A novel whole-team training programme for adult eating disorder services in England: rationale, development and preliminary evaluation.

AIMS AND METHOD: In response to recommendations for improving the quality and coordination of care delivered by eating disorder services, a whole-team training programme was commissioned by Health Education England in 2020. This paper describes the development and evaluation of the Eating Disorder Services for Adults (EDSA) whole-team training course, delivered to National Health Service adult eating disorder community teams in England. Course participants (n = 561) in the first two EDSA training cohorts (2021 and 2022) were asked to complete questionnaires at intake and after each session, asking about their views on the training. RESULTS: All course aspects were rated as highly enjoyable, meeting participants' training needs and fostering reflective practice. Thematic analysis identified themes relating to key innovative features of the course and suggestions for improvements. CLINICAL IMPLICATIONS: Preliminary evaluation suggests that EDSA is valued by clinicians to enhance their knowledge, skills and ability to improve eating disorder patient care.

Autopsy of a failed trial part 2: Outcomes, challenges, and lessons learnt from the DAISIES trial.

OBJECTIVE: The relative merits of inpatient or day-treatment for adults with anorexia nervosa (AN) are unknown. The DAISIES trial aimed to establish the non-inferiority of a stepped-care day patient treatment (DPT) approach versus inpatient treatment as usual (IP-TAU) for improving body mass index (BMI) at 12 months in adults with AN. The trial was terminated due to poor recruitment. This paper presents outcomes and investigates the reasons behind the trial's failure. METHOD: Fifteen patients with AN (of 53 approached) participated and were followed-up to 6 or 12 months. Summary statistics were calculated due to low sample size, and qualitative data concerning treatment experiences were analysed using thematic analysis. RESULTS: At baseline, participants in both trial arms rated stepped-care DPT as more acceptable. At 12 months, participants' BMIs had increased in both trial arms. Qualitative analysis highlighted valued and challenging aspects of care across settings. Only 6/12 sites opened for recruitment. Among patients approached, the most common reason for declining participation was their treatment preference (n = 12/38). CONCLUSIONS: No conclusions can be drawn concerning the effectiveness of IP-TAU and stepped-care DPT, but the latter was perceived more positively. Patient-related, service-related and systemic factors (COVID-19) contributed to the trial's failure. Lessons learnt can inform future studies.

The clinical effectiveness and cost-effectiveness of a 'stepping into day treatment' approach versus inpatient treatment as usual for anorexia nervosa in adult specialist eating disorder services (DAISIES trial): a study protocol of a randomised controlled multi-centre open-label parallel group non-inferiority trial.

BACKGROUND: Anorexia nervosa (AN) is a serious and disabling mental disorder with a high disease burden. In a proportion of cases, intensive hospital-based treatments, i.e. inpatient or day patient treatment, are required, with day patient treatment often being used as a 'step-down' treatment after a period of inpatient treatment. Demand for such treatment approaches has seen a sharp rise. Despite this, the relative merits of these approaches for patients, their families, and the NHS and wider society are relatively unknown. This paper describes the rationale for, and protocol of, a two-arm multi-centre open-label parallel group non-inferiority randomised controlled trial, evaluating the effectiveness and cost-effectiveness of these two intensive treatments for adults with severe AN: inpatient treatment as usual and a stepped care day patient approach (the combination of day patient treatment with the option of initial inpatient treatment for medical stabilisation). The main aim of this trial is to establish whether, in adults with severe AN, a stepped care day patient approach is non-inferior to inpatient treatment as usual in relation to improving body mass index (BMI) at 12 months post-randomisation. METHODS: 386 patients with a Diagnostic and Statistical Manual 5th edition diagnosis of severe AN or related disorder, with a BMI of ≤16 kg/m2 and in need of intensive treatment will be randomly allocated to either inpatient treatment as usual or a stepped care day patient approach. Patients in both groups will receive treatment until they reach a healthy weight or get as close to this point as possible. Assessments will be conducted at baseline (prior to randomisation), and at 6 and 12 months post-randomisation, with additional monthly symptom monitoring. The primary outcome will be BMI at the 12-month post-randomisation assessment. Other outcomes will include psychosocial adjustment; treatment motivation, expectations and experiences; cost-effectiveness; and carer burden. DISCUSSION: The results of this study will provide a rigorous evaluation of two intensive treatment approaches which will inform future national and international treatment guidelines and service provision. TRIAL REGISTRATION: ISRCTN ISRCTN10166784 . Registered 28 February 2020. ISRCTN is a primary registry of the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) network and includes all items from the WHO Trial Registration Data Set.

Randomised controlled feasibility trial of real versus sham repetitive transcranial magnetic stimulation treatment in adults with severe and enduring anorexia nervosa: the TIARA study.

OBJECTIVE: Treatment options for severe, enduring anorexia nervosa (SE-AN) are limited. Non-invasive neuromodulation is a promising emerging intervention. Our study is a feasibility randomised controlled trial of repetitive transcranial magnetic stimulation (rTMS) in individuals with SE-AN, which aims to inform the design of a future large-scale trial. DESIGN: Double-blind, parallel group, two-arm, sham-controlled trial. SETTING: Specialist eating disorders centre. PARTICIPANTS: Community-dwelling people with anorexia nervosa, an illness duration of ≥3 years and at least one previous completed treatment. INTERVENTIONS: Participants received 20 sessions (administered over 4 weeks) of MRI-guided real or sham high-frequency rTMS to the left dorsolateral prefrontal cortex in addition to treatment-as-usual. OUTCOMES: Primary outcomes were recruitment, attendance and retention rates. Secondary outcomes included body mass index (BMI), eating disorder symptoms, mood, quality of life and rTMS safety and tolerability. Assessments were conducted at baseline, post-treatment and follow-up (ie, at 0 month, 1 month and 4 months post-randomisation). RESULTS: Thirty-four participants (17 per group) were randomly allocated to real or sham rTMS. One participant per group was withdrawn prior to the intervention due to safety concerns. Two participants (both receiving sham) did not complete the treatment. rTMS was safe and well tolerated. Between-group effect sizes of change scores (baseline to follow-up) were small for BMI (d=0.2, 95% CI -0.49 to 0.90) and eating disorder symptoms (d=0.1, 95% CI -0.60 to 0.79), medium for quality of life and moderate to large (d=0.61 to 1.0) for mood outcomes, all favouring rTMS over sham. CONCLUSIONS: The treatment protocol is feasible and acceptable to participants. Outcomes provide preliminary evidence for the therapeutic potential of rTMS in SE-AN. Largest effects were observed on variables assessing mood. This study supports the need for a larger confirmatory trial to evaluate the effectiveness of multi-session rTMS in SE-AN. Future studies should include a longer follow-up period and an assessment of cost-effectiveness. TRIAL REGISTRATION NUMBER: ISRCTN14329415; Pre-results.

The NOURISHED randomised controlled trial comparing mentalisation-based treatment for eating disorders (MBT-ED) with specialist supportive clinical management (SSCM-ED) for patients with eating disorders and symptoms of borderline personality disorder.

BACKGROUND: In this multi-centre randomized controlled trial (RCT) we compared modified mentalisation-based treatment (MBT-ED) to specialist supportive clinical management (SSCM-ED) in patients with eating disorders (EDs) and borderline personality disorder symptoms (BPD). This group of patients presents complex challenges to clinical services, and a treatment which addresses their multiple problems has the potential to improve outcome. MBT has been shown to be effective in improving outcome in patients with BPD, but its use has not been reported in ED. METHODS: Sixty-eight eligible participants were randomised to MBT-ED or SSCM-ED. The primary outcome measure was the global score on the Eating Disorder Examination. Secondary outcomes included measures of BPD symptoms (the Zanarini Rating Scale for Borderline Personality Disorder), general psychiatric state, quality of life and service utilisation. Participants were assessed at baseline and at 6, 12 and 18 months after randomisation. Analysis was performed using linear mixed models. RESULTS: Only 15 participants (22 %) completed the 18 month follow-up. Early drop-out occurred significantly more in the SSCM-ED group. Drop-out did not vary with treatment model later in therapy and was sometimes attributed to participants moving away. There was higher drop--out amongst smokers and those with higher neuroticism scores. 47.1 % of participants in the MBT-ED arm and 37.1 % in the SSCM-ED arm attended at least 50 % of therapy sessions offered. Amongst those remaining in the trial, at 12 and 18 months MBT-ED was associated with a greater reduction in Shape Concern and Weight Concern in the Eating Disorder Examination compared to SSCM-ED. At 6, 12 and 18 months there was a decline of ED and BPD symptoms in both groups combined. Ten participants were reported as having had adverse events during the trial, mostly self-harm, and there was one death, attributed as 'unexplained' by the coroner. CONCLUSIONS: The high drop-out rate made interpretation of the results difficult. Greater involvement of research staff in clinical management might have improved compliance with both therapy and research assessment. MBT-ED may have had an impact on core body image psychopathology. TRIAL REGISTRATION: Current Controlled Trials: ISRCTN51304415 . Registered on 19 April 2011.

Clinical outcomes and neural correlates of 20 sessions of repetitive transcranial magnetic stimulation in severe and enduring anorexia nervosa (the TIARA study): study protocol for a randomised controlled feasibility trial.

BACKGROUND: Anorexia nervosa (AN) is a serious mental disorder with multiple comorbidities and complications. In those with a severe and enduring form of the illness (SEED-AN), treatment responsivity is poor and the evidence base limited. Thus, there is a need for novel treatment strategies. This paper describes the theoretical background and protocol of a feasibility randomised controlled trial (RCT) of real versus sham (placebo) therapeutic repetitive transcranial magnetic stimulation (rTMS) in SEED-AN. The aim of this trial is to obtain information that will guide decision making and protocol development in relation to a future large-scale RCT of rTMS in this group of patients, and also to assess the preliminary efficacy and neural correlates of rTMS treatment. DESIGN: Forty-four adults from the community with a DSM-5 diagnosis of AN, an illness duration>3 years and a previous course of unsuccessful treatment will be randomly allocated to receive 20 sessions of either real or sham rTMS, in a parallel group design. As this is a feasibility study, no primary outcome has been defined and a broad range of outcome variables will be examined. These include weight/body mass index (BMI), eating disorder psychopathology, other psychopathology (for example, depression, anxiety), quality of life, neuropsychological processes (such as self-regulation, attentional bias and food choice behaviour), neuroimaging measures (that is, changes in brain structure or function), tolerability and acceptability of rTMS, and additional service utilisation. The feasibility of conducting a large-scale RCT of rTMS and the appropriateness of rTMS as a treatment for SEED-AN will be evaluated through: assessment of recruitment and retention rates, acceptability of random allocation, blinding success (allocation concealment), completion of treatment sessions and research assessments (baseline, post-treatment and follow-up assessments). The acceptability and tolerability of the treatment will be assessed via semi-structured interviews. DISCUSSION: The effect sizes generated and other findings from this trial will inform a future large-scale RCT with respect to decisions on primary outcome measures and other aspects of protocol development. Additionally, results from this study will provide a preliminary indication of the efficacy of rTMS treatment for AN, the neural correlates of the illness, and potential biomarkers of clinical response. TRIAL REGISTRATION: ISRCTN14329415 . Date of registration: 23 July 2015.

Exploring autistic traits in anorexia: a clinical study.

BACKGROUND: The objectives of this study were to explore associations between autistic traits and self-reported clinical symptoms in a population with anorexia nervosa (AN). Experimental and self-report evidence reveals similarities between AN and autism spectrum condition (ASC) populations in socio-emotional and cognitive domains; this includes difficulties with empathy, set-shifting and global processing. Focusing on these similarities may lead to better tailored interventions for both conditions. METHODS: A cross-sectional independent-groups design was employed. Participants with AN (n = 66) and typical controls (n = 66) completed self-report questionnaires including the Short (10-Item) Version Autism Spectrum Quotient (AQ-10) questionnaire (the first time this has been implemented in this population), the Eating Disorder Examination Questionnaire, the Hospital Anxiety and Depression Scale and the Work and Social Adjustment Scale. Group differences and the relationship between autistic traits and other questionnaire measures were investigated. RESULTS: The AN group had a significantly higher AQ-10 total score and a greater proportion scored above the clinical cut-off than the control group. Seven out of ten AQ-10 items significantly discriminated between groups. In the AN group, levels of autistic traits correlated with a greater self-reported anxiety and depression and a lower ability to maintain close relationships; however, eating disorder symptoms were not associated with autistic traits. CONCLUSIONS: Women with anorexia possess a greater number of autistic traits than typical women. AQ-10 items that discriminated between groups related to 'bigger picture' (global) thinking, inflexibility of thinking and problems with social interactions, suggesting that autistic traits may exacerbate factors that maintain the eating disorder rather than cause the eating disorder directly. Using screening instruments may improve understanding of patients' problems, leading to better tailoring of intervention. We conclude that further investigation of autistic traits in AN could inform new intervention approaches based on joint working between ASC and eating disorder services.

Harnessing clinical psychiatric data with an electronic assessment tool (OPCRIT+): the utility of symptom dimensions.

Progress in personalised psychiatry is dependent on researchers having access to systematic and accurately acquired symptom data across clinical diagnoses. We have developed a structured psychiatric assessment tool, OPCRIT+, that is being introduced into the electronic medical records system of the South London and Maudsley NHS Foundation Trust which can help to achieve this. In this report we examine the utility of the symptom data being collected with the tool. Cross-sectional mental state data from a mixed-diagnostic cohort of 876 inpatients was subjected to a principal components analysis (PCA). Six components, explaining 46% of the variance in recorded symptoms, were extracted. The components represented dimensions of mania, depression, positive symptoms, anxiety, negative symptoms and disorganization. As indicated by component scores, different clinical diagnoses demonstrated distinct symptom profiles characterized by wide-ranging levels of severity. When comparing the predictive value of symptoms against diagnosis for a variety of clinical outcome measures (e.g. 'Overactive, aggressive behaviour'), symptoms proved superior in five instances (R(2) range: 0.06-0.28) whereas diagnosis was best just once (R(2):0.25). This report demonstrates that symptom data being routinely gathered in an NHS trust, when documented on the appropriate tool, have considerable potential for onward use in a variety of clinical and research applications via representation as dimensions of psychopathology.

Neurobiology of depression and novel antidepressant drug targets.

Depression is one of the most common psychiatric conditions affecting numerous individuals in the world. However, the currently available antidepressant medication shows low response and remission rates. Thus, new antidepressants need to be discovered or developed. Aiming to describe the current neurobiological hypotheses regarding the pathophysiology of depression and in order to give an overview of novel possible antidepressant drug targets, we reviewed publications and studies referring to the neurobiology of depression. This review included genetics, epigenetics and gene expression, neuroanatomy and structural anatomy, neurochemistry, neuroendocrinology, neuroimmunology and novel drug targets using a MEDLINE/Pubmed search. The search was augmented by a manual search of bibliographies, textbooks, and abstracts from recent scientific meetings. On the one hand, the literature reveals in part contradictory information, but on the other hand, it shows convergent information regarding the relevance of research targets apart from the monoamine deficiency hypothesis of depression such as epigenetic phenomena and changes in neuronal and glial function and structure. Recent neurobiological findings in these areas of research provide multidimensional perspectives for the progress in the psychopharmacological treatment of depression.

Combined effects of exonic polymorphisms in CRHR1 and AVPR1B genes in a case/control study for panic disorder.

Accumulating evidence from animal studies suggests that the corticotropin releasing hormone (CRH) and arginine vasopressin (AVP) neuropeptide systems, contribute to anxiety behavior. To investigate whether polymorphisms in the genes regulating these two systems may alter susceptibility to anxiety disorders in humans, we genotyped 71 single nucleotide polymorphisms (SNPs) in CRH, CRHR1, CRHR2, AVP, AVPR1A, AVPR1B in a German sample from Munich with patients suffering from panic disorder and matched healthy controls (n = 186/n = 299). Significant associations were then replicated in a second German sample with 173 patients with panic disorder and 495 controls. In both samples separately and the combined sample, SNPs within CHRH1 and AVPR1B were nominally associated with panic disorder. We then tested two locus multiplicative and interaction effects of polymorphisms of these two genes on panic disorder. Fifteen SNP pairs showed significant multiplicative effects in both samples. The SNP pair with the most significant association in the combined sample (P = 0.00057), which withstood correction for multiple testing, was rs878886 in CRHR1 and rs28632197 in AVPR1B. Both SNPs are of potential functional relevance as rs878886 is located in the 3' untranslated region of the CRHR1 and rs28632197 leads to an arginine to histidine amino acid exchange at position 364 of AVPR1B which is located in the intracellular C-terminal domain of the receptor. These data suggest that polymorphisms in the AVPR1B and the CRHR1 genes alter the susceptibility to panic disorder.

Polymorphisms in the galanin gene are associated with symptom-severity in female patients suffering from panic disorder.

BACKGROUND: Galanin (GAL) is a neuropeptide, which is expressed primarily in limbic nuclei in the brain and mediates miscellaneous physiological processes and behaviors. In animal studies, both the application of GAL and antagonism of its receptors have been shown to affect anxiety-like and depression-related behavior. In humans, intravenous administration of the neuropeptide galanin has been reported to have fast antidepressant efficacy. Furthermore, GAL is involved in hypothalamic-hypophysiotropic signalling and cosecreted with luteinizing hormone-releasing hormone (LHRH), possibly acting as a mediator of estrogen action. METHODS: In this study six single nucleotide polymorphisms (SNPs) within the gene coding for GAL were analyzed for possible associations with diagnosis and severity of symptoms in 121 male and female patients suffering from panic disorder (PD). RESULTS: Our results suggest an association between genetic variations in the GAL-gene and severity of PD-symptoms in female patients. The most pronounced effects could be observed for two haplotypes containing the closely linked, non-protein-coding SNPs rs948854 and rs4432027. Both polymorphisms are located within CpG-dinucleotides in the promoter region of GAL and thus might be involved in epigenetic regulation of the GAL-gene. LIMITATIONS: A relatively small patient sample was analyzed in this study, the herein presented results need to be validated in independent studies. CONCLUSIONS: The results of this study underline the potential of further genetic research concerning GAL and a possible role of this neuropeptide in the pathogenesis of female PD. In this regard, GAL and its receptors appear to be a promising target for pharmacological therapy of anxiety and affective disorders.

Polymorphisms in the serotonin receptor gene HTR2A are associated with quantitative traits in panic disorder.

Anxiety disorders and specifically panic disorder (PD) are caused by complex interactions of environmental and genetic factors. The latter comprise many different genes, from which those involved in serotonergic neurotransmission have received particular attention. Here we report the results from an association candidate-gene approach, where we analyzed 15 single nucleotide polymorphisms (SNPs) within the gene coding for the serotonin-receptor 2A (HTR2A) in patients suffering from PD and a control sample. We found that the SNP rs2296972 shows an association between the number of T-alleles and severity of symptoms in PD. By performing tests according to the Fisher product method (FPM), an association between HTR2A and the personality trait reward dependence could be shown. Most pronounced effects were observable for the SNPs rs2770304, rs6313, and rs6311. Furthermore, the polymorphisms rs3742278, rs2296972, and rs2770292 form a haplotype, which may be associated with higher susceptibility for PD. These results further underline a possible important role of genetic variations within the system controlling serotonergic neurotransmission for the development and course of disease in PD.

Association of polymorphisms in P2RX7 and CaMKKb with anxiety disorders.

BACKGROUND: There is considerable evidence that genetic factors play an important role in the pathophysiology of affective disorders including bipolar disorder, major depressive disorder and anxiety disorders. Long-term follow up studies as well as drug treatment studies suggest that these clinical conditions share a number of pathophysiological commonalities including genetic variables. One possible candidate region is located on chromosome 12q24.31, originated from previous linkage and association studies with bipolar disorder and unipolar depression. This region contains two candidate genes for purinergic ligand-gated ion channels, P2RX7 and P2RX4, and one gene coding for calmodulin-dependent protein kinase kinase b (CaMKKb). METHODS: In the present study, we investigated the genetic associations between 15 SNPs in the candidate genes P2RX7, P2RX4 and CaMKKb on chromosome 12q24.31 in 179 patients with anxiety disorders and syndromal panic attacks versus 462 healthy controls. RESULTS: One nominal case-control association could be detected for a SNP in the 5'UTR region of P2RX4, which did not remain significant after correction for multiple testing. We found, however, a prominent association between severity of panic- and agoraphobia symptoms and an exonic SNP (rs3817190) in the CaMKKb gene and a trend for association with an exonic SNP in P2RX7 (rs1718119) with severity scores in the panic- and agoraphobia scale. CONCLUSION: The locus 12q24.31 seems to be an important genetic region for anxiety, bipolar and unipolar disorders, suggesting a genetic overlap in the group of affective disorders. The specific contribution of the herein reported gene polymorphisms to the clinical condition is still unclear and warrants further analysis.

Association of a Met88Val diazepam binding inhibitor (DBI) gene polymorphism and anxiety disorders with panic attacks.

Several lines of evidence suggest that anxiety disorders have a strong genetic component, but so far only few susceptibility genes have been identified. There is preclinical and clinical evidence for a dysregulation of the central gamma-aminobutyric acid (GABA)-ergic tone in the pathophysiology of anxiety disorders. Diazepam binding inhibitor (DBI) has been suggested to play a pivotal role in anxiety disorders through direct and indirect, i.e. via synthesis of neuroactive steroids, modulation of GABA(A) receptor function. These findings suggest that the DBI gene can be postulated as a candidate for a genetic association study in this disorder. Thus, single nucleotide polymorphisms (SNPs) of the DBI gene were investigated for putative disease associations in a German sample of anxiety disorder patients suffering from panic attacks and matched controls. We were able to detect a significant association between a non-synonymous coding variant of DBI with anxiety disorders with panic attacks. The rare allele of this polymorphism was more frequent in controls than in patients (OR=0.43; 95% CI: 0.19-0.95). In conclusion, these results suggest a central role of DBI genetic variants in the susceptibility for the development of anxiety disorders that are characterized by the occurrence of panic attacks.

Combined dexamethasone/corticotropin releasing hormone test predicts treatment response in major depression - a potential biomarker?

BACKGROUND: Exaggerated corticotropin (ACTH) and cortisol response to the combined dexamethasone (DEX)/corticotropin releasing hormone (CRH) test, indicating impaired regulation of the hypothalamus-pituitary-adrenocortical (HPA) system, is frequently observed in depression. In the present study, we examined whether change in HPA system function during the first weeks of hospitalization predicts response to antidepressant treatment in major depression and thus constitutes a potential biomarker. METHODS: We conducted the DEX/CRH test in 50 inpatients suffering from severe major depression, once after study inclusion and a second time 2 to 3 weeks later while under continuous antidepressant treatment. RESULTS: We found increased ACTH and cortisol responses to the first DEX/CRH test compared with healthy control subjects. In the second DEX/CRH test 2 to 3 weeks later, 36 of the 50 patients showed an attenuated cortisol response, while 14 patients did not display improvement or exhibited even aggravation of the altered HPA system function. Improved HPA system regulation in the second DEX/CRH test was associated with beneficial treatment response after 5 weeks and a higher remission rate at the end of hospitalization. CONCLUSIONS: The results suggest that change in HPA system regulation assessed with repeated DEX/CRH tests is a potential biomarker that may predict clinical outcome at follow-up. There is consensus that the drug development process could be improved, once reliable biomarkers become available that help to allow a judgement regarding the efficacy of a novel drug candidate. The combined DEX/CRH test seems to be a promising candidate for such a biomarker.

Regulation of the hypothalamic-pituitary-adrenocortical system in patients with panic disorder.

Anxiety and depressive disorders are among the most common psychiatric disorders with a high number of hospital admissions and a lifetime prevalence of up to 25%. So far, the pathophysiological mechanisms for anxiety disorders remain to be found. Preclinical studies suggest that changes in hypothalamic-pituitary-adrenocortical (HPA) system function are causally related to the expression of anxiety-related behavior. The findings on HPA system function in patients with anxiety disorders are, however, heterogeneous. Both hypo- and hyperresponsiveness of HPA response in various anxiety disorders under different experimental conditions were found. In order to characterize putative case/control differences in HPA system function, we performed a Dex-CRH test, a widely used test to pick up changes in HPA system regulation with high sensitivity, in 30 patients with panic disorder, 35 patients with major depressive episode and in 30 controls individually matched for ethnicity, age and gender. The results indicate a similar dysregulation of the HPA system response in the Dex-CRH test in both patient groups. This finding further underlines the hypothesis that both, depression and panic disorder, share impaired HPA system regulation, supporting the notion that the impairment is involved in the pathophysiology of these clinical conditions. However, differences in the suppression effects and psychopathological correlation patterns between depressed and panic patients suggest different biological mechanisms of HPA system dysregulation in both disorders.

Hypothalamus-pituitary-adrenal system regulation and suicidal behavior in depression.

BACKGROUND: One of the most demanding tasks in psychiatry is to protect patients from suicidal attempts. Preventive strategies could be improved by increasing our knowledge on the pathophysiologic disturbances underlying this behavior. More than 70-80% of suicides occur in the context of depressive disorders, in which dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis is one of the most prominent neurobiological findings. So far data on the involvement of the HPA axis in the pathophysiology of suicidal behavior in depressed patients are controversial. METHODS: In this retrospective study, we administered the combined dexamethasone-suppression/CRH stimulation (Dex/CRH) test to 310 patients with a depressive syndrome characterized at admission for acute and past suicidal behavior within the first 10 days after hospitalization. RESULTS: Suicidal behavior in depressed patients, including past and recent suicide attempts as well as suicidal ideation, was associated with a lower adrenocorticotropin and cortisol response in the combined Dex/CRH test, with lowest hormone levels observed in patients with a recent suicide attempt. DISCUSSION: The findings suggest that suicidal behavior may alter HPA axis regulation in depressed patients. Large-scale prospective studies assessing neuroendocrine changes may help to develop predictors for an early identification of patients at risk for committing suicide.

Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment.

The stress hormone-regulating hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the causality as well as the treatment of depression. To investigate a possible association between genes regulating the HPA axis and response to antidepressants and susceptibility for depression, we genotyped single-nucleotide polymorphisms in eight of these genes in depressed individuals and matched controls. We found significant associations of response to antidepressants and the recurrence of depressive episodes with single-nucleotide polymorphisms in FKBP5, a glucocorticoid receptor-regulating cochaperone of hsp-90, in two independent samples. These single-nucleotide polymorphisms were also associated with increased intracellular FKBP5 protein expression, which triggers adaptive changes in glucocorticoid receptor and, thereby, HPA-axis regulation. Individuals carrying the associated genotypes had less HPA-axis hyperactivity during the depressive episode. We propose that the FKBP5 variant-dependent alterations in HPA-axis regulation could be related to the faster response to antidepressant drug treatment and the increased recurrence of depressive episodes observed in this subgroup of depressed individuals. These findings support a central role of genes regulating the HPA axis in the causality of depression and the mechanism of action of antidepressant drugs.

Intravenous L-lactate application in minipigs partially protects acetylcholinesteratic but not butyrylcholinesteratic activity in plasma from inhibition by paraoxon.

OBJECTIVE: Intoxications with organophosphorous compounds such as paraoxon, an inhibitor of serine hydrolases, mainly butyrylcholinesterase and acetylcholinesterase, are frequent. Oximes are the only enzyme reactivators clinically available. In vitro studies have shown that L(+)-lactate reduces the inhibition of acetylcholinesteratic (AChEA) and butyrylcholinesteratic activity of plasma (BChEA) by paraoxon. DESIGN: The purpose of this in vivo study was to determine whether intravenous L(+)-lactate application under normoxic/normocapnic/normohydrogenemic conditions is able to protect AChEA and BChEA from paraoxon inhibition. SETTING: University research institute. SUBJECTS: Eighteen female minipigs. INTERVENTIONS: Animals were anesthetized, intubated, and mechanically ventilated. Every animal received 1 mg of paraoxon per kilogram of body weight in 50 mL of saline over 50 mins. In addition to receiving paraoxon, six pigs of 18 received 2.5 g (0.125 g kg-1 of body weight) of intravenous L(+)-lactate in 50 mL of saline over 50 mins, and six other pigs received 10 g of L(+)-lactate (0.5 g kg-1 of body weight), whereas the six remaining served as controls. MEASUREMENTS AND MAIN RESULTS: In central venous blood, plasma acetylcholinesteratic and butyrylcholinesteratic activity were measured before paraoxon (baseline, 0 mins), immediately after paraoxon (50 mins after start), and 110, 170, 230, 290, 530, and 1010 mins after the start of infusion. Although 10 g of intravenous L(+)-lactate application had a statistically significant protective effect in vivo on AChEA, 2.5 g did not. No significant protective effect on BChEA was achieved with either 2.5 g or 10 g of L(+)-lactate. CONCLUSIONS: Ten grams of L(+)-lactate can increase AChEA when administered simultaneously with paraoxon. Further study of the in vivo effects of L(+)-lactate after paraoxon intoxication and a formal comparison with standard oxime therapy seem warranted. Also, methods for achieving a prolonged elevated lactate concentration in vivo should be investigated.