Biological Psychiatry

A brief summary of the articles appearing in this issue of Biological Psychiatry

2009-12-01

In this review, Tam et al. (pages 1005–1012) discuss the recent progress in the detection and interpretation of copy number variations in schizophrenia. These previously unknown deletions and duplications in the genome of schizophrenia patients have begun to provide insight into the underlying susceptibility genetic factors, biological pathways and genetic architecture related to schizophrenia, and may continue to reveal information about other psychiatric disorders.

Endophenotypes: Bridging Genomic Complexity and Disorder Heterogeneity

Thomas R. Insel, Bruce N. Cuthbert — 2009-12-01

As will be familiar to most readers of this journal, endophenotypes are relatively well-specified physiological or behavioral measures that are considered to occupy the terrain between disease symptoms and risk genotypes. The endophenotype concept has been an enduring feature in psychiatry for nearly 40 years, since its introduction in the classic monograph by Gottesman and Shields (). However, endophenotypes have enjoyed accelerating popularity in recent years due to their potential associations with genomic data to provide a way forward for parsing complex, heterogeneous disease phenotypes such as schizophrenia. Several excellent articles on theory and data for schizophrenia endophenotypes have appeared recently (e.g., []), but detailed consideration of these articles is beyond the scope of this brief commentary. Rather, we wish to note some salient issues with respect to endophenotype research for schizophrenia and other psychiatric disorders. The two articles on candidate endophenotypes relevant to schizophrenia that appear in this issue, each excellent in their own way, represent topical illustrations of these issues.

Mixture Model Clustering of Phenotype Features Reveals Evidence for Association of DTNBP1 to a Specific Subtype of Schizophrenia

2009-09-28

Background: While DTNBP1, DISC1, and NRG1 have been extensively studied as candidate genes of schizophrenia, results remain inconclusive. Possible explanations for this are that the genes might be relevant only to certain subtypes of the disease and/or only in certain populations.Methods: We performed unsupervised clustering of individuals from Finnish schizophrenia families, based on extensive clinical and neuropsychological data, including Structured Clinical Interview for DSM-IV (SCID) information. Families with at least one affected member with DSM-IV diagnosis of a schizophrenia spectrum psychosis were included in a register-based ascertainment. Final sample consisted of 904 individuals from 288 families. We then used the cluster phenotypes in a genetic association study of candidate genes.Results: A robust three-class clustering of individuals emerged: 1) psychotic disorder with mood symptoms (n = 172), 2) core schizophrenia (n = 223), and 3) absence of psychotic disorder (n = 509). One third of the individuals diagnosed with schizophrenia were assigned to cluster 1. These individuals had fewer negative and positive psychotic symptoms and cognitive deficits but more depressive symptoms than individuals in cluster 2. There was a significant association of cluster 2 cases with the DTNBP1 gene, while the DISC1 gene indicated a significant association with schizophrenia spectrum disorders based on the DSM-IV criteria.Conclusions: In the Finnish population, DTNBP1 gene is associated with a schizophrenia phenotype characterized by prominent negative symptoms, generalized cognitive impairment, and few mood symptoms. Identification of genes and pathways related to schizophrenia necessitates novel definitions of disease phenotypes associated more directly with underlying biology.

Tolcapone Effects on Gating, Working Memory, and Mood Interact with the Synonymous Catechol-O-methyltransferase rs4818C/G Polymorphism

Panos Roussos, Stella G. Giakoumaki, Panos Bitsios — 2009-08-25

Background: The functional catechol-O-methyltransferase (COMT) valine158methionine (val158met) polymorphism determines prepulse inhibition (PPI) levels and working memory performance and the effects of tolcapone on these functions. Here, we explored the effects of the synonymous COMT rs4818 C/G polymorphism and tolcapone on PPI and working memory.Methods: Thirteen G/G (low prefrontal cortex [PFC] dopamine [DA]) and 12 C/C (high PFC DA) healthy male subjects entered and completed the study. Subjects participated in two weekly sessions associated with either acute oral tolcapone (200 mg) or placebo according to a balanced, crossover, double-blind design. Prepulse inhibition was assessed with 5 dB and 15 dB above background prepulses at 30-msec, 60-msec, and 120-msec intervals. Subjective mood and working memory performance (n-back and letter-number sequencing) were also assessed.Results: Prepulse inhibition was lower and reaction time in the n-back was slower in the G/G compared with the C/C group in the placebo condition. Tolcapone increased PPI and improved performance in both working memory tasks in the G/G group only. Baseline startle was greater in the C/C group and was not affected by tolcapone. Mood profile was worse in the C/C group and tended to deteriorate with tolcapone. Status of val158met alone could not explain these results.Conclusions: Catechol-O-methyltransferase haplotype analyses are essential in future research. Prepulse inhibition and working memory may both relate to PFC DA levels according to an inverted U-shaped curve function. Tolcapone could be potentially useful in the treatment of conditions with deficient sensorimotor gating and working memory such as schizophrenia and prodromal states but only in a genotype-specific manner.

The Role of DNA Copy Number Variation in Schizophrenia

Gloria W.C. Tam, Richard Redon, Nigel P. Carter, Seth G.N. Grant — 2009-09-14

Schizophrenia is a major psychiatric disease with strong evidence of genetic risk factors. Recent studies based on genome-wide study of copy number variations (CNVs) have detected novel recurrent submicroscopic copy number changes, including recurrent deletions at 1q21.11, 15q11.3, 15q13.3, and the recurrent CNV at the 2p16.3 neurexin 1 locus. These schizophrenia susceptibility CNV loci demonstrate that schizophrenia is, at least in part, genetic in origin and provide the basis for further investigation of mutations associated with the disease. The studies combined have also established the role of rare and—in sporadic cases—de novo variants in schizophrenia. Furthermore, neuronal-related genes and genetic pathways are starting to emerge from the CNV loci associated with schizophrenia. Here, we review the major findings in the recent literature, which begin to unravel the genetic and biological architecture of this complex human neuropsychiatric disorder.

Inflammatory Markers in Schizophrenia: Comparing Antipsychotic Effects in Phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness Study

2009-07-30

Background: C-reactive protein (CRP), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin are systemic inflammatory markers (IM) that positively correlate with cardiovascular (CV) risk. Despite the known CV effects of atypical antipsychotics, there is limited prospective data on IM changes during treatment.Methods: The IM outcomes were compared between antipsychotic treatment groups in the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) schizophrenia trial phase 1 with subjects with laboratory assessments at baseline and 3 months (n = 789).Results: There were significant treatment differences in CRP, E-selectin, and ICAM-1 at 3 months, with a differential impact of baseline values on the CRP and ICAM-1 results. In overall comparisons, quetiapine and olanzapine had the highest median levels for CRP, and olanzapine for E-selectin and ICAM-1. Olanzapine was significantly different after baseline adjustment than perphenazine (p = .001) for E-selectin, and in those with low baseline CRP (<1 mg/L), olanzapine was significantly different than perphenazine (p < .001), risperidone (p < .001), and ziprasidone (p = .002) for CRP. Perphenazine had the lowest 3-month ICAM-1 levels in subjects with baseline ICAM-1 above the median, but the differences were not statistically significant versus olanzapine (p = .010), quetiapine (p = .010), and risperidone (p = .006) after controlling for multiple comparisons. The 18-month repeated measures CRP analysis confirmed the significantly higher values for olanzapine in those with low baseline CRP.Conclusions: This analysis provides further evidence for differential antipsychotic metabolic liabilities as measured by changes in systemic inflammation. C-reactive protein might emerge as a useful target for CV risk outcomes in schizophrenia patients.

Efficacy of Using Cognitive Status in Predicting Psychosis: A 7-Year Follow-Up

2009-09-07

Background: Despite extensive early detection research in schizophrenic psychoses, methods for identifying at-risk individuals and predicting their transition to psychosis are still unreliable. Moreover, there are sparse data on long-term prediction. We therefore investigated long-term psychosis transition in individuals with an At Risk Mental State (ARMS) and examined the relative efficacy of clinical and neuropsychological status in optimizing the prediction of transition.Methods: Sixty-four individuals with ARMS for psychosis were identified from all referrals to our early detection clinic between March 1, 2000 and February 29, 2004. Fifty-three (83%) were followed up for up to 7 (mean 5.4) years.Results: Twenty-one of the 53 staying in follow-up developed psychosis, corresponding to a transition rate of .34 (Kaplan–Meier estimates). Median time to transition was 10 months (range <1–55). Six of all transitions (29%) occurred only after 12 months from referral. Best transition predictors within this population were selected attenuated psychotic symptoms (suspiciousness), negative symptoms (anhedonia/asociality), and cognitive deficits (reduced speed of information processing). With these predictors in an integrated model for predicting transition to psychosis, the overall predictive accuracy was 80.9% with a sensitivity of 83.3% and a specificity of 79.3%.Conclusions: Follow-up of ARMS subjects should exceed the usual 12 months. Prediction of transitions could be improved by a stronger weighting of certain early symptoms and by introducing neurocognitive tests into a stepwise risk assessment. Confirmatory research will hopefully further improve risk algorithm, including psychopathology and neuropsychological performance, for clinical application in early detection clinics.

Metacognition in Schizophrenia: Processes Underlying Patients' Reflections on Their Own Episodic Memory

Elisabeth Bacon, Marie Izaute — 2009-09-03

Background: The aim of the study was to explore the processes underlying schizophrenia patients' reflections on their own memory. Cognitive deficits and insight problems are considered core symptoms of schizophrenia. Even when people fail to recall a solicited target, they can provide feeling of knowing (FOK) judgments that reflect their ability to judge the accessibility of the target in memory. The metamemory approach allows for direct and experimental quantification of the correspondence between the subjective judgments and the objective measures of memory performance. According to the accessibility hypothesis, FOK evaluations rely on the accessibility of partial and/or contextual information relevant to the memory target.Methods: The accessibility of partial information relating to a memory target was investigated in 21 patients and 21 healthy comparison subjects matched for age, gender, and level of education. The material to be learned consisted of four-letter nonsense tetragrams, with each letter providing partial information about the four-letter target.Results: The results show that despite memory recall (p < .01) and recognition impairments (p = .02) and lower FOK ratings (p < .05), patients' metamemory judgments increased linearly with the amount of partial information recalled (from one letter to four letters, p < .01). The products of memory retrieval were predictive of both their FOK judgments and their subsequent memory performance.Conclusions: Schizophrenia patients are as capable as comparison subjects of relying on the products of memory retrieval to monitor accurately their awareness of what they do or do not know. The finding may be of interest for cognitive remediation.

Clozapine Administration in Adolescence Prevents Postpubertal Emergence of Brain Structural Pathology in an Animal Model of Schizophrenia

Yael Piontkewitz, Yaniv Assaf, Ina Weiner — 2009-09-03

Background: Schizophrenia is a neuropsychiatric disorder of a neurodevelopmental origin manifested symptomatically after puberty. Structural neuroimaging studies show that neuroanatomical aberrations occur before onset of symptoms, raising a question of whether schizophrenia can be prevented. Treatment with atypical antipsychotic drugs before the development of the full clinical phenotype might reduce the risk of transition to psychosis, but it remains unknown whether neuroanatomical abnormalities can be prevented. We used a neurodevelopmental animal model of schizophrenia to assess the efficacy of the atypical antipsychotic clozapine to prevent neuroanatomical deterioration.Methods: Pregnant rats received injection on gestational day 15 with the viral mimic polyriboinosinic-polyribocytidylic acid (PolyI:C) or saline. Structural brain changes in the male offspring were assessed at adolescence and adulthood (35 days and 120 days) with structural neuroimaging. In the second part, male offspring of PolyI:C- and saline-treated dams received daily clozapine (7.5 mg/kg) or saline injection in adolescence (days 34–47) and underwent behavioral testing and imaging at adulthood (from 90 days onward).Results: In utero exposure to maternal infection led in the offspring to postpubertal emergence of hallmark structural abnormalities associated with schizophrenia, enlarged ventricles, and smaller hippocampus. These abnormalities were not observed in the offspring of mothers who received PolyI:C that were treated with clozapine in adolescence. This was paralleled by prevention of behavioral abnormalities phenotypic of schizophrenia, attentional deficit, and hypersensitivity to amphetamine.Conclusions: This is the first demonstration that pharmacological intervention during adolescence can prevent the emergence of brain structural changes resulting from in-utero insult.

Gyral and Sulcal Cortical Thinning in Adolescents with First Episode Early-Onset Psychosis

2009-09-01

Background: Psychosis is associated with volumetric decreases of cortical structures. Whether these volumetric decreases imply abnormalities in cortical thickness, surface, or cortical folding is not clear. Due to differences in cytoarchitecture, cortical gyri and sulci might be differentially affected by psychosis. Therefore, we examined differences in gyral and sulcal cortical thickness, surface, folding, and volume between a minimally treated male adolescent population with early-onset first-episode psychosis (EOP) and a healthy control group, with surface-based morphometry.Methods: Magnetic resonance imaging brain scans were obtained from 49 adolescent EOP patients and 34 healthy control subjects. Subjects were younger than 18 years (age range 12 years–18 years), and EOP patients had a duration of positive symptoms of <6 months.Results: Early-onset first-episode psychosis was associated with local bilateral cortical thinning and volume deficits in both the gyri and sulci of the superior temporal cortex and the inferior, middle, medial, and superior prefrontal cortex. In the pars triangularis and opercularis cortex of patients, gyral cortical thickness was thinner, whereas sulcal thickness was not. Patients exhibited cortical thinning together with a decreased degree of cortical folding in the right superior frontal cortex.Conclusions: Cortical thinning of both gyri and sulci seem to underlie most cortical volume deficits in adolescent patients with EOP. Except for the right superior frontal region, the degree of cortical folding was normal in regions showing decreased cortical thickness, suggesting that the process of cortical thinning in adolescent patients with EOP primarily takes place after the formation of cortical folds.

Elucidating a Magnetic Resonance Imaging-Based Neuroanatomic Biomarker for Psychosis: Classification Analysis Using Probabilistic Brain Atlas and Machine Learning Algorithms

2009-09-04

Background: No objective diagnostic biomarkers or laboratory tests have yet been developed for psychotic illness. Magnetic resonance imaging (MRI) studies consistently find significant abnormalities in multiple brain structures in psychotic patients relative to healthy control subjects, but these abnormalities show substantial overlap with anatomic variation that is in the normal range and therefore nondiagnostic. Recently, efforts have been made to discriminate psychotic patients from healthy individuals using machine-learning-based pattern classification methods on MRI data.Methods: Three-dimensional cortical gray matter density (GMD) maps were generated for 36 patients with recent-onset psychosis and 36 sex- and age-matched control subjects using a cortical pattern matching method. Between-group differences in GMD were evaluated. Second, the sparse multinomial logistic regression classifier included in the Multivariate Pattern Analysis in Python machine-learning package was applied to the cortical GMD maps to discriminate psychotic patients from control subjects.Results: Patients showed significantly lower GMD, particularly in prefrontal, cingulate, and lateral temporal brain regions. Pattern classification analysis achieved 86.1% accuracy in discriminating patients from controls using leave-one-out cross-validation.Conclusions: These results suggest that even at the early stage of illness, psychotic patients present distinct patterns of regional cortical gray matter changes that can be discriminated from the normal pattern. These findings indicate that we can detect complex patterns of brain abnormality in early stages of psychotic illness, which has critical implications for early identification and intervention in individuals at ultra-high risk for developing psychosis/schizophrenia.

Paternal Transmission of Complex Phenotypes in Inbred Mice

2009-07-06

Background: Inbred mice are genetically identical but nonetheless demonstrate substantial variability in complex behaviors such as activity levels in a novel environment. This variability has been associated with levels of parental care experienced early in development. Although maternal effects have been reported in biparental and uniparental strains, there have been no investigations of paternal effects in non-biparental strains in which offspring are reared exclusively by mothers.Methods: In the uniparental inbred Balb/cJ mouse strain, we examined the relationship of paternal open-field activity to the activity of both male and female offspring in the open-field. Potential mediators of paternal transmission of behavior were examined, including maternal care, growth parameters, litter characteristics, and time the father was present with the pregnant mother prenatally.Results: An association of paternal open-field activity with the open-field activity of female but not male offspring was found. Variation in maternal postnatal care was associated with female but not male offspring activity in the open-field but did not mediate paternal effects on offspring behavior. Paternal effects on offspring growth parameters were present, but these effects also did not mediate paternal effects on behavior.Conclusions: Paternal transmission of complex traits in genetically identical mice reared only by mothers suggests a nongenetic mechanism of inheritance potentially mediated by epigenetic factors. The exclusion of multiple mediators of paternal effects on offspring suggests the possibility of germline paternal inheritance via sperm of complex phenotypes in inbred mice. Future studies are required to examine these interesting possibilities.

Microstructural Organization of Cerebellar Tracts in Schizophrenia

2009-09-07

Background: Dysconnectivity theories of schizophrenia would suggest that the connectivity of the cerebellum is impaired and that the impairment may be restricted to certain tracts. Attempts to examine the structural connectivity of the cerebellum using diffusion tensor imaging have yielded conflicting results. However, previous studies have employed region-of-interest approaches or have used small or unmatched samples, with a consequent risk of type II error.Methods: We conducted an appropriately powered case-control study of 33 patients with schizophrenia and 33 matched healthy control subjects. We used tractography to dissect the four white matter tracts of the cerebellum and measured fractional anisotropy (FA) and mean diffusivity (MD) over each tract for each subject.Results: Repeated-measures analysis of variance found that FA was lower in the schizophrenia group compared with the control group, but there were no tract-specific differences between the groups. Mean diffusivity did not differ between the groups.Conclusions: Though structural connectivity is impaired in the cerebellum, it is not local to any particular tract but appears to have a wider, possibly global, distribution. Reduced fractional anisotropy with normal MD would point to the differences being due to disordered neuronal architecture rather than disordered myelination.

The following Biological Psychiatry articles in press are now available in full text at http://www.sobp.org/journal

2009-12-01

Our goal is to rapidly disseminate information to our readers. Pre-publication abstracts of accepted articles are posted on our website weekly, and upon availability of a corrected proof, full articles are immediately posted and citable. Articles posted since the last issue are listed below. Interested readers are encouraged to contact authors directly for information prior to publication and to read the associated article in its entirety upon publication.

In Memory of Elizabeth Young

Huda Akil, Stanley J. Watson, Gregory W. Dalack, John F. Greden, Jon-Kar Zubieta — 2009-12-01

Dr. Elizabeth Young, Professor of Psychiatry and Senior Research Professor at the Molecular and Behavioral Neuroscience Institute (MBNI) and member of the Depression Center at the University of Michigan passed away on September 1, 2009 after a yearlong battle with leukemia. She was 59 years old.

Editorial Board

2009-12-01

Subscribers Page

2009-12-01

Biological Psychiatry (ISSN 0006-3223) is published semimonthly by Elsevier Inc., 360 Park Avenue South, New York, NY 10010-1710. Periodicals postage paid at New York, NY and additional mailing offices.

2009-12-01

Guide for Authors

2009-12-01

Biological Psychiatry is the official journal of the Society of Biological Psychiatry. The Journal rapidly publishes reports of novel results on a broad range of topics related to the pathophysiology and treatment of major neuropsychiatric disorders. Both basic and clinical neuroscience contributions are encouraged, particularly those addressing genetic and environmental risk factors, neural circuitry and neurochemistry, and important new therapeutic approaches.

Manuscript Submission Form—Biological Psychiatry

2009-12-01

Section 1: Instructions. A copy of this form, with signatures included from ALL authors on the manuscript, must accompany every new manuscript submission before it will be considered for publication. Please fully complete to eliminate delays in submission. Use an additional form if there are more than 10 authors. Please scan this completed form and attach it electronically during the submission process. If you are unable to do so, fax the completed form to the Editorial Office at (214) 648-0881.

Biological Psychiatry

A brief summary of the articles appearing in this issue of Biological Psychiatry

Endophenotypes: Bridging Genomic Complexity and Disorder Heterogeneity

Mixture Model Clustering of Phenotype Features Reveals Evidence for Association of DTNBP1 to a Specific Subtype of Schizophrenia

Tolcapone Effects on Gating, Working Memory, and Mood Interact with the Synonymous Catechol-O-methyltransferase rs4818C/G Polymorphism

The Role of DNA Copy Number Variation in Schizophrenia

Inflammatory Markers in Schizophrenia: Comparing Antipsychotic Effects in Phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness Study

Efficacy of Using Cognitive Status in Predicting Psychosis: A 7-Year Follow-Up

Metacognition in Schizophrenia: Processes Underlying Patients' Reflections on Their Own Episodic Memory

Clozapine Administration in Adolescence Prevents Postpubertal Emergence of Brain Structural Pathology in an Animal Model of Schizophrenia

Gyral and Sulcal Cortical Thinning in Adolescents with First Episode Early-Onset Psychosis

Elucidating a Magnetic Resonance Imaging-Based Neuroanatomic Biomarker for Psychosis: Classification Analysis Using Probabilistic Brain Atlas and Machine Learning Algorithms

Paternal Transmission of Complex Phenotypes in Inbred Mice

Microstructural Organization of Cerebellar Tracts in Schizophrenia

The following Biological Psychiatry articles in press are now available in full text at http://www.sobp.org/journal

In Memory of Elizabeth Young

Editorial Board

Subscribers Page

Table of Contents

Guide for Authors

Manuscript Submission Form—Biological Psychiatry