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Zusammenfassung Ziel der Studie Alkohol- und substanzbezogene Störungen (ICD 10 F1x.x) zählen zu den häufigsten Diagnosen in der stationär-somatischen und psychiatrischen Versorgung. Um den Behandlungserfolg zu überprüfen, sind die Etablierung und der Einsatz von Ergebnisindikatoren in der Praxis von hoher Relevanz. Methodik An 10 Vitos-Versorgungskliniken in Hessen wurden globale Behandlungsindikatoren zu Aufnahme und bei Entlassung im Jahre 2016 erhoben (CGI und GAF). Insgesamt konnten mehr als 10000 Patienten mit ICD10-F1x-Diagnosen in die Auswertung einbezogen werden. Ergebnisse Die Auswertungen belegen signifikante Besserungen des klinischen Zustandes sowie Unterschiede in Behandlungsdauer, Remissionen sowie Geschlechtsunterschiede. Schlussfolgerung Die Resultate der Auswertung stützen den Einsatz von globalen möglichen Indikatoren der Ergebnisqualität. Limitationen des Studiendesigns, der Instrumente und der Stichprobe werden kritisch betrachtet.

Background German S3 guidelines are subject to the highest methodological standards. This includes that they are only valid for a certain time period. Following the first edition in 2012 the first update of the S3 guidelines on bipolar disorder has now been published (2019). Objective What has changed in the field of pharmacological recommendations comparing the first edition with the update in 2019? Material and methods Comparison of the 1st edition from 2012 with the update from 2019 of the S3 guidelines for the diagnostics and treatment of bipolar disorders. Results The three principle treatment targets of acute treatment of bipolar depression, acute treatment of mania and phase prophylaxis (maintenance treatment) can be distinguished. For acute treatment of bipolar depression, for the first time a medication has received a level A recommendation: quetiapine. For the acute treatment of mania, several drugs are still recommended with the same level of recommendation (B). Asenapine has been added as the tenth substance. Lithium is still the only drug with a level A recommendation for maintenance and prophylactic treatment and is also the only drug approved for this indication without restrictions. A new recommendation is that in the absence of contraindications, phase prophylaxis with a serum level of at least 0.6 mmol/l should be carried out. With a B recommendation, quetiapine has been added to the drugs for phase prophylactic treatment. Conclusion The S3 guidelines make recommendations at the highest scientific level. In view of these findings, lithium is clearly underutilized for maintenance therapy. In the absence of clear contraindications (advanced renal insufficiency), every patient with bipolar disease should be given the chance of lithium prophylaxis for an adequately long period.

ZUSAMMENFASSUNGIn diesem Artikel wird eine Übersicht über psychoedukative Interventionen bei adulter ADHS gegeben, bestehende Manuale beschrieben, ein Praxisbeispiel einer Spezialambulanz im versorgungspsychiatrischen Spektrum mit Responsemessungen sowie die Studienlage zur Wirksamkeit referiert. Psychoedukation und Coaching kommt als psychotherapeutischer Basisintervention ein besonderer Stellenwert in einem multimodal angelegten Gesamtbehandlungskonzept der ADHS zu. Mittels Psychoedukation sollen die Betroffenen als auch ihre Angehörigen in der emotionalen Verarbeitung und der Akzeptanz der Diagnose unterstützt werden sowie umfassend über ihre Störung und adäquate Behandlungsmöglichkeiten inklusive der Pharmakotherapie aufgeklärt werden. Darüber hinaus sollen Selbstmanagement-Fertigkeiten geschult, Leidensdruck reduziert sowie die Funktionsfähigkeit und Alltagsadaptation verbessert werden.

Background Stressful life events influence the course of affective disorders, however, the mechanisms by which they bring about phenotypic change are not entirely known. Methods We explored the role of DNA methylation in response to recent stressful life events in a cohort of bipolar patients from the longitudinal PsyCourse study (n = 96). Peripheral blood DNA methylomes were profiled at two time points for over 850,000 methylation sites. The association between impact ratings of stressful life events and DNA methylation was assessed, first by interrogating methylation sites in the vicinity of candidate genes previously implicated in the stress response and, second, by conducting an exploratory epigenome-wide association analysis. Third, the association between epigenetic aging and change in stress and symptom measures over time was investigated. Results Investigation of methylation signatures over time revealed just over half of the CpG sites tested had an absolute difference in methylation of at least 1% over a 1-year period. Although not a single CpG site withstood correction for multiple testing, methylation at one site (cg15212455) was suggestively associated with stressful life events (p −5). Epigenetic aging over a 1-year period was not associated with changes in stress or symptom measures. Conclusions To the best of our knowledge, our study is the first to investigate epigenome-wide methylation across time in bipolar patients and in relation to recent, non-traumatic stressful life events. Limited and inconclusive evidence warrants future longitudinal investigations in larger samples of well-characterized bipolar patients to give a complete picture regarding the role of DNA methylation in the course of bipolar disorder.

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

Contrary to the practice in some countries, access to flexible and integrated forms of psychiatric care (FIT models) is limited in Germany. Several legislations have been introduced to improve this situation, notably the recent §64b (flexible and integrative treatment model; FIT64b) of the German Social Code, which allows for a capitation-based accounting of fees for services. The aim of this study was to explore the effects of FIT64b implementation on various stakeholders (patients, informal caregivers and staff) in 12 psychiatric hospital departments across Germany. Structural as well as quantitative and qualitative data are included, with integration of different methodological approaches. In all departments, the implementation of the new accounting system resulted into a relatively stable set of structural and processual changes where rigid forms of mainly inpatient care shifted to more flexible and integrated types of outpatient and outreach treatments. These changes were more likely to be perceived by patients and staff, and likewise received better evaluations, in those departments showing higher level or longer duration of implementation. Patients' evaluations, furthermore, were largely influenced by the advent of continuous forms of care, better accessibility, and by their degree of autonomy in steering of their services.

Selvaraj S, Arnone D, Job D, Stanfield A, Farrow TFD, Nugent AC, Scherk H, Gruber O, Chen X, Sachdev PS, Dickstein DP, Malhi GS, Ha TH, Ha K, Phillips ML, McIntosh AM. Grey matter differences in bipolar disorder: a meta-analysis of voxel-based morphometry studies. Bipolar Disord 2012: 14: 135–145. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objective: Several neuroimaging studies have reported structural brain differences in bipolar disorder using automated methods. While these studies have several advantages over those using region of interest techniques, no study has yet estimated a summary effect size or tested for between-study heterogeneity. We sought to address this issue using meta-analytic techniques applied for the first time in bipolar disorder at the level of the individual voxel. Methods: A systematic review identified 16 voxel-based morphometry (VBM) studies comparing individuals with bipolar disorder with unaffected controls, of which eight were included in the meta-analysis. In order to take account of heterogeneity, summary effect sizes were computed using a random-effects model with appropriate correction for multiple testing. Results: Compared with controls, subjects with bipolar disorder had reduced grey matter in a single cluster encompassing the right ventral prefrontal cortex, insula, temporal cortex, and claustrum. Study heterogeneity was widespread throughout the brain; though the significant cluster of grey matter reduction remained once these extraneous voxels had been removed. We found no evidence of publication bias (Eggers p = 0.63). Conclusions: Bipolar disorder is consistently associated with reductions in right prefrontal and temporal lobe grey matter. Reductions elsewhere may be obscured by clinical and methodological heterogeneity.

Prefrontal and anterior cingulate cortical regions are assumed to be involved in the pathophysiology of mood regulation. Reduced prefrontal and anterior cingulate function indicated by decreased N-acetyl-aspartate (NAA) levels in patients with bipolar disorder has been reported inconsistently. A positive correlation between lithium serum level and NAA concentrations has been found previously. The aim of this study was to re-investigate prefrontal and anterior cingulate neurochemistry in a sample of euthymic patients with bipolar I disorder.NAA, choline (Cho), creatine (Cr) and myo-inositol (Ins) in left dorsolateral prefrontal cortex and left anterior cingulate cortex were measured in 33 euthymic patients with bipolar I disorder and 29 healthy comparison subjects by using proton magnetic resonance spectroscopy ([(1)H]MRS).Metabolic ratios did not differ between patients with bipolar I disorder and comparison subjects in prefrontal and anterior cingulate cortex neither in the total sample nor in the pairwise matched sub-sample. We could not observe an association between lithium level and NAA ratios. Lithium treated patients demonstrated unchanged NAA or myo-inositol ratios compared to alternatively treated patients.In contrast to prior findings, we could not observe any metabolic alterations in euthymic patients with bipolar disorder.

Objective: Subcortical regions such as hippocampus, thalamus and ventral putamen are assumed to be involved in the pathophysiology of mood regulation. Disturbed hippocampal neuronal function indicated by reduced N-acetyl-aspartate (NAA) levels in bipolar patients was shown by several studies. Results in thalamus and putamen are inconsistent. Method: N-acetyl-aspartate, choline (Cho), creatine (Cr) and myo-inositol (Ins) were measured in left hippocampus, left thalamus and left putamen using proton magnetic resonance spectroscopy in 13 euthymic patients with bipolar I disorder and 13 pairwise matched healthy control subjects. Metabolic ratios NAA/Cr, NAA/Cho, Cho/Cr and Ins/Cr were calculated. Results: Patients with bipolar I disorder demonstrated significantly reduced NAA/Cr in the left hippocampus compared with healthy control subjects. No alterations were found in thalamus or putamen. Conclusion: We hypothesize that this NAA/Cr reduction might reflect neuronal dysfunction in the left hippocampus in patients with bipolar disorder.

The anterior limb of the internal capsule (ALIC), connecting cortical and subcortical structures, is involved in functional important circuits. To detect volumetric changes in ALIC, including the influence of genetic factors, a magnetic resonance imaging (MRI) study of families affected with schizophrenia was performed.The study sample comprised 22 family members with schizophrenia (FM-SZ), 34 family members without schizophrenia (FM-NSZ), and 43 control subjects. In addition to manual tracing of ALIC, subjects underwent proton magnetic resonance spectroscopy in the left prefrontal cortex, psychopathological rating, and neuropsychological assessment of frontal lobe function.Compared with controls, a significant reduction of right ALIC volume was seen in all family members (12%-16% reduction, p.01) and a reduction of left ALIC volume in FM-NSZ (10% reduction, p = .028) was also observed. Both groups of family members showed a bilateral reduction in maximal cross sectional area of the ALIC. FM-SZ performed significantly worse on neurocognitive measures (Subject Ordered Pointing Task [SOPT] and Wisconsin Card Sorting Test), and performance correlated negatively with the ALIC volume (SOPT, r = -.6, p = .03).A reduced volume of ALIC in affected families supports the hypothesis of disturbed frontothalamic connectivity in schizophrenia and demonstrates functional relevance by an association with reduced neurocognitive performance.

Background Gray matter reduction and ventricular enlargement belong to the best replicated findings in schizophrenia. Brain morphologic changes were also found in non-schizophrenic family members (FM). The intention of this study was to examine whether non-psychotic first-degree relatives reveal similar morphologic changes as schizophrenic patients and how state of genetic loading contribute to these abnormalities. Methods Forty-nine schizophrenic patients, 71 non-schizophrenic FM and 48 control subjects took part in this volumetric MRI study. All subjects were between 18 and 59 years old. Dependent variables were gray matter, white matter and total cerebrospinal fluid (CSF) volume, determined by SPM99 segmentation algorithm. As an important part of CSF lateral ventricle volume was determined manually by removing surrounding CSF areas. Results In schizophrenic patients compared to controls and non-schizophrenic FM total CSF volumes and lateral ventricles were increased. Gray and, to a lesser degree, white matter volumes were decreased as well. For CSF, gray and white matter there was no significant difference between uni- and multiple affected families. CSF correlated significantly negative with gray matter (r = −0.78) and, less intensive, with white matter (r = −0.40). There were negative correlations between gray and white matter volume as well (r = −0.26). These correlations were not significantly different between the diagnostic groups. Conclusion CSF enlargement and gray matter reductions in schizophrenic patients compared to controls and non-affected FM seem to be interdependent findings. However, this correlation is independent of the factor diagnosis and is therefore not specific for schizophrenia.

PURPOSE OF REVIEW This review highlights the recent findings of different effects of typical and atypical antipsychotics on brain structure. RECENT FINDINGS Studies examining the effect of treatment with typical antipsychotics on brain structure revealed a significant increase in basal ganglia volumes and decreased grey matter volume in different cortical regions. These volume changes were detectable even after a 12-week treatment. In contrast to these results, treatment with atypical antipsychotics does not seem to change basal ganglia volumes in neuroleptic-naive patients. Moreover, switching from typical to atypical antipsychotic treatment reduces the increased basal ganglia volume to normal values compared with healthy controls. Only the volumes of thalamus and cortical grey matter increased after atypical antipsychotic treatment. SUMMARY Currently, there is growing evidence that atypical antipsychotics might ameliorate structural changes caused by the disease process underlying schizophrenia and effects of typical antipsychotics. Further studies have to investigate the mechanism leading to these varying effects on brain structure.

The brain serotonin-2A receptor (5-HT(2A)R) has been implicated in both the pathology of schizophrenia and the therapeutic action of atypical antipsychotics. However, little is known about the 5-HT(2A)R status before the onset of schizophrenia and before the exposure to antipsychotics. We used [18F] altanserin and positron emission tomography (PET) in a pilot study of 6 individuals suspected to be at elevated risk for schizophrenia and seven age-matched controls to test the hypothesis that regional 5-HT(2A)R binding is altered in the prodromal stages of schizophrenia. Distribution volume ratios (DVRs) as a proxy for 5-HT(2A)R availability were significantly reduced in prefrontal cortex regions of at-risk subjects, implicating early abnormalities of serotonergic neurotransmission that antecede the onset of schizophrenia.

In brains of patients with schizophrenic and affective disorders pathomorphological changes have been shown focussing in frontal and temporal cortex. The volume reduction in prefrontal cortex of schizophrenic patients is hypothesized to be based on a reduction of neuropil. A decrease of synaptic proteins and a decrease of dendritic spines of pyramidal cells can additionally be the origin of disconnections of neurons. Affection of the glutamatergic, GABA-ergic and dopaminergic system and reduction of interneurons could be the correlate of a deficient neuronal network which might be combined with exogen factors generate psychotic symptoms. Reelin and associated proteins are candidate molecules. Their dysregulation might explain essential features of the dysfunctional network of schizophrenia.

Cerebrospinal fluid (CSF) space enlargement in schizophrenia is a prominent finding. This study was initiated to examine the influence of genetic loading, obstetric complications and premorbid adjustment on the extent of this enlargement. The sample of this MRI study consisted of 40 schizophrenic patients, 24 psychiatric and 40 healthy family members from 10 uniaffected and 19 multiple affected families with schizophrenia, such as 27 control subjects from non-affected families. The ventricle-to-brain-ratio (VBR), and the areas of the third ventricle, sylvian fissure, temporal horn and interhemispheric fissure at the slice where these structures reached their maximum were examined relatively to the corresponding total brain areas. The sum of CSF areas was calculated as a parameter for global atrophy. From MANCOVA adjusted for intervening variables the right VBR and the sum of CSF areas revealed significant differences between diagnostic groups. For these areas schizophrenic patients showed an increase compared to control subjects and family members with psychiatric disorder. Genetic loading influenced the interhemispheric fissure, enlarged in multiple affected compared to uniaffected families, and the temporal horn asymmetry, which was right sided (right > left) in control subjects and multiple affected families, but inverted in uniaffected families. Neonatal obstetric complications influenced only the size of the VBR, while premorbid adjustment predicted various CSF areas. In conclusion, schizophrenic subjects from multiple and uniaffected families showed a global atrophy, which was most pronounced in the VBR. Genetic loading seems to have an impact on frontal regions as the interhemispheric fissure and on the temporal horn.

Affective deficits are one common denominator of schizophrenia (SZ), bipolar disorder (BD) and obsessive compulsive disorder (OCD) with the amygdala indicated as one of the major structures involved in emotion regulation. Previous findings of differences in amygdala volume between healthy controls and patients with SZ, BD or OCD diverge with respect to the affected hemisphere, size and direction of the effect. Variability in the CACNA1C gene has been linked to BD, SZ as well as structural and functional variation in the amygdala in healthy people and patients with BD. We were interested to investigate whether amygdala volumes differ between hemispheres, diagnostic or genotype groups, and whether any interactive effects exist. We combined genotyping of SNP rs1006737 in CACNA1C with structural MRI measurements of relative gray matter (GM) amygdala volume in patients with SZ, BD or OCD as well as healthy controls (N Total = 72). The CACNA1C genotype showed a significant effect on relative GM amygdala volume in patients with SZ. There was a significant left versus right relative GM amygdala volume decrease in patients with SZ or BD. The effects of hemisphere and diagnosis (controls vs. patients with SZ) on relative GM amygdala volume were genotype specific. Our data suggest that the CACNA1C genotype may account for some heterogeneity in the effects of hemisphere and diagnosis on amygdala volume when comparing patients with SZ and controls and point to disturbed Ca(2+)-signaling as a plausible mechanism contributing to the pathology in patients with SZ.

The German Association for Psychiatry and Psychotherapy (DGPPN) has committed itself to establish a prospective national cohort of patients with major psychiatric disorders, the so-called DGPPN-Cohort. This project will enable the scientific exploitation of high-quality data and biomaterial from psychiatric patients for research. It will be set up using harmonised data sets and procedures for sample generation and guided by transparent rules for data access and data sharing regarding the central research database. While the main focus lies on biological research, it will be open to all kinds of scientific investigations, including epidemiological, clinical or health-service research.

Objective Suboptimal availability of circulating thyroid hormones may contribute to the high rate of treatment failures in bipolar disorder. This study tested the efficacy of adjunctive treatment with supraphysiologic doses of levothyroxine in patients with bipolar depression and the hypothesis that women would display a better outcome compared to men. Method The aims of this multicenter, 6-week, double-blind, randomized, placebo-controlled fixed-dose (300 μg/d) trial conducted from 2004 to 2009 were to assess efficacy and tolerability of levothyroxine adjunctive to continuing treatment with mood stabilizer and/or antidepressant medication for patients with bipolar I or II disorder, currently depressed (DSM-IV), and to investigate gender differences in treatment response. The primary efficacy variable was mean change in Hamilton Depression Rating Scale (HDRS) score. Results Of 74 patients enrolled in the study, 62 (35 with bipolar I; mean age = 44.9 years) were randomized. Mean change in HDRS score from randomization to week 6 was larger in the levothyroxine group compared to the placebo group, with a 2.7-point difference (decline of -7.8 [38.3%] vs -5.1 [25.5%]; last-observation-carried-forward analysis). The course of HDRS scores over time from randomization to week 6 was significantly different between groups at week 4 (P = .046) but not at the end of the placebo-controlled phase (P = .198). The secondary analysis of women (n = 32) revealed a significant difference between groups in mean change in HDRS score (-16.6% placebo vs -42.4% levothyroxine, P = .018). A mixed-effects model for repeated-measures analysis showed a significant between-group difference in HDRS score (6.8, P = .012) for women. High thyroid-stimulating hormone levels, indicating suboptimal levels of circulating thyroid hormones, were predictive for positive treatment outcome in women treated with levothyroxine in a linear regression model (F3 = 3.47; P = .05). Discussion This trial demonstrated that patients treated with levothyroxine did numerically better than those treated with placebo; however, the study failed to detect a statistically significant difference between the 2 groups in the primary outcome measure due to a high placebo response rate. Previous findings that women show better improvement in depression scores with levothyroxine compared to men were confirmed. Trial registration ClinicalTrials.gov identifier: NCT01528839.

DISC1 (Disrupted-In-Schizophrenia 1), one of the top candidate genes for schizophrenia, has been associated with a range of major mental illnesses over the last two decades. DISC1 is crucially involved in neurodevelopmental processes of the human brain. Several haplotypes and single nucleotide polymorphisms of DISC1 have been associated with changes of grey matter volumes in brain regions known to be altered in schizophrenia and other psychiatric disorders. The aim of the present study was to investigate the effects of two single nucleotide polymorphisms (SNPs) of DISC1 on grey matter volumes in human subjects using voxel-based morphometry (VBM). 114/113 participating subjects (psychiatric patients and healthy controls) were genotyped with respect to two at-risk SNPs of DISC1, rs6675281 and rs821616. All participants underwent structural magnetic resonance imaging (MRI). MRI data was statistically analyzed using voxel-based morphometry. We found significant alterations of grey matter volumes in prefrontal and temporal brain regions in association with rs6675281 and rs821616. These effects of DISC1 polymorphisms on brain morphology provide further support for an involvement of DISC1 in the neurobiology of major psychiatric disorders such as schizophrenia.

Several neuroimaging studies have reported structural brain differences in bipolar disorder using automated methods. While these studies have several advantages over those using region of interest techniques, no study has yet estimated a summary effect size or tested for between-study heterogeneity. We sought to address this issue using meta-analytic techniques applied for the first time in bipolar disorder at the level of the individual voxel.A systematic review identified 16 voxel-based morphometry (VBM) studies comparing individuals with bipolar disorder with unaffected controls, of which eight were included in the meta-analysis. In order to take account of heterogeneity, summary effect sizes were computed using a random-effects model with appropriate correction for multiple testing.Compared with controls, subjects with bipolar disorder had reduced grey matter in a single cluster encompassing the right ventral prefrontal cortex, insula, temporal cortex, and claustrum. Study heterogeneity was widespread throughout the brain; though the significant cluster of grey matter reduction remained once these extraneous voxels had been removed. We found no evidence of publication bias (Eggers p = 0.63).Bipolar disorder is consistently associated with reductions in right prefrontal and temporal lobe grey matter. Reductions elsewhere may be obscured by clinical and methodological heterogeneity.

Usher J, Menzel P, Schneider-Axmann T, Kemmer C, Reith W, Falkai P, Gruber O, Scherk H. Increased right amygdala volume in lithium-treated patients with bipolar I disorder. Objective: The amygdala plays a major role in processing emotional stimuli. Fourteen studies using structural magnetic resonance imaging (MRI) have examined the amygdala volume in paediatric and adult patients with bipolar disorder (BD) compared with healthy controls (HC) and reported inconsistent findings. Lithium has been found to increase grey matter volume, and first evidence points towards an effect on regional brain volume such as the amygdala. Method: We examined the amygdala volume of euthymic patients with BD treated with lithium (n = 15), without lithium (n = 24) and HC (n = 41) using structural MRI. Results: Patients treated with lithium exhibited in comparison to HC a larger right absolute (+17.9%, P = 0.015) and relative (+18%, P = 0.017) amygdala volume. There was no significant difference in amygdala volume between patients without lithium treatment and HC. Conclusion: Lithium appears to have a sustained effect on a central core region of emotional processing and should therefore be considered in studies examining BD.

Objective: Meta-analytic findings support the hypothesis of specific neurocognitive deficits for bipolar patients in the domains of attention, processing speed, memory and executive functions. This study aims to show neurocognitive impairment in euthymic patients with bipolar I disorder compared with healthy controls while detailing the impact of medication side-effects or illness characteristics on neuropsychological test performance. Method: Forty euthymic patients with bipolar I disorder were compared with 40 healthy controls in a cross-sectional design. Clinical features and neuropsychological measures of IQ, psychomotor speed, verbal fluency, learning and memory, executive functions and attention were assessed. Results: Patients without antipsychotic drug use did not differ significantly from healthy controls in any neuropsychological measure. Yet patients treated with antipsychotics showed significant underperformance in the domains of semantic fluency, verbal learning and recognition memory as well as executive functions related to planning abilities, even when clinical features were controlled for. Conclusion: The impact of antipsychotic medication needs to be further clarified for euthymic bipolar patients and should be considered when neuropsychological test performance is interpreted.

Cognitive dysfunction is a common finding in schizophrenia. Nevertheless the specific pattern of neuropsychological impairment in schizophrenia compared to other severe mental illnesses has not been intensively studied. Twenty-four patients with schizophrenia belonging to different stages of the disease (11 first-episode patients, 13 patients with multiple episodes), 18 patients with bipolar disorder and 23 healthy control subjects underwent standardized neuropsychological assessment. Statistical analysis of covariance (ANCOVA) demonstrated that, compared to control subjects, patients with schizophrenia performed significantly worse in the trail-making test (P = 0.012), verbal fluency (category letter, P = 0.004), verbal learning/memory (P = 0.005), and the Wisconsin Card Sorting Test (WCST) (P = 0.004 for administered trials; P = 0.025 for perseverative responses, T value) indicating significant deficits in attention and psychomotor performance, and in particular in verbal working memory and cognitive flexibility for schizophrenic patients. A significant difference between schizophrenic and bipolar patients was found only in the WCST. Schizophrenic patients made significantly more perseverative responses (P = 0.002, ANCOVA), indicating a more pronounced and specific deficit in cognitive flexibility and frontally based executive function. In conclusion, these results may suggest a cognitive endophenotype in schizophrenia and underline the role of the prefrontal cortex in schizophrenic pathophysiology.

The amygdala has gained special interest regarding the neuropathology of bipolar disorder (BD). Structural magnetic resonance imaging (MRI) studies with patients suffering from BD have yielded quite inconsistent results with respect to amygdala volume. We performed a meta-analysis of structural MRI studies that investigated right and left amygdala volume in pediatric and adult patients with BD. The aim was to assess the heterogeneous findings and to investigate whether a correlation between amygdala volume and the patient's age exists. Studies were searched for in "Pub Med" (last search June 2007), and data for right and left amygdala volume in cm 3 were extracted and combined in a meta-analysis. Thirteen studies with 389 scans of patients and 488 scans of healthy control subjects (HC) were included. The impact of age on the difference in amygdala volume between patients and HC was assessed by meta-regression. The amygdala volume was bilaterally reduced in the overall sample of patients with BD and the pediatric subsample. The results of the adult studies were less homogeneous, and on average, no significant difference between adult patients and HC was found. A meta-regression analysis revealed a positive correlation between mean age and amygdala volume in patients with BD. We speculate that amygdala volume is reduced at the onset of the disease and increases with age.

The SNAP-25 gene is an integral part of the vesicle docking and fusion machinery that controls neurotransmitter release. Several post mortem studies revealed a reduction of SNAP-25 protein in the hippocampus of patients with schizophrenia and bipolar disorder (BD). Thirty-eight patients with schizophrenia, BD or obsessive-compulsive disorder and 17 healthy controls participated in the study. Proton magnetic resonance spectroscopy in left hippocampus was performed in each individual. Three single nucleotide polymorphisms (SNP) of the SNAP-25 gene were genotyped. Individuals with the homozygous CC genotype of the DdeI SNP presented a significantly higher ratio of N-acetyl-aspartate (NAA)/choline-containing compounds (Cho) in the left hippocampus compared to the group of individuals with the homozygous TT genotype. The SNAP-25 genotype may modulate synaptic plasticity and neurogenesis in the left hippocampus, and altered NAA/Cho ratio may be an indicator for this genetic modulation of neuronal function in the hippocampus. peerReviewed

Dopaminergic activity in the brain is modulated by the dopamine transporter (DAT). Several lines of evidence suggest that a variable number of tandem repeats (VNTR) polymorphism of the DAT1 gene (SLC6A3) influences its gene expression. The aim of this study was to determine whether the DAT1VNTR polymorphism alters the metabolic ratios NAA/Cho, NAA/Cr, Cho/Cr and Ins/Cr in the left dorsolateral prefrontal cortex, anterior cingulate cortex, and putamen in healthy subjects and psychiatric patients irrespective of clinical diagnosis.Sixty-four individuals (30 patients with bipolar disorder, 18 patients with obsessive-compulsive disorder, and 16 healthy subjects) participated in the study. The 3'-UTR VNTR polymorphism of DAT1 (SLC6A3) gene was genotyped in all individuals. (1)H-MRS was performed in the above-mentioned brain regions.The individuals with the homozygous DAT1 10-repeat genotype presented significantly higher ratios of NAA/Cho and NAA/Cr in the left putamen compared to the group of individuals with the 9/9-repeat or 9/10-repeat genotype.The VNTR polymorphism of the DAT1-gene modulates NAA/Cho and NAA/Cr in the left putamen independent of psychiatric diagnosis status. These results suggest an association of DAT1 VNTR polymorphism, dopaminergic activity, and neuronal function in putamen.

Recommendations of treatment guidelines concerning the use of second-generation antipsychotic (SGA) agents for acute mania vary substantially across committees or working groups. Meta-analyses addressing the use of SGAs in the treatment of acute mania are lacking.To conduct a meta-analysis of the efficacy and safety of SGAs in the treatment of acute mania.Randomized controlled trials comparing SGAs with placebo, first-generation antipsychotic drugs, or mood stabilizers (MSs) in the treatment of acute mania were searched for in the PsiTri and MEDLINE databases (last search: May 2006).The abstracts, titles, and index terms of studies were searched using the following key words: aripiprazole, amisulpride, clozapine, olanzapine, quetiapine, risperidone, ziprasidone, and zotepine in conjunction with mania, manic, and bipolar.Data on efficacy, global dropout, dropout due to adverse events, dropout due to inefficacy, weight gain, rate of somnolence, and extrapyramidal symptoms were extracted and combined in a meta-analysis.A total of 24 studies with 6187 patients were included. The SGAs were significantly more efficacious than placebo. The analysis demonstrated that adding antipsychotic agents to MS treatment was significantly more effective than treatment with MSs alone. The SGAs displayed efficacy comparable with that of MSs. Some SGAs seemed to induce more extrapyramidal symptoms than placebo. The SGAs were also associated with higher rates of somnolence than placebo.Currently available data suggest that combining SGAs and MSs is the most efficacious treatment of acute mania.

We used proton magnetic resonance spectroscopy ( 1 H MRS) to examine biochemical characteristics of the brain tissue in subjects at risk for schizophrenia. Nineteen participants fulfilling research criteria for an early ( n = 10) or a late ( n = 9) at-risk syndrome, 21 patients with full disease according to DSM IV and 31 healthy control subjects were included in the study. Single-voxel 1 H MRS was performed in the left frontal lobe, the anterior cingulate gyrus and the left superior temporal lobe. Subjects were followed longitudinally to detect conversion to schizophrenia. We observed a significant reduction of the metabolic ratios NAA/Cr and NAA/Cho in the left frontal lobe and of NAA/Cr in the anterior cingulate gyrus in both at-risk groups and in the schizophrenic patients compared with healthy controls. Those at-risk subjects, who converted to schizophrenia within the observation period, had a higher Cho/Cr and a lower NAA/Cho ratio in the anterior cingulate gyrus compared with non-converters. NAA/Cr did not differ between converters and non-converters. Six at-risk subjects were taking antidepressants, two were taking antipsychotics. There was no difference in any metabolic ratio in any region between at-risk subjects with and without medication. We conclude that the reduction of the neuronal marker NAA in the left prefrontal lobe and the anterior cingulate gyrus may represent a vulnerability indicator for schizophrenia in at-risk subjects, while elevated Cho in the anterior cingulate gyrus may be a predictor for conversion from the prodromal state to the full disease.

This study examined cognitive functions of patients with obsessive-compulsive disorder (OCD) compared to patients with bipolar disorder (BD) and a healthy control (HC) group. The aim of this study was to show if there were distinguishable cognitive profiles and characteristics. 15 OCD patients without current depression, 18 euthymic patients with BD and 23 HC participants were tested. All participants passed through a neuropsychological test battery including attention, speeded information processing, learning and memory, executive functions and interference performance. Overall bipolar patients were more impaired than OCD patients. Both groups of patients revealed deficits in general information processing speed as well as in verbal learning and memory. By contrast, only BD patients showed significantly increased reaction times in the intermodal comparison and divided attention tests. In summary, this study provides evidence for both commonalities and disease-specific differences of cognitive deficit patterns in OCD and BD.

The neurobiological basis of bipolar affective disorders is unknown. However, neuroanatomic circuits of mood regulation have been hypothesized. Neuroimaging revealed volumetric changes of specific brain structures in these circuits. The most prominent abnormality is enlargement of the amygdala. In addition there might be structural changes in the frontal lobe, cerebellum, and pituitary. The findings in bipolar disorder differ from those in unipolar depression and schizophrenia. For further identification of the neurobiological basis of bipolar disorders, structural neuroimaging combined with functional neuroimaging such as magnetic resonance spectroscopy, neuroendocrinological studies, and genetical analyses are required to subgroup patients with bipolar disorder by diagnostic, prognostic, and therapeutic criteria.

Various polymorphisms of the X-chromosomal monoamine oxidase A (MAO-A) gene were investigated for association with affective disorders. However, none of the studied variants could consistently be associated with either major depressive or bipolar affective disorder. Recently, a positive association between panic disorder and a novel functional repeat polymorphism in the MAO-A gene promoter, with the longer alleles being more active, was reported. Since monoaminergic neurotransmission is supposed to play an important role in affective disorders, we investigated a potential association of this polymorphism with major depressive illness in a sample of 146 unrelated patients of German descent and a control group of 101 individuals with a negative life history for affective disorders. Similarly to the recent findings in panic disorder, we observed a significantly increased frequency of genotypes containing only long alleles in female patients with recurrent major depression in comparison with age- and sex-matched controls. Thus, our data suggest that an excess of high-activity MAO-A gene promoter alleles resulting in an elevated MAO-A activity is a risk factor for major depressive disorder in females. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:801-803, 2000.

Context Hippocampal volume is lower than expected in patients with schizophrenia; however, whether this represents a fixed deficit is uncertain. Exercise is a stimulus to hippocampal plasticity. Objective To determine whether hippocampal volume would increase with exercise in humans and whether this effect would be related to improved aerobic fitness. Design Randomized controlled study. Setting Patients attending a day hospital program or an outpatient clinic. Patients or Other Participants Male patients with chronic schizophrenia and matched healthy subjects. Interventions Aerobic exercise training (cycling) and playing table football (control group) for a period of 3 months. Main Outcome Measures Magnetic resonance imaging of the hippocampus. Secondary outcome measures were magnetic resonance spectroscopy, neuropsychological (Rey Auditory Verbal Learning Test, Corsi block-tapping test), and clinical (Positive and Negative Syndrome Scale) features. Results Following exercise training, relative hippocampal volume increased significantly in patients (12%) and healthy subjects (16%), with no change in the nonexercise group of patients (−1%). Changes in hippocampal volume in the exercise group were correlated with improvements in aerobic fitness measured by change in maximum oxygen consumption ( r = 0.71; P = .003). In the schizophrenia exercise group (but not the controls), change in hippocampal volume was associated with a 35% increase in the N -acetylaspartate to creatine ratio in the hippocampus. Finally, improvement in test scores for short-term memory in the combined exercise and nonexercise schizophrenia group was correlated with change in hippocampal volume ( r = 0.51; P Conclusion These results indicate that in both healthy subjects and patients with schizophrenia hippocampal volume is plastic in response to aerobic exercise.

Background and aimsDTNBP1, which encodes dysbindin-1, is one of the best-supported susceptibility genes for schizophrenia, and hippocampal volume reduction is one of the major neuropathological findings in schizophrenia. Consistent with these findings, dysbindin-1 has been shown to be diminished in glutamatergic hippocampal neurons in schizophrenic patients. The aim of this study was to directly investigate the effects of two single nucleotide polymorphisms of the DTNBP1 gene on regional brain volumes in human subjects.Methods128 subjects participated in the study. All subjects were genotyped with respect to two single nucleotide polymorphisms of the DTNBP1 gene (rs2619522 and rs1018381) and underwent structural magnetic resonance imaging (MRI). MRI data were preprocessed and statistically analyzed using standard procedures as implemented in SPM5, in particular the voxel-based morphometry (VBM) toolbox.ResultsWe found significant effects of the DTNBP1-SNP rs2619522 on regional brain volumes bilaterally in the hippocampus as well as in the anterior middle frontal gyrus and the intraparietal cortex. T/T homozygotes showed significantly lower grey matter volumes in these brain regions than carriers of the G allele.ConclusionsCompatible with previous findings on a role of the dysbindin-1 gene in hippocampal functions as well as in major psychoses, the present study provides first direct in-vivo evidence that the DTNBP1-SNP rs2619522 is associated with variation of grey matter volumes bilaterally in the human hippocampus.