CLEAR - clozapine in early psychosis: study protocol for a multi-centre, randomised controlled trial of clozapine vs other antipsychotics for young people with treatment resistant schizophrenia in real world settings.

BACKGROUND: Clozapine is an antipsychotic drug with unique efficacy, and it is the only recommended treatment for treatment-resistant schizophrenia (TRS: failure to respond to at least two different antipsychotics). However, clozapine is also associated with a range of adverse effects which restrict its use, including blood dyscrasias, for which haematological monitoring is required. As treatment resistance is recognised earlier in the illness, the question of whether clozapine should be prescribed in children and young people is increasingly important. However, most research to date has been in older, chronic patients, and evidence regarding the efficacy and safety of clozapine in people under age 25 is lacking. The CLEAR (CLozapine in EARly psychosis) trial will assess whether clozapine is more effective than treatment as usual (TAU), at the level of clinical symptoms, patient rated outcomes, quality of life and cost-effectiveness in people below 25 years of age. Additionally, a nested biomarker study will investigate the mechanisms of action of clozapine compared to TAU. METHODS AND DESIGN: This is the protocol of a multi-centre, open label, blind-rated, randomised controlled effectiveness trial of clozapine vs TAU (any other oral antipsychotic monotherapy licenced in the British National Formulary) for 12 weeks in 260 children and young people with TRS (12-24 years old). AIM AND OBJECTIVES: The primary outcome is the change in blind-rated Positive and Negative Syndrome Scale scores at 12 weeks from baseline. Secondary outcomes include blind-rated Clinical Global Impression, patient-rated outcomes, quality of life, adverse effects, and treatment adherence. Patients will be followed up for 12 months and will be invited to give consent for longer term follow-up using clinical records and potential re-contact for further research. For mechanism of action, change in brain magnetic resonance imaging (MRI) biomarkers and peripheral inflammatory markers will be measured over 12 weeks. DISCUSSION: The CLEAR trial will contribute knowledge on clozapine effectiveness, safety and cost-effectiveness compared to standard antipsychotics in young people with TRS, and the results may guide future clinical treatment recommendation for early psychosis. TRIAL REGISTRATION: ISRCTN Number: 37176025, IRAS Number: 1004947. TRIAL STATUS: In set-up. Protocol version 4.0 01/08/23. Current up to date protocol available here: https://fundingawards.nihr.ac.uk/award/NIHR131175# /.

Randomized controlled trial of multi-modular motion-assisted memory desensitization and reconsolidation (3MDR) for male military veterans with treatment-resistant post-traumatic stress disorder.

OBJECTIVE: To explore the potential efficacy of multi-modular motion-assisted memory desensitization and reprocessing (3MDR) in British military veterans with treatment-resistant service-related PTSD. METHODS: Exploratory single-blind, randomized, parallel arm, cross-over controlled trial with nested process evaluation to assess fidelity, adherence and factors that influence outcome. RESULTS: A total of 42 participants (all male) were randomized with 83% retention at 12 weeks and 86% at 26 weeks. The difference in mean Clinician-Administered PTSD Scale for DSM-5 scores between the immediate and delayed 3MDR arms was -9.38 (95% CI -17.33 to -1.44, P = 0.021) at 12 weeks and -3.59 (-14.39 to 7.20, P = 0.513) at 26 weeks when both groups had received 3MDR. The likely effect size of 3MDR was found to be 0.65. Improvements were maintained at 26-week follow-up. 3MDR was found to be acceptable to most, but not all, participants. Several factors that may impact efficacy and acceptability of 3MDR were identified. CONCLUSION: 3MDR is a promising new intervention for treatment-resistant PTSD with emerging evidence of effect.

Psychological sequelae of colonic resections.

AIM: The prevalence of anxiety, depression and post-traumatic stress disorder (PTSD) in the general population has been estimated to be 5.9%, 3.3% and 4.4% respectively. The aim of this study was to determine whether psychological problems are more prevalent following colorectal surgery. METHOD: Patients who had undergone colorectal resection in a 2-year period across four centres were asked to complete validated screening questionnaires for anxiety, depression and PTSD (GAD-7, PHQ-9, PCL-5) 12-48 months after surgery. Risk factors were identified using multiple linear regression analysis. RESULTS: After excluding those who had died or received palliative diagnoses, questionnaires were sent to 1150 patients. 371 responded (32.3% response rate); median age 67 (20-99) years; 51% were men. 58% of patients underwent surgery for cancer; 23% had emergency surgery. 28% of patients screened positive for at least one psychological condition, with 20% screening positive for anxiety, 22% for depression and 14% for PTSD. Patients who were younger, women, had surgery as an emergency, for benign conditions, had stomas and had critical care stay were more likely to have poorer psychological outcomes. Multiple linear regression found that only younger age (P = 0.000) and female gender (P = 0.048) were significant risk factors. CONCLUSION: The prevalence of anxiety, depression and PTSD appears to be high in patients who have undergone colorectal surgery. Younger patients and women are particularly at risk. Further work is needed to determine how best to prevent, detect and treat people with adverse psychological outcomes following colorectal surgery.

Childhood adversity, mental health and suicide (CHASE): a methods protocol for a longitudinal case-control linked data study.

INTRODUCTION: Suicide is a tragic outcome with devastating consequences. In 2018, Scotland experienced a 15% increase in suicide from 680 to 784 deaths. This was marked among young people, with an increase of 53% in those aged 15-24, the highest since 2007. Early intervention in those most at risk is key, but identification of individuals at risk is complex, and efforts remain largely targeted towards universal suicide prevention strategies with little evidence of effectiveness.Recent evidence suggests childhood adversity is a predictor of subsequent poor social and health outcomes, including suicide. This protocol reports on methodology for harmonising lifespan hospital contacts for childhood adversity, mental health, and suicidal behaviour. This will inform where to 1) focus interventions, 2) prioritise trauma-informed approaches, and 3) adapt support avenues earlier in life for those most at risk. METHODS: This study will follow a case-control design. Scottish hospital data (physical health SMR01; mental health SMR04; maternity/birth record SMR02; mother's linked data SMR01, SMR04, death records) from 1981 to as recent as available will be extracted for people who died by suicide aged 10-34, and linked on Community Health Index unique identifier. A randomly selected control population matched on age and geography at death will be extracted in a 1:10 ratio. International Classification of Disease (ICD) codes will be harmonised between ICD9-CM, ICD9, ICD10-CM and ICD10 for childhood adversity, mental health, and suicidal behaviour. RESULTS: ICD codes for childhood adversity from four key studies are reported in two categories, 1) Maltreatment or violence-related codes, and 2) Codes suggestive of maltreatment. 'Clinical Classifications Software' ICD codes to operationalise mental health codes are also reported. Harmonised lifespan ICD categories were achieved semi-automatically, but required labour-intensive supplementary manual coding. Cross-mapped codes are reported. CONCLUSION: There is a dearth of evidence about touchpoints prior to suicide. This study reports methods and harmonised ICD codes along the lifespan to understand hospital contact patterns for childhood adversity, which come to the attention of hospital practitioners. KEY WORDS: Childhood Adversity, Adverse Childhood Experiences, Mental Health, Self-harm, Suicide, Suicidality, Violence, Hospital episodes, Routine Data, Data Linkage, Study Protocol.

Internet-delivered cognitive behavioural therapy for post-traumatic stress disorder: systematic review and meta-analysis.

OBJECTIVE: To determine whether Internet-delivered cognitive behavioural therapy (i-CBT) is an effective treatment for those who meet diagnostic criteria for post-traumatic stress disorder (PTSD). METHOD: A systematic review was undertaken according to Cochrane Collaboration Guidelines. The primary outcome measures were reduction in PTSD symptoms and drop-out. Categorical outcomes were meta-analysed as risk ratios (RRs) and continuous outcomes as mean differences (MDs) or standardised mean differences (SMDs). RESULTS: Ten studies with 720 participants were included. Evidence showed that i-CBT may be associated with a clinically important reduction in post-treatment PTSD symptoms compared with wait list (SMD -0.60, 95% confidence interval -0.97 to -0.24; N = 560); however, only three studies reported follow-up data, and there was no evidence to support the maintenance of symptom improvement at follow-up of 3-6 months. There was no evidence of a difference in PTSD symptoms between i-CBT and Internet-delivered non-CBT post-treatment. There was evidence of greater treatment effect from trauma-focused i-CBT than i-CBT without a trauma focus, as well as evidence that treatment effect was increased by the provision of guidance. CONCLUSIONS: While the review found some beneficial effects of i-CBT for PTSD post-treatment, the quality of the evidence was very low because of the small number of included trials and there was insufficient evidence to support the maintenance of improvement at follow-up of 3-6 months. Further work is required to establish non-inferiority to current first-line interventions; to determine long-term efficacy; to explore mechanisms of effect; and to establish optimal levels of guidance.

The International Trauma Questionnaire: development of a self-report measure of ICD-11 PTSD and complex PTSD.

OBJECTIVE: The purpose of this study was to finalize the development of the International Trauma Questionnaire (ITQ), a self-report diagnostic measure of post-traumatic stress disorder (PTSD) and complex PTSD (CPTSD), as defined in the 11th version of the International Classification of Diseases (ICD-11). METHOD: The optimal symptom indicators of PTSD and CPTSD were identified by applying item response theory (IRT) analysis to data from a trauma-exposed community sample (n = 1051) and a trauma-exposed clinical sample (n = 247) from the United Kingdom. The validity of the optimized 12-item ITQ was assessed with confirmatory factor analyses. Diagnostic rates were estimated and compared to previous validation studies. RESULTS: The latent structure of the 12-item, optimized ITQ was consistent with prior findings, and diagnostic rates of PTSD and CPTSD were in line with previous estimates. CONCLUSION: The ITQ is a brief, simply worded measure of the core features of PTSD and CPTSD. It is consistent with the organizing principles of the ICD-11 to maximize clinical utility and international applicability through a focus on a limited but central set of symptoms. The measure is freely available and can be found in the body of this paper.

A Mixture of Five Bacterial Strains Attenuates Skin Inflammation in Mice.

BACKGROUND: There is a growing interest in the effects of probiotics for the prevention and treatment of skin diseases due to their immunomodulatory and antiinflammatory properties. OBJECTIVE: To assess a mixture of five bacterial strains in the prevention of chronic skin inflammation in mice. METHODS: Hairless SKH-1 mice received daily oral treatment with the probiotic mixture at the dose of 1x109 Colony-Forming Unit (CFU)/day (or vehicle) for three weeks. Chronic skin inflammation was induced by repeated applications of 12-O-tetradecanoylphorbol-13- acetate (TPA; control mice received acetone). Macroscopic and microscopic evaluations of skin lesions were performed and serum levels of interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-α, IL-17, IL-22, IL-10 and IL-4 measured at the end of the study. RESULTS: Treatment with the probiotic mixture significantly limited the induced chronic skin inflammation at both the macroscopic and microscopic levels. This limitation was consistent with downregulated levels of pro-inflammatory cytokines (IL-1ß, IL-6, TNF-α, IL- 17 and IL-22) and up-regulated levels of the anti-inflammatory cytokines, IL-10 and IL-4. CONCLUSION: The results suggest that the probiotic mixture tested could help in preserving skin integrity and homeostasis and that its use could be beneficial in dermatological conditions such as atopic dermatitis and psoriasis.

Antibiotic prophylaxis in veterinary cancer chemotherapy: A review and recommendations.

Bacterial infection following cancer chemotherapy-induced neutropenia is a serious cause of morbidity and mortality in human and veterinary patients. Antimicrobial prophylaxis is controversial in the human oncology field, as any decreased incidence in bacterial infections is countered by patient adverse effects and increased antimicrobial resistance. Comprehensive guidelines exist to aid human oncologists in prescribing antimicrobial prophylaxis but similar recommendations are not available in veterinary literature. As the veterinarian's role in antimicrobial stewardship is increasingly emphasized, it is vital that veterinary oncologists implement appropriate antimicrobial use. By considering the available human and veterinary literature we present an overview of current clinical practices and are able to suggest recommendations for prophylactic antimicrobial use in veterinary cancer chemotherapy patients.

Lactobacillus salivarius LA307 and Lactobacillus rhamnosus LA305 attenuate skin inflammation in mice.

Oral probiotics potential for the management of dermatological diseases is vast. However, results of available studies in skin diseases, such as atopic dermatitis (AD), are inconsistent, partly because probiotic effects are strain specific. Careful selection of probiotic strains is therefore indispensable to ensure efficacy of treatment. In this study, Lactobacillus salivarius LA307, Lactobacillus rhamnosus LA305 and Bifidobacterium bifidum PI22, three strains that were previously identified for their interesting immunomodulatory properties in allergy and/or colitis models, were assessed in the prevention of chronic skin inflammation induced by repeated applications of 12-O-tetradecanoylphorbol-13-acetate in hairless SKH-1 mice. Macroscopic and microscopic evaluation of skin lesions was performed together with measurements of serum levels of interleukin (IL)-1ß, IL-6, tumour necrosis factor alpha (TNF-α), IL-17, IL-22, IL-10 and IL-4. Daily oral treatment with the three strains at the dose of 1×109 cfu/day for 3 weeks limited the development of chronic skin inflammation, the effects being strain dependent. Indeed the two Lactobacillus strains significantly limited the intensity of skin inflammation both at the macroscopic and microscopic levels. Macroscopic observations were correlated to the histological observations and the resulting microscopic score. This limitation of the development of AD-like skin lesions involved the modulation of cytokine production. Treatment with the two Lactobacillus strains induced a decrease in the serum levels of pro-inflammatory cytokines IL-1ß, IL-6, TNF-α, IL-17, IL-22 and at the opposite an increase in the production of the anti-inflammatory cytokine IL-10 and also of IL-4. Globally, B. bifidum PI22 had lower benefits. These results obtained in mice suggest that L. salivarius LA307 and L. rhamnosus LA305 could be good candidates for preserving skin integrity and homeostasis via the modulation of the gut microbiota and that their use could be beneficial in dermatological conditions such as AD.

Largest GWAS of PTSD (N=20 070) yields genetic overlap with schizophrenia and sex differences in heritability.

The Psychiatric Genomics Consortium-Posttraumatic Stress Disorder group (PGC-PTSD) combined genome-wide case-control molecular genetic data across 11 multiethnic studies to quantify PTSD heritability, to examine potential shared genetic risk with schizophrenia, bipolar disorder, and major depressive disorder and to identify risk loci for PTSD. Examining 20 730 individuals, we report a molecular genetics-based heritability estimate (h2SNP) for European-American females of 29% that is similar to h2SNP for schizophrenia and is substantially higher than h2SNP in European-American males (estimate not distinguishable from zero). We found strong evidence of overlapping genetic risk between PTSD and schizophrenia along with more modest evidence of overlap with bipolar and major depressive disorder. No single-nucleotide polymorphisms (SNPs) exceeded genome-wide significance in the transethnic (overall) meta-analysis and we do not replicate previously reported associations. Still, SNP-level summary statistics made available here afford the best-available molecular genetic index of PTSD-for both European- and African-American individuals-and can be used in polygenic risk prediction and genetic correlation studies of diverse phenotypes. Publication of summary statistics for ∼10 000 African Americans contributes to the broader goal of increased ancestral diversity in genomic data resources. In sum, the results demonstrate genetic influences on the development of PTSD, identify shared genetic risk between PTSD and other psychiatric disorders and highlight the importance of multiethnic/racial samples. As has been the case with schizophrenia and other complex genetic disorders, larger sample sizes are needed to identify specific risk loci.

A comparison of DSM-5 and ICD-11 PTSD prevalence, comorbidity and disability: an analysis of the Ukrainian Internally Displaced Person's Mental Health Survey.

OBJECTIVE: Recently, the American Psychiatric Association (DSM-5) and the World Health Organization (ICD-11) have both revised their formulation of post-traumatic stress disorder (PTSD). The primary aim of this study was to compare DSM-5 and ICD-11 PTSD prevalence and comorbidity rates, as well as the level of disability associated with each diagnosis. METHOD: This study was based on a representative sample of adult Ukrainian internally displaced persons (IDPs: N = 2203). Post-traumatic stress disorder prevalence was assessed using the PTSD Checklist for DSM-5 and the International Trauma Questionnaire (ICD-11). Anxiety and depression were measured using the Generalized Anxiety Disorder Scale and the Patient Health Questionnaire-Depression. Disability was measured using the WHO Disability Assessment Schedule 2.0. RESULTS: The prevalence of DSM-5 PTSD (27.4%) was significantly higher than ICD-11 PTSD (21.0%), and PTSD rates for females were significantly higher using both criteria. ICD-11 PTSD was associated with significantly higher levels of disability and comorbidity. CONCLUSION: The ICD-11 diagnosis of PTSD appears to be particularly well suited to identifying those with clinically relevant levels of disability.

Validation of post-traumatic stress disorder (PTSD) and complex PTSD using the International Trauma Questionnaire.

OBJECTIVE: The 11th version of the International Classification of Diseases (ICD-11) has proposed two related trauma diagnoses: Post-traumatic stress disorder (PTSD) and Complex PTSD (CPTSD). Using a newly developed, disorder-specific measure of PTSD and CPTSD called the International Trauma Questionnaire (ITQ) the current study will (i) assess the factorial validity of ICD-11 PTSD and CPTSD; (ii) provide the first test of the discriminant validity of these constructs; and (iii) provide the first comparison of ICD-11, and Diagnostic and Statistical Manual, Fifth Edition (DSM-5), PTSD diagnostic rates using disorder-specific measures. METHOD: ICD-11 and DSM-5 PTSD-specific measures were completed by a British clinical sample of trauma-exposed patients (N = 171). The structure and validity of ICD-11 PTSD and CPTSD were assessed by means of factor analysis and assessing relationships with criterion variables. RESULTS: Diagnostic rates under ICD-11 were significantly lower than those under DSM-5. A two-factor second-order model reflecting the distinction between PTSD and CPTSD best represented the data from the ITQ; and the PTSD and CPTSD factors differentially predicted multiple psychological variables. CONCLUSION: The factorial and discriminant validity of ICD-11 PTSD and CPTSD was supported, and ICD-11 produces fewer diagnostic cases than DSM-5.

Retrospective analysis of self-reporting pain scores and pain management during head and neck IMRT radiotherapy: A single institution experience.

AIMS: Head and neck carcinomas are relatively rare in the United Kingdom with an estimated 9000 cases diagnosed annually. However, pain associated with disease and treatment side effects such as oral mucositis present a major issue for therapy radiographers in providing effective care and maintaining radiotherapy treatment compliance, all factors that can compromise patient outcome if not managed appropriately. METHOD: This retrospective analysis of self-reporting pain scores collected during a course of radiotherapy aims to assess the perceived pain intensity scores in 30 patients. Data was collected during radiographer review sessions held weekly to determine if any variables to perceived pain scores occurred during a course of radiotherapy. RESULTS: As treatment progressed, the self-reporting pain scores within the cohort increased, in week one the total cohort pain score was 35, this increased to 114 in week 3 and in the final week had totalled 151. An escalation in pain was observed in week 3 of treatment possibly as a result of radiation induced inflammation alongside cytotoxic chemotherapy. CONCLUSIONS: The findings of this study provide further evidence to an individualised approach to patient pain relief and providing regular on treatment reviews, thus maintaining patient comfort and ensuring continued treatment compliance.

Alternative models of disorders of traumatic stress based on the new ICD-11 proposals.

OBJECTIVE: Although there is emerging evidence for the factorial validity of the distinction between post-traumatic stress disorder (PTSD) and complex PTSD (CPTSD) proposed in ICD-11, such evidence has been predominantly based on using selected items from individual scales that describe these factors. We have attempted to address this gap in the literature by testing a range of alternative models of disorders of traumatic stress using a broader range of symptoms and standardized measures. METHOD: Participants in this cross-sectional study were a sample of individuals who were referred for psychological therapy to a National Health Service (NHS) trauma centre in Scotland (N = 195). Participants were recruited over a period of 18 months and completed measures of stressful life events, DSM-5 PTSD, emotion dysregulation, self-esteem and interpersonal difficulties. RESULTS: Overall, results indicate that a structural model incorporating six first-order factors (re-experiencing, avoidance of traumatic reminders, sense of threat, affective dysregulation, negative self-concept and disturbances in relationships) and two second-order factors (PTSD and disturbances in self-organization [DSO]) was the best fitting. The model presented with good concurrent validity. Childhood trauma was found to be more strongly associated with DSO than with PTSD. CONCLUSION: Our results are in support of the ICD-11 proposals for PTSD and CPTSD.

Coping strategies and mental health outcomes of conflict-affected persons in the Republic of Georgia.

AIMS: Adults who experienced the 1992 and 2008 armed conflicts in the Republic of Georgia were exposed to multiple traumatic events and stressors over many years. The aim was to investigate what coping strategies are used by conflict-affected persons in Georgia and their association with mental disorders. METHOD: A cross-sectional survey was conducted with 3600 adults, representing internally displaced persons (IDPs) from conflicts in the 1990s (n = 1200) and 2008 (n = 1200) and former IDPs who returned to their homes after the 2008 conflict (n = 1200). Post-traumatic stress disorder, depression, anxiety and coping strategies were measured using the Trauma Screening Questionnaire, Patient Health Questionnaire-9, Generalised Anxiety and adapted version of the Brief Coping Inventory, respectively. Descriptive and multivariate regression analyses were used. RESULTS: Coping strategies such as use of humour, emotional support, active coping, acceptance and religion were significantly associated with better mental health outcomes. Coping strategies of behavioural and mental disengagement, denial, venting emotions, substance abuse and gambling were significantly associated with poorer mental health outcomes. The reported use of coping strategies varied significantly between men and women for 8 of the 15 strategies addressed. CONCLUSIONS: Many conflict-affected persons in Georgia are still suffering mental health problems years after the conflicts. A number of specific coping strategies appear to be associated with better mental health and should be encouraged and supported where possible.

Risk of post-traumatic stress disorder following traumatic events in a community sample.

AIMS: Post-traumatic stress disorder (PTSD) is typically associated with high-risk population groups, but the risk of PTSD that is associated with trauma experienced in the community, and effect of changes in diagnostic criteria in DSM-5 on prevalence in the general population, is unknown. METHODS: Cross-sectional analysis of population-based data from 4558 adults aged 25-83 years resident in Caerphilly county borough, Wales, UK. Exposure to different traumatic events was assessed using categorisation of free-text descriptions of trauma. PTSD caseness was determined using items assessing Diagnostic and Statistical Manual IV (DSM-IV) and DSM-5 A criteria and the Traumatic Screening Questionnaire. RESULTS: Of the 4558 participants, 1971 (47.0%) reported a traumatic event. The most common DSM-IV A1 qualifying trauma was life-threatening illnesses and injuries (13.6%). The highest risk of PTSD was associated with assaultive violence [34.1%]. The prevalence of PTSD using DSM-IV A criteria was 14.3% (95% confidence interval [CI] = 12.8, 15.9%). Using DSM-5 A criteria reduced the prevalence to 8.0 (95% CI = 6.9, 9.4%), primarily due to exclusion of DSM-IV A1 qualifying events, such as life-threatening illnesses. CONCLUSIONS: Nearly one-half of a general community sample had experienced a traumatic event and of these around one in seven was a DSM-IV case of PTSD. Although the majority of research has concentrated on combat, rape and assaultive violence, life threatening illness is a more common cause of PTSD in the community. Removal of this traumatic event in DSM-5 could reduce the number of cases of PTSD by around 6.0%.

Behavioral and neurochemical effects of dietary methyl donor deficiency combined with unpredictable chronic mild stress in rats.

Methyl donor deficiencies and chronic stress cause depression independently, but their interaction has never been thoroughly evaluated. In our study, methyl donor deficient diet and chronic stress condition consisted respectively of a B2, B9, B12, and choline-free diet and a chronic mild stress procedure. Rats were randomly assigned to six groups with three "diet" conditions (free-feeding, pair-fed and methyl donor deficient diet) and two "stress" conditions (no-stress and stress) and were evaluated in the open-field, the elevated plus-maze and the forced swimming test. After the behavioral evaluation, corticosterone and homocysteine plasma levels were measured and dopamine, DOPAC, serotonin, 5HIAA concentrations were evaluated in several brain areas. Rats given a methyl donor deficient diet for 11 weeks causing elevated plasma homocysteine levels were compared to pair-fed and free-feeding rats with or without unpredictable chronic mild stress. Regardless of stress environmental conditions, the methyl donor deficient diet decreased plasma corticosterone levels and caused disinhibition in the elevated plus-maze condition relative to both control groups. However, stress potentiated the effects of the deficient regimen on rearing in the open-field and climbing in the forced swim test. The dietary changes involved in behavior and plasma corticosterone could be caused by homocysteine-induced decreases in dopamine and 5-hydroxytryptamine metabolites in selective brain regions and it can be noted that regardless of stress-conditions, methyl donor deficient diet decreases DOPAC/dopamine and 5HIAA/serotonin ratios in striatum and hypothalamus and selectively 5HIAA/serotonin ratio in the sensorimotor cortex. Our experimental data is particularly relevant in the context of neuropsychiatric disorders frequently associated with folate deficiency and hyperhomocysteinemia.

What happened to harmonization of the PTSD diagnosis? The divergence of ICD11 and DSM5.

The development of ICD11 and DSM5 was seen as an opportunity to harmonize the two major classification systems for mental disorders. The proposed ICD11 and DSM5 diagnostic criteria for PTSD are markedly different. The implications of this remain to be seen, but have the potential to cause confusion to PTSD sufferers, clinicians, researchers and others impacted on by the condition.

Systemically active human opiorphin is a potent yet non-addictive analgesic without drug tolerance effects.

Human opiorphin QRFSR-peptide protects enkephalins from degradation by human neutral endopeptidase (hNEP) and aminopeptidase-N (hAP-N) and inhibits pain perception in a behavioral model of mechanical acute pain (1). Here, using two other pain rat models, the tail-flick and the formalin tests, we assess the potency and duration of the antinociceptive action of opiorphin with reference to morphine. The occurrence of adverse effects with emphasis on the side-effect profile at equi-analgesic doses was compared. We demonstrate that opiorphin elicits minimal adverse morphine-associated effects, at doses (1-2 mg/kg, i.v.) that produce a comparable analgesic potency in both spinally controlled thermal-induced acute and peripheral chemical-induced tonic nociception. The analgesic response induced by opiorphin in the formalin-induced pain model preferentially requires activation of endogenous mu-opioid pathways. However, in contrast to exogenous mu-opioid agonists such as morphine, opiorphin, does not develop significant abuse liability or antinociceptive drug tolerance after subchronic treatment. In addition, anti-peristaltism was not observed. We conclude that opiorphin, by inhibiting the destruction of endogenous enkephalins, which are released according to the painful stimulus, activates restricted opioid pathways specifically involved in pain control, thus contributing to a greater balance between analgesia and side-effects than found with morphine. Therefore, opiorphin could give rise to new analgesics endowed with potencies similar to morphine but with fewer adverse effects than opioid agonists. Its chemical optimization, to generate functional derivatives endowed with better bioavailability properties than the native peptide, could lead to a potent class of physiological type analgesics.