Right Orbitofrontal Corticolimbic and Left Corticocortical White Matter Connectivity Differentiate Bipolar and Unipolar Depression

Objectives: The absence of pathophysiologically relevant diagnostic markers of bipolar disorder (BD) leads to its frequent misdiagnosis as unipolar depression (UD). We aimed to determine whether whole brain white matter connectivity differentiated BD from UD depression. Methods: We employed a three-way analysis of covariance, covarying for age, to examine whole brain fractional anisotropy (FA), and corresponding longitudinal and radial diffusivity, in currently depressed adults: 15 with BD-type I (mean age 36.3 years, SD 12.0 years), 16 with recurrent UD (mean age 32.3 years, SD 10.0 years), and 24 healthy control adults (HC) (mean age 29.5 years, SD 9.43 years). Depressed groups did not differ in depression severity, age of illness onset, and illness duration. Results: There was a main effect of group in left superior and inferior longitudinal fasciculi (SLF and ILF) (all F >= 9.8; p <= .05, corrected). Whole brain post hoc analyses (all t >= 4.2; p <= .05, corrected) revealed decreased FA in left SLF in BD, versus UD adults in inferior temporal cortex and, versus HC, in primary sensory cortex (associated with increased radial and decreased longitudinal diffusivity, respectively); and decreased FA in left ILF in UD adults versus HC. A main effect of group in right uncinate fasciculus (in orbitofrontal cortex) just failed to meet significance in all participants but was present in women. Post hoc analyses revealed decreased right uncinate fasciculus FA in all and in women, BD versus HC. Conclusions: White matter FA in left occipitotemporal and primary sensory regions supporting visuospatial and sensory processing differentiates BD from UD depression. Abnormally reduced FA in right fronto-temporal regions supporting mood regulation, might underlie. predisposition to depression in BD. These measures might help differentiate pathophysiologic processes of BD versus UD depression.

Screening for serious mental illness in the general population with the K6 screening scale: results from the WHO World Mental Health (WMH) survey initiative

Data are reported on the background and performance of the K6 screening scale for serious mental illness (SMI) in the World Health Organization (WHO) World Mental Health (WMH) surveys. The K6 is a six-item scale developed to provide a brief valid screen for Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM-IV) SMI based on the criteria in the US ADAMHA Reorganization Act. Although methodological studies have documented good K6 validity in a number of countries, optimal scoring rules have never been proposed. Such rules are presented here based on analysis of K6 data in nationally or regionally representative WMH surveys in 14 countries (combined N = 41,770 respondents). Twelve-month prevalence of DSM-IV SMI was assessed with the fully-structured WHO Composite International Diagnostic Interview. Nested logistic regression analysis was used to generate estimates of the predicted probability of SMI for each respondent from K6 scores, taking into consideration the possibility of variable concordance as a function of respondent age, gender, education, and country. Concordance, assessed by calculating the area under the receiver operating characteristic curve, was generally substantial (median 0.83; range 0.76-0.89; inter-quartile range 0.81-0.85). Based on this result, optimal scaling rules are presented for use by investigators working with the K6 scale in the countries studied. Copyright (c) 2010 John Wiley & Sons, Ltd.

AGE DIFFERENCES IN THE PREVALENCE AND CO-MORBIDITY OF DSM-IV MAJOR DEPRESSIVE EPISODES: RESULTS FROM THE WHO WORLD MENTAL HEALTH SURVEY INITIATIVE

Background: Although depression appears to decrease in late life, this could be due to misattribution of depressive symptoms to physical disorders that increase in late we. Methods: We investigated this issue by studying age differences in co-morbidity of DSM-IV major depressive episodes (MDE) with chronic physical conditions in the WHO World Mental Health (WMH) surveys, a series of community epidemiological surveys of respondents in 10 developed countries (n = 52,485) and 8 developing countries (n = 37,265). MDE and other mental disorders were assessed with the Composite International Diagnostic Interview (CIDI). Organic exclusion rules were not used to avoid inappropriate exclusion of cases with physical co-morbidity. Physical conditions were assessed with a standard chronic conditions checklist. Results: Twelve-month DSM-IV/CIDI MDE was significantly less prevalent among respondents ages 65+ than younger respondents in developed but not developing countries. Prevalence of co-morbid mental disorders generally either decreased or remained stable with age, while co-morbidity of MDE with mental disorders generally increased with age. Prevalence of physical conditions, in comparison, generally increased with age, while co-morbidity of MDE with physical conditions generally decreased with age. Depression treatment was lowest among the elderly in developed and developing countries. Conclusions: The weakening associations between MDE and physical conditions with increasing age argue against the suggestion that the low estimated prevalence of MDE among the elderly is due to increased confounding with physical disorders. Future study is needed to investigate processes that might lead to a decreasing impact of physical illness on depression among the elderly. Depression and Anxiety 27:351-364, 2010. (C) 2009 Wiley-Liss, Inc.

Elevated Amygdala Activity to Sad Facial Expressions: A State Marker of Bipolar but Not Unipolar Depression

Background: Difficulties in emotion processing and poor social function are common to bipolar disorder (BD) and major depressive disorder (MDD) depression, resulting in many BID depressed individuals being misdiagnosed with MDD. The amygdala is a key region implicated in processing emotionally salient stimuli, including emotional facial expressions. It is unclear, however, whether abnormal amygdala activity during positive and negative emotion processing represents a persistent marker of BD regardless of illness phase or a state marker of depression common or specific to BID and MDD depression. Methods: Sixty adults were recruited: 15 depressed with BID type 1 (BDd), 15 depressed with recurrent MDD, 15 with BID in remission (BDr), diagnosed with DSM-IV and Structured Clinical Interview for DSM-IV Research Version criteria; and 15 healthy control subjects (HC). Groups were age- and gender ratio-matched; patient groups were matched for age of illness onset and illness duration; depressed groups were matched for depression severity. The BDd were taking more psychotropic medication than other patient groups. All individuals participated in three separate 3T neuroimaging event-related experiments, where they viewed mild and intense emotional and neutral faces of fear, happiness, or sadness from a standardized series. Results: The BDd-relative to HC, BDr, and MDD-showed elevated left amygdala activity to mild and neutral facial expressions in the sad (p < .009) but not other emotion experiments that was not associated with medication. There were no other significant between-group differences in amygdala activity. Conclusions: Abnormally elevated left amygdala activity to mild sad and neutral faces might be a depression-specific marker in BID but not MDD, suggesting different pathophysiologic processes for BD versus MDD depression.

Recovery of Renal Function in Heart Transplantation Patients After Conversion From a Calcineurin Inhibitor-Based Therapy to Sirolimus

Background. Renal failure is the most important comorbidity in patients with heart transplantation, it is associated with increased mortality. The major cause of renal dysfunction is the toxic effects of calcineurin inhibitors (CNI). Sirolimus, a proliferation signal inhibitor, is an imunossupressant recently introduced in cardiac transplantation. Its nonnephrotoxic properties make it an attractive immunosuppressive agent for patients with renal dysfunction. In this study, we evaluated the improvement in renal function after switching the CNI to sirolimus among patients with new-onset kidney dysfunction after heart transplantation. Methods. The study included orthotopic cardiac transplant (OHT) patients who required discontinuation of CNI due to worsening renal function (creatinine clearance <50 mL/min). We excluded subjects who had another indication for initiation of sirolimus, that is, rejection, malignancy, or allograft vasculopathy. The patients were followed for 6 months. The creatinine clearance (CrCl) was estimated according to the Cockcroft-Gault equation using the baseline weight and the serum creatinine at the time of introduction of sirolimus and 6 months there after. Nine patients were included, 7 (78%) were males and the overall mean age was 60.1 +/- 12.3 years and time since transplantation 8.7 +/- 6.1 years. The allograft was beyond 1 year in all patients. There was a significant improvement in the serum creatinine (2.98 +/- 0.9 to 1.69 +/- 0.5 mg/dL, P = .01) and CrCl (24.9 +/- 6.5 to 45.7 +/- 17.2 mL/min, P = .005) at 6 months follow-up. Conclusion. The replacement of CNI by sirolimus for imunosuppressive therapy for patients with renal failure after OHT was associated with a significant improvement in renal function after 6 months.

The impact of trauma and post-traumatic stress disorder on the treatment response of patients with obsessive-compulsive disorder

Few case series studies have addressed the issue of treatment response in patients with obsessive-compulsive disorder (OCD) and comorbid post-traumatic stress disorder (PTSD), and there are no prospective studies addressing response to conventional treatment in OCD patients with a history of trauma (HT). The present study aimed to investigate, prospectively, the impact of HT or PTSD on two systematic, first-line treatments for OCD. Two hundred and nineteen non-treatment-resistant OCD outpatients were treated with either group cognitive-behavioral therapy (GCBT n = 147) or monotherapy with a selective serotonin reuptake inhibitor (SSRI n = 72). Presence of HT and PTSD were assessed at intake, as part of a broader clinical and demographical baseline characterization of the sample. Severity and types of OCD symptoms were assessed with the Yale-Brown Obsessive-Compulsive Scale (YBOCS) and the Dimensional YBOCS (DYBOCS), respectively. Depression and anxiety symptoms were measured with the Beck Depression Inventory (BDI) and the Beck Anxiety Inventory (BAI). Both treatments had 12-week duration. Treatment response was considered as a categorical [35% or greater reduction in baseline YBOCS scores plus a Clinical Global Impression-Improvement rating of better (2) or much better (1)] and continuous variable (absolute number reduction in baseline YBOCS scores). Treatment response was compared between the OCD + HT group versus the OCD without HT group and between the OCD + PTSD group versus the OCD without PTSD group. Parametric and non-parametric tests were used when indicated. Data on HT and PTSD were available for 215 subjects. Thirty-eight subjects (17.67% of the whole sample) had a positive HT (OCD + HT group) and 22 subjects (57.89% of the OCD + HT group and 10.23% of the whole sample) met full DSM-IV criteria for PTSD. The OCD + HT and OCD without HT groups presented similar response to GCBT (60% of responders in the first group and 63% of responders in the second group, p = 1.00). Regarding SSRI treatment, the difference between the response of the OCD + HT (47.4%) and OCD without HT (22.2%) groups was marginally significant (p = 0.07). In addition, the OCD + PTSD group presented a greater treatment response than the OCD without PTSD group when treatment response was considered as a continuous variable (p = 0.01). The age when the first trauma occurred had no impact on treatment response. In terms of specific OCD symptom dimensions, as measured by the DYBOCS, OCD treatment fostered greater reductions for the OCD + PTSD group than for the OCD without PTSD group in the scores of contamination obsessions and cleaning compulsions, collecting and hoarding and miscellaneous obsessions and related compulsions (including illness concerns and mental rituals, among others). The OCD + PTSD group also presented a greater reduction in anxiety scores than the OCD without PTSD group (p = 0.003). The presence of HT or PTSD was not related to a poorer treatment response in this sample of non-treatment-resistant OCD patients. Unexpectedly, OCD patients with PTSD presented a greater magnitude of response when compared with OCD without PTSD patients in specific OCD symptom dimensions. Future studies are needed to clarify if trauma and PTSD have a more significant impact on the onset and clinical expression of OCD than on the conventional treatment for this condition, and whether OCD stemming from trauma would constitute a subtype of OCD with a distinct response to conventional treatment.

Apolipoprotein E genotype and Cognition in Bipolar Disorder

Apolipoprotein E (APOE) has been extensively studied as a risk factor for sporadic and late onset Alzheimer`s Disease (AD). APOE allele *3, the most frequent variant, is not associated to cognitive dysfunction (CD) or to increased AD risk. Differently, the *4 allele is a well-established risk factor for CD, while the *2 allele is associated with survival and longevity. CD is an important feature of Bipolar Disorder (BD) and recent data suggest that CD may be one of its endophenotypes, although controversial results exist. The aim of this research is to study the association of APOE genotype (APOE) and neurocognitive function in a sample of drug free young BD-type I patients. Sample consisted of 25 symptomatic BD (type I) patients (age 18-35 years old). They were submitted to an extensive neuropsychological evaluation and genotyped for APOE. Subjects with allele *2 presented better cognitive performance. The presence of allele *4 was associated with worse performance in a few executive tasks. APOE *3*3 was associated with overall severe dysfunction on cognitive performance. In young individuals with nontreated BD-type I, APOE may predict cognitive performance. Further and larger studies on APOE and cognition in BD are required to clarify whether APOE is a BD cognitive endophenotype.

The Aging Process of the Heart: Obesity Is the Main Risk Factor for Left Atrial Enlargement During Aging The MONICA/KORA (Monitoring of Trends and Determinations in Cardiovascular Disease/Cooperative Research in the Region of Augsburg) Study

Objectives This prospective study evaluated the association of obesity and hypertension with left atrial (LA) volume over 10 years. Background Although left atrial enlargement (LAE) is an independent risk factor for atrial fibrillation, stroke, and death, little information is available about determinants of LA size in the general population. Methods Participants (1,212 men and women, age 25 to 74 years) originated from a sex-and age-stratified random sample of German residents of the Augsburg area (MONICA S3). Left atrial volume was determined by standardized echocardiography at baseline and again after 10 years. Left atrial volume was indexed to body height (iLA). Left atrial enlargement was defined as iLA >= 35.7 and >= 33.7 ml/m in men and women, respectively. Results At baseline, the prevalence of LAE was 9.8%. Both obesity and hypertension were independent predictors of LAE, obesity (odds ratio [OR]: 2.4; p < 0.001) being numerically stronger than hypertension (OR: 2.2; p < 0.001). Adjusted mean values for iLA were significantly lower in normal-weight hypertensive patients (25.4 ml/m) than in obese normotensive individuals (27.3 ml/m; p = 0.016). The highest iLA was found in the obese hypertensive subgroup (30.0 ml/m; p < 0.001 vs. all other groups). This group also presented with the highest increase in iLA (+6.0 ml/m) and the highest incidence (31.6%) of LAE upon follow-up. Conclusions In the general population, obesity appears to be the most important risk factor for LAE. Given the increasing prevalence of obesity, early interventions, especially in young obese individuals, are essential to prevent premature onset of cardiac remodeling at the atrial level. (J Am Coll Cardiol 2009; 54: 1982-9) (C) 2009 by the American College of Cardiology Foundation

Innovative psychosocial approaches in old age psychiatry

Purpose of review To identify and discuss recent research studies that propose innovative psychosocial interventions in old age psychiatry. Recent findings Studies have shown that cognitive training research for healthy elderly has advanced in several ways, particularly in the refinement of study design and methodology. Studies have included larger samples and longer training protocols. Interestingly, new research has shown changes in biological markers associated with learning and memory after cognitive training. Among mild cognitive impairment patients, results have demonstrated that they benefit from interventions displaying cognitive plasticity. Rehabilitation studies involving dementia patients have suggested the efficacy of combined treatment approaches, and light and music therapies have shown promising effects. For psychiatric disorders, innovations have included improvements in well known techniques such as cognitive behavior therapy, studies in subpopulations with comorbidities, as well as the use of new computer-aided resources. Summary Research evidence on innovative interventions in old age psychiatry suggests that this exciting field is moving forward by means of methodological refinements and testing of creative new ideas.

Ultrasound evaluation of prognosis in fetuses with posterior urethral valves

Purpose: The aim of this study was to evaluate the ability of prenatal ultrasound markers to predict postnatal renal prognosis in fetuses with posterior urethral valves. Methods: Medical files on fetuses with prenatal diagnosis of posterior urethral valves from 2000 to 2006 were reviewed retrospectively. Data from prenatal follow-up included gestational age at diagnosis, ultrasound renal parenchyma evaluation, and presence and time of oligohydramnios onset. Prenatal parameters studied were correlated to postnatal renal function. Results: Thirty-one male fetuses were included. Six pregnancies were terminated. Of the remaining 25 pregnancies that were continued, 4 children had abnormal creatine and 21 normal creatinine levels at follow-up. Presence and time of oligohydramnios onset did not differ between groups (P = .43). Ultrasound detected bilateral renal abnormalities in 3 fetuses (75%) with altered renal function, and 10 fetuses (55%) with normal creatinine, at follow-up. Conclusions: None of the ultrasound parameters evaluated were able to reliably predict postnatal renal function. (C) 2011 Elsevier Inc. All rights reserved.

Abnormal Amygdala-Prefrontal Effective Connectivity to Happy Faces Differentiates Bipolar from Major Depression

Background: Bipolar disorder is frequently misdiagnosed as major depressive disorder, delaying appropriate treatment and worsening outcome for many bipolar individuals. Emotion dysregulation is a core feature of bipolar disorder. Measures of dysfunction in neural systems supporting emotion regulation might therefore help discriminate bipolar from major depressive disorder. Methods: Thirty-one depressed individuals-15 bipolar depressed (BD) and 16 major depressed (MDD), DSM-IV diagnostic criteria, ages 18-55 years, matched for age, age of illness onset, illness duration, and depression severity-and 16 age- and gender-matched healthy control subjects performed two event-related paradigms: labeling the emotional intensity of happy and sad faces, respectively. We employed dynamic causal modeling to examine significant among-group alterations in effective connectivity (EC) between right- and left-sided neural regions supporting emotion regulation: amygdala and orbitomedial prefrontal cortex (OMPFC). Results: During classification of happy faces, we found profound and asymmetrical differences in EC between the OMPFC and amygdala. Left-sided differences involved top-down connections and discriminated between depressed and control subjects. Furthermore, greater medication load was associated with an amelioration of this abnormal top-down EC. Conversely, on the right side the abnormality was in bottom-up EC that was specific to bipolar disorder. These effects replicated when we considered only female subjects. Conclusions: Abnormal, left-sided, top-down OMPFC-amygdala and right-sided, bottom-up, amygdala-OMPFC EC during happy labeling distinguish BD and MDD, suggesting different pathophysiological mechanisms associated with the two types of depression.

Early onset of primary hypogonadism revealed by serum anti-Mullerian hormone determination during infancy and childhood in trisomy 21

Male patients with an extra sex chromosome or autosome are expected to present primary hypogonadism at puberty owing to meiotic germ-cell failure. Scarce information is available on trisomy 21, a frequent autosomal aneuploidy. Our objective was to assess whether trisomy 21 presents with pubertal-onset, germ-cell specific, primary hypogonadism in males, or whether the hypogonadism is established earlier and affects other testicular cell populations. We assessed the functional status of the pituitary-testicular axis, especially Sertoli cell function, in 117 boys with trisomy 21 (ages: 2 months-20 year). To compare with an adequate control population, we established reference levels for serum anti-Mullerian hormone (AMH) in 421 normal males, from birth to adulthood, using a recently developed ultrasensitive assay. In trisomy 21, AMH was lower than normal, indicating Sertoli cell dysfunction, from early infancy, independently of the existence of cryptorchidism. The overall prevalence rate of AMH below the 3rd percentile was 64.3% in infants with trisomy 21. Follicle-stimulating hormone was elevated in patients <6 months and after pubertal onset. Testosterone was within the normal range, but luteinizing hormone was elevated in most patients <6 months and after pubertal onset, indicating a mild Leydig cell dysfunction. We conclude that in trisomy 21, primary hypogonadism involves a combined dysfunction of Sertoli and Leydig cells, which can be observed independently of cryptorchidism soon after birth, thus prompting the search for new hypotheses to explain the pathophysiology of gonadal dysfunction in autosomal trisomy.

Systemic lupus erythematosus in the elderly: antimalarials in disease remission

To analyze the long-term antimalarials (AM) usage on elderly systemic lupus erythematosus (SLE) patients from 2002 to 2008. Fifty-seven consecutive SLE patients, a parts per thousand yen65 years, were enrolled. The patients were divided into groups A (disease remission) and B (disease activity: with clinical and/or laboratory alterations attributed to SLE activity, and/or using steroid and immunosuppressors). Forty-three patients (75.4%) were in group A. The mean age in groups A and B was, respectively, 69.8 +/- A 4.5 versus 67.8 +/- A 4.8 years (P = 0.210), with similar disease onset (46.9 +/- A 11.2 vs. 42.3 +/- A 11.6 years; P = 0.220). There was no difference in gender, ethnicity, and clinical previous manifestations. In 21 out of 57 cases (10 from group A and 11, group B, P < 0.001), AM had been suspended after 5.2 +/- A 1.3 years, because of its side effects (maculopathy). The disease remission was strongly associated to AM usage (OR 12.91; 95% CI 2.87-58.13). In summary, SLE remission was significantly associated with the long-term AM usage.

The frequency of anti-beta(2)-glycoprotein I antibodies is low and these antibodies are associated with pulmonary hypertension in mixed connective tissue disease

The objective of this study is to evaluate the prevalence of antiphospholipid antibodies, mainly anti-beta(2)-glycoprotein I (anti-beta(2)-GPI), and their possible clinical and laboratory relevance in mixed connective tissue disease (MCTD). This study included 39 consecutive patients with MCTD (Kasukawa`s criteria) from January, 2005, to March, 2007, and compared them with 21 age- and sex-matched healthy controls. IgG and IgM anticardiolipin (aCL) and anti-beta(2)-GPI were measured by ELISA. Lupus anticoagulant (LA) was detected by functional coagulation tests. Medium to high titres of aCL and anti-beta(2)-GPI antibodies were found in sera from four (10.2%) MCTD patients. One of these patients was found to be positive for IgM aCL, IgM anti-beta(2)-GPI and LA antibodies simultaneously. Additionally, this patient had a previous history of foetal loss in the second trimester and new-onset pulmonary arterial hypertension (PAH). The other three patients had none of the manifestations of antiphospholipid syndrome (APS) or PAH. The mean value of IgG anti-beta(2)-GPI was higher among those MCTD patients with PAH than in the group without PAH (34.2 +/- 46.8 vs 12.3 +/- 9.1, P = 0.018). None of the controls were positive for antiphospholipid antibodies. High to moderate titres of anti-beta(2)-GPI as well as APS were rare in MCTD, and these antibodies may be correlated with the development of PAH in these patients. Lupus (2009) 18, 618-621.

Orbitofrontal cortex gray matter volumes in bipolar disorder patients: a region-of-interest MRI study

Objectives: Functional and postmortem studies suggest that the orbitofrontal cortex (OFC) is involved in the pathophysiology of bipolar disorder (BD). This anatomical magnetic resonance imaging (MRI) study examined whether BD patients have smaller OFC gray matter volumes compared to healthy comparison subjects (HC). Methods: Twenty-eight BD patients were compared to 28 age- and gender-matched HC. Subjects underwent a 1.5T MRI with 3D spoiled gradient recalled acquisition. Total OFC and medial and lateral subdivisions were manually traced by a blinded examiner. Images were segmented and gray matter volumes were calculated using an automated method. Results: Analysis of covariance, with intracranial volume as covariate, showed that BD patients and HC did not differ in gray matter volumes of total OFC or its subdivisions. However, total OFC gray matter volume was significantly smaller in depressed patients (n = 10) compared to euthymic patients (n = 18). Moreover, total OFC gray matter volumes were inversely correlated with depressive symptom intensity, as assessed by the Hamilton Depression Rating Scale. OFC gray matter volumes were not related to lithium treatment, age at disease onset, number of episodes, or family history of mood disorders. Conclusions: Our results suggest that abnormal OFC gray matter volumes are not a pervasive characteristic of BD, but may be associated with specific clinical features of the disorder.