Amisulpride augmentation of clozapine for treatment-refractory schizophrenia: a double-blind, placebo-controlled trial.

BACKGROUND: A second antipsychotic is commonly added to clozapine to treat refractory schizophrenia, notwithstanding the limited evidence to support such practice. METHODS: The efficacy and adverse effects of this pharmacological strategy were examined in a double-blind, placebo-controlled, 12-week randomized trial of clozapine augmentation with amisulpride, involving 68 adults with treatment-resistant schizophrenia and persistent symptoms despite a predefined trial of clozapine. RESULTS: There were no statistically significant differences between the amisulpride and placebo groups on the primary outcome measure (clinical response defined as a 20% reduction in total Positive and Negative Syndrome Scale score) or other mental state measures. However, the trial under recruited and was therefore underpowered to detect differences in the primary outcome, meaning that acceptance of the null hypothesis carries an increased risk of type II error. The findings suggested that amisulpride-treated participants were more likely to fulfil the clinical response criterion, odds ratio 1.17 (95% confidence interval 0.40-3.42) and have a greater reduction in negative symptoms, but these numerical differences were not statistically significant and only evident at 12 weeks. A significantly higher proportion of participants in the amisulpride group had at least one adverse event compared with the control group (p = 0.014), and these were more likely to be cardiac symptoms. CONCLUSIONS: Treatment for more than 6 weeks may be required for an adequate trial of clozapine augmentation with amisulpride. The greater side-effect burden associated with this treatment strategy highlights the need for safety and tolerability monitoring, including vigilance for indicators of cardiac abnormalities, when it is used in either a clinical or research setting.

Amisulpride augmentation in clozapine-unresponsive schizophrenia (AMICUS): a double-blind, placebo-controlled, randomised trial of clinical effectiveness and cost-effectiveness.

BACKGROUND: When treatment-refractory schizophrenia shows an insufficient response to a trial of clozapine, clinicians commonly add a second antipsychotic, despite the lack of robust evidence to justify this practice. OBJECTIVES: The main objectives of the study were to establish the clinical effectiveness and cost-effectiveness of augmentation of clozapine medication with a second antipsychotic, amisulpride, for the management of treatment-resistant schizophrenia. DESIGN: The study was a multicentre, double-blind, individually randomised, placebo-controlled trial with follow-up at 12 weeks. SETTINGS: The study was set in NHS multidisciplinary teams in adult psychiatry. PARTICIPANTS: Eligible participants were people aged 18-65 years with treatment-resistant schizophrenia unresponsive, at a criterion level of persistent symptom severity and impaired social function, to an adequate trial of clozapine monotherapy. INTERVENTIONS: Interventions comprised clozapine augmentation over 12 weeks with amisulpride or placebo. Participants received 400 mg of amisulpride or two matching placebo capsules for the first 4 weeks, after which there was a clinical option to titrate the dosage of amisulpride up to 800 mg or four matching placebo capsules for the remaining 8 weeks. MAIN OUTCOME MEASURES: The primary outcome measure was the proportion of 'responders', using a criterion response threshold of a 20% reduction in total score on the Positive and Negative Syndrome Scale. RESULTS: A total of 68 participants were randomised. Compared with the participants assigned to placebo, those receiving amisulpride had a greater chance of being a responder by the 12-week follow-up (odds ratio 1.17, 95% confidence interval 0.40 to 3.42) and a greater improvement in negative symptoms, although neither finding had been present at 6-week follow-up and neither was statistically significant. Amisulpride was associated with a greater side effect burden, including cardiac side effects. Economic analyses indicated that amisulpride augmentation has the potential to be cost-effective in the short term [net saving of between £329 and £2011; no difference in quality-adjusted life-years (QALYs)] and possibly in the longer term. LIMITATIONS: The trial under-recruited and, therefore, the power of statistical analysis to detect significant differences between the active and placebo groups was limited. The economic analyses indicated high uncertainty because of the short duration and relatively small number of participants. CONCLUSIONS: The risk-benefit of amisulpride augmentation of clozapine for schizophrenia that has shown an insufficient response to a trial of clozapine monotherapy is worthy of further investigation in larger studies. The size and extent of the side effect burden identified for the amisulpride-clozapine combination may partly reflect the comprehensive assessment of side effects in this study. The design of future trials of such a treatment strategy should take into account that a clinical response may be not be evident within the 4- to 6-week follow-up period usually considered adequate in studies of antipsychotic treatment of acute psychotic episodes. Economic evaluation indicated the need for larger, longer-term studies to address uncertainty about the extent of savings because of amisulpride and impact on QALYs. The extent and nature of the side effect burden identified for the amisulpride-clozapine combination has implications for the nature and frequency of safety and tolerability monitoring of clozapine augmentation with a second antipsychotic in both clinical and research settings. TRIAL REGISTRATION: EudraCT number 2010-018963-40 and Current Controlled Trials ISRCTN68824876. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 49. See the NIHR Journals Library website for further project information.

Surgical and psychosocial outcomes in the rural injured--a follow-up study of the 2001 earthquake victims.

INTRODUCTION: After a major disaster in a developing country, the graphic media coverage of the dead and injured invariably leads to an influx of volunteering healthcare personnel to the disaster zone. Very few studies document the outcomes of the treatment rendered in this field setting, under compromised conditions. We revisited the rural victims of the 2001 Gujarat earthquake in an attempt to analyse their surgical outcome and the status of their physical/psychosocial rehabilitation, 2 years after the disaster. METHOD: We traced displaced victims treated for earthquake-related injuries to their new homes. A community health worker interviewed patients with an oral questionnaire in the local language about injuries, the examining physician and first aid, orthopaedic implants, amputations, wounds, disability, deformity, residual pain, occupational and economic rehabilitation, post traumatic stress disorder (PTSD) and perceptions of healthcare rendered. RESULTS: We located 133 of the 179 non-urban victims, from 11 villages. There were 10% missed injuries, 19% infection rate, restricted range of motion in 12%, non-union rate in 23% and reoperations in 30.5% patients. Fifty-one percent had resumed their previous occupation, but only 30% had recovered economically. Of 98% who had destroyed homes, 89% had their homes rebuilt. Residual sadness was the only significant PTSD symptom. CONCLUSION: This trauma outcome study highlights the shortcomings of surgeons for disaster-related work. One-tenth of the injuries were missed, suggesting that field examination at the site of disaster was more difficult than in the comfort of the hospital emergency room. Further there were inappropriately timed, aggressive implant operations, short time commitments, a lack of follow-up and a high rate of reoperations contributing to subsequent morbidity. These pointed to a need for training in disaster medicine within the curriculum of surgical residency. On the brighter side, despite poor sterility, prolonged transport times and no prehospital care, the postoperative infection rate was lower than expected. This perhaps was due to use of potent antibiotics in a previously unexposed rural population. Good physiotherapy given in the temporary shelters, by the informal carers within the family and by voluntary groups, kept up a good range of motion and reduced the final disability. PTSD was marked 3-6 months after the event, but was minimal 2 years postquake. Sadness about the event was the only residual PTSD symptom. While there were varying perceptions of satisfactory outcome, we found good coping mechanisms in place. The simple village folks were largely happy to be alive and accepted the residual deformities and cosmetic blemishes as a "small price to pay".

Pathways to care and ethnicity. 1: Sample characteristics and compulsory admission

BACKGROUND: Many studies have found high levels of compulsory admission to psychiatric hospital in the UK among African–Caribbean and Black African patients with a psychotic illness. AIMS: To establish whether African–Caribbean and Black African ethnicity is associated with compulsory admission in an epidemiological sample of patients with a first episode of psychosis drawn from two UK centres. METHOD: All patients with a first episode of psychosis who made contact with psychiatric services over a 2-year period and were living in defined areas were included in the (ÆSOP) study. For this analysis we included all White British, other White, African–Caribbean and Black African patients from the ÆSOP sampling frame. Clinical, socio-demographic and pathways to care data were collected from patients, relatives and case notes. RESULTS: African–Caribbean patients were significantly more likely to be compulsorily admitted than White British patients, as were Black African patients. African–Caribbean men were the most likely to be compulsorily admitted. CONCLUSION: These findings suggest that factors are operating at or prior to first presentation to increase the risk of compulsory admission among African–Caribbean and Black African patients.

Pathways to care and ethnicity. 2: Source of referral and help-seeking

BACKGROUND: Previous research has found that African–Caribbean and Black African patients are likely to come into contact with mental health services via more negative routes, when compared with White patients. We sought to investigate pathways to mental health care and ethnicityin a sample of patients with a first episode of psychosis drawn from two UK centres. METHOD: We included all White British, other White, African–Caribbean and Black African patients with a first episode of psychosis who made contact with psychiatric services over a 2-year period and were living in defined areas. Clinical, socio-demographic and pathways to care data were collected from patients, relatives and case notes. RESULTS: Compared with White British patients, general practitioner referral was less frequent for both African–Caribbean and Black African patients and referral by a criminal justice agency was more common. With the exception of criminal justice referrals for Black African patients, these findings remained significant after adjusting for potential confounders. CONCLUSIONS: These findings suggest that factors are operating during a first episode of psychosis to increase the risk that the pathway to care for Black patients will involve non-health professionals.

Pathways to care and ethnicity. 1: Sample characteristics and compulsory admission.

Background Many studies have found high levels of compulsory admission to psychiatric hospital in the UK among African–Caribbean and Black African patients with a psychotic illness. Aims To establish whether African–Caribbean and Black African ethnicity is associated with compulsory admission in an epidemiological sample of patients with a first episode of psychosis drawn from two UK centres. Method All patients with a firstepisode of psychosis who made contact with psychiatric services over a 2-year period and were living in defined areas were included in the (ÆSOP)study. For this analysis we included all White British, other White, African–Caribbean and Black African patients from the ÆSOP sampling frame. Clinical, socio-demographic and pathways to care data were collected frompatients, relatives and case notes. Results African–Caribbean patients were significantly more likely to be compulsorily admitted than White British patients, as were Black African patients. African–Caribbean men were the most likely to be compulsorily admitted. Conclusions These findings suggest that factors are operating at or prior to first presentation to increase the risk of compulsory admission among African–Caribbean and Black African patients.

Pathways to care and ethnicity. 2: Source of referral and help-seeking.

Background Previous research has found that African–Caribbean and Black African patients are likely to come into contact with mental health services via more negative routes, when compared with White patients. We soughtto investigate pathways to mental health care and ethnicityin a sample of patients with a first episode of psychosis drawn from two UK centres. Method We included all White British, other White, African–Caribbean and Black African patients with a first episode of psychosis who made contact with psychiatric services over a 2-year period and were living in defined areas. Clinical, socio-demographic and pathways to care data were collected from patients, relatives and case notes. Results Compared with White British patients, general practitioner referral was less frequent for both African–Caribbean and Black African patients and referral by a criminal justice agency was more common. With the exception of criminal justice referrals for Black African patients, these findings remained significant after adjusting for potential confounders. Conclusions These findings suggest that factors are operating during a first episode of psychosis to increase the risk that the pathway to care for Black patients will involve non-health professionals.