Autobiographical memory following weight gain in adult patients with Anorexia Nervosa: A longitudinal study.

BACKGROUND: Patients with anorexia nervosa (AN) show overgeneralization of memory (OGM) when generating autobiographical episodes related to food and body shape. These memories are central for the construction of a coherent self-concept, interpersonal relationships, and problem-solving abilities. The current study aims to investigate changes in autobiographical memory following weight gain. METHODS: OGM was assessed with an adapted version of the Autobiographical Memory Test including food-, body-, depression-related, and neutral cues. N = 41 female patients with AN (28 restricting-, 13 binge-eating/purging-subtype; mean disease duration: 4.5 years; mean BMI: 14.5 kg/m2) and N = 27 healthy controls (HC) were included at baseline. After inpatient treatment (mean duration: 11 weeks), 24 patients with AN and 24 age-matched HC were reassessed. Group differences were assessed using independent samples t-tests for cross-sectional comparisons and repeated measures ANOVAs for longitudinal data. RESULTS: At baseline, patients with AN generated significantly fewer specific memories than HC, independent of word category (F(1.66) = 27.167, p < 0.001). During inpatient stay, the average weight gain of patients with AN was 3.1 body mass index points. At follow-up, patients with AN showed a significant improvement in the number of specific memories for both depression-related and neutral cues, but not for food- and body-related cues. CONCLUSIONS: Generalised OGM (i.e., independent of word category) in patients with AN before weight restoration may be a general incapacity to recall autobiographical memory. After weight gain, the previously well-studied pattern of eating disorder-related OGM emerges. The clinical relevance of the continuing disorder-related OGM in patients with AN after weight gain is discussed.

Unexpected identification of obesity-associated mutations in LEP and MC4R genes in patients with anorexia nervosa.

Mutations leading to a reduced or loss of function in genes of the leptin-melanocortin system confer a risk for monogenic forms of obesity. Yet, gain of function variants in the melanocortin-4-receptor (MC4R) gene predispose to a lower BMI. In individuals with reduced body weight, we thus expected mutations leading to an enhanced function in the respective genes, like leptin (LEP) and MC4R. Therefore, we have Sanger sequenced the coding regions of LEP and MC4R in 462 female patients with anorexia nervosa (AN), and 445 healthy-lean controls. In total, we have observed four and eight variants in LEP and MC4R, respectively. Previous studies showed different functional in vitro effects for the detected frameshift and non-synonymous variants: (1) LEP: reduced/loss of function (p.Val94Met), (2) MC4R: gain of function (p.Val103Ile, p.Ile251Leu), reduced or loss of function (p.Thr112Met, p.Ser127Leu, p.Leu211fsX) and without functional in vitro data (p.Val50Leut). In LEP, the variant p.Val94Met was detected in one patient with AN. For MC4R variants, one patient with AN carried the frameshift variant p.Leu211fsX. One patient with AN was heterozygous for two variants at the MC4R (p.Val103Ile and p.Ser127Leu). All other functionally relevant variants were detected in similar frequencies in patients with AN and lean individuals.

Words count in psychotherapy: Differentiating language characteristics of cognitive behavioral therapy and focal psychodynamic therapy for anorexia nervosa.

It is generally assumed that psychodynamic therapy and cognitive behavioral therapy (CBT) differ in terms of applied techniques and processes. To date, however, little is known about whether and how such differences can actually be observed at a basic linguistic level and in what the two treatment approaches differ most strongly (i.e., how psychodynamic and CBT therapists differ in what they actually say word-by-word in therapy sessions). Building on theoretical models and previous research that used observer ratings, we formulated specific hypotheses regarding which word categories psychodynamic and CBT therapists who treat patients with an eating disorder should differ in. To investigate these hypotheses, we used verbatim transcripts from 297 therapy sessions of a randomized controlled trial in which patients with anorexia nervosa (n = 88) received either focal psychodynamic therapy (FPT) or CBT. These transcripts were then examined using computerized quantitative text analysis. In line with our hypotheses, we found that CBT therapists overall spoke more than their FPT counterparts and that they used more words related to eating. Also in line with our hypotheses, FPT therapists used more words related to social processes. Contrary to our expectations, CBT therapists did not show a stronger focus on the future but talked more about emotions than FPT therapists. The latter effect, however, appears to be driven by a stronger focus on positive emotions. These findings suggest that computerized quantitative text analysis can differentiate meaningful language characteristics of CBT and FPT on spoken-word level and that it holds potential as a tool for researchers and therapists. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Lipocalin 2 - mutation screen and serum levels in patients with anorexia nervosa or obesity and in lean individuals.

Context: The bone-derived adipokine lipocalin-2 is relevant for body weight regulation by stimulating the leptin-melanocortin pathway. Objective: We aimed to (i) detect variants in the lipocalin-2 gene (LCN2) which are relevant for body weight regulation and/or anorexia nervosa (AN); (ii) describe and characterize the impact of LCN2 and MC4R variants on circulating lipocalin-2 level. Methods: Sanger sequencing of the coding region of LCN2 in 284 children and adolescents with severe obesity or 287 patients with anorexia nervosa. In-silico analyses to evaluate functional implications of detected LCN2 variants. TaqMan assays for rare non-synonymous variants (NSVs) in additional independent study groups. Serum levels of lipocalin-2 were measured by ELISA in 35 females with NSVs in either LCN2 or MC4R, and 33 matched controls without NSVs in the two genes. Results: Fourteen LCN2-variants (five NSVs) were detected. LCN2-p.Leu6Pro and p.Gly9Val located in the highly conserved signal peptide region may induce functional consequences. The secondary structure change of lipocalin-2 due to LCN2-p.Val89Ile may decrease solubility and results in a low lipocalin-2 level in a heterozygotes carrier (female recovered from AN). Lean individuals had lower lipocalin-2 levels compared to patients with obesity (p = 0.033). Conclusion: Lipocalin-2 levels are positively associated with body mass index (BMI). Single LCN2-variants might have a profound effect on lipocalin-2 levels.

Genetic variants in genes involved in creatine biosynthesis in patients with severe obesity or anorexia nervosa.

Increased thermogenesis in brown adipose tissue might have an obesity-reducing effect in humans. In transgenic mice, depletion of genes involved in creatine metabolism results in disrupted thermogenic capacity and altered effects of high-fat feeding on body weight. Data analyses of a sex-stratified genome-wide association study (GWAS) for body mass index (BMI) within the genomic regions of genes of this pathway (CKB, CKMT1B, and GATM) revealed one sex-dimorphic BMI-associated SNP in CKB (rs1136165). The effect size was larger in females than in males. A mutation screen of the coding regions of these three candidate genes in a screening group (192 children and adolescents with severe obesity, 192 female patients with anorexia nervosa, and 192 healthy-lean controls) identified five variants in each, CKB and GATM, and nine variants in the coding sequence of CKMT1B. Non-synonymous variants identified in CKB and CKMT1B were genotyped in an independent confirmation study group (781 families with severe obesity (trios), 320 children and adolescents with severe obesity, and 253 healthy-lean controls). In silico tools predicted mainly benign yet protein-destabilizing potentials. A transmission disequilibrium test in trios with severe obesity indicated an obesity-protective effect of the infrequent allele at rs149544188 located in CKMT1B. Subsequent correlation analyses in 1,479 individuals of the Leipzig Obesity BioBank revealed distinct correlations of CKB with the other two genes in omental visceral adipose tissue (VAT) and abdominal subcutaneous adipose tissue (SAT). Furthermore, between-subject comparisons of gene expression levels showed generally higher expressions of all three genes of interest in VAT than in SAT. Future in vitro analyses are needed to assess the functional implications of these findings.

The role of general change mechanisms in sudden gains in the treatment of anorexia nervosa.

Previous research has shown a robust association between sudden gains (SGs) and treatment outcome in psychotherapy for various mental disorders including anorexia nervosa (AN). However, little is known about factors contributing to SGs. This study investigated the role of general change mechanisms in body-weight related SGs in AN. Data were drawn from a randomized-controlled trial on cognitive-behavioral therapy (CBT) and focal psychodynamic therapy (FPT) for adult outpatients with AN. Session-level data on the general change mechanisms 'clarification' (insight), 'mastery' (coping), and 'therapeutic relationship' were analyzed. Pre-gain sessions were compared with control (pre-pre-gain) sessions in 99 patients with a SG in body weight. Additionally, propensity score matching was used to compare data from pre-gain sessions from 44 patients with SG and data from the corresponding session from 44 patients without SG. In the pre-gain session, patients experienced higher levels of clarification and mastery but not therapeutic relationship. Compared to patients without a SG, patients with a SG likewise experienced more clarification and mastery but not a better therapeutic relationship in the pre-gain/corresponding session. CBT and FPT did not differ regarding these effects. The findings suggest that general change mechanisms contribute to SGs in CBT and FPT for AN.

Mentalization-enhancing therapeutic interventions in the psychotherapy of anorexia nervosa: An analysis of use and influence on patients' mentalizing capacity.

OBJECTIVE: Improvement in patients' mentalizing capacities is considered a possible mechanism of change in psychotherapy. This improvement might take place via mentalization-enhancing interventions (MEIs) performed by psychotherapists. The study aimed to explore the use of MEIs in two evidence-based psychotherapeutic treatments for patients with anorexia nervosa (enhanced cognitive-behavior therapy, focal psychodynamic therapy) and their association with the patients' capacity to mentalize in sessions ("in-session reflective functioning" / in-session RF). Additionally, it was explored, if the amount of MEIs used could either predict change in in-session RF or outcome (end of treatment, one year follow-up). METHOD: 84 audiotapes from psychotherapy sessions of 28 patients of the ANTOP-study (three sessions per patient) were transcribed and rated with both the MEI Rating Scale and the In-Session RF Scale by trained raters. RESULTS: MEIs were applied in both treatments. A moderate correlation between the amount of MEIs and patients' in-session RF as well as its change over the course of treatment was found, but no relation to change in BMI or eating disorder symptoms. CONCLUSION: A greater use of MEIs was related to patients' in-session-mentalizing. However, there seems to be no simple relation between RF as shown in sessions and symptom change.

Neurophysiological correlates of disorder-related autobiographical memory in anorexia nervosa.

BACKGROUND: Anorexia nervosa (AN) is characterized by an overgeneralization of food/body-related autobiographical memories (AM). This is regarded as an emotion regulation strategy with adverse long-term effects implicated in disorder maintenance and treatment resistance. Therefore, we aimed to examine neural correlates of food/body-related AM-recall in AN. METHODS: Twenty-nine female patients with AN and 30 medication-free age-sex-matched normal-weight healthy controls (HC) underwent functional magnetic resonance imaging while recalling AMs in response to food/body-related and neutral cue words. To control for general knowledge retrieval, participants engaged in a semantic generation and riser detection task. RESULTS: In comparison to HC, patients with AN generated fewer and less specific AMs in response to food/body-related words, but not for neutral cue words. Group comparisons revealed reduced activation in regions associated with self-referential processing and memory retrieval (precuneus and angular gyrus) during the retrieval of specific food/body-related AM in patients with AN. Brain connectivity in regions associated with memory functioning and executive control was reduced in patients with AN during the retrieval of specific food/body-related AM. Finally, resting-state functional connectivity analysis revealed no differences between groups, arguing against a general underlying disconnection of brain networks implicated in memory and emotional processing in AN. CONCLUSIONS: These results indicate impaired neural processing of food/body-related AM in AN, with a reduced involvement of regions involved in self-referential processing. Our findings are discussed as possible neuronal correlates of emotional avoidance in AN and provide new insights of AN-pathophysiology underscoring the importance of targeting dysfunctional emotion regulation strategies during treatment.

Verbal memory following weight gain in adult patients with anorexia nervosa: A longitudinal study.

BACKGROUND: Patients with Anorexia Nervosa (AN) show a moderate deficit in overall neuropsychological functioning. Since previous studies on memory performance mainly employed cross-sectional designs, the present study aims to investigate changes in verbal memory following weight-gain. METHODS: Verbal memory was assessed with the Wechsler Memory Scale-Revised (WMS-R; 'logical memory'-story-recall-subtest) and the California Verbal Learning Test-II (CVLT-II; 'verbal learning'). Included were 31 female patients with AN (18 restricting-, 13 purging-subtype; average disease duration: 5.1 years; average baseline BMI: 14.4 kg/m2 ) and 24 medication-free normal-weight healthy women adjusted for age at baseline (T0). In a post-treatment assessment of approx. 6 weeks with weight increase (T1), 18 patients with AN and 20 healthy women were assessed again. Group differences in verbal memory (i.e., WMS-R, CVLT-II) were assessed for the baseline comparisons with a multivariate ANOVA and longitudinal data were analysed with repeated measures (RM) ANOVAs. RESULTS: At baseline, patients with AN as compared to healthy women displayed deficits in logical memory. In the follow-up assessment, patients with AN improved their logical memory significantly compared to healthy controls (p < 0.006). Furthermore, groups did not differ in verbal learning neither before nor after inpatient treatment. CONCLUSIONS: Enhanced logical memory in patients with AN following weight-gain is probably due to the impaired memory as compared to healthy controls at T0. A survivorship bias could explain the improved memory performance in longitudinal data in contrast to cross-sectional studies. Patients with AN with poorer memory performance before inpatient treatment are at higher risk to drop out and need support.

Calcineurin signaling promotes takotsubo syndrome.

Takotsubo syndrome (TTS) is an acute heart failure syndrome that mimics the symptoms of acute myocardial infarction and is often preceded by emotional and/or physical stress. There is currently no treatment for TTS. Here we show that injection of 2.5 mg kg-1 of epinephrine (EPI) into mice recapitulates numerous features of human TTS, including increased myocardial damage and mortality in males. Gene set enrichment analysis of myocardial RNA sequencing after EPI injection revealed significant enrichment of calcineurin-dependent pro-inflammatory gene networks, which was more pronounced in male than in female mice, in agreement with observed sex discrepancies in the mouse phenotype. An increase in calcineurin activity was detected in the circulating cells of patients with TTS, suggesting a systemic nature of the syndrome. Preventive and therapeutic treatment of mice injected with EPI using calcineurin inhibitors cyclosporine and tacrolimus improved heart function and reduced myocardial injury. Our findings suggest that calcineurin inhibition could be a potential therapy for TTS.

The serotonin receptor 3E variant is a risk factor for female IBS-D.

Irritable bowel syndrome (IBS) is a gut-brain disorder of multifactorial origin. Evidence of disturbed serotonergic function in IBS accumulated for the 5-HT3 receptor family. 5-HT3Rs are encoded by HTR3 genes and control GI function, and peristalsis and secretion, in particular. Moreover, 5-HT3R antagonists are beneficial in the treatment of diarrhea predominant IBS (IBS-D). We previously reported on functionally relevant SNPs in HTR3A c.-42C > T (rs1062613), HTR3C p.N163K (rs6766410), and HTR3E c.*76G > A (rs56109847 = rs62625044) being associated with IBS-D, and the HTR3B variant p.Y129S (rs1176744) was also described within the context of IBS. We performed a multi-center study to validate previous results and provide further evidence for the relevance of HTR3 genes in IBS pathogenesis. Therefore, genotype data of 2682 IBS patients and 9650 controls from 14 cohorts (Chile, Germany (2), Greece, Ireland, Spain, Sweden (2), the UK (3), and the USA (3)) were taken into account. Subsequent meta-analysis confirmed HTR3E c.*76G > A (rs56109847 = rs62625044) to be associated with female IBS-D (OR = 1.58; 95% CI (1.18, 2.12)). Complementary expression studies of four GI regions (jejunum, ileum, colon, sigmoid colon) of 66 IBS patients and 42 controls revealed only HTR3E to be robustly expressed. On top, HTR3E transcript levels were significantly reduced in the sigma of IBS patients (p = 0.0187); more specifically, in those diagnosed with IBS-D (p = 0.0145). In conclusion, meta-analysis confirmed rs56109847 = rs62625044 as a risk factor for female IBS-D. Expression analysis revealed reduced HTR3E levels in the sigmoid colon of IBS-D patients, which underlines the relevance of HTR3E in the pathogenesis of IBS-D.

Forebrain corticosteroid receptors promote post-myocardial infarction depression and mortality.

Myocardial infarction (MI) with subsequent depression is associated with increased cardiac mortality. Impaired central mineralocorticoid (MR) and glucocorticoid receptor (GR) equilibrium has been suggested as a key mechanism in the pathogenesis of human depression. Here, we investigate if deficient central MR/GR signaling is causative for a poor outcome after MI in mice. Mice with an inducible forebrain-specific MR/GR knockout (MR/GR-KO) underwent baseline and follow-up echocardiography every 2 weeks after MI or sham operation. Behavioral testing at 4 weeks confirmed significant depressive-like behavior and, strikingly, a higher mortality after MI, while cardiac function and myocardial damage remained unaffected. Telemetry revealed cardiac autonomic imbalance with marked bradycardia and ventricular tachycardia (VT) upon MI in MR/GR-KO. Mechanistically, we found a higher responsiveness to atropine, pointing to impaired parasympathetic tone of 'depressive' mice after MI. Serum corticosterone levels were increased but-in line with the higher vagal tone-plasma and cardiac catecholamines were decreased. MR/GR deficiency in the forebrain led to significant depressive-like behavior and a higher mortality after MI. This was accompanied by increased vagal tone, depleted catecholaminergic compensatory capacity and VTs. Thus, limbic MR/GR disequilibrium may contribute to the impaired outcome of depressive patients after MI and possibly explain the lack of anti-depressive treatment benefit.

Serotonin type 3 receptor subunit gene polymorphisms associated with psychosomatic symptoms in irritable bowel syndrome: A multicenter retrospective study.

BACKGROUND: Single-nucleotide polymorphisms (SNPs) of the serotonin type 3 receptor subunit (HTR3) genes have been associated with psychosomatic symptoms, but it is not clear whether these associations exist in irritable bowel syndrome (IBS). AIM: To assess the association of HTR3 polymorphisms with depressive, anxiety, and somatization symptoms in individuals with IBS. METHODS: In this retrospective study, 623 participants with IBS were recruited from five specialty centers in Germany, Sweden, the United States, the United Kingdom, and Ireland. Depressive, anxiety, and somatization symptoms and sociodemographic characteristics were collected. Four functional SNPs - HTR3A c.-42C>T, HTR3B c.386A>C, HTR3C c.489C>A, and HTR3E c.*76G>A - were genotyped and analyzed using the dominant and recessive models. We also performed separate analyses for sex and IBS subtypes. SNP scores were calculated as the number of minor alleles of the SNPs above. The impact of HTR3C c.489C>A was tested by radioligand-binding and calcium influx assays. RESULTS: Depressive and anxiety symptoms significantly worsened with increasing numbers of minor HTR3C c.489C>A alleles in the dominant model (F depressive = 7.475, P depressive = 0.006; F anxiety = 6.535, P anxiety = 0.011). A higher SNP score (range 0-6) was linked to a worsened depressive symptoms score (F = 7.710, P-linear trend = 0.006) in IBS. The potential relevance of the HTR3C SNP was corroborated, showing changes in the expression level of 5-HT3AC variant receptors. CONCLUSION: We have provided the first evidence that HTR3C c.489C>A is involved in depressive and anxiety symptoms in individuals with IBS. The SNP score indicated that an increasing number of minor alleles is linked to the worsening of depressive symptoms in IBS.

In-Session-Reflective-Functioning in Anorexia Nervosa: An Analysis of Psychotherapeutic Sessions of the ANTOP Study.

Objective: Previous research suggests that patients with anorexia nervosa (AN) show an impaired capacity to mentalize (reflective functioning, RF). RF is discussed as a possible predictor of outcome in psychotherapeutic processes. The study aimed to explore RF in sessions of patients with AN and its association with outcome and type of treatment. Methods: A post-hoc data analysis of selected cases from a randomized trial on outpatient psychotherapy for AN was conducted. Transcripts from 84 sessions of 28 patients (early phase, middle phase, and end of treatment) were assessed using the In-Session-Reflective-Functioning-Scale [14 cognitive-behavior therapy, enhanced (CBT-E); 14 focal psychodynamic therapy (FPT); 16 with good, 12 with poor outcome after 1 year]. Relations between the level of RF, type of treatment, and outcome were investigated using mixed linear models. Additionally, associations with depressive symptoms, weight gain, and therapeutic alliance were explored. Results: Mean in-session RF was low. It was higher in FPT when compared to CBT-E treatments. The findings point to an association between RF increase and a positive outcome. An increase in BMI in the first half of treatment was associated with higher subsequent in-session RF. There was no association between RF and depressive symptoms or the therapeutic alliance. Discussion: Patients with AN show a low capacity to mentalize in sessions, which seems to be at least partly dependent on the degree of starvation. The results suggest a possible relationship between an increase in in-session RF and outcome, which has to be replicated by further studies.

PTBP2 - a gene with relevance for both Anorexia nervosa and body weight regulation.

Genetic factors are relevant for both eating disorders and body weight regulation. A recent genome-wide association study (GWAS) for anorexia nervosa (AN) detected eight genome-wide significant chromosomal loci. One of these loci, rs10747478, was also genome-wide and significantly associated with body mass index (BMI). The nearest coding gene is the Polypyrimidine Tract Binding Protein 2 gene (PTBP2). To detect mutations in PTBP2, Sanger sequencing of the coding region was performed in 192 female patients with AN (acute or recovered) and 191 children or adolescents with (extreme) obesity. Twenty-five variants were identified. Twenty-three of these were predicted to be pathogenic or functionally relevant in at least one in silico tool. Two novel synonymous variants (p.Ala77Ala and p.Asp195Asp), one intronic SNP (rs188987764), and the intronic deletion (rs561340981) located in the highly conserved region of PTBP2 may have functional consequences. Ten of 20 genes interacting with PTBP2 were studied for their impact on body weight regulation based on either previous functional studies or GWAS hits for body weight or BMI. In a GWAS for BMI (Pulit et al. 2018), the number of genome-wide significant associations at the PTBP2 locus was different between males (60 variants) and females (two variants, one of these also significant in males). More than 65% of these 61 variants showed differences in the effect size pertaining to BMI between sexes (absolute value of Z-score >2, two-sided p < 0.05). One LD block overlapping 5'UTR and all coding regions of PTBP2 comprises 56 significant variants in males. The analysis based on sex-stratified BMI GWAS summary statistics implies that PTBP2 may have a more pronounced effect on body weight regulation in males than in females.

Focal psychodynamic therapy, cognitive behaviour therapy, and optimised treatment as usual in female outpatients with anorexia nervosa (ANTOP study): 5-year follow-up of a randomised controlled trial in Germany.

BACKGROUND: Anorexia nervosa is a serious illness leading to substantial morbidity and mortality. The Anorexia Nervosa Treatment of Outpatients (ANTOP) study is the largest randomised controlled trial (RCT) globally that uses psychotherapy in outpatients with anorexia nervosa. In this Article, we report the results of the 5-year follow-up. METHODS: The ANTOP study is an open-label, multicentre RCT involving 242 adult female outpatients with anorexia nervosa. Participants were recruited from ten university hospitals in Germany, had to be aged at least 18 years and female, and have a diagnosis of anorexia nervosa with a body-mass index (BMI) of 15·0-18·5 kg/m2. Participants were randomly allocated (1:1:1) to 10 months of treatment with focal psychodynamic therapy, enhanced cognitive behaviour therapy, or optimised treatment as usual; complete masking of the participants was not possible. The mean duration of the follow-up was 5·96 years (SD 0·2) after randomisation. The primary outcome was change in BMI from baseline at the end of treatment; here, we present the change in BMI from baseline to the 5-year follow-up, using an intention-to-treat approach with a mixed model for repeated measurements. Groups were also compared according to global outcome (based on the combination of BMI and measures of anorexia severity), eating pathology (based on the Eating Disorder Inventory 2), and other secondary mental health outcomes. We did a linear regression analysis to identify the predictors of BMI at follow-up. FINDINGS: Between May, 2007, and June, 2009, we screened 727 patients for eligibility; at baseline, 242 patients with a mean BMI of 16·7 kg/m2 (SD 1·0) were included and randomly allocated to 10 months of treatment with focal psychodynamic therapy, enhanced cognitive behaviour therapy, or optimised treatment as usual. 154 (64%) of 242 patients completed the 5-year follow-up assessment (53 [66%] of 80 in the focal psychodynamic therapy group, 55 [69%] of 80 in the enhanced cognitive behaviour therapy group, and 46 [56%] of 82 in the optimised treatment-as-usual group), with a mean age of 32·4 years; all reported their ethnicity as White. At the 5-year follow-up, there was an improvement in mean BMI, eating pathology, and global outcome in all treatment groups with no significant differences between treatment groups. Estimated mean BMI was: 18·64 kg/m2 (95% CI 18·07-19·21) in the focal psychodynamic therapy group (with an estimated mean BMI gain from baseline to 5-year follow-up of 1·91 kg/m2 [1·34-2·48]); 18·70 kg/m2 (18·15-19·25) in the enhanced cognitive behaviour therapy group (with an estimated mean BMI gain of 1·98 kg/m2 [1·43-2·53]); and 18·99 kg/m2 (18·39-19·59) in the optimised treatment-as-usual group (with an estimated mean BMI gain of 2·26 kg/m2 [1·67-2·86]). There were no significant differences between treatment groups regarding BMI at the 5-year follow-up; the estimated difference was -0·06 (-0·85 to 0·73) between the focal psychodynamic therapy and enhanced cognitive behaviour therapy groups; -0·35 (-1·18 to 0·47) between the focal psychodynamic therapy and optimised treatment-as-usual groups; and -0·29 (-1·10 to 0·52) between the enhanced cognitive behaviour therapy and optimised treatment-as-usual groups. On the basis of observed data, global outcome at the 5-year follow-up showed 41% (33-49) full recoveries, 41% (33-49) partial recoveries, and 18% (12-24) with full-syndrome anorexia nervosa. One patient initially treated in the enhanced cognitive behaviour therapy group died by suicide between the 1-year and 5-year follow-up. BMI at the 5-year follow-up was predicted by BMI at baseline (p=0·0021), illness duration (p=0·0004), and depression at baseline (p=0·012). INTERPRETATION: The long-term results of the ANTOP trial confirm the improvement in BMI of patients with anorexia nervosa in all groups; however, a substantial proportion of patients had a poor global outcome. The predictors for the long-term course of anorexia nervosa in our ANTOP study show that we need to treat patients with anorexia nervosa at an earlier stage of the disease, with a clear focus on weight gain and considering other comorbidities (especially depression). FUNDING: German Federal Ministry of Education and Research.

Secondary traumatisation in psychosocial emergency care personnel-A longitudinal study accompanying German trainees.

Psychosocial emergency care personnel form an important first responder subgroup, in which trained volunteers provide psychological first aid to accident and trauma survivors, their relatives, eye witnesses, bystanders and first responders themselves. This is the first longitudinal study to assess psychological burden due to secondary traumatisation and relevant resilience factors in psychosocial emergency care personnel. We asked 100 German psychosocial emergency care workers to assess their feeling of preparedness and resilience factors prior training. After training, when participants had worked emergency responses, we assessed secondary traumatisation. Overall, the level of secondary traumatisation was sub-clinical (M = 37.50, SD = 5.35) after training and reported resilience factor levels were high. Three regression analyses were conducted to examine the moderation effect of preparedness on specific expertise (R2  = 0.479, p < 0.001), performance competence (R2  = 0.419, p = 0.002) and inner attitude (R2  = 0.336, p = 0.002) in regard to the relationship between resilience factors and secondary traumatisation. Feeling prepared and competent for emergency responses were protective factors. Practical implications include the following: volunteers should not take part in emergency responses if they are under excessive stress; the volunteers' resilience factors should be taken into account; emergency response training should promote the feeling of preparedness in specific expertise and performance competence.

The alternative serotonin transporter promoter P2 impacts gene function in females with irritable bowel syndrome.

Irritable bowel syndrome (IBS) is a gut-brain disorder in which symptoms are shaped by serotonin acting centrally and peripherally. The serotonin transporter gene SLC6A4 has been implicated in IBS pathophysiology, but the underlying genetic mechanisms remain unclear. We sequenced the alternative P2 promoter driving intestinal SLC6A4 expression and identified single nucleotide polymorphisms (SNPs) that were associated with IBS in a discovery sample. Identified SNPs built different haplotypes, and the tagging SNP rs2020938 seems to associate with constipation-predominant IBS (IBS-C) in females. rs2020938 validation was performed in 1978 additional IBS patients and 6,038 controls from eight countries. Meta-analysis on data from 2,175 IBS patients and 6,128 controls confirmed the association with female IBS-C. Expression analyses revealed that the P2 promoter drives SLC6A4 expression primarily in the small intestine. Gene reporter assays showed a functional impact of SNPs in the P2 region. In silico analysis of the polymorphic promoter indicated differential expression regulation. Further follow-up revealed that the major allele of the tagging SNP rs2020938 correlates with differential SLC6A4 expression in the jejunum and with stool consistency, indicating functional relevance. Our data consolidate rs2020938 as a functional SNP associated with IBS-C risk in females, underlining the relevance of SLC6A4 in IBS pathogenesis.

[Promoting research competence in psychosocial medicine - A new curriculum for medical students]. / Wissenschaft verstehen und anwenden. Ein neues Curriculum für Medizinstudierende zur Entwicklung von Forschungskompetenz in der psychosozialen Medizin.

Promoting research competence in psychosocial medicine - A new curriculum for medical students Objectives: The objective of this study is the introduction and evaluation of a new graduate-students curriculum to enhance research competence in psychosocial medicine. Method: N = 57 students have participated in the curriculum to date. All participants completed questionnaires regarding teaching quality and pre-post changes in subjective research competence. Results: All items on teaching quality were scored significantly higher (p < 0.05) compared to data of three other comparable psychosocial seminars. In addition, a substantial increase in subjective research competence was found (p < 0.05). Conclusions: The presented curriculum provides an opportunity to strengthen research competence and evidence-based critical thinking of prospective physicians at an early stage. As a consequence of these encouraging results, the curriculum has been implemented permanently at the medical faculty in Heidelberg.

The effect of intestinal glucose load on neural regulation of food craving.

Objectives: Excess sugar consumption, particularly in the form of sweetened beverages, has been identified as a pivotal contributor to the epidemic of obesity and associated metabolic disorders. However, the impact of sugar-sweetened beverages on food craving is still inconclusive. Therefore, the present study aimed to specifically investigate the effects of an intestinal glucose load on neural processing of food cues. Methods: Using a single-blind fMRI design, 26 normal-weight women were scanned on two occasions, after receiving either a glucose or water infusion directly into the stomach using a nasogastric tube, without being aware of the type of infusion. Participants had to either view neutral and food images, or were asked to distract themselves from these images by solving an arithmetic task. Results: In response to viewing high-caloric food cues, we observed increased activation in reward-related brain areas. During food distraction, fronto-parietal brain regions were recruited, which are commonly related to attentional deployment and hedonic valuation. Furthermore, activity in the dorsolateral prefrontal cortex showed increased functional connectivity with the insula and was correlated with subjective craving levels to food cues. Despite an increase of blood glucose levels in response to the glucose compared to the water infusion, neither subjective food craving nor neural regulation of food craving showed significant differences. Conclusions: These findings support a decreased satiation effect of sweet beverages, as intestinal glucose ingestion and signalling showed no significant effect on cortical brain circuits associated with food craving. This trial was registered at clinicaltrials.gov as NCT03075371.