Multiple-therapy-resistant major depressive disorder: a clinically important concept.

Many novel therapeutic options for depression exist that are either not mentioned in clinical guidelines or recommended only for use in highly specialist services. The challenge faced by clinicians is when it might be appropriate to consider such 'non-standard' interventions. This analysis proposes a framework to aid this decision.Declaration of interestIn the past 3 years R.H.M.W. has received support for research, expenses to attend conferences and fees for lecturing and consultancy work (including attending advisory boards) from various pharmaceutical companies including Astra Zeneca, Cyberonics, Eli Lilly, Janssen, LivaNova, Lundbeck, MyTomorrows, Otsuka, Pfizer, Roche, Servier, SPIMACO and Sunovion. D.M.B.C. has received fees from LivaNova for attending an advisory board. In the past 3 years A.J.C. has received fees for lecturing from Astra Zeneca and Lundbeck; fees for consulting from LivaNova, Janssen and Allergan; and research grant support from Lundbeck.In the past 3 years A.C. has received fees for lecturing from pharmaceutical companies namely Lundbeck and Sunovion. In the past 3 years A.L.M. has received support for attending seminars and fees for consultancy work (including advisory board) from Medtronic Inc and LivaNova. R.M. holds joint research grants with a number of digital companies that investigate devices for depression including Alpha-stim, Big White Wall, P1vital, Intel, Johnson and Johnson and Lundbeck through his mindTech and CLAHRC EM roles. M.S. is an associate at Blueriver Consulting providing intelligence to NHS organisations, pharmaceutical and devices companies. He has received honoraria for presentations and advisory boards with Lundbeck, Eli Lilly, URGO, AstraZeneca, Phillips and Sanofi and holds shares in Johnson and Johnson. In the past 3 years P.R.A.S. has received support for research, expenses to attend conferences and fees for lecturing and consultancy work (including attending an advisory board) from life sciences companies including Corcept Therapeutics, Indivior and LivaNova. In the past 3 years P.S.T. has received consultancy fees as an advisory board member from the following companies: Galen Limited, Sunovion Pharmaceuticals Europe Ltd, myTomorrows and LivaNova. A.H.Y. has undertaken paid lectures and advisory boards for all major pharmaceutical companies with drugs used in affective and related disorders and LivaNova. He has received funding for investigator initiated studies from AstraZeneca, Eli Lilly, Lundbeck and Wyeth.

Inhibitors of the catalytic domain of mitochondrial ATP synthase.

An understanding of the mechanism of ATP synthase requires an explanation of how inhibitors act. The catalytic F1-ATPase domain of the enzyme has been studied extensively by X-ray crystallography in a variety of inhibited states. Four independent inhibitory sites have been identified by high-resolution structural studies. They are the catalytic site, and the binding sites for the antibiotics aurovertin and efrapeptin and for the natural inhibitor protein, IF1.

[Multisite validation study of questionnaire assessing out-patient satisfaction with care questionnaire in ambulatory chemotherapy or radiotherapy treatment]. / Validation multicentrique d'un questionnaire de satisfaction des soins lors d'un traitement de chimiothérapie ou radiothérapie ambulatoire.

Patient satisfaction is now recognised as an important quality of care outcome which is particularly relevant in oncology. Adapted from the EORTC In-Patsat32, the Out-Patsat35 is a 35-item satisfaction with care questionnaire measuring cancer outpatients' perception of hospital doctors and nurses, as well as aspects of care organisation and services. This study assessed the psychometric properties of this scale. Patients undergoing ambulatory chemotherapy (CT) or radiotherapy (RT) in 7 cancer centres in France were invited to complete at home the Out-Patsat35 as well as EORTC QLQ-C30 for psychometric testing. Of 416 eligible patients recruited, 96% returned the questionnaire. Most patients (71% in CT; 69% in RT) completed this scale within 15 minutes and the mean rate of item omission was only 4.4%. Confirmatory analyses revealed good convergent validity and excellent internal consistency, although some subscales within the Out-Patsat35 were relatively highly correlated. Items and subscales of the Out-Patsat35 and of the QLQ-C30 were not significantly correlated, underlying that the two questionnaires are assessing quite distinct concepts. The subscales of the Out-Patsat35 were not related to age, gender and education, suggesting a cultural evolution in French cancer patients towards a greater homogeneity in their opinion toward care. This study supports the acceptability to patients, and the psychometric properties of the EORTC Out-Patsat35 questionnaire.

A child's admission to hospital: a qualitative study examining the experiences of parents.

AIMS: To compare the experiences of parents and children during inpatient admission to either a paediatric intensive care unit (PICU) or a general paediatric ward (GPW) with a specific focus on identifying factors which may influence psychological outcome. METHODS: Semi-structured qualitative interviews of 20 parents whose children had been admitted to hospital. Cases were sampled purposively to ensure representation of both groups (PICU and GPW admissions). Interviews were tape recorded, transcribed and subjected to a thematic analysis. RESULTS: The experiences of parents were explored with regard to illness onset, admission to PICU or GPW and the discharge period. In the PICU group, the sources of stress differed according to the stage: at onset, they were mainly related to their child's illness; during admission, concerns were focused on their child's appearance; finally, on discharge, possible relapse of the illness, impact of the admission on the child and family and the lack of clear follow-up were the central themes. In the GPW group, parents reported similar themes but with lower levels of associated stress. Both groups identified good communication with the medical team and opportunities for participation as helpful in reducing stress. CONCLUSIONS: Admission to hospital is stressful for parents particularly if the child is admitted to PICU. Hospital staff should enhance communication with parents and maximise opportunities for parental participation in the child's treatment. Such interventions may reduce parents' experience of stress during the admission and have the potential to improve psychological outcome.

Psychological outcome in women undergoing termination of pregnancy for ultrasound-detected fetal anomaly in the first and second trimesters: a pilot study.

OBJECTIVE: To ascertain and compare psychological morbidity following first- and second-trimester termination for fetal anomaly. METHODS: This was a cohort study of 30 women aged 20-40 years in a north London teaching hospital, 14 of whom had had a first-trimester termination and 16 a second-trimester termination for fetal anomaly. The main outcome measures were questionnaire data (General Health Questionnaire-28, Beck Depression Inventory, Perinatal Grief Scale, Impact of Event Scale (IES)) at 6 weeks, 6 months and 12 months after termination. RESULTS: There were high levels of psychological distress in both groups at each time point, and for the combined group the mean total scores on the IES remained above the cut-off for the entire study period. Those having second-trimester terminations had a significantly higher level of post-traumatic stress symptomatology 6 weeks after termination (14/16 vs. 6/14; odds ratio = 9.3; 95% CI, 1.5-57.7). CONCLUSIONS: Psychological morbidity following termination of pregnancy for fetal anomaly is prevalent and persistent. Our data suggest that in the short term (as assessed at a 6-week follow-up), second-trimester termination may be more stressful compared with first-trimester termination.

'Parcours de Femme 2001': a French opinion survey on overall disease and everyday life management in 1870 women presenting with gynecological or breast cancer and their caregivers.

PURPOSE: The aim of the survey 'Parcours de Femmes 2001' was to evaluate the overall management and care of women with female cancers and to determine their needs. METHODS: Women with breast or gynecological cancer who had either received at least 3 months of treatment or had completed treatment <1 year before the study were enrolled in this cross-sectional, observational study. RESULTS: From February to November 2001, 2839 questionnaires were distributed; 1870 were returned (66% response rate), mainly by breast cancer patients (87%). While 92% of women reported having received information at diagnosis, 34% of relapsed patients complained of lack of information concerning their disease and treatment. Only 18% of patients were included in the treatment decision process and 66% of women obtained complementary information from the media, patients and care professionals. Fatigue was the most severe problem quoted (78% of cases) and was poorly managed by caregivers due to diagnostic and treatment difficulties. Problems relating to family and to affective and socio-professional life were poorly identified and remained largely unmanaged. CONCLUSIONS: Information given to female cancer patients must be improved in relapsed patients, particularly regarding the adverse effects of treatment. Psychosocial management requires a more holistic approach through new channels, together with the coordination of existing structures.

Psychiatric and social outcome following liver transplantation for alcoholic liver disease: a controlled study.

Psychiatric outcome, quality of life, and alcohol consumption were compared between patients transplanted for alcoholic liver disease and those transplanted for other chronic liver diseases. Instruments used included the Clinical Interview Schedule, the 28-item General Health Questionnaire, the Hospital Anxiety and Depression Scale, and the Nottingham Health Profile. There was no difference between the two groups with regard to median scores or "caseness" on these instruments, except for physical mobility on the Nottingham Health Profile, where the alcoholic group was more likely to experience difficulties (p = 0.03). The majority of those transplanted for alcoholic liver disease remained abstinent, although 7 of the 31 in the alcoholic group (23%) were drinking above recommended safe limits. Psychosocial outcome is similar for individuals transplanted for alcoholic liver disease and those transplanted for other chronic liver diseases. Patients should not be excluded from transplantation on grounds of their drinking history.

The crystal growth technique--a laboratory evaluation of bond strengths.

An ex vivo study was carried out to determine differences in the bond strengths achieved with brackets placed using a crystal growth technique compared with a conventional acid-etch technique. A solution of 37 per cent phosphoric acid was used for acid-etching and a commercially available polyacrylic acid gel, Crystal-lok for crystal growth. A heavily-filled composite resin was used for all samples to bond brackets to healthy premolar teeth extracted for orthodontic purposes. Polycrystalline ceramic and stainless steel brackets were used and tested to both tensile and shear failure using an Instron Universal Testing machine. The tensile and shear bond strengths were recorded in kgF. In view of difficulties experienced with previous authors using different units to describe their findings, the data were subsequently converted to a range of units in order to facilitate direct comparison. The crystal growth technique produced significantly lower bond strengths than the acid-etch technique for ceramic and stainless steel brackets, both in tensile and shear mode. The tensile bond strength for stainless steel brackets with crystal growth was 2.2 kg compared with 6.01 kg for acid-etch, whilst with ceramic brackets the tensile bond strengths were 3.9 kg for crystal growth and 5.55 kg for acid-etch. The mean shear bond strength for stainless steel brackets with crystal growth was 12.61 kg compared with 21.55 kg for acid-etch, whilst with ceramic brackets the shear bond strengths were 7.93 kg with crystal growth compared with 16.55 kg for acid-tech. These bond strengths were below those previously suggested as clinically acceptable.

Psychiatrists and their patients: views on forms of dress and address.

BACKGROUND: Dress styles and forms of address vary among psychiatrists. METHOD: A semi-structured interview was administered to a sample of psychiatric in-patients, and a questionnaire was sent to junior and consultant psychiatrists, to identify preferences for dress styles and terms of address. RESULTS: Forty-nine (71%) of the in-patient sample participated. A preference was found for smart attire and white coats. Of the 69 (80%) doctors returning questionnaires, the majority supported smart dress as the most appropriate attire. Most patients preferred to be called by their first name while addressing doctors by title and surname. Junior doctors preferred to use first names when talking to patients while almost all consultants used title and surname. Doctors of all grades liked to be called by their title and surname. CONCLUSIONS: Paying more attention to the way we present ourselves and interact at work may help to facilitate the therapeutic alliance.

The use of risperidone in treatment-resistant schizophrenia: two case reports.

The role of risperidone in the management of treatment-resistant schizophrenia remains unclear. We describe two patients with treatment-resistant schizophrenia characterized by unremitting delusions, thought disorder and self-neglect who had a sustained improvement in their symptoms soon after starting risperidone. Risperidone may be a suitable alternative to clozapine in some patients unresponsive to conventional antipsychotics.

Biological effects of stable overexpression of aromatase in human hormone-dependent breast cancer cells.

Aromatase is a key enzyme in the conversion of androstenedione and testosterone to oestrone and oestradiol. Intratumoral aromatase activity is expressed by around 70% of breast carcinomas, but it is not clear what effect this has on the tumour phenotype. To address this question we expressed human aromatase in hormone-dependent MCF-7 breast cancer cells. Clone Arom. 1 expressed aromatase at 1,000 times the endogenous level in wild-type (WT) cells. Clone Arom. 2 incorporated the expression construct but did not express aromatase at levels above WT. There was no morphological difference between the two clones and WT, all three cell lines expressed oestrogen receptor at equivalent levels, and all manifested a mitogenic response to oestradiol. In steroid-depleted medium Arom. 1 cells showed significant growth enhancement over WT and Arom. 2, and this growth advantage was increased by exogenous androstenedione or testosterone. Both the enzyme activity and androgen-stimulated growth of Arom. 1 cells were completely reversible by aromatase inhibitor CGS 16949A. The Arom. 1 cell line may contribute to the development of an in vivo model of intratumoral aromatase, to study the biological significance of this phenomenon.

Control of aromatase in breast cancer cells and its importance for tumor growth.

Three approaches have been taken to elucidate further the biological importance of intratumoural aromatase activity. (i) MCF7 and T47D hormone-dependent breast cancer cell lines both showed detectable aromatase activity in vitro. The up-regulation of this by TGF alpha indicates the possible existence of an autocrine growth stimulatory loop involving aromatase. (ii) Both tamoxifen and cytotoxic chemotherapy caused the suppression of aromatase activity in breast carcinomas in vivo. Aromatase activity prior to treatment did not predict for clinical response to tamoxifen. (iii) Transfection of aromatase into MCF7 cells led to their growth being stimulated by low doses of androgens and this was inhibited by the aromatase inhibitor CGS 16949A.

Progesterone receptor induction by danazol in cultured cancer cells and the rat uterus.

We have previously reported that clinical trials relating to the use of danazol in the management of benign breast disease show a positive correlation between favourable clinical response and an induction of progesterone receptors in the affected tissue which is maintained for a period of at least 6 months subsequent to the cessation of treatment. Further studies designed at elucidating more clearly the actions of danazol at the cellular and molecular levels have confirmed that progesterone receptors are down-regulated by short-term progestin action at the level of the mRNA transcript, but that danazol is subsequently able to produce an enhanced cellular response, inducing progesterone receptors in the presence of oestrogenic agents. Uteri from danazol-treated rats showed a doubling of progesterone receptor concentrations compared with the control uteri. In the mammary cancer cell line T-47D, cells treated with danazol had increased progesterone receptor concentrations of 558.4 +/- 32.0 compared with 152.6 +/- 7.0 fmol/mg protein in the control cells. In both cases, these inductions were observed following a period of progesterone receptor suppression. Short-term molecular studies on T-47D cells indicated that progesterone and danazol initially inhibit mRNA transcription, but that 24 h after treatment an induction is observed. This is especially marked in the danazol-treated cells.

Discrepancies between antibody (EIA) and saturation analysis of oestrogen receptor content in breast tumour samples.

The use of different techniques for assay of oestrogen receptors (ER) in breast cancer raises the question of their relative effectiveness in measuring concentrations of functional receptors. Data were obtained on soluble receptors from supernatants from 58 primary breast tumour homogenates, using the ligand ([3H]oestradiol) binding assay with dextran-coated charcoal (DCC) separation, either at a single saturating ligand dose, or by Scatchard analysis, and by using the Abbott enzyme immunoassay (EIA) kit. As previous reports have shown, the two methods gave reasonably good correlation (r = 0.8), but EIA values were systematically higher than DCC (slope = 3.0). Similar values were obtained when the ER + ve/progesterone receptor (PR) + ve subgroup were examined separately (n = 34, r = 0.86, slope = 3.0). However the two sets of data were in much better agreement in the ER + ve/PR - ve subgroup (n = 10, r = 0.98, slope = 1.24). When analysed by isoelectric focusing on polyacrylamide gels (IEF), two major specific binding components were identified, at pI 6.1 and at pI 6.6. Both isoforms were present in 50/66 ER + ve PR + ve breast tumour samples, but only the pI 6.6 (4S) was present in most ER + ve/PR - ve samples (13/20). It appears that, compared with DCC, the EIA method gives much higher values for the 8S isoform, whereas the two methods detect the 4S isoform with similar sensitivity. In assays on the tumour cell lines, T47D and MCF-7, still greater discrepancies, at least 10-fold, were found between EIA and DCC data.