Implementing high-value, cost-conscious care: experiences of Irish doctors and the role of education in facilitating this approach.

BACKGROUND: Adopting high-value, cost-conscious care (HVCCC) principles into medical education is growing in importance due to soaring global healthcare costs and the recognition that efficient care can enhance patient outcomes and control costs. Understanding the current opportunities and challenges doctors face concerning HVCCC in healthcare systems is crucial to tailor education to doctors' needs. Hence, this study aimed to explore medical students, junior doctors, and senior doctors' experiences with HVCCC, and to seek senior doctors' viewpoints on how education can foster HVCCC in clinical environments. METHODS: Using a mixed-methods design, our study involved a cross-sectional survey using the Maastricht HVCCC-Attitude Questionnaire (MHAQ), with a subset of consultants engaging in semi-structured interviews. Descriptive analysis provided insights into both categorical and non-categorical variables, with differences examined across roles (students, interns, junior doctors, senior doctors) via Kruskal-Wallis tests, supplemented by two-group analyses using Mann-Whitney U testing. We correlated experience with MHAQ scores using Spearman's rho, tested MHAQ's internal consistency with Cronbach's alpha, and employed thematic analysis for the qualitative data. RESULTS: We received 416 responses to the survey, and 12 senior doctors participated in the semi-structured interviews. Overall, all groups demonstrated moderately positive attitudes towards HVCCC, with more experienced doctors exhibiting more favourable views, especially about integrating costs into daily practice. In the interviews, participants agreed on the importance of instilling HVCCC values during undergraduate teaching and supplementing it with a formal curriculum in postgraduate training. This, coupled with practical knowledge gained on-the-job, was seen as a beneficial strategy for training doctors. CONCLUSIONS: This sample of medical students and hospital-based doctors display generally positive attitudes towards HVCCC, high-value care provision, and the integration of healthcare costs, suggesting receptiveness to future HVCCC training among students and doctors. Experience is a key factor in HVCCC, so early exposure to these concepts can potentially enhance practice within existing healthcare budgets.

Assessing the impact of COVID-19 on healthcare staff at a combined elderly care and specialist palliative care facility: A cross-sectional study.

BACKGROUND: In the pre-COVID-19 era, healthcare professionals experienced stress and burnout. The international literature confirms that COVID-19 placed significant additional burdens on healthcare workers. AIM: To describe and characterise the magnitude and variety of ways in which the COVID-19 pandemic affected the personal, social and professional lives of healthcare workers representing several multidisciplinary specialties in a fully-integrated palliative and elderly care service. DESIGN: All staff were invited to complete an anonymised standardised questionnaire evaluating the impact of COVID-19 across a diverse range of domains. The study was conducted over a 6-week period commencing 11 September 2020. SETTING: The setting incorporates two distinct but integrated services operating under a single management structure in Ireland: (i) Specialist palliative care across hospice (44 beds), community and hospitals and (ii) Elderly Care Service (long-term and respite care) delivered in a 63-bed inpatient unit. RESULTS: 250 respondents (69.8%) completed the questionnaire. Nurses and healthcare assistants comprised the majority of respondents (60%) and other disciplines were represented proportionately. 230 participants (92%) agreed that their personal workload had changed significantly in response to COVID-19 and 182 (72.8%) agreed that their responsibilities had increased. 196 (78.4%) reported greater work-related stress. Highest-rated sources of stress included fear of contracting COVID-19 or transmitting it to friends/family, interacting with isolated frail/dying patients, changes to workplace protocols and reduced social interaction with colleagues. CONCLUSIONS: This study demonstrates the profound impact of COVID-19 on personal and professional wellbeing of staff. The greatest burden was carried by those providing prolonged, direct and intimate patient care.

Age-related hearing loss and provider-patient communication across primary and secondary care settings: a cross-sectional study.

BACKGROUND: The prevalence of age-related hearing loss (ARHL) increases with age. Older adults are amongst the most dependent users of healthcare and most vulnerable to medical error. This study examined health professionals' strategies, as well as level of formal training completed, for communication with older adults with ARHL, and their views on the contribution of ARHL to suboptimal quality of patient care. METHODS: A 17-item questionnaire was distributed to a sample of Irish primary care physicians, as well as hospital-based clinicians providing inpatient palliative care and geriatric services. RESULTS: A total of 172 primary care physicians and 100 secondary care providers completed the questionnaire. A total of 154 (90%) primary and 97 (97%) secondary care providers agreed that ARHL had a negative impact on quality of care. Across both settings, 10% of respondents reported that communication issues contributed to multiple medication error events each year. Although only 3.5% of secondary care providers and 13% of primary care physicians attended formal training on communication with hearing-impaired patients, 66.5% of respondents were confident in their capacity to communicate with these patients. Primary care physicians reported that they either never used assistive hearing technology (44%) or were unfamiliar with this technology (49%). CONCLUSIONS: Primary and secondary care health providers reported that ARHL reduces patient care quality and may initiate errors leading to patient harm. Formal training addressing the communication needs of ARHL patients appears to be underdeveloped, and there is a limited familiarity with assistive hearing technology. This is both an error in health professional training and healthcare services.

Strategies for Enhancing Resilience in Medical Students: a Group Concept Mapping Analysis.

OBJECTIVE: Research has consistently shown that medical students have greater rates of stress and mental-ill health in comparison with non-medical students. The objective of this study was to investigate the resilience strategies employed by medical students in an Irish medical school to inoculate themselves against the deleterious effects of stress on health and wellbeing. METHODS: Group concept mapping was utilized incorporating qualitative and quantitative methodologies. The stages undertaken by year 3 students at an Irish medical school involved brainstorming/idea generation, categorization, and rating of resilience strategies students employed to manage stress during medical school. The data was analyzed utilizing The Concept System® software through multidimensional scaling and hierarchical clustering. RESULTS: Categories of resilience strategies employed included "friends and family," "de-stress through exercise/sport," "extra-curricular non-medical activities," "self-enabled distraction," "organization," and "enhancing emotional and mental wellbeing." Students rated spending time with "friends and family" to be most effective when seeking to relieve stress, whereas students rated "de-stressing through exercise/sport" as being of greatest importance in relation to inclusion in a resilience-based intervention. Students recognized the value of incorporating strategies to enhance emotional and mental wellbeing into a resilience-promoting program. "Self-enabled distraction" rated poorly on both scales. CONCLUSIONS: Strategies rated by students to be important to incorporate in a stress reduction management program are accessible, are feasible, and can be implemented into the medical curriculum.

Internet skills of medical faculty and students: is there a difference?

BACKGROUND: The shift from a more didactic to student-centred pedagogical approach has led to the implementation of new information communication technology (ICT) innovations and curricula. Consequently, analysis of the digital competency of both faculty and students is of increasing importance. The aim of this research is to measure and compare the internet skills of medical school faculty and students and to investigate any potential skills gap between the two groups. METHODS: A survey of medical school faculty and students across three universities in Ireland was carried out using a validated instrument (Internet Skills Scale) measuring five internet skills (Operational, Information Navigation, Social, Creative and Mobile). Three focus groups comprising a total of fifteen students and four semi-structured interviews with faculty across three institutions were carried out to explore further findings and perceptions towards digital literacy, give further insight and add context to the findings. RESULTS: Seventy-eight medical faculty (response rate 45%) and 401 students (response rate 15%) responded to the survey. Mean scores for each internet skill were high (above 4 out of 5) for all skills apart from Creative (mean of 3.08 for students and 3.10 for faculty). There were no large differences between student and faculty scores across the five skills. Qualitative results supported survey findings with a deeper investigation into topics such as online professionalism, use of licencing and mobile application development. Needs based skills training and support were highlighted as areas for faculty development. CONCLUSION: Both medical educators and students tend to have similar competencies with respect to internet skills. When implementing online and distance learning methodologies however, medical schools need to ensure appropriate skills training and support for faculty as well as providing targeted training to improve the creative skills of both their educators and students.

Monitoring neurointerventional radiation doses using dose-tracking software: implications for the establishment of local diagnostic reference levels.

OBJECTIVES: There is potential for high radiation exposure during neurointerventional procedures. Increasing regulatory requirements mandate dose monitoring of patients and staff, and justification of high levels of radiation exposure. This paper demonstrates the potential to use radiation dose-tracking software to establish local diagnostic reference levels. METHODS: Consecutive neurointerventional procedures, performed in a single institution within a one-year period, were retrospectively studied. Dose area product (DAP) data were collected using dose-tracking software and clinical data obtained from a prospectively generated patient treatment database. RESULTS: Two hundred and sixty-four procedures met the selection criteria. Median DAP was 100 Gy.cm2 for aneurysm coiling procedures, 259 Gy.cm2 for arteriovenous malformation (AVM) embolisation procedures, 87 Gy.cm2 for stroke thrombolysis/thrombectomy, and 74 Gy.cm2 for four-vessel angiography. One hundred and nine aneurysm coiling procedures were further studied. Six significant variables were assessed using stepwise regression analysis to determine effect on DAP. Aneurysm location (anterior vs posterior circulation) had the single biggest effect (p = 0.004). CONCLUSIONS: This paper confirms variable radiation exposures during neurointerventional procedures. The 75th percentile (used to define diagnostic reference levels) of DAP measurements represents a reasonable guidance metric for monitoring purposes. Results indicate that aneurysm location has the greatest impact on dose during coiling procedures and that anterior and posterior circulation coiling procedures should have separate diagnostic reference levels. KEY POINTS: • Dose-tracking software is useful for monitoring patient radiation dose during neurointerventional procedures • This paper provides a template for methodology applicable to any interventional suite • Local diagnostic reference levels were defined by using the 75th percentile of DAP as per International Commission on Radiological Protection recommendations • Aneurysm location is the biggest determinant of radiation dose during coiling procedures. • Anterior and posterior circulation coiling procedures should have separate diagnostic reference levels.

Medical students' perceptions of professional misconduct: relationship with typology and year of programme.

AIM: To examine the contribution of programme year and demographic factors to medical students' perceptions of evidence-based classification categories of professional misconduct. METHODS: Students at an Irish medical school were administered a cross-sectional survey comprising 31 vignettes of professional misconduct, which mapped onto a 12-category classification system. Students scored each item using a 5-point Likert scale, where 1 represents the least severe form of misconduct and 5 the most severe. RESULTS: Of the 1012 eligible respondents, 561 students completed the survey, providing a response rate of 55%. Items pertaining to disclosure of conflict of interest were ranked as the least severe examples of professional misconduct, and this perception was highest among finalyear students. While ratings of severity declined for items related to 'inappropriate conduct not in relation to patient' and 'inappropriate use of social media' between years 1 and 3, ratings for both categories increased again among clinical cycle (fourth and final year) students. CONCLUSIONS: Increased clinical exposure during years 4 and 5 of the undergraduate programme was associated with better recognition of the importance of selected professional domains. Disclosure of conflict of interest is identified as an area of medical professionalism that requires greater emphasis for students who are at the point of transition from student to doctor.

Burnout syndrome among non-consultant hospital doctors in Ireland: relationship with self-reported patient care.

OBJECTIVE: Intensive workload and limited training opportunities for Irish non-consultant hospital doctors (NCHDs) has a negative effect on their health and well-being, and can result in burnout. Burnout affects physician performance and can lead to medical errors. This study examined the prevalence of burnout syndrome among Irish NCHDs and its association with self-reported medical error and poor quality of patient care. METHODS: A cross-sectional quantitative survey-based design. SETTING: All teaching hospitals affiliated with University College Cork. PARTICIPANTS: NCHDs of all grades and specialties. INTERVENTION(S): The following instruments were completed by all participants: Maslach Burnout Inventory-Human Service Survey (MBI-HSS), assessing three categories of burnout syndrome: Emotional exhaustion (EE), Personal Achievement (PA) and Depersonalization (DP); questions related to self-reported medical errors/poor patient care quality and socio-demographic information. MAIN OUTCOME MEASURE(S): Self-reported measures of burnout and poor quality of patient care. RESULTS: Prevalence of burnout among physicians (n = 265) was 26.4%. There was a significant gender difference for EE and DP, but none for PA. A positive weak correlation was observed between EE and DP with medical error or poor patient care. A negative association was reported between PA and medical error and reduced quality of patient care. CONCLUSIONS: Burnout is prevalent among NCHDs in Ireland. Burnout syndrome is associated with self-reported medical error and quality of care in this sample population. Measures need to be taken to address this issue, with a view to protecting health of NCHDs and maintaining quality of patient care.

Gene × Environment Interactions in Schizophrenia: Evidence from Genetic Mouse Models.

The study of gene × environment, as well as epistatic interactions in schizophrenia, has provided important insight into the complex etiopathologic basis of schizophrenia. It has also increased our understanding of the role of susceptibility genes in the disorder and is an important consideration as we seek to translate genetic advances into novel antipsychotic treatment targets. This review summarises data arising from research involving the modelling of gene × environment interactions in schizophrenia using preclinical genetic models. Evidence for synergistic effects on the expression of schizophrenia-relevant endophenotypes will be discussed. It is proposed that valid and multifactorial preclinical models are important tools for identifying critical areas, as well as underlying mechanisms, of convergence of genetic and environmental risk factors, and their interaction in schizophrenia.

Resolving pathobiological mechanisms relating to Huntington disease: gait, balance, and involuntary movements in mice with targeted ablation of striatal D1 dopamine receptor cells.

Progressive cell loss is observed in the striatum, cerebral cortex, thalamus, hypothalamus, subthalamic nucleus and hippocampus in Huntington disease. In the striatum, dopamine-responsive medium spiny neurons are preferentially lost. Clinical features include involuntary movements, gait and orofacial impairments in addition to cognitive deficits and psychosis, anxiety and mood disorders. We utilized the Cre-LoxP system to generate mutant mice with selective postnatal ablation of D1 dopamine receptor-expressing striatal neurons to determine which elements of the complex Huntington disease phenotype relate to loss of this neuronal subpopulation. Mutant mice had reduced body weight, locomotor slowing, reduced rearing, ataxia, a short stride length wide-based erratic gait, impairment in orofacial movements and displayed haloperidol-suppressible tic-like movements. The mutation was associated with an anxiolytic profile. Mutant mice had significant striatal-specific atrophy and astrogliosis. D1-expressing cell number was reduced throughout the rostrocaudal extent of the dorsal striatum consistent with partial destruction of the striatonigral pathway. Additional striatal changes included up-regulated D2 and enkephalin mRNA, and an increased density of D2 and preproenkephalin-expressing projection neurons, and striatal neuropeptide Y and cholinergic interneurons. These data suggest that striatal D1-cell-ablation alone may account for the involuntary movements and locomotor, balance and orofacial deficits seen not only in HD but also in HD phenocopy syndromes with striatal atrophy. Therapeutic strategies would therefore need to target striatal D1 cells to ameliorate deficits especially when the clinical presentation is dominated by a bradykinetic/ataxic phenotype with involuntary movements.

Convergence and translation: attitudes to inter-professional learning and teaching of creative problem-solving among medical and engineering students and staff.

BACKGROUND: Healthcare worldwide needs translation of basic ideas from engineering into the clinic. Consequently, there is increasing demand for graduates equipped with the knowledge and skills to apply interdisciplinary medicine/engineering approaches to the development of novel solutions for healthcare. The literature provides little guidance regarding barriers to, and facilitators of, effective interdisciplinary learning for engineering and medical students in a team-based project context. METHODS: A quantitative survey was distributed to engineering and medical students and staff in two universities, one in Ireland and one in Belgium, to chart knowledge and practice in interdisciplinary learning and teaching, and of the teaching of innovation. RESULTS: We report important differences for staff and students between the disciplines regarding attitudes towards, and perceptions of, the relevance of interdisciplinary learning opportunities, and the role of creativity and innovation. There was agreement across groups concerning preferred learning, instructional styles, and module content. Medical students showed greater resistance to the use of structured creativity tools and interdisciplinary teams. CONCLUSIONS: The results of this international survey will help to define the optimal learning conditions under which undergraduate engineering and medicine students can learn to consider the diverse factors which determine the success or failure of a healthcare engineering solution.

Attitudes towards professionalism in graduate and non-graduate entrants to medical school.

BACKGROUND: The number of places available in Ireland and the United Kingdom (UK) for graduate entry to medical school has increased in the past decade. Research has primarily focused on academic and career outcomes in this cohort, but attitudes towards professionalism in medicine have not been systematically assessed. The purpose of this study was to compare the importance of items related to professional behaviour among graduate entrants and their 'school-leaver' counterparts. METHODS: This was a quantitative cross-sectional study, conducted in University College Cork (UCC), Ireland. A validated questionnaire was distributed to undergraduate-entry (UG) and graduate-entry (GE) students with items addressing the following areas: Demographic and academic characteristics and attitudes towards several classes of professional behaviours in medicine. RESULTS: GE students ascribed greater importance, relative to UG students, to various aspects of professionalism across the personal characteristics, interaction with patients and social responsibility categories. Additionally, in UG students, a significant decrease in perceived importance of the following professionalism items was evident across the course of the degree programme: Respect for patients as individuals, treating the underprivileged and reporting dishonesty of others. Among both groups of students, individual mentoring was rated the most important method for teaching professionalism in medicine. DISCUSSION: This study is the first comparison of attitudes to professionalism in UG and GE students. This study highlighted important group differences between GE and UG students in attitudes towards professional behaviours, together with different perspectives regarding how professionalism might be incorporated within the curriculum.

Patient-healthcare provider communication and age-related hearing loss: a qualitative study of patients' perspectives.

BACKGROUND: The prevalence of age-related hearing loss (ARHL) significantly increases in people aged 60 and older. Medical errors are frequently reported because of communication breakdown, especially for patients with ARHL. AIMS: This qualitative study focuses on identifying the communication challenges faced by people aged over 65 with ARHL and potential ameliorative strategies based on the participants' personal experiences. METHODS: Thirteen participants, attending a support service for older adults with hearing loss in the South of Ireland, were recruited using convenience sampling. Semi-structured interviews were conducted with participants. Interviews were audio-recorded and transcribed using NVivo 12 software. Braun and Clarke's thematic analysis methodology was used to identify themes arising from two main study domains: difficulties faced during the most recent healthcare interaction and suggestions for improving overall healthcare communication. RESULTS: Older adults with hearing loss identified general mishearing, lack of awareness and use of medical terminology to be the cause of ineffective communication. Raising awareness of the impact of presbycusis on clinical interaction among healthcare professionals was cited as being of crucial importance. Other helpful strategies include repeat and rephrase, use of written information, providing context, minimizing ambient noise, continuity of care, longer consultation length and good body language. CONCLUSION: Effective clinical communication can be achieved through a clear understanding of the patient's perspective. Healthcare providers should be made aware of the hearing issues and associated communication difficulties posed, within the context of the development of patient-centred strategies to improve patient safety.

Patients' and doctors' views and experiences of the patient safety trajectory of breast cancer care.

INTRODUCTION: Successful breast cancer outcomes can be jeopardised by adverse events. Understanding and integrating patients' and doctors' perspectives into care trajectories could improve patient safety. This study assessed their views on, and experiences of, medical error and patient safety. METHODS: A cross-sectional, quantitative 20-40 item questionnaire for patients attending Cork University Hospital Cancer Centre and breast cancer doctors in the Republic of Ireland was developed. Domains included demographics, medical error experience, patient safety opinions and concerns. RESULTS: 184 patients and 116 doctors completed the survey. Of the doctors, 41.4% felt patient safety had deteriorated over the previous five years and 54.3% felt patient safety measures were inadequate compared to 13.0% and 27.7% of patients respectively. Of the 30 patients who experienced medical errors/negligence claims, 18 reported permanent or long-term physical and emotional effects. Forty-two of 48 (87.5%) doctors who experienced medical errors/negligence claims reported emotional health impacts. Almost half of doctors involved in negligence claims considered early retirement. Forty-four patients and 154 doctors didn't experience errors but reported their patient safety concerns. Doctors were more concerned about communication and administrative errors, staffing and organisational factors compared to patients. Multiple barriers to error reporting were highlighted. CONCLUSION: This is the first study to assess patients' and doctors' patient safety views and medical error/negligence claims experiences in breast cancer care in Ireland. Experience of medical error/negligence claims had long-lasting implications for both groups. Doctors were concerned about a multitude of errors and causative factors. Failure to embed these findings is a missed opportunity to improve safety.

Overshadowing and salience attribution in relation to cannabis use.

Aberrant attentional salience has been implicated in the cannabis-psychosis association. Here, history and frequency of cannabis use were examined against changes in overshadowing (OS), a cue competition paradigm that involves salience processing. Additionally, we examined the association between OS and alternative measures of aberrant salience, as well as schizotypy, in a non-clinical adult sample. 280 participants completed an online geometry learning-based OS task, while a subset (N = 149) also completed the Salience Attribution Task (SAT) measure of aberrant salience. All completed the Schizotypal Personality Questionnaire (SPQ), Aberrant Salience Inventory (ASI), and the modified Cannabis Experience Questionnaire (CEQmv). Differences across OS and SAT performance stages and between cannabis use groups were assessed using mixed ANOVAs. Multiple regression and correlational analyses assessed the relationships between OS and SAT task metrics and SPQ and ASI subscale scores. Current cannabis users had significantly lower OS scores during the testing phase relative to those who do not use cannabis, at medium effect sizes. Schizotypy or ASI scores did not mediate this relationship. In the SAT, current cannabis users presented significantly higher implicit aberrant salience relative to non-users. Scores in the first training phase of the OS task significantly predicted higher explicit aberrant and adaptive salience scores in the SAT. These data indicate an association between regular cannabis use and abnormalities in cue competition effects in a healthy adult sample. Comparisons of OS and SAT cast new light on putative overlapping mechanisms underlying performance across different measures of salience.

Genetic models of schizophrenia and related psychotic disorders: progress and pitfalls across the methodological "minefield".

The challenge of modelling a complex and multifaceted disorder such as schizophrenia is epitomised by the considerable degree of phenotypic variability described in patients and by the absence of specific and consistent neuropathological biomarkers. The pattern and severity of a range of clinical features, including florid psychotic symptoms such as hallucinations and delusions, negative symptoms and cognitive dysfunction, together with age at onset, course of illness and other indices, can vary greatly between individual patients. The undefined nature of the relationship between diagnosis and underlying aetiology has complicated research in the field of clinical and preclinical neuroscience, thereby making it difficult to generate or evaluate appropriate disease models of schizophrenia. In the present review, we explore those conceptual and practical issues that relate specifically to the genetic modelling of schizophrenia and related disorders in rodents. Practical issues that impact on the robustness of endophenotypic findings and their translational relevance are discussed with reference to evidence from selective genetic models of candidate risk genes and copy number variants implicated in schizophrenia.

Genetic vs. pharmacological inactivation of COMT influences cannabinoid-induced expression of schizophrenia-related phenotypes.

Catechol-O-methyltransferase (COMT) is an important enzyme in the metabolism of dopamine and disturbance in dopamine function is proposed to be central to the pathogenesis of schizophrenia. Clinical epidemiological studies have indicated cannabis use to confer a 2-fold increase in risk for subsequent onset of psychosis, with adolescent-onset use conveying even higher risk. There is evidence that a high activity COMT polymorphism moderates the effects of adolescent exposure to cannabis on risk for adult psychosis. In this paper we compared the effect of chronic adolescent exposure to the cannabinoid WIN 55212 on sensorimotor gating, behaviours related to the negative symptoms of schizophrenia, anxiety- and stress-related behaviours, as well as ex-vivo brain dopamine and serotonin levels, in COMT KO vs. wild-type (WT) mice. Additionally, we examined the effect of pretreatment with the COMT inhibitor tolcapone on acute effects of this cannabinoid on sensorimotor gating in C57BL/6 mice. COMT KO mice were shown to be more vulnerable than WT to the disruptive effects of adolescent cannabinoid treatment on prepulse inhibition (PPI). Acute pharmacological inhibition of COMT in C57BL/6 mice also modified acute cannabinoid effects on startle reactivity, as well as PPI, indicating that chronic and acute loss of COMT can produce dissociable effects on the behavioural effects of cannabinoids. COMT KO mice also demonstrated differential effects of adolescent cannabinoid administration on sociability and anxiety-related behaviour, both confirming and extending earlier reports of COMT×cannabinoid effects on the expression of schizophrenia-related endophenotypes.

Phenotypic effects of repeated psychosocial stress during adolescence in mice mutant for the schizophrenia risk gene neuregulin-1: a putative model of gene × environment interaction.

There is a paucity of animal models by which the contributions of environmental and genetic factors to the pathobiology of psychosis can be investigated. This study examined the individual and combined effects of chronic social stress during adolescence and deletion of the schizophrenia risk gene neuregulin-1 (NRG1) on adult mouse phenotype. Mice were exposed to repeated social defeat stress during adolescence and assessed for exploratory behaviour, working memory, sucrose preference, social behaviour and prepulse inhibition in adulthood. Thereafter, in vitro cytokine responses to mitogen stimulation and corticosterone inhibition were assayed in spleen cells, with measurement of cytokine and brain-derived neurotrophic factor (BDNF) mRNA in frontal cortex, hippocampus and striatum. NRG1 mutants exhibited hyperactivity, decreased anxiety, impaired sensorimotor gating and reduced preference for social novelty. The effects of stress on exploratory/anxiety-related parameters, spatial working memory, sucrose preference and basal cytokine levels were modified by NRG1 deletion. Stress also exerted varied effect on spleen cytokine response to concanavalin A and brain cytokine and BDNF mRNA expression in NRG1 mutants. The experience of psychosocial stress during adolescence may trigger further pathobiological features that contribute to the development of schizophrenia, particularly in those with underlying NRG1 gene abnormalities. This model elaborates the importance of gene × environment interactions in the etiology of schizophrenia.

Mutant mouse models in evaluating novel approaches to antipsychotic treatment.

In this review we consider the application of mutant mouse phenotypes to the study of psychotic illness in general and schizophrenia in particular, as they relate to behavioral, psychopharmacological, and cellular phenotypes of putative import for antipsychotic drug development. Mutant models appear to be heuristic at two main levels; firstly, by indicating the functional roles of neuronal components thought to be of relevance to the putative pathobiology of psychotic illness, they help resolve overt behavioral and underlying cellular processes regulated by those neuronal components; secondly, by indicating the functional roles of genes associated with risk for psychotic illness, they help resolve overt behavioral and underlying cellular processes regulated by those risk genes. We focus initially on models of dopaminergic and glutamatergic dysfunction. Then, we consider advances in the genetics of schizophrenia and mutant models relating to replicable risk genes. Lastly, we extend this discussion by exemplifying two new variant approaches in mutant mice that may serve as prototypes for advancing antipsychotic drug development. There is continuing need not only to address numerous technical challenges but also to develop more "real-world" paradigms that reflect the milieu of gene × environment and gene × gene interactions that characterize psychotic illness and its response to antipsychotic drugs.