression, Unipolar; Bipolar, Diffusion Tensor Imaging, Imaging, Clinical or Preclinical, Neurodegeneration; Neuroprotection, Pharmacogenetics; Pharmacogenomics, White Matter
2.  Different Neural Responses to a Moral Valence Decision Task in Unipolar and Bipolar Depression 
ISRN Psychiatry  2013;2013:568617.
Objectives. Patients affected by bipolar disorder (BP) and major depressive disorder (UP) share the susceptibility to experience depression and differ in their susceptibility to mania, but clinical studies suggest that the biological substrates of the two disorders could influence the apparently similar depressive phases. The few brain imaging studies available described different brain metabolic and neural correlates of UP and BP. Methods. We studied the BOLD neural response to a moral valence decision task targeting the depressive biases in information processing in 36 subjects (14 BP, 11 UP, and 11 controls). Results. Main differences between UP and controls and between UP and BP were detected in left ventrolateral prefrontal cortex (PFC, BA 47). Neural responses of BP patients differed from those of control subjects in multiple brain areas, including anterior cingulate cortex (ACC) and medial PFC, bilateral dorsolateral PFC, temporal cortex and insula, and parietal and occipital cortex. Conclusions. Our results are in agreement with hypotheses of dysfunctions in corticolimbic circuitries regulating affects and emotions in mood disorders and suggest that specific abnormalities, particularly in ventrolateral PFC, are not the same in UP and BP depression.
PMCID: PMC3877629  PMID: 24455401
3.  Long-term remission in schizophrenia and schizoaffective disorder: results from the risperidone long-acting injectable versus quetiapine relapse prevention trial (ConstaTRE) 
The objective of this study was to report the long-term remission results from the ConstaTRE relapse prevention trial, in which clinically stable adults with schizophrenia or schizoaffective disorder treated with oral risperidone, olanzapine, or oral conventional antipsychotics were randomized to risperidone long-acting injectable (RLAI) or oral quetiapine, dosed according to package-insert recommendations.
In the ConstaTRE trial, efficacy and tolerability were recorded for up to 24 months. This post hoc analysis presents remission data, defined, according to the Schizophrenia Working Group criteria, as achieving and maintaining eight core symptoms of schizophrenia that are mild or less over 6 months. Additional secondary outcome measures are also presented.
A total of 710 patients were randomized to RLAI (n = 355) or quetiapine (n = 355). Mean mode ± standard deviation (SD) drug doses were RLAI 33 ± 10 mg every 2 weeks and quetiapine 413 ± 159 mg daily. Full remission was achieved by 51.1% of patients with RLAI and 39.3% with quetiapine (p = 0.003). Mean ± SD of full remission durations were not significantly different with RLAI (540 ± 181 days) and quetiapine (508 ± 188 days). Overall tolerability was similar between treatment groups.
Among stable patients with schizophrenia or schizoaffective disorder, remission was more likely after switching to RLAI than quetiapine.
PMCID: PMC3805434  PMID: 24167692
antipsychotics; long-acting injectable risperidone; quetiapine; remission; schizophrenia
4.  The Reality Monitoring Deficit as a Common Neuropsychological Correlate of Schizophrenic and Affective Psychosis 
Behavioral Sciences  2013;3(2):244-252.
For many decades, Neuropsychological functioning has been a key point in the study of psychotic disorders. The main aim of these studies is to give a description of the neurocognitive “profile” of schizophrenia, with only little attention being paid to the common and discriminating features of different psychotic disorders. Recent studies support the hypothesis that patients affected by psychiatric disorders with psychotic symptoms have specific abnormalities of reality testing of ongoing perception, which become evident with source monitoring task. Ninety-eight patients and 50 controls were studied. Patients were divided by diagnosis and previous history of psychotic features and were administered Source Monitoring Task to test reality testing of ongoing perception. Frequencies of correct and false attributions were recorded. To obtain measures of observer sensitivity and response biases, a signal detection analysis was performed. Aims: Studying neuropsychological correlate of psychosis in euthymic mood disordered patients and patients with schizophrenia with or without delusions. Results: Patients with psychotic features use more lax criteria in evaluating self-generated, but not perceived stimuli compared to patients without psychotic features. Conclusions: Our findings support the hypothesis of selective biases in reality monitoring as neuropsychological correlates of psychosis.
PMCID: PMC4217621  PMID: 25379237
reality monitoring; neuropsychology; psychosis; schizophrenia; affective disorder
6.  Seasonality and Sleep: A Clinical Study on Euthymic Mood Disorder Patients 
Background. Research on mood disorders has progressively focused on the study of seasons and on the mood in association with them during depressive or manic episodes yet few studies have focused on the seasonal fluctuation that characterizes the patient's clinical course both during an illness episode and during euthymic periods. Methods. 113 euthymic outpatients 46 affected by major recurrent depression and 67 affected by bipolar disorder were recruited. We evaluated the impact of clinical “rhythmical” factors: seasonality, sleep disturbance, and chronotype. Patients completed the SPAQ+ questionnaire, the MEQ questionnaire, and the medical outcomes study (MOS) sleep scale. We used t-test analyses to compare differences of clinical “rhythmical” and sociodemographic variables and of differences in the assessment scales among the diagnostic groups. Results. Patients reporting a family history for mood disorders have higher fluctuations throughout seasons. Sleep disturbance is more problematic in unipolars when compared to bipolars. Conclusions. Sleep, light, and seasonality seem to be three interconnected features that lie at the basis of chronobiology that, when altered, have an important effect both on the psychopathology and on the treatment of mood disorders.
PMCID: PMC3235681  PMID: 22203895
7.  Relapse Prevention in Schizophrenia and Schizoaffective Disorder with Risperidone Long-Acting Injectable vs Quetiapine: Results of a Long-Term, Open-Label, Randomized Clinical Trial 
Neuropsychopharmacology  2010;35(12):2367-2377.
Chronic management of schizophrenia and schizoaffective disorders is frequently complicated by symptomatic relapse. An open-label, randomized, active-controlled, 2-year trial evaluated 710 patients with schizophrenia or related disorders who were switched from stable treatment with oral risperidone, olanzapine, or conventional neuroleptics to risperidone long-acting injectable (RLAI) or oral quetiapine. Primary effectiveness evaluation was time-to-relapse. Safety evaluations included adverse events (AEs) reported for the duration of the study, Extrapyramidal Symptom Rating Scale (ESRS), clinical laboratory tests, and vital signs. A total of 666 patients (n=329 RLAI, n=337 quetiapine) were evaluable for effectiveness measures. Baseline demographics were similar between treatment groups. Kaplan–Meier estimate of time-to-relapse was significantly longer with RLAI (p<0.0001). Relapse occurred in 16.5% of patients with RLAI and 31.3% with quetiapine. RLAI and quetiapine were both safe and well tolerated. Weight gain affected 7% of patients with RLAI and 6% with quetiapine, with mean end point increases of 1.25±6.61 and 0±6.55 kg, respectively. There were no significant between-group differences in weight gain. ESRS total scores decreased similarly after randomization to either RLAI or quetiapine. Extrapyramidal AEs occurred in 10% of patients with RLAI and 6% with quetiapine. Treatment-emergent potentially prolactin-related AEs were reported in 15 (5%) patients with RLAI and 5 (2%) patients with quetiapine; hyperprolactinemia was reported in 43 (13.1%) patients with RLAI and 5 (1.5%) patients with quetiapine. Somnolence occurred in 2% of patients with RLAI and 11% with quetiapine. To our knowledge, this is the first report of a randomized clinical trial directly comparing relapse prevention with a second-generation long-acting injectable antipsychotic and oral therapy. Time-to-relapse in stable patients with schizophrenia or schizoaffective disorder was significantly longer in patients randomized to RLAI compared with those randomized to oral quetiapine. Both antipsychotics were generally well tolerated.
PMCID: PMC3055334  PMID: 20686456
risperidone; quetiapine; relapse prevention; schizophrenia; long-acting injectable; schizoaffective disorder; psychiatry & behavioral sciences; biological psychiatry; clinical pharmacology/clinical trials; schizophrenia/antipsychotics; risperidone; quetiapine; relapse prevention; long-acting injectable
8.  The effect of verbalization strategy on wisconsin card sorting test performance in schizophrenic patients receiving classical or atypical antipsychotics 
BMC Psychiatry  2006;6:3.
A number of reports showed en encouraging remediation in some patients' executive deficits thanks to the use of 'information processing strategies'. Moreover the impact of antipsychotics on cognitive functions of the schizophrenics is an important issue, especially if an integrated psychosocial treatment is needed.
The aim of this paper is to evaluate different executive performance and response to verbalization, a strategy of the Wisconsin Card Sorting Test (WCST) remediation, in subjects on classical vs atypical antipsychotic (AP) treatment.
Sixty-three schizophrenic subjects undertook the WCST under standard and modified (verbalization) administration. Subjects were stratified by the kind of WCST response (i.e. good, poor and remediable) and AP treatment (i.e. atypical vs. classical).
Subjects on atypical APs showed a better performance than those on classical ones. More poor performers who did not remediate were seen in the sample with classical Aps while subjects who remediated the performance were seen in the subgroup with atypical APs only. An increase of perseverative and total errors was seen in poor performers subjects on classical APs.
Subjects on atypicals showed a better cognitive pattern in terms of WCST performance. Since the naturalistic assignment of medication we cannot draw conclusions about its effect on cognitive performance and its interaction with cognitive remediation potential. However the data lead us to hypothesize that subjects with potential room for remediation did so with the atypical APs.
PMCID: PMC1373618  PMID: 16438712
9.  Neural network analysis in pharmacogenetics of mood disorders 
BMC Medical Genetics  2004;5:27.
The increasing number of available genotypes for genetic studies in humans requires more advanced techniques of analysis. We previously reported significant univariate associations between gene polymorphisms and antidepressant response in mood disorders. However the combined analysis of multiple gene polymorphisms and clinical variables requires the use of non linear methods.
In the present study we tested a neural network strategy for a combined analysis of two gene polymorphisms. A Multi Layer Perceptron model showed the best performance and was therefore selected over the other networks. One hundred and twenty one depressed inpatients treated with fluvoxamine in the context of previously reported pharmacogenetic studies were included. The polymorphism in the transcriptional control region upstream of the 5HTT coding sequence (SERTPR) and in the Tryptophan Hydroxylase (TPH) gene were analysed simultaneously.
A multi layer perceptron network composed by 1 hidden layer with 7 nodes was chosen. 77.5 % of responders and 51.2% of non responders were correctly classified (ROC area = 0.731 – empirical p value = 0.0082). Finally, we performed a comparison with traditional techniques. A discriminant function analysis correctly classified 34.1 % of responders and 68.1 % of non responders (F = 8.16 p = 0.0005).
Overall, our findings suggest that neural networks may be a valid technique for the analysis of gene polymorphisms in pharmacogenetic studies. The complex interactions modelled through NN may be eventually applied at the clinical level for the individualized therapy.
PMCID: PMC539307  PMID: 15588300

Results 1-9 (9)