Copeptin response to panic provocation with CO2 in healthy adults.

Repeated panic attacks are the core symptom of panic disorder and severely stressful for patients. Additional to the psychological response, the physiological symptoms are an important aspect of the experienced panic. However, data on the extent of hypothalamic-pituitary-adrenal (HPA)-axis activation during panic attacks is inconsistent. Therefore, in the present study, we aimed at investigating the stress-axis activity in more detail by including Copeptin (CoP) as a stable surrogate parameter for the vasopressinergic hypothalamic activity during experimentally induced panic attacks in healthy adults (N = 21). During a placebo-controlled panic challenge with 35% CO2 compared to normal air inhalation, we measured CoP and the peripheral effector hormones Adrenocorticotropic Releasing Hormone (ACTH) and cortisol in plasma along with the psychological response to panic anxiety. We analyzed hormonal secretion patterns, their correlations and individual panic ratings over time and explored differences between female and male participants. We found a significant CO2-induced increase of CoP plasma levels and psychological panic symptoms after CO2-administration, while no positive correlations of CoP levels with the peripheral HPA-axis hormones and with panic symptoms were present. No differences between female and male participants concerning their psychological response nor their baseline CoP levels, the release of CoP or its increase during the experiment were found. CoP could be a sensitive indicator for an organism's physiologic acute hypothalamic response during stress and panic attacks.

Improvement of functioning in patients with schizophrenia: real-world effectiveness of aripiprazole once-monthly (REACT study).

BACKGROUND: Functional impairment affects many patients with schizophrenia. Treatment with the long-acting injectable antipsychotic aripiprazole once-monthly (AOM) may help improve functioning. OBJECTIVES: To explore changes in functioning in patients with schizophrenia who received AOM treatment in observational studies. METHODS: Here we report functional outcomes in the form of Global Assessment of Functioning (GAF) scores in a pooled analysis of data from two observational studies from Canada (NCT02131415) and Germany (vfa non-interventional studies registry 15960N). Data from 396 patients were analyzed. RESULTS: At baseline, the mean GAF score was 47.7 (SD 13.4). During 6 months of treatment with AOM, the mean GAF score increased to 59.4 (SD 15.8). Subgroups stratified by patient age (≤35 years/>35 years), sex, disease duration (≤5 years/>5 years) and disease severity at baseline had all significantly improved their GAF at month 6. 51.5% of the patients showed a GAF score increase of at least 10 points, which was regarded as clinically meaningful, and were considered responders. CONCLUSIONS: These data show that treatment with AOM may help improve patient functioning in a routine treatment setting. TRIAL REGISTRATION: NCT02131415 (May 6, 2014), vfa non-interventional studies registry 15960N.

Morning salivary dehydroepiandrosterone (DHEA) qualifies as the only neuroendocrine biomarker separating depressed patients with and without prior history of depression: An HPA axis challenge study.

BACKGROUND: Hypothalamic-pituitary-adrenal (HPA) axis abnormalities in major depression (MDD) have been consistently reported in psychiatry and extend to several neurosteroids. However, recurrence and chronicity may heavily influence HPA axis dynamics in MDD along its course and also explain conflicting results in literature. Thus, the mechanistic understanding of HPA axis (re)activity changes over time could be of major importance for unravelling the dynamic pathophysiology of MDD. METHODS: This study simultaneously assessed several baseline and dynamic HPA-axis-related endocrine biomarkers in both saliva (dehydroepiandrosterone, DHEA; sulfated DHEA, DHEA-s; cortisol, CORT) and plasma (CORT; adrenocorticotropic hormone, ACTH; copeptin, CoP) over three consecutive days using overnight HPA axis stimulation (metyrapone) and suppression (dexamethasone) challenges in order to investigate differences between antidepressant-free MDD patients (n = 14) with and without history of prior depressive episodes (i.e., first vs. recurrent episode). RESULTS: Our results suggest group differences only with respect to saliva DHEA levels, with recurrent-episode MDD patients showing overall lower saliva DHEA levels across the three days, and statistically significant differences mainly at day 1 (baseline) across all three timepoints (awakening, +30 min, +60 min), even after adjustment for confounders. CONCLUSIONS: Our study supports that salivary DHEA levels could represent a significant biomarker of MDD progression and individual stress resilience. DHEA deserves additional attention in the research of pathophysiology, staging and individualized treatment of MDD. Prospective longitudinal studies are needed to evaluate HPA axis reactivity along MDD course and progression to better understand temporal effects on stress-system-related alterations, related phenotypes and appropriate treatment.

BPRS domains, items and subgroups analyses, and CGI-I ratings in pooled data from non-interventional studies of aripiprazole once-monthly in schizophrenia (REACT study).

BACKGROUND: Patients with schizophrenia may benefit from treatment with long-acting injectable (LAI) formulations of antipsychotics. Aripiprazole once-monthly (AOM) is an LAI that was tested in two non-interventional studies in Germany and Canada. METHODS: Here, we report on analyses of pooled data from the two non-interventional studies. Patients were treated with AOM under real-life conditions. Data were analyzed for a timeframe of 6 months. We analyzed data on Brief Psychiatric Rating Scale (BPRS) domains and items, BPRS total scores in various patient subgroups (male vs. female patients, patients with disease duration ≤ 5 years and > 5 years, patients with different levels of disease severity at baseline), Clinical Global Impression - Improvement (CGI-I) ratings for the total population and subgroups, and comorbidities for the total population. RESULTS: Data from 409 patients were included. 65.5% of the patients had comorbidities. Improvements were found in all BPRS domains and items. Furthermore, improvements were similar for male and female patients, patients with disease duration ≤ 5 years and > 5 years, and across different levels of disease severity at baseline. Numerically, more favorable results were found for younger patients, female patients, and those with shorter disease duration. CONCLUSIONS: AOM can be an effective treatment in the broad range of patients, across sexes, regardless of patient age and duration of disease, independently of disease severity, and across symptoms. TRIAL REGISTRATION: NCT02131415 (May 6, 2014), vfa non-interventional studies registry 15960N.

Disentangling the roles of dopamine and noradrenaline in the exploration-exploitation tradeoff during human decision-making.

Balancing the exploration of new options and the exploitation of known options is a fundamental challenge in decision-making, yet the mechanisms involved in this balance are not fully understood. Here, we aimed to elucidate the distinct roles of dopamine and noradrenaline in the exploration-exploitation tradeoff during human choice. To this end, we used a double-blind, placebo-controlled design in which participants received either a placebo, 400 mg of the D2/D3 receptor antagonist amisulpride, or 40 mg of the ß-adrenergic receptor antagonist propranolol before they completed a virtual patch-foraging task probing exploration and exploitation. We systematically varied the rewards associated with choice options, the rate by which rewards decreased over time, and the opportunity costs it took to switch to the next option to disentangle the contributions of dopamine and noradrenaline to specific choice aspects. Our data show that amisulpride increased the sensitivity to all of these three critical choice features, whereas propranolol was associated with a reduced tendency to use value information. Our findings provide novel insights into the specific roles of dopamine and noradrenaline in the regulation of human choice behavior, suggesting a critical involvement of dopamine in directed exploration and a role of noradrenaline in more random exploration.

Real-world effectiveness of aripiprazole once-monthly REACT study: Pooled analysis of two noninterventional studies.

BACKGROUND: Noninterventional naturalistic studies are an important complement to randomized controlled trials. Aripiprazole once-monthly (AOM) is an atypical antipsychotic in a long-acting injectable formulation. METHODS: A pooled analysis of two noninterventional studies was undertaken to validate previous results on AOM effectiveness and safety in a larger population and improve statistical power for preplanned subgroup analyses. We analyzed data from 409 patients with schizophrenia who were treated with AOM and were enrolled in noninterventional studies in Germany (via noninterventional studies registry 15,960 N) and Canada (NCT02131415). Data collected at baseline, 3 and 6 months were analyzed. Among the endpoints were psychopathology (brief psychiatric rating scale [BPRS]) and disease severity (clinical global impression [CGI]). RESULTS: Mean patient age was 38.9 (SD 14.8) years, and 59.9% were male. BPRS decreased from 48.1 (SD 15.6) at baseline to 36.5 (SD 13.7) at month 6 (p < 0.001). CGI decreased from 4.47 (SD 0.90) at baseline to 3.64 (SD 1.16) at month 6 (p < 0.001). A total of 54.4% were responders (at least 20% reduction) on the BPRS, and 56.5% had a CGI-S-score that was at least 1 level better than baseline. A total of 43.4% were considered responders on both the BPRS and CGI scales. A total of 45.2% were considered in remission. Adverse events were rare and corresponded to the previously known safety profile of AOM. CONCLUSIONS: Treatment with AOM for patients with schizophrenia appeared effective and safe under real-life conditions.

Immune signature of multiple sclerosis-associated depression.

Multiple neurobiological pathways have been implicated in the pathobiology of major depressive disorder (MDD). The identification of reliable biological substrates across the entire MDD spectrum, however, is hampered by a vast heterogeneity in the clinical presentation, presumably as a consequence of heterogeneous pathobiology. One way to overcome this limitation could be to explore disease subtypes based on biological similarity such as "inflammatory depression". As such a subtype may be particularly enriched in depressed patients with an underlying inflammatory condition, multiple sclerosis (MS) could provide an informative disease context for this approach. Few studies have explored immune markers of MS-associated depression and replications are missing. To address this, we analyzed data from two independent case-control studies on immune signatures of MS-associated depression, conducted at two different academic MS centers (overall sample size of n = 132). Using a stepwise data-driven approach, we identified CD4+CCR7lowTCM cell frequencies as a robust correlate of depression in MS. This signature was associated with core symptoms of depression and depression severity (but not MS severity per se) and linked to neuroinflammation as determined by magnetic resonance imaging (MRI). Furthermore, exploratory analyses of T cell polarization revealed this was largely driven by cells with a TH1-like phenotype. Our findings suggest (neuro)immune pathways linked to affective symptoms of autoimmune disorders such as MS, with potential relevance for the understanding of "inflammatory" subtypes of depression.

Atrial natriuretic peptide (ANP) as an endogenous anxiolytic in patients with heart failure? - No replication of previous results showing an inverse association of anxiety and plasma ANP parameters.

OBJECTIVE: An acute anxiolytic-like effect of atrial natriuretic peptide (ANP) has been demonstrated in several preclinical and clinical studies. In a so far singular study (Herrmann-Lingen et al., 2003), patients with congestive heart failure, who pathognomonicly display increased plasma ANP, showed a significant inverse association of anxiety symptoms and pro-ANP levels, giving rise to speculations about ANP as an endogenous anxiolytic. We tried to replicate and extend this preliminary finding. METHODS: In 56 patients suffering from heart failure with reduced left ventricular ejection fraction we measured ANP, mid-regional pro-ANP (MR-proANP) and cyclic guanosine monophosphate (cGMP) as plasma parameters of ANP functioning and characterized anxiety symptoms using the Hospital Anxiety and Depression Scale (HADS) and in addition the State Trait Anxiety Inventory (STAI) for state anxiety. Spearman rank correlation coefficients were calculated. RESULTS: None of our plasma ANP parameters showed a significant association with anxiety symptoms as per HADS ratings. The same picture emerged with STAI state anxiety. ANP, MR-proANP and cGMP significantly correlated with each other. CONCLUSION: In another sample of patients with heart failure we were unable to replicate previous and preliminary cross-sectional findings of low anxiety in subjects with high plasma pro-ANP. Direct measurement of effector hormone ANP and its second messenger as well did not support our hypothesis. Chronically elevated ANP in heart failure might attenuate its potential anxiolytic effects. Longitudinal studies experimentally increasing ANP levels in anxious heart failure patients are needed to test if this approach has clinical psychotropic utility.

Autoantibody-associated psychiatric syndromes in children: link to adult psychiatry.

Studies show that psychiatric symptoms in adults and children are sometimes associated with serum neural autoantibodies. The significance of serum neural autoantibodies associated with psychiatric symptoms in children remains often unclear, but might be relevant for the extent and occurrence of psychiatric disease manifestation in later life, as well as therapy and outcome. For this narrative review, we sought articles listed in PubMed and published between 1988 and 2020 addressing the maternal-fetal transfer of neural autoantibodies and psychiatric disorders associated with serum neural autoantibodies. We identified six major subgroups of psychiatric disorders in children that are associated with serum neural autoantibodies: patients with attentional deficit hyperactivity disorder, autism spectrum disorder, obsessive compulsive disorder, Gilles de la Tourette syndrome, psychosis and catatonia. Furthermore, we summarized study findings from maternal-fetal transfer of Contactin-associated protein-like 2, N-methyl-D-aspartate receptor and fetal brain autoantibodies associated with behavioral effects in animals and humans. We hypothesize that the maternal transfer of serum neuronal autoantibodies during or after birth could result (1) in the ignition of an autoimmune-mediated inflammation having neurodevelopmental consequences for their children (autoimmune-priming-attack hypothesis) and (2) has a potential impact on the later manifestation of psychiatric disorders. Through this narrative review, we propose a diagnostic pathway for the clinical diagnosis of a potentially autoimmune origin of psychiatric symptoms in children while considering recent guidelines.

Acute stress leaves fear generalization in healthy individuals intact.

Because threatening situations often occur in a similar manner, the generalization of fear to similar situations is adaptive and can avoid harm to the organism. However, the overgeneralization of fear to harmless stimuli is maladaptive and assumed to contribute to anxiety disorders. Thus, elucidating factors that may modulate fear (over)generalization is important. Based on the known effects of acute stress on learning, which are at least partly due to noradrenergic arousal, we investigated whether stress may promote fear overgeneralization and whether we could counteract this effect by reducing noradrenergic arousal. In a placebo-controlled, double-blind, between-subjects design, 120 healthy participants underwent a fear-conditioning procedure on Day 1. Approximately 24 hours later, participants received orally either a placebo or the beta-adrenergic receptor antagonist propranolol and were exposed to a stress or control manipulation before they completed a test of fear generalization. Skin conductance responses as well as explicit rating data showed a successful acquisition of conditioned fear on Day 1 and a pronounced fear generalization 24 hours later. Although physiological data confirmed the successful stress manipulation and reduction of noradrenergic arousal, the extent of fear generalization remained unaffected by stress and propranolol. The absence of a stress effect on fear generalization was confirmed by a second study and a Bayesian analysis across both data sets. Our findings suggest that acute stress leaves fear generalization processes intact, at least in a sample of healthy, young individuals.

BDNF influences neural cue-reactivity to food stimuli and food craving in obesity.

There is increasing evidence that brain-derived neurotrophic factor (BDNF) impacts on the development of obesity. We are the first to test the hypothesis that BDNF levels might be associated with neural reactivity to food cues in patients suffering from obesity and healthy controls. We assessed visual food cue-induced neural response in 19 obese patients and 20 matched controls using functional magnetic resonance imaging and analyzed the associations between BDNF levels, food cue-reactivity and food craving. Whole-brain analysis in both groups revealed that food cues elicited higher neural activation in clusters of mesolimbic brain areas including the insula (food > neutral). Patients suffering from obesity showed a significant positive correlation between plasma BDNF levels and visual food cue-reactivity in the bilateral insulae. In addition, patients suffering from obesity with positive food cue-induced insula activation also reported significantly higher food craving than those with low cue-reactivity-an effect that was absent in normal weight participants. The present findings implicate that BDNF levels in patients suffering from obesity might be involved in food craving and obesity in humans. This highlights the importance to consider BDNF pathways when investigating obesity and obesity treatment.

Noradrenergic stimulation increases fear memory expression.

Fear responses are typically not limited to the actual threatening stimulus but generalize to other stimuli resembling the threatening stimulus. Although this fear generalization is generally adaptive, fear overgeneralization is maladaptive and assumed to contribute to anxiety disorders. Despite the clinical relevance of fear (over)generalization, how the extent of fear generalization is modulated remains not well understood. Based on the known effects of stress on learning and memory, we tested here the impact of major stress mediators, glucocorticoids and noradrenergic arousal, on fear generalization. In a laboratory-based, placebo-controlled, double-blind, between-subject design, 125 healthy participants first underwent a fear conditioning procedure. About 24 h later, participants received orally either a placebo, hydrocortisone, the α2-adrenoceptor antagonist yohimbine, leading to increased noradrenergic stimulation, or both drugs before a test of fear generalization. Skin conductance responses as well as explicit rating data revealed that yohimbine intake led to enhanced fear memory expression, i.e. an enhanced responding to the CS+ but not to stimuli resembling the CS+. Moreover, neither enhanced safety learning nor a mere enhancement of perceptual discrimination ability could explain this result. In contrast to yohimbine, hydrocortisone had no significant effect on fear memory. These findings suggest that noradrenergic arousal strengthens fear memory expression and have important implications for mental disorders in which the overgeneralization of conditioned fear is prominent.

No association between major depression with and without childhood adversity and the stress hormone copeptin.

Background: Adverse childhood experiences (ACE) are associated with an increased risk of major depressive disorder (MDD) and hypothalamic-pituitary-adrenal (HPA) axis dysregulation. Within the HPA axis, corticotropin-releasing hormone and vasopressin (AVP) synergistically stimulate the release of adrenocorticotropic hormone, which promotes cortisol release. The cleavage product copeptin is produced during AVP synthesis and is a surrogate marker of AVP release. Children with ACE and young adults with depressive symptoms have higher levels of copeptin than healthy controls. Objective: To uncover the effects of MDD and ACE on copeptin levels in adult females. Methods: We recruited 94 women (mean age: 34.0 ± 3.6 years): 23 with MDD and ACE, 24 with MDD without ACE, 22 with ACE without MDD, and 25 healthy controls. ACE was defined as repeated sexual or physical abuse at least once a month over at least one year before the age of 18 years. MDD was defined by the DSM-IV criteria. Copeptin plasma levels were measured with an immunoluminometric assay. Results: The four groups did not differ in demographic variables. We found a significant negative correlation between body mass index (BMI) and copeptin plasma levels (r = -.21; p = .045). Copeptin plasma levels did not differ between the four groups after controlling for BMI. Conclusion: Neither MDD nor ACE was associated with altered plasma copeptin levels. Thus, copeptin does not seem to play a major role in MDD and ACE in adult females.

Antecedentes: Las experiencias adversas de la infancia (EAI) se asocian con un mayor riesgo de trastorno depresivo mayor (TDM) y desregulación del eje hipotalámico-pituitario-adrenal (HPA). Dentro del eje HPA, la hormona liberadora de corticotropina y la vasopresina (AVP) estimulan sinérgicamente la liberación de la hormona adrenocorticotrópica, que promueve la liberación de cortisol. El producto de escisión copeptina se produce durante la síntesis de AVP y es un marcador sustituto de la liberación de AVP. Los niños con EAI y los adultos jóvenes con síntomas depresivos tienen niveles más altos de copeptina que los controles sanos.Objetivo: Descubrir los efectos del TDM y la EAI en los niveles de copeptina en mujeres adultas.Métodos: Se reclutaron 94 mujeres (edad media: 34,0 ± 3,6 años): 23 con TDM y EAI, 24 con TDM sin EAI, 22 con EAI sin TDM y 25 controles sanos. La EAI se definió como abuso sexual o físico repetido al menos una vez al mes durante al menos un año antes de los 18 años. El TDM fue definido por los criterios del DSM-IV. Los niveles plasmáticos de copeptina se midieron con un ensayo inmunoluminométrico.Resultados: Los cuatro grupos no difirieron en las variables demográficas. Encontramos una correlación negativa significativa entre el índice de masa corporal (IMC) y los niveles plasmáticos de copeptina (r = −.21; p = .045). Los niveles plasmáticos de copeptina no difirieron entre los cuatro grupos después de controlar el IMC.Conclusión: Ni el TDM ni la EAI se asociaron con niveles alterados de copeptina plasmática. Por tanto, la copeptina no parece desempeñar un papel importante en el TDM y la EAI en mujeres adultas.

Stress-induced modulation of multiple memory systems during retrieval requires noradrenergic arousal.

Stress has been shown to favor dorsal striatum-dependent 'habit' memory over hippocampus-dependent 'cognitive' memory during learning. Here, we investigated whether stress may modulate the engagement of these 'cognitive' and 'habit' systems also during memory retrieval and if so, whether such a stress-induced shift in the control of memory retrieval depends on noradrenergic activation. To this end, participants acquired a probabilistic classification learning (PCL) task that can be solved by both the 'cognitive' and the 'habit' system, reflected in the distinct behavioral strategies. Twenty-four hours later, participants received either the beta-adrenergic receptor antagonist propranolol or a placebo before they underwent a psychosocial stressor or a non-stressful control manipulation, followed by a retrieval version of the PCL task. Overall, participants showed a practice-dependent shift from 'cognitive' to 'habit' memory. Stressed participants that had received a placebo fell back to a 'cognitive' strategy during retrieval, which was linked to an impairment in retrieval performance. Propranolol blocked this stress-induced shift towards the less efficient strategy. Moreover, our results showed that salivary cortisol was related to the retrieval strategy only when paralleled by increased autonomic arousal. Together, these results indicate that stress effects on the modulation of multiple memory system during retrieval necessitate noradrenergic arousal, with relevant implications for retrieval performance under stress.

Cortisol, DHEA and DHEA-S during exposure therapy in patients with obsessive-compulsive disorder - secretion patterns and prediction of treatment response.

The cortisol response in patients with obsessive-compulsive disorder (OCD) during exposure with response prevention (ERP), a stressful but very effective psychotherapeutic treatment, has shown contradictory findings in three prior studies with low sample sizes. In a larger cohort of 51 patients with OCD we repeatedly measured subjective units of distress (SUD) and the adrenocortical stress hormones cortisol, dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S) in saliva during the very first session of ERP and on the day before. Expectedly, SUD were increased on the ERP day before the session and further rose during ERP, but salivary cortisol and DHEA were statistically indistinguishable from the comparison condition. Interestingly, DHEA-S was significantly elevated throughout the ERP versus the comparison day, but did not further increase in acute response to ERP. According to an explorative analysis in a subsample, hormone levels on the comparison or the ERP day did not predict anti-OCD treatment response one month later. These results corroborate our prior findings of cortisol non-response despite considerable subjective stress in ERP. The role of DHEA-S in anticipatory anxiety and the effects of augmentative cortisol therapy in ERP need further study.

Vasopressin Surrogate Marker Copeptin as a Potential Novel Endocrine Biomarker for Antidepressant Treatment Response in Major Depression: A Pilot Study.

BACKGROUND: Major depressive disorder (MDD) constitutes the leading cause of disability worldwide. Although efficacious antidepressant pharmacotherapies exist for MDD, only about 40-60% of the patients respond to initial treatment. However, there is still a lack of robustly established and applicable biomarkers for antidepressant response in everyday clinical practice. OBJECTIVE: This study targets the assessment of the vasopressin (AVP) surrogate marker Copeptin (CoP), as a potential peripheral hypothalamic-level biomarker of antidepressant treatment response in MDD. METHODS: We measured baseline and dynamic levels of plasma CoP along with plasma ACTH and cortisol (CORT) in drug-naive outpatients with MDD before and after overnight manipulation of the hypothalamic-pituitary-adrenal (HPA) axis [i.e., stimulation (metyrapone) and suppression (dexamethasone)] on three consecutive days and their association with treatment response to 4 weeks of escitalopram treatment. RESULTS: Our findings suggest significantly higher baseline and post-metyrapone plasma CoP levels in future non-responders, a statistically significant invert association between baseline CoP levels and probability of treatment response and a potential baseline plasma CoP cut-off level of above 2.9 pmol/L for future non-response screening. Baseline and dynamic plasma ACTH and CORT levels showed no association with treatment response. CONCLUSIONS: This pilot study provide first evidence in humans that CoP may represent a novel, clinically easily applicable, endocrine biomarker of antidepressant response, based on a single-measurement, cut-off level. These findings, underline the role of the vasopressinergic system in the pathophysiology of MDD and may represent a significant new tool in the clinical and biological phenotyping of MDD enhancing individual-tailored therapies.

(Lack of) Effects of noradrenergic stimulation on human working memory performance.

RATIONALE: Working memory depends on prefrontal cortex functioning, which is particularly sensitive to levels of noradrenaline. Studies in non-human primates have shown that modest levels of noradrenaline improve working memory, and that higher levels of noradrenaline impair working memory performance. However, research in humans provided inconsistent findings concerning noradrenergic effects on working memory. OBJECTIVE: The present study aimed at assessing dose-dependent effects of yohimbine, an alpha-2 adrenoceptor antagonist, on working memory performance in healthy humans. We further aimed to explore a potential interactive effect between noradrenergic arousal and lack of control over aversive events on working memory performance. METHODS: We used a double-blind, fully crossed, placebo-controlled, between-subject design. Participants (N = 121) performed an adaptive n-back task before and after oral administration of either a placebo, 20 mg, or 40 mg yohimbine and a manipulation of controllability, during which participants could either learn to avoid electric shocks (controllability groups), had no instrumental control over shock administration (uncontrollability groups), or did not receive any shocks (no-shock control group). RESULTS: While no significant results of noradrenergic stimulation through yohimbine were obtained using conventional frequentist analyses, additional Bayesian analyses provided strong evidence for the absence of an association between pharmacological treatment and working memory performance. We further observed no effect of controllability and no interaction between noradrenergic stimulation and the manipulation of controllability. CONCLUSIONS: Our results suggest that noradrenergic stimulation through yohimbine does not affect (non-spatial) working memory in healthy human participants.

Leptin predicts cortical and subcortical gray matter volume recovery in alcohol dependent patients: A longitudinal structural magnetic resonance imaging study.

The neuroprotective effects of leptin and its role in addictive disorders has been highlighted by several recent studies. However, its potential effects on morphological alterations in alcohol dependence are yet to be investigated. Associations between leptin and the longitudinal courses of gray matter volume (GMV) and cortical thickness (CT) were investigated in N = 62 alcohol-dependent patients that underwent structural magnetic resonance imaging after a mean abstinence of 12 (baseline) and 27 days (follow-up) respectively. Blood samples were collected at baseline to determine leptin levels. A cohort of N = 74 healthy individuals served as a reference sample. At baseline, alcohol-dependent patients compared to healthy controls displayed smaller GMV in the insula, parts of the superior, middle and inferior frontal gyri and hippocampal regions and thinner CT in the insula, parts of the superior and middle frontal cortices, the lateral orbitofrontal cortex and parts of the occipital and lingual cortices that partially recovered during abstinence (pFWE < 0.05). In alcohol-dependent patients, leptin was a significant predictor of GMV and CT recovery in the areas that showed the strongest whole-brain effects, specifically GMV in the right insula (R2 = 0.070, pFDR = 0.040) and left inferior frontal triangular gyrus (R2 = 0.076, pFDR = 0.040), as well as CT in the left insula (R2 = 0.158, pFDR = 0.004) and right superior frontal cortex (R2 = 0.180, pFDR = 0.004). Present results support the role of leptin in predicting GMV and CT recovery during the first month of abstinence in alcohol-dependent patients.

The use of long-acting Aripiprazole in a multi-center, prospective, uncontrolled, open-label, cohort study in Germany: a report on global assessment of functioning and the WHO wellbeing index.

BACKGROUND: In this non-interventional study, the functionality and well-being of patients with schizophrenia with aripiprazole once-monthly (AOM) was evaluated under real-life conditions in a naturalistic population. METHODS: This non-interventional, prospective, multicenter 6-month study included 242 predominantly symptomatically stable patients (mean age 43.1 ± 15.1 years, 55% male) who switched their treatment to AOM after 9.7 (± 22.3) months of oral treatment. Outcome parameters included functionality (Global Assessment of Functioning, GAF), patient's wellbeing (WHO-5 Well-Being Index, WHO-5), and both patient's and clinician's assessment of efficacy and tolerability of AOM. Treatment emergent adverse events (TRAE) were also recorded. RESULTS: At baseline, the mean GAF score was 47.0 (±13.9), indicating that patients experienced serious impairment in functioning. A continuous increase to 60.2 (±17.0) during treatment was found, with a robust and significant increase already after 4 weeks. At study start, patients reported diminished wellbeing, with a mean score of 10.6 (±5.6) on the WHO-5 scale. During treatment, patient wellbeing increased continuously with strong and significant improvements even after 4 weeks and an overall improvement of 4.8 (±6.9) over the course of 6 months with an endpoint of 15.4 (±5.5). Stratification of these results showed that more pronounced effects were achieved in younger patients ≤35 years (p<0.05 for GAF). The effectiveness and tolerability of AOM was rated good/very good by most patients (89.2 and 93.7%) and physicians (91.4 and 96.8%). Only few TRAEs occurred. CONCLUSIONS: Our results show a significant positive effect after initiation of AOM treatment in predominantly stable patients with schizophrenia on their functioning and wellbeing, which was even more pronounced in patients aged ≤35 years, thereby supporting previous randomized controlled findings under routine conditions in clinical practice.