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Background: Widely used psychotropic medications for obsessive-compulsive disorder (OCD) may change the volumes of subcortical brain structures, and differently in children vs. adults. We measured subcortical volumes cross-sectionally in patients finely stratified for age taking various common classes of OCD drugs. Methods: The ENIGMA-OCD consortium sample (1081 medicated/1159 unmedicated OCD patients and 2057 healthy controls aged 6–65) was divided into six successive 6–10-year age-groups. Individual structural MRIs were parcellated automatically using FreeSurfer into 8 regions-of-interest (ROIs). ROI volumes were compared between unmedicated and medicated patients and controls, and between patients taking serotonin reuptake inhibitors (SRIs), tricyclics (TCs), antipsychotics (APs), or benzodiazepines (BZs) and unmedicated patients. Results: Compared to unmedicated patients, volumes of accumbens, caudate, and/or putamen were lower in children aged 6–13 and adults aged 50–65 with OCD taking SRIs (Cohen's d = −0.24 to −0.74). Volumes of putamen, pallidum (d = 0.18–0.40), and ventricles (d = 0.31–0.66) were greater in patients aged 20–29 receiving APs. Hippocampal volumes were smaller in patients aged 20 and older taking TCs and/or BZs (d = −0.27 to −1.31). Conclusions: Results suggest that TCs and BZs could potentially aggravate hippocampal atrophy of normal aging in older adults with OCD, whereas SRIs may reduce striatal volumes in young children and older adults. Similar to patients with psychotic disorders, OCD patients aged 20–29 may experience subcortical nuclear and ventricular hypertrophy in relation to APs. Although cross-sectional, present results suggest that commonly prescribed agents exert macroscopic effects on subcortical nuclei of unknown relation to therapeutic response.

OBJECTIVE: Circadian rhythm disruption is commonly observed in bipolar disorder (BD). Daylight is the most powerful signal to entrain the human circadian clock system. This exploratory study investigated if solar insolation at the onset location was associated with the polarity of the first episode of BD I. Solar insolation is the amount of electromagnetic energy from the Sun striking a surface area of the Earth.METHODS: Data from 7488 patients with BD I were collected at 75 sites in 42 countries. The first episode occurred at 591 onset locations in 67 countries at a wide range of latitudes in both hemispheres. Solar insolation values were obtained for every onset location, and the ratio of the minimum mean monthly insolation to the maximum mean monthly insolation was calculated. This ratio is largest near the equator (with little change in solar insolation over the year), and smallest near the poles (where winter insolation is very small compared to summer insolation). This ratio also applies to tropical locations which may have a cloudy wet and clear dry season, rather than winter and summer.RESULTS: The larger the change in solar insolation throughout the year (smaller the ratio between the minimum monthly and maximum monthly values), the greater the likelihood the first episode polarity was depression. Other associated variables were being female and increasing percentage of gross domestic product spent on country health expenditures. (All coefficients: P ≤ 0.001).CONCLUSION: Increased awareness and research into circadian dysfunction throughout the course of BD is warranted.

BACKGROUND: Temporal processing, crucial to guide behavior toward a goal, may have a role in forming a depressive episode, yet it remains unclear which properties of temporal processing are central to antidepressant response. Production of a short duration oscillates in a circadian manner. Altered circadian organization of physiology and behavior are a hallmark of bipolar disorder. We thus tested whether circadian dynamics of time production associate with treatment response in bipolar disorder. METHODS: Over the three cycles of total sleep deprivation combined with light therapy (chronotherapeutics) in one week, 20 inpatients with a major depressive episode in the course of bipolar disorder produced 10s and rated their subjective mood and vigilance levels repeatedly. RESULTS: Eleven patients (58%) among 19 completers achieved remission. Produced time intervals (PTIs) fluctuated more synchronously with mood levels (r=-0.77) than vigilance levels (r=-0.59) during treatment. A higher degree of shortening of PTIs, but not changes in mood or vigilance levels, during the initial 24-h period of treatment predicted better response (LR χ2=4.58, P=0.032). Strong opposite daily changes for PTIs and mood levels observed at baseline were both attenuated after treatment only in remitters (F=7.25, P=0.015). LIMITATIONS: Potential external confounders that affect time perception were not controlled. CONCLUSIONS: The results are the first to demonstrate an association of the circadian properties of time perception with antidepressant effects of chronotherapeutics and suggest the potential utility of time production in predicting clinical outcome of bipolar depression.

Dysfunctional glutamatergic neurotransmission has been proposed both, as a biological underpinning of mood disorder and as a target for rapid-acting antidepressant treatments. Total sleep deprivation and light therapy (TSD + LT) can prompt antidepressant response in drug-resistant bipolar depression. Here we explored the effects of TSD + LT on dorsolateral prefrontal cortex (DLPFC) glutamate and/or glutamine+glutamate (Glx) levels.We studied single voxelHigher concentration of Glu (adjusted Z = -2189, p = 0,0285) and Glx (adjusted Z = -3,13, p = 0,0017) were observed in BD patients compared to HC. Treatment caused a significant rapid reduction of depressive symptom severity over time (F = 63.98, p 0.01). Change in depression levels after TSD + LT treatment was significantly influenced by delta change in Glu levels (LR χA reduction in Glu and Glx levels associated with depression could contribute to the mechanism of action of TSD + LT, directly acting on glutamatergic neurons, or to the interaction between the glutamatergic system and dopamine (DA) and serotonin (5-HT) levels, known to be targeted by TSD. This is in line with several studies showing a glutamatergic modulation effects of antidepressants and mood stabilizing agents. This finding deepens our understanding of antidepressant effect of chronoterapeutics.

Dysfunctional glutamatergic neurotransmission has been proposed both, as a biological underpinning of mood disorder and as a target for rapid-acting antidepressant treatments. Total sleep deprivation and light therapy (TSD+LT) can prompt antidepressant response in drug-resistant bipolar depression. Here we explored the effects of TSD+LT on dorsolateral prefrontal cortex (DLPFC) glutamate and/or glutamine+glutamate (Glx) levels.

The relationship between bipolar disorder (BD) and biological rhythms has been extensively investigated. Alterations in biological rhythms, including sleep, have been identified in patients, and polymorphisms in genes that make up the genesis of circadian rhythms have been associated with the disorder and linked to its phenotypic particularities. Moreover, different studies have also reported the presence of abnormalities in infradian rhythms. Finally, antidepressants and mood stabilizers affect the circadian clock, and chronobiological treatments have shown to have an important effect on mood. Nowadays, there is an ample debate whether the effects of the disruption of biological rhythms are merely symptoms of this psychiatric disorder, or rather contributing causes. Nonetheless the circadian clock influences multiple systems and pathways, not least immune system and metabolism, which are thought to underlie mood disorders and in most cases there are reciprocal interactions which in turn regulate circadian rhythms.

ObjectiveNo diagnostic biomarkers are available for obsessive-compulsive disorder (OCD). Magnetic resonance imaging (MRI) studies have provided evidence for structural abnormalities in distinct brain regions, but effect sizes are small and have limited clinical relevance. To investigate whether individual patients can be distinguished from healthy controls, we performed multivariate analysis of structural neuroimaging data from the ENIGMA-OCD consortium.MethodWe included 46 data sets with neuroimaging and clinical data from adult (≥18 years) and pediatric (1images from 2,304 OCD patients and 2,068 healthy controls were analyzed using standardized processing to extract regional measures of cortical thickness, surface area and subcortical volume. Machine learning classification performance was tested using cross-validation, and possible effects of clinical variables were investigated by stratification.ResultsClassification performance for OCD versus controls using the complete sample with different classifiers and cross-validation strategies was poor (AUC—0.57 (standard deviation (SD)=0.02;Pcorr=0.19) to 0.62 (SD=0.03;Pcorrcorr>.99) to 0.54 (SD=0.08;Pcorr>.99)). In contrast, good classification performance (>0.8 AUC) was achieved within subgroups of patients split according to their medication status.ConclusionsParcellated structural MRI data do not enable good distinction between patients with OCD and controls. However, classifying subgroups of patients based on medication status enables good identification at the individual subject level. This underlines the need for longitudinal studies on the short- and long-term effects of medication on brain structure.

ObjectiveAttention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) are common neurodevelopmental disorders that frequently co-occur. We aimed to directly compare all three disorders. The ENIGMA consortium is ideally positioned to investigate structural brain alterations across these disorders.MethodsStructural T1-weighted whole-brain MRI of controls (n=5,827) and patients with ADHD (n=2,271), ASD (n=1,777), and OCD (n=2,323) from 151 cohorts worldwide were analyzed using standardized processing protocols. We examined subcortical volume, cortical thickness and surface area differences within a mega-analytical framework, pooling measures extracted from each cohort. Analyses were performed separately for children, adolescents, and adults using linear mixed-effects models adjusting for age, sex and site (and ICV for subcortical and surface area measures).ResultsWe found no shared alterations among all three disorders, while shared alterations between any two disorders did not survive multiple comparisons correction. Children with ADHD compared to those with OCD had smaller hippocampal volumes, possibly influenced by IQ. Children and adolescents with ADHD also had smaller ICV than controls and those with OCD or ASD. Adults with ASD showed thicker frontal cortices compared to adult controls and other clinical groups. No OCD-specific alterations across different age-groups and surface area alterations among all disorders in childhood and adulthood were observed.ConclusionOur findings suggest robust but subtle alterations across different age-groups among ADHD, ASD, and OCD. ADHD-specific ICV and hippocampal alterations in children and adolescents, and ASD-specific cortical thickness alterations in the frontal cortex in adults support previous work emphasizing neurodevelopmental alterations in these disorders.

Accepted Manuscript, BACKGROUND: Lateralized dysfunction has been suggested in obsessive-compulsive disorder (OCD). However, it is currently unclear whether OCD is characterized by abnormal patterns of brain structural asymmetry. Here we carried out what is by far the largest study of brain structural asymmetry in OCD.METHODS: We studied a collection of 16 pediatric datasets (501 patients with OCD and 439 healthy control subjects), as well as 30 adult datasets (1777 patients and 1654 control subjects) from the OCD Working Group within the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Consortium. Asymmetries of the volumes of subcortical structures, and of measures of regional cortical thickness and surface areas, were assessed based on T1-weighted magnetic resonance imaging scans, using harmonized image analysis and quality control protocols. We investigated possible alterations of brain asymmetry in patients with OCD. We also explored potential associations of asymmetry with specific aspects of the disorder and medication status.RESULTS: In the pediatric datasets, the largest case-control differences were observed for volume asymmetry of the thalamus (more leftward; Cohen's d = 0.19) and the pallidum (less leftward; d = -20.21). Additional analyses suggested putative links between these asymmetry patterns and medication status, OCD severity, or anxiety and depression comorbidities. No significant case-control differences were found in the adult datasets.CONCLUSIONS: The results suggest subtle changes of the average asymmetry of subcortical structures in pediatric OCD, which are not detectable in adults with the disorder. These findings may reflect altered neurodevelopmental processes in OCD., This research was funded by the Max Planck Society (Germany). Additional funding was from the Japan Society for the Promotion of Science (KAKENHI Grant No. 18K15523 [to YA], KAKENHI Grant No. 16K04344 [to YH], KAKENHI Grant Nos. 16K19778 and 18K07608 [to TNakam], and KAKENHI Grant No. 26461762 [to AN]); the Carlos III Health Institute (Grant No. PI14/00419 [to PA], Grant No. PI040829 cofunded by European Regional Development Fund [to LL], Grant No. FI17/00294 [to IM-Z], Grant No. PI16/00950 [to JMM], and Grant Nos. CPII16/00048, PI13/01958, and PI16/00889 cofunded by European Regional Development Funds [to CS-M]); the Ontario Mental Health Foundation (Research Training Fellowship [to SHA]); Alberta Innovates Translational Health Chair in Child and Youth Mental Health (to PDA), the Ontario Brain Institute (to PDA); the National Institute of Mental Health (Grant No. K23MH104515 [to JTB], Grant No. K23-MH092397 [to BPB], Grant No. K23MH082176 [to KDF), Grant No. R21MH101441 [to RM], Grant No. R01MH081864 [to JO and JP], and Grant No. R01MH085900 [to JO and JF], Grant No. R21MH093889 [to HBS]); Fundação de Amparo à Pesquisa do Estado de São Paulo (Grant No. 2011/21357–9 [to MCB], Grant No. 2011/21357–9 [to GFB], Grant No. 2011/21357–9 [to MQH], and Grant No. 2011/21357–9 [to ECM]); the Swiss National Science Foundation (Grant No. 320030_130237 [to SB; principal investigator, Susanne Walitza]); the Hartmann Müller Foundation (Grant No. 1460 [to SB]); the David Judah Fund at the Massachusetts General Hospital (to BPB); EU FP7 Project TACTICS (Grant No. 278948 [to JB]); the National Natural Science Foundation of China (Grant No. 81560233 [to YC] and Grant No. 81371340 [to ZW]); the International OCD Foundation (Grant No. K23 MH115206 [to PG]); the Wellcome Sir Henry Dale Fellowship (Grant No. 211155/Z/18/Z [to TUH]); the Jacobs Foundation (to TUH); the Brain and Behavior Research Foundation (2018 NARSAD Young Investigator Grant No. 27023 [to TUH]); the Agency for Medical Research and Development (Grant No. JP18dm0307002 [to YH]); the Michael Smith Foundation for Health Research (to FJ-F); the Federal Ministry of Education and Research of Germany (Grant No. BMBF-01GW0724 [to NK]); the Deutsche Forschungsgemeinschaft (Grant No. KO 3744/7–1 [to KK]); the Helse Vest Health Authority (Grant Nos. 911754 and 911880 [to GK]); the Norwegian Research Council (Grant No. HELSEFORSK 243675 [to GK]); the Marató TV3 Foundation (Grant Nos. 01/2010 and 091710 [to LL]); the Agency for Management of University and Research Grants (Grant No. 2017 SGR 881 [to LL] and 2017 SGR 1247 from the Generalitat de Catalunya [to JMM]); Fundação para a Ciência e a Tecnologia (Grant No. PDE/BDE/113604/2015 from the PhD-iHES Program [to RM], Grant No. PDE/BDE/113601/2015 from the PhD-iHES Program [to PSM]); the Japanese Ministry of Education, Culture, Sports, Science and Technology (Grant-in-Aid for Scientific Research (Grant Nos. 22591262, 25461732, and 16K10253 [to TNakao]); the Government of India Department of Science and Technology (DST INSPIRE Faculty Grant No. -IFA12-LSBM-26 [to JCN] and Grant No. SR/S0/HS/0016/2011 [to YCJR]); the Government of India Department of Biotechnology (Grant No. BT/06/IYBA/2012 [to JCN] and Grant No. BT/PR13334/Med/30/259/2009 [to YCJR]); the New York State Office of Mental Health (to HBS); the Italian Ministry of Health (Grant No. RC13-14-15-16A [to GS]); the National Center for Advancing Translational Sciences (Grant No. UL1TR000067/KL2TR00069 [to ERS]); the Canadian Institutes of Health Research (to SES); the Michael Smith Foundation for Health Research (to SES); the British Columbia Provincial Health Services Authority (to SES); the Netherlands Organization for Scientific Research (Grant No. NWO/ZonMW Vidi 917.15.318 [to GAvW]); the Wellcome-DBT India Alliance (Grant No. 500236/Z/11/Z [to GV]); the Shanghai Key Laboratory of Psychotic Disorders (Grant No. 13dz2260500 [to ZW]).

Backgrounds: Bipolar depression is still a very difficult to treat condition with low success rates of antidepressant drugs, high rates of morbidity and suicide risk and antidepressant-emergent mania risk. Despite a growing body of evidence has been generated over the last decade about Light Therapy (LT) as an effective treatment for depression the management of it continues to be a point of debate for Bipolar Disorder especially when considering non-seasonal pattern. Methods: We systematically screened current literature using the PubMed electronic platform. We considered “mood disorder”, “depression” and “light therapy” as keywords for the search. Results: We retrieved 1907 papers. After the screening, we selected 11 papers to be included in the analysis, treating 195 patients affected by bipolar depression. 5 studies were RCT studies. The overall analysis, including non-RCTs, showed a positive effect of the treatment in all the included studies (ESs: -1.46, 95% CI:-1.677 to -1.242; p

Background The combination of three cycles of sleep deprivation (SD), light therapy (LT), and lithium has recently been proposed as a possible first-line treatment for bipolar depression. However, it is unclear whether early improvement predicts final response/remission in bipolar depression treated with this regimen. Method We studied 220 consecutively admitted inpatients with a major depressive episode in the course of bipolar disorder. The relation between response to first SD and response/remission at the end of the treatment (day 6) was analyzed using logistic regression analysis. Severity of depression was rated using the Hamilton Depression Rating Scale (HDRS). Clinical response was defined as a ≥50% reduction in HDRS scores, and remission was defined as an HDRS score of ≤7. Results Among the 217 completers, 67.7% showed response and 54.4% reached remission at the end of the treatment. Multiple logistic regression analysis revealed that response after first recovery sleep (day 2) predicted final response and remission at the end of the treatment with high odds ratios (10.9 for response and 8.2 for remission); however, response immediately after the first SD (day 1) did not predict final response or remission. Limitations Whether our results can be generalized to unipolar depression remains uncertain. Conclusion Clinical status after first recovery sleep is a strong predictor of successful final outcome in patients with bipolar depression treated with the combination of repeated SD, LT, and lithium. Recovery sleep may play a role in inducing the antidepressant effect associated with the success of treatment.

Aim The high heterogeneity of obsessive-compulsive disorder (OCD) is best described by a multidimensional model involving symptom dimensions. We aimed to investigate white matter alterations associated with OCD, focusing on the impact of long-lasting effect of symptom dimensions assessed at onset of illness. Furthermore, we investigated white matter alterations associated with this disorder, controlling for the impact of medications and for the prevailing current symptom dimension. Methods We studied 58 patients affected by OCD and 58 age- and sex-matched healthy controls. We divided patients according to symptom dimension at onset of illness, assessed with the five-factor model. T-tests were performed in order to investigate differences between subgroups. Similar analyses were performed considering the prevailing current symptom dimension. Analyses were conducted with tract-based spatial statistics on diffusion tensor imaging. Results Doubt/checking and rituals/superstition symptom dimensions at onset and symmetry/perfectionism current symptom dimensions were characterized by significant alterations in diffusion tensor imaging measures. An association of white matter alterations and symmetry/perfectionism current dimension was found only when controlling for the effect of doubt/checking dimension at onset. Finally, results pointed out that the observed differences between patients and healthy controls were carried by the effect of previous and current medications. Conclusion Our findings evidenced that onset symptom dimensions are associated with enduring alterations of white matter microstructure. Onset symptom dimensions may reflect underlying endophenotypes. In addition, present results confirm the effect of medications on white matter in OCD, showing a large effect of current treatment on myelination.

Background Alteration of circadian rhythms and sleep disruption are prominent trait-like features of bipolar disorder (BD). Diffusion tensor imaging (DTI) measures suggest a widespread alteration of white matter (WM) microstructure in patients with BD. Sleep promotes myelination and oligodendrocyte precursor cells proliferation. We hypothesized a possible association between DTI measures of WM microstructure and sleep quantity measures in BD. Methods We studied 69 inpatients affected by a depressive episode in course of type I BD. We used whole brain tract-based spatial statistics on DTI measures of WM microstructure: axial, radial, and mean diffusivity (AD, RD, MD), and fractional anisotropy (FA). Self-assessed measures of time asleep (TA) and total sleep time (TST) were extracted from the Pittsburgh Sleep Quality Index (PSQI). Actigraphic recordings were performed on a subsample of 23 patients. Results We observed a positive correlation of DTI measures of FA with actigraphic measures of TA and TST, and with PSQI measure of TA. DTI measures of RD inversely associated with actigraphic measure of TA, and with PSQI measures of TA and TST. Several WM tracts were involved, including corpus callosum, cyngulate gyrus, uncinate fasciculus, left superior and inferior longitudinal and fronto-occipital fasciculi, thalamic radiation, corona radiata, retrolenticular part of internal capsule and corticospinal tract. Limitations The study is correlational in nature, and no conclusion about a causal connection can be drawn. Conclusions Reduced FA with increased RD and MD indicate higher water diffusivity associated with less organized myelin and/or axonal structures. Our findings suggest an association between sleep disruption and these measures of brain microstructure in specific tracts contributing to the functional connectivity in BD.

Aim Studies have demonstrated neuropsychological deficits across a variety of cognitive domains in depression. These deficits are observable both in major depression (MDD) and in bipolar disorder (BD) and are present in each phase of the disorders, including euthymia. Adverse childhood experiences (ACE) have been associated to an increased risk to develop psychiatric disorders and cognitive deficits. The aim of the study was to assess neuropsychological performances in a sample of MDD and BD patients during a depressive episode compared to healthy controls and secondly to investigate if ACE affect the cognitive profile in the three groups. Method 76 bipolar patients, 57 MDD patients and 57 healthy controls underwent neuropsychological assessment for cognitive performances through the Brief Assessment of Cognition in schizophrenia (BACS) and Wisconsin Card Sorting tests (WCST). Results Both bipolar and MDD patients obtained significantly lower domain scores across the entire battery compared to healthy subjects. Splitting the sample according to exposure to ACE (high and low), the differences observed in the whole sample persisted only in the subsample of those patients exposed to high ACE. Conclusions This study confirms that cognitive impairment is present both in MDD and BD, whereas in different degrees of severity, and highlights the importance of early stress as moderator factor when investigating cognitive functions in mood disorders.

Objective: structural brain imaging studies in obsessive compulsive disorder (OCD) have produced inconsistent findings. This may be partially due to limited statistical power from relatively small samples and clinical heterogeneity related to variation in illness profile and developmental stage. To address these limitations, the authors conducted meta and mega-analyses of data from OCD sites worldwide. Method: T-1 images from 1,830 OCD patients and 1,759 control subjects were analyzed, using coordinated and standardized processing, to identify subcortical brain volumes that differ between OCD patients and healthy subjects. The authors performed a meta analysis on the mean of the left and right hemisphere measures of each subcortical structure, and they performed a mega-analysis by pooling these volumetric measurements from each site. The authors additionally examined potential modulating effects of clinical characteristics on morphological differences in OCD patients. Results: the meta-analysis indicated that adult patients had significantly smaller hippocampal volumes (Cohen's d=-0.13; % difference=-2.80) and larger pallidum volumes (d=0.16; % difference=3.16) compared with adult controls. Both effects were stronger in medicated patients compared with controls (d=-0.29, % difference=-4.18, and d=0.29, % difference=4.38, respectively). Unmedicated pediatric patients had significantly larger thalamic volumes (d=0.38, % difference=3.08) compared with pediatric controls. None of these findings were mediated by sample characteristics, such as mean age or scanning field strength. The mega-analysis yielded similar results. Conclusions: the results indicate different patterns of sub cortical abnormalities in pediatric and adult OCD patients. The patlidum and hippocampus seem to be of importance in adult OCD, whereas the thalamus seems to be key in pediatric OCD. These findings highlight the potential importance of neurodevelopmental alterations in OCD and suggest that further research on neuroplasticity in OCD may be useful.

ImportanceMicrostructural alterations in cortico-subcortical connections are thought to be present in Obsessive-Compulsive Disorder (OCD). However, prior studies have yielded inconsistent findings, perhaps because small sample sizes provided insufficient power to detect subtle abnormalities.ObjectiveTo investigate microstructural white matter alterations and their relation to clinical features in the largest dataset of adult and pediatric OCD to date.Design, Setting, and ParticipantsIn this cross-sectional case-control magnetic resonance study, we investigated diffusion tensor imaging metrics from 700 adult patients and 645 adult controls, as well as 174 pediatric patients and 144 pediatric controls across 19 sites participating in the ENIGMA-OCD Working Group.Main Outcomes and MeasuresWe extracted measures of fractional anisotropy (FA) as main outcome, and mean diffusivity, radial diffusivity, and axial diffusivity as secondary outcomes for 25 white matter regions. We meta-analyzed patient-control group differences (Cohen’s d) across sites, after adjusting for age and sex, and investigated associations with clinical characteristics.ResultsAdult OCD patients showed significant FA reduction in the sagittal stratum (d=-0.21, z=-3.21, p=0.001) and posterior thalamic radiation (d=-0.26, z=-4.57, pConclusions and RelevanceMicrostructural alterations in projection and association fibers to posterior brain regions were found in adult OCD, and related to disease course and medication status. Such results are relevant to models positing deficits in connectivity as a crucial mechanism in OCD.KEY POINTSQuestionDo patients with Obsessive-Compulsive Disorder (OCD) show white matter microstructural alterations, and are these alterations related to clinical features?FindingsData from 19 sites of the ENIGMA-OCD Consortium were included, involving 700 adult patients and 645 adult controls, 174 pediatric patients and 144 pediatric controls. Diffusion tensor imaging data were meta-analyzed using a harmonized data processing and analysis protocol. Adult, but not pediatric, patients showed alterations in the sagittal stratum and posterior thalamic radiation; sagittal stratum differences were associated with clinical features.MeaningMicrostructural abnormalities found in adult but not in the pediatric cohort, are related to illness duration and medication status.

Patient diurnal mood fluctuation, sleep characteristics and factors affecting sleep homeostasis predict antidepressant response to the combination of total sleep deprivation and light therapy (TSD + LT). In order to study if chronotype could influence response to TSD+LT, we considered 194 bipolar depressed patients. Severity of depression was rated with Hamilton Depression Rating Scale; perceived mood levels were assessed by a self-administered 10-cm visual analogue scale and chronotype was assessed using the Mornigness-Eveningness Questionnaire. More than 60% of patients resulted responders to treatment with chronotype influencing the antidepressant response with evening type subjects showing higher response rates.

Objective: Brain imaging studies of structural abnormalities in OCD have yielded inconsistent results, partly because of limited statistical power, clinical heterogeneity, and methodological differences. The authors conducted meta- and mega-analyses comprising the largest study of cortical morphometry in OCD ever undertaken. Method: T1-weighted MRI scans of 1,905 OCD patients and 1,760 healthy controls from 27 sites worldwide were processed locally using FreeSurfer to assess cortical thickness and surface area. Effect sizes for differences between patients and controls, and associations with clinical characteristics, were calculated using linear regression models controlling for age, sex, site, and intracranial volume. Results: In adult OCD patients versus controls, we found a significantly lower surface area for the transverse temporal cortexand a thinner inferiorparietalcortex.Medicated adult OCD patients also showed thinner cortices throughout the brain. In pediatric OCD patients compared with controls, we found significantly thinner inferior and superior parietal cortices, but none of the regions analyzed showedsignificant differences in surface area. However, medicated pediatric OCD patients had lower surface area in frontal regions. Cohen's d effect sizes varied from 20.10 to 20.33. Conclusions: The parietal cortex was consistently implicated in both adults and children with OCD. More widespread cortical thickness abnormalities were found in medicated adult OCD patients, and more pronounced surface area deficits (mainly in frontal regions) were found in medicated pediatric OCD patients. These cortical measures represent distinct morphological features and may be differentially affected during different stages of development and illness, and possibly moderated by disease profile and medication.

The identification of antidepressant response predictors in bipolar disorder (BD) may provide new potential enhancements in treatment selection. Repeated total sleep deprivation combined with light therapy (TSD+LT) can acutely reverse depressive symptoms and has been proposed as a model antidepressant treatment. This study aims at investigating the effect of TSD+LT on effective connectivity and neural response in cortico-limbic circuitries during implicit processing of fearful and angry faces in patients with BD. fMRI and Dynamic Causal Modeling (DCM) were combined to study the effect of chronotherapeutics on neural responses in healthy controls (HC, n = 35) and BD patients either responder (RBD, n = 26) or non responder (nRBD, n = 11) to 3 consecutive TSD+LT sessions. Twenty-four DCMs exploring connectivity between anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (DLPFC), Amygdala (Amy), fusiform gyrus and visual cortex were constructed. After treatment, patients significantly increased their neural responses in DLPFC, ACC and insula. nRBD showed lower baseline and endpoint neural responses than RBD. The increased activity in ACC and in medial prefrontal cortex, associated with antidepressant treatment, was positively associated with the improvement of depressive symptomatology. Only RBD patients increased intrinsic connectivity from DLPFC to ACC and reduced the modulatory effect of the task on Amy-DLPFC connection. A successful antidepressant treatment was associated with an increased functional activity and connectivity within cortico-limbic networks, suggesting the possible role of these measures in providing possible biomarkers for treatment efficacy.

There are complex relationships among sleep, sleep disorders, and psychiatric illnesses: not only can sleep abnormalities be symptoms of psychiatric disorders, but also some sleep disorders increase the risks of developing episodes of psychiatric disorders. During the past few decades, a number of sleep investigations have been performed in patients with the aim of identifying specific sleep patterns associated with psychiatric disorders. Although the majority of these studies have focused on major unipolar depression, sleep abnormalities have also been reported in other psychiatric disorders, such as bipolar disorder, schizophrenia, alcohol-related and drug abuse disorders, borderline personality disorder, and eating disorders.

The high heterogeneity of obsessive-compulsive disorder (OCD) is best described by a multidimensional model involving symptom dimensions. We aimed to investigate white matter alterations associated with OCD, focusing on the impact of long-lasting effect of symptom dimensions assessed at onset of illness. Furthermore, we investigated white matter alterations associated with this disorder, controlling for the impact of medications and for the prevailing current symptom dimension.We studied 58 patients affected by OCD and 58 age- and sex-matched healthy controls. We divided patients according to symptom dimension at onset of illness, assessed with the five-factor model. T-tests were performed in order to investigate differences between subgroups. Similar analyses were performed considering the prevailing current symptom dimension. Analyses were conducted with tract-based spatial statistics on diffusion tensor imaging.Doubt/checking and rituals/superstition symptom dimensions at onset and symmetry/perfectionism current symptom dimensions were characterized by significant alterations in diffusion tensor imaging measures. An association of white matter alterations and symmetry/perfectionism current dimension was found only when controlling for the effect of doubt/checking dimension at onset. Finally, results pointed out that the observed differences between patients and healthy controls were carried by the effect of previous and current medications.Our findings evidenced that onset symptom dimensions are associated with enduring alterations of white matter microstructure. Onset symptom dimensions may reflect underlying endophenotypes. In addition, present results confirm the effect of medications on white matter in OCD, showing a large effect of current treatment on myelination.

Human genetic studies have implicated specific genes that constitute the molecular clock in the manifestation of bipolar disorder (BD). Among the clock genes involved in the control system of circadian rhythms, CLOCK 3111 T/C and Period3 (PER3) influence core psychopathological features of mood disorders, such as patterns of sleep, rest, and activity, diurnal preference, cognitive performances after sleep loss, age at the onset of the illness, and response to antidepressant treatment. Furthermore, several studies pointed out that bipolar symptomatology is associated with dysfunctions in white matter (WM) integrity, suggesting these structural alterations as a possible biomarker of the disorder. We hypothesise that CLOCK and PER3 polymorphisms could be potential factors affecting WM microstructure integrity in bipolar patients. The relationship between these clock genes and DTI measures of WM integrity in a sample of 140 (53 M; 87 F) patients affected by BD type I was studied. Tract-based spatial statistics analyses on DTI measures of WM integrity were performed for each clock gene polymorphism, between the genetic groups. We accounted for the effect of nuisance covariates known to influence WM microstructure: age, sex, lithium treatment, age at the onset of the illness, and the number of illness episodes. We found that compared to T homozygotes, CLOCK C carriers showed a widespread increase of the mean diffusivity in several WM tracts. Compared with PER35/5 homozygotes, PER34/4 homozygotes showed significantly increased radial diffusivity and reduced fractional anisotropy in several brain WM tracts. No significant difference was observed between heterozygotes and the other subgroups. Altogether, this pattern of results suggests WM disruption in CLOCK C carrier and in PER34 homozygotes. Sleep promotes myelination and oligodendrocyte precursor cell proliferation and associates with higher expression of genes coding for phospholipid synthesis and myelination in oligodendrocytes. These clock genes play a pivotal role in maintaining circadian rhythms and the sleep-wake cycle. Thus, it may be suggested that CLOCK rs1801260*C and PER34/4 influence myelination processes by regulating sleep quality and quantity.

Studies have demonstrated neuropsychological deficits across a variety of cognitive domains in depression. These deficits are observable both in major depressive disorder (MDD) and in bipolar disorder (BD) and are present in each phase of the illness, including euthymia. Adverse childhood experiences (ACE) have been associated with an increased risk of developing psychiatric disorders and cognitive deficits. The aim of this study was to assess neuropsychological performances in a sample of MDD and BD patients during a depressive episode compared to healthy controls (HC) and, to investigate if ACE affect the cognitive profiles in the three groups.Seventy-six BD patients, 57 MDD patients, and 57 HC underwent neuropsychological assessment for cognitive performances through the Brief Assessment of Cognition in Schizophrenia and Wisconsin Card Sorting Test.Both BD and MDD patients obtained significantly lower domain scores across the entire battery compared to HC. Splitting the sample according to exposure to ACE (high and low), the differences observed in the whole sample persisted only in the subsample of those patients exposed to high ACE.This study confirms that cognitive impairment is present both in MDD and BD, albeit in different degrees of severity, and highlights the importance of early stress as a moderator factor when investigating cognitive functions in mood disorders.

Background The discrepancy between subjective and objective severity of depressive syndromes has been proposed as a predictor of treatment outcome and suicidal risk in depression, and is associated with depressive cognitive distortions. A recent study reported that evening-type depressed patients showed higher depressive cognitions than morning-type patients. Therefore, it can be hypothesized that genetic factors affecting evening preference, such as carrying of the CLOCK rs1801260*C allele, may influence the discrepancy. Method We tested this hypothesis in 132 patients affected by a major depressive episode in the course of bipolar disorder. The severity of depression was evaluated using self-rated (Beck Depression Inventory: BDI) and observer-rated (Hamilton Depression Rating Scale: HDRS) measures. The BDI-HDRS discrepancy score was calculated and the effects of the rs1801260 polymorphism on this score and on depressive cognitive distortions, as measured on the Cognitions Questionnaire, were examined. Results The rs1801260*C carriers showed higher BDI-HDRS discrepancy scores than T/T homozygotes. Mediation analysis using bootstrapping procedures revealed that the dimension of depressive cognition “hopelessness” fully mediates the association between the rs1801260 polymorphism and the BDI-HDRS discrepancy. Limitations Many gene polymorphisms other than CLOCK rs1801260 may also influence the BDI-HDRS discrepancy and depressive cognitive distortions. Conclusion Our current results suggest that factors affecting the biological clock can influence the “non-clock” psychopathological features of mood disorders.

Background Combined Total sleep deprivation (TSD) and light therapy (LT) cause a rapid improvement in bipolar depression which has been hypothesized to be paralleled by changes in sleep homeostasis. Recent studies showed that bipolar patients had lower changes of EEG theta power after sleep and responders to antidepressant TSD+LT slept less and showed a lower increase of EEG theta power then non-responders. A polymorphism in PER3 gene has been associated with diurnal preference, sleep structure and homeostatic response to sleep deprivation in healthy subjects. We hypothesized that the individual variability in the homeostatic response to TSD could be a correlate of antidepressant response and be influenced by genetic factors. Methods We administered three TSD+LT cycles to bipolar depressed patients. Severity of depression was rated on Hamilton Depression Rating Scale. Actigraphic recordings were performed in a group of patients. Results PER3 polymorphism influenced changes in total sleep time ( F =2.24; p =0.024): while PER3 4/4 and PER3 4/5 patients showed a reduction in it after treatment, PER3 5/5 subjects showed an increase of about 40 min, suggesting a higher homeostatic pressure. The same polymorphism influenced the change of depressive symptomatology during treatment ( F =3.72; p =0.028). Limitations Sleep information was recorded till the day after the end of treatment: a longer period of observation could give more information about the possible maintenance of allostatic adaptation. Conclusions A higher sleep homeostatic pressure reduced the antidepressant response to TSD+LT, while an allostatic adaptation to sleep loss was associated with better response. This process seems to be under genetic control.

Background Chronotherapeutic techniques (sleep deprivation and light therapy) are effective treatments for bipolar depression, but viable predictors of response for the daily clinical practice have not yet been established. The discrepancy between subjective and objective severity of the depressive syndrome has been proposed as a possible predictor of treatment outcome in depression. This study examined whether this discrepancy could predict response to chronotherapeutics in bipolar depression. Method We studied 149 consecutively admitted inpatients with a major depressive episode in course of bipolar disorder. Patients were treated with the combination of repeated sleep deprivation and bright light therapy. Severity of depression was evaluated using self-rated (Beck Depression Inventory: BDI) and observer-rated (Hamilton Depression Rating Scale: HDRS) measures. BDI-HDRS discrepancy score at baseline was calculated, and its associations with clinical response and with depressive cognitive distortions, as measured on the Cognitions Questionnaire, were examined. Results Among the 147 completers, 66% responded to treatment (50% reduction of HDRS score). The response rate in patients with low discrepancy scores and in patients with high discrepancy scores were 80.2% and 48.5%, respectively. High BDI-HDRS discrepancy predicted negative response to treatment with odds ratio of 3.79 (95%CI: 1.61–8.93). BDI-HDRS discrepancy was positively associated with depressive cognitive distortions. Limitations Potential factors affecting the discrepancy and outcome other than cognitive distortion were not examined in this study. Conclusion Higher BDI-HDRS discrepancy can predict poorer response to chronotherapeutics in bipolar depression. The tendency to generalize hopelessness may be a factor influencing the link between the discrepancy and outcome.

"\"Borderline personality disorder (BPD) is a severe clinical condition characterised by different maladaptive traits such as impulsivity and affective lability. Mood and emotion dysregulation are core features of affective disorders. Indeed patients affected by mood disorder (MD) have a significantly higher prevalence of comorbid BPD, resulting in more unstable mood and poorer response to medication. Blood oxygen level-dependent functional magnetic resonance imaging has been used to investigate the neural correlates of emotional face processing. Images for each subject were entered into an analysis of variance (ANOVA) dividing participants into three groups (MD, MD + BPD, Controls). MD + BPD patients show lower activations in the dorsolateral prefrontal cortex and higher activations in the cingulate cortex and hippocampus. The present study identifies the neural basis of the interaction between BPD and MD. The lower rate of response to treatment in MD + BPD could be related to a more severe emotional dysregulation syndrome. (C) 2012 Elsevier Ireland Ltd. All rights reserved.\""

"BACKGROUND:. Light Therapy (LT) when combined with standard antidepressant treatment for unipolar depression hastens recovery. We studied the influence of LT timing on the antidepressant efficacy of LT and the influence of the season of treatment and recurrence on the response to treatment.. METHODS:. We studied 70 inpatients affected by Unipolar Depression, treated for three weeks with combined LT and venlafaxine. Two-third of the patients received LT following a predictive algorithm based on MEQ scores; the others received LT at 11:00 a.m. Severity of depression was rated on the Hamilton Depression Rating Scale (HDRS). A subgroup of patients wore activity monitors.. RESULTS:. HDRS scores significantly decreased during treatment (Friedman's ANOVA: χ2=186.82, p

"BACKGROUND:. . Glycogen synthase kinase 3-β (GSK3-β) is involved in the control of cell behavior and in the mechanism of action of lithium and serotonergic antidepressants, and in humans a promoter variant (rs334558*C) was associated with reduced activity and better antidepressant response. The short form of a polymorphism in the promoter in the serotonin transporter (5-HTTLPR) has been consistently associated with worse antidepressant response. In animals the knockout of GSK3-β counteracts the depressive-like behavioral effects of 5-HT inhibition.. METHODS:. . With a translational approach, we studied the effect of 5-HTTLPR and rs334558 on antidepressant response to sleep deprivation in a unique sample of 122 patients affected by a major depressive episode in course of bipolar disorder. Mood was self rated on Visual Analog Scales, and severity of depression was rated on Montgomery-Asberg rating scale.. RESULTS:. . We observed a triple interaction of 5-HTTLPR, rs334558 and treatment on severity of depression. While among rs334558 T\/T homozygotes the best antidepressant response was associated with 5-HTTLPR l\/l homozygosity, among the rs334558 C carriers the 5-HTTLPR s\/s showed the best response to treatment.. CONCLUSIONS:. . A gene promoter polymorphism which reduces the activity of GSK3-β counteracts the detrimental influence of the short form of the 5-HT promoter on antidepressant response. A key component of Wnt pathway, and upstream of the mTOR signaling cascade, GSK3-β influences synaptic plasticity and cell resilience. Gene-gene interactions between components of the monoaminergic signal transduction pathways and of plasticity related pathways can shape the individual antidepressant response."

"\"BACKGROUND: Bipolar disorder (BD) is a recurrent and disabling illness, characterized by periods of depression and mania. The history of the illness differs widely between patients, with episode frequency emerging as a strong predictor of poor illness outcome. Lithium salts are the first-choice long-term mood-stabilizing therapy, but not all patients respond equally to the treatment. Evidence suggests that alterations in glutamatergic systems may contribute to the pathophysiology of depression. Moreover, glutamate signaling is involved in brain development and synaptic plasticity, both of which are modified in individuals affected by BD, and has been implicated in the etiology of the disorder. The inactivation of glutamate is handled by a series of molecular glutamate transporters (excitatory amino acid transporters [EAATs]), among which EAAT2\\\/SLC1A2 is responsible for up to 95% of extracellular glutamate clearance. A functional single-nucleotide polymorphism at -181 bp from the transcription start site of the SLC1A2 gene has been described. This T-to-G (DNA forward strand) polymorphism, commonly known as SLC1A2 -181A>C, affects transporter expression, with the variant G allele inducing a 30% reduction in promoter activity compared with the T allele.. . OBJECTIVE: The aims of the study were to investigate if factors affecting glutamate function, such as SLC1A2 -181A>C (rs4354668), could affect recurrence of illness in BD, and if they interact with lithium salt treatment.. . METHODS: We performed an observational study in our university hospital in Milan. We enrolled 110 subjects (76 females, 34 males) affected by BD type I. The exclusion criteria were other diagnoses on Axis I, mental retardation on Axis II, a history of epilepsy, and major medical and neurologic disorders. Fifty-four patients had been treated with lithium salts for more than 6 months. Patients were genotyped for SLC1A2 -181A>C by polymerase chain reaction-restriction fragment length polymorphism, and the influence of genotype on BD episode recurrence rates, and the interaction between the single nucleotide polymorphism and lithium treatment, were analyzed.. . RESULTS: The SLC1A2 -181A>C genotype significantly influenced the total recurrence of episodes, with T\\\/T homozygotes showing a significantly lower frequency of episodes (F = 3.26; p = 0.042), and an interaction between lithium treatment and genotype (F = 3.77; p = 0.026) was found to influence the history of the illness.. . CONCLUSION: According to our results, the glutamatergic system could be hypothesized to exert some influence on the history of illness in BD. The SLC1A2 functional polymorphism was shown to significantly influence the total episode recurrence rate, with wild-type T homozygotes presenting the lowest number of episodes, G homozygotes reporting the highest number, and heterozygotes showing an intermediate phenotype. We confirmed the efficacy of lithium treatment in reducing the recurrence of illness in BD, and we found an interaction between lithium treatment and the SLC1A2 -181A>C genotype, confirming previous studies reporting an interaction between lithium salts and the glutamatergic system.. . \""

Alteration of the sleep-wake cycle and of the sleep structure are core symptoms of a major depressive episode, and occur both in course of bipolar disorder and of major depressive disorder. Many other circadian rhythms, such as the daily profiles of body temperature, cortisol, thyrotropin, prolactin, growth hormone, melatonin and excretion of various metabolites in the urine, are disrupted in depressed patients, both unipolar and bipolar individuals. These disrupted rhythms seem to return to normality with patient recovery. Research on circadian rhythms and sleep have led to the definition of nonpharmacological therapies of mood disorder that can be used in everyday practice. These strategies, named chronotherapeutics, are based on controlled exposures to environmental stimuli that act on biological rhythms, and demonstrate good efficacy in the treatment of illness episodes. They include manipulations of the sleep-wake rhythm (such as partial and total sleep deprivation, and sleep phase advance) and of the exposure to the light-dark cycle (light therapy and dark therapy). In recent years, an increasing literature about the safety and efficacy of chronobiological treatments in everyday psychiatric settings has supported the inclusion of these techniques among the first-line antidepressant strategies for patients affected by mood disorders.

Resumen Fundamento La resonancia magnetica (RM) mediante tensor de difusion permite el estudio de la integridad de los tractos de sustancia blanca (SB). Los estudios publicados sugieren que en el trastorno bipolar podria estar alterada su integridad. La heterogeneidad de los metodos de diagnostico por imagen cerebral, de las muestras estudiadas y de los tratamientos farmacologicos no contribuye a dilucidar la localizacion, la naturaleza y la gravedad de las anomalias de la SB. Metodos Aplicamos el programa informatico FSL con la herramienta tract-based spatial statistics (TASS) a los parametros de RM mediante tensor de difusion para comparar la anisotropia fraccional (AF) y la difusividad media y radial de la estructura de SB en un grupo de 40 pacientes ingresados consecutivamente, afectados por un episodio depresivo mayor, sin caracteristicas psicoticas, con un diagnostico de trastorno bipolar de tipo I, y 21 individuos voluntarios, sanos, no emparentados, de la poblacion general. Resultados Comparado con los individuos de control, en los pacientes se identifico una menor AF en la rodilla del cuerpo calloso y en la parte anterior y supraposterior derecha de la corona radiada y mayores valores de difusividad radial en los tractos de SB del esplenio, rodilla y cuerpo del cuerpo calloso, parte mediodorsal derecha del haz del cingulo, parte anterior izquierda y superior y posterior bilateral de la corona radiada, fasciculo longitudinal superior bilateral y radiacion talamica posterior derecha. En los pacientes no se detectaron areas cerebrales con mayores valores de AF o menores valores de difusividad que en los individuos de control. Conclusiones La disminucion de la AF con un aumento de la difusividad media y radial sugiere una desmielinizacion y/o dismielinizacion significativa sin una perdida axonica. Comparando nuestros hallazgos con otras observaciones de muestras homogeneas de pacientes eutimicos y maniacos, se puede formular la hipotesis de que los cambios en los parametros de la integridad de la SB podrian ser comparables a las fases de la enfermedad en el trastorno bipolar.

Benedetti F, Absinta M, Rocca MA, Radaelli D, Poletti S, Bernasconi A, Dallaspezia S, Pagani E, Falini A, Copetti M, Colombo C, Comi G, Smeraldi E, Filippi M. Tract-specific white matter structural disruption in patients with bipolar disorder. Bipolar Disord 2011: 13: 414–424. © 2011 The Authors. Journal compilation © 2011 John Wiley & Sons A/S. Objectives: A growing body of evidence suggests that, independent of localized brain lesions, mood disorders can be associated with dysfunction of brain networks involved in the modulation of emotional and cognitive behavior. We used diffusion tensor (DT) tractography to quantify the presence and extent of structural injury to the connections between the amygdala and other brain regions, which included the subgenual, the supragenual and posterior cingulate, the parahippocampal, the orbitofrontal and dorsolateral prefrontal cortices, as well as the insula. Methods: Using a 3.0 Tesla scanner, conventional and DT magnetic resonance imaging sequences of the brain were acquired from 15 adult patients with major depressive disorder (MDD), 15 with bipolar disorder (BD), and 21 age-matched healthy controls. Using FSL software, diffusivity changes of the white matter (WM) fiber bundles belonging to the emotional network were measured. Results: Compared to controls and MDD patients, BD patients had significantly decreased average fractional anisotropy, increased average mean diffusivity, and increased average axial and radial diffusivity values in the majority of the WM fiber bundles connecting structures of the anterior limbic network (p-values ranging from 0.002 to 0.040). Medication load did not influence the results with the exception of lithium, which was associated with normal diffusivity values in tracts connecting the amygdala with the subgenual cingulate cortex. Conclusions: We detected specific WM abnormalities, suggestive of disrupted integrity of fiber bundles in the brains of patients with BD. These abnormalities might contribute to understanding both mood dysregulation and cognitive disturbances in BD, and might provide an objective marker to monitor treatment efficacy in this condition.

Background: Diffusion tensor imaging allows the study of integrity of white matter (WM) tracts. Literature suggests that WM integrity could be altered in bipolar disorder. Heterogeneity of brain imaging methods, the studied samples, and drug treatments make localization, nature, and severity of the WM abnormalities unclear. Methods: We applied tract-based spatial statistics of diffusion tensor imaging measures to compare fractional anisotropy (FA), mean, and radial diffusivity of the WM skeleton in a group of 40 consecutively admitted inpatients affected by a major depressive episode without psychotic features with a diagnosis of bipolar disorder type I and 21 unrelated healthy volunteers from the general population. Results: Compared with control subjects, patients showed lower FA in the genu of the corpus callosum and in anterior and right superior-posterior corona radiata and higher values of radial diffusivity in WM tracts of splenium, genu and body of corpus callosum, right mid-dorsal part of the cingulum bundle, left anterior and bilateral superior and posterior corona radiata, bilateral superior longitudinal fasciculus, and right posterior thalamic radiation. Patients had no brain areas with higher FA or lower diffusivity values than control subjects. Conclusions: Reduced FA with increased mean and radial diffusivity suggests significant demyelination and/or dysmyelination without axonal loss. Comparing our findings with other observations in homogeneous samples of euthymic and manic patients, it can be hypothesized that changes in measures of WM integrity might parallel illness phases of bipolar illness. ""Background: Diffusion tensor imaging allows the study of integrity of white matter (WM) tracts. Literature suggests that WM integrity could be altered in bipolar disorder. Heterogeneity of brain imaging methods, the studied samples, and drug treatments make localization, nature, and severity of the WM abnormalities unclear. Methods: We applied tract-based spatial statistics of diffusion tensor imaging measures to compare fractional anisotropy (FA), mean, and radial diffusivity of the WM skeleton in a group of 40 consecutively admitted inpatients affected by a major depressive episode without psychotic features with a diagnosis of bipolar disorder type I and 21 unrelated healthy volunteers from the general population. Results: Compared with control subjects, patients showed lower FA in the genu of the corpus callosum and in anterior and right superior-posterior corona radiata and higher values of radial diffusivity in WM tracts of splenium, genu and body of corpus callosum, right mid-dorsal part of the cingulum bundle, left anterior and bilateral superior and posterior corona radiata, bilateral superior longitudinal fasciculus, and right posterior thalamic radiation. Patients had no brain areas with higher FA or lower diffusivity values than control subjects. Conclusions: Reduced FA with increased mean and radial diffusivity suggests significant demyelination and\\\/or dysmyelination without axonal loss. Comparing our findings with other observations in homogeneous samples of euthymic and manic patients, it can be hypothesized that changes in measures of WM integrity might parallel illness phases of bipolar illness.""

Background: Catechol-O-methyltransferase (COMT) inactivates catecholamines, and a G-A transition in the COMT gene (rs4680) influences the enzyme activity and the interaction between cortical and subcortical dopaminergic neurotransmission. Studies in healthy participants and in patients affected by schizophrenia suggested that rs4680 can influence the propensity to develop psychotic symptoms, with the Met low-activity allele exerting a protective role. Previous studies in bipolar patients reported non-significant trends in the same direction. Methods: We genotyped rs4680 in a sample of 467 patients affected by bipolar disorder type I with or without a previous illness episode with psychotic features (DSM-IV criteria: delusions or hallucinations). Results: We observed a significant association between homozygosis for the rs4680 COMT low-activity variant and a reduced risk of experiencing illness episodes with psychotic features during the course of the illness. The Met/Met genotype was more common among patients without psychotic features, and while in the non-psychotic group the Val/Val genotype had a distribution similar to Met/Met, in the group of patients who experienced episodes with psychotic symptoms the proportion of Val/Val homozygotes was the double of Met/Met. Conclusions: We suggest that rs4680 could be an inheritable aspect of the mechanisms of dopamine regulation that could influence the individual susceptibility of patients with bipolar disorder to develop psychotic symptoms. (C) 2010 Elsevier B.V. All rights reserved. Background: Catechol-O-methyltransferase (COMT) inactivates catecholamines, and a G-A transition in the COMT gene (rs4680) influences the enzyme activity and the interaction between cortical and subcortical dopaminergic neurotransmission. Studies in healthy participants and in patients affected by schizophrenia suggested that rs4680 can influence the propensity to develop psychotic symptoms, with the Met low-activity allele exerting a protective role. Previous studies in bipolar patients reported non-significant trends in the same direction. Methods: We genotyped rs4680 in a sample of 467 patients affected by bipolar disorder type I with or without a previous illness episode with psychotic features (DSM-IV criteria: delusions or hallucinations). Results: We observed a significant association between homozygosis for the rs4680 COMT low-activity variant and a reduced risk of experiencing illness episodes with psychotic features during the course of the illness. The Met/Met genotype was more common among patients without psychotic features, and while in the non-psychotic group the Val/Val genotype had a distribution similar to Met/Met, in the group of patients who experienced episodes with psychotic symptoms the proportion of Val/Val homozygotes was the double of Met/Met. Conclusions: We suggest that rs4680 could be an inheritable aspect of the mechanisms of dopamine regulation that could influence the individual susceptibility of patients with bipolar disorder to develop psychotic symptoms. (C) 2010 Elsevier B.V. All rights reserved.

Background. Despite behavioural signs of flattened affect, patients affected by schizophrenia show enhanced sensitivity to negative stimuli. The current literature concerning neural circuitry for emotions supports dysregulations of cortico-limbic networks, but gives contrasting results. Adverse childhood experiences (ACEs) could persistently influence emotional regulation and neural correlates of response to emotional stimuli in healthy humans. This study evaluated the effect of ACEs and chronic undifferentiated schizophrenia on neural responses to emotional stimuli (negative facial expression). Method. Brain blood-oxygen-level-dependent functional magnetic resonance imaging neural responses to a face-matching paradigm, and regional grey matter (GM) volumes were studied at 3.0 T in the amygdala, hippocampus, anterior cingulated cortex (ACC) and prefrontal cortex (PFC). The severity of ACEs was assessed. Participants included 20 consecutively admitted in-patients affected by chronic undifferentiated schizophrenia, and 20 unrelated healthy volunteers from the general population. Results. Patients reported higher ACEs than controls. Worse ACEs proportionally led to decreasing responses in the amygdala and hippocampus, and to increasing responses in the PFC and ACC in all participants. Patients showed higher activations in the amygdala and hippocampus, and lower activations in the PFC and ACC. Higher ACEs were associated with higher GM volumes in the PFC and ACC, and schizophrenia was associated with GM reduction in all studied regions. Conclusions. Structural and functional brain correlates of emotional reactivity are influenced by both current chronic undifferentiated schizophrenia and the severity of past ACEs. "Background. Despite behavioural signs of flattened affect, patients affected by schizophrenia show enhanced sensitivity to negative stimuli. The current literature concerning neural circuitry for emotions supports dysregulations of cortico-limbic networks, but gives contrasting results. Adverse childhood experiences (ACEs) could persistently influence emotional regulation and neural correlates of response to emotional stimuli in healthy humans. This study evaluated the effect of ACEs and chronic undifferentiated schizophrenia on neural responses to emotional stimuli (negative facial expression). Method. Brain blood-oxygen-level-dependent functional magnetic resonance imaging neural responses to a face-matching paradigm, and regional grey matter (GM) volumes were studied at 3.0 T in the amygdala, hippocampus, anterior cingulated cortex (ACC) and prefrontal cortex (PFC). The severity of ACEs was assessed. Participants included 20 consecutively admitted in-patients affected by chronic undifferentiated schizophrenia, and 20 unrelated healthy volunteers from the general population. Results. Patients reported higher ACEs than controls. Worse ACEs proportionally led to decreasing responses in the amygdala and hippocampus, and to increasing responses in the PFC and ACC in all participants. Patients showed higher activations in the amygdala and hippocampus, and lower activations in the PFC and ACC. Higher ACEs were associated with higher GM volumes in the PFC and ACC, and schizophrenia was associated with GM reduction in all studied regions. Conclusions. Structural and functional brain correlates of emotional reactivity are influenced by both current chronic undifferentiated schizophrenia and the severity of past ACEs."

At the crossroad of multiple pathways regulating trophism and metabolism, glycogen synthase kinase (GSK)3 is considered a key factor in influencing the susceptibility of neurons to harmful stimuli (neuronal resilience) and is a target for several psychiatric drugs that directly inhibit it or increase its inhibitory phosphorylation. Inhibition of GSK3 prevents apoptosis and could protect against the neuropathological processes associated with psychiatric disorders. A GSK3-beta promoter single-nucleotide polymorphism (rs334558) influences transcriptional strength, and the less active form was associated with less detrimental clinical features of mood disorders. Here we studied the effect of rs334558 on grey matter volumes (voxel-based morphometry) of 57 patients affected by chronic schizophrenia. Carriers of the less active C allele variant showed significantly higher brain volumes in an area encompassing posterior regions of right middle and superior temporal gyrus, within the boundaries of Brodmann area 21. The temporal lobe is the brain parenchymal region with the most consistently documented morphometric abnormalities in schizophrenia, and neuropathological processes in these regions develop soon at the beginning of the illness. These results support the interest for GSK3-beta as a factor affecting neuropathology in major behavioural disorders, such as schizophrenia, and thus as a possible target for treatment.