Consortium neuroscience of attention deficit/hyperactivity disorder and autism spectrum disorder: The ENIGMA adventure.

Neuroimaging has been extensively used to study brain structure and function in individuals with attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) over the past decades. Two of the main shortcomings of the neuroimaging literature of these disorders are the small sample sizes employed and the heterogeneity of methods used. In 2013 and 2014, the ENIGMA-ADHD and ENIGMA-ASD working groups were respectively, founded with a common goal to address these limitations. Here, we provide a narrative review of the thus far completed and still ongoing projects of these working groups. Due to an implicitly hierarchical psychiatric diagnostic classification system, the fields of ADHD and ASD have developed largely in isolation, despite the considerable overlap in the occurrence of the disorders. The collaboration between the ENIGMA-ADHD and -ASD working groups seeks to bring the neuroimaging efforts of the two disorders closer together. The outcomes of case-control studies of subcortical and cortical structures showed that subcortical volumes are similarly affected in ASD and ADHD, albeit with small effect sizes. Cortical analyses identified unique differences in each disorder, but also considerable overlap between the two, specifically in cortical thickness. Ongoing work is examining alternative research questions, such as brain laterality, prediction of case-control status, and anatomical heterogeneity. In brief, great strides have been made toward fulfilling the aims of the ENIGMA collaborations, while new ideas and follow-up analyses continue that include more imaging modalities (diffusion MRI and resting-state functional MRI), collaborations with other large databases, and samples with dual diagnoses.

Effects of socioeconomic status in cognition of people with schizophrenia: results from a Latin American collaboration network with 1175 subjects.

BACKGROUND: Cognition heavily relies on social determinants and genetic background. Latin America comprises approximately 8% of the global population and faces unique challenges, many derived from specific demographic and socioeconomic variables, such as violence and inequality. While such factors have been described to influence mental health outcomes, no large-scale studies with Latin American population have been carried out. Therefore, we aim to describe the cognitive performance of a representative sample of Latin American individuals with schizophrenia and its relationship to clinical factors. Additionally, we aim to investigate how socioeconomic status (SES) relates to cognitive performance in patients and controls. METHODS: We included 1175 participants from five Latin American countries (Argentina, Brazil, Chile, Colombia, and Mexico): 864 individuals with schizophrenia and 311 unaffected subjects. All participants were part of projects that included cognitive evaluation with MATRICS Consensus Cognitive Battery and clinical assessments. RESULTS: Patients showed worse cognitive performance than controls across all domains. Age and diagnosis were independent predictors, indicating similar trajectories of cognitive aging for both patients and controls. The SES factors of education, parental education, and income were more related to cognition in patients than in controls. Cognition was also influenced by symptomatology. CONCLUSIONS: Patients did not show evidence of accelerated cognitive aging; however, they were most impacted by a lower SES suggestive of deprived environment than controls. These findings highlight the vulnerability of cognitive capacity in individuals with psychosis in face of demographic and socioeconomic factors in low- and middle-income countries.

Influence of emotional stimulus valence on inhibitory control in adults with and without ADHD.

Human behavior is influenced both by approach and avoidance automatic reactions to positive and negative stimulus, respectively, but these reactions have not been well studied in attention-deficit/hyperactivity disorder (ADHD) patients. Moreover, studies employing spatial stimulus-response compatibility tasks in ADHD and healthy control (HC) subjects are scarce and inconclusive. The present study investigated inhibitory control and emotional processing in ADHD adults with a modified stimulus-response compatibility task in which spatial and emotional features of affective stimuli had to be processed together to select the correct response. Manual responses to figures of Favorite and Rival soccer team players were measured, and compatible or incompatible responses were chosen according to the soccer team figure. Eighteen HC participants and sixteen ADHD adults performed the task. We found an ordinary spatial compatibility effect for the Favorite soccer team and a reversed one for the Rival team in the ADHD group but not in the HC group. The effects may be due to stronger approach and withdrawal reactions toward the Favorite soccer team and away from the Rival one, respectively, indicating poor inhibitory control for the ADHD group. These results show that differences between ADHD and HC subjects become prominent when response selection involves both emotional and spatial features of the stimulus.

The physician's quality of life: Relationship with ego defense mechanisms and object relations.

OBJECTIVE: To assess whether ego defense mechanisms and object relations (the way an individual subjectively experiences his/her relationships with others) are related to quality of life among physicians. METHODS: In this cross-sectional mail survey, 602 physicians from Botucatu, SP, Brazil, were sent a socio-demographic questionnaire, the Bell Object Relations and Reality Testing Inventory-Form O (BORRTI-O), the Defense Style Questionnaire-40 (DSQ-40), and the World Health Organization Abbreviated Instrument for Quality of Life Assessment (WHOQOL-BREF). RESULTS: 198 questionnaires (33%) with valid responses were obtained. High BORRTI-O scores (indicative of pathology) on the alienation, egocentricity and insecure attachment subscales were associated with reduced WHOQOL-BREF scores for the psychological health and social relationship domains. Immature ego defense mechanisms were associated with lower WHOQOL-BREF scores for all domains. No significant associations of WHOQOL-BREF scores with working hours, workplace or monthly income were observed in the study population CONCLUSIONS: WHOQOL-BREF scores correlated with mature defense mechanisms and normal object relations, suggesting an association between psychological maturity and quality of life among physicians.

The burden of caregivers of schizophrenia outpatients during the COVID-19 pandemic: A same-sample comparison with the pre-pandemic burden.

BACKGROUND: The coronavirus disease 2019 (COVID-19) has affected the vulnerable Brazilian population. In this study, we investigated the burden of COVID-19 on caregivers for patients with schizophrenia. OBJECTIVE: This study assessed objective and subjective burden of caregivers for patients with schizophrenia during the COVID-19 pandemic and compared the measurements obtained in the study to that before the pandemic. METHODS: The study included 50 caregivers who were assessed using the Sociodemographic Questionnaire, and the Family Burden Interview Schedule, Brazilian version (FBIS-BR). An adaptation of the Clinical Global Impression-Improvement (CGI-I) was made, in which caregivers evaluated their 'clinical' impression about the patient during the COVID-19 pandemic in comparison to pre-pandemic mental status. RESULTS: Most caregivers were female, aged between 24 and 80 years, who were in contact with the patient for about 88.56 hours/week. In relation to caregiver burden, there was a significant increase in the total subjective burden (p < .001), but not in the total objective burden. The following subjective domains of the burden showed a significant increase: assistance in daily life (p < .001) and worries about patients' present and future life (p = .033). There was a decrease in the objective burden related to supervision of patients' problematic behaviors (p = .031). Although the caregiver's income did not change significantly during the COVID-19 pandemic, there was an increase in the percentage of caregivers who perceived the frequency of financial burden imposed by the patient as 'very frequent' and 'always or almost always'; conversely there was a significant decrease in the subjective perception of the caregiver that the patient imposed financially 'no burden' or a 'seldom burden' (from 34% to 4%). CONCLUSION: Although the objective burden of the caregivers, during the pandemic, was similar the pre-pandemic levels, caregivers' subjective burden increased reinforcing the need for special attention to the caregiver in this global emergency.

Burden on caregivers of schizophrenia outpatients in Brazil: Relationship to symptomatology and functioning.

BACKGROUND: To investigate the objective and subjective burden on caregivers of schizophrenia outpatients and their associations with sociodemographic factors, symptomatology, and functioning. METHODS: This study included 60 schizophrenic outpatients aged 18 to 65 years who were clinically stable for at least 6 months, and 60 caregivers aged 18 to 80 years who were in contact with the patient for ⩾30 hours/week. The patients were assessed using a sociodemographic questionnaire, the Clinical Global Impression Scale for Schizophrenia (CGI-SCH), and the Personal and Social Performance scale (PSP). The caregivers were assessed using a sociodemographic questionnaire and the Family Burden Interview Schedule, Brazilian version (FBIS-BR). RESULTS: The objective burden was positively correlated with CGI-SCH cognitive symptom scores (p = .032) and number of hours spent weekly with the patient (p = .028), and negatively correlated with PSP score (r = -.346, p = .007). The subjective burden showed a negative correlation with age of disease onset (r = -.338, p = .08). The independent variables included in the regression model were family income (p = .005), PSP score (p = .009), patient marital status (p = .012), patient gender (p = .046), and reception of financial benefit (p = .027) for objective burden; and disease duration (p = .045) and father/mother or sibling relationship (p = .001) for subjective burden. The coefficient of determination (R2) of the linear regression model for objective burden was 39.4%; subjective burden, 21.6%. CONCLUSION: Caring for female, single patients with longer disease duration, more severe cognitive symptoms, impaired functioning, and more caregiving time required per week were associated with higher caregiver burden levels.

Gray Matter Volume in Elderly adults With ADHD: Associations of Symptoms and Comorbidities With Brain Structures.

Objective: To investigate total and selected region-of-interest-based gray matter volume (GMV) in older adults with ADHD. Method: Twenty-five elderly (≥65 years old) patients with ADHD and 34 healthy controls underwent 1.5-T magnetic resonance imaging (MRI). We used voxel-based morphometry to compare GMV between groups and performed a correlation analysis with ADHD symptoms and comorbidities. Results: Findings revealed a smaller total GMV in males with ADHD and a smaller GMV in the right medial frontal orbital area extending toward the medial frontal superior, the frontal superior, and the subgenual anterior cingulate cortex (ACC) besides correlations between inattentiveness and ACC (bilaterally) and left cerebellum, hyperactivity/impulsivity and the left frontal inferior orbital, depression and caudate (bilaterally), and the right inferior parietal lobule. Conclusion: Neural correlates in regions related to attention, executive control, and affective processing suggest that impairments in frontostriatal and frontoparietal-cerebellar areas observed in adults with ADHD persist into old age.

Cortical surface abnormalities are different depending on the stage of schizophrenia: A cross-sectional vertexwise mega-analysis of thickness, area and gyrification.

BACKGROUND: Brain magnetic resonance imaging studies have not investigated the cortical surface comprehensively in schizophrenia subjects by assessing thickness, surface area and gyrification separately during the first-episode of psychosis (FEP) or chronic schizophrenia (ChSch). METHODS: We investigated cortical surface abnormalities in 137 FEP patients and 240 ChSch subjects compared to 297 Healthy Controls (HC) contributed by five cohorts. Maps showing results of vertexwise between-group comparisons of cortical thickness, area, and gyrification were produced using T1-weighted datasets processed using FreeSurfer 5.3, followed by validated quality control protocols. RESULTS: FEP subjects showed large clusters of increased area and gyrification relative to HC in prefrontal and insuli cortices (Cohen's d: 0.049 to 0.28). These between-group differences occurred partially beyond the effect of sample. ChSch subjects displayed reduced cortical thickness relative to HC in smaller fronto-temporal foci (d: -0.73 to -0.35), but not beyond the effect of sample. Differences between FEP and HC subjects were associated with male gender, younger age, and earlier illness onset, while differences between ChSch and HC were associated with treatment-resistance and first-generation antipsychotic (FGA) intake independently of sample effect. CONCLUSIONS: Separate assessments of FEP and ChSch revealed abnormalities that differed in regional distribution, phenotypes affected and effect size. In FEP, associations of greater cortical area and gyrification abnormalities with earlier age of onset suggest an origin on anomalous neurodevelopment, while thickness reductions in ChSch are at least partially explained by treatment-resistance and FGA intake. Associations of between-group differences with clinical variables retained statistical significance beyond the effect of sample.

Treatment of Patients with Recently Exacerbated Schizophrenia with Paliperidone Palmitate: A Pilot Study of Efficacy and Tolerability.

BACKGROUND: Paliperidone palmitate is a long-acting, second-generation antipsychotic (SGA) indicated for the treatment of acute exacerbations and maintenance treatment of adults with schizophrenia. This study addressed the response to paliperidone palmitate in Latin American patients with acute symptoms and recently diagnosed schizophrenia. OBJECTIVE: Explore the efficacy and tolerability of paliperidone palmitate administered once a month for 4 months in patients with acute phase and recent diagnosis (within 1-6 years) of schizophrenia in 3 Latin American countries. METHODS: This was a non-randomized, open-label, multicenter study with paliperidone palmitate injected intramuscularly in the deltoid muscle at an initial loading dose of 150 mg eq. (234 mg) on day 1 and 100 mg eq. (156 mg) on day 8 (± 4 days). The recommended maintenance dose was 75 mg eq. (117 mg) from day 36 to day 92. Efficacy was evaluated with PANSS and CGI-S. The last observation carried forward (LOCF) was used for efficacy analysis for imputation of missing data; no adjustments were made for multiplicity. Adverse events were evaluated during treatment. RESULTS: The patient retention rate was 84.0% (144 patients received study drug; 121 finished the study). The percentage of patients with a reduction of at least 30% in PANSS total score compared to baseline gradually increased during the study, and at the end, 78.4% of patients showed response. The PANSS total score and CGI-S scores decreased significantly from baseline to LOCF endpoint (P <0.0001 for both); significant reduction in PANSS total score was observed at day 8 and persisted to the end of the study. Most common adverse events were muscle rigidity (11.8%), akathisia (11.1%), injection-site pain (7.6%), weight gain (7.6%), and insomnia (7.6%). CONCLUSION: Paliperidone palmitate was efficacious in Latin American patients studied with an acute exacerbation and recent diagnosis of schizophrenia, and no new safety signals were identified.

Aripiprazole for patients with schizophrenia and schizoaffective disorder: an open-label, randomized, study versus haloperidol.

INTRODUCTION: Aripiprazole, a dopamine D2 receptor partial agonist, has also partial agonist activity at serotonin (5-HT)1A receptors and antagonist activity at 5-HT2A receptors. METHODS: In this 8-week, multicenter, randomized, parallel-group, open-label, flexible-dose study, patients diagnosed with schizophrenia or schizoaffective disorder were randomized to aripiprazole 15-30 mg/day or haloperidol 10-15 mg/day. RESULTS: Patients treated with both aripiprazole and haloperidol improved from baseline in Positive and Negative Syndrome Scale total, positive, and negative scores as well as in Clinical Global Impressions scores (all P<.001). At the end of the study, the percentage of patients classified as responders--according to >or=40% reduction in the Positive and Negative Syndrome Scale negative subscale score--was significantly higher in the aripiprazole group (20%) than in the haloperidol group (0%) (P<.05). Additionally, a higher number of patients receiving haloperidol required more anticholinergic medications (P<.001) than aripiprazole-treated patients, whereas more aripiprazole (45.5%) than haloperidol-treated patients (12.9%) required benzodiazepines (P=.002). At endpoint, rates of preference of medication were higher in the aripiprazole group (63.2%) than in the haloperidol group (21.7%), as expressed by patients and caregivers (P=.001). CONCLUSION: Aripiprazole and haloperidol had similar efficacy in terms of reduction of overall psychopathology. Although aripiprazole has been demonstrated to be superior concerning negative symptoms and in terms of tolerability (extrapyramidal symptoms) and preferred by patients and caregivers than haloperidol, significantly more aripiprazole-treated patients required benzodiazepines.

Longitudinal Neuropsychological Assessment in Two Elderly Adults With Attention-Deficit/Hyperactivity Disorder: Case Report.

The neuropsychological deficits in attention-deficit/hyperactivity disorder (ADHD) may present clinical features similar to mild and/or major neurocognitive disorder and may act as a confounding factor, making it difficult to detect cognitive decline. In this paper, we present the results of longitudinal neuropsychological evaluations in two elderly women with ADHD. Three neuropsychological assessments were performed in two women with ADHD (60 and 77 years old) between 2010 and 2013 at intervals varying from 12 to 15 months. We used structural magnetic resonance imaging to rule out significant abnormalities that could account for cognitive impairment. The results showed two different cognitive profiles with fluctuations in performance over these 2 years, sometimes with improvement and sometimes with decline of some functions such as attention, memory, inhibitory control, and reaction time. To minimize confounding aspects of these fluctuations in clinical practice, we used a longer follow-up with the application of a reliable change index and a minimum of three spaced assessments to provide a more consistent baseline cognitive profile. Our findings did not indicate a consistent cognitive decline, suggesting a less pessimistic perspective about cognitive impairments that could be a prodrome of ADHD-related dementia.

Insight, cognitive dysfunction and symptomatology in schizophrenia.

Lack of insight is frequent in schizophrenia and usually influences negatively both patient's treatment and prognosis. This study aimed to investigate the relationship between insight, symptomatology and cognitive dysfunctions in schizophrenia using the PANSS five-factor model (modified from Gaag et al. in Schizophr Res 85:280-287, 2006). Forty patients diagnosed with chronic schizophrenia (DSM-IV) were evaluated with the scale to assess unawareness of mental disorder (SUMD), the PANSS and a neuropsychological battery. Spearman correlation and linear regression analyses were performed to investigate the relationship between clinical, neurocognitive and insight measures. The SUMD current and past awareness of symptoms score showed a correlation with WCST indices (correct answers and non-persevering errors). The negative and disorganization factor of the PANSS showed a positive correlation with current and past awareness of symptoms. However, when submitted to a linear regression model only the disorganization factor emerged as significant contributor for insight. Considering that the core items of the "disorganization factor" of the PANSS are related to cognition (e.g., poor attention, difficult in abstract thinking), insight is associated cognitive symptoms although no direct relationship between insight and neuropsychological tests was observed.

Fractionating Executive Functions of Adults With ADHD.

OBJECTIVE: To evaluate the performance of adults with ADHD considering the fractionation of executive functions into six different domains. METHOD: Participants were adult ADHD patients who were not under the acute effects of medication ( n = 48). Their performance was compared with that of a healthy control group ( n = 20) of comparable age, education, and nonverbal intelligence quotient. The cognitive domains assessed were executive shifting, updating, inhibition of prepotent responses, dual-task performance, planning, and access to long-term memory. We also assessed the symptoms of inattention, hyperactivity/impulsivity, anxiety, and depression by validated questionnaires. RESULTS: Compared with controls, patients reported more symptoms related to ADHD, anxiety and depression symptoms and were impaired in the shifting cost measure and phonemic fluency (measure of access to long-term memory). CONCLUSION: ADHD in adults selectively impaired executive shifting and access to long-term memory, domains that may alter performance in a wide range of daily tasks.

High IQ May "Mask" the Diagnosis of ADHD by Compensating for Deficits in Executive Functions in Treatment-Naïve Adults With ADHD.

OBJECTIVE: To evaluate and compare the performance of adults with ADHD with high and standard IQ in executive functions (EF) tasks. METHOD: We investigated the neuropsychological performance of 51 adults with ADHD, compared with 33 healthy controls (HC) while performing a wide battery of neuropsychological tests that measure executive functioning. Adults with clinical diagnosis of ADHD were divided into two groups according to their IQ level (IQ ≥ 110-ADHD group with more elevated IQ, and IQ < 110-ADHD group with standard IQ). RESULTS: The ADHD group with standard IQ presented a worse executive functioning compared with the HC group in the following measures: Stroop 2 ( p = .000) and 3 ( p = .000), Trail Making Test (TMT) B ( p = .005), Wisconsin Card-Sorting Test (WCST)-perseverative errors ( p = .022) and failures to maintain set ( p = .020), Continuous Performance Test (CPT)-omission errors ( p = .005) and commission errors ( p = .000), and Frontal Assessment Battery (FAB)-conceptualization ( p = .016). The ADHD group with more elevated IQ presented only impairments in the CPT-commission errors ( p = .019) when compared with the control group. CONCLUSION: Adults with ADHD and more elevated IQ show less evidence of executive functioning deficits compared with those with ADHD and standard IQ, suggesting that a higher degree of intellectual efficiency may compensate deficits in executive functions, leading to problems in establishing a precise clinical diagnosis.

Attention deficit hyperactivity disorder (ADHD) in adults: social-demographic profile from a university hospital ADHD outpatient unit in São Paulo, Brazil.

PURPOSE: To describe the social-demographic variables, including interpersonal, academic, and professional performance in adult individuals with the diagnoses of attention deficit hyperactivity disorder (ADHD). There are no reports of this kind in the Brazilian population with ADHD. The ADHD is a common disorder, which can reach up to 3% of the general population. METHOD: Descriptive study of adults with ADHD, according to the DSM-IV criteria (American Psychiatric Association). The sample was selected from a specialized outpatient service in São Paulo city. The social-demographic data was obtained by personal interviews. RESULTS: There was a predominance of males in the sample (61.2%) and a high education level (90.2% had at least a high school degree) and 52% of the 102 patients had repeated their class at a least once during their school lives. In addition, 22.5% of the population sample were unemployed at the time of the interview. CONCLUSION: The distribution of the socio-demographic variables in adult ADHD is similar to other ADHD samples reported in other countries, despite the high education level met in our sample. Similarities between child and adult ADHD could also be traced.

Ego Defense Mechanisms and Types of Object Relations in Adults With ADHD.

OBJECTIVE: This research evaluates the personality structure of adults with ADHD from a psychodynamic perspective. The hypothesis was that possible structural characteristics in personality could be correlated with this syndrome. METHOD: Assessment tools for ego functions (Bell Object Relations and Reality Testing Inventory [BORRTI-Form O], Defense Style Questionnaire ( DSQ-40)) were applied to a sample of 90 adults with ADHD, recruited in a specialized clinic. RESULTS: Among the ADHD sample, 84.4% of the participants were identified as having object relations pathologies. Pathological elevations were observed mainly in the Alienation, Egocentricity, and Insecure Attachment subscales. Statistically, significant differences were found especially in the use of immature and neurotic defense mechanisms, compared with normative data. CONCLUSION: The findings indicate that adults with ADHD make more use of immature and neurotic defense mechanisms, and presented pathological internalized object relations that are typical of an archaic and poorly structured egoic structure.

Cognition and impulsivity in adults with attention deficit hyperactivity disorder with and without cocaine and/or crack dependence.

BACKGROUND: Substance use disorder (SUD) is a common comorbidity in adults with attention deficit-hyperactivity disorder (ADHD). However,there have been few studies on cognitive profiles of these patients. Impulsivity is also commonly increased in both disorders. The central aim of this study was to compare cognition and impulsivity in subjects who had ADHD and cocaine dependence (ADHD+COC group) to those with ADHD only (ADHD-noSUD group). We hypothesized that the ADHD+COC group would show more marked cognitive dysfunction and greater impulsivity than their counterparts with ADHD only. METHODS: A total of 70 adult patients diagnosed with ADHD according to (DSM-IV-TR) criteria were enrolled; 36 with ADHD+COC and 34 with ADHD-noSUD. All study participants were evaluated with a sociodemographic questionnaire; the Mini International Neuropsychiatric Interview; the Adult ADHD Self-Report Scale; the Addiction Severity Index; the Alcohol, Smoking and Substance Involvement Screening Test; the Barratt Impulsiveness Scale; and a comprehensive neurocognitive battery. RESULTS: Compared to individuals with ADHD-noSUD, ADHD+COC individuals had significantly lower mean IQ and higher motor impulsivity. On average, the ADHD+COC group also performed more poorly on tasks assessing verbal skills, vigilance, implicit learning during decision making, and ADHD-noSUD performed more poorly on selective attention, information processing, and visual search. CONCLUSIONS: Our results support the integrative theory of ADHD based on the cognitive and affective neuroscience model, and suggests that ADHD-noSUD patients have impairments in cognitive regulation, while ADHD+COC patients have impairments in both cognitive and affective regulation.

Patterns of regional gray matter loss at different stages of schizophrenia: A multisite, cross-sectional VBM study in first-episode and chronic illness.

BACKGROUND: Structural brain abnormalities in schizophrenia have been repeatedly demonstrated in magnetic resonance imaging (MRI) studies, but it remains unclear whether these are static or progressive in nature. While longitudinal MRI studies have been traditionally used to assess the issue of progression of brain abnormalities in schizophrenia, information from cross-sectional neuroimaging studies directly comparing first-episode and chronic schizophrenia patients to healthy controls may also be useful to further clarify this issue. With the recent interest in multisite mega-analyses combining structural MRI data from multiple centers aiming at increased statistical power, the present multisite voxel-based morphometry (VBM) study was carried out to examine patterns of brain structural changes according to the different stages of illness and to ascertain which (if any) of such structural abnormalities would be specifically correlated to potential clinical moderators, including cumulative exposure to antipsychotics, age of onset, illness duration and overall illness severity. METHODS: We gathered a large sample of schizophrenia patients (161, being 99 chronic and 62 first-episode) and controls (151) from four previous morphometric MRI studies (1.5 T) carried out in the same geographical region of Brazil. Image processing and analyses were conducted using Statistical Parametric Mapping (SPM8) software with the diffeomorphic anatomical registration through exponentiated Lie algebra (DARTEL) algorithm. Group effects on regional gray matter (GM) volumes were investigated through whole-brain voxel-wise comparisons using General Linear Model Analysis of Co-variance (ANCOVA), always including total GM volume, scan protocol, age and gender as nuisance variables. Finally, correlation analyses were performed between the aforementioned clinical moderators and regional and global brain volumes. RESULTS: First-episode schizophrenia subjects displayed subtle volumetric deficits relative to controls in a circumscribed brain regional network identified only in small volume-corrected (SVC) analyses (p < 0.05, FWE-corrected), including the insula, temporolimbic structures and striatum. Chronic schizophrenia patients, on the other hand, demonstrated an extensive pattern of regional GM volume decreases relative to controls, involving bilateral superior, inferior and orbital frontal cortices, right middle frontal cortex, bilateral anterior cingulate cortices, bilateral insulae and right superior and middle temporal cortices (p < 0.05, FWE-corrected over the whole brain). GM volumes in several of those brain regions were directly correlated with age of disease onset on SVC analyses for conjoined (first-episode and chronic) schizophrenia groups. There were also widespread foci of significant negative correlation between duration of illness and relative GM volumes, but such findings remained significant only for the right dorsolateral prefrontal cortex after accounting for the influence of age of disease onset. Finally, significant negative correlations were detected between life-time cumulative exposure to antipsychotics and total GM and white matter volumes in schizophrenia patients, but no significant relationship was found between indices of antipsychotic usage and relative GM volume in any specific brain region. CONCLUSION: The above data indicate that brain changes associated with the diagnosis of schizophrenia are more widespread in chronic schizophrenia compared to first-episode patients. Our findings also suggest that relative GM volume deficits may be greater in (presumably more severe) cases with earlier age of onset, as well as varying as a function of illness duration in specific frontal brain regions. Finally, our results highlight the potentially complex effects of the continued use of antipsychotic drugs on structural brain abnormalities in schizophrenia, as we found that cumulative doses of antipsychotics affected brain volumes globally rather than selectively on frontal-temporal regions.