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MOTIVATION:Polygenic risk score (PRS) methods based on genome-wide association studies (GWAS) have a potential for predicting the risk of developing complex diseases and are expected to become more accurate with larger training datasets and innovative statistical methods. The area under the ROC curve (AUC) is often used to evaluate the performance of PRSs, which requires individual genotypic and phenotypic data in an independent GWAS validation dataset. We are motivated to develop methods for approximating AUC of PRSs based on the summary level data of the validation dataset, which will greatly facilitate the development of PRS models for complex diseases. RESULTS:We develop statistical methods and an R package SummaryAUC for approximating the AUC and its variance of a PRS when only the summary level data of the validation dataset are available. SummaryAUC can be applied to PRSs with SNPs either genotyped or imputed in the validation dataset. We examined the performance of SummaryAUC using a large-scale GWAS of schizophrenia. SummaryAUC provides accurate approximations to AUCs and their variances. The bias of AUC is typically

Schizophrenia has a heritability of 60-80% 1 , much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Phylogenetic, developmental, and brain-imaging studies suggest that human personality is the integrated expression of three major systems of learning and memory that regulate (1) associative conditioning, (2) intentionality, and (3) self-awareness. We have uncovered largely disjoint sets of genes regulating these dissociable learning processes in different clusters of people with (1) unregulated temperament profiles (i.e., associatively conditioned habits and emotional reactivity), (2) organized character profiles (i.e., intentional self-control of emotional conflicts and goals), and (3) creative character profiles (i.e., self-aware appraisal of values and theories), respectively. However, little is known about how these temperament and character components of personality are jointly organized and develop in an integrated manner. In three large independent genome-wide association studies from Finland, Germany, and Korea, we used a data-driven machine learning method to uncover joint phenotypic networks of temperament and character and also the genetic networks with which they are associated. We found three clusters of similar numbers of people with distinct combinations of temperament and character profiles. Their associated genetic and environmental networks were largely disjoint, and differentially related to distinct forms of learning and memory. Of the 972 genes that mapped to the three phenotypic networks, 72% were unique to a single network. The findings in the Finnish discovery sample were blindly and independently replicated in samples of Germans and Koreans. We conclude that temperament and character are integrated within three disjoint networks that regulate healthy longevity and dissociable systems of learning and memory by nearly disjoint sets of genetic and environmental influences., (© 2019. The Author(s).)

Recent advances in the neuroscience of episodic memory provide a framework to integrate object relations theory, a psychoanalytic model of mind development, with potential neural mechanisms. Object relations are primordial cognitive-affective units of the mind derived from survival- and safety-level experiences with caretakers during phase-sensitive periods of infancy and toddlerhood. Because these are learning experiences, their neural substrate likely involves memory, here affect-enhanced episodic memory. Inaugural object relations are encoded by the hippocampus-amygdala synaptic plasticity, and systems-consolidated by medial prefrontal cortex (mPFC). Self- and object-mental representations, extracted from these early experiences, are at first dichotomized by contradictory affects evoked by frustrating and rewarding interactions ("partial object relations"). Such affective dichotomization appears to be genetically hardwired the amygdala. Intrinsic propensity of mPFC to form schematic frameworks for episodic memories may pilot non-conscious integration of dichotomized mental representations in neonates and infants. With the emergence of working memory in toddlers, an activated self- and object-representation of a particular valence can be juxtaposed with its memorized opposites creating a balanced cognitive-affective frame (conscious "integration of object relations"). Specific events of object relations are forgotten but nevertheless profoundly influence the mental future of the individual, acting (i) as implicit schema-affect templates that regulate attentional priorities, relevance, and preferential assimilation of new information based on past experience, and (ii) as basic units of experience that are, under normal circumstances, integrated as attractors or "focal points" for interactive self-organization of functional brain networks that underlie the mind. A failure to achieve integrated object relations is predictive of poor adult emotional and social outcomes, including personality disorder. Cognitive, cellular-, and systems-neuroscience of episodic memory appear to support key postulates of object relations theory and help elucidate neural mechanisms of psychodynamic psychotherapy. Derived through the dual prism of psychoanalysis and neuroscience, the gained insights may offer new directions to enhance mental health and improve treatment of multiple forms of psychopathology., Competing Interests: CZ is on Scientific Advisory Board of Sage Therapeutics. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Svrakic and Zorumski.)

Experimental studies of learning suggest that human temperament may depend on the molecular mechanisms for associative conditioning, which are highly conserved in animals. The main genetic pathways for associative conditioning are known in experimental animals, but have not been identified in prior genome-wide association studies (GWAS) of human temperament. We used a data-driven machine learning method for GWAS to uncover the complex genotypic-phenotypic networks and environmental interactions related to human temperament. In a discovery sample of 2149 healthy Finns, we identified sets of single-nucleotide polymorphisms (SNPs) that cluster within particular individuals (i.e., SNP sets) regardless of phenotype. Second, we identified 3 clusters of people with distinct temperament profiles measured by the Temperament and Character Inventory regardless of genotype. Third, we found 51 SNP sets that identified 736 gene loci and were significantly associated with temperament. The identified genes were enriched in pathways activated by associative conditioning in animals, including the ERK, PI3K, and PKC pathways. 74% of the identified genes were unique to a specific temperament profile. Environmental influences measured in childhood and adulthood had small but significant effects. We confirmed the replicability of the 51 Finnish SNP sets in healthy Korean (90%) and German samples (89%), as well as their associations with temperament. The identified SNPs explained nearly all the heritability expected in each sample (37-53%) despite variable cultures and environments. We conclude that human temperament is strongly influenced by more than 700 genes that modulate associative conditioning by molecular processes for synaptic plasticity and long-term memory.

Human personality is 30-60% heritable according to twin and adoption studies. Hundreds of genetic variants are expected to influence its complex development, but few have been identified. We used a machine learning method for genome-wide association studies (GWAS) to uncover complex genotypic-phenotypic networks and environmental interactions. The Temperament and Character Inventory (TCI) measured the self-regulatory components of personality critical for health (i.e., the character traits of self-directedness, cooperativeness, and self-transcendence). In a discovery sample of 2149 healthy Finns, we identified sets of single-nucleotide polymorphisms (SNPs) that cluster within particular individuals (i.e., SNP sets) regardless of phenotype. Second, we identified five clusters of people with distinct profiles of character traits regardless of genotype. Third, we found 42 SNP sets that identified 727 gene loci and were significantly associated with one or more of the character profiles. Each character profile was related to different SNP sets with distinct molecular processes and neuronal functions. Environmental influences measured in childhood and adulthood had small but significant effects. We confirmed the replicability of 95% of the 42 SNP sets in healthy Korean and German samples, as well as their associations with character. The identified SNPs explained nearly all the heritability expected for character in each sample (50 to 58%). We conclude that self-regulatory personality traits are strongly influenced by organized interactions among more than 700 genes despite variable cultures and environments. These gene sets modulate specific molecular processes in brain for intentional goal-setting, self-reflection, empathy, and episodic learning and memory.

Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (odds ratio (OR) = 1.11, P = 5.7 × 10 -15 ), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 × 10 -6 ). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 × 10 -11 ) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 × 10 -5 ). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by nonallelic homologous recombination.

Fractional anisotropy (FA) analysis of diffusion tensor-images (DTI) has yielded inconsistent abnormalities in schizophrenia (SZ). Inconsistencies may arise from averaging heterogeneous groups of patients. Here we investigate whether SZ is a heterogeneous group of disorders distinguished by distinct patterns of FA reductions. We developed a Generalized Factorization Method (GFM) to identify biclusters (i.e., subsets of subjects associated with a subset of particular characteristics, such as low FA in specific regions). GFM appropriately assembles a collection of unsupervised techniques with Non-negative Matrix Factorization to generate biclusters, rather than averaging across all subjects and all their characteristics. DTI tract-based spatial statistics images, which output is the locally maximal FA projected onto the group white matter skeleton, were analyzed in 47 SZ and 36 healthy subjects, identifying 8 biclusters. The mean FA of the voxels of each bicluster was significantly different from those of other SZ subjects or 36 healthy controls. The eight biclusters were organized into four more general patterns of low FA in specific regions: 1) genu of corpus callosum (GCC), 2) fornix (FX)+external capsule (EC), 3) splenium of CC (SCC)+retrolenticular limb (RLIC)+posterior limb (PLIC) of the internal capsule, and 4) anterior limb of the internal capsule. These patterns were significantly associated with particular clinical features: Pattern 1 (GCC) with bizarre behavior, pattern 2 (FX+EC) with prominent delusions, and pattern 3 (SCC+RLIC+PLIC) with negative symptoms including disorganized speech. The uncovered patterns suggest that SZ is a heterogeneous group of disorders that can be distinguished by different patterns of FA reductions associated with distinct clinical features., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Clinically significant depression is present in one of every four people with type 2 diabetes mellitus (T2DM). Depression increases the risk of the development of T2DM and the subsequent risks of hyperglycemia, insulin resistance, and micro- and macrovascular complications. Conversely, a diagnosis of T2DM increases the risk of incident depression and can contribute to a more severe course of depression. This linkage reflects a shared etiology consisting of complex bidirectional interactions among multiple variables, a process that may include autonomic and neurohormonal dysregulation, weight gain, inflammation, and hippocampal structural alterations. Two recent meta-analyses of randomized controlled depression treatment trials in patients with T2DM concluded that psychotherapy and antidepressant medication (ADM) were each moderately effective for depression and that cognitive behavior therapy (CBT) had beneficial effects on glycemic control. However, the number of studies (and patients exposed to randomized treatment) included in these analyses is extremely small and limits the certainty of conclusions that can be drawn from the data. Ultimately, there is no escaping the paucity of the evidence base and the need for additional controlled trials that specifically address depression management in T2DM. Future trials should determine both the effects of treatment and the change in depression during treatment on measures of mood, glycemic control, and medical outcome.

Objective: The authors sought to demonstrate that schizophrenia is a heterogeneous group of heritable disorders caused by different genotypic networks that cause distinct clinical syndromes., Method: In a large genome-wide association study of cases with schizophrenia and controls, the authors first identified sets of interacting single-nucleotide polymorphisms (SNPs) that cluster within particular individuals (SNP sets) regardless of clinical status. Second, they examined the risk of schizophrenia for each SNP set and tested replicability in two independent samples. Third, they identified genotypic networks composed of SNP sets sharing SNPs or subjects. Fourth, they identified sets of distinct clinical features that cluster in particular cases (phenotypic sets or clinical syndromes) without regard for their genetic background. Fifth, they tested whether SNP sets were associated with distinct phenotypic sets in a replicable manner across the three studies., Results: The authors identified 42 SNP sets associated with a 70% or greater risk of schizophrenia, and confirmed 34 (81%) or more with similar high risk of schizophrenia in two independent samples. Seventeen networks of SNP sets did not share any SNP or subject. These disjoint genotypic networks were associated with distinct gene products and clinical syndromes (i.e., the schizophrenias) varying in symptoms and severity. Associations between genotypic networks and clinical syndromes were complex, showing multifinality and equifinality. The interactive networks explained the risk of schizophrenia more than the average effects of all SNPs (24%)., Conclusions: Schizophrenia is a group of heritable disorders caused by a moderate number of separate genotypic networks associated with several distinct clinical syndromes.

Objective: The goal of this study was to investigate psychometric properties and factorial structure of the Croatian adaptation of the Temperament and Character Inventory-Revised (TCI-R) in a sample of psychiatric outpatients (n=328)., Method: The participants filled out the TCI-R, as well as self-report measures of the Big-Five personality traits (IPIP-50), trait impulsivity (BIS-11), depression (BDI-II), suicidality (SBQ-R), and life satisfaction (SWLS). We explored the internal consistency of 7 domains and 29 subscales and compared it with the Croatian version of the original TCI used in prior studies. Principal component analysis with promax rotation was conducted on temperament and character subscales separately, while concurrent validity was examined through the TCI-R's relations with the abovementioned psychological measures., Results: The TCI-R scales showed adequate internal consistencies, with Cronbach's alpha values ranging from 0.77 to 0.93. The internal consistency showed to be higher in comparison with the Croatian version of the original TCI. The postulated four-factor structure of temperament and the three-factor structure of character were confirmed. The meaningful associations with other measures supported the concurrent validity of the TCI-R., Conclusion: The Croatian adaptation of the TCI-R exhibited satisfactory reliability and validity in a sample of psychiatric outpatients. These findings support the use of the TCI-R in Croatian clinical settings over its predecessor (TCI)., (Copyright © 2014 Elsevier Inc. All rights reserved.)

More than 200 million prescriptions are written annually for opioid analgesics despite limited evidence of their long-term efficacy. These medications currently are prescribed to 10% - 15% of Americans with use of long-acting opioids projected to double in the next three to four years. Despite this widespread use, little is known about the risks of opioids, particularly with chronic use. New data from our research group published in the Journal of General Internal Medicine provides clear evidence that prescription opioid used for non-cancer, non-HIV pain increases significantly the risk of development of major depressive disorder in opioid naïve individuals with no recent history of depression and substance used disorders. The risk of depression increased as the dose and/or the duration of opioid use increased. The purpose of the present paper is to elucidate the details of this study, to examine potential neurobiological mechanisms responsible for the depressogenic effect of opioid analgesics, and to discuss management options that emphasize depression prophylaxis.

Background: Prescription opioid analgesic use has quintupled recently. Evidence linking opioid use with depression emanates from animal models and studies of persons with co-occurring substance use and major depression. Little is known about depressogenic effects of opioid use in other populations., Objective: The purpose of this study was to determine whether prescription opioids are associated with increased risk of diagnosed depression., Design: Retrospective cohort study, new user design., Patients: Medical record data from 49,770 US Department of Veterans Affairs (VA) health care system patients with no recent (24-month) history of opioid use or a diagnosis of depression in 1999 and 2000., Main Measures: Propensity scores were used to control for bias by indication, and the data were weighted to balance the distribution of covariates by duration of incident opioid exposure. Cox proportional hazard models with adjustment for painful conditions were used to estimate the association between duration of prescription opioid use and the subsequent risk of development of depression between 2001 and 2007., Key Results: Of 49,770 patients who were prescribed an opioid analgesic, 91 % had a prescription for < 90 days, 4 % for 90-180 days, and 5 % for > 180 days. Compared to patients whose prescription was for < 90 days, the risk of depression increased significantly as the duration of opioid prescription increased (HR = 1.25; 95 % CI: 1.05-1.46 for 90-180 days, and HR = 1.51; 95 % CI:1.31-1.74 for > 180 days)., Conclusions: In this sample of veterans with no recent (24-month) history of depression or opioid analgesic use, the risk of development of depression increased as the duration of opioid analgesic exposure increased. The potential for depressogenic effect should be considered in risk-benefit discussions, and patients initiating opioid treatment should be monitored for development of depression.

Background and Objectives: Clinics licensed to provide pharmacotherapy for opiate dependence disorder are required to perform random urine drug screen (RUDS) tests. The results provide the empirical basis of individual treatment and programmatic effectiveness, and public health policy. Patients consent to witnessed testing but most tests are unwitnessed. The purpose of the present study was to compare treatment effectiveness estimates derived from witnessed versus unwitnessed urine samples., Methods: We adopted a policy requiring visually witnessed urine drug screens (WUDS) and studied its impact (a single group, pretest-posttest design) on the RUDS test results in 115 male veterans enrolled in the St. Louis VA Opioid Treatment Program., Results: The percentage of opioid-positive urine samples increased significantly following implementation of WUDS (25% vs. 41%, χ(2) = 66.5, p < .001)., Conclusions and Scientific Significance: Results of this preliminary study suggest that random testing alone does not ensure the integrity of UDS testing. Outcome calculations based on random unwitnessed tests may overestimate the effectiveness of opioid dependence disorder treatment., (Copyright © American Academy of Addiction Psychiatry.)

Whether and how the co-occurrence of depression and diabetes in pregnancy may worsen infant development has not been reported. Pregnant women with diabetes and with (n = 34) or without (n = 34) major depressive disorder (MDD) were followed during pregnancy and 6-months postpartum. The MDD subset received randomly assigned treatment with cognitive behavior therapy (CBT) or supportive counseling (SC). Depression severity was measured with the Beck Depression Inventory (BDI); infant developmental outcomes were measured with the Bayley Scales of Infant Development (BSID) and its Behavior Rating Scale (BRS). Infants of women with MDD had lower BRS scores (p = .02). Reduction in depression scores was associated with better infant outcomes on the BSID and BRS (p values <.03). These preliminary findings suggest depression occurring in pregnant women with diabetes is associated with poorer infant development and improvement in prepartum depression is associated with improvement in measures of infant development.

Background: Drug addiction and alcoholism involve a complex etiopathogenesis with a variable degree of risk contributions from the host (person), environment, and addictive substances. In this work, temperament and character features of individuals addicted to opiates or alcohol are compared with normal controls to study personality factors in the overall risk for drug addiction., Methods: The study was done in a permissive environment, with easy access to alcohol and heroin, which facilitated analyses of personality factors in drug choice. Participants included 412 consecutive patients (312 opiate addicts, 100 alcohol addicts) treated at the Specialized Hospital for Chemical Dependency in Belgrade, Serbia, and a community sample of 346 controls., Results: Opiate addicts manifested antisocial temperament configuration (high Novelty Seeking, low Reward Dependence) coupled with high Self-transcendence (ie, susceptibility to fantasy and imagination). Alcohol addicts manifested sensitive temperament configuration (high Novelty Seeking coexisting with high Harm Avoidance). Immature personality was observed far more frequently in opiate addicts than in alcoholics or normals., Conclusions: Novelty Seeking appears to be a general risk factor for drug addiction. High Harm Avoidance appears to channel individuals with high Novelty Seeking towards alcoholism. Immature character traits and probable Personality Disorder increase the risk of illegal drugs. Based on equivalent research in nonpermissive environments, at least a portion of our opiate addicts could have developed alcoholism instead in environments with more limited access to opiates. Personality factors provide useful guidelines for preventive work with young individuals with personality risk factors for drug addiction., (Copyright © American Academy of Addiction Psychiatry.)

Empirical and clinical studies clearly demonstrate significant adverse effects of cannabis smoking on physical and mental health as well as its interference with social and occupational functioning. These negative data far outweigh a few documented benefits for a limited set of medical indications, for which safe and effective alternative treatments are readily available. If there is any medical role for cannabinoid drugs, it lies with chemically defined compounds, not with unprocessed cannabis plant. Legalization or medical use of smoked cannabis is likely to impose significant public health risks, including an increased risk of schizophrenia, psychosis, and other forms of substance use disorders.

Schizophrenia (SZ) is a highly heritable disorder, with about 80% of the variance attributable to genetic factors. There is accumulating evidence that both common genetic variants with small effects and rare genetic lesions with large effects determine risk of SZ. As recently shown, thousands of common single nucleotide polymorphisms (SNPs), each with small effect, cumulatively could explain about 30% of the underlying genetic risk of SZ. On the other hand, rare and large copy number variants (CNVs) with high but incomplete penetrance, variable in different individual, could explain about additional 30% of SZ cases. Although these rare CNVs frequently develop de novo, it is not clear whether they affect risk independently or via interaction with a polygenic liability in the background. Finally, the role of environmental risk factors has been well established in SZ. Environmental factors are rarely sufficient to cause SZ independently, but act in parallel or in synergy with the underlying genetic liability. Epigenetic misregulation of the genome and direct CNS injury are probably the main mechanism to mediate prenatal environmental effects (e.g., viruses, ethanol, or nutritional deficiency) whereas postnatal risk factors (e.g., stress, urbanicity, cannabis use) may also affect risk via use-based potentiation of vulnerable CNS pathways implicated in SZ. In this review, we outline a general theoretical background of epigenetic mechanisms involved in GxE interactions, and then discuss epigenetic and neurodevelopmental features of SZ based on available information from genetics, epigenetics, epidemiology, neuroscience, and clinical research. We argue that epigenetic model of SZ provides a framework to integrate a variety of diverse empirical data into a powerful etiopathogenetic synthesis. The promising future of this model is the possibility to develop truly specific prevention and treatment strategies for SZ.

Objective: In this work, we report data on construct validity and cross cultural applicability of the revised Temperament and Character Inventory (TCI R) (Cloninger, C.R., Przybeck, T.R., Svrakic, D.M., & Wetzel, R.D. (1999). The Temperament and Character Inventory-revised, Washington University, St. Louis), a 5-point scale scoring formatrevision of the original, true-false version TCI (Cloninger, C.R., Przybeck, T.R., Svrakic, D.M., & Wetzel, R.D. (1994). The Temperament and Character Inventory-A guide to its development and use, Washington University, St. Louis). Both versions are based on the seven factor Psychobiological Model of Personality (Cloninger CR, Svrakic, DM & Przybeck TR (1993). A Psychobiological Model of temperament and Character, Archives of General Psychiatry, 50, 975-990)., Methods: The sample consisted of 473 normal adult subjects representing a number of Serbian cities and towns, recruited consecutively while registering at the National Employment Center, located in Belgrade, Serbia. The sample was the designed to be highly representative of urban and suburban population in Serbia to match to TCI R sample in the US. The 240-item, 5-point scale scoring TCI R was used to assess temperament and character traits. In addition to a number of other revisions, the scoring format in the TCI R was changed into a 5-point Likert scale to increase its sensitivity to subtle variations in personality expression. The TCI R mean scores and standard deviations were compared between Serbian and US subjects, internal consistency of the TCI R scales was estimated using Cronbach's alpha coefficients, and principal component analysis was used separately for temperament and character (because of their non-linear relationship) to test the underlying factorial structure of the TCI R. Parallel analysis and randomized simulation data were used to determine the number of factors for temperament and character., Results: The results generally supported the construct validity and the cross cultural applicability of the TCI R in Serbia. With a few exceptions, the observed internal consistency for the TCI R scales was acceptable. For the most part, the US and Serbian subjects manifested comparable temperament traits, whereas US subjects had higher character scores. The observed differences are understood as partly reflective of local culture and partly of dramatic socio-economic change in Serbia over the last 20 years. Principal component analysis fully supported the four factor structure of temperament and the three factor structure of character, as postulated by theory. The inadequacy of using linear statistical methods in studying complex non-linear systems such as personality is discussed in some detail., (Published by Elsevier Inc.)

After 30 years of clinical work and research based on categorical criteria for personality disorders (Diagnostic and Statistical manual of Mental Disorders - DSM IV TR) and (International Classification of Diseases - ICD 10th revision), a solid conceptual understanding and treatment of these disorders have not been established. For the field to move forward, it is imperative that future classifications introduce major revisions of the concept, diagnosis, and classification of personality disorders. This paper proposes one such revision. Based on recent advances in molecular biology and epigenetics, we define personality disorders as maladaptive syndromes developed trough person-environment interaction. We conceptualize maladaptation as a failure of integrative functions of personality (i.e., those that carry out adaptive processes) caused by strong biogenetic dispositions or by pathological environmental effects, or both. Hence, accurate diagnosis of personality disorder depends upon neurobiological (innate) and adaptive (interactive) etiological factors. We propose a 2-step diagnostic algorithm for personality disorders: adaptive processes (i.e., character) are used to diagnose maladaptation, whereas biological aspects (i.e., temperament) are used to specify dominant clinical presentation and for differential diagnosis. We suggest that the term "Personality Disorder" be replaced by a more appropriate term "Adaptation Disorder" as the latter reflects more accurately the real nature of the disorder and distributes the causality of maladaptive syndromes more evenly, between the person and the environment. Diagnostic, research, and treatment advantages of the proposed solution are discussed in some detail.

Background: Personality assessment provides a description of a person's fundamental emotional needs and of the higher cognitive processes that modulate thoughts, feelings, and behavior. Prior studies by us examined personality and mood at the same time. Assessing personality may allow prediction of mood changes over time in a longitudinal study, as described in earlier prospective studies by Paula Clayton and others., Method: A group of 631 adults representative of the general population completed the Temperament and Character Inventory (TCI) and Center for Epidemiological Studies depression scale (CES-D) at baseline and one year later., Results: TCI scores at baseline accounted for gender differences in levels of depression. TCI personality scores were strongly stable (range in r=.78 to .85 for each of seven dimensions) whereas mood was only moderately stable (r=.62) over the twelve-month follow-up. Baseline personality scores (particularly high Harm Avoidance and low Self-Directedness) explained 44% of the variance in the change in depression. Baseline levels and changes in Harm Avoidance and Self-Directedness explained 52% of the variance in the change in depression at follow-up., Limitations: The follow-up sample was representative of the target population except for slightly lower Novelty Seeking scores., Clinical Relevance: Observable personality levels strongly predict mood changes. Personality development may reduce vulnerability to future depression.

Schizophrenia is a common disorder with high heritability and a 10-fold increase in risk to siblings of probands. Replication has been inconsistent for reports of significant genetic linkage. To assess evidence for linkage across studies, rank-based genome scan meta-analysis (GSMA) was applied to data from 20 schizophrenia genome scans. Each marker for each scan was assigned to 1 of 120 30-cM bins, with the bins ranked by linkage scores (1 = most significant) and the ranks averaged across studies (R(avg)) and then weighted for sample size (N(sqrt)[affected casess]). A permutation test was used to compute the probability of observing, by chance, each bin's average rank (P(AvgRnk)) or of observing it for a bin with the same place (first, second, etc.) in the order of average ranks in each permutation (P(ord)). The GSMA produced significant genomewide evidence for linkage on chromosome 2q (PAvgRnk<.000417). Two aggregate criteria for linkage were also met (clusters of nominally significant P values that did not occur in 1,000 replicates of the entire data set with no linkage present): 12 consecutive bins with both P(AvgRnk) and P(ord)<.05, including regions of chromosomes 5q, 3p, 11q, 6p, 1q, 22q, 8p, 20q, and 14p, and 19 consecutive bins with P(ord)<.05, additionally including regions of chromosomes 16q, 18q, 10p, 15q, 6q, and 17q. There is greater consistency of linkage results across studies than has been previously recognized. The results suggest that some or all of these regions contain loci that increase susceptibility to schizophrenia in diverse populations.

Objective: In this paper, we explore the underlying dimensional structure of personality disorder, propose a novel approach to its diagnosis, and outline our concepts of its etiology and treatment based on the seven factor psychobiological model of temperament and character., Method: Temperament and character traits were evaluated in a consecutive series of 109 psychiatric out-patients, with or without personality disorder and varying mood and anxiety states., Results: Low scores on character dimensions consistently correlated with high symptom counts for personality disorder. Each subtype of personality disorder created a unique combination of correlations with the four temperament traits., Conclusion: Temperament and Character Inventory (TCI) temperament and character traits efficiently diagnose personality disorder and differentiate its individual subtypes. Character traits are used to diagnose the presence and the severity of personality disorder, whereas temperament traits are used for differential diagnosis. The distinction between temperament and character provides an attractive theoretical basis for etiological postulates and treatment of personality disorder., (Copyright Blackwell Munksgaard 2002.)

The transmission/disequilibrium test was used for fine mapping of the linkage of schizophrenia to the chromosome 15q13-14 region, the site of a candidate gene, the alpha7 nicotinic acetylcholine receptor subunit gene (CHRNA7), in parent-child triads from the NIMH Schizophrenia Genetics Initiative families. This candidate gene was identified from neurobiological studies of deficits in schizophrenics of the inhibitory gating of the P50 auditory evoked potential. The neurobiological deficit was also used as a phenotype for subsequent linkage analysis. In the present study, significant genotype-wise disequilibrium (P < 0.007) was found at D15S165, a polymorphic simple sequence marker physically located within 1 megabase of both CHRNA7 and a partially duplicated, expressed sequence that includes exons 5-10 of CHRNA7. Replication of this result was found in an additional set of families. The results support this region as a chromosomal location involved in the genetic transmission of schizophrenia.

A preliminary effort to validate the Junior Temperament and Character Inventory with a convenience sample of 322 children ages 9 to 12 years is described.

Background: Personality assessment may allow reliable measurement of risk of mood disorders., Methods: A group of adults (804) representative of the general population were assessed by questionnaire. Personality types were measured by the Temperament and Character Inventory (TCI)., Results: Specific TCI configurations define personality types that can be described as hyperthymic, cyclothymic, irritable, and depressive. Each type had a unique profile of emotions, suicide attempts, and hospitalization., Conclusions: TCI traits are associated with mood disorders., Limitations: Different ways of measuring Kraepelinean subtypes may disagree. Whether differences in personality cause psychopathology, or vice versa, remains uncertain., Clinical Relevance: Personality profiles help in assessing suicidality and planning treatment.

Linkage of a neurophysiological deficit associated with schizophrenia, i.e., the failure to inhibit the auditory P50 response, was previously reported at chromosome 15q14. The marker with the highest pairwise lod score, D15S1360, was isolated from a yeast artificial chromosome containing a candidate gene, the alpha7-nicotinic acetylcholine receptor gene. In the present study, this linkage was further investigated in a subset of the NIMH Genetics Initiative schizophrenia families. These families have not been studied neurophysiologically, as were the families in the original report. Therefore, the DSMIII-R diagnosis of schizophrenia was used as the affected phenotype. Twenty families fulfilled the criteria of at least one sibpair concordant for schizophrenia, along with their two parents or another affected relative outside the nuclear family, available for genotyping. Sibpair analysis showed a significant proportion of D15S1360 alleles shared identical-by-descent (0.58; P < 0.0024). The results further support the involvement of this chromosomal locus in the genetic transmission of schizophrenia.

Schizophrenia has a complex pattern of inheritance, indicative of interactions among multiple genes and environmental factors. The detection and replication of specific susceptibility loci for such complex disorders are facilitated by the availability of large samples of affected sib pairs and their nuclear families, along with standardized assessment and systematic ascertainment procedures. The NIMH Genetics Initiative on Schizophrenia, a multisite collaborative study, was established as a national resource with a centralized clinical data base and cell repository. The Millennium Schizophrenia Consortium has completed a genome-wide scan to detect susceptibility loci for schizophrenia in 244 individuals from the nuclear families of 92 independent pairs of schizophrenic sibs ascertained by the NIMH Genetics Initiative. The 459 marker loci used in the scan were spaced at 10-cM intervals on average. Individuals of African descent were higher than those of European descent in their average heterozygosity (79% vs. 76%, P < .0001) and number of alleles per marker (9.2 vs. 8.4, P < .0001). Also, the allele frequencies of 73% of the marker loci differed significantly (P < .01) between individuals of European and African ancestry. However, regardless of ethnic background, this sample was largely comprised of schizophrenics with more than a decade of psychosis associated with pervasive social and occupational impairment.

Normal and abnormal personality development can be quantified in terms of 15 specific steps in the self-organization of character as a complex adaptive system. Character is measured as three dimensions of Self-directedness, Cooperativeness, and Self-transcendence, each with five components corresponding to steps in personality development. Each of these steps is differentially influenced by heritable temperament dimensions, antecedent steps in character development, and life experiences. Predictions about the nonlinear dynamics of personality development, such as equifinality and multifinality, are confirmed in longitudinal data about individuals representative of the general population. The stepwise development of character determines large differences between individuals in their risk of psychopathology, as well as varying degrees of maturity and health.

A Developmental approach to integrative psychobiology provides a flexible framework for both clinical assessment and treatment planning. Assessment of seven dimensions of personality using the Temperament and Character Inventory (TCI) allows for comprehensive description of individual differences in feelings, thoughts, and actions. Four temperament factors that are stable throughout life can be decomposed in terms of their underlying genetic structure. Character factors that mature in response to social learning can be decomposed in terms of the components that unfold in a stepwise fashion from infancy through adulthood. Pharmacotherapy and psychotherapy can be systematically matched to the personality structure and stage of character development of each individual. This provides comprehensive paradigm that integrates psychodynamic, cognitive-behavioral, interpersonal, and neurobiological insights into case formulation. Use of the TCI in clinical assessment and treatment planning was illustrated by a case independently assessed by Mardi Horowitz using another approach.

The Cloninger Temperament and Character Inventory (TCI) and the Millon Clinical Multiaxial Inventory (MCMI-II) are both self-report inventories that can be used to assess personality reliably in clinical samples. Both instruments were administered to 103 consecutive psychiatric out-patients with or without personality disorders. The goals were to assess the convergent validity of the two instruments, to replicate the findings of Svrakic et al. (1993) Archives of General Psychiatry, 50, 991-999, about the differential diagnosis of Axis II disorders, and to analyse the relations of Millon's measures of Axis I disorders with Cloninger's measures. We observed a strong convergent validity between the instruments; the seven dimensions of the TCI accounted for most of the variance in MCMI-II measures of both Axis 1 and Axis 2 disorders. As reported by Svrakic et al. (1993) Archives of General Psychiatry, 50, 991-999, in in-patients, low self-directedness and low cooperativeness were confirmed to be the essential features of all personality disorders in out-patients. In addition, self-transcendence, the third of Cloninger's character dimensions, was observed to be a strong correlate of severe Axis-1 psychopathology, including manic and delusional disorders.

Kraepelin viewed alcoholism as a symptom complex caused by heritable individual differences in emotional predisposition and volitional control. Recent clinical and genetic research has distinguished subtypes of alcoholics with different personality traits, symptoms, course, mode of inheritance, and response to treatment. The heritable personality traits that influence the initiation, continuation, and severity of alcoholism were examined by interview of a national area probability sample of 1019 non-institutionalized adults across the continental United States of America. We found that harm avoidance inhibits the initiation and frequency of drinking, but increases the risk of developing problems once frequent drinking has begun. Novelty seeking increases the initiation of drinking and the probabilities of frequent and problem drinking. This supports Kraepelin's description of the etiology and course of alcoholism as a symptom complex related to individual differences in emotional predisposition.

We used multiaxial structured interviews and questionnaires to evaluate the ability of self-reports on seven personality dimensions to predict independent interview diagnoses of DSM-III-R personality disorders. We studied 136 consecutive adult psychiatric inpatients, excluding those with psychosis, organic mental disorders, and severe agitation. Sixty-six patients had interview diagnoses of DSM-III-R personality disorders. Most also had mood disorders. We confirmed the hypotheses that self-reports of low self-directedness and cooperativeness strongly predicted the number of personality symptoms in all interview categories, whereas the other factors distinguished among subtypes as predicted. Self-directedness and cooperativeness also predicted the presence of any personality disorder by differentiating patients varying in risk from 11% to 94%. Patients in clusters A, B, and C were differentiated by low reward dependence, high novelty seeking, and high harm avoidance, respectively. We conclude that low self-directedness and cooperativeness are core features of all personality disorders and are validly measured by the seven-factor Temperament and Character Inventory, but not the five-factor Neuroticism-Extraversion-Openness inventory. Each DSM-III-R personality disorder category is associated with a unique profile of scores in the seven-factor model, providing an efficient guide to differential diagnosis and treatment.

In this study, we describe a psychobiological model of the structure and development of personality that accounts for dimensions of both temperament and character. Previous research has confirmed four dimensions of temperament: novelty seeking, harm avoidance, reward dependence, and persistence, which are independently heritable, manifest early in life, and involve preconceptual biases in perceptual memory and habit formation. For the first time, we describe three dimensions of character that mature in adulthood and influence personal and social effectiveness by insight learning about self-concepts. Self-concepts vary according to the extent to which a person identifies the self as (1) an autonomous individual, (2) an integral part of humanity, and (3) an integral part of the universe as a whole. Each aspect of self-concept corresponds to one of three character dimensions called self-directedness, cooperativeness, and self-transcendence, respectively. We also describe the conceptual background and development of a self-report measure of these dimensions, the Temperament and Character Inventory. Data on 300 individuals from the general population support the reliability and structure of these seven personality dimensions. We discuss the implications for studies of information processing, inheritance, development, diagnosis, and treatment.

This study evaluates the relationship of personality to mood and anxiety states in a sample of 50 psychiatric out patients. In order to overcome arbitrariness inherent in categorical diagnoses of affective, personality and anxiety disorders, we use a dimensional approach to personality, mood and anxiety. According to our results, mood and anxiety states affect personality domains differentially. Namely, relatively large portions of personality and behavior, such as higher-order traits of novelty seeking and reward dependence, seem independent from mood and anxiety states. In contrast, the higher-order dimension of harm avoidance and its corresponding lower-order traits reflect changes in mood and anxiety to a much greater extent. Both the likelihood that large portions of personality may be independent from current mood and the likelihood that some precisely delineated personality domains tend to change simultaneously with current mood may improve our understanding of the relationship of personality to emotionality and affective disorders.

In this article we analyze the relationship between personality traits assessed by the Tridimensional Personality Questionnaire, and six mood states assessed by the Profile of Mood States-bipolar form. Our data suggest that large portions of personality and/or behavior, e.g., higher order dimensions of Novelty Seeking and Reward Dependence, can be relatively independent from current mood. In contrast, the Harm Avoidance dimension covaries with mood and anxiety. Also, we analyze the psychometric properties of the Profile of Mood States-bipolar form, and discuss some practical aspects of our findings.

The conception of personality disorders (PDs) as distinct units of mental disorders is neither precise nor useful. At least some PDs, classified as separate units, reflect different behavioral expression of the same personality deviation. In this article we describe structural, developmental, and clinical continuum between relatively distinct entities of antisocial PD and narcissistic PD. The two disorders represent different endpoints sharing a borderline level of personality organization and pathological narcissism. We propose a spectrum relation for antisocial and narcissistic PD because the disorders tend to co-occur in the same individual and to run in the same family more often than expected by chance.

The Tridimensional Personality Questionnaire is a self-report personality inventory measuring three major personality dimensions: Novelty Seeking, Harm Avoidance, and Reward Dependence. Normative data, based on a U.S. national probability sample of 1,019 adults, are presented and the psychometric properties of the questionnaire are discussed.

Present classifications fall short of helping clinicians to systematically approach syndromes of antisocial (A-S) behavior. Various clinical forms of A-S behavior derive from different levels of personality organization (normal, neurotic, and borderline level) whereas certain personality disorders (PD) display specific antisocial "profiles" and form the horizontal continuum of antisocial behavior. The borderline level of personality and pathological narcissism stand behind A-S PD, Narcissistic PD, and Histrionic PD. The authors propose that the disorders should be regarded as spectrum disorders. Paranoid PD and "pure" Borderline PD complete the list of PDs manifesting A-S behaviors. Finally, diagnostic instruments for clinical approach to and research of A-S PD are presented.