Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for the treatment of schizophrenia and related disorders

Background: The Royal Australian and New Zealand College of Psychiatrists is co-ordinating the development of clinical practice guidelines (CPGs) in psychiatry, funded under the National Mental Health Strategy (Australia) and the New Zealand Health Funding Authority. This paper presents CPGs for schizophrenia and related disorders. Over the past decade schizophrenia has become more treatable than ever before. A new generation of drug therapies, a renaissance of psychological and psychosocial interventions and a first generation of reform within the specialist mental health system have combined to create an evidence-based climate of realistic optimism. Progressive neuroscientific advances hold out the strong possibility of more definitive biological treatments in the near future. However, this improved potential for better outcomes and quality of life for people with schizophrenia has not been translated into reality in Australia. The efficacy-effectiveness gap is wider for schizophrenia than any other serious medical disorder. Therapeutic nihilism, under-resourcing of services and a stalling of the service reform process, poor morale within specialist mental health services, a lack of broad-based recovery and life support programs, and a climate of tenacious stigma and consequent lack of concern for people with schizophrenia are the contributory causes for this failure to effectively treat. These guidelines therefore tackle only one element in the endeavour to reduce the impact of schizophrenia. They distil the current evidence-base and make recommendations based on the best available knowledge. Method: A comprehensive literature review (1990-2003) was conducted, including all Cochrane schizophrenia reviews and all relevant meta-analyses, and a number of recent international clinical practice guidelines were consulted. A series of drafts were refined by the expert committee and enhanced through a bi-national consultation process. Treatment recommendations: This guideline provides evidence-based recommendations for the management of schizophrenia by treatment type and by phase of illness. The essential features of the guidelines are: (i) Early detection and comprehensive treatment of first episode cases is a priority since the psychosocial and possibly the biological impact of illness can be minimized and outcome improved. An optimistic attitude on the part of health professionals is an essential ingredient from the outset and across all phases of illness. (ii) Comprehensive and sustained intervention should be assured during the initial 3-5 years following diagnosis since course of illness is strongly influenced by what occurs in this 'critical period'. Patients should not have to 'prove chronicity' before they gain consistent access and tenure to specialist mental health services. (iii) Antipsychotic medication is the cornerstone of treatment. These medicines have improved in quality and tolerability, yet should be used cautiously and in a more targeted manner than in the past. The treatment of choice for most patients is now the novel antipsychotic medications because of their superior tolerability and, in particular, the reduced risk of tardive dyskinesia. This is particularly so for the first episode patient where, due to superior tolerability, novel agents are the first, second and third line choice. These novel agents are nevertheless associated with potentially serious medium to long-term side-effects of their own for which patients must be carefully monitored. Conventional antipsychotic medications in low dosage may still have a role in a small proportion of patients, where there has been full remission and good tolerability; however, the indications are shrinking progressively. These principles are now accepted in most developed countries. (vi) Clozapine should be used early in the course, as soon as treatment resistance to at least two antipsychotics has been demonstrated. This usually means incomplete remission of positive symptomatology, but clozapine may also be considered where there are pervasive negative symptoms or significant or persistent suicidal risk is present. (v) Comprehensive psychosocial interventions should be routinely available to all patients and their families, and provided by appropriately trained mental health professionals with time to devote to the task. This includes family interventions, cognitive-behaviour therapy, vocational rehabilitation and other forms of therapy, especially for comorbid conditions, such as substance abuse, depression and anxiety. (vi) The social and cultural environment of people with schizophrenia is an essential arena for intervention. Adequate shelter, financial security, access to meaningful social roles and availability of social support are essential components of recovery and quality of life. (vii) Interventions should be carefully tailored to phase and stage of illness, and to gender and cultural background. (viii) Genuine involvement of consumers and relatives in service development and provision should be standard. (ix) Maintenance of good physical health and prevention and early treatment of serious medical illness has been seriously neglected in the management of schizophrenia, and results in premature death and widespread morbidity. Quality of medical care for people with schizophrenia should be equivalent to the general community standard. (x) General practitioners (GPs)s should always be closely involved in the care of people with schizophrenia. However, this should be truly shared care, and sole care by a GP with minimal or no special Optimal treatment of schizophrenia requires a multidisciplinary team approach with a consultant psychiatrist centrally involved.

Molecular mechanisms and effects of a rasgap-derived peptide on metastatic progression

Cancer is the second leading cause of mortality worldwide. Cancer progression leads to metastasis formation, which accounts for more than ninety percent of cancer-related death. Metastases are more difficult to be surgically removed because of their invasive behavior and shape. In addition, during their transformation journey, they become more and more resistant to anticancer drugs. Significant improvements have been achieved in therapy against cancer in recent years but targeting the metastatic cascade remains the Achilles heel of the cure against cancer. A First step in the metastatic process is the escape of cancer cells from the primary tumor site. This involves an increase in cell motility and the concomitant ability to clear a path through the extracellular matrix. From a therapeutic point of view, inhibition of cell migration is a logical approach to develop anti-metastatic drugs. Our lab previously developed a cell permeable peptide derived from a caspase-3-generaied fragment of the RasGAP protein called TAT-RasGAP317-326. This peptide efficiently and specifically sensitizes cancer cells to chemotherapy- and radiotherapy-induced ceil death, which allows decreasing the anticancer drug doses and eventually their associated side- effects. In the present study we discovered that TAT-RasGAP317.326 also increases cell adhesion which was associated with inhibition of cell migration and invasion into the extracellular matrix. The ability of TAT-RasGAP317.326 to increase ceil adhesion involves the dramatic depolymerization of actin cytoskekton together with redistribution of focal adhesions. We found that the inhibitory effects on migration were mediated by a RhoGAP tumor and metastasis suppressor cailed DLC1 (Deleted in Liver Cancer 1). Moreover. DEC 1 was found to be a direct RasGAP-interacting protein and this interaction requires the RasGAP tryptophan 317 residue, the very first RasGAP residue of TAT-RasGAP317.326. We then evaluated the roie of RasGAP fragments in the in vivo metastatic cascade. We found that breast cancer cells overexpressing the parental RasGAP fragment, to which the TAT-RasGAP317.326 peptide belongs, have a markedly decreased ability to form lung metastases. Unfortunately, we were not able to recapitulate these an ti-metastatic effects when TAT-RasGAP317.326 was injected. However, we later understood that this was due to the fact that TAT-RasGAP317.326 was not properly delivered to the primary tumors. Further work, aimed at better understanding of how TAT-RasGAP317.326 functions, revealed that the ten amino acid TAT-RasGAP317.326 peptide could, be narrowed down to a three amino acid TAT-RasGAP317.329 peptide while keeping its sensitizer activity. In parallel, investigations on the RasGAP-DLCl binding indicated that the arginine linger of the DLC1 GAP domain is required for this interaction, which suggests that TAT-RasGAP317.326 modulates the GAP activity of DLC1. Additional work should be performed to fully elucidate its mechanism of action and render TAT-RasGAP317.326 usable as a tool to fight cancer on two fronts, by improving chemotherapy and preventing metastatic progression. - Le cancer est la deuxième cause de mortalité dans le monde. La formation de métastases est la dernière étape de la progression cancéreuse et représente plus du nonante pour cent des morts induites par le cancer. De par leur morphologie et comportement invasifs, ii est difficile d'avoir recours à la chirurgie pour exciser des métastases. De plus, les cellules cancéreuses en progression deviennent souvent de plus en plus résistantes aux drogues anticancéreuses. Ces dernières années, des avancements significatifs ont contribué à l'amélioration de la lutte contre le cancer. Néanmoins, pouvoir cibler spécifiquement la cascade métastatique demeure cependant le talon d'Achille des thérapies anticancéreuses. Une première étape dans ie processus métastatique est l'évasion des cellules cancéreuses du site de la tumeur primaire. Ceci requiert une augmentation de la motiliié cellulaire couplée à la capacité de se frayer un chemin au sein de la matrice extracelluiaire. D'un point de vue thérapeutique, inhiber la migration cellulaire est une approche attrayante. Notre laboratoire a développé un peptide, nommé TAT-RasGAP317.326 dérivé d'un fragment qui est lui-même le résultat du clivage de la protéine RasGAP par la caspase-3. Ce peptide est capable de pénétrer les cellules cancéreuses et de les sensibiliser spécifiquement à la mort induite par la radiothérapie et la chimiothérapie. La finalité des effets de ce peptide est de pouvoir diminuer les doses des traitements anti-cancéreux et donc des effets secondaires qu'ils engendrent. Dans cette étude, nous avons découvert que TAT-RasGAP317.326 augmente l'adhésion des cellules et inhibe la migration cellulaire ainsi que l'invasion des cellules à travers une matrice extracellulaire. La capacité de TAT-RasGAP317.326 à induire l'adhésion repose sur ia dépolymérisation du cytosquelette d'actine associée à une redistribution des points d'ancrage cellulaire. Nous avons découvert que l'inhibition de ia migration par TAT-RasGAP317.326 nécessitait la présence d'un suppresseur de tumeur et de métastases appelé DLC1 (Deleted in Liver Cancer l), qui par ailleurs s'avère aussi être une protéine RhoGAP. De plus, nous avons aussi trouvé que DLC1 était un partenaire d'interaction de RasGAP et que cette interaction s'effectuait via l'acide aminé tryptophane 317 de RasGAP. qui s'avère être le premier acide aminé du peptide TAT-RasGAP317.326. Nous avons ensuite évalué le rôle joué par certains fragments de RasGAP dans le processus de métastatisation. Dans ce contexte, des cellules de cancer du sein qui sur-expriment un fragment de RasGAP contenant la séquence TAT-RasGAP317.326 ont vu leur potentiel métastatique diminuer drastiquerment. Malheureusement, aucun effet anti-métastatique n'a été obtenu après injection de TAT-RasGAP317.326 dans les souris. Cependant, nous avons réalisé rétrospectivement que TAT-RasGAP317.326 n'était pas correctement délivré à la tumeur primaire, ce qui nous empêche de tirer des conclusions sur le rôle anti-métastatique de ce peptide. La suite de cette étude visant à mieux comprendre comment TAT-RasGAP317.326 agit, a mené à la découverte que les dix acides aminés de TAT-RasGAP317.326 pouvaient être réduits à trois acides aminés, TAT-RasGAP317.329, tout en gardant l'effet sensibilisateur à la chimiothérapie. En visant à élucider le mode d'interaction entre RasGAP et DLC1, nous avons découvert qu'un acide aminé nécessaire à l'activité GAP de DLC1 était requis pour lier RasGAP, ce qui laisse présager que TAT-RasGAp317.32c, module i'activité GAP de DLC1. Des travaux supplémentaires doivent encore être effectués pour complètement élucider les mécanismes d'action de TAT-RasGAP317.326 et afin de pouvoir l'utiliser comme un outil pour combattre le cancer sur deux fronts, en améliorant les chimiothérapies et en inhibant la formation de métastases.

Early and late skin reactions to radiotherapy for breast cancer and their correlation with radiation-induced DNA damage in lymphocytes

INTRODUCTION Radiotherapy outcomes might be further improved by a greater understanding of the individual variations in normal tissue reactions that determine tolerance. Most published studies on radiation toxicity have been performed retrospectively. Our prospective study was launched in 1996 to measure the in vitro radiosensitivity of peripheral blood lymphocytes before treatment with radical radiotherapy in patients with breast cancer, and to assess the early and the late radiation skin side effects in the same group of patients. We prospectively recruited consecutive breast cancer patients receiving radiation therapy after breast surgery. To evaluate whether early and late side effects of radiotherapy can be predicted by the assay, a study was conducted of the association between the results of in vitro radiosensitivity tests and acute and late adverse radiation effects. METHODS Intrinsic molecular radiosensitivity was measured by using an initial radiation-induced DNA damage assay on lymphocytes obtained from breast cancer patients before radiotherapy. Acute reactions were assessed in 108 of these patients on the last treatment day. Late morbidity was assessed after 7 years of follow-up in some of these patients. The Radiation Therapy Oncology Group (RTOG) morbidity score system was used for both assessments. RESULTS Radiosensitivity values obtained using the in vitro test showed no relation with the acute or late adverse skin reactions observed. There was no evidence of a relation between acute and late normal tissue reactions assessed in the same patients. A positive relation was found between the treatment volume and both early and late side effects. CONCLUSION After radiation treatment, a number of cells containing major changes can have a long survival and disappear very slowly, becoming a chronic focus of immunological system stimulation. This stimulation can produce, in a stochastic manner, late radiation-related adverse effects of varying severity. Further research is warranted to identify the major determinants of normal tissue radiation response to make it possible to individualize treatments and improve the outcome of radiotherapy in cancer patients.

Lupus erythematosus and other autoimmune diseases related to statin therapy: a systematic review.

BACKGROUND: Statins have been increasingly associated with drug-induced autoimmune reactions, including lupus erythematosus. OBJECTIVE: To identify and determine the clinical and biological characteristics of statin-induced autoimmune reactions. MATERIAL AND METHODS: The MEDLINE database (1966 to September 2005) was used to identify all reported cases of statin-induced autoimmune diseases. The keywords used were statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, adverse effects, autoimmune disease, lupus erythematosus, dermatomyositis and polymyositis. RESULTS: Twenty-eight cases of statin-induced autoimmune diseases have been published so far. Systemic lupus erythematosus was reported in 10 cases, subacute cutaneous lupus erythematosus in three cases, dermatomyositis and polymyositis in 14 cases and lichen planus pemphigoides in one case. Autoimmune hepatitis was observed in two patients with systemic lupus erythematosus. The mean time of exposure before disease onset was 12.8+/-18 months; range 1 month-6 years. Systemic immunosuppressive therapy was required in the majority of cases. In many patients, antinuclear antibodies were still positive many months after clinical recovery. A lethal outcome has been recorded in two patients despite aggressive immunosuppressive therapy. CONCLUSION: Long-term exposure to statins may be associated with drug-induced lupus erythematosus and other autoimmune disorders. Fatal cases have been reported despite early drug discontinuation and aggressive systemic immunosuppressive therapy.