A Reliable High-Throughput Screening Model for Antidepressant.

Depression is the most frequent affective disorder and is the leading cause of disability worldwide. In order to screen antidepressants and explore molecular mechanisms, a variety of animal models were used in experiments, but there is no reliable high-throughput screening method. Zebrafish is a common model organism for mental illness such as depression. In our research, we established chronic unpredictable mild stress (CUMS) models in C57BL/6 mice and zebrafish; the similarities in behavior and pathology suggest that zebrafish can replace rodents as high-throughput screening organisms. Stress mice (ip., 1 mg/kg/d, 3 days) and zebrafish (10 mg/L, 20 min) were treated with reserpine. As a result, reserpine caused depression-like behavior in mice, which was consistent with the results of the CUMS mice model. Additionally, reserpine reduced the locomotor ability and exploratory behavior of zebrafish, which was consistent with the results of the CUMS zebrafish model. Further analysis of the metabolic differences showed that the reserpine-induced zebrafish depression model was similar to the reserpine mice model and the CUMS mice model in the tyrosine metabolism pathway. The above results showed that the reserpine-induced depression zebrafish model was similar to the CUMS model from phenotype to internal metabolic changes and can replace the CUMS model for antidepressants screening. Moreover, the results from this model were obtained in a short time, which can shorten the cycle of drug screening and achieve high-throughput screening. Therefore, we believe it is a reliable high-throughput screening model.

Eriodictyol produces antidepressant-like effects and ameliorates cognitive impairments induced by chronic stress.

Eriodictyol, a natural flavonoid compound identified in numerous medicinal plants, has been reported to have anti-inflammatory, antioxidative and antiproliferative activities and exert protective effects on the neurons, thus drawing attention to its therapeutic potential. However, the effect of eriodictyol on depression remains unclear. In the present study, we investigated the behavioral effects of chronic eriodictyol treatment in rat models of depression induced by lipopolysaccharide (LPS, 1 mg/kg) challenge and chronic unpredictable mild stress (CUMS). We found that chronic eriodictyol (10, 30, and 100 mg/kg) treatment by oral gavage once daily for 14 days dose-dependently produced antidepressant effect in the forced swim test (FST), but did not alter locomotor activity in the open field test. Moreover, oral administration with eriodictyol (100 mg/kg) for 28 days reversed the depressive- and anxiety-like behaviors induced by LPS or CUMS, as evidenced by significantly increased sucrose preference in the sucrose preference test, reduced immobility time in the FST, and reduced latency to feeding in the novelty-suppressed feeding test. In addition, co-administration of subthreshold doses of eriodictyol (30 mg/kg) and transient potential vanilloid 1 receptor antagonist capsazepine (1.5 mg/kg) produced a synergistic effect in these tests. Chronic eriodictyol administration at a dose of 100 mg/kg also rescued the memory deficits induced by CUMS as indicated by the increased exploration index in the novel object recognition test. Altogether, these results demonstrate that eriodictyol attenuates depressive- and anxiety-like behaviors and cognitive impairments in rats, and might be a potential therapeutic avenue for depression.

Alcohol, psychomotor-stimulants and behaviour: methodological considerations in preclinical models of early-life stress.

BACKGROUND: In order to assess the risk associated with early-life stress, there has been an increase in the amount of preclinical studies investigating early-life stress. There are many challenges associated with investigating early-life stress in animal models and ensuring that such models are appropriate and clinically relevant. OBJECTIVES: The purpose of this review is to highlight the methodological considerations in the design of preclinical studies investigating the effects of early-life stress on alcohol and psychomotor-stimulant intake and behaviour. METHODS: The protocols employed for exploring early-life stress were investigated and summarised. Experimental variables include animals, stress models, and endpoints employed. RESULTS: The findings in this paper suggest that there is little consistency among these studies and so the interpretation of these results may not be as clinically relevant as previously thought. CONCLUSION: The standardisation of these simple stress procedures means that results will be more comparable between studies and that results generated will give us a more robust understanding of what can and may be happening in the human and veterinary clinic.

Factors associated with psychological distress amongst outpatient chemotherapy patients: An analysis of depression, anxiety and stress using the DASS-21.

AIM: This study sought to identify clinical, demographic and service-related factors associated with psychological distress amongst outpatient chemotherapy patients. BACKGROUND: Distress in cancer patients leads to increased risk of psychological comorbidity, contributing to sub-optimal treatment adherence and potentially leading to poorer health outcomes. Screening and recognition of distress and risk factors is an important aspect of holistic care within a multidisciplinary team environment. METHODS: Data were obtained via survey and chart review of ambulatory chemotherapy patients at three public tertiary referral hospitals in Perth, Western Australia. The DASS-21 was used to screen for psychological distress. Regression analyses were used to assess the relationship between distress and a range of cancer, socioeconomic and treatment factors. RESULTS: Patients with a Karnofsky Performance Score≤80 (OR 3.8, 95% CI [1.7, 78.7]) and average waiting time (between oncology outpatient appointment and commencement of chemotherapy infusion) >60min (OR 2.4, 95% CI [1.04, 5.5]) were at increased risk of moderate-severe distress. Patients with a household income between $AU 50-75,000 p.a. had a lower risk of distress compared to <$25,000 p.a. (OR 0.05, 95% CI [0.01, 0.52]). On sub-scale analysis, depression and anxiety contributed more to overall distress than the stress subscales. CONCLUSIONS: Performance status, waiting times and household income were key predictors of distress. Findings could assist clinicians to identify higher-risk population subsets that could benefit from targeted screening and additional psychological and social work support. Findings could also assist administrators to consider the contribution of modifiable factors such as waiting times to patient distress.

Responsibilities of the Occupational and Environmental Medicine Provider in the Treatment and Prevention of Climate Change-Related Health Problems.

: Workers are uniquely susceptible to the health hazards imposed by environmental changes. Occupational and environmental medicine (OEM) providers are at the forefront of emerging health issues pertaining to working populations including climate change, and must be prepared to recognize, respond to, and mitigate climate change-related health effects in workers. This guidance document from the American College of Occupational and Environmental Medicine focuses on North American workers health effects that may occur as a result of climate change and describes the responsibilities of the OEM provider in responding to these health challenges.

Evidence for Stress-like Alterations in the HPA-Axis in Women Taking Oral Contraceptives.

Using oral contraceptives has been implicated in the aetiology of stress-related disorders like depression. Here, we followed the hypothesis that oral contraceptives deregulate the HPA-axis by elevating circulating cortisol levels. We report for a sample of 233 pre-menopausal women increased circulating cortisol levels in those using oral contraceptives. For women taking oral contraceptives, we observed alterations in circulating phospholipid levels and elevated triglycerides and found evidence for increased glucocorticoid signalling as the transcript levels of the glucocorticoid-regulated genes DDIT4 and FKBP5 were increased in whole blood. The effects were statistically mediated by cortisol. The associations of oral contraceptives with higher FKBP5 mRNA and altered phospholipid levels were modified by rs1360780, a genetic variance implicated in psychiatric diseases. Accordingly, the methylation pattern of FKBP5 intron 7 was altered in women taking oral contraceptives depending on the rs1360780 genotype. Moreover, oral contraceptives modified the association of circulating cortisol with depressive symptoms, potentially explaining conflicting results in the literature. Finally, women taking oral contraceptives displayed smaller hippocampal volumes than non-using women. In conclusion, the integrative analyses of different types of physiological data provided converging evidence indicating that oral contraceptives may cause effects analogous to chronic psychological stressors regarding the regulation of the HPA axis.

Impact of [d-Lys(3)]-GHRP-6 and feeding status on hypothalamic ghrelin-induced stress activation.

Ghrelin administration directly into hypothalamic nuclei, including the arcuate nucleus (ArcN) and the paraventricular nucleus (PVN), alters the expression of stress-related behaviors. In the present study we investigated the effect of feeding status on the ability of ghrelin to induce stress and anxiogenesis. Adult male Sprague Dawley rats were implanted with guide cannula targeting either the ArcN or PVN. In the first experiment we confirmed that ArcN and PVN ghrelin treatment produced anxiety-like behavior as measured using the elevated plus maze (EPM) paradigm. Ghrelin was administered during the early dark cycle. Immediately after microinjections rats were placed in the EPM for 5min. Both ArcN and PVN treatment reduced open arm exploration. The effect was attenuated by pretreatment with the ghrelin 1a receptor antagonist [d-Lys(3)]-GHRP-6. In a separate group of animals ghrelin was injected into either nucleus and rats were returned to their home cages for 60min with free access to food. An additional group of rats was returned to home cages with no food access. After 60min with or without food access all rats were tested in the EPM. Results indicated that food consumption just prior to EPM testing reversed the avoidance of the open arms of the EPM. In contrast, rats injected with ghrelin, placed in their home cage for 60min without food, and subsequently tested in the EPM, exhibited an increased avoidance of the open arms, consistent with stress activation. Overall, our findings demonstrate that ghrelin 1a receptor blockade and feeding status appear to impact the ability of ArcN and PVN ghrelin to elicit stress and anxiety-like behaviors.

Ghrelin enhancer, rikkunshito, improves postprandial gastric motor dysfunction in an experimental stress model.

BACKGROUND: Functional dyspepsia (FD) is one of the most common disorders of gastrointestinal (GI) diseases. However, no curable treatment is available for FD because the detailed mechanism of GI dysfunction in stressed conditions remains unclear. We aimed to clarify the association between endogenous acylated ghrelin signaling and gastric motor dysfunction and explore the possibility of a drug with ghrelin signal-enhancing action for FD treatment. METHODS: Solid gastric emptying (GE) and plasma acylated ghrelin levels were evaluated in an urocortin1 (UCN1) -induced stress model. To clarify the role of acylated ghrelin on GI dysfunction in the model, exogenous acylated ghrelin, an endogenous ghrelin enhancer, rikkunshito, or an α2 -adrenergic receptor (AR) antagonist was administered. Postprandial motor function was investigated using a strain gauge force transducer in a free-moving condition. KEY RESULTS: Exogenous acylated ghrelin supplementation restored UCN1-induced delayed GE. Alpha2 -AR antagonist and rikkunshito inhibited the reduction in plasma acylated ghrelin and GE in the stress model. The action of rikkunshito on delayed GE was blocked by co-administration of the ghrelin receptor antagonist. UCN1 decreased the amplitude of contraction in the antrum while increasing it in the duodenum. The motility index of the antrum but not the duodenum was significantly reduced by UCN1 treatment, which was improved by acylated ghrelin or rikkunshito. CONCLUSIONS & INFERENCES: The UCN1-induced gastric motility dysfunction was mediated by abnormal acylated ghrelin dynamics. Supplementation of exogenous acylated ghrelin or enhancement of endogenous acylated ghrelin secretion by rikkunshito may be effective in treating functional GI disorders.

A pilot feasibility and acceptability study of yoga/meditation on the quality of life and markers of stress in persons living with HIV who also use crack cocaine.

BACKGROUND: Persons living with HIV (PLWH) who also use crack cocaine may have stressful, chaotic lives and typically do not engage in standard medical care that addresses a multitude of extenuating life circumstances. Yoga/meditation (YM) improves quality of life (QOL) and biomarkers of stress, but the effect of this intervention is almost unknown in PLWH, particularly those who use crack cocaine. OBJECTIVES: This pilot study sought to compare the feasibility and acceptability of 60-minute, twice-per-week sessions of YM for 2 months with those of no-contact control and to evaluate the effects of the intervention on QOL (according to the Short Form-36, Perceived Stress Scale [PSS], and Impact of Events Scale [IES]) and salivary cortisol and dehydroepiandrosterone sulfate (DHEA-S) among PLWH who use crack cocaine. DESIGN: Participants were randomly assigned to YM or no-contact control and were assessed at baseline, 2 months after the intervention, and 4 months' follow-up. RESULTS: The YM program was acceptable and feasible, with high overall attendance (89%) and individual participation in yoga sessions (83%). YM participants showed modest improvements on QOL. The PSS total score and the IES intrusion score improved significantly 2 months after the intervention, but cortisol and DHEA-S did not change. CONCLUSIONS: This pilot study showed a high level of feasibility and acceptability and modest effects on measures of QOL among PLWH who use crack cocaine. The results suggest utility of YM as a simple, safe, and inexpensive format to improve QOL in a population that has many medical difficulties and extenuating stressors.

Efecto neuroprotector de la semilla de Prunus dulcis Almendra sobre el tejido nervioso en ratones inducidos a estrés por desorientación motora / Neuroprotective effect of the seed of Prunus dulcis Almond on nerve tissue in mice induced to stress of motor disorientation

Objetivo: Determinar el efecto neuroprotector de la administración de la semilla de Prunus dulcis “almendra” sobre el tejido nervioso en ratones inducidos a estrés por desorientación motora. Diseño: Estudio analítico, transversal, experimental y prospectivo. Lugar: Laboratorios del Centro de Investigación de Bioquímica y Nutrición Alberto Guzmán Barrón, Facultad de Medicina, UNMSM, Lima, Perú. Materiales: Ratones albinos BALB/c (Mus musculus) machos y Prunus dulcis “almendra”. Métodos: Se utilizó 42 ratones, según expertos, de 3 meses de edad y 31 ± 4,49 de peso, distribuidos aleatoriamente en seis grupos (n=7). Todos los grupos recibieron la misma dieta balanceada y agua ad libitum durante 5 días. Recibieron los siguientes tratamientos, por cinco días, vía peroral: grupo I y II: suero fisiológico (NaCI 0,9g por ciento 10mL/kg), grupo III: vitamina E 400mg/kg, grupo IV: almendra 100 mg/kg, grupo V: almendra 500 mg/kg y grupo VI: almendra 1000 mg/kg; 12 horas antes de finalizar el Tto., se cortaron los bigotes de los ratones, excepto al grupo 1; y luego de 12 horas se realizó el sacrificio. Principales medidas de los resultados: Nivel de lipoperoxidación expresado en sustancias reactivas al ácido tiobarbitúrico (TBARs) y nivel de Grupos sulfhídrilos no proteicos (GS-NP), además de cambios histopatológicos de tejido de cerebro y cerebelo. Resultados: La administración de Prunus dulcis “almendra” aumenta significativamente (p<0.05) los niveles de GS-NP en todos los grupos (excepto G VI) en comparación con el G II en cerebro; los niveles de TBARs disminuyen significativamente (p<0.05) en el grupo V y VI comparado con el grupo II, y en relación a los cambios histológicos se observa una mejora leve en el G V en comparación con el G II. Conclusiones: La administración de la suspensión de la semilla del Prunus dulcis "almendra" expresó un efecto neuroprotector en los indicadores bioquímicos (TBARs y GS-NP), sobre el tejido nervioso en ratones inducidos a estrés por...

Objective: Determine the neuroprotective effect of administration of Prunus dulcis seed "almond" on the nervous tissue in motor stress induced disorientation mice. Design: Analytical, transverse, experimental and prospective study. Location: Laboratories of the Research Center of Biochemistry and Nutrition Alberto Guzman Barron, Faculty of Medicine, UNMSM, Lima, Peru. Materials: Mice albinos BALB / c (Mus musculus) males and Prunus dulcis “almond”. Methods: 42 mice was used, experts say, 3 months and 31 ± 4,49 in weight, randomized into six groups (n=7). AII groups received the same balanced diet and water ad libitum for 5 days. They received the following treatments for five days, perorally: group I and II: saline (NaCI 0.9g per cent 10 mL/kg), group III: Vitamin E 400 mg/kg, group IV: almond 100 mg/kg, group V: almond 500 mg/kg and group VI: almond 1000 mg/kg; 12 hours before the end of treatment cut whiskers of mice, except the group 1; and after 12 hours they were sacrificed. Main outcome measures: Level of lipid peroxidation expressed in thiobarbituric acid (TBARS) and level of non-protein sulfhydryl groups (GS-NP) substances in addition to histo-pathological changes of brain tissue and cerebellum. Results: Administration of Prunus dulcis “almond” significantly increased (p<0.05) levels of GS-NP in all groups (except G VI) compared to the G II in brain; TBARS levels decreased significantly (p<0.05) in the V and VI group compared with group II, and in relation to the histological changes seen a slight improvement in the G V compared to G II. Conclusions: The administration of the suspension of Prunus dulcis seed “almond” demonstrated the neuroprotective effect in biochemical (TBARs y GS-NP) on the nervous tissue in mice induced to stress motor disorientation.

Noradrenaline is a stress-associated metaplastic signal at GABA synapses.

Exposure to a stressor sensitizes behavioral and hormonal responses to future stressors. Stress-associated release of noradrenaline enhances the capacity of central synapses to show plasticity (metaplasticity). We found noradrenaline-dependent metaplasticity at GABA synapses in the paraventricular nucleus of the hypothalamus in rat and mouse that controls the hypothalamic-pituitary-adrenal axis. In vivo stress exposure was required for these synapses to undergo activity-dependent long-term potentiation (LTPGABA). The activation of ß-adrenergic receptors during stress functionally upregulated metabotropic glutamate receptor 1 (mGluR1), allowing for mGluR1-dependent LTPGABA during afferent bursts. LTPGABA was expressed postsynaptically and manifested as the emergence of new functional synapses. Our findings provide, to the best of our knowledge, the first demonstration that noradrenaline release during an in vivo challenge alters information storage capacity at GABA synapses. Because these GABA synapses become excitatory following acute stress, this metaplasticity may contribute to neuroendocrine sensitization to stress.

Plants as medicinal stressors, the case of depurative practices in Chazuta valley (Peruvian Amazonia).

ETHNOPHARMACOLOGICAL RELEVANCE: Depurative practices, based on taking emetic plants and the restriction of food intake, are very much used in the traditional medicine of Chazuta (Peruvian Amazon) not only to restore health but also to maintain it. AIM OF THE STUDY: To describe Chazuta's depurative practices, within a theoretical framework that involves the stress system and which defines the role played by the medicinal plants used as medicinal stressors. This biomedical model is more inclusive in relation to the variety of medicinal uses found for these practices. MATERIAL AND METHODS: The information was obtained in the valley of Chazuta from October 2004 to August 2005 through semi-structured interviews to the 6.3% of its rural adult population (i.e., 140 individuals, 75% belonging to the San Martin Quechua's ethnic group). Thereafter, results were analysed and confronted to the existing literature. RESULTS: Overall, 191 depurative practices were reported in Chazuta where 114 different plant species were recorded and identified. Depending on their level of severity and duration, depurative practices can be classified as mild or strict. The wide range of medicinal uses reported supports both the involvement of adaptive stress responses in depurative practices and the consideration of the plants employed in this practices as medicinal stressors. CONCLUSIONS: By inducing moderate stress within safe levels, depurative practices in Chazuta could produce adaptive responses that would protect against the detrimental consequences of chronic stress and stress-related diseases. This hypothesis could help to understand the diversity of the medicinal uses recorded in the field. Thus, plant remedies used in these practices in Chazuta could be considered as "medicinal stressors" as through vomiting the necessary neuroendocrine stress activation would be produced. In addition, other bioactivities that plants may harbour could converge with the whole stress reactivity process.

Prenatal stress and peripubertal stimulation of the endocannabinoid system differentially regulate emotional responses and brain metabolism in mice.

The central endocannabinoid system (ECS) and the hypothalamic-pituitary-adrenal-axis mediate individual responses to emotionally salient stimuli. Their altered developmental adjustment may relate to the emergence of emotional disturbances. Although environmental influences regulate the individual phenotype throughout the entire lifespan, their effects may result particularly persistent during plastic developmental stages (e.g. prenatal life and adolescence). Here, we investigated whether prenatal stress--in the form of gestational exposure to corticosterone supplemented in the maternal drinking water (100 mg/l) during the last week of pregnancy--combined with a pharmacological stimulation of the ECS during adolescence (daily fatty acid amide hydrolase URB597 i.p. administration--0.4 mg/kg--between postnatal days 29-38), influenced adult mouse emotional behaviour and brain metabolism measured through in vivo quantitative magnetic resonance spectroscopy. Compared to control mice, URB597-treated subjects showed, in the short-term, reduced locomotion and, in the long term, reduced motivation to execute operant responses to obtain palatable rewards paralleled by reduced levels of inositol and taurine in the prefrontal cortex. Adult mice exposed to prenatal corticosterone showed increased behavioural anxiety and reduced locomotion in the elevated zero maze, and altered brain metabolism (increased glutamate and reduced taurine in the hippocampus; reduced inositol and N-Acetyl-Aspartate in the hypothalamus). Present data further corroborate the view that prenatal stress and pharmacological ECS stimulation during adolescence persistently regulate emotional responses in adulthood. Yet, whilst we hypothesized these factors to be interactive in nature, we observed that the consequences of prenatal corticosterone administration were independent from those of ECS drug-induced stimulation during adolescence.

Effects of inhaled lavender essential oil on stress-loaded animals: changes in anxiety-related behavior and expression levels of selected mRNAs and proteins.

Inhalation of various essential oils elicits behavioral changes as a consequence of a complex centrally coordinated response. To understand the molecular mechanisms of action of aromatic compounds on emotional responses, we evaluated the stress-induced changes in mouse brain and the efficacy of inhaled essential oil from Lavandula officinalis (LvEO) using two approaches: a behavioral test, and examining the expression levels of selected genes {fast nerve growth factor receptor (NGFR) mRNA, activity regulated cytoskeletal-associated protein (Arc) mRNA} and proteins {galactokinase 1 (GLK1) and brain-derived neurotrophic factor (BDNF)}. Animals were randomly divided into 4 groups depending on the treatment given: stress (-)/H20, stress (-)/LvEO, stress (+)/H2O, and stress (+)/LvEO group. For behavioral testing, using an elevated plus-maze test, significant anxiolytic-like effects were seen in both the stress (-)/LVEO and stress (+)/LvEO groups, indicating that LvEO exerts anxiolytic-like effects regardless of the administration of water immersion stress. On expression analysis, the levels of NGFR and Arc mRNA were significantly lower in animals subjected to stress. Inhalation of LvEO, however, reversed this change, thus suggesting that LvEO negates the impact of stress on gene expression levels. Meanwhile, significant decreases in expression levels were also observed in the stress (-)/LvEO group, which implies that LvEO, when given in a stress-free situation, may act as a stress stimulus. Taken together, our data suggest that inhalation of LvEO exerts bidirectional influences in the central nervous system (CNS) of animals, either attenuating the effects of stress or acting as a stressor, depending on the subject state.

Neuroendocrine disorders in adult rats treated prenatally with hydrocortisone acetate.

We investigated the effects of hydrocortisone acetate administered to pregnant rats over the last gestational week on some neuroendocrine characteristics in adult female and male offspring. Prenatal glucocorticoid eliminated sex dimorphism of the neurons nuclei volumes in the medial preoptic area and the suprachiasmatic nuclei. There was no elevation of blood plasma corticosterone level after noradrenaline infusion into the third brain ventricle in experimental males; meanwhile, in females adrenocortical response was augmented. Male offspring exhibited a decrease of plasma corticosterone response to an acute stress (1h restraint) that was not accompanied by post-stress changes neither in the hypothalamic noradrenaline content nor hippocampal glutamate decarboxylase activity. On the contrary, moderate augmentation of adrenocortical stress reactivity and inhibitory effect of GABAergic system were found in females. It was concluded that exposure to prenatal glucocorticoid is able to alter development of the neuroendocrine systems related to reproduction and stress responses both in males and females and resulted in modification of its sex-dimorphic features in adult life.

Effect of 1-oxo-5beta, 6beta-epoxy-witha-2-ene-27-ethoxy-olide isolated from the roots of Withania somnifera on stress indices in Wistar rats.

OBJECTIVE: Isolation of biologically active fractions and compounds from the roots of Withania somnifera, a plant used extensively as a constituent of rasayana, in Ayurveda and to test their adaptogenic activity on stress indices using the cold-hypoxia-restraint (C-H-R) model. DESIGN: Bioactivity-guided fractionation of an aqueous extract of the roots of Withania somnifera led to the isolation of a new species of withanolide 1-oxo-5beta, 6beta-epoxy-witha-2-ene-27-ethoxy-olide. Structure elucidation, was carried out using proton nuclear magnetic resonance, infrared (IR), ultraviolet (UV), and mass spectroscopic analysis. Stress-related indices were evaluated, namely serum creatine phosphokinase (CPK) activity, serum lactate dehydrogenase (LDH) activity, serum corticosterone levels, and serum lipid peroxidation (LPO) levels. RESULTS: There was a significant decrease in a serum CPK, LDH, and LPO levels in animals pretreated with (1) fraction-I (20 mg/kg body weight), (2) 1-oxo-5beta, 6beta-epoxy-witha-2-ene-27-ethoxy-olide (2.5 mg/kg body weight) in comparison to control when subjected to C-H-R stress. CONCLUSIONS: The results show that the a new species of withanolide, 1-oxo-5beta, 6beta-epoxy-witha-2-ene-27-ethoxy-olide (compound-1) could prove to be an effective agent to counteract C-H-R stress.

Impact of two different dose-intensity chemotherapy regimens on psychological distress in early breast cancer patients.

In order to improve outcome, new, often more toxic chemotherapy regimens are continuously investigated in early breast cancer patients. Because the expected survival improvement is small, the possible increase in the negative effects of the new treatments should be carefully evaluated. Negative effects are represented not only by acute and chronic toxicity, but also by the adverse psychological impact of chemotherapy. The aim of this study was to evaluate the effect on patient-reported psychological distress of an increase in the dose-intensity of adjuvant chemotherapy compared with a standard regimen. Psychological distress was evaluated at baseline, during chemotherapy and after 6 and 12 months in breast cancer patients enrolled in a phase III multicentre study comparing the standard adjuvant chemotherapy with cyclophosphamide, epirubicin and 5-fluorouracil every 21 days (CEF21) with the same chemotherapy given every 14 days (CEF14). 392 patients were randomised in participating centres, and 363 were evaluable for this study. Overall, 1095 out of 1446 expected questionnaires (75.7%) were collected and evaluable. At baseline, the mean scores of psychological distress were similar in the two arms. During chemotherapy, a significantly higher psychological distress was observed in the CEF14 compared with the CEF21 arm (32.3 +/- 1.3 versus 27.6 +/- 1.3; P=0.009), as well as a higher cumulative incidence of anaemia, mucositis, diarrhoea, alopecia, bone pain and fatigue was observed in the CEF14 arm. In multivariate analyses, mucositis (P=0.01), asthenia (P=0.059), and CEF14 treatment (P=0.054) were independently associated with a higher psychological distress. After 6 months, psychological distress was again similar in the two arms and significantly lower when compared with baseline within each arm. A dose-intensive adjuvant regimen induces a higher, although transient, psychological distress in early breast cancer patients. Final results of the randomised trial will indicate whether such higher adverse effects of the dose-intensive regimen are counterbalanced by a higher efficacy of the experimental treatment in terms of survival.

Effects of coping style and relaxation on cancer chemotherapy side effects and emotional responses.

This study was designed to determine (a) the relationship of coping style to cancer chemotherapy side effects and (b) whether coping style moderated the impact of a relaxation intervention on anxiety, depression, and nausea associated with chemotherapy. Forty-eight cancer patients were assigned randomly to receive either progressive muscle relaxation training before chemotherapy (experimental group) or standard care (control group). Spearman correlations indicated that a "blunting" or distraction-oriented coping style was associated with less anticipatory anxiety, less depression, and less nausea during and after chemotherapy. Spearman correlations also indicated that a "monitoring" or information-gathering coping style was associated with more anticipatory anxiety, and more nausea before and during chemotherapy. Although there was a significant effect of the relaxation intervention on posttreatment nausea, there were no other between-group differences. The results did suggest, however, that relaxation was effective in reducing anticipatory anxiety among "blunters," but not "monitors," perhaps because relaxation is a distraction strategy and therefore is consistent with a blunting coping style. The effects of coping and relaxation on pretreatment anxiety may have important implications, because anxiety is a key factor in classic conditioning models of anticipatory nausea and vomiting.

Physical and psychologic distress associated with adjuvant chemotherapy in women with breast cancer.

The incidence of physical toxicity and psychosocial effects associated with adjuvant chemotherapy for stage II breast cancer have been reported in previous studies. The purpose of this exploratory study was to quantify the degree of physical and psychologic distress experienced by patients and identify life-style changes. A semistructured interview was conducted with 78 subjects to elicit demographic data, distress, and life-style changes using the Symptoms Distress Scale (SDS), the Psychiatric Status Schedule (PSS), and questions and scales developed by the investigator. All subjects received adjuvant chemotherapy (cyclophosphamide, methotrexate, and 5-fluorouracil with or without vincristine and prednisone) following primary treatment for breast carcinoma. Fifty subjects were currently on therapy and 28 had completed treatment. Fatigue was the most distressful physical symptom. Although physical distress was rated higher by subjects receiving treatment, generally all rating scores indicated only mild symptom distress. Subjects perceived more distress for the psychologic and emotional response to disease and treatment, and this persisted for women who completed therapy. Changes in role performance and daily activity were minimal.