Association between acute care collaborations and health care utilization as compared to stand-alone facilities in the Netherlands: a quasi-experimental study.

Health systems invest in coordination and collaboration between emergency departments (ED) and after-hours primary care providers (AHPCs) to alleviate pressure on the acute care chain. There are substantial gaps in the existing evidence, limited in sample size, follow-up care, and costs. We assess whether acute care collaborations (ACCs) are associated with decreased ED utilization, hospital admission rates, and lower costs per patient journey, compared with stand-alone facilities. The design is a quasi-experimental study using claims data. The study included 610 845 patients in the Netherlands (2017). Patient visits in ACCs were compared to stand-alone EDs and AHPCs. The number of comorbidities was similar in both groups. Multiple logistic and gamma regressions were used to determine whether patient visits to ACCs were negatively associated with ED utilization, hospital admission rates, and costs. Logistic regression analysis did not find an association between patients visiting ACCs and ED utilization compared to patients visiting stand-alone facilities [odds ratio (OR), 1.01; 95% confidence interval (CI), 1.00-1.03]. However, patients in ACCs were associated with an increase in hospital admissions (OR, 1.07; 95% CI, 1.04-1.09). ACCs were associated with higher total costs incurred during the patient journey (OR, 1.02; 95% CI, 1.01-1.03). Collaboration between EDs and AHPCs was not associated with ED utilization, but was associated with increased hospital admission rates, and higher costs. These collaborations do not seem to improve health systems' financial sustainability.

Measuring Active Purchasing in Healthcare: Analysing Reallocations of Funds Between Providers to Evaluate Purchasing Systems Performance in the Netherlands.

BACKGROUND: Purchasing systems aim to improve resource allocation in healthcare markets. The Netherlands is characterized by four different purchasing systems: managed competition in the hospital market, a non-competitive single payer system for long-term care (LTC), municipal procurement for home care and social services, and self-procurement via personal budgets. We hypothesize that managed competition and competitive payer reforms boost reallocations of provider market share by means of active purchasing, ie, redistributing funds from high-quality providers to low-quality providers. METHODS: We define a Market Activity Index (MAI) as the sum of funds reallocated between providers annually. Provider expenditures are extracted from provider financial statements between 2006 and 2019. We compare MAI in six healthcare sectors under four different purchasing systems, adjusting for reforms, and market entry/exit. Next, we perform in-depth analyses on the hospital market. Using multivariate linear regressions, we relate reallocations to selective contracting, provider quality, and market characteristics. RESULTS: No difference was found between reallocations in the hospital care market under managed competition and the non-competitive single payer LTC (MAI between 2% and 3%), while MAI was markedly higher under procurement by municipalities and personal budget holders (between 5% and 15%). While competitive reforms temporarily increased MAI, no structural effects were found. Relatively low hospital MAI could not be explained by market characteristics. Furthermore, the extent of selective contracting or hospital quality differences had no significant effects on reallocations of funds. CONCLUSION: Dutch managed competition and competitive purchaser reforms had no discernible effect on reallocations of funds between providers. This casts doubt on the mechanisms advocated by managed competition and active purchasing to improve allocative efficiency.

Cascade of decisions meet personal preferences in sciatica treatment decisions.

STUDY DESIGN: An in-depth interview study including patients, general practitioners, neurologists and neurosurgeons. OBJECTIVE: To gain insight in decision-making in sciatica care, by identifying patients' and physicians' preferences for treatment options, and the differences between and within both groups. SUMMARY OF BACKGROUND DATA: Sciatica is a self-limiting condition, which can be treated both conservatively and surgically. The value of both options has been disputed, and the care pathway is known for a substantial amount of practice variation. Most Dutch patients are taken care of by general practitioners before they are referred to hospital-based neurologists, who might refer to a neurosurgeon, who can perform a surgical intervention. Dutch sciatica care thus follows the principles of stepped care, and a cascade of decisions precedes surgery. Better understanding of the decision-making within this cascade might reveal opportunities to improve shared decision-making and to reduce unwarranted practice variation. METHODS: Interviews with 10 patients and 22 physicians were analysed thematically. RESULTS: While physicians were confident of their clinical diagnosis, patients preferred confirmation trough imaging to exclude other possible explanations. Furthermore, many patients showed reluctance towards the use of (strong) opioids, while all physicians favoured this and underlined the benefits of opioids in the management of sciatica complaints, to buy time and to allow patients to recover naturally. Finally, individual physicians differed strongly in their opinion on benefits and optimal timing of surgical treatment and epidural injections. CONCLUSIONS: Dutch sciatica care is characterised by a cascade of decisions preceding surgery. Preferences differ within and between patients and physicians, which adds to the practice variation. To improve decision-making, physicians and patients should invest not necessarily more in the exchange of options or preferences, but in making sure the other understands the rationale behind them.

Density of Patient-Sharing Networks: Impact on the Value of Parkinson Care.

BACKGROUND: Optimal care for Parkinson's disease (PD) requires coordination and collaboration between providers within a complex care network. Individual patients have personalised networks of their own providers, creating a unique informal network of providers who treat ('share') the same patient. These 'patient-sharing networks' differ in density, ie, the number of identical patients they share. Denser patient-sharing networks might reflect better care provision, since providers who share many patients might have made efforts to improve their mutual care delivery. We evaluated whether the density of these patient-sharing networks affects patient outcomes and costs. METHODS: We analysed medical claims data from all PD patients in the Netherlands between 2012 and 2016. We focused on seven professional disciplines that are commonly involved in Parkinson care. We calculated for each patient the density score: the average number of patients that each patient's providers shared. Density scores could range from 1.00 (which might reflect poor collaboration) to 83.00 (which might reflect better collaboration). This score was also calculated at the hospital level by averaging the scores for all patients belonging to a specific hospital. Using logistic and linear regression analyses we estimated the relationship between density scores and health outcomes, healthcare utilization, and healthcare costs. RESULTS: The average density score varied considerably (average 6.7, SD 8.2). Adjusted for confounders, higher density scores were associated with a lower risk of PD-related complications (odds ratio [OR]: 0.901; P<.001) and with lower healthcare costs (coefficients: -0.018, P=.005). Higher density scores were associated with more frequent involvement of neurologists (coefficient 0.068), physiotherapists (coefficient 0.052) and occupational therapists (coefficient 0.048) (P values all <.001). CONCLUSION: Patient sharing networks showed large variations in density, which appears unwanted as denser networks are associated with better outcomes and lower costs.

Medicalization Defined in Empirical Contexts - A Scoping Review.

BACKGROUND: Medicalization has been a topic of discussion and research for over four decades. It is a known concept to researchers from a broad range of disciplines. Medicalization appears to be a concept that speaks to all, suggesting a shared understanding of what it constitutes. However, conceptually, the definition of medicalization has evolved over time. It is unknown how the concept is applied in empirical research, therefore following research question was answered: How is medicalization defined in empirical research and how do the definitions differ from each other? METHODS: We performed a scoping review on the empirical research on medicalization. The 5 steps of a scoping review were followed: (1) Identifying the research question; (2) Identifying relevant studies; (3) Inclusion and exclusion criteria; (4) Charting the data; and (5) Collating, summarizing and reporting the results. The screening of 3027 papers resulted in the inclusion of 50 empirical studies in the review. RESULTS: The application of the concept of medicalization within empirical studies proved quite diverse. The used conceptual definitions could be divided into 10 categories, which differed from each other subtly though importantly. The ten categories could be placed in a framework, containing two axes. The one axe represents a continuum from value neutral definitions to value laden definitions. The other axe represents a continuum from a micro to a macro perspective on medicalization. CONCLUSION: This review shows that empirical research on medicalization is quite heterogeneous in its definition of the concept. This reveals the richness and complexity of medicalization, once more, but also hinders the comparability of studies. Future empirical research should pay more attention to the choice made with regard to the definition of medialization and its applicability to the context of the study.

Characteristics and health care utilization among patients with chronic heart failure: a longitudinal claim database analysis.

AIMS: This study aimed to determine the characteristics of patients with heart failure and high costs (top 1% and top 2-5% highest costs in perspective of the general population) and to explore the longitudinal health care utilization and persistency of high costs. METHODS AND RESULTS: Longitudinal observational study using claims data from 2006 to 2014 in the Netherlands. We identified all patients that received a hospital treatment for chronic heart failure between 1 January 2008 and 31 December 2010. Of each selected patient, all claims from the Dutch curative health system and with a starting date between 1 January 2006 and 31 December 2014 were extracted. Pharmaceutical and hospital claims were used to establish characteristics and indicators for health care utilization. Descriptive analyses and generalized estimating equation models were used to analyse characteristics, longitudinal health care utilization and to identify factors associated with high costs. Our findings revealed that the difference in costs between top 1%, top 2-5%, and bottom 95% patients with heart failure was mainly driven by hospital costs; and the top 1% group experienced a remarkable increase of mental health costs. Top 1% and top 2-5% patients with heart failure differed from lower cost patients in their higher rate of chronic conditions, excessive polypharmacy, hospital admissions, and heart-related surgeries. Heart-related surgeries contributed to the incidental high costs in 54% of top 1% patients, and the costs of the remaining top 1% patients were driven by mental health and pharmaceuticals use and rates of chronic conditions and multimorbidity. Top 1% patients were relatively young. Anaemia, dementia, diseases of arteries, veins and lymphatic vessels, influenza, and kidney failure were significantly associated with high costs. The end-of-life period was predictive of top 1% and top 5% costs. More than 90% of the population incurred at least one top 5% year during follow-up, and 31.8% incurred at least one top 1% year. Fifty-seven per cent incurred multiple top 5% years whereas only 8.6% incurred multiple top 1% years. Top 5% years were more frequently consecutive than top 1% years. CONCLUSIONS: Top 1% utilization occurs predominantly incidentally and among less than a third of patients with heart failure, whereas almost all patients with heart failure experience at least one top 5% year, and more than half experience two or more top 5% years. Both medical and psychiatric/psychosocial needs contribute to high costs in heart failure patients. Comprehensive and integrated efforts are needed to further improve quality of care and reduce unnecessary costs.

Sex-Specific Patient Journeys in Early Parkinson's Disease in the Netherlands.

Objective: To reconstruct a sex-specific patient journey for Dutch persons with Parkinson's disease (PD) during the first 5 years after diagnosis. Method: We analyzed a national administrative medical claims database containing data of all patients newly diagnosed with PD between 2012 and 2016 in the Netherlands. We performed time-to-event analysis to identify the moments when patients received care from neurologists, allied healthcare therapists or general practitioners. We also extracted relevant clinical milestones: unexpected hospitalization for PD, pneumonia, orthopedic injuries, nursing home admission, and death. Using these data, we constructed the patient journey stratified for sex. Results: We included claims data of 13,518 men and 8,775 women with newly diagnosed PD in the Netherlands. While we found little difference in neurologist consultations, women visited general practitioners and physiotherapists significantly earlier and more often (all p-values < 0.001). After 5 years, 37.9% (n = 3,326) of women had visited an occupational therapist and 18.5% (n = 1,623) a speech and language therapist at least once. This was 33.1% (n = 4,474) and 23.7% (n = 3,204) for men. Approximately 2 years after diagnosis, PD-related complications (pneumonia, orthopedic injuries, and PD-related hospitalization) occurred for the first time (women: 1.8 years; men: 2.3 years), and after 5 years, 72.9% (n = 6,397) of women, and 68.7% (n = 9,287) of men had experienced at least one. Discussion: Considering the strengths and limitations of our methods, our findings suggest that women experience complications and access most healthcare services sooner after diagnosis and more frequently than men. The identified sex differences extend the debate about phenotypical differences in PD between men and women.

A challenge to all. A primer on inter-country differences of high-need, high-cost patients.

BACKGROUND: Across countries, a small group of patients accounts for the majority of health care spending. These patients are more likely than other patients to experience problems with quality and safety in their care, suggesting that efforts targeting efficiency and quality among this population might have significant payoffs for health systems. Better understanding of similarities and differences in patient characteristics and health care use in different countries may ultimately inform further efforts to improve care for HNHC patients in these health systems. METHODS: We conducted a cross-sectional descriptive study using one year of patient-level data on high-cost patients in seven high-income OECD member countries. Countries were selected based on availability of detailed information (large enough samples of claims, administrative, and survey data of high-cost patients). We studied concentration of spending among high-cost patients, characteristics of high-cost patients, and per capita spending on high-cost patients. FINDINGS: Cost-concentration of the top 5% of patients varied across countries, from 41% in Japan to 60% in Canada, driven primarily by variation in the top 1% of spenders. In general, high-cost patients were more likely to be female (57.7% on average), had a significant number of multi-morbidities (up to on average 10 major diagnostic categories (ICD chapters), and had a lower socioeconomic status. Characteristics of high-cost patients varied as well: median age ranged from 62 in the Netherlands to 75 in Germany and the difference in socioeconomic status is particularly stark in the US. Lastly, utilization, particularly for inpatient care, varied with an average number of inpatient days ranging from 6.6 nights (US) to 97.7 nights in Japan. INTERPRETATION: In this descriptive study, there is substantial variation in the cost concentration, characteristics, and per capita spending on high-cost patient populations across high-income countries. Differences in the way that health systems are structured likely explains some of this variation, which suggests the potential of cross-system learning opportunities. Our findings highlight the need for further studies including comparable performance metrics and institutional analysis.

Do quality improvements in assisted reproduction technology increase patient numbers in a managed competition setting?

In a system of managed competition, selective contracting and patient choice reward providers for quality improvements through increases in patient numbers and revenue. We research whether these mechanisms function as envisioned by investigating the relationship between quality improvements and patient numbers in assisted reproduction technology in the Netherlands. Success rate improvements primarily reduce volume as fewer secondary treatments are necessary, but this can be compensated by attracting new patients. Using nationwide registry data from 1996 to 2016, we find limited evidence that high-quality clinics attract new patients, and insufficiently as to compensate for the reduction in secondary treatments. The net effect of quality increases appears to be a small decline in revenue. Therefore, we conclude that patient choice and active purchasing reward quality improvements insufficiently. Nevertheless, clinics have improved quality drastically over the last years, showing that financial incentives are perhaps less important factors for quality improvements than factors such as intrinsic motivation and professional autonomy.

Systematic review of high-cost patients' characteristics and healthcare utilisation.

OBJECTIVES: To investigate the characteristics and healthcare utilisation of high-cost patients and to compare high-cost patients across payers and countries. DESIGN: Systematic review. DATA SOURCES: PubMed and Embase databases were searched until 30 October 2017. ELIGIBILITY CRITERIA AND OUTCOMES: Our final search was built on three themes: 'high-cost', 'patients', and 'cost' and 'cost analysis'. We included articles that reported characteristics and utilisation of the top-X% (eg, top-5% and top-10%) patients of costs of a given population. Analyses were limited to studies that covered a broad range of services, across the continuum of care. Andersen's behavioural model was used to categorise characteristics and determinants into predisposing, enabling and need characteristics. RESULTS: The studies pointed to a high prevalence of multiple (chronic) conditions to explain high-cost patients' utilisation. Besides, we found a high prevalence of mental illness across all studies and a prevalence higher than 30% in US Medicaid and total population studies. Furthermore, we found that high costs were associated with increasing age but that still more than halve of high-cost patients were younger than 65 years. High costs were associated with higher incomes in the USA but with lower incomes elsewhere. Preventable spending was estimated at maximally 10% of spending. The top-10%, top-5% and top-1% high-cost patients accounted for respectively 68%, 55% and 24% of costs within a given year. Spending persistency varied between 24% and 48%. Finally, we found that no more than 30% of high-cost patients are in their last year of life. CONCLUSIONS: High-cost patients make up the sickest and most complex populations, and their high utilisation is primarily explained by high levels of chronic and mental illness. High-cost patients are diverse populations and vary across payer types and countries. Tailored interventions are needed to meet the needs of high-cost patients and to avoid waste of scarce resources.

Limit, lean or listen? A typology of low-value care that gives direction in de-implementation.

BACKGROUND: Overuse of unnecessary care is widespread around the world. This so-called low-value care provides no benefit for the patient, wastes resources and can cause harm. The concept of low-value care is broad and there are different reasons for care to be of low-value. Hence, different strategies might be necessary to reduce it and awareness of this may help in designing a de-implementation strategy. Based on a literature scan and discussions with experts, we identified three types of low-value care. RESULTS: The type ineffective care is proven ineffective, such as antibiotics for a viral infection. Inefficient care is in essence effective, but is of low-value through inefficient provision or inappropriate intensity, such as chronic benzodiazepine use. Unwanted care is in essence appropriate for the clinical condition it targets, but is low-value since it does not fit the patients' preferences, such as a treatment aimed to cure a patient that prefers palliative care. In this paper, we argue that these three types differ in their most promising strategy for de-implementation and that our typology gives direction in choosing whether to limit, lean or listen. CONCLUSION: We developed a typology that provides insight in the different reasons for care to be of low-value. We believe that this typology is helpful in designing a tailor-made strategy for reducing low-value care.

Antimicrobial Stewardship Initiatives Throughout Europe: Proven Value for Money.

Antimicrobial stewardship is recognized as a key component to stop the current European spread of antimicrobial resistance. It has also become evident that antimicrobial resistance is a problem that cannot be tackled by single institutions or physicians. Prevention of antimicrobial resistance needs rigorous actions at ward level, institution level, national level and at supra-national levels. Countries can learn from each other and possibly transplant best practices across borders to prevent antimicrobial resistance. The aim of this study is to highlight some of the success stories of proven cost-effective interventions, and to describe the actions that have been taken, the outcomes that have been found, and the difficulties that have been met. In some cases we came across substantial scope for real-life cost savings. Although the best approach to effectively hinder the spread of antimicrobial resistance remains unclear and may vary significantly among settings, several EU-wide examples demonstrate that cost-effective antimicrobial stewardship is possible. Such examples can encourage others to implement (the most cost-effective) elements in their system.

Medicalisation and Overdiagnosis: What Society Does to Medicine.

The concept of overdiagnosis is a dominant topic in medical literature and discussions. In research that targets overdiagnosis, medicalisation is often presented as the societal and individual burden of unnecessary medical expansion. In this way, the focus lies on the influence of medicine on society, neglecting the possible influence of society on medicine. In this perspective, we aim to provide a novel insight into the influence of society and the societal context on medicine, in particularly with regard to medicalisation and overdiagnosis.

A new approach to the tradeoff between quality and accessibility of health care.

INTRODUCTION: Quality of care is associated with patient volume. Regionalization of care is therefore one of the approaches that is suited to improve quality of care. A disadvantage of regionalization is that the accessibility of the facilities can decrease. By investigating the tradeoff between quality and accessibility it is possible to determine the optimal amount of treatment locations in a health care system. In this article we present a new model to quantitatively 'solve' this tradeoff. We use the condition breast cancer in the Netherlands as an example. MATERIALS AND METHODS: We calculated the expected quality gains in Quality Adjusted Lifetime Years (QALY's) due to stepwise regionalization using 'volume-outcome' literature for breast cancer. Decreased accessibility was operationalized as increased (travel) costs due to regionalization by using demographic data, drive-time information, and the national median income. The total sum of the quality and accessibility function determines the optimum range of treatment locations for this particular condition, given the 'volume-quality' relationship and Dutch demographics and geography. RESULTS: Currently, 94 locations offer breast cancer treatment in the Netherlands. Our model estimates that the optimum range of treatment locations for this particular condition in the Netherlands varies from 15 locations to 44 locations. CONCLUSION: Our study shows that the Dutch society would benefit from regionalization of breast cancer care as possible quality gains outweigh heightened travel costs. In addition, this model can be used for other medical conditions and in other countries.

Biochemical and behavioral effects of long-term citalopram administration and discontinuation in rats: role of serotonin synthesis.

We have investigated effects of continuous SSRI administration and abrupt discontinuation on biochemical and behavioral indices of rat brain serotonin function, and attempted to identify underlying mechanisms. Biochemistry of serotonin was assessed with brain tissue assays and microdialysis; behavior was assessed as the acoustic startle reflex. Long-term SSRI administration to rats reduced the content of 5-HT and its main metabolite shortly after inhibition of 5-HT synthesis in many brain areas with more than 50%. Turnover was not appreciably decreased, but significantly increased within 48h of drug discontinuation. The microdialysis experiments indicate that neuronal release of 5-HT depends strongly on new synthesis and emphasize the role of 5-HT(1B) receptors in the regulation of these processes. Discontinuation of the SSRI rapidly increased behavioral reactivity to the external stimulus. Additional startle experiments suggest that the increased reactivity is more likely related to the reduced extracellular 5-HT levels than to impaired synthesis. The combination of the marked reduction of serotonin content and limited synthesis may destabilize brain serotonin transmission during long-term SSRI treatment. These combined effects may compromise the efficacy of an SSRI therapy and facilitate behavioral changes following non-compliance.

The development of peripartum depressive symptoms is associated with gene polymorphisms of MAOA, 5-HTT and COMT.

BACKGROUND: Polymorphisms of monoamine-related genes have been associated with depression following life events. The peripartum is a physiologically and psychologically challenging period, characterized by fluctuations in depressive symptoms, therefore facilitating prospective investigations in this gene x environment (G x E) interaction. METHODS: Eighty nine pregnant women filled in two Edinburgh Postpartum Depression Scale (EPDS) questionnaires during pregnancy and two in the postpartum period. MAOA, COMT and 5-HTT polymorphisms were analyzed. RESULTS: We found a significant interaction between the development of depressive symptoms in the course of pregnancy and polymorphisms in 5-HTT (p=0.019); MAOA (p=0.044) and COMT (p=0.026), and MAOA x COMT (p<0.001). Particularly, women carrying the combination of low activity variants of MAOA and COMT showed increased EPDS scores at week 36 of pregnancy and 6 weeks postpartum, but not during early pregnancy or 12 weeks postpartum. CONCLUSION: We found that MAOA in combination with COMT appears to regulate not only the stress response in laboratory experiments, but also seems to influence the stress-evoked onset of mood during normal, mild, stressful events, such as experienced in the peripartum period. These findings support the GxE concept for depression, but they underline the complexity of this concept, as the cumulating effects of these polymorphic genes (i.e. MAOA+COMT) might be needed and the effects of these polymorphic genes becomes apparent in special environmental or physiological conditions (i.e. the peripartum period). We therefore suggest that G x E interactions become especially noticeable from longitudinal study designs in specific physiological or social challenging periods.

Abrupt rather than gradual hormonal changes induce postpartum blues-like behavior in rats.

AIMS: Postpartum blues is thought to be related to hormonal events accompanying delivery. We investigated whether blues-like symptoms depend on the rate of the decline of hormones, by comparing the behavioral consequences of an abrupt versus a gradual decline of gonadal hormones in an animal model. METHODS: Female rats were treated with estrogen and progesterone for 23 days, administered either by injections or by subcutaneously implanted tubes filled with hormones. A gradual hormone decline was achieved by discontinuation of the injections; and rapid decline by removal of the tubes. Control groups received either a continued treatment or no hormones. In the period following the decline the stress-reactivity was tested with an acoustic startle test on 3 consecutive days, and anxiety behavior with an open-field test on the 2nd day. The Hypothalamus-, Pituitary-, Adrenal-axis (HPA-axis) response to stress was measured by assessing the corticosterone levels and hypothalamic c-fos expression stress-response at the 4th day. KEY FINDINGS: The rapid decline of hormones induced an increased startle response lasting for two days, and increased anxiety-like behavior in the open field. This was not found in the gradual-decline and control groups. The HPA-axis response to stress was decreased in all hormone-treated animals. SIGNIFICANCE: This animal study suggests that: 1) abrupt rather than gradual hormonal changes induce increased stress-reactivity and anxiety-like behavior; 2) postpartum blues may result from differences in the capacity to adapt to the changes of gonadal hormones; 3) Recovery of pregnancy-induced diminished HPA-axis response is independent of the postpartum hormone kinetics.

Low plasma tryptophan in carcinoid patients is associated with increased urinary cortisol excretion.

BACKGROUND: Previously we observed in patients suffering from a metastatic carcinoid tumor that irritability, aggression and lack of impulse control are associated with low levels of plasma tryptophan and presumably with low brain serotonin function. In rats we showed that a diet of low tryptophan resulted in higher stress responses and higher corticosterone production. Here we tested in carcinoid patients whether tryptophan depletion due to tumor 5-HT overproduction is associated with high cortisol production. METHODS: Urinary excretion of cortisol, serotonin, 5-hydroxyindole acetic acid (the main metabolite of serotonin a marker of tumor activity), plasma levels of tryptophan and platelet content of serotonin (index of peripheral serotonin synthesis) were determined in metastatic midgut carcinoid patients. Patients (N = 25) were divided into two groups based on their plasma tryptophan levels (< or = 25 micromol/l, n = 12 and > or = 49 micromol/l, n = 13). RESULTS: Carcinoid patients with low plasma tryptophan levels had significantly higher urinary excretion of free cortisol (p < 0.01), independent of tumor activity. The inter-individual differences in the low tryptophan group, however, were substantial. CONCLUSIONS: In a subgroup of the patients suffering from metastatic carcinoid disease the cerebral access of plasma tryptophan is impaired, thus rendering cerebral serotonin neurotransmission suboptimal and leading to hypercortisolism. The present study provides further support to the idea that low serotonergic function is a risk for developing stress-associated psychopathology.

Sustained release of corticosterone in rats affects reactivity, but does not affect habituation to immobilization and acoustic stimuli.

Depression is often preceded by stressful life events and accompanied with elevated cortisol levels and glucocorticoid resistance. It has been suggested that a major depressive disorder may result from impaired coping with and adaptation to stress. The question is whether or not hypothalamus-pituitary-adrenal (HPA)-axis dysfunction influences the process of adaptation. We examined the effect of a dysregulated HPA-axis on the adaptation to acoustic stimuli in rats with or without preceding restraint stress. HPA-axis function was altered via slow release of corticosterone (CORT, 90 mg) from subcutaneously implanted pellets for 7 or 14 days. The rate of body temperature increases during restraint (10 min) and the response to acoustic stimuli (of 80+120 dB) were used to quantify daily stress reactivity. Rats habituated to either stress regardless of CORT treatment. CORT treatment combined with restraint decreased the initial reactivity and the variability in response, but the rate of habituation was not influenced. These results show that suppressing normal HPA-axis function by chronic exposure to CORT does affect the course of habituation, but not habituation per se. This implies that altered HPA-axis function in depressed patients may not be causally related to stress coping, but instead may influence the course of the disorder.