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In current diagnostic systems, schizophrenia and bipolar disorder are still conceptualized as distinct categorical entities. Recently, both clinical and genomic evidence have challenged this Kraepelinian dichotomy. There are only few longitudinal studies addressing potential overlaps between these conditions. Here, we present design and first results of the PsyCourse study (N = 891 individuals at baseline), an ongoing transdiagnostic study of the affective-to-psychotic continuum that combines longitudinal deep phenotyping and dimensional assessment of psychopathology with an extensive collection of biomaterial. To provide an initial characterization of the PsyCourse study sample, we compare two broad diagnostic groups defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) classification system, that is, predominantly affective (n = 367 individuals) versus predominantly psychotic disorders (n = 524 individuals). Depressive, manic, and psychotic symptoms as well as global functioning over time were contrasted using linear mixed models. Furthermore, we explored the effects of polygenic risk scores for schizophrenia on diagnostic group membership and addressed their effects on nonparticipation in follow-up visits. While phenotypic results confirmed expected differences in current psychotic symptoms and global functioning, both manic and depressive symptoms did not vary between both groups after correction for multiple testing. Polygenic risk scores for schizophrenia significantly explained part of the variability of diagnostic group. The PsyCourse study presents a unique resource to research the complex relationships of psychopathology and biology in severe mental disorders not confined to traditional diagnostic boundaries and is open for collaborations.

OBJECTIVES: Bipolar disorder (BD) with early disease onset is associated with an unfavorable clinical outcome and constitutes a clinically and biologically homogenous subgroup within the heterogeneous BD spectrum. Previous studies have found an accumulation of early age at onset (AAO) in BD families and have therefore hypothesized that there is a larger genetic contribution to the early-onset cases than to late onset BD. To investigate the genetic background of this subphenotype, we evaluated whether an increased polygenic burden of BD- and schizophrenia (SCZ)-associated risk variants is associated with an earlier AAO in BD patients. METHODS: A total of 1995 BD type 1 patients from the Consortium of Lithium Genetics (ConLiGen), PsyCourse and Bonn-Mannheim samples were genotyped and their BD and SCZ polygenic risk scores (PRSs) were calculated using the summary statistics of the Psychiatric Genomics Consortium as a training data set. AAO was either separated into onset groups of clinical interest (childhood and adolescence [≤18 years] vs adulthood [>18 years]) or considered as a continuous measure. The associations between BD- and SCZ-PRSs and AAO were evaluated with regression models. RESULTS: BD- and SCZ-PRSs were not significantly associated with age at disease onset. Results remained the same when analyses were stratified by site of recruitment. CONCLUSIONS: The current study is the largest conducted so far to investigate the association between the cumulative BD and SCZ polygenic risk and AAO in BD patients. The reported negative results suggest that such a polygenic influence, if there is any, is not large, and highlight the importance of conducting further, larger scale studies to obtain more information on the genetic architecture of this clinically relevant phenotype. peerReviewed

Objective The absence of neurobiological diagnostic markers of bipolar disorder (BD) leads to its frequent misdiagnosis as unipolar depression (UD). We investigated if changes in fractional anisotropy (FA) could help to differentiate BD from UD in the state of depression. Methods Using diffusion tensor imaging (DTI) we employed a voxel-based analysis approach to examine fractional anisotropy (FA) in 86 patients experiencing an acute major depressive episode according to DSM-IV (N=39 BD, mean age 39.2 years; N=43 UD, mean age 39.0 years), and 42 healthy controls (HC, mean age 36.1 years). The groups did not differ in sex, age or total education time. FA was investigated in white matter (FA >.2) and hypothesis-driven anatomically defined tracts (region-of-interest [ROI] analysis). Additionally, an exploratory gray matter FA analysis was performed. Results White matter analysis showed decreased FA in the right corticospinal tract in UD vs HC and in the right corticospinal tract/superior longitudinal fascicle in BD vs HC and also in BD vs UD. ROI analysis revealed decreased FA in BD vs UD in the corpus callosum and in the cingulum. Gray matter exploratory analysis revealed decreased FA in the left middle frontal gyrus and in the right inferior frontal gyrus in UD vs HC, and in the left superior medial gyrus in BD vs HC. Conclusion This is one of very few studies directly showing differences in FA between BD and UD. Gray matter FA changes in prefrontal areas might be precursors for future prefrontal gray matter abnormalities in these disorders.

INTRODUCTION: It’s imperative to understand the specific and shared aetiologies of major depression and cardio-metabolic disease, as both traits are frequently comorbid and each represents a major burden to society. This study examined whether there is a genetic association between major depression and cardio-metabolic traits and if this association is stratified by age at onset for major depression. METHODS: Polygenic risk scores analysis and linkage disequilibrium score regression was performed to examine whether differences in shared genetic aetiology exist between depression case control status (N cases = 40,940, N controls = 67,532), earlier (N = 15,844), and later onset depression (N = 15,800) with body mass index, coronary artery disease, stroke, and type 2 diabetes in eleven data sets from the Psychiatric Genomics Consortium, Generation Scotland, and UK Biobank. RESULTS: All cardio-metabolic polygenic risk scores were associated with depression status. Significant genetic correlations were found between depression and body mass index, coronary artery disease, and type 2 diabetes. Higher polygenic risk for body mass index, coronary artery disease and type 2 diabetes was associated with both early and later onset depression, while higher polygenic risk for stroke was associated with later onset depression only. Significant genetic correlations were found between body mass index and later onset depression, and between coronary artery disease and both early and late onset depression. CONCLUSIONS: The phenotypic associations between major depression and cardio-metabolic traits may partly reflect their overlapping genetic aetiology irrespective of the age depression first presents.

Tumour necrosis factor alpha (TNFα) has been implicated in the pathophysiology of neurodegenerative and neuropsychiatric disease, with research highlighting a role for TNFα in hippocampal and striatal regulation. TNFα signals are primarily transduced by TNF receptors 1 and 2 (TNFR1 and TNFR2), encoded by TNFRSF1A and TNFRSF1B, which exert opposing effects on cell survival (TNFR1, neurodegenerative; TNFR2, neuroprotective). We therefore sought to explore the respective roles of TNFR1 and TNFR2 in the regulation of hippocampal and striatal morphology in an imaging genetics study. Voxel-based morphometry was used to analyse the associations between TNFRSF1A (rs4149576 and rs4149577) and TNFRSF1B (rs1061624) genotypes and grey matter structure. The final samples comprised a total of 505 subjects (mean age = 33.29, SD = 11.55 years; 285 females and 220 males) for morphometric analyses of rs1061624 and rs4149576, and 493 subjects for rs4149577 (mean age = 33.20, SD = 11.56 years; 281 females and 212 males). Analyses of TNFRSF1A single nucleotide polymorphisms (SNPs) rs4149576 and rs4149577 showed highly significant genotypic associations with striatal volume but not the hippocampus. Specifically, for rs4149576, G homozygotes were associated with reduced caudate nucleus volumes relative to A homozygotes and heterozygotes, whereas for rs4149577, reduced caudate volumes were observed in C homozygotes relative to T homozygotes and heterozygotes. Analysis of the TNFRSF1B SNP rs1061624 yielded a significant association with hippocampal but not with striatal volume, whereby G homozygotes were associated with increased volumes relative to A homozygotes and heterozygotes. Our findings indicate a role for TNFR1 in regulating striatal but not hippocampal morphology, as well as a complementary role for TNFR2 in hippocampal but not in striatal morphology.

Depression has been associated with various alterations in magnetic resonance imaging (MRI) derived resting‐state functional connectivity. Recently, homotopic connectivity, defined as functional connectivity between homotopic regions across hemispheres, has been reported to be reduced in patients with major depressive disorder (MDD). However, little is known about structural factors underlying alterations of homotopic connectivity, which would contribute to the understanding of the altered neurophysiological architecture in patients with MDD. We compared 368 patients with MDD and 461 never‐depressed controls regarding voxel‐mirrored homotopic connectivity (VMHC) and potential underlying mechanisms such as the structural connectivity of the corpus callosum, measured by DTI‐derived fractional anisotropy (FA), and left–right symmetries in homotopic gray matter volumes. Compared to controls, patients with MDD exhibited reduced VMHC in the cuneus, putamen, superior temporal gyrus, insula, and precuneus. Within these regions, no differences in left–right symmetries in homotopic gray matter volumes were evident across cohorts. FA of the corpus callosum correlated with VMHC in the entire sample. However, patients with MDD and controls did not differ with regard to callosal FA. The findings indicate that MDD is associated with a loss of interhemispheric synchrony in regions known to be implicated in self‐referential and reward processing. They also suggest that additional mechanisms are implicated in altered homotopic connectivity of patients with MDD, other than direct callosal fiber pathways or asymmetries in homotopic gray matter volumes. Hum Brain Mapp 37:1209–1217, 2016. © 2015 Wiley Periodicals, Inc.

Regulator of G-protein Signaling 2 (RGS2) is a key regulator of G-protein-coupled signaling pathways involved in fear and anxiety. Data from rodent models and genetic analysis of anxiety-related traits and disorders in humans suggest down-regulation of RGS2 expression to be a risk factor for anxiety. Here we investigated, whether genetic variation in microRNAs mediating posttranscriptional down-regulation of RGS2 may be a risk factor for anxiety as well. 75 microRNAs predicted to regulate RGS2 were identified by four bioinformatic algorithms and validated experimentally by luciferase reporter gene assays. Specificity was confirmed for six microRNAs (hsa-miR-1271-5p, hsa-miR-22-3p, hsa-miR-3591-3p, hsa-miR-377-3p, hsa-miR-4717-5p, hsa-miR-96-5p) by disrupting their seed sequence at the 3' untranslated region of RGS2. Hsa-miR-4717-5p showed the most robust effect on RGS2 and regulated two other candidate genes of anxiety disorders (CNR1 and IKBKE) as well. Two SNPs (rs150925, rs161427) within and 1,000 bp upstream of the hostgene of hsa-miR-4717-5p (MIR4717) show a minor allele frequency greater than 0.05. Both were in high linkage disequilibrium (r(2) = 1, D' = 1) and both major (G) alleles showed a trend for association with panic disorder with comorbid agoraphobia in one of two patient/control samples (combined npatients = 497). Dimensional anxiety traits, as described by Anxiety Sensitivity Index (ASI) and Agoraphobic Cognitions Questionnaire (ACQ) were significantly higher among carriers of both major (G) alleles in a combined patient/control sample (ncombined = 831). Taken together, data indicate that MIR4717 regulates human RGS2 and contributes to the genetic risk towards anxiety-related traits. © 2015 Wiley Periodicals, Inc.

Background Obesity has been characterized by alterations in brain structure and function associated with emotion processing and regulation. Particularly, aberrations in food-related reward processing have been frequently demonstrated in obese subjects. However, it remains unclear whether reward-associated functional aberrations in obesity are specific for food-related stimuli or represent a general deficit in reward processing, extending to other stimulus domains. Given the crucial role of rewarding effects in the development of obesity and the ongoing discussion on overlapping neurobiological traits of obesity and psychiatric disorders such as depression and substance-related disorders, this study aimed to investigate the possibility of altered reward processing in obese subjects to occur in the absence of food-related stimuli during a monetary reward condition. Methods Twenty-nine healthy obese subjects (body mass index >30) and 29 healthy, age-, and sex-matched control subjects of normal weight underwent functional MRI during a frequently used card guessing paradigm. A Group × Condition (win vs. loss) ANOVA was conducted to investigate differences between obese and normal-weight subjects. Results We found significant Group × Condition interaction effects in brain areas involved in emotion regulation and reward processing including the insula, the striatum, and the orbitofrontal cortex (OFC). This interaction was predominantly driven by a significant increase in blood oxygenation level dependent (BOLD) response in obese individuals while experiencing reward. Conclusions Enhanced neural activation in obesity during reward processing seems to be apparent even in the absence of food-related stimuli and, thus, might point to generalized dysfunctions in reward-related brain circuits in obese individuals. Hum Brain Mapp 36:2330–2337, 2015. © 2015 Wiley Periodicals, Inc.

Background The serotonin transporter (5-HTT) and the 5-HTTLPR/rs25531 polymorphisms in its gene (SLC6A4) have been associated with depression, increased stress-response, and brain structural alterations such as reduced hippocampal volumes. Recently, epigenetic processes including SLC6A4 promoter methylation were shown to be affected by stress, trauma, or maltreatment and are regarded to be involved in the etiology of affective disorders. However, neurobiological correlates of SLC6A4 promoter methylation have never been studied or compared to genotype effects by means of human neuroimaging hitherto Methods Healthy subjects were recruited in two independent samples (N = 94, N = 95) to obtain structural gray matter images processed by voxel-based morphometry (VBM8), focusing on hippocampal, amygdala, and anterior cingulate gyrus gray matter structure. SLC6A4 promoter methylation within an AluJb element and 5-HTTLPR/rs25531 genotypes were analyzed in view of a possible impact on local gray matter volume Results Strong associations of AluJb methylation and hippocampal gray matter volumes emerged within each sample separately, which in the combined sample withstood most conservative alpha-corrections for the entire brain. The amygdala, insula, and caudate nucleus showed similar associations. The 5-HTTLPR/rs25531 showed no main effect on gray matter, and the effect of methylation rates on hippocampal structure was comparable among the genotype groups Conclusions Methylation within the AluJb appears to have strong effects on hippocampal gray matter volumes, indicating that epigenetic processes can alter brain structures crucially involved in stress-related disorders. Different ways of regulating SLC6A4 expression might involve exonization or transcription factor binding as potentially underlying mechanisms, which, however, is speculative and warrants further investigation. Hum Brain Mapp 35:5356–5367, 2014. © 2014 Wiley Periodicals, Inc.

Background Bipolar disorder and Major depressive disorder are difficult to differentiate during depressive episodes, motivating research for differentiating neurobiological markers. Dysfunctional amygdala responsiveness during emotion processing has been implicated in both disorders, but the important rapid and automatic stages of emotion processing in the amygdala have so far never been investigated in bipolar patients. Methods fMRI data of 22 bipolar depressed patients (BD), 22 matched unipolar depressed patients (MDD), and 22 healthy controls (HC) were obtained during processing of subliminal sad, happy and neutral faces. Amygdala responsiveness was investigated using standard univariate analyses as well as pattern-recognition techniques to differentiate the two clinical groups. Furthermore, medication effects on amygdala responsiveness were explored. Results All subjects were unaware of the emotional faces. Univariate analysis revealed a significant group × emotion interaction within the left amygdala. Amygdala responsiveness to sad>neutral faces was increased in MDD relative to BD. In contrast, responsiveness to happy>neutral faces showed the opposite pattern, with higher amygdala activity in BD than in MDD. Most of the activation patterns in both clinical groups differed significantly from activation patterns of HC—and therefore represent abnormalities. Furthermore, pattern classification on amygdala activation to sad>happy faces yielded almost 80% accuracy differentiating MDD and BD patients. Medication had no significant effect on these findings. Conclusions Distinct amygdala excitability during automatic stages of the processing of emotional faces may reflect differential pathophysiological processes in BD versus MDD depression, potentially representing diagnosis-specific neural markers mostly unaffected by current psychotropic medication. Hum Brain Mapp 35:2995–3007, 2014. © 2013 Wiley Periodicals, Inc.

Objectives: Although homework assignments are an integral component of cognitive-behavioral therapy (CBT) and relate to positive therapy outcomes, it is unclear whether specific homework types and their completion have specific effects on outcome. Method: Data from N = 292 patients (75% female, mean age 36 years) with panic disorder and agoraphobia and treated with standardized CBT were analyzed with homework compliance quality and quantity for different types of homework serving as predictors for different outcome variables. Results: Quality ratings of homework completion were stronger outcome predictors than quantitative compliance ratings. Exposure homework was a better outcome predictor than homework relating to psychoeducation and self-monitoring. Conclusion: Different aspects of homework compliance and specific homework types might differentially relate to CBT outcome.

Panic disorder (PD) is a common mental disorder, ranking highest among the anxiety disorders in terms of disease burden. The pathogenesis of PD is multifactorial with significant heritability, however only a few convincing risk genes have been reported thus far. One of the most promising candidates is the gene encoding monoamine oxidase A (MAOA), due to its key role in monoaminergic neurotransmission, established validity of animal models, and the efficacy of MAO inhibitors in the treatment of PD. A promoter repeat polymorphism in MAOA (MAOA-uVNTR) impacts on gene expression; high-expression alleles have been reported to increase the risk for PD. To further scrutinize the role of this polymorphism, we performed a formal meta-analysis on MAOA-uVNTR and PD using original data from four published European (Estonian, German, Italian, and Polish) samples and genotypes from three hitherto unpublished German PD samples, resulting in the largest (n = 1,115 patients and n = 1,260 controls) genetic study on PD reported to date. In the unpublished samples, evidence for association of MAOA-uVNTR with PD was obtained in one of the three samples. Results of the meta-analysis revealed a significant and female-specific association when calculating an allelic model (OR = 1.23, P = 0.006). This sex-specific effect might be explained by a gene-dose effect causing higher MAOA expression in females. Taken together, our meta-analysis therefore argues that high-expression MAOA-uVNTR alleles significantly increase the risk towards PD in women. However, epigenetic mechanisms might obfuscate the genetic association, calling for ascertainment in larger samples as well as assessment of the MAOA promoter methylation status therein. © 2012 Wiley Periodicals, Inc.

Udo Dannlowski, Harald Kugel, Franziska Huber, Anja Stuhrmann, Ronny Redlich, Dominik Grotegerd, Katharina Dohm, Christina Sehlmeyer, Carsten Konrad, Bernhard T. Baune, Volker Arolt, Walter Heindel, Pienie Zwitserlood and Thomas Suslow

While cognitive impairments are well documented for the acute episode of major depressive disorder (MDD), less is known about cognitive functioning in the euthymic state. For working memory, dysfunctional activation of lateral prefrontal and cingulate cortex has been reported in the acute episode. This study investigates working‐memory function and its neurobiological correlate in euthymic MDD patients, particularly whether dysfunctional activation persists when depressive symptoms improve. We investigated 56 subjects with functional magnetic resonance imaging (fMRI) at 3 Tesla. To challenge working‐memory function, a classical verbal n‐back task (0‐, 1‐, and 2‐back) was used in 28 well‐characterized, euthymic, unipolar MDD patients and 28 healthy control subjects matched according to age, sex, and educational level. Data were analyzed using SPM5. In the absence of significant behavioral differences, we observed comparable overall patterns of brain activation in both groups. As expected, both groups showed stronger activation of the typical working‐memory network with increasing memory load. However, significant hyperactivation of the cingulate cortex was observed in euthymic patients, while lateral prefrontal activation was comparable between patients and controls. Working‐memory challenge in the euthymic state of MDD revealed a dissociation of lateral prefrontal and cingulate brain function. Cingulate function, which is important for both emotional and cognitive processing and their integration, is still abnormal when mood is restored. This could reflect a different speed of normalization in prefrontal and limbic cortices, persistent systematic changes in neuronal networks after an episode of MDD, or a compensatory mechanism to maintain working‐memory performance. Hum Brain Mapp, 2009. © 2008 Wiley‐Liss, Inc.

Recent evidence suggests a role for tumor necrosis factor alpha (TNF) in the functioning of the central nervous system (CNS). The aim of this work was to examine the effect of a deficiency of TNF (TNF(-/-)) and its main receptors (TNF-R1(-/-) and TNF-R2(-/-)) on cognitive function. A standardized survey on cognition-like behavior assessing learning and retention, spatial learning/memory, cognitive flexibility, and learning effectiveness was used in B6.WT and B6.TNF gene targeted mice strains (B6.wild-type, B6.TNF(-/-), B6.TNF-R1(-/-), B6.TNF-R2(-/-) mice). All studied mice strains demonstrated successful exploration and learning processes during the training phases of the tests, which made the specific cognition-like tests valid in these mice strains. In the specific cognition-like tests, the B6.TNF(-/-) mice demonstrated significantly poorer learning and retention in the novel object test compared to B6.WT, B6.TNF-R1(-/-) and B6.TNF-R2(-/-) mice. In addition, spatial learning and learning effectiveness were significantly poorer in B6.TNF(-/-) mice compared to B6.WT mice. Moreover, the moderately impaired cognitive performance with similar degrees in B6.TNF-R1(-/-) or B6.TNF-R2(-/-) mice was generally better than in TNF(-/-) mice but also poorer than in B6.WT mice. While the absence of TNF was correlated with poor cognitive functioning, the deletion of both TNF-receptors was involved in partially reduced cognitive functioning. Low-levels of TNF under non-inflammatory immune conditions appear essential for normal cognitive function. TNF displays an interesting candidate gene for cognitive function. Translational research is required to investigate associations between genetic variants of TNF and cognitive function in healthy subjects and neuropsychiatric samples.

Rapid transcranial magnetic stimulation is being increasingly used in the treatment of psychiatric disorders, especially major depression. However, its mechanisms of action are still unclear. The aim of this study was to assess metabolic changes by proton magnetic resonance spectroscopy following high-frequency rapid transcranial magnetic stimulation (20 Hz), both immediately after a single session and 24 h after a series of five consecutive sessions. Twelve healthy volunteers were enrolled in a prospective single-blind, randomized study [sham (n = 5) vs. real (n = 7)]. Three brain regions were investigated (right, left dorsolateral prefrontal cortex, left anterior cingulate cortex). A single as well as a series of consecutive rapid transcranial magnetic stimulations affected cortical glutamate/glutamine levels. These effects were present not only close to the stimulation site (left dorsolateral prefrontal cortex), but also in remote (right dorsolateral prefrontal cortex, left cingulate cortex) brain regions. Remarkably, the observed changes in glutamate/glutamine levels were dependent on the pre-transcranial magnetic stimulation glutamate/glutamine concentration, i.e. the lower the pre-stimulation glutamate/glutamine level, the higher the glutamate/glutamine increase observed after short- or long-term stimulation (5 days). In general, the treatment was well tolerated and no serious side-effects were reported. Neither transient mood changes nor significant differences in the outcome of a series of neuropsychological test batteries after real or sham transcranial magnetic stimulation occurred in our experiment. In summary, these data indicate that rapid transcranial magnetic stimulation may act via stimulation of glutamatergic prefrontal neurons.

Panic disorder is an anxiety disorder with an estimated heritability of 48%. Variation in the gene of the nuclear transcription factor “cAMP-responsive element modulator” (CREM) might contribute to its pathogenesis. CREM knock-out mice exhibit significantly less anxiety behavior than wild-type mice and the alternative CREM gene product “inducible cAMP early repressor” (ICER) plays a pivotal role in the hypothalamo-pituitary-adrenal (HPA) axis, which is disturbed in panic disorder. We characterized the genomic organization of the human CREM gene and performed a systematic mutation screening by means of single stranded conformational analysis (SSCA) in a sample of 40 German patients with panic disorder (DSM-III-R). Four novel single nucleotide polymorphisms in CREM promoters P 1 and P 4, one trinucleotide (ATT)-repeat polymorphism in CREM promoter P 2—generating the ICER isoform—and a rare amino acid substitution in CREM exon glut 2 were identified. Association analysis in an extended sample of German patients (n = 88) revealed a significant excess of the shorter CREM P 2 promoter eight-repeat trinucleotide allele and of genotypes containing the eight-repeat trinucleotide allele in panic disorder (P = 0.02), in particular in panic disorder without agoraphobia (P = 0.001). A replication study in independent Italian (n = 76) and Spanish (n = 62) samples, however, failed to confirm this observation. This suggests that the CREM P 2 promoter trinucleotide polymorphism is not a major susceptibility factor in the pathogenesis of panic disorder. Functional analysis of the observed CREM P 2 promoter polymorphism as well as studies in independent panic disorder samples are necessary. © 2003 Wiley-Liss, Inc.

Exposure‐based psychological interventions currently represent the empirically best established first line form of cognitive‐behavioural therapy for all types of anxiety disorders. Although shown to be highly effective in both randomized clinical and other studies, there are important deficits: (1) the core mechanisms of action are still under debate, (2) it is not known whether such treatments work equally well in all forms of anxiety disorders, including comorbid diagnoses like depression, (3) it is not known whether an intensified treatment with more frequent sessions in a shorter period of time provides better outcome than distributed sessions over longer time intervals. This paper reports the methods and design of a large‐scale multicentre randomized clinical trial (RCT) involving up to 700 patients designed to answer these questions. Based on substantial advances in basic research we regard extinction as the putative core candidate model to explain the mechanism of action of exposure‐based treatments. The RCT is flanked by four add‐on projects that apply experimental neurophysiological and psychophysiological, (epi)genetic and ecological momentary assessment methods to examine extinction and its potential moderators. Beyond the focus on extinction we also involve stakeholders and routine psychotherapists in preparation for more effective dissemination into clinical practice.

A hallmark of alexithymia is the difficulty putting emotional states into words which has to be differentiated from problems to communicate emotion to others. Shame proneness is a personality trait that is expected to be closely related to a reduced emotional self-disclosure in social interactions. The present investigation was conducted to examine construct validity of the Difficulties Describing Feelings scale of the 20-Item Toronto Alexithymia Scale (TAS-20). The TAS-20 was administered to 68 subjects (30 psychiatric inpatients and 38 normals) along with the Levels of Emotional Awareness Scale (LEAS), a direct measure of the ability to express feelings verbally, and the Shame-Guilt-Scale. Difficulties Describing Feelings was associated with shame assessing scales but not with guilt assessing scales or the LEAS. Thus, in view of our data one should be cautious in interpreting scores from the TAS-20 scale Difficulties Describing Feelings as indices of a difficulty to symbolize one's emotions. Instead, this TAS-20 scale seems to evaluate aspects of social shame.

The difficulties in defining the borders of the schizophrenia spectrum is one major source of variance in linkage studies of schizophrenia. The employment of biological markers may prove advantageous. Due to empirical evidence, eye tracking dysfunction (ETD) has been discussed to be the most promising marker for genetic liability to schizophrenia. With respect to the recent progress in genomic scans, which have pointed to the short arm of chromosome 6, we carried out a scan of the 6p21-23 region with 16 microsatellite markers to test for linkage between chromosomal markers and ETD as well as schizophrenia. We tested 5 models of inheritance of ETD and found maximum two-point lod scores of 3.51 for D6S271 and 3.44 for D6S282. By including these markers in a multipoint analysis, a lod score of 4.02 was obtained. In the case of schizophrenia, 7 models were tested; however, with non-significant results. Our findings, together with another recent linkage report, point to the possibility of a second susceptibility locus for schizophrenia which may be located centromeric to the HLA region. Also, the evidence of ETD being a susceptibility marker for schizophrenia receives further support.

One, as yet unemployed, approach to investigating immunology in depression is the assessment of the cytokine production by leucocytes, which would allow the determination of immune response under standardized conditions. Thus we measured the production of mitogen-induced cytokines (IL-1 beta, IL-2, IL-6, IL-10, interferon-gamma) and sIL-2R in a whole blood assay, and serum protein levels such as C-reactive protein (CRP), haptoglobin (Hp) and alpha 2-macroglobulin (alpha 2 M) in a longitudinal 6-week study in an attempt to assess leucocyte function during and after acute clinical stage of depression in 39 patients. Shortly after admission to hospital we found higher levels of all measured cytokines in the patients. Serum protein levels were significantly higher in the patients than in controls, and decreased over the study period. Whereas slightly elevated monokine levels in patients tended to reach control values, lymphokines showed a significant decrease over the 6 weeks as compared to baseline. These results suggest that the increase in immune activity seen at the beginning of the study may be followed by a suppressed cell-mediated immune function.

Objectives: To compare performance characteristics of the Confusion Assessment Method (CAM) algorithm for screening and delirium diagnosis with criteria for delirium from the International Classification of Diseases, Tenth Revision (ICD-10) and Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) in high-risk individuals. Design: Prospective cohort study. Setting: Academic geriatric hospital. Participants: One hundred two individuals aged 80 to 100 hospitalized for acute medical illness. Measurements: Complete CAM instrument (nine items), scored using the four-item CAM diagnostic algorithm. Criterion standard classification of delirium was rated independently according to expert consensus based on DSM-IV and ICD-10 criteria for delirium. Results: In 79 hospitalized participants, the CAM performed well for delirium screening (delirium prevalence of 24% according to DSM-IV and 14% according to ICD-10). Of all CAM features, acute onset and fluctuating course are most important for diagnosis (area under the receiver operating characteristic curve (AUC) = 0.92 in DSM-IV and 0.83 in ICD-10). The CAM diagnostic algorithm had a sensitivity of 0.74, a specificity of 1.0, and an AUC of 0.88 compared with the DSM-IV reference standard and a sensitivity of 0.82, a specificity of 0.91, and an AUC of 0.85 compared with the ICD-10. Compared with the ICD-10, adding psychomotor change to the CAM algorithm improved specificity to 97%, but sensitivity fell to 55% (AUC = 0.96). Applying psychomotor change sequentially only to the group that the CAM algorithm identified as having no delirium improved sensitivity to 91% with specificity of 85% (AUC = 0.95). Conclusion: Although the CAM diagnostic algorithm performed well against a DSM-IV reference standard, adding psychomotor change to the CAM algorithm improved specificity and diagnostic value against ICD-10 criteria overall in older adults with dementia and improved sensitivity and screening performance when applied sequentially in CAM-negative individuals.