MIR137 polygenic risk for schizophrenia and ephrin-regulated pathway: Role in lateral ventricles and corpus callosum volume.

Background/Objective. Enlarged lateral ventricle (LV) volume and decreased volume in the corpus callosum (CC) are hallmarks of schizophrenia (SZ). We previously showed an inverse correlation between LV and CC volumes in SZ, with global functioning decreasing with increased LV volume. This study investigates the relationship between LV volume, CC abnormalities, and the microRNA MIR137 and its regulated genes in SZ, because of MIR137's essential role in neurodevelopment. Methods. Participants were 1224 SZ probands and 1466 unaffected controls from the GENUS Consortium. Brain MRI scans, genotype, and clinical data were harmonized across cohorts and employed in the analyses. Results. Increased LV volumes and decreased CC central, mid-anterior, and mid-posterior volumes were observed in SZ probands. The MIR137-regulated ephrin pathway was significantly associated with CC:LV ratio, explaining a significant proportion (3.42 %) of CC:LV variance, and more than for LV and CC separately. Other pathways explained variance in either CC or LV, but not both. CC:LV ratio was also positively correlated with Global Assessment of Functioning, supporting previous subsample findings. SNP-based heritability estimates were higher for CC central:LV ratio (0.79) compared to CC or LV separately. Discussion. Our results indicate that the CC:LV ratio is highly heritable, influenced in part by variation in the MIR137-regulated ephrin pathway. Findings suggest that the CC:LV ratio may be a risk indicator in SZ that correlates with global functioning.

Early weight measures and long-term neuropsychological outcome of critically ill neonates and infants: a secondary analysis of the PEPaNIC trial.

Neonates and infants surviving critical illness show impaired growth during critical illness and are at risk for later neuropsychological impairments. Early identification of individuals most at risk is needed to provide tailored long-term follow-up and care. The research question is whether early growth during hospitalization is associated with growth and neuropsychological outcomes in neonates and infants after pediatric intensive care unit admission (PICU). This is a secondary analysis of the PEPaNIC trial. Weight measurements upon PICU admission, at PICU discharge, at hospital discharge, at 2- and 4-year follow-up, and of different subgroups were compared using (paired) t-tests. Multiple linear regression analyses were performed to investigate the association between early growth in weight measures and neuropsychological outcomes at 4-year follow-up. One hundred twenty-one infants were included, and median age upon admission was 21 days. Growth in weight per week was less than the age-appropriate norm, resulting in a decrease in weight-for-age Z-score during hospitalization. Weight is normalized at 2- and 4-year follow-up. Weight gain in kilograms per week and change in weight Z-score were not associated with neurodevelopmental outcome measures at 4-year follow-up. Lower weight-for-age Z-score at PICU admission and at hospital discharge was associated only with lower weight and height Z-scores at 4-year follow-up. CONCLUSION: Growth in weight during hospital stay of young survivors of critical illness is impaired. Worse early growth in weight is associated with lower weight and height but not with neuropsychological outcomes at 4-year follow-up. WHAT IS KNOWN: • Critically ill neonates and infants show impaired early growth during admission and are at risk for later neuropsychological impairments. • Unraveling the association between early growth and later neuropsychological impairments is crucial since the first year of life is critical for brain development. WHAT IS NEW: • Critically ill neonates and infants had age appropriate weight measures at 4-year follow-up. • Poor growth in weight during hospital stay was not associated with poorer cognitive, emotional, or behavioral functioning four years after critical illness.

Simvastatin Augmentation for Patients With Early-Phase Schizophrenia-Spectrum Disorders: A Double-Blind, Randomized Placebo-Controlled Trial.

Schizophrenia-spectrum disorders (SSD) are associated with increased inflammatory markers, both in brain and periphery. Augmentation with drugs that lower this pro-inflammatory status may improve clinical presentation. Simvastatin crosses the blood-brain barrier, has anti- inflammatory and neuroprotective effects and reduces metabolic syndrome. In this study, we investigated if 12 months of simvastatin augmentation can improve symptoms and cognition in patients with early SSD. This double-blind placebo-controlled trial included 127 SSD patients across the Netherlands, <3 years after their diagnosis. From these, 119 were randomly assigned 1:1 to simvastatin 40 mg (n = 61) or placebo (n = 58), stratified for sex and study site. Primary outcomes were symptom severity and cognition after 12 months of treatment. Depression, symptom subscores, general functioning, metabolic syndrome, movement disorders, and safety were secondary outcomes. Intention to treat analyses were performed using linear mixed models and ANCOVA. No main effect of simvastatin treatment was found on total symptom severity after 12 months of treatment as compared to placebo (X2(1) = 0.01, P = .90). Group differences varied over time (treatment*time X2(4) = 11.2; P = .025), with significantly lower symptom severity in the simvastatin group after 6 months (mean difference = -4.8; P = .021; 95% CI: -8.8 to -0.7) and at 24 months follow-up (mean difference = -4.7; P = .040; 95% CI: -9.3 to -0.2). No main treatment effect was found for cognition (F(1,0.1) = 0.37, P = .55) or secondary outcomes. SAEs occurred more frequently with placebo (19%) than with simvastatin (6.6%). This negative finding corroborates other large scale studies on aspirin, minocycline, and celecoxib that could not replicate positive findings of smaller studies, and suggests that anti-inflammatory augmentation does not improve the clinical presentation of SSD.

The ACCEPT-study: design of an RCT with an active treatment control condition to study the effectiveness of the Dutch version of PEERS® for adolescents with autism spectrum disorder.

BACKGROUND: Social skills interventions are commonly deployed for adolescents with autism spectrum disorder (ASD). Because effective and appropriate social skills are determined by cultural factors that differ throughout the world, the effectiveness of these interventions relies on a good cultural fit. Therefore, the ACCEPT study examines the effectiveness of the Dutch Program for the Education and Enrichment of Relational Skills (PEERS®) social skills intervention. METHODS/DESIGN: This study is a two-arm parallel group randomized controlled trial (RCT) in which adolescents are randomly assigned (after baseline assessment) to one of two group interventions (PEERS® vs. active control condition). In total, 150 adolescents are to be included, with multi-informant involvement of their parents and teachers. The ACCEPT study uses an active control condition (puberty psychoeducation group training, focussing on social-emotional development) and explores possible moderators and mediators in improving social skills. The primary outcome measure is the Contextual Assessment of Social Skills (CASS). The CASS assesses social skills performance in a face to face social interaction with an unfamiliar, typically developing peer, making this a valuable instrument to assess the social conversational skills targeted in PEERS®. In addition, to obtain a complete picture of social skills, self-, parent- and teacher-reported social skills are assessed using the Social Skills improvement System (SSiS-RS) and Social Responsiveness Scale (SRS-2). Secondary outcome measures (i.e. explorative mediators) include social knowledge, social cognition, social anxiety, social contacts and feelings of parenting competency of caregivers. Moreover, demographic and diagnostic measures are assessed as potential moderators of treatment effectiveness. Assessments of adolescents, parents, and teachers take place at baseline (week 0), intermediate (week 7), post intervention (week 14), and at follow-up (week 28). CONCLUSION: This is the first RCT on the effectiveness of the PEERS® parent-assisted curriculum which includes an active control condition. The outcome of social skills is assessed using observational assessments and multi-informant questionnaires. Additionally, factors related to social learning are assessed at several time points, which will enable us to explore potential mediators and moderators of treatment effect. TRAIL REGISTRATION: Dutch trail register NTR6255 (NL6117). Registered February 8th, 2017 - retrospectively registered.

Change in IQ in schizophrenia patients and their siblings: a controlled longitudinal study.

BACKGROUND: Lower intelligence quotient (IQ) has frequently been reported in patients with schizophrenia. However, it is unclear whether IQ declines (further) after illness onset and what the familial contribution is to this change. Therefore, we investigate IQ changes during the course of illness in patients with non-affective psychosis, their siblings and controls. METHODS: Data are part of the longitudinal Genetic Risk and Outcome of Psychosis (GROUP) study in the Netherlands and Belgium. Participants underwent three measurements, each approximately 3 years apart. A total of 1022 patients with non-affective psychosis [illness duration: 4.34 (s.d. = 4.50) years], 977 of their siblings, and 565 controls had at least one measure of IQ (estimated from four subtests of the WAIS-III). RESULTS: At baseline, IQ was significantly lower in patients (IQ = 97.8) and siblings (IQ = 108.2; p < 0.0001) than in controls (IQ = 113.0; p < 0.0001), and in patients as compared with siblings (p < 0.0001). Over time, IQ increased in all groups. In siblings, improvement in IQ was significantly more pronounced (+0.7 points/year) than in patients (+0.5 points/year; p < 0.0001) and controls (+0.3 points/year; p < 0.0001). IQ increase was not significantly correlated with improvement in (sub)clinical outcome in any of the groups. CONCLUSIONS: During the first 10 years of the illness, IQ increases to a similar (and subtle) extent in a relatively high-functioning group of schizophrenia patients and controls, despite the lower IQ in patients at baseline. In addition, the siblings' IQ was intermediate at baseline, but over time the increase in IQ was more pronounced.

Reward-related brain structures are smaller in patients with schizophrenia and comorbid metabolic syndrome.

OBJECTIVE: Metabolic syndrome (MS) is highly prevalent in schizophrenia and often a consequence of unhealthy behaviour. Reward-related brain areas might be associated with MS, since they play a major role in regulating health behaviour. This study examined the relationship between MS and brain volumes related to the reward system in schizophrenia. METHOD: We included patients with schizophrenia, with MS (MS+; n = 23), patients with schizophrenia, without MS (MS-; n = 48), and healthy controls (n = 54). Global brain volumes and volumes of (sub)cortical areas, part of the reward circuit, were compared between patients and controls. In case of a significant brain volume difference between patients and controls, the impact of MS in schizophrenia was examined. RESULTS: Patients had smaller total brain (TB; P = 0.001), GM (P = 0.010), larger ventricles (P = 0.026), and smaller reward circuit volume (P < 0.001) than controls. MS+ had smaller TB (P = 0.017), GM (P = 0.008), larger ventricles (P = 0.015), and smaller reward circuit volume (P = 0.002) than MS-. MS+ had smaller orbitofrontal cortex (OFC; P = 0.002) and insula volumes (P = 0.005) and smaller OFC (P = 0.008) and insula cortical surface area (P = 0.025) compared to MS-. CONCLUSION: In schizophrenia, structural brain volume reductions in areas of the reward circuitry appear to be related to comorbid MS.

Prefrontal cortical thinning links to negative symptoms in schizophrenia via the ENIGMA consortium.

BACKGROUND: Our understanding of the complex relationship between schizophrenia symptomatology and etiological factors can be improved by studying brain-based correlates of schizophrenia. Research showed that impairments in value processing and executive functioning, which have been associated with prefrontal brain areas [particularly the medial orbitofrontal cortex (MOFC)], are linked to negative symptoms. Here we tested the hypothesis that MOFC thickness is associated with negative symptom severity. METHODS: This study included 1985 individuals with schizophrenia from 17 research groups around the world contributing to the ENIGMA Schizophrenia Working Group. Cortical thickness values were obtained from T1-weighted structural brain scans using FreeSurfer. A meta-analysis across sites was conducted over effect sizes from a model predicting cortical thickness by negative symptom score (harmonized Scale for the Assessment of Negative Symptoms or Positive and Negative Syndrome Scale scores). RESULTS: Meta-analytical results showed that left, but not right, MOFC thickness was significantly associated with negative symptom severity (ß std = -0.075; p = 0.019) after accounting for age, gender, and site. This effect remained significant (p = 0.036) in a model including overall illness severity. Covarying for duration of illness, age of onset, antipsychotic medication or handedness weakened the association of negative symptoms with left MOFC thickness. As part of a secondary analysis including 10 other prefrontal regions further associations in the left lateral orbitofrontal gyrus and pars opercularis emerged. CONCLUSIONS: Using an unusually large cohort and a meta-analytical approach, our findings point towards a link between prefrontal thinning and negative symptom severity in schizophrenia. This finding provides further insight into the relationship between structural brain abnormalities and negative symptoms in schizophrenia.

Impaired self-agency inferences in schizophrenia: The role of cognitive capacity and causal reasoning style.

BACKGROUND: The sense of self-agency, i.e., experiencing oneself as the cause of one's own actions, is impaired in patients with schizophrenia. Normally, inferences of self-agency are enhanced when actual outcomes match with pre-activated outcome information, where this pre-activation can result from explicitly set goals (i.e., goal-based route) or implicitly primed outcome information (i.e., prime-based route). Previous research suggests that patients show specific impairments in the prime-based route, implicating that they do not rely on matches between implicitly available outcome information and actual action-outcomes when inferring self-agency. The question remains: Why? Here, we examine whether neurocognitive functioning and self-serving bias (SSB) may explain abnormalities in patients' agency inferences. METHODS: Thirty-six patients and 36 healthy controls performed a commonly used agency inference task to measure goal- and prime-based self-agency inferences. Neurocognitive functioning was assessed with the Brief Assessment of Cognition in Schizophrenia (BACS) and the SSB was assessed with the Internal Personal and Situational Attributions Questionnaire. RESULTS: Results showed a substantial smaller effect of primed outcome information on agency experiences in patients compared with healthy controls. Whereas patients and controls differed on BACS and marginally on SSB scores, these differences were not related to patients' impairments in prime-based agency inferences. CONCLUSIONS: Patients showed impairments in prime-based agency inferences, thereby replicating previous studies. This finding could not be explained by cognitive dysfunction or SSB. Results are discussed in the context of the recent surge to understand and examine deficits in agency experiences in schizophrenia.

Positive symptoms associate with cortical thinning in the superior temporal gyrus via the ENIGMA Schizophrenia consortium.

OBJECTIVE: Based on the role of the superior temporal gyrus (STG) in auditory processing, language comprehension and self-monitoring, this study aimed to investigate the relationship between STG cortical thickness and positive symptom severity in schizophrenia. METHOD: This prospective meta-analysis includes data from 1987 individuals with schizophrenia collected at seventeen centres around the world that contribute to the ENIGMA Schizophrenia Working Group. STG thickness measures were extracted from T1-weighted brain scans using FreeSurfer. The study performed a meta-analysis of effect sizes across sites generated by a model predicting left or right STG thickness with a positive symptom severity score (harmonized SAPS or PANSS-positive scores), while controlling for age, sex and site. Secondary models investigated relationships between antipsychotic medication, duration of illness, overall illness severity, handedness and STG thickness. RESULTS: Positive symptom severity was negatively related to STG thickness in both hemispheres (left: ßstd = -0.052; P = 0.021; right: ßstd = -0.073; P = 0.001) when statistically controlling for age, sex and site. This effect remained stable in models including duration of illness, antipsychotic medication or handedness. CONCLUSION: Our findings further underline the important role of the STG in hallmark symptoms in schizophrenia. These findings can assist in advancing insight into symptom-relevant pathophysiological mechanisms in schizophrenia.

A study of genetic and environmental contributions to structural brain changes over time in twins concordant and discordant for bipolar disorder.

This is the first longitudinal twin study examining genetic and environmental contributions to the association between liability to bipolar disorder (BD) and changes over time in global brain volumes, and global and regional measures of cortical surface area, cortical thickness and cortical volume. A total of 50 twins from pairs discordant or concordant for BD (monozygotic: 8 discordant and 3 concordant pairs, and 1 patient and 3 co-twins from incomplete pairs; dizygotic: 6 discordant and 2 concordant pairs, and 1 patient and 7 co-twins from incomplete pairs) underwent magnetic resonance imaging twice. In addition, 57 twins from healthy twin pairs (15 monozygotic and 10 dizygotic pairs, and 4 monozygotic and 3 dizygotic subjects from incomplete pairs) were also scanned twice. Mean follow-up duration for all twins was 7.5 years (standard deviation: 1.5 years). Data were analyzed using structural equation modeling software OpenMx. The liability to BD was not associated with global or regional structural brain changes over time. Although we observed a subtle increase in cerebral white matter in BD patients, this effect disappeared after correction for multiple comparisons. Heritability of brain changes over time was generally low to moderate. Structural brain changes appear to follow similar trajectories in BD patients and healthy controls. Existing brain abnormalities in BD do not appear to progressively change over time, but this requires additional confirmation. Further study with large cohorts is recommended to assess genetic and environmental influences on structural brain abnormalities in BD, while taking into account the influence of lithium on the brain.

Subcortical brain volume abnormalities in 2028 individuals with schizophrenia and 2540 healthy controls via the ENIGMA consortium.

The profile of brain structural abnormalities in schizophrenia is still not fully understood, despite decades of research using brain scans. To validate a prospective meta-analysis approach to analyzing multicenter neuroimaging data, we analyzed brain MRI scans from 2028 schizophrenia patients and 2540 healthy controls, assessed with standardized methods at 15 centers worldwide. We identified subcortical brain volumes that differentiated patients from controls, and ranked them according to their effect sizes. Compared with healthy controls, patients with schizophrenia had smaller hippocampus (Cohen's d=-0.46), amygdala (d=-0.31), thalamus (d=-0.31), accumbens (d=-0.25) and intracranial volumes (d=-0.12), as well as larger pallidum (d=0.21) and lateral ventricle volumes (d=0.37). Putamen and pallidum volume augmentations were positively associated with duration of illness and hippocampal deficits scaled with the proportion of unmedicated patients. Worldwide cooperative analyses of brain imaging data support a profile of subcortical abnormalities in schizophrenia, which is consistent with that based on traditional meta-analytic approaches. This first ENIGMA Schizophrenia Working Group study validates that collaborative data analyses can readily be used across brain phenotypes and disorders and encourages analysis and data sharing efforts to further our understanding of severe mental illness.

Genetic and environmental influences on cortical surface area and cortical thickness in bipolar disorder.

BACKGROUND: The risk of developing bipolar disorder (BD) has been linked to structural brain abnormalities. The degree to which genes and environment influence the association of BD with cortical surface area remains to be elucidated. In this twin study, genetic and environmental contributions to the association between liability to develop BD and surface area, thickness and volume of the cortex were examined. METHOD: The study cohort included 44 affected monozygotic (nine concordant, 12 discordant) and dizygotic (four concordant, 19 discordant) twin pairs, and seven twins from incomplete discordant monozygotic and dizygotic discordant twin pairs. In addition, 37 monozygotic and 24 dizygotic healthy control twin pairs, and six twins from incomplete monozygotic and dizygotic control pairs were included. RESULTS: Genetic liability to develop BD was associated with a larger cortical surface in limbic and parietal regions, and a thicker cortex in central and parietal regions. Environmental factors related to BD were associated with larger medial frontal, parietal and limbic, and smaller orbitofrontal surfaces. Furthermore, thinner frontal, limbic and occipital cortex, and larger frontal and parietal, and smaller orbitofrontal volumes were also associated with environmental factors related to BD. CONCLUSIONS: Our results suggest that unique environmental factors play a prominent role in driving the associations between liability to develop BD and cortical measures, particularly those involving cortical thickness. Further evaluation of their influence on the surface and thickness of the cortical mantle is recommended. In addition, cortical volume appeared to be primarily dependent on surface and not thickness.

Schizophrenia genetic variants are not associated with intelligence.

BACKGROUND: Schizophrenia is associated with lower pre-morbid intelligence (IQ) in addition to (pre-morbid) cognitive decline. Both schizophrenia and IQ are highly heritable traits. Therefore, we hypothesized that genetic variants associated with schizophrenia, including copy number variants (CNVs) and a polygenic schizophrenia (risk) score (PSS), may influence intelligence. METHOD: IQ was estimated with the Wechsler Adult Intelligence Scale (WAIS). CNVs were determined from single nucleotide polymorphism (SNP) data using the QuantiSNP and PennCNV algorithms. For the PSS, odds ratios for genome-wide SNP data were calculated in a sample collected by the Psychiatric Genome-Wide Association Study (GWAS) Consortium (8690 schizophrenia patients and 11 831 controls). These were used to calculate individual PSSs in our independent sample of 350 schizophrenia patients and 322 healthy controls. RESULTS: Although significantly more genes were disrupted by deletions in schizophrenia patients compared to controls (p = 0.009), there was no effect of CNV measures on IQ. The PSS was associated with disease status (R 2 = 0.055, p = 2.1 × 10-7) and with IQ in the entire sample (R 2 = 0.018, p = 0.0008) but the effect on IQ disappeared after correction for disease status. CONCLUSIONS: Our data suggest that rare and common schizophrenia-associated variants do not explain the variation in IQ in healthy subjects or in schizophrenia patients. Thus, reductions in IQ in schizophrenia patients may be secondary to other processes related to schizophrenia risk.

Is there change in intelligence quotient in chronically ill schizophrenia patients? A longitudinal study in twins discordant for schizophrenia.

BACKGROUND: Intellectual deficits are commonly found in schizophrenia patients. These intellectual deficits have been found to be heritable. However, whether the intellectual deficits change over time and, if so, whether the change is related with an increased genetic risk for the disease are not known. METHOD: We investigated change of intelligence quotient (IQ) in a twin sample of chronically ill schizophrenia patients, the discordant co-twins and healthy controls during a follow-up period of 5 years. A total of 52 twins completed two IQ assessments: nine patients [three monozygotic (MZ) and six dizygotic (DZ)], 10 unaffected co-twins (three MZ and seven DZ) and 33 healthy control twins (21 MZ and 12 DZ). RESULTS: A significant interaction effect over time was found between IQ measurement and illness (F=4.22, df=1, p<0.05), indicating that change in IQ over time is significantly different between the groups. A stable course in IQ over time was found in the patients with schizophrenia (mean IQ from 109.78 at baseline to 108.44 at follow-up) relative to both the healthy control twins who showed a small increase (from 114.61 at baseline to 119.18 at follow-up) (t=2.06, p<0.05) and the unaffected co-twins (from 111.60 to 117.60, t=-2.32, p<0.05). IQ change in the unaffected co-twins of schizophrenia patients was comparable with that in healthy control twins (t=-0.49, p=0.63). CONCLUSIONS: Patients with schizophrenia in the chronic phase of the disease, but not the discordant co-twins, show a lack of increase in IQ, which is probably due to environmental (non-genetic) factors related to the disease.

Symptom dimensions are associated with progressive brain volume changes in schizophrenia.

BACKGROUND: There is considerable variation in progressive brain volume changes in schizophrenia. Whether this is related to the clinical heterogeneity that characterizes the illness remains to be determined. This study examines the relationship between change in brain volume over time and individual variation in psychopathology, as measured by five continuous symptom dimensions (i.e. negative, positive, disorganization, mania and depression). METHODS: Global brain volume measurements from 105 schizophrenia patients and 100 healthy comparison subjects, obtained at inclusion and 5-year follow-up, were used in this study. Symptom dimension scores were calculated by factor analysis of clinical symptoms. Using linear regression analyses and independent-samples t-tests, the relationship between symptom dimensions and progressive brain volume changes, corrected for age, gender and intracranial volume, was examined. Antipsychotic medication, outcome and IQ were investigated as potential confounders. RESULTS: In patients, the disorganization dimension was associated with change in total brain (ß=-0.295, p=0.003) and cerebellar (ß=-0.349, p<0.001) volume. Furthermore, higher levels of disorganization were associated with lower IQ, irrespective of psychiatric status (i.e. patient or control). In healthy comparison subjects, disorganization score was not associated with progressive brain volume changes. CONCLUSION: Heterogeneity in progressive brain volume changes in schizophrenia is particularly associated with variation in disorganization. Schizophrenia patients with high levels of disorganization exhibit more progressive decrease of global brain volumes and have lower total IQ. We propose that these patients form a phenotypically and biologically homogenous subgroup that may be useful for etiological (e.g., genetic) studies.

Brain volume reductions in medication-naive patients with schizophrenia in relation to intelligence quotient.

BACKGROUND: Global brain abnormalities such as brain volume loss and grey- and white-matter deficits are consistently reported in first-episode schizophrenia patients and may already be detectable in the very early stages of the illness. Whether these changes are dependent on medication use or related to intelligence quotient (IQ) is still debated. METHOD: Magnetic resonance imaging scans were obtained for 20 medication-naive patients with first-episode schizophrenia and 26 matched healthy subjects. Volume measures of total brain grey and white matter, third and lateral ventricles and cortical thickness/surface were obtained. Differences between the groups were investigated, taking into account the effect of intelligence. RESULTS: Medication-naive patients showed statistically significant reductions in whole-brain volume and cerebral grey- and white-matter volume together with lateral ventricle enlargement compared to healthy subjects. IQ was significantly lower in patients compared to controls and was positively associated with brain and white-matter volume in the whole group. No significant differences in cortical thickness were found between the groups but medication-naive patients had a significantly smaller surface in the left superior temporal pole, Heschl's gyrus and insula compared to controls. CONCLUSIONS: Our findings suggest that brain volume loss is present at illness onset, and can be explained by the reduced surface of the temporal and insular cortex. These abnormalities are not related to medication, but IQ.

Cigarette smoking and progressive brain volume loss in schizophrenia.

It is unknown whether the reported brain loss in schizophrenia can be attributed to the effects of tobacco smoking. 96 Patients (54 smokers/42 non-smokers) and 113 control subjects (35/78) were included in a 5-year longitudinal MRI study. Despite the higher prevalence of smoking behavior and the higher number of cigarettes consumed per day in the patients, cigarette smoking did not explain the excessive cerebral (gray matter) volume decreases in the patients. Moreover, smoking was not associated with brain volume change over time in the healthy subjects. However, extremely heavy smoking may contribute to excessive gray matter volume loss in schizophrenia.

Psychosis and brain volume changes during the first five years of schizophrenia.

The underlying mechanisms explaining brain volume changes in schizophrenia are not yet understood, but psychosis might be related to these changes. Forty-eight patients with first-episode schizophrenia underwent Magnetic Resonance Imaging brain scanning at inclusion and after five years. An association was found between longer duration of psychosis, larger gray matter volume decrease and larger ventricular volume increase. These findings strongly suggest that psychosis contributes to brain volume reductions found in schizophrenia.

Schizophrenia as a progressive brain disease.

There is convincing evidence that schizophrenia is characterized by abnormalities in brain volume. At the Department of Psychiatry of the University Medical Centre Utrecht, Netherlands, we have been carrying out neuroimaging studies in schizophrenia since 1995. We focused our research on three main questions. First, are brain volume abnormalities static or progressive in nature? Secondly, can brain volume abnormalities in schizophrenia be explained (in part) by genetic influences? Finally, what environmental factors are associated with the brain volume abnormalities in schizophrenia? Based on our findings we suggest that schizophrenia is a progressive brain disease. We showed different age-related trajectories of brain tissue loss suggesting that brain maturation that occurs in the third and fourth decade of life is abnormal in schizophrenia. Moreover, brain volume has been shown to be a useful phenotype for studying schizophrenia. Brain volume is highly heritable and twin and family studies show that unaffected relatives show abnormalities that are similar, but usually present to a lesser extent, to those found in the patients. However, also environmental factors play a role. Medication intake is indeed a confounding factor when interpreting brain volume (change) abnormalities, while independent of antipsychotic medication intake brain volume abnormalities appear influenced by the outcome of the illness. In conclusion, schizophrenia can be considered as a progressive brain disease with brain volume abnormalities that are for a large part influenced by genetic factors. Whether the progressive volume change is also mediated by genes awaits the results of longitudinal twin analyses. One of the main challenges for the coming years, however, will be the search for gene-by-environment interactions on the progressive brain changes in schizophrenia.