Comorbid Bipolar and Alcohol Use Disorder-A Therapeutic Challenge.

Comorbidity rates in Bipolar disorder rank highest among major mental disorders, especially comorbid substance use. Besides cannabis, alcohol is the most frequent substance of abuse as it is societally accepted and can be purchased and consumed legally. Estimates for lifetime comorbidity of bipolar disorder and alcohol use disorder are substantial and in the range of 40-70%, both for Bipolar I and II disorder, and with male preponderance. Alcohol use disorder and bipolarity significantly influence each other's severity and prognosis with a more complicated course of both disorders. Modern treatment concepts acknowledge the interplay between these disorders using an integrated therapy approach where both disorders are tackled in the same setting by a multi-professional team. Motivational interviewing, cognitive behavioral and socio- therapies incorporating the family and social environment are cornerstones in psychotherapy whereas the accompanying pharmacological treatment aims to reduce craving and to optimize mood stability. Adding valproate to lithium may reduce alcohol consumption whereas studies with antipsychotics or naltrexone and acamprosate did not affect mood fluctuations or drinking patterns. In summary, there is a continuous need for more research in order to develop evidence-based approaches for integrated treatment of this frequent comorbidity.

[Quality of treatment outcomes in alcohol- and substance-related disorders: an evaluation of inpatients from ten psychiatric hospitals]. / Ergebnisqualität bei alkohol- und substanzbezogenen Störungen: eine Auswertung stationär behandelter Patienten aus 10 psychiatrischen Kliniken.

AIM OF THE STUDY: Alcohol and substance-related disorders (ICD 10 F1x.x) are among the most frequent diagnoses made in hospitalized patients requiring somatic and psychiatric care. In order to assess the success of treatment, it is important to establish and implement outcome indicators in practice. METHOD: In 2016, global treatment indicators for admission and at discharge were collected at 10 Vitos clinics in Hesse (CGI and GAF). More than 10,000 patients with ICD10 F1x diagnoses were included in the evaluation. RESULTS: The evaluations show significant improvements of the clinical status as well as differences in treatment duration, remissions and gender differences. CONCLUSION: The study suggests that global indicators of outcome quality are useful in the assessment of treatment success of alcohol and substance-related disorders. Limitations of the study design, instruments and sample are critically reviewed.

Implementation of a Global Treatment Budget in Psychiatric Departments in Germany-Results and Critical Factors for Success From the Staff Perspective.

BACKGROUND: Despite evidence from other countries for its effectiveness, flexible and integrative psychiatric treatment (FIT) is not part of the German standard healthcare system. Since 2013, German legislative reform has enabled a test implementation of FIT based on a global treatment budget. Because the budget is not restricted to any particular activity, this legislation opens the possibility of enhancing linkages between inpatient-, outpatient- and day-patient treatment structures. As staff involvement is a relevant component in successful implementation, we aimed in this study to judge the degree of FIT implementation based on staff members' experiences and evaluations of FIT. METHOD: Within an exploratory study design, we administered a standardized written survey to rate experiences and evaluations of physicians, psychologists, and nurses in the first 13 FIT projects between October 2016 and February 2017. The sample consisted of 352 nurses, 127 physicians, 84 psychologists, and 132 special therapists. We identified critical factors for successful implementation from the staff perspective by logistic regression analysis. RESULTS: Staff evaluations of the degree of FIT implementation were generally favorable, although some staff reported no experiences with one or several FIT-specific components. We found considerable differences in the assessments between the occupational groups. The only common factor for successful FIT implementation shared by physicians, psychologists, and nurses was the opportunity to join training programs on the objectives of FIT. Other critical factors for successful implementation were work conditions, the number of nurses/special therapists per physician/psychologist, and project duration. These factors together explained 49% of the variance of physician/psychologist evaluations and 34% for nurse evaluations. Individual staff members' characteristics were less important than structural- or FIT characteristics as explanatory factors for the degree of FIT implementation. IMPLICATIONS: Results point to the importance of new forms of multi-professional cooperation, training programs, improvement of work conditions, and guidance of the implementation process by systematic Change Management for future implementations of FIT. Our exploratory findings require further validation to guide practical improvements in FIT implementation. Longitudinal observations and a multilevel analysis should yield a better understanding of the relevant variables from different organization levels and their possible interactions.

Changes in German Mental Health Care by Implementing a Global Treatment Budget-A Mixed-Method Process Evaluation Study.

BACKGROUND: Internationally, there is a broad spectrum of outreach and integrative care models, whereas in Germany acute psychiatric treatment is still mostly provided in inpatient settings. To overcome this, a new legal framework (§64b Social Code V) has been introduced, promoting "Flexible and Integrative Treatment" Models (FIT64b), based on a "Global Treatment Budget" (GTB) financing approach. 23 hospitals have implemented the framework according to local needs and concepts. Prior research has already identified specific components of FIT64b. Based on this, our paper aims to examine the implementation process and underpinning change mechanisms of GTB-based FIT64b models from a staff, service user and caregiver perspective. METHOD: 31 focus groups and 15 semi-structured interviews were conducted with hospital staff (n = 138), service users (n = 63), and caregivers (n = 35) in 10 psychiatric hospitals implementing FIT64b. Using qualitative analysis, we identified 5 core themes describing the implementation process, which were theoretically modeled into a logical diagram. The core mechanisms of change were thus identified across themes. Additional structural and semi-quantitative performance data was collected from all study departments. RESULTS: The qualitative analysis showed that the shift from a daily- and performance-based payment to a lump-sum GTB and the shift of resources from in- to outpatient settings were of crucial importance for the process of change. Saved budget shares could be reinvested to integrate in-, out-, and day-patient units and to set up outreach home care. Clinicians reported feeling relieved by the increase of treatment options. They also emphasized a stronger relationship with and a better understanding of service users and a simplification of bureaucracy. Finally, service users and caregivers experienced higher need-adaptedness of treatment, a feeling of deeper understanding and safety, and the possibility to maintain everyday life during treatment. Finally, two FIT64b implementation prototypes were classified according to the semi-quantitative performance data. CONCLUSION: Based on the results, we developed 3 core mechanisms of change of FIT64b models: (1) Need-adaptedness and flexibility; (2) Continuity of care; (3) Maintaining everyday life. Our findings outline and emphasize the potential a GTB approach may have for improving psychiatric hospital services.

The role of environmental stress and DNA methylation in the longitudinal course of bipolar disorder.

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 < 1.0 × 10-5). 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.

The genetic relationship between educational attainment and cognitive performance in major psychiatric disorders.

Cognitive deficits are a core feature of psychiatric disorders like schizophrenia and bipolar disorder. Evidence supports a genome-wide polygenic score (GPS) for educational attainment (GPSEDU) can be used to explain variability in cognitive performance. We aimed to identify different cognitive domains associated with GPSEDU in a transdiagnostic clinical cohort of chronic psychiatric patients with known cognitive deficits. Bipolar and schizophrenia patients from the PsyCourse cohort (N = 730; 43% female) were used. Likewise, we tested whether GPSs for schizophrenia (GPSSZ) and bipolar disorder (GPSBD) were associated with cognitive outcomes. GPSEDU explained 1.5% of variance in the backward verbal digit span, 1.9% in the number of correctly recalled words of the Verbal Learning and Memory Test, and 1.1% in crystallized intelligence. These effects were robust to the influences of treatment and diagnosis. No significant associations between GPSSZ or GPSBD with cognitive outcomes were found. Furthermore, these risk scores did not confound the effect of GPSEDU on cognitive outcomes. GPSEDU explains a small fraction of cognitive performance in adults with psychiatric disorders, specifically for domains related to linguistic learning and working memory. Investigating such a proxy-phenotype longitudinally, could give intriguing insight into the disease course, highlighting at what time genes play a more influential role on cognitive performance. Better understanding the origin of these deficits might help identify those patients at risk for lower levels of functioning and poor social outcomes. Polygenic estimates may in the future be part of predictive models for more personalized interventions.

The influence of religious activity and polygenic schizophrenia risk on religious delusions in schizophrenia.

BACKGROUND: Religious delusions are a common symptom in patients experiencing psychosis, with varying prevalence rates of religious delusions across cultures and societies. To enhance our knowledge of this distinct psychotic feature, we investigated the mutually-adjusted association of genetic and environmental factors with occurrence of religious delusions. METHODS: We studied 262 adult German patients with schizophrenia or schizoaffective disorder. Association with lifetime occurrence of religious delusions was tested by multiple logistic regression for the following putative predictors: self-reported degree of religious activity, DSM-IV diagnosis, sex, age, education level, marital status, presence of acute delusion at the time of interview and an individual polygenic schizophrenia-risk score (SZ-PRS, available in 239 subjects). RESULTS: Of the 262 patients, 101 (39%) had experienced religious delusions. The risk of experiencing religious delusions was significantly increased in patients with strong religious activity compared to patients without religious affiliation (OR = 3.6, p = 0.010). Low or moderate religious activity had no significant effect. The same analysis including the SZ-PRS confirmed the effect of high religious activity on occurrence of religious delusions (OR = 4.1, p = 0.008). Additionally, the risk of experiencing religious delusions increased with higher SZ-PRS (OR 1.4, p = 0.020, using pT = 0.05 for SZ-PRS calculation). None of the other variables were significantly associated with lifetime occurrence of religious delusions. CONCLUSIONS: Our results suggest that strong religious activity and high SZ-PRS are independent risk factors for the occurrence of religious delusions in schizophrenia and schizoaffective disorder.

A longitudinal approach to biological psychiatric research: The PsyCourse study.

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.

Evaluation of Flexible and Integrative Psychiatric Treatment Models in Germany-A Mixed-Method Patient and Staff-Oriented Exploratory Study.

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.

HDAC1 links early life stress to schizophrenia-like phenotypes.

Schizophrenia is a devastating disease that arises on the background of genetic predisposition and environmental risk factors, such as early life stress (ELS). In this study, we show that ELS-induced schizophrenia-like phenotypes in mice correlate with a widespread increase of histone-deacetylase 1 (Hdac1) expression that is linked to altered DNA methylation. Hdac1 overexpression in neurons of the medial prefrontal cortex, but not in the dorsal or ventral hippocampus, mimics schizophrenia-like phenotypes induced by ELS. Systemic administration of an HDAC inhibitor rescues the detrimental effects of ELS when applied after the manifestation of disease phenotypes. In addition to the hippocampus and prefrontal cortex, mice subjected to ELS exhibit increased Hdac1 expression in blood. Moreover, Hdac1 levels are increased in blood samples from patients with schizophrenia who had encountered ELS, compared with patients without ELS experience. Our data suggest that HDAC1 inhibition should be considered as a therapeutic approach to treat schizophrenia.

Hippocampal integrity and neurocognition in first-episode schizophrenia: a multidimensional study.

OBJECTIVES: Impairments in memory and executive function are key components of schizophrenia. These disturbances have been linked to several subcortical and cortical networks. For example, anatomical and functional changes in the hippocampus have been linked to deficits in these cognitive domains. However, the association between hippocampal morphometry, neurochemistry and function is controversial. Therefore, we aimed to investigate the relationship between hippocampal anomalies and their functional relevance. METHODS: Fifty-seven first-episode schizophrenia patients (FE-SZ) and 61 healthy control subjects (HC) participated in this study. Hippocampal volumes were investigated using structural magnetic resonance imaging (sMRI) and hippocampal neurochemistry was determined using proton magnetic resonance spectroscopy (1H MRS). Verbal memory was used as a hippocampus-dependent cognitive task whereas working memory and cognitive flexibility assessed frontal lobe function. RESULTS: FE-SZ presented smaller volumes of the left hippocampus, with a significant correlation between left hippocampal volume and verbal memory performance (immediate recall). There was also an inverse correlation between neurochemical ratios (NAA/Cho and Cho/Cr) and verbal memory (delayed recognition). Tests of cognitive flexibility and working memory were not correlated with MRI and 1H MRS values. Compared to HC, FE-SZ demonstrated reduced performance in all of the assessed neurocognitive domains. CONCLUSIONS: These results point to a relationship between verbal memory and hippocampal integrity in schizophrenia patients which might be independent from deficits in other memory domains. Disturbed verbal memory functions in FE-SZ might be linked specifically to hippocampal function.

CACNA1C genotype explains interindividual differences in amygdala volume among patients with schizophrenia.

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.

Supraphysiologic doses of levothyroxine as adjunctive therapy in bipolar depression: a randomized, double-blind, placebo-controlled study.

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.

Grey matter differences in bipolar disorder: a meta-analysis of voxel-based morphometry studies.

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.

Association of the brain-derived neurotrophic factor val66met polymorphism with magnetic resonance spectroscopic markers in the human hippocampus: in vivo evidence for effects on the glutamate system.

The brain-derived neurotrophic factor (BDNF) is a key regulator of synaptic plasticity and has been suggested to be involved in the pathophysiology and pathogenesis of psychotic disorders, with particular emphasis on dysfunctions of the hippocampus. The aim of the present study was to replicate and to extend prior findings of BDNF val66met genotype effects on hippocampal volume and N-acetyl aspartate (NAA) levels. Hundred and fifty-eight caucasians (66 schizophrenic, 45 bipolar, and 47 healthy subjects; 105 subjects underwent MRI and 103 MRS scanning) participated in the study and were genotyped with regard to the val66met polymorphism (rs6265) of the BDNF gene. Hippocampal volumes were determined using structural magnetic resonance imaging (MRI), and measures of biochemical markers were taken using proton magnetic resonance spectroscopy ((1)H-MRS) in the hippocampus and other brain regions. Verbal memory was assessed as a behavioral index of hippocampal function. BDNF genotype did not impact hippocampal volumes. Significant genotype effects were found on metabolic markers specifically in the left hippocampus. In particular, homozygous carriers of the met-allele exhibited significantly lower NAA/Cre and (Glu + Gln)/Cre metabolic ratios compared with val/val homozygotes, independently of psychiatric diagnoses. BDNF genotype had a numerical, but nonsignificant effect on verbal memory performance. These findings provide first in vivo evidence for an effect of the functional BDNF val66met polymorphism on the glutamate system in human hippocampus.

Correlation between amygdala volume and age in bipolar disorder - a systematic review and meta-analysis of structural MRI studies.

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.

Hippocampal plasticity in response to exercise in schizophrenia.

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 < .05). CONCLUSION: These results indicate that in both healthy subjects and patients with schizophrenia hippocampal volume is plastic in response to aerobic exercise.

Reduced prefrontal gyrification in obsessive-compulsive disorder.

Structural magnetic resonance imaging (MRI) studies reveal evidence for brain abnormalities in obsessive-compulsive disorder (OCD), for instance, reduction of gray matter volume in the prefrontal cortex. Disturbances of gyrification in the prefrontal cortex have been described several times in schizophrenia pointing to a neurodevelopmental etiology, while gyrification has not been studied so far in OCD patients. In 26 OCD patients and 38 healthy control subjects MR-imaging was performed. Prefrontal cortical folding (gyrification) was measured bilaterally by an automated version of the automated-gyrification index (A-GI), a ratio reflecting the extent of folding, from the slice containing the inner genu of the corpus callosum up to the frontal pole. Analysis of covariance (ANCOVA, independent factor diagnosis, covariates age, duration of education) demonstrated that compared with control subjects, patients with OCD displayed a significantly reduced A-GI in the left hemisphere (p = 0.021) and a trend for a decreased A-GI in the right hemisphere (p = 0.076). Significant correlations between prefrontal lobe volume and A-GI were only observed in controls, but not in OCD patients. In conclusion, prefrontal hypogyrification in OCD patients may be a structural correlate of the impairment in executive function of this patient group and may point to a neurodevelopmental origin of this disease.

Pathological amygdala activation during working memory performance: Evidence for a pathophysiological trait marker in bipolar affective disorder.

Recent evidence suggests that deficits of working memory may be a promising neurocognitive endophenotype of bipolar affective disorder. However, little is known about the neurobiological correlates of these deficits. The aim of this study was to determine possible pathophysiological trait markers of bipolar disorder in neural circuits involved in working memory. Functional magnetic resonance imaging was performed in 18 euthymic bipolar patients and 18 matched healthy volunteers using two circuit-specific experimental tasks established by prior systematic neuroimaging studies of working memory. Both euthymic bipolar patients and healthy controls showed working memory-related brain activations that were highly consistent with findings from previous comparable neuroimaging studies in healthy subjects. While these patterns of brain activation were completely preserved in the bipolar patients, only the patients exhibited activation of the right amygdala during the articulatory rehearsal task. In the same task, functional activation in right frontal and intraparietal cortex and in the right cerebellum was significantly enhanced in the patients. These findings indicate that the right amygdala is pathologically activated in euthymic bipolar patients during performance of a circuit-specific working memory task (articulatory rehearsal). This pathophysiological abnormality appears to be a trait marker in bipolar disorders that can be observed even in the euthymic state and that seems to be largely independent of task performance and medication.

Cortical neurochemistry in euthymic patients with bipolar I disorder.

OBJECTIVE: 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. METHODS: 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). RESULTS: 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. CONCLUSION: In contrast to prior findings, we could not observe any metabolic alterations in euthymic patients with bipolar disorder.