Seeking Optimal Region-Of-Interest (ROI) Single-Value Summary Measures for fMRI Studies in Imaging Genetics.

A data-driven hypothesis-free genome-wide association (GWA) approach in imaging genetics studies allows screening the entire genome to discover novel genes that modulate brain structure, chemistry, and function. However, a whole brain voxel-wise analysis approach in such genome-wide based imaging genetic studies can be computationally intense and also likely has low statistical power since a stringent multiple comparisons correction is needed for searching over the entire genome and brain. In imaging genetics with functional magnetic resonance imaging (fMRI) phenotypes, since many experimental paradigms activate focal regions that can be pre-specified based on a priori knowledge, reducing the voxel-wise search to single-value summary measures within a priori ROIs could prove efficient and promising. The goal of this investigation is to evaluate the sensitivity and reliability of different single-value ROI summary measures and provide guidance in future work. Four different fMRI databases were tested and comparisons across different groups (patients with schizophrenia, their siblings, vs. normal control subjects; across genotype groups) were conducted. Our results show that four of these measures, particularly those that represent values from the top most-activated voxels within an ROI are more powerful at reliably detecting group differences and generating greater effect sizes than the others.

Altered hippocampal-parahippocampal function during stimulus encoding: a potential indicator of genetic liability for schizophrenia.

IMPORTANCE: Declarative memory-the ability to learn, store, and retrieve information-has been consistently reported to be altered in schizophrenia, and hippocampal-parahippocampal dysfunction has been implicated in this deficit. To elucidate the possible role of genetic risk factors in such findings, it is necessary to study healthy relatives of patients with schizophrenia who carry risk-associated genes but not the confounding factors related to the disorder. OBJECTIVE: To investigate whether altered brain responses, particularly in the hippocampus and parahippocampus, during the encoding phase of a simple declarative memory task are also observed in unaffected siblings who are at increased genetic risk for schizophrenia. DESIGN, SETTING, AND PARTICIPANTS: Functional magnetic resonance imaging was used with a simple visual declarative memory paradigm to test for differences in neural activation across normal control participants, patients with schizophrenia, and their healthy siblings. This study was conducted at a research center and included a total of 308 participants (181 normal control participants, 65 healthy siblings, and 62 patients with schizophrenia); all participants were white of European ancestry. MAIN OUTCOMES AND MEASURES: All participants completed a declarative memory task involving incidental encoding of neutral visual scenes interleaved with crosshair fixation while undergoing functional magnetic resonance imaging. Differences in hippocampus and parahippocampus activation and coupling across groups and correlations with accuracy were analyzed. Analyses were repeated in pairwise-matched samples. RESULTS: Both patients with schizophrenia and their healthy siblings showed reduced parahippocampal activation (bilaterally) and hippocampal-parietal (BA 40) coupling during the encoding of novel stimuli when compared with normal control participants. There was a significant positive correlation between parahippocampal activation during encoding and the visual-memory score. CONCLUSIONS AND RELEVANCE: These results suggest that altered hippocampal-parahippocampal function during encoding is an intermediate biologic phenotype related to increased genetic risk for schizophrenia. Therefore, measuring hippocampal-parahippocampal function with neuroimaging represents a potentially useful approach to understanding genetic mechanisms that confer risk for schizophrenia.

Effects of neuregulin 3 genotype on human prefrontal cortex physiology.

The neuregulin 3 gene (NRG3) plays pleiotropic roles in neurodevelopment and is a putative susceptibility locus for schizophrenia. Specifically, the T allele of NRG3 rs10748842 has been associated with illness risk, altered cognitive function, and the expression of a novel splice isoform in prefrontal cortex (PFC), but the neural system effects are unexplored. Here, we report an association between rs10748842 and PFC physiology as measured by functional magnetic resonance imaging of human working memory performance, where a convincing link between increased genetic risk for schizophrenia and increased activation in some PFC areas has been established. In 410 control individuals (195 males, 215 females), we detected a highly significant effect of NRG3 genotype manifesting as an unanticipated increase in ventrolateral PFC activation in nonrisk-associated C allele carriers. An additional analysis including 78 patients with schizophrenia spectrum disorders (64 males, 14 females) and 123 unaffected siblings (53 males, 70 females) revealed a whole-brain significant genotype by group interaction in right dorsolateral PFC (DLPFC), manifesting as a relative activation increase in healthy controls and siblings (C > T/T) and as a hypoactivation in patients (T/T > C). These observed genotype-dependent effects in PFC were not explained by task performance and did not conform to established locales of prefrontal inefficiency linked to genetic risk for schizophrenia. Our data indicate a complex modulation of brain physiology by rs10748842, which does not fit the simple inefficiency model of risk association in DLPFC and suggests that other neurobiological mechanisms are involved.

Effect of tolcapone on brain activity during a variable attentional control task: a double-blind, placebo-controlled, counter-balanced trial in healthy volunteers.

BACKGROUND: Attention is the capacity to flexibly orient behaviors and thoughts towards a goal by selecting and integrating relevant contextual information. The dorsal cingulate (dCC) and prefrontal (PFC) cortices play critical roles in attention. Evidence indicates that catechol-O-methyltransferase (COMT) modulates dopaminergic tone in the PFC and dCC. OBJECTIVE: In this study, we explored the effect of tolcapone, a CNS penetrant COMT inhibitor that increases cortical dopamine levels, on brain activity during a Variable Attentional Control (VAC) task. STUDY DESIGN: We performed a double-blinded, placebo-controlled, counter-balanced trial with tolcapone (Tasmar, tablets, 100 mg three times a day for 1 day and then 200 mg three times a day for 6 days; ClinicalTrials.gov identifier: NCT00044083). SETTING: The study was conducted in the Clinical Center of the National Institute of Mental Health from 2005 to 2009. PATIENTS: Twenty healthy volunteers (11 males; mean age = 32.7 years) with good imaging and performance data on both arms of the study were investigated. INTERVENTION: Participants underwent 3T blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) while performing the event-related VAC task, which varies attention over three levels of load: LOW, INT (intermediate), and HIGH. MAIN OUTCOME MEASURE: Changes in behavioral data and individual contrast images were analyzed using ANOVA with drug and task load as co-factors. RESULTS: There was a significant main effect of increasing task load, with resulting decreased accuracy and increased reaction time. While there was no significant effect of tolcapone on these behavioral measures, the neuroimaging data showed a significant effect on load-related changes in dCC, with significantly lower dCC activation on tolcapone compared with placebo. Further, neural activity in dCC correlated positively with COMT enzyme activity (i.e., lower COMT activity and presumably more dopamine was associated with lower activation in dCC, i.e., more efficient information processing). CONCLUSION: Our results show that pharmacological reduction of COMT activity modulates the engagement of attentional mechanisms, selectively enhancing the efficiency of dCC processing in healthy volunteers, reflected as decreased activity for the same level of performance.

Altered cerebral response during cognitive control: a potential indicator of genetic liability for schizophrenia.

Aberrant activity in brain regions underlying various aspects of executive cognition has been reported in patients with schizophrenia and in their healthy relatives, suggesting an association with genetic liability. The aim of this study was to investigate brain responses to selective aspects of cognitive control in unaffected siblings who are at increased genetic risk of schizophrenia. Altogether, 65 non-affected siblings, 70 patients with schizophrenia spectrum disorders, and 235 normal controls participated in this study. Blood-oxygen-level-dependent functional magnetic resonance imaging was conducted while participants performed a cognitive control task ('flanker task') to identify brain activity and connectivity associated with response inhibition and conflict monitoring, and suppression. Behaviorally, similar to patients with schizophrenia, siblings were less accurate when inhibiting prepotent responses relative to normal controls. During response inhibition, again similar to patients with schizophrenia, siblings showed decreased activity in the anterior cingulate (ACC), along with increased functional coupling with the dorsolateral prefrontal cortex (PFC) when compared to normal controls. Our findings show altered ACC activity and PFC connectivity in unaffected siblings and patients with schizophrenia during response inhibition. These results suggest that such changes in the neural activity underlying aspects of cognitive control may represent a potential intermediate phenotype for the investigation of the genetic basis of schizophrenia.

Altered cortical network dynamics: a potential intermediate phenotype for schizophrenia and association with ZNF804A.

CONTEXT: Studies have shown patterns of abnormal dorsolateral prefrontal cortex (DLPFC) functional connectivity with other brain areas in schizophrenia and association of these patterns with a putative susceptibility gene (ZNF804A). However, whether these patterns are trait phenomena linked to genetic risk for illness is unclear. OBJECTIVE: To test the hypotheses that altered DLPFC connectivity is (1) a familial, likely heritable feature of genetic risk for schizophrenia, (2) a novel intermediate phenotype independent of altered DLPFC engagement, and (3) selectively modulated by a polymorphism in ZNF804A. DESIGN: Cross-sectional case-control study using blood oxygen level-dependent functional magnetic resonance imaging during a working memory task and genotyping of rs1344706 in ZNF804A. SETTING: Research center. PARTICIPANTS: A total of 402 subjects (153 cognitively normal controls, 171 healthy siblings of patients with schizophrenia, and 78 patients). MAIN OUTCOME MEASURES: Task-independent and task-dependent physiologic coupling between the DLPFC and other brain "target" regions investigated with (1) seeded connectivity and (2) psychophysiological interaction analysis. RESULTS: Siblings and patients showed greater DLPFC "inefficiency" than controls. Abnormal DLPFC functional coupling with the hippocampus and, to a lesser degree, the rest of the prefrontal cortex, was observed in patients and siblings when compared with controls using both connectivity analyses. Prefrontal activation and connectivity measures within siblings did not correlate, implying that they were independent phenomena. The ZNF804A genotype significantly modulated DLPFC coupling with the hippocampus and prefrontal cortex but not DLPFC activity in the control group. Similarly, ZNF804A genotype modulated right DLPFC-hippocampal formation coupling in siblings and patients. CONCLUSIONS: Coupling between the DLPFC and hippocampus is compromised in siblings of patients with schizophrenia and is independent of DLPFC engagement. The selective association with a single-nucleotide polymorphism in ZNF804A suggests that this intermediate phenotype proxies a distinct neural system mechanism related to genetic risk for schizophrenia and the biology of this gene.

Intermediate phenotypes in psychiatric disorders.

The small effect size of most individual risk factors for psychiatric disorders likely reflects biological heterogeneity and diagnostic imprecision, which has encouraged genetic studies of intermediate biological phenotypes that are closer to the molecular effects of risk genes than are the clinical symptoms. Neuroimaging-based intermediate phenotypes have emerged as particularly promising because they map risk associated gene effects onto physiological processes in brain that are altered in patients and in their healthy relatives. Recent evidence using this approach has elucidated discrete, dissociable biological mechanisms of risk genes at the level of neural circuitries, and their related cognitive functions. This approach may greatly contribute to our understanding of the genetics and pathophysiology of psychiatric disorders.

Modulatory effects of modafinil on neural circuits regulating emotion and cognition.

Modafinil differs from other arousal-enhancing agents in chemical structure, neurochemical profile, and behavioral effects. Most functional neuroimaging studies to date examined the effect of modafinil only on information processing underlying executive cognition, but cognitive enhancers in general have been shown to have pronounced effects on emotional behavior, too. We examined the effect of modafinil on neural circuits underlying affective processing and cognitive functions. Healthy volunteers were enrolled in this double-blinded placebo-controlled trial (100 mg/day for 7 days). They underwent BOLD fMRI while performing an emotion information-processing task that activates the amygdala and two prefrontally dependent cognitive tasks-a working memory (WM) task and a variable attentional control (VAC) task. A clinical assessment that included measurement of blood pressure, heart rate, the Hamilton anxiety scale, and the profile of mood state (POMS) questionnaire was also performed on each test day. BOLD fMRI revealed significantly decreased amygdala reactivity to fearful stimuli on modafinil compared with the placebo condition. During executive cognition tasks, a WM task and a VAC task, modafinil reduced BOLD signal in the prefrontal cortex and anterior cingulate. Although not statistically significant, there were trends for reduced anxiety, for decreased fatigue-inertia and increased vigor-activity, as well as decreased anger-hostility on modafinil. Modafinil in low doses has a unique physiologic profile compared with stimulant drugs: it enhances the efficiency of prefrontal cortical cognitive information processing, while dampening reactivity to threatening stimuli in the amygdala, a brain region implicated in anxiety.

Evidence that altered amygdala activity in schizophrenia is related to clinical state and not genetic risk.

OBJECTIVE: Although amygdala dysfunction is reported in schizophrenia, it is unknown whether this deficit represents a heritable phenotype that is related to risk for schizophrenia or whether it is related to disease state. The purpose of the present study was to examine amygdala response to threatening faces among healthy siblings of schizophrenia patients in whom a subtler heritable deficit might be observed. METHOD: Participants were 34 schizophrenia patients, 29 unaffected siblings, and 20 healthy comparison subjects. Blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) was conducted during an implicit facial information processing task. The N-back working memory task, which has been shown to elicit prefrontal cortex abnormalities in unaffected siblings of schizophrenia patients, was employed as a positive experimental control. RESULTS: Schizophrenia patients demonstrated a deficit in amygdala reactivity to negative face stimuli and an alteration, correlated with neuroleptic drug dosage, in the functional coupling between the amygdala and subgenual cingulate. In contrast, unaffected siblings showed a pattern that was not statistically different from that of healthy comparison subjects. During the N-back working memory task, both schizophrenia patients and their unaffected siblings demonstrated a pattern of inefficient prefrontal cortex engagement, which is consistent with earlier evidence that this pattern is related to genetic risk for schizophrenia. CONCLUSIONS: These data suggest that the pathophysiological mechanism underlying the inability of individuals with schizophrenia to normally engage the amygdala in processing fearful and angry facial representations is more likely a phenomenon related to the disease state, specifically to treatment.

Exploring the role of face processing in facial emotion recognition in schizophrenia.

OBJECTIVE: Impairment in emotion perception represents a fundamental feature of schizophrenia with important consequences in social functioning. A fundamental unresolved issue is the relationship between emotion perception and face perception. The aim of the present study was to examine whether facial identity recognition (Identity Discrimination) is a factor predicting facial emotion recognition in the context of the other factors, known as contributing to emotion perception, such as cognitive functions and symptoms. METHODS: We enrolled 58 stable schizophrenic out-patients and 47 healthy subjects. Facial identity recognition and emotion perception were assessed with the Comprehensive Affect Testing System. Different multiple regression models with backward elimination were performed in order to discover the relation of each significant variable with emotion perception. RESULTS: In a regression including the six significant variables (age, positive symptomatology, Identity Discrimination, attentive functions, verbal memory-learning, executive functions) versus emotion processing, only attentive functions (standardised ß = 0.264, p = 0.038) and Identity Discrimination (standardised ß = 0.279, p = 0.029) reached a significant level. Two partial regressions were performed including five variables, one excluding attentive functions and the other excluding Identity Discrimination. When we excluded attentive functions, the only significant variable was Identity Discrimination (standardised ß = 0.278, p = 0.032). When we excluded Identity Discrimination, both verbal memory-learning (standardised ß = 0.261, p = 0.042) and executive functions (standardised ß = 0.253, p = 0.048) were significant. CONCLUSIONS: Our results emphasised the role of face perception and attentional abilities on affect perception in schizophrenia. We additionally found a role of verbal memory-learning and executive functions on emotion perception. The relationship between those above-mentioned variables and emotion processing could have implications for cognitive rehabilitation.

Differentiating allocation of resources and conflict detection within attentional control processing.

Increasing demands for conflict detection and for allocation of attentional resources increase the need for attentional control. While prior evidence suggests that different cortical regions are preferentially engaged by these two attentional processes, the effect of increasing demand for conflict detection and/or allocation of attentional resources has been relatively unexplored. We designed a novel task (the 'variable attentional control'--VAC--task) that varies the demand for attentional control by increasing conflict detection and allocation of attentional resources within the same stimuli. We studied 34 subjects who underwent event-related functional magnetic resonance imaging while performing the VAC task. Increasing demand for attentional control, as reflected by longer reaction time and reduced accuracy, was associated with greater activation in the dorsolateral prefrontal cortex, parietal cortex and dorsal cingulate. Furthermore, an increase in conflict detection was associated with greater dorsal cingulate activity, whereas an increase in demand for allocation of attentional resources implied greater activation in the dorsolateral prefrontal and parietal cortices. In essence, in addition to allowing the exploration of the overall effects of increasing demand for attentional control, our novel task also allowed parsing of the neural components of attentional control into those related to allocation of attentional resources and those related to conflict detection.

Tolcapone improves cognition and cortical information processing in normal human subjects.

Prefrontal cortical dopamine (DA) regulates various executive cognitive functions, including attention and working memory. Efforts to enhance prefrontal-related cognition, which have focused on catecholaminergic stimulant drugs, have been unsatisfactory. Recently, the demonstration that a functional polymorphism in the catecholamine-O-methyltransferase (COMT) gene impacts prefrontal cognition raises the possibility of a novel pharmacological approach for the treatment of prefrontal lobe executive dysfunction. To explore in a proof of concept study the effects of tolcapone, a CNS penetrant specific COMT inhibitor, we performed a randomized, double blind, placebo controlled, and crossover design of this drug in normal subjects stratified by COMT (val158met) genotype. COMT enzyme activity was determined in peripheral blood. Forty-seven normal volunteers with no family history of psychiatric disorders underwent neuropsychological testing and 34 of those subjects underwent physiological measurement of prefrontal information processing assessed by blood oxygen level-dependent functional magnetic resonance imaging (fMRI). We found significant drug effects on measures of executive function and verbal episodic memory and a significant drug by genotype interaction on the latter, such that individuals with val/val genotypes improved, whereas individuals with met/met genotypes worsened on tolcapone. fMRI revealed a significant tolcapone-induced improvement in the efficiency of information processing in prefrontal cortex during a working memory test. This study demonstrates enhancement of prefrontal cortical function in normal human subjects with a nonstimulant drug having COMT inhibitory activity. Our results are consistent with data from animal studies and from computational models of the effects of selective enhancement of DA signaling in the prefrontal cortex.

Neuropsychological correlates of reality distortion in schizophrenic patients.

The present study aims at exploring the relationship between content-related aspects of delusions and hallucinations in schizophrenia and the basic domains of cognition, controlling for the other clinical and demographic variables that could produce bias in the interpretation of the results. Seventy stable schizophrenic patients were evaluated through psychiatric assessment and a neuropsychological battery including tests on attention, memory, perceptual-motor speed and executive functions. We found that the severity of negative symptoms was strongly correlated with poor performance in almost all domains of cognitive functions, while only the attentional deficit was correlated with positive symptoms. The relationships between different cognitive domains and specific types of delusions and hallucinations showed that thought insertion, guilt, grandiose, religious and somatic delusions were associated with impairment in different cognitive functions (verbal and visual memory, attention and executive functions). Voices arguing and tactile hallucinations were correlated to delay-recall memory function. Our results suggest that no specific cognitive pattern is associated with typical-content delusions and hallucinations. On the basis of our findings, cognitive impairments associated with delusions and hallucinations, as measured by our battery, seem not to play a central role in the genesis and the maintenance of these symptoms, suggesting a more complex model of pathogenesis.

Depressive and negative symptoms in schizophrenia: different effects on clinical features.

OBJECTIVE: The primary aim of this study was to investigate whether depressive symptoms were significantly associated with functional outcome measures in a clinically stable group of outpatients with schizophrenia. We also analyzed whether depressive and negative symptoms presented different patterns of predictors. METHOD: Seventy-eight consecutive outpatients meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria for schizophrenia in the stable period were enrolled in this cross-sectional study. Assessment were performed using the Calgary Depression Scale for Schizophrenia, Positive and Negative Syndromes Scale (PANSS), Clinical Global Impression Scale-severity, Social and Occupational Functioning Assessment Scale, Sheehan Disability Scale, and Quality of Life Scale. A neuropsychologic battery including the vocabulary and block design subtests of the Wechsler Adult Intelligence Scale-Revised, Wechsler Memory Scale, Wisconsin Card Sorting Test, and Continuous Performance Test was also administered to the patients. Two multiple regressions were performed testing demographic and clinical factors, rating scales, and cognitive measures as independent variables and Calgary Depression Scale for Schizophrenia and PANSS-negative subscale scores as dependent variables. RESULTS: Four variables were predictors of depressive symptoms in our sample of schizophrenic patients: 2 outcome measures (Sheehan Disability Scale and Quality of Life Scale), gender, and Continuous Performance Test reaction time. Predictors of negative symptoms were the measures of severity of psychopathology (Clinical Global Impression Scale-severity and PANSS-general psychopathology subscale) and the cognitive tests Wechsler Adult Intelligence Scale-Revised block design and Wechsler Memory Scale. CONCLUSION: We found that depressive symptoms in schizophrenia are mainly a function of the level of social adjustment and quality of life, whereas negative symptoms constitute an indicator of severity of schizophrenia. The 2 symptom dimensions showed also distinct cognitive correlates.

Spontaneous electrical activity and dendritic spine size in mature cerebellar Purkinje cells.

Previous experiments have shown that in the mature cerebellum both blocking of spontaneous electrical activity and destruction of the climbing fibres by a lesion of the inferior olive have a similar profound effect on the spine distribution on the proximal dendrites of the Purkinje cells. Many new spines develop that are largely innervated by parallel fibers. Here we show that blocking electrical activity leads to a significant decrease in size of the spines on the branchlets. We have also compared the size of the spines of the proximal dendritic domain that appear during activity block and after an inferior olive lesion. In this region also, the spines in the absence of activity are significantly smaller. In the proximal dendritic domain, the new spines that develop in the absence of activity are innervated by parallel fibers and are not significantly different in size from those of the branchlets, although they are shorter. Thus, the spontaneous activity of the cerebellar cortex is necessary not only to maintain the physiological spine distribution profile in the Purkinje cell dendritic tree, but also acts as a signal that prevents spines from shrinking.

Relationships of age at onset with clinical features and cognitive functions in a sample of schizophrenia patients.

BACKGROUND: A number of studies investigated the relationships of age at onset with clinical presentation and cognitive performance of schizophrenic patients. The aim of the present study was to assess demographic and clinical characteristics; psychopathologic, social functioning, and quality-of-life ratings; and neuropsychological measures in a sample of patients with stabilized schizophrenia and to identify which factors independently contributed to a multiple regression model with age at onset as the dependent variable. METHOD: Ninety-six consecutive outpatients with schizophrenia (DSM-IV-TR criteria) were included in the study. Assessment instruments were as follows: a semistructured interview, the Clinical Global Impressions scale, the Comprehensive Psychopathological Rating Scale, and the Positive and Negative Syndrome Scale (PANSS) for psycho-pathology of schizophrenia; the Calgary Depression Scale for Schizophrenia (CDSS) for depression; the Social and Occupational Functioning Assessment Scale and the Sheehan Disability Scale for social functioning; the Quality of Life Scale; and a neuro-psychological battery including the Wisconsin Card Sorting Test (WCST) and the Continuous Performance Test. Two models of multiple regression were tested: the first included clinical features and psychopathologic, social functioning, and quality-of-life scales; the second also considered neuro-psychological variables. Data were collected from October 2001 to November 2002. RESULTS: The first multiple regression showed that age at onset was significantly related to scores on the PANSS subscale for negative symptoms (p =.042) and the CDSS (p =.041); the second regression found a relation of age at onset with PANSS score for negative symptoms (p =.002) and 2 neuropsychological measures, number of preservative errors on the WCST and Continuous Performance Test reaction time (p =.0005 for both). CONCLUSION: Our data indicate that, when results of neuropsychological tests are considered, early age at onset of schizophrenia is associated with severity of negative symptoms and compromised cognitive measures of executive functioning and sustained attention.

Predictors of psychiatric disorders in liver transplantation candidates: logistic regression models.

This study has two goals. The first goal is to assess the prevalence of psychiatric disorders in orthotopic liver transplantation (OLT) candidates by means of standardized procedures because there has been little research concerning psychiatric problems of potential OLT candidates using standardized instruments. The second goal focuses on identifying predictors of these psychiatric disorders. One hundred sixty-five elective OLT candidates were assessed by our unit. Psychiatric diagnoses were based on the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Patients also were assessed using the Hamilton Depression Rating Scale (HDRS) and the Spielberger Anxiety Index, State and Trait forms (STAI-X1 and STAI-X2). Severity of cirrhosis was assessed by applying Child-Pugh score criteria. Chi-squared and general linear model analysis of variance were used to test the univariate association between patient characteristics and both clinical psychiatric diagnoses and severity of psychiatric diseases. Variables with P less than.10 in univariate analyses were included in multiple regression models. Forty-three percent of patients presented at least one psychiatric diagnosis. Child-Pugh score and previous psychiatric diagnoses were independent significant predictors of depressive disorders. Severity of psychiatric symptoms measured by psychometric scales (HDRS, STAI-X1, and STAI-X2) was associated with Child-Pugh score in the multiple regression model. Our data suggest a high rate of psychiatric disorders, particularly adjustment disorders, in our sample of OLT candidates. Severity of liver disease emerges as the most important variable in predicting severity of psychiatric disorders in these patients.

A comparison of paroxetine versus paroxetine plus amisulpride in the treatment of dysthymic disorder: efficacy and psychosocial outcomes.

Dysthymic disorder is a chronic depressive condition with considerable psychosocial impairment. Even if DD patients respond to various antidepressant medications, there has been little systematic study on antidepressant-refractory DD. Only a few trials have evaluated the effects of treatment on psychosocial functioning of dysthymic patients. In this 3-month, open-label study, 60 outpatients with DSM-IV criteria for dysthymic disorder who failed to respond to 3-month treatment with paroxetine 20 mg/day were randomly assigned to treatment with paroxetine 40 mg/day or paroxetine 20 mg/day plus amisulpride 50 mg/day. The effects of the two treatments were assessed for both mood symptoms (21-item Hamilton Rating Scale for Depression, Montgomery-Asberg Depression Rating Scale, Clinical Global Impression, severity and improvement) and psychosocial outcomes (DSM-IV Global Assessment of Functioning, Social Adaptation Self-evaluation Scale). Analysis of variance on all rating scales showed that both treatments were effective over this observation period. Response and remission rates did not differ in the treatment groups. A significantly greater psychosocial improvement was observed in the group receiving combined treatment compared with patients receiving paroxetine alone. Both treatments appeared to be effective in our sample of dysthymic subjects. Combined treatment with paroxetine and amisulpride resulted in a better outcome in terms of social functioning.