Comorbid cerebral amyloid angiopathy in dementia and prodromal stages-Prevalence and effects on cognition.

OBJECTIVES: To determine the contribution of cerebral amyloid angiopathy to cognitive impairment in MCI and dementia. METHODS: Patients with subjective memory impairment (SMI), amnestic and non-amnestic mild cognitive impairment ((n)aMCI), Alzheimer's disease (AD), mixed and vascular dementia (MD/VD) from our memory clinic were included in this retrospective analysis. Patients underwent neuropsychological testing and cranial magnetic resonance imaging (MRI). Magnetic resonance imaging data sets were analyzed regarding the presence of CAA-related MRI biomarkers to determine CAA prevalence. ANOVAs were used to investigate the contribution of CAA to cognitive impairment within diagnostic groups and to determine whether differences in cognitive test performance between the diagnostic groups are mediated by total CAA burden. RESULTS: 475 patients (222 male, 253 female) with SMI (n = 47), naMCI (n = 41), aMCI (n = 189), early AD (n = 9), AD (n = 114), MD (n = 71) and VD (n = 4) were included. Mean age was 73.2 (9.9) years. CAA prevalence was 14.9% in SMI, 14.6% in naMCI, 24.3% in aMCI, 22.2% in early onset AD, 18.4% in late onset AD, 46.5% in MD and 25% in VD. Patients with possible and probable CAA were older than patients without CAA. In particular, diagnosis of aMCI, early onset AD, MD and VD showed high CAA prevalence. In AD but not in aMCI, CAA diagnosis significantly influenced test performance in the CERAD word list recall (F (1,78) = 4505; p = 0.037; partial eta-square = 0.055). Differences in cognitive test performance between the diagnostic groups of naMCI, aMCI, AD and MD were mediated by total CAA burden within AAT simply nouns subtest (F (2,39) = 4059; p = 0.025; partial eta-square = 0.172) and in CERAD verbal fluency test (F (3,129) = 3533; p = 0.017; partial eta-square = 0.076). CONCLUSION: This retrospective analysis demonstrates high prevalence rates of CAA in cognitive diagnoses. Our data suggest that comorbid CAA independently impacts cognitive test performance in the course of AD with presumably stage-dependent effects. Especially in patients with AD comorbid CAA additionally impairs memory function. Total CAA small vessel disease burden further modulates psychometric differences in cognitive test performance between diagnostic groups regarding word finding and word fluency capabilities.

[Exposure therapy for panic disorder and agoraphobia in the context of existing antidepressive medication]. / Expositionstherapie bei Panikstörung und Agoraphobie im Kontext bestehender antidepressiver Medikation.

BACKGROUND: Cognitive behavioral therapy (CBT) and pharmacotherapy with antidepressants are both a highly effective treatment for agoraphobia and/or panic disorder; however, a combination of CBT and antidepressants is under debate due to potentially unfavorable interference effects. The associations of existing antidepressant medication with panic and agoraphobia symptom burden and their change in the context of a structured 5­week day hospital and exposure-focused treatment in a naturalistic setting were investigated. METHODS: Out of a total of n = 488 patients medication use during treatment was retrospectively determined for n = 380: n = 100 (26.3%) were taking antidepressants of different drug classes. Calculations were performed using multiple linear regression analysis, t­tests, response analyses, and χ2-tests. RESULTS: Patients with existing antidepressant medication more often met the criteria for comorbid depressive disorder (p < 0.001). The measure of symptom change and treatment response rates did not differ between patients with and without antidepressants with respect to anxiety symptoms. DISCUSSION: In the context studied, patients with and without existing antidepressant medication benefited equally from CBT with respect to anxiety symptoms.

Predictors of subjective cognitive deficits in patients with mild cognitive impairment.

BACKGROUND: Detailed examination of cognitive deficits in patients with mild cognitive impairment (MCI) yields substantial diagnostic and prognostic value, specifically with respect to memory. Magnitude and characteristics of subjective cognitive deficits, however, often receive less attention in this population at risk for developing dementia. METHODS: We investigated predictors of subjective cognitive deficits in patients with MCI, using a detailed assessment for such impairments associated with different cognitive domains, as well as demographic and clinical variables including magnetic resonance imaging data. RESULTS: The strongest predictor for subjective memory deficits was depressed mood, whereas subjective performance issues associated with attention or executive functions also corresponded to measurable impairments in the respective cognitive domains. Reduced hippocampal thickness and hemispheric entorhinal cortex thickness asymmetry were associated with objective memory impairment but not with subjective deficits or symptoms of depression. CONCLUSIONS: Whereas low objective memory performance and reduced cortical thickness within medial temporal lobe subregions could be associated with neurodegeneration, greater subjective memory deficits in patients with MCI may indicate psychological burden.

Efficacy of cognitive-behavioral group therapy in patients at risk for serious mental illness presenting with subthreshold bipolar symptoms: Results from a prespecified interim analysis of a multicenter, randomized, controlled study.

OBJECTIVE: Most patients with bipolar disorders (BD) exhibit prodromal symptoms before a first (hypo)manic episode. Patients with clinically significant symptoms fulfilling at-risk criteria for serious mental illness (SMI) require effective and safe treatment. Cognitive-behavioral psychotherapy (CBT) has shown promising results in early stages of BD and in patients at high risk for psychosis. We aimed to investigate whether group CBT can improve symptoms and functional deficits in young patients at risk for SMI presenting with subthreshold bipolar symptoms. METHOD: In a multicenter, randomized, controlled trial, patients at clinical risk for SMI presenting with subthreshold bipolar symptoms aged 15-30 years were randomized to 14 weeks of at-risk for BD-specific group CBT or unstructured group meetings. Primary efficacy endpoints were differences in affective symptomatology and psychosocial functioning at 14 weeks. At-risk status was defined as a combination of subthreshold bipolar symptomatology, reduction of psychosocial functioning and a family history for (schizo)affective disorders. A prespecified interim analysis was conducted at 75% of the targeted sample. RESULTS: Of 128 screened participants, 75 were randomized to group CBT (n = 38, completers = 65.8%) vs unstructured group meetings (n = 37, completers = 78.4%). Affective symptomatology and psychosocial functioning improved significantly at week 14 (P < .001) and during 6 months (P < .001) in both groups, without significant between-group differences. Findings are limited by the interim character of the analysis, the use of not fully validated early detection interviews, a newly adapted intervention manual, and the substantial drop-outs. CONCLUSIONS: Results suggest that young patients at-risk for SMI presenting with subthreshold bipolar symptoms benefit from early group sessions. The degree of specificity and psychotherapeutic interaction needed requires clarification.

Melatonin suppression by melanopsin-weighted light in patients with bipolar I disorder compared to healthy controls

Background: Multiple lines of evidence suggest that the onset and course of bipolar disorder is influenced by environmental light conditions. Increased suppression of melatonin by light (supersensitivity) in patients with bipolar disorder has been postulated as an endophenotype by several studies. However, due to methodological shortcomings, the results of these studies remain inconclusive. This study investigated melatonin suppression in euthymic patients with bipolar I disorder using evening blue light specifically targeting the melanopsin system. Methods: Melatonin suppression was assessed in euthymic patients with bipolar I disorder and healthy controls by exposure to monochromatic blue light (λmax = 475 nm; photon density = 1.6 × 1013 photons/cm2/s) for 30 minutes at 2300 h, administered via a ganzfeld dome for highly uniform light exposure. Serum melatonin concentrations were determined from serial blood sampling via radioimmunoassay. All participants received mydriatic eye drops and were genotyped for the PER3 VNTR polymorphism to avoid or adjust for potential confounding. As secondary outcomes, serum melatonin concentrations during dark conditions and after monochromatic red light exposure (λmax = 624 nm; photon density = 1.6 × 1013 photons/cm2/s) were also investigated. Changes in subjective alertness were investigated for all 3 lighting conditions. Results: A total of 90 participants (57 controls, 33 bipolar I disorder) completed the study. Melatonin suppression by monochromatic blue light did not differ between groups (F1,80 = 0.56; p = 0.46). Moreover, there were no differences in melatonin suppression by monochromatic red light (F1,82 = 1.80; p = 0.18) or differences in melatonin concentrations during dark conditions (F1,74 = 1.16; p = 0.29). Healthy controls displayed a stronger increase in subjective alertness during exposure to blue light than patients with bipolar I disorder (t85 = 2.28; p = 0.027). Limitations: Large interindividual differences in melatonin kinetics may have masked a true difference. Conclusion: Despite using a large cohort and highly controlled laboratory conditions, we found no differences in melatonin suppression between euthymic patients with bipolar I disorder and healthy controls. These findings do not support the notion that supersensitivity is a valid endophenotype in bipolar I disorder.

[Analysis of risk factors, etiology and treatment standard of lithium poisoning]. / Analyse zu Risikofaktoren, Ätiologie und Behandlungsstandard der Lithiumintoxikation.

Despite unlimited access to therapeutic drug monitoring lithium poisoning is still a common and potentially life-threatening but in most cases preventable complication of lithium treatment; however, it is still considered to be the gold standard in the treatment of affective disorders. The necessity of drug monitoring and potential lithium toxicity substantiate the skepticism of many therapists with respect to this often very effective treatment. This therefore limits the use of lithium although the unique therapeutic effects and high efficiency are well known. This retrospective data analysis of risk factors and etiology of lithium poisoning cases identified 58 cases of lithium poisoning, which were treated internally in this hospital between 2010 and 2014. Of the patients 67.2% were female and the majority were classified as chronic poisoning (66.1%). The most relevant patient-related risk factor seemed to be insufficient self-management as 26% of cases of lithium poisoning occurred during febrile infections or exsiccosis. Regarding practitioner-related risk factors, an insufficient consideration of drug interactions, insufficient therapeutic drug monitoring after dose increase and a paucity of experience and knowledge concerning lithium treatment were most relevant. This study illustrates the most important risk factors for lithium poisoning and their frequencies and contributes to raise awareness for this highly relevant topic. These data can help to prevent further cases of lithium poisoning. Furthermore, the results enable a comparison between the actual treatment reality and currently available evidence for the treatment of lithium poisoning.

Impact of cognitive reserve on clinical and neuropsychological measures in patients with mild cognitive impairment.

OBJECTIVE: Cognitive reserve influences age of onset, speed of progression, and clinical manifestations of Alzheimer's disease. We investigated whether cognitive reserve interacts with clinical and neuropsychological parameters in mild cognitive impairment (MCI). METHODS: In this cross-sectional study, we recruited 273 people (70.6 ± 10.1 years, 54.6% women) suffering from subjective memory complaints (n = 65), MCI (n = 121), or dementia (n = 87). Patients underwent neuropsychological evaluation, laboratory testing, and brain imaging. Additionally, we obtained information on years of education and help-seeking motivation. RESULTS: MCI patients with a university degree were significantly older than those without (71.6 ± 9.6 vs. 66.9 ± 10.3, p = 0.02). University-educated MCI patients demonstrated superior performance in verbal fluency. Intrinsic help-seeking motivation (self-referral) was associated with higher cognitive reserve. Female MCI patients presented with greater intrinsic motivation. CONCLUSION: Cognitive reserve modulates clinical and neuropsychological measures in patients with MCI.

A Novel Study Design to Systematically Explore the Impact of Trial Methodology on Psychopharmacological Treatment Outcome in Patients with Depression.

INTRODUCTION: Randomized, double-blind, placebo-controlled trials were developed to draw rather unbiased conclusions regarding the efficacy of antidepressants in the treatment of a major depressive episode (internal validity), mostly with the purpose of formal approval of new compounds in this indication. However, at the same time, data suggest that the very process of randomization and blinded administrations of placebo will have a significant impact on the efficacy of the antidepressant tested and therefore may limit the external validity of results obtained from this type of studies. Therefore, there is an urgent need to systematically study the impact of randomization/placebo control/blinding on patient population, efficacy, tolerability, and external validity in the psychopharmacological treatment of patients with a major depressive episode. METHODS: To develop a study design that allows the systematic exploration of the impact of trial design on characteristics of included patient population and outcome. RESULTS: We propose a study design including sample size calculation and statistical analysis in which patients with a major depressive episode are randomized to 3 distinct study designs that differ with regard to control, randomization, and blindness. DISCUSSION: The results of the proposed study design may have substantial consequences when it comes to how to best interpret the results of traditional randomized, double-blind, placebo-controlled trials in the acute treatment of major depressive disorder. Furthermore, they may lead to the implementation of new study designs that may be more suitable for assessing the effectiveness of new antidepressant compounds in everyday clinical practice.

[Folic acid and vitamin B12 determination in the assessment of cognitive disorders : Overview and data analysis from a university outpatient memory clinic]. / Folsäure- und Vitamin-B12-Bestimmung in der Diagnostik kognitiver Störungen : Übersicht und Datenanalyse einer universitären Gedächtnisambulanz.

Vitamin B12 and folic acid deficiencies are particularly frequent conditions in older people. Since these metabolic disorders represent relevant dyscognitive factors, the assessment of vitamin B12 and folic acid levels is essential in the diagnostic approach of cognitive disorders, such as mild cognitive impairment and dementia in an outpatient memory clinic. This article summarizes the relevant diagnostic and therapeutic aspects of vitamin B12 and folic acid deficiencies and their effects on cognition. The literature review is supplemented by a data analysis of a naturalistic cohort of 250 patients from this outpatient memory clinic.

Personality differences in early versus late suicide attempters.

BACKGROUND: Suicidality is an individual behaviour caused by a complex framework of internal and external factors. The predictive values of personality traits for a suicide attempt have been demonstrated, especially in conjunction with Cloninger's TCI and impulsivity. Two issues remain unsolved, namely whether these traits alter over time after a suicide attempt, and how they may be influenced by depressive symptoms. METHODS: We studied two patient cohorts: one sample of 81 patients after a suicide attempt no longer than 3 months previously (SA early) and another sample of 32 patients whose attempt had taken place more than 6 months previously (SA late). We carried out structured interviews with these subjects addressing diagnosis (MINI), suicidality (Scale for suicide ideation), depression (HAMD-17), temperament and character inventory (TCI), and impulsivity (BIS-10). Data analysis was done using SPSS 16.0. RESULTS: Our two groups did not differ significantly in sociodemographics or suicidality. However, patients in the SA early group were significantly more depressed (p < 0.001), and scored lower in reward dependence (p < 0.001) and persistence (p = 0.005) but higher in harm avoidance (p < 0.001); they did not differ significantly in impulsivity (p < 0.01). Reward dependence, persistence, and harm avoidance remained significantly different between the two groups after controlling for depressive symptoms. CONCLUSIONS: Our findings suggest that some personality traits vary after a suicide attempt. Further investigations are necessary to verify our results, ideally in longitudinal studies with larger, carefully-described cohorts. It would be also clinically important to investigate the influence of therapeutic strategies on the variability of personality traits and their impact on suicidal behavior.

Young people at risk for developing bipolar disorder: Two-year findings from the multicenter prospective, naturalistic Early-BipoLife study.

Early identification and intervention of individuals with an increased risk for bipolar disorder (BD) may improve the course of illness and prevent long­term consequences. Early-BipoLife, a multicenter, prospective, naturalistic study, examined risk factors of BD beyond family history in participants aged 15-35 years. At baseline, positively screened help-seeking participants (screenBD at-risk) were recruited at Early Detection Centers and in- and outpatient depression and attention-deficit/hyperactivity disorder (ADHD) settings, references (Ref) drawn from a representative cohort. Participants reported sociodemographics and medical history and were repeatedly examined regarding psychopathology and the course of risk factors. N = 1,083 screenBD at-risk and n = 172 Ref were eligible for baseline assessment. Within the first two years, n = 31 screenBD at-risk (2.9 %) and none of Ref developed a manifest BD. The cumulative transition risk was 0.0028 at the end of multistep assessment, 0.0169 at 12 and 0.0317 at 24 months (p = 0.021). The transition rate with a BD family history was 6.0 %, 4.7 % in the Early Phase Inventory for bipolar disorders (EPIbipolar), 6.6 % in the Bipolar Prodrome Interview and Symptom Scale-Prospective (BPSS-FP) and 3.2 % with extended Bipolar At-Risk - BARS criteria). In comparison to help-seeking young patients from psychosis detection services, transition rates in screenBD at-risk participants were lower. The findings of Early-BipoLife underscore the importance of considering risk factors beyond family history in order to improved early detection and interventions to prevent/ameliorate related impairment in the course of BD. Large long-term cohort studies are crucial to understand the developmental pathways and long-term course of BD, especially in people at- risk.

Using naltrexone to validate a human laboratory test system to screen new medications for alcoholism (TESMA)- a randomized clinical trial.

This registered clinical trial sought to validate a laboratory test system devised to screen medications for alcoholism treatment (TESMA) under different contingencies of alcohol reinforcement. Forty-six nondependent, but at least medium-risk drinkers were given the opportunity to earn intravenous infusions of ethanol, or saline, as rewards for work in a progressive-ratio paradigm. Work demand pattern and alcohol exposure dynamics were devised to achieve a gradual shift from low-demand work for alcohol (WFA) permitting quickly increasing breath alcohol concentrations (BrAC) to high-demand WFA, which could only decelerate an inevitable decrease of the previously earned BrAC. Thereby, the reward contingency changed, modeling different drinking motivations. The experiment was repeated after at least 7 days of randomized, double-blinded treatment with naltrexone, escalated to 50 mg/d, or placebo. Subjects treated with naltrexone reduced their cumulative WFA (cWFA) slightly more than participants receiving placebo. This difference was not statistically significant in the preplanned analysis of the entire 150 min of self-administration, i.e., our primary endpoint (p = 0.471, Cohen's d = 0.215). Naltrexone serum levels correlated with change in cWFA (r = -0.53; p = 0.014). Separate exploratory analyses revealed that naltrexone significantly reduced WFA during the first, but not the second half of the experiment (Cohen's d = 0.643 and 0.14, respectively). Phase-dependent associations of WFA with changes in subjective stimulation, wellbeing and desire for alcohol suggested that the predominant reinforcement of WFA was positive during the first phase only, and might have been negative during the second. We conclude that the TESMA is a safe and practical method. It bears the potential to quickly and efficiently screen new drugs for their efficacy to attenuate positively reinforced alcohol consumption. It possibly also provides a condition of negative reinforcement, and for the first time provides experimental evidence suggesting that naltrexone's effect might depend on reward contingency.

Machine Learning Prediction of Estimated Risk for Bipolar Disorders Using Hippocampal Subfield and Amygdala Nuclei Volumes.

The pathophysiology of bipolar disorder (BD) remains mostly unclear. Yet, a valid biomarker is necessary to improve upon the early detection of this serious disorder. Patients with manifest BD display reduced volumes of the hippocampal subfields and amygdala nuclei. In this pre-registered analysis, we used structural MRI (n = 271, 7 sites) to compare volumes of hippocampus, amygdala and their subfields/nuclei between help-seeking subjects divided into risk groups for BD as estimated by BPSS-P, BARS and EPIbipolar. We performed between-group comparisons using linear mixed effects models for all three risk assessment tools. Additionally, we aimed to differentiate the risk groups using a linear support vector machine. We found no significant volume differences between the risk groups for all limbic structures during the main analysis. However, the SVM could still classify subjects at risk according to BPSS-P criteria with a balanced accuracy of 66.90% (95% CI 59.2-74.6) for 10-fold cross-validation and 61.9% (95% CI 52.0-71.9) for leave-one-site-out. Structural alterations of the hippocampus and amygdala may not be as pronounced in young people at risk; nonetheless, machine learning can predict the estimated risk for BD above chance. This suggests that neural changes may not merely be a consequence of BD and may have prognostic clinical value.

Supersensitivity of Patients With Bipolar I Disorder to Light-Induced Phase Delay by Narrow Bandwidth Blue Light.

Background: Bipolar disorder is a severe chronic mental disorder. There is a bidirectional relationship between disease course and circadian phase. Significant circadian phase shifts occur during transitions between episodes, but episodes can also be elicited during euthymia by forced rapid changes in circadian phase. Although an instability of circadian phase has been described in multiple observational reports, no studies quantifying the propensity to phase shift following an experimental standardized stimulus have been published. This study therefore aimed to assess whether patients with bipolar I disorder (BDI) are more prone to phase delay following blue light exposure in the evening than healthy control subjects. Methods: Euthymic participants with BDI confirmed by Structured Clinical Interview for DSM-IV Axis I (n = 32) and healthy control subjects (n = 55) underwent a 3-day phase shift protocol involving exposure to a standardized dose of homogeneous, constant, narrow bandwidth blue light (478 nm, half bandwidth = 18 nm, photon flux = 1.29 × 1015 photons/cm2/s) for 2 hours at 9:00 pm via a ganzfeld dome on day 2. On days 1 and 3, serial serum melatonin assessments during total darkness were performed to determine the dim light melatonin onset. Results: Significant differences in the light-induced phase shift between BDI and healthy control subjects were detected (F 1,82 = 4.110; p = .046), with patients with bipolar disorder exhibiting an enhanced phase delay (η2 = 0.49). There were no significant associations between the magnitude of the phase shift and clinical parameters. Conclusions: Supersensitivity of patients with BDI to light-induced phase delay may contribute to the observed phase instability and vulnerability to forced phase shifts associated with the disorder.

Integrated Care for Pregnant Women and Parents With Methamphetamine-Related Mental Disorders.

Background: Methamphetamine use is a rapidly increasing cause of morbidity and mortality. Pregnant women and new parents who consume methamphetamine are at high risk since they seldom seek health services despite having multiple needs. We addressed this care gap by implementing an easily accessible program that pools resources from psychiatric, obstetric, and pediatric departments as well as community and government agencies. Method: This real-life observational study evaluated an integrated care program in 27 expecting parents and 57 parents of minors. The outcome criteria were treatment retention, psychosocial functioning, and abstinence. We compared participant demographics according to outcome and applied ordinal logistic regression to predict treatment success. Results: Patients received integrated care for almost 7 months on average. Nearly half achieved stable abstinence and functional recovery. Only one pregnant woman dropped out before a care plan could be implemented, and all women who gave birth during treatment completed it successfully. Three-fourths of patients had psychiatric comorbidities. Patients with depressive disorders were almost 5 times less likely to succeed with treatment. Attention-deficit hyperactivity disorder (ADHD) was diagnosed in nearly 30% of patients who dropped out of a care plan, which was about 4 times more often than in the successful outcome group. Conclusion: Our program engaged pregnant women and parents in treatment and helped them recover from methamphetamine-related mental disorders. Management of comorbid ADHD and depression should be an integral part of care initiatives to counter the methamphetamine crisis that affects parents and children across the globe.

Cardiovascular Effects of Combining Subcutaneous or Intravenous Esketamine and the MAO Inhibitor Tranylcypromine for the Treatment of Depression: A Retrospective Cohort Study.

BACKGROUND: (Es)ketamine and monoamine oxidase inhibitors (MAOIs), e.g., tranylcypromine, are therapeutic options for treatment-resistant major depression. Simultaneous administration is currently not recommended because of concern about hypertensive crises. OBJECTIVE: Our objective was to evaluate whether changes in systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) during esketamine administration differed between patients who concomitantly received tranylcypromine and those who did not. METHODS: This was a retrospective cohort study utilizing cardiovascular monitoring data from inpatients treated for severe depression in unipolar, bipolar, and schizoaffective disorder. Primary outcomes were change in mean BP and HR during the first hour after intravenous or subcutaneous esketamine administration compared with baseline, controlled for confounders. Secondary analyses quantify differences in absolute BP during esketamine treatment and comparisons of BP peaks, temporal effects, and intraindividual comparisons before and after tranylcypromine initiation. RESULTS: Our analysis included 509 esketamine administrations in 43 patients, 14 of whom concomitantly received tranylcypromine. Controlling for creatinine and age, mean ± standard deviation (SD) BP changes were significantly increased by concomitant tranylcypromine treatment (ΔSBP: F[1,503] = 86.73, p < 0.001; ΔDBP: F[1,503] = 55.71, p < 0.001), but HR remained unaffected. Mean SBP change during esketamine administration was 2.96 ± 18.11 mmHg in patients receiving tranylcypromine (TCP+) and -8.84 ± 11.31 mmHg in those who did not (TCP-). Changes in DBP were -2.81 ± 11.20 mmHg for TCP+ and -10.77 ± 9.13 mmHg for TCP-. Moreover, we found a significant dose-response relationship between tranylcypromine dose and BP (SBP: B = 0.35, standard error [SE] = 0.12, 95% confidence interval [CI] 0.12-0.60, p = 0.004; adjusted R2 = 0.11, p = 0.008; DBP: B = 0.21, SE = 0.08, 95% CI 0.06-0.36, p = 0.007; adjusted R2 = 0.08; p = 0.023). CONCLUSIONS: Although statistically significant changes in BP were identified in patients receiving tranylcypromine and esketamine, these changes were clinically insignificant. Thus, combining esketamine and this MAOI appears to be safe at standard doses. The dose-response relationship calls for caution with higher doses of tranylcypromine.

Individuals at increased risk for development of bipolar disorder display structural alterations similar to people with manifest disease.

In psychiatry, there has been a growing focus on identifying at-risk populations. For schizophrenia, these efforts have led to the development of early recognition and intervention measures. Despite a similar disease burden, the populations at risk of bipolar disorder have not been sufficiently characterized. Within the BipoLife consortium, we used magnetic resonance imaging (MRI) data from a multicenter study to assess structural gray matter alterations in N = 263 help-seeking individuals from seven study sites. We defined the risk using the EPIbipolar assessment tool as no-risk, low-risk, and high-risk and used a region-of-interest approach (ROI) based on the results of two large-scale multicenter studies of bipolar disorder by the ENIGMA working group. We detected significant differences in the thickness of the left pars opercularis (Cohen's d = 0.47, p = 0.024) between groups. The cortex was significantly thinner in high-risk individuals compared to those in the no-risk group (p = 0.011). We detected no differences in the hippocampal volume. Exploratory analyses revealed no significant differences in other cortical or subcortical regions. The thinner cortex in help-seeking individuals at risk of bipolar disorder is in line with previous findings in patients with the established disorder and corresponds to the region of the highest effect size in the ENIGMA study of cortical alterations. Structural alterations in prefrontal cortex might be a trait marker of bipolar risk. This is the largest structural MRI study of help-seeking individuals at increased risk of bipolar disorder.

Urothelial toxicity of esketamine in the treatment of depression.

RATIONALE: Ketamine is the first widely used substance with rapid-onset antidepressant action. However, there are uncertainties regarding its potential urothelial toxicity, particularly after repeated application. In the context of rising recreational ketamine use, severe side effects affecting the human urinary tract have been reported. It is assumed that ketamine interacts with bladder urothelial cells and induces apoptosis. OBJECTIVES: This study aimed to assess whether single or repeated doses of esketamine used in an antidepressant indication are associated with urinary toxicity. METHODS: We included male and female inpatients with a current episode of depression and a diagnosis of recurrent depressive disorder, bipolar disorder or schizoaffective disorder according to ICD-10 criteria (n = 25). The esketamine treatment schedule involved a maximum of 3× weekly dosing at 0.25-0.5 mg/kg i.v. or s.c. The primary outcome was the change in urine toxicity markers (leukocytes, erythrocytes, protein and free haemoglobin). Description of demographic, clinical and laboratory data was conducted using means, standard deviations, frequencies and percentages. Changes in urinary toxicity markers over time were evaluated using linear mixed models with gender as a covariate. RESULTS: The participants received an average of 11.4 (SD 8) esketamine treatments, and an average number of 11.2 (SD 8) urine samples were analysed over the course of treatment. Neither urinary leukocyte concentration (F(20; 3.0) = 3.1; p = 0.2) nor erythrocyte concentration (F(20;2.2) = 4.1; p = 0.2) showed a significant trend towards increase during the course of esketamine treatment. Similarly, free haemoglobin and protein concentrations, which were analysed descriptively, did not display a rise during treatment. There was a significant improvement in depression ratings after esketamine treatment (p < 0.001). CONCLUSIONS: This study is, to the best of our knowledge, the first to focus on urothelial toxicity of esketamine used in antidepressant indication and dose. The results indicate that the use of single or repeated doses of esketamine is unlikely to cause urothelial toxicity. The results are in need of confirmation as sample size was small.