Jose Apud - Academia.edu (original) (raw)

Papers by Jose Apud

Schizophrenia Research, 2010

NeuroRX, 2004

Background: Analyses of categorical repeated measures of clinical data using conventional methods... more Background: Analyses of categorical repeated measures of clinical data using conventional methods can give biased estimates of treatment effects and associated SEs when dropouts are not completely at random (depending on observed clinical outcomes). We test the utility of multiple imputation (MI) analysis in reducing these biases.

Background: Weight gain is one of the major side effects of antipsychotic drugs. The mechanism un... more Background: Weight gain is one of the major side effects of antipsychotic drugs. The mechanism underlying antipsychoticinduced weight gain remains unclear. The great differences between individuals suggest that genetic factors could play a significant role in this process and make some patients more susceptible to weight increase. In recent genome-wide association (GWA) studies variants of FTO and SH2B1 genes have been strongly associated with obesity in general population. The aim of this study was to determine whether weight increase during the first year of antipsychotic treatment was influenced by the rs9939609 single nucleotide polymorphism (SNP) of fat mass and obesity associated (FTO) gene and the rs7498665 of (SH2B adapter protein 1) SH2B1 gene. Methods: We carried out a prospective study on 239 first episode psychotic patients. Weight measurements were obtained prior to starting medication and after one year. Patients were genotyped for rs9939609 using Mass-array iPLEX system and rs7498665 was genotyped using SNPlex multiplex system. Analyses of covariance were carried out to determine the association between weight gain and genotypes. The sample size of our study, based on an additive model, provides 80% power to detect an effect of ≥ 2.8 kg, assuming an α = 0.05 and a MAF≥ 30% (Quanto program). Results: 85% of the patients completed the follow-up at 1 year. Rs9939609 was successfully genotyped in 84.9% and rs7498665 in 93% of the samples. At baseline, patients with the AA risk genotype of the FTO rs9939609 variant had higher body mass index (BMI) than the AT/TT group (24.2 ± 3.8 vs 22.8 ± 3.3; F = 5.744; p = 0.018) as described in previous studies. After one year of antipsychotic treatment the magnitude of weight increase was similar in the three genotype groups. No association was found between rs7498665 and BMI at baseline or weight gain during the first 12 months of antipsychotic therapy.

Neuropsychopharmacology, 2015

Dopamine D2 and serotonin 5-HT2A receptors contribute to modulate prefrontal cortical physiology ... more Dopamine D2 and serotonin 5-HT2A receptors contribute to modulate prefrontal cortical physiology and response to treatment with antipsychotics in schizophrenia. Similarly, functional variation in the genes encoding these receptors is also associated with these phenotypes. In particular, the DRD2 rs1076560 T allele predicts a lower ratio of expression of D2 short/long isoforms, suboptimal working memory processing, and better response to antipsychotic treatment compared with the G allele. Furthermore, the HTR2A T allele is associated with lower 5-HT2A expression, impaired working memory processing, and poorer response to antipsychotics compared with the C allele. Here, we investigated in healthy subjects whether these functional polymorphisms have a combined effect on prefrontal cortical physiology and related cognitive behavior linked to schizophrenia as well as on response to treatment with second-generation antipsychotics in patients with schizophrenia. In a total sample of 620 healthy subjects, we found that subjects with the rs1076560 T and rs6314 T alleles have greater fMRI prefrontal activity during working memory. Similar results were obtained within the attentional domain. Also, the concomitant presence of the rs1076560 T/rs6314 T alleles also predicted lower behavioral accuracy during working memory. Moreover, we found that rs1076560 T carrier/rs6314 CC individuals had better responses to antipsychotic treatment in two independent samples of patients with schizophrenia (n=63 and n=54, respectively), consistent with the previously reported separate effects of these genotypes. These results indicate that DRD2 and HTR2A genetic variants together modulate physiological prefrontal efficiency during working memory and also modulate the response to antipsychotics. Therefore, these results suggest that further exploration is needed to better understand the clinical consequences of these genotype-phenotype relationships.Neuropsychopharmacology advance online publication, 28 January 2015; doi:10.1038/npp.2015.5.

Frontiers in psychiatry, Jan 6, 2014

Previous studies of perceptual category learning in patients with schizophrenia generally demonst... more Previous studies of perceptual category learning in patients with schizophrenia generally demonstrate impaired perceptual category learning; however, traditional cognitive studies have often failed to address the relationship of different cortical regions to perceptually based category learning and judgments in healthy participants and patients with schizophrenia. In the present study, perceptual category learning was examined in 26 patients with schizophrenia and 25 healthy participants using a dot-pattern category learning task. In the training phase, distortions of a prototypical dot pattern were presented. In the test phase, participants were shown the prototype, low and high distortions of the prototype, and random dot patterns. Participants were required to indicate whether the presented dot pattern was a member of the category of dot-patterns previously presented during the study phase. Patients with schizophrenia displayed an impaired ability to make judgments regarding marg...

Journal of Neuroscience, 2009

Functional neuroimaging studies of probabilistic category learning in healthy adults report activ... more Functional neuroimaging studies of probabilistic category learning in healthy adults report activation of cortical-striatal circuitry. Based on previous findings of normal learning rate concurrent with an overall performance deficit in patients with schizophrenia, we hypothesized that relative to healthy adults, patients with schizophrenia would display preserved caudate nucleus and abnormal prefrontal cortex activation during probabilistic category learning. Forty patients with schizophrenia receiving antipsychotic medication and 25 healthy participants were assessed on interleaved blocks of probabilistic category learning and control tasks while undergoing blood oxygenation level-dependent functional magnetic resonance imaging. In addition to the whole sample of patients with schizophrenia and healthy adults, a subset of patients and healthy adults matched for good learning was also compared. In the whole sample analysis, patients with schizophrenia displayed impaired performance in conjunction with normal learning rate relative to healthy adults. The matched comparison of patients and healthy adults classified as good learners revealed greater caudate and dorsolateral prefrontal cortex activity in the healthy adults and greater activation in a more rostral region of the dorsolateral prefrontal, cingulate, parahippocampal and parietal cortex in patients. These results demonstrate that successful probabilistic category learning can occur in the absence of normal frontal-striatal function. Based on analyses of the patients and healthy adults matched on learning and performance, a minority of patients with schizophrenia achieve successful probabilistic category learning and performance levels through differential activation of a circumscribed neural network which suggests a compensatory mechanism in patients showing successful learning.

Schizophrenia Research, 2008

Schizophrenia Research, 2009

Schizophrenia Bulletin, 1997

Although the new generation of atypical antipsychotic agents could some day eliminate concerns ab... more Although the new generation of atypical antipsychotic agents could some day eliminate concerns about tardive dyskinesia (TD), this disorder remains a significant clinical problem for both patients and physicians. Fortunately, many, if not most, cases of TD are mild. For patients with mild to moderate TD, therapeutic efforts are primarily directed at minimizing neuroleptic exposure or, when possible, changing to atypical agents. Most cases of TD do not seem to progress, suggesting that the risk of remaining on typical neurolep-Hcs is probably small. Patients with moderate to severe forms of TD present greater challenges. These patients frequently require medication to suppress their dyskinesias. A variety of suppressive agents have been tried with limited success. No treatment strategy has emerged that is clearly superior or even successful in most patients. Increasing doses of typical neuroleptics may be useful for short-term suppression; however, the long-term efficacy and risk of this strategy have not been studied carefully. Data on atypical neuroleptics are scant. Clozapine's short-term suppressive effects seem, at best, weak, but patients may improve with long-term treatment Medications with relatively few side effects that may have suppressive efficacy for some patients include calcium channel blockers, adrenergic antagonists, and vitamin E. Gammaamino-butyric acid agonists agents and dopamine depleters are frequently useful, but have troubling side effects of their own. A variety of other medications have been employed, but are not well studied. For patients with tardive dystonia, anticholinergic agents or botulinum toxin has been particularly effective. Efforts to understand the neurobiology of TD may shed light on this persistent clinical conundrum.

Psychiatry Research, 2008

Impairments in source monitoring have been widely reported in schizophrenia, with patients typica... more Impairments in source monitoring have been widely reported in schizophrenia, with patients typically misattributing selfgenerated items to external sources. Some studies have reported that patients with more severe positive symptoms (notably hallucinations) exhibit a greater impairment on these tasks, although findings are not uniformly positive. The emotional content of the items to be remembered also may affect subsequent retrieval, with some studies suggesting a greater misattribution bias for affectively-laden material. Recently, it has been proposed that schizophrenic patients have a fundamental deficit in binding different contextual elements together in memory. The effect of clinical symptomatology and item content on source monitoring and context binding has yet to be examined in a single study. Twenty-one patients with schizophrenia and 21 healthy control subjects completed a task wherein memory for affective and neutral word pairs was assessed in conjunction with memory for both source and temporal information. Schizophrenic patients performed more poorly than controls overall, and tended to exhibit a more fractionated retrieval of word pairs across all levels of affective valence. Current intellectual level and overall verbal memory performance were significantly correlated with context binding performance for positive and neutral word pairs. Clinical symptomatology was unrelated to source monitoring performance. The results of this pilot study provide tentative support for the notion that schizophrenia is associated with an impairment in combining contextual cues together to form a coherent memory of an event, irrespective of the affective valence of the material. Clinical symptomatology bore no significant relationship to source memory performance. Published by Elsevier Ireland Ltd.

Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2002

Brain metabolic abnormalities and aberrant dopamine (DA) metabolism have been reported in patient... more Brain metabolic abnormalities and aberrant dopamine (DA) metabolism have been reported in patients with schizophrenia. The authors hypothesized that mitochondria is a primary target of damage by increased free radical generation secondary to increased DA metabolism by monoamine oxidase (MAO). Epstein-Barr virus (EBV)-transformed human B-lymphocytes cell lines derived from patients with schizophrenia and normal controls were incubated in the absence or presence of DA, hydrogen peroxide (H2O2), or rotenone (Rot). The cells were then stained with rhodamine 123 (Rh 123) and analyzed for uptake using flow cytometry. Compared with untreated cells, DA significantly decreased Rh 123 uptake by the mitochondria. This effect was similar to the control cells treated with H2O2 or Rot. Nevertheless, there were no differences in Rh 123 uptake between the cells of schizophrenic patients and normal controls. This study shows that DA can impair the mitochondria membrane potential but that mechanism may not be evident in schizophrenia.

Proceedings of the National Academy of Sciences, 2009

The human brain's capacity for cognitive function is thought to depend on coordinated activity in... more The human brain's capacity for cognitive function is thought to depend on coordinated activity in sparsely connected, complex networks organized over many scales of space and time. Recent work has demonstrated that human brain networks constructed from neuroimaging data have economical small-world properties that confer high efficiency of information processing at relatively low connection cost. However, it has been unclear how the architecture of complex brain networks functioning at different frequencies can be related to behavioral performance on cognitive tasks. Here, we show that impaired accuracy of working memory could be related to suboptimal cost efficiency of brain functional networks operating in the classical ␤ frequency band, 15-30 Hz. We analyzed brain functional networks derived from magnetoencephalography data recorded during working-memory task performance in 29 healthy volunteers and 28 people with schizophrenia. Networks functioning at higher frequencies had greater global cost efficiency than low-frequency networks in both groups. Superior task performance was positively correlated with global cost efficiency of the ␤-band network and specifically with cost efficiency of nodes in left lateral parietal and frontal areas. These results are consistent with biophysical models highlighting the importance of ␤-band oscillations for long-distance functional connections in brain networks and with pathophysiological models of schizophrenia as a dysconnection syndrome. More generally, they echo the saying that ''less is more'': The information processing performance of a network can be enhanced by a sparse or low-cost configuration with disproportionately high efficiency. efficiency ͉ graph theory ͉ schizophrenia ͉ working memory ͉ magnetoencephalography Cost-Efficient Functional Networks. Economical small-world properties were generally most salient in conservatively thresholded MEG networks, which supported high efficiency E for disproportionately low cost C, i.e., they had positive cost efficiency, (CE) Ͼ 0; see . Maximum cost efficiency max(CE) was typically observed for networks comprising 5-10% of the total number of possible functional connections (37,400) between all 275 sensors. For all subjects, the average mutual information between sensors was greatest in the lowest-frequency networks and decreased monotonically with increasing frequency; maxi-

Neuropsychopharmacology, 2010

Modafinil differs from other arousal-enhancing agents in chemical structure, neurochemical profil... more 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 doubleblinded placebo-controlled trial (100 mg/day for 7 days). They underwent BOLD fMRI while performing an emotion informationprocessing task that activates the amygdala and two prefrontally dependent cognitive tasksFa 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.

Neuropsychopharmacology, 2007

Prefrontal cortical dopamine (DA) regulates various executive cognitive functions, including atte... more 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.

Neuropsychopharmacology, 2014

Neurexins are presynaptic neuronal adhesion molecules that interact with postsynaptic neuroligins... more Neurexins are presynaptic neuronal adhesion molecules that interact with postsynaptic neuroligins to form an inter-synaptic complex required for synaptic specification and efficient neurotransmission. Deletions and point mutations in the neurexin 1 (NRXN1) gene are associated with a broad spectrum of neuropsychiatric and neurodevelopmental disorders, including autism, intellectual disability, epilepsy, developmental delay, and schizophrenia. Recently, small nucleotide polymorphisms in NRXN1 have been associated with antipsychotic drug response in patients with schizophrenia. Based on previous suggestive evidence of an impact on clozapine response in patients with schizophrenia, we conducted an association study of NRXN1 polymorphisms (rs12467557 and rs10490162) with antipsychotic treatment response in 54 patients with schizophrenia in a double blind, placebo-controlled NIMH inpatient crossover trial and examined for association with risk for schizophrenia in independent case-control and family-based clinical cohorts. Pharmacogenetic analysis in the placebo controlled trial revealed significant association of rs12467557and rs10490162 with drug response, whereby individuals homozygous for the A allele, at either SNP, showed significant improvement in positive symptoms, general psychopathology, thought disturbance, and negative symptoms, whereas patients carrying the G allele showed no overall response. Although we did not find evidence of the same NRXN1 SNPs being associated with results of the NIMH sponsored CATIE trial, other SNPs showed weakly positive signals. The family and case-control analyses for schizophrenia risk were negative. Our results provide confirmatory evidence of genetically determined differences in drug response in patients with schizophrenia related to NRXN1 variation. Furthermore, these findings potentially implicate NRXN1 in the therapeutic actions of antipsychotic drugs.

Human Brain Mapping, 2009

The "default network" represents a baseline condition of brain function and is of interest in sch... more The "default network" represents a baseline condition of brain function and is of interest in schizophrenia research because its component brain regions are believed to be aberrant in the disorder. We hypothesized that MEG source localization analysis would reveal abnormal resting activity within particular frequency bands in schizophrenia.

Brain, 2010

Higher rates of non-right-handedness (i.e. left-and mixed-handedness) have been reported in schiz... more Higher rates of non-right-handedness (i.e. left-and mixed-handedness) have been reported in schizophrenia and have been a centrepiece for theories of anomalous lateralization in this disorder. We investigated whether non-right-handedness is (i) more prevalent in patients as compared with unaffected siblings and healthy unrelated control participants; (ii) familial; (iii) associated with disproportionately poorer neurocognition; and (iv) associated with grey matter volume asymmetries. We examined 1445 participants (375 patients with schizophrenia, 502 unaffected siblings and 568 unrelated controls) using the Edinburgh Handedness Inventory, a battery of neuropsychological tasks and structural magnetic resonance imaging data. Patients displayed a leftward shift in Edinburgh Handedness Inventory laterality quotient scores as compared with both their unaffected siblings and unrelated controls, but this finding disappeared when sex was added to the model. Moreover, there was no evidence of increased familial risk for non-right-handedness. Non-right-handedness was not associated with disproportionate neurocognitive disadvantage or with grey matter volume asymmetries in the frontal pole, lateral occipital pole or temporal pole. Non-righthandedness was associated with a significant reduction in left asymmetry in the superior temporal gyrus in both patients and controls. Our data neither provide strong support for 'atypical' handedness as a schizophrenia risk-associated heritable phenotype nor that it is associated with poorer neurocognition or anomalous cerebral asymmetries.

Biological Psychiatry, 2004

The gene encoding catechol- O-methyltransferase (COMT), an enzyme that regulates prefrontal corte... more The gene encoding catechol- O-methyltransferase (COMT), an enzyme that regulates prefrontal cortex dopamine, contains a common functional polymorphism (val 108/158 met) that influences prefrontal cortex function in an allelic dose-dependent manner. A recent study reported that the COMT val 108/158 met polymorphism influences cognitive-and physiologic-related prefrontal cortex responses to antipsychotic treatment. The present study tested the effects of several COMT polymorphisms on the cognitive response to antipsychotic medication in patients with schizophrenia. Methods: Twenty inpatients with schizophrenia or schizoaffective disorder (5 with the val-val genotype, 11 with val-met, and 4 with met-met) were administered cognitive tests at two time points: once after 4 weeks of treatment with antipsychotic medication and once after 4 weeks of placebo administration, according to a counterbalanced, double-blind, within-subject study design. Results: Patients homozygous for the COMT met allele displayed significant improvement on the working memory task after treatment. Patients homozygous for the COMT val allele did not show working memory improvement with treatment. Other COMT polymorphisms were not associated with significant differences between treatment and placebo conditions. Conclusions: These results support other data suggesting that the COMT val 108/158 met polymorphism might be an important factor in the cognitive response to antipsychotic medication.