Travelling overseas for proton beam therapy: A retrospective interview study.

INTRODUCTION: Travelling for cancer treatment comes with unique challenges, particularly for a young patient and his or her family. The aims of this study were to (1) gain an understanding of the experiences of families and patients who travelled overseas (OS) from Australia for proton beam therapy (PBT) and (2) identify the supportive care needs patients and their families require when living away from home, while having PBT. METHODS: This was a retrospective, qualitative study using semi-structured interviews, conducted with participants aged under 25 years and their families who travelled OS for PBT between 2017 and 2020. Data were analysed using Microsoft Excel Software, where key themes were identified and coded based on their responses. A total of 17 participants were included in interviews from seven Australian families who travelled to America or Europe for PBT. RESULTS: The majority of participants reported a lack of coordination with travel and treatment arrangements prior to arrival OS. Families who stayed in hotel accommodation while OS reported greater feelings of isolation compared with those who stayed in share house-style accommodation. The acuity of cancer diagnosis played a significant part in patient experience, with those patients requiring the greatest amount of supportive care and availability of service provision at stand-alone centres reporting a lack of appropriate care provision. CONCLUSIONS: This study has identified services, accommodation provisions and care coordination requirements that are largely missing from the travel and treatment experience in patients travelling OS for PBT. Future use of consumer-led working groups or committees in creating models of care for families travelling for PBT treatment could be advantageous, with many families willing to share their experiences and provide support to others who are travelling for PBT.

Establishing a consumer advisory group at the Australian Bragg Centre for Proton Therapy and Research.

The Australian Bragg Centre for Proton Therapy and Research (ABCPTR) established the Bragg Consumer Advisory Group (BCAG) in 2023. The ABCPTR, being the first of its kind in Australia, will offer proton therapy treatment for challenging solid tumours with the potential to reduce radiation-induced side effects. With over 110 Proton Beam Therapy (PBT) centres globally, Australian patients currently can apply to access government funded treatment overseas, however, international travel for treatment presents various, significant challenges. Consumer engagement in healthcare plays a pivotal role in navigating the multifaceted journey of cancer treatment and can complement cancer control strategies by ensuring the practicalities of the cancer journey are realised. The ABCPTR aims to involve consumers in decision-making processes, especially as it prepares to open Australia's first national proton therapy centre. The aim of this commentary is to highlight the importance of involving consumers in cancer care, and to demonstrate how this was done in Australia's first proton therapy centre. To establish a consumer engagement team, ABCPTR utilised existing clinical staff. The team's formation and upskilling were integral to the project's success. The engagement framework was developed based on the five stages of commitment by the Australian Health Research Alliance and Western Australian Health Translation Network. The ABCPTR consumer engagement team successfully created a community engagement framework and upskilled in consumer engagement principles over 9-12 months. An Expression of Interest (EOI) was launched, resulting in the formation of the BCAG comprising of 10 members with diverse backgrounds and experiences. The BCAG has been actively involved in decision-making processes, with a consumer-led chair and co-chair in place. The group's feedback is expected to influence key performance indicators for the centre. The establishment of the BCAG at the ABCPTR emphasises the importance of integrating patient and community perspectives into clinical initiatives. This proactive approach ensures that processes remain patient-centred. The ongoing multi-level consumer engagement strategy aims to shape a more inclusive approach to cancer care in Australia, especially concerning PBT.

Proton beam therapy in paediatric cancer: Anticipating the opening of the Australian Bragg Centre for Proton Therapy and Research.

Proton Beam Therapy (PBT) has the potential to improve paediatric cancer care by reducing radiation exposure and thus long-term toxicities. Ethical concerns and debates surrounding the treatment, such as eligibility and accessibility, are ongoing in Australia. The Australian Bragg Centre for Proton Therapy and Research (ABCPTR) (named after Sir William Henry Bragg who described the Bragg peak in his laboratory at the University of Adelaide in 1903) aims to increase access to PBT in Australasia and offer a patient-centred care approach. Research is underway to assess PBT's safety and cost-effectiveness, using tools including Normal Tissue Complication Probability (NTCP) models. Collaborative efforts are focused on developing tailored survivorship clinics to enhance patient follow-up and quality of life. With the anticipated opening of the ABCPTR, Australia is preparing to take a significant step in radiation oncology, offering new research opportunities and creating a publicly funded treatment centre. The initiative aims to balance treatment efficacy with patient care, setting the stage for a future in which radiation therapy will reduce long-term side effects compared to the current standard of care. The implementation of PBT in Australia represents a complex and promising approach to paediatric oncology. This article provides an overview of the current landscape, highlighting the potential benefits and challenges of a treatment that could redefine the quality of survivorship and contribute to global research and best clinical practice.

Minimum data elements for the Australian Particle Therapy Clinical Quality Registry.

INTRODUCTION: Construction of the first Australian particle therapy (PT) centre is underway. Establishment of a national registry, to be known as the Australian Particle Therapy Clinical Quality Registry (ASPIRE), has been identified as a mandatory requirement for PT treatment to be reimbursed by the Australian Medicare Benefits Schedule. This study aimed to determine a consensus set of Minimum Data Elements (MDEs) for ASPIRE. METHODS: A modified Delphi and expert consensus process was completed. Stage 1 compiled currently operational English-language international PT registries. Stage 2 listed the MDEs included in each of these four registries. Those included in three or four registries were automatically included as a potential MDE for ASPIRE. Stage 3 interrogated the remaining data items, and involved three rounds - an online survey to a panel of experts, followed by a live poll session of PT-interested participants, and finally a virtual discussion forum of the original expert panel. RESULTS: One hundred and twenty-three different MDEs were identified across the four international registries. The multi-staged Delphi and expert consensus process resulted in a total of 27 essential MDEs for ASPIRE; 14 patient factors, four tumour factors and nine treatment factors. CONCLUSIONS: The MDEs provide the core mandatory data items for the national PT registry. Registry data collection for PT is paramount in the ongoing global effort to accumulate more robust clinical evidence regarding PT patient and tumour outcomes, quantifying the magnitude of clinical benefit and justifying the relatively higher costs of PT investment.

Therapeutic and Economic Benefits of Service Dogs Versus Emotional Support Dogs for Veterans With PTSD.

OBJECTIVE: This work aimed to assess the therapeutic and economic benefits of service dogs versus emotional support dogs for veterans with posttraumatic stress disorder (PTSD). METHODS: Veterans with PTSD (N=227) participating in a multicenter trial were randomly assigned to receive a service or emotional support dog; 181 veterans received a dog and were followed up for 18 months. Primary outcomes included overall functioning (assessed with World Health Organization Disability Assessment Scale II [WHODAS 2.0]) and quality of life (Veterans RAND 12-Item Health Survey [VR-12]). Secondary outcomes included PTSD symptoms (PTSD Checklist for DSM-5), suicidal ideation, depression, sleep quality, health care costs and utilization, medication adherence, employment, and productivity. RESULTS: Participants paired with a dog had a mean±SD age of 50.6±13.6 years (range 22-79), and most were male (80%), White (66%), and non-Hispanic (91%). Adjusted linear mixed repeated-measures models indicated no difference between the two groups on WHODAS 2.0 or VR-12 scores. Participants with service dogs had a 3.7-point greater reduction in PTSD symptoms versus participants with emotional support dogs (p=0.036). No reduced health care utilization or cost was associated with receiving a service dog. Veterans with service dogs had an increase of 10 percentage points in antidepressant adherence compared with those with emotional support dogs (p<0.01). CONCLUSIONS: Both groups appeared to benefit from having a service or emotional support dog. No significant differences in improved functioning or quality of life were observed between the groups. Those in the service dog group had a greater reduction in PTSD symptoms and better antidepressant adherence, improvements that should be explored further.

If we build it, will they come? Modeling of public hospital care requirements for the Australian Bragg Centre for Proton Therapy and Research.

INTRODUCTION: The Australian Bragg Centre for Proton Therapy and Research (ABCPTR) will be Australia's first proton beam therapy (PBT) facility. A model was developed to predict associated public hospital care requirements for patients during PBT, to facilitate resource planning for pediatric, adolescent and young adult (AYA), and adult public hospitals in South Australia. METHODS: National incidence rates for specific cancer indications were obtained from the Australian Childhood Cancer Registry, Australian Institute of Health and Welfare and published data. Australian Bureau of Statistics national population projections were used to estimate new cases in 2025 and beyond. Radiation oncologists and pediatric oncologists from the Central Adelaide Local and Women's and Children's Health Network, along with international colleagues, provided guidance on chemotherapy utilization and inpatient admission estimates. RESULTS: It was estimated 180 patients (40.4%) within the adult population (≥25 years) and 265 patients (59.6%) within the pediatric/AYA population (<25 years) would be eligible for PBT in 2025. There was no indication adult cancers would require concurrent outpatient/inpatient chemotherapy, in contrast with pediatric and AYA patients (59.5% and 62.8% outpatient and 18.9% and 41.9% inpatient, respectively). It was estimated 53% and 29% of pediatric and AYA patients could require inpatient admission for toxicity related to disease, concurrent chemotherapy or PBT. CONCLUSION: Associated public hospital care requirements related to the delivery of a national PBT service were estimated. This has particular implications for planning of the new Women's and Children's hospital, co-located with the ABCPTR. True data accuracy will be determined on future data generation and analysis.

Design and challenges for a randomized, multi-site clinical trial comparing the use of service dogs and emotional support dogs in Veterans with post-traumatic stress disorder (PTSD).

Posttraumatic stress disorder (PTSD) is a leading cause of impairments in quality of life and functioning among Veterans. Service dogs have been promoted as an effective adjunctive intervention for PTSD, however published research is limited and design and implementation flaws in published studies limit validated conclusions. This paper describes the rationale for the study design, a detailed methodological description, and implementation challenges of a multisite randomized clinical trial examining the impact of service dogs on the on the functioning and quality of life of Veterans with PTSD. Trial design considerations prioritized participant and intervention (dog) safety, selection of an intervention comparison group that would optimize enrollment in all treatment arms, pragmatic methods to ensure healthy well-trained dogs, and the selection of outcomes for achieving scientific and clinical validity in a Veteran PTSD population. Since there is no blueprint for conducting a randomized clinical trial examining the impact of dogs on PTSD of this size and scope, it is our primary intent that the successful completion of this trial will set a benchmark for future trial design and scientific rigor, as well as guiding researchers aiming to better understand the role that dogs can have in the management of Veterans experiencing mental health conditions such as PTSD.

Psychological resilience is associated with more intact social functioning in veterans with post-traumatic stress disorder and depression.

Patients with depression or post-traumatic stress disorder (PTSD), common sequelae among individuals exposed to stressful or traumatic events, often report impairment in social functioning. Resilience is a multidimensional construct that enables adaptive coping with life adversity. Relationship between resilience and social functioning among veterans with depression and PTSD is not entirely clear and is the focus of this report. Resilience was assessed in 264 veterans using the Connor-Davidson Resilience Scale, PTSD with the PTSD Symptom Scale, depression with the Beck Depression Inventory, and social functioning with the Short Form Health Survey. Higher resilience was associated with more intact social functioning after PTSD and depression severity, childhood maltreatment, physical health, gender, education, marital status, and employment were simultaneously adjusted for. Childhood maltreatment, gender, marital status, education, and employment did not predict social functioning; however, greater severity of PTSD, depression, or physical health problems was each significantly associated with more impaired social functioning. Our findings suggest that higher resilience was associated with more intact social functioning regardless of the severity of PTSD and depression. Given the importance of social functioning in depression and/or PTSD recovery, studies are needed to examine if enhancing resilience presents a complementary approach to alleviating impaired social functioning.

Prevalence of childhood physical and sexual abuse in veterans with psychiatric diagnoses.

We examined the prevalence of childhood (≤ 18 years) physical and sexual abuse reported among patients admitted to the psychiatric inpatient service and the differential rates of this abuse associated with psychiatric diagnoses. This study consisted of a retrospective chart review of 603 patients admitted to a psychiatric ward during a period of 1 year at Atlanta Veterans Affairs Medical Center who had data on childhood physical and sexual abuse. The prevalence of reported childhood physical or sexual abuse in this inpatient clinical population was 19.4% (117/603). The prevalence of reported physical abuse was 22.6% (19/84) in the women and 12.0% (62/519) in the men (p = 0.008); the prevalence of sexual abuse was 33.3% (28/84) in the women and 7.7% (40/519) in the men (p < 0.0001). More patients with depressive disorders reported sexual abuse than did those without these disorders. More patients with posttraumatic stress disorder (PTSD) reported physical and sexual abuse than did those without these disorders. Stratifying by race, sex, and diagnoses, multivariate analyses showed that the women with PTSD had a greater likelihood to report physical abuse (p = 0.03) and sexual abuse histories (p = 0.008) than did the women without PTSD. The men with substance-induced mood disorder (p = 0.01) were more likely to report physical abuse compared with the men without substance-induced mood disorder. Screening for abuse in patients with depressive disorders and PTSD is warranted to tailor individualized treatments for these patients. More research is needed to better understand the potential implications of childhood abuse on psychiatric diagnoses.

PTSD and gene variants: new pathways and new thinking.

Posttraumatic Stress Disorder (PTSD) is an anxiety disorder which can develop as a result of exposure to a traumatic event and is associated with significant functional impairment. Family and twin studies have found that risk for PTSD is associated with an underlying genetic vulnerability and that more than 30% of the variance associated with PTSD is related to a heritable component. Using a fear conditioning model to conceptualize the neurobiology of PTSD, three primary neuronal systems have been investigated - the hypothalamic-pituitary-adrenal axis, the locus coeruleus-noradrenergic system, and neurocircuitry interconnecting the limbic system and frontal cortex. The majority of the initial investigations into main effects of candidate genes hypothesized to be associated with PTSD risk have been negative, but studies examining the interaction of genetic polymorphisms with specific environments in predicting PTSD have produced several positive results which have increased our understanding of the determinants of risk and resilience in the aftermath of trauma. Promising avenues of inquiry into the role of epigenetic modification have also been proposed to explain the enduring impact of environmental exposures which occur during key, often early, developmental periods on gene expression. Studies of PTSD endophenotypes, which are heritable biomarkers associated with a circumscribed trait within the more complex psychiatric disorder, may be more directly amenable to analysis of the underlying genetics and neural pathways and have provided promising targets for elucidating the neurobiology of PTSD. Knowledge of the genetic underpinnings and neuronal pathways involved in the etiology and maintenance of PTSD will allow for improved targeting of primary prevention amongst vulnerable individuals or populations, as well as timely, targeted treatment interventions. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.

More than military sexual trauma: interpersonal violence, PTSD, and mental health in women veterans.

Military sexual trauma (MST) is reported by 20-40% of female veterans. The purpose of this study of female veterans referred for MST treatment was to examine the relationships between lifetime trauma (physical, sexual, and psychological) and posttraumatic stress disorder (PTSD), depression, physical health, and quality of life using retrospective cross-sectional data from medical records. Of the 135 participants, 95.4% reported at least one trauma in addition to MST, most notably sexual abuse as adult civilians (77.0%) and as children (52.6%). PTSD, depression, and sleep difficulty rates were clinically significant. Chronic pain (66.4%) was associated with childhood abuse, physical health, sleep difficulties, and coping. Integrating mental and physical health treatment is necessary to treat MST and PTSD in female veterans.

An evolving integrative treatment program for military sexual trauma (MST) and one veteran's experience.

Military sexual trauma (MST) increases the risk for Posttraumatic Stress Disorder (PTSD) and multiple other comorbidities, presenting substantial challenges for nurses and psychiatric and medical clinicians. A specialized VA Medical Center outpatient program is patterned after Herman's three-phased, empirically-supported, recovery treatments. We use a case example of a female veteran MST survivor to illustrate our treatment model. She presented to our program meeting diagnostic criteria for PTSD, Major Depressive Disorder, and a history of substance abuse. Post-treatment she demonstrated improved scores on measures of PTSD, quality of life, and socialization. This model shows promise for treatment of MST survivors with PTSD.

Pain symptomatology and pain medication use in civilian PTSD.

The comorbidity of pain syndromes and trauma-related syndromes has been shown to be high. However, there have been limited data, especially in civilian medical populations, on the role of trauma-related disorders such as posttraumatic stress disorder (PTSD) on chronic pain and pain medication use. We analyzed 647 general hospital patients in primary care and obstetrics and gynecological waiting rooms for the experience of trauma and PTSD-related stress disorders. PTSD symptoms were found to be significantly positively correlated with pain ratings (r=.282, P<0.001) and pain-related functional impairment (r=0.303, P<0.001). Those with a current PTSD diagnosis had significantly higher subjective pain and pain-related impairment ratings than those with no PTSD. Furthermore, those with a current diagnosis of PTSD were significantly more likely to have used opioid analgesics for pain control compared to those without a diagnosis of PTSD (χ(2)=8.98, P=0.011). When analyzing the separate PTSD symptom subclusters (re-experiencing, avoidance, and hyperarousal), all symptom clusters were significantly related to pain and pain-related impairment ratings, but only the avoidance cluster was significantly related to prior opioid pain medication use. We conclude that PTSD and trauma-related disorders are common in impoverished medical populations and that their presence should be examined in patients with pain syndromes. Furthermore, these data suggest that PTSD and pain may share a vulnerability pathway, including the endogenous opioid neurotransmission systems.

Posttraumatic stress disorder is a risk factor for metabolic syndrome in an impoverished urban population.

OBJECTIVE: Metabolic syndrome is associated with elevated risk for cardiovascular disease and diabetes and has increased prevalence in low-income African Americans, which constitutes a significant health disparity. The mechanisms responsible for this disparity remain unclear; the current study investigated the relationship between posttraumatic stress disorder (PTSD) and metabolic syndrome. METHOD: We assessed childhood and adult trauma history, major depressive disorder, PTSD and the components of metabolic syndrome in an urban population. We recruited 245 low-socioeconomic-status, primarily African American subjects from general medical clinics in an inner-city hospital. RESULTS: Trauma exposure was extremely prevalent, with 90.6% of subjects reporting at least one significant trauma and 18.8% of subjects meeting criteria for current PTSD. Metabolic syndrome was also prevalent in this population (33.2%), with significantly higher rates among patients with current PTSD (47.8%, P<.05). After controlling for demographics, smoking history, antipsychotic use, depression and exercise, current PTSD remained the only significant predictor of metabolic syndrome (P=.006). CONCLUSIONS: PTSD is associated with increased rates of metabolic syndrome within a traumatized, impoverished urban population. Further studies should investigate if PTSD treatment may reduce the rates of metabolic syndrome, improve overall health outcomes and decrease health care disparities in minority populations.

The CRF1 receptor antagonist, R121919, attenuates the severity of precipitated morphine withdrawal.

Corticotropin-releasing factor (CRF) regulates the hypothalamic-pituitary-adrenal axis, coordinates the mammalian stress response, and acting primarily via the CRF(1) receptor, has been strongly implicated in the pathophysiology of depression and anxiety. Furthermore, the behavioral and autonomic activation that occurs following withdrawal in drug dependent animals resembles the mammalian stress response. Concordant with this view is evidence of enhanced CRF transcription, release and activity following withdrawal from several drugs of abuse. Conversely, CRF receptor antagonists have been demonstrated to reduce the severity of many drug withdrawal symptoms, implicating a specific role for activation of CRF neurons in mediating the anxiogenic and stress-like reactions observed during withdrawal. To extend these findings, we investigated whether pretreatment with a selective CRF(1) receptor antagonist, R121919, is capable of similarly decreasing the autonomic, behavioral and neuroendocrine activation observed following precipitation of morphine withdrawal in dependent rats. The results indicate that pretreatment with R121919 attenuates the global severity of the precipitated morphine withdrawal syndrome as measured by the Gellert-Holtzman scale. In addition, rats pretreated with R121919 prior to precipitation of morphine withdrawal demonstrated decreased hypothalamic-pituitary-adrenal axis activation, as measured by plasma ACTH concentrations, and decreased early expression of the CRF gene in the paraventricular nucleus of the hypothalamus, as measured by CRF heteronuclear RNA. These findings suggest that activation of CRF neuronal systems via the CRF(1) receptor may be one element of the neurobiological mechanisms activated during drug withdrawal and that CRF(1) receptor antagonists may have a potential therapeutic role in the treatment of human drug withdrawal syndromes.

The CRF1 receptor antagonist R121919 attenuates the neuroendocrine and behavioral effects of precipitated lorazepam withdrawal.

RATIONALE: Corticotropin-releasing factor (CRF) is the primary physiologic regulator of the hypothalamic-pituitary-adrenal (HPA) axis and serves to globally coordinate the mammalian stress response. Hyperactivity of central nervous system CRF neurotransmission, acting primarily via the CRF(1) receptor, has been strongly implicated in the pathophysiology of depression and anxiety. Furthermore, there is evidence of enhanced CRF transcription, release, and neuronal activity after the administration of and withdrawal from several drugs of abuse, including cannabis, cocaine, ethanol, and morphine. Treatment with CRF antagonists has been demonstrated to reduce the severity of certain drug withdrawal symptoms, implicating a specific role for activation of CRF neurons in mediating the anxiogenic and stress-like reactions observed after abrupt drug discontinuation. OBJECTIVES/METHODS: To extend these findings, we investigated whether pretreatment with the selective CRF(1) receptor antagonist R121919 decreases the behavioral and neuroendocrine activation observed after the precipitation of benzodiazepine (BZ) withdrawal in BZ-dependent rats. RESULTS: Pretreatment with R121919 attenuated the subsequent HPA axis activation, behavioral measures of anxiety, and expression of the CRF gene in the paraventricular nucleus of the hypothalamus, as measured by CRF heteronuclear RNA, which occurs after flumazenil-precipitation of withdrawal from the BZ, lorazepam. CONCLUSIONS: These results indicate that the activation of CRF neuronal systems may be a common neurobiological mechanism in withdrawal from drugs of abuse and moreover, that the CRF(1) receptor subtype plays a major role in mediating the effects of CRF on neuroendocrine and behavioral responses during BZ withdrawal. Therefore, CRF(1) receptor antagonists may be of therapeutic utility in the treatment of drug withdrawal syndromes.

Spontaneous withdrawal from the triazolobenzodiazepine alprazolam increases cortical corticotropin-releasing factor mRNA expression.

Corticotropin-releasing factor (CRF) is the major physiologic regulator of the hypothalamic-pituitary-adrenal (HPA) axis and plays a key role in coordinating the mammalian stress response. Substantial data implicates hyperactivity of CRF neuronal systems in the pathophysiology of depression and anxiety disorders. Enhanced CRF expression, release, and function have also been demonstrated during acute withdrawal from several drugs of abuse. Previous studies revealed that chronic administration of the anxiolytic alprazolam reduced indices of CRF and CRF1 receptor function. Conversely, measures of urocortin I and CRF2 receptor function were increased. To further scrutinize these findings, we sought to determine whether CRF neuronal systems are activated during spontaneous withdrawal from the triazolobenzodiazepine alprazolam in dependent rats and to characterize the time course, extent, and regional specificity of the patterns of activation. After 14 d of alprazolam administration (90 mg x kg(-1) x d(-1)), spontaneous withdrawal produced activation of the HPA axis, as well as suppression of food intake and weight loss that peaked 24-48 hr after withdrawal. Remarkably, CRF mRNA expression in the cerebral cortex was markedly (>300%) increased over the same time period. Other indices of CRF-CRF1 and urocortin I-CRF2A function, altered by chronic alprazolam treatment as previously described, returned to pretreatment levels over 96 hr. The physiologic significance of this dramatic induction of cortical CRF mRNA expression, as well as whether this occurs during withdrawal from other drugs of abuse is yet to be determined. The marked increase in CRFergic neurotransmission is hypothesized to play a major role in benzodiazepine withdrawal.

The effects of chronic treatment with the mood stabilizers valproic acid and lithium on corticotropin-releasing factor neuronal systems.

Corticotropin-releasing factor (CRF) plays a preeminent role in coordinating the endocrine, autonomic, and behavioral responses to stress. Dysregulation of both hypothalamic and extrahypothalamic CRF systems have been reported in patients with major depression and post-traumatic stress disorder. Moreover, effective treatment of these conditions leads to normalization of these CRF systems. Although there is virtually no data concerning alterations of CRF systems in bipolar disorder (manic depressive illness), previous work indicates that valproic acid, an anticonvulsant also effective in the treatment of acute mania, alters central CRF neuronal systems. In the current studies, we chronically administered valproic acid and lithium, two clinically effective mood stabilizers, in nonstressed rats to extend our previous findings. Chronic valproic acid administration decreased CRF mRNA expression in the paraventricular nucleus of the hypothalamus; lithium administration increased CRF mRNA expression in the central nucleus of the amygdala. Although valproic acid increased CRF(1) receptor mRNA expression in the cortex, CRF(1) receptor binding was decreased in both the basolateral amygdala and cortex, suggesting that chronic valproate treatment may in fact dampen the overall tone in this central stress pathway. Valproate treatment decreased CRF(2A) mRNA expression in both the lateral septum and hypothalamus, although CRF(2A) receptor binding was unchanged. Lithium administration decreased CRF(1) mRNA expression in both the amygdala and frontal cortex, but CRF(1) receptor binding also remained unchanged. These results suggest that the therapeutic actions of these mood stabilizers may, in part, result from their actions on central CRF neuronal systems. The distinct actions of each drug on CRF systems may underlie their synergistic clinical effects.

The corticotropin-releasing factor1 receptor antagonist R121919 attenuates the behavioral and endocrine responses to stress.

Corticotropin-releasing factor (CRF) is the major physiological regulator of the hypothalamic-pituitary-adrenal (HPA) axis and serves to coordinate the mammalian endocrine, autonomic, and behavioral responses to stress. Considerable literature from clinical and preclinical data suggests that hypersecretion of hypothalamic and/or extrahypothalamic CRF systems is a major factor in the pathogenesis of affective and anxiety disorders. Based on this premise, a CRF(1) receptor antagonist has been hypothesized to possess anxiolytic and/or antidepressant properties. In this study, an acute dose of the lipophilic CRF(1) receptor antagonist 3-[6-(dimethylamino)-4-methyl-pyrid-3-yl]-2,5-dimethyl-N,N-dipropyl-pyrazolo[2,3-a]pyrimidin-7-amine (R121919), administered i.v. to rats with surgically implanted jugular cannula 60 min before a 5-min restraint stress, dose dependently attenuated peak plasma adrenocorticopin hormone (ACTH) and corticosterone concentrations by 91 and 75%, respectively. In a second study, acute administration of R121919 reduced measures of anxiety in a rodent defensive withdrawal paradigm. R121919 dose dependently decreased latency to exit the tube, and total time spent in the tube 60 min after a single subcutaneous administration. In addition, the ACTH and corticosterone response to novelty was decreased by 82 and 97%, respectively, at the 10-mg/kg dose of R121919. In another study, this dose was associated with approximately an 85% occupancy of the CRF(1) receptor in the cortex measured 75-min postsubcutaneous injection. These data confirm that R121919 acts as a CRF(1) receptor antagonist in vivo, attenuates HPA axis responsivity, and possesses anxiolytic properties.

Are CRF receptor antagonists potential antidepressants?

Corticotropin-releasing factor (CRF) is the major regulator of the hypothalamic-pituitary-adrenal (HPA) axis, and plays a key role in coordinating the endocrine, as well as autonomic and behavioral responses of an organism to stress. Direct CNS administration of CRF to laboratory animals produces an aggregate of effects that mimic the mammalian stress response. Impeding CRF function with CNS administration of a peptidergic CRF antagonist can block these manifestations of the stress response whether produced by exogenous CRF or occurring naturally in response to a stressor. A role for hypersecretion of CRF in the pathophysiology of depression is suggested by the finding that CNS administration of CRF mirrors many of the signs and symptoms utilized as diagnostic criteria for major depression. In addition, a large body of clinical evidence points to excess hypothalamic secretion of CRF and an accompanying HPA axis hyperactivity in patients with major depression. The recent development of selective, small molecule CRF(1) receptor antagonists, which block the effects of CRF both in vitro and in vivo, suggest that these compounds may be effective in the treatment of affective and anxiety disorders. Early evidence indicates that these agents possess anxiolytic and antidepressant activity in animal behavioral models. Copyright 2001 John Wiley & Sons, Ltd.