首页 Fluoxetine and suicide

Fluoxetine and suicide

举报
开通vip

Fluoxetine and suicide children's attitudes toward physical activity within the school environment. 26 Supported by the Danish Health Insurance Foundation, the Danish Health Services Development Foundation, the Danish Heart Foundation, the Health Insurance Foundation of Denmark, t...

Fluoxetine and suicide
children's attitudes toward physical activity within the school environment. 26 Supported by the Danish Health Insurance Foundation, the Danish Health Services Development Foundation, the Danish Heart Foundation, the Health Insurance Foundation of Denmark, the Danish Medical Research Council, the Funen Prevention Council, the Danish Sports Research Council, and the Rosalie Petersen Foundation. I WHO Scientific Group. Primary prevention of essential hypertension. WHO Tech Rep Ser 1983;686:1-40. 2 The 1988 report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1988;148:1023-38. 3 Nelson L, Jennings GL, Esler MD, Korner PI. Effect of changing levels of physical activity on blood pressure and haemodynamics in essential hypertension. Lancet 1986;ii:473-6. 4 Jennings G, Nelson L, Nestel P, Esler M, Korner P, Burton D, et al. The effects of changes in physical activity on major cardiovascular risk factors, hemodvnamics, sympathetic function, and glucose utilization in man: a controlled study of four levels of activity. Circulation 1986;73:30-40. 5 Seals DR, Hagberg JM. The effect ofexercise training on human hypertension: a review. Med Sci Sports Exerc 1984;16:207-15. 6 Subcommittee on Nonpharmacological Therapy. Nonpharmacological approaches to the control of high blood pressure. Hypertension 1986;8: 4-4-67. 7 Report of the Second Task Force on Blood Pressure Control in Children- 1987. Pediatrics 1987;79:1-25. 8 Fagard R. Habitual physical activity, training, and blood pressure in normo- and hypertension. Int-J Sports Med 1985;6:57-67. 9 Montoyc HJ. Physical activity, physical fitness, and heart disease risk factors in children. In: Stull GA, Eckert HM, eds. Effects of physical actizvity on children. Champaign, Illinois: Human Kinetics Publishers, 1986:127-52. (American Academy of Physical Education Papers, No 19.) 10 Vaccaro P, Mahon AD. The effects of exercise on coronary heart disease risk factors in children. Sports Med 1989;8:139-53. 11 Hansen HS, Hyldebrandt N, Nielsen JR, Froberg K. Blood pressure distribution in a school-age population aged 8-10 years-the Odense schoolchild study.tHvpertens 1990;8:641-6. 12 Fanner JM, ed. Gr(rwth at adolescence. Oxford: Blackwell Scientific Publica- tions, 1962. 13 Hanscn HS, Froberg K, Nielsen JR, Hyldebrandt N. A new approach to assessing maximal aerobic power in children: the Odense school child study. Eurj Appl Phystol 1989;58:618-24. 14 Cole IWL, Grizzle IE. Applications of multivariate analysis of variance to repeated measures experiments. Biometrics 1966;22:810-28. 15 O'Brien RG, Kaiser M1K. MANOVA method for analyzing repeated measttres designs: an extensive primer. Psychol Bull 1985;97:316-33. 16 SPSS Inc. SPSSX user's guide. New York: McGraw-Hill Book Company, 1983:487-8. 17 Gunsollev JC, Chinchilli VM, Koertge TE, Palcanis KG, Sarbin AG, Brooks CN. The use of repeated measures analysis of variance for plaque and gingival indices. J Clin Periodontol 1989;16:156-63. 18 Eriksson BO, Koch G. Effect of physical training on haemodynamic response during submaximal and maximal exercise in 11-13-year old boys. Acta PhvsiolScand 1973;87:27-39. 19 Dwyer T, Coonan WE, Leitch DR, Hetzel BS, Baghurst RA. An investigation of the effects of daily physical activity on the health of primary school students in South Australia. Intj Epidemiol 1983;12:308-13. 20 Linder CW, DuRant RH, Mahoney OM. The effect of physical conditioning on serum lipids and lipoproteins in white male adolescents. Med Sci Sports Exerc 1983;15:232-6. 21 Stone EJ. School-based health research funded by the National Heart, Lung, and Blood Institute. J Sch Health 1985;55:168-74. 22 Puska P, Vartiainen E, Pallonen U, Salonen JT, Poyhia P, Koskela K, et al. The North Karelia Youth Project: evaluation of two years of intervention on health behavior and CVD risk factors among 13 to 15-year-old children. PrevMed 1982;11:550-70. 23 Tell GS, Vellar OD. Non-communicable disease risk factor intervention in Norwegian adolescents: the Oslo youth study. In: Hetzel BS, Berenson GS, eds. Cardiovascular risk factors in childhood: epidemiologv and prevention. Amsterdam: Elsevier, 1987:203-17. 24 Walter HJ, Hofman A, Vaughan AD, Wynder EL. Modification of risk factors for coronary heart disease. N Englj Med 1988;318: 1093-1 100. 25 Berenson GS, Shear CL, Chiang YK, Webber LS, Voors AW. Combined low- dose medication and primary intervention over a 30-month period f'or sustained high blood pressure in childhood. Amj Med Sci 1990;299:79-86. 26 Demarco T, Sidney K. Enhancing children's participation in physical activity. J Sch Health 1989;59:337-40. (Accepted 43Julv 1991) Fluoxetine and suicide: a meta-analysis of controlled trials of treatment for depression Charles M Beasley Jr, Bruce E Dornseif, Janet C Bosomworth, Mary E Sayler, Alvin H Rampey Jr, John H Heiligenstein, Vicki L Thompson, David J Murphy, Daniel N Masica Division of Clinical Neurosciences, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA Charles M Beasley Jr, MD, clinical resource physician Bruce E Dornseif, PHD, research scientist Janet C Bosomworth, BS, statistician Mary E Sayler, MS, statistician Alvin H Rampey Jr, PHD, senior statistician John H Heiligenstein, MD, clinical research physician Vicki L Thompson, MSN, clinical research administrator David J Murphy, BBA, senior information analyst Daniel N Masica, MD, international research adviser Correspondence to: Dr Charles M Beasley Jr, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center 2128, Indianapolis, Indiana 46285, USA. B.J 1991;303:685-92 Abstract Objective-A comprehensive meta-analysis of clinical trial data was performed to assess the possible association of fluoxetine and suicidality (suicidal acts and ideation). Design-Retrospective analysis of pooled data from 17 double blind clinical trials in patients with major depressive disorder comparing fluoxetine (n= 1765) with a tricyclic antidepressant (n=731) or placebo (n= 569), or both. Main outcome measures-Multiple data sources were searched to identify patients with suicidal acts. Suicidal ideation was assessed with item 3 of the Hamilton depression rating scale, which systematically rates suicidality. Emergence of substantial suicidal ideation was defined as a change in the rating of this item from 0 or 1 at baseline to 3 or 4 during double blind treatment; worsening was defined as any increase from baseline; improvement was defined as a decrease from baseline at the last visit during the treatment. Results-Suicidal acts did not differ significantly in comparisons of fluoxetine with placebo (0-2% v 0-2%, p=0 494, Mantel-Haenszel adjusted incidence difference) and with tricyclic antidepressants (0-7% v 0-4%, p=0-419). The pooled incidence of suicidal acts was 0*3% for fluoxetine, 0-2% for placebo, and 0-4% for tricyclic antidepressants, and fluoxetine did not differ significantly from either placebo (p=0 533, Pearson's x2) or tricyclic antidepressants (p=0 789). Suicidal ideation emerged marginally significantly less often with fluoxetine than with placebo (0-9% v 2-6%, p=0.094) and numerically less often than with tricyclic antidepressants (1.7% v 3-6%, p=0-102). The pooled incidence of emergence of substantial suicidal ideation was 1-2% for fluoxetine, 2-6% for placebo, and 3-6% for tricyclic antidepressants. The incidence was significantly lower with fluoxetine than with placebo (p=0042) and tricyclic anti- depressants (p=0-001). Any degree of worsening of suicidal ideation was similar with fluoxetine and placebo (15-4%v 17-9%, p=0- 196) and with fluoxetine and tricyclic antidepressants (15-6% v 16-3%, p=0-793). The pooled incidence of worsening of suicidal ideation was 15-3% for fluoxetine, 17*9% for placebo, and 16-3% for tricyclic antidepressants. The incidence did not differ significantly with fluoxetine and placebo (p=0-141) or tricyclic anti- depressants (p=0542). Suicidal ideation improved significantly more with fluoxetine than with placebo (72-0% v 54-8%, p<0001) and was similar to the improvement with tricyclic antidepressants (72-5% v 69-8%, p=0294). The pooled incidence of improve- ment of suicidal ideation was 72-2% for fluoxetine, 54-8% for placebo, and 69-8% for tricyclic anti- depressants. The incidence with fluoxetine was significantly greater than with placebo (p<0-001) and did not differ from that with tricyclic antidepressants (p=0296). Conclusion-Data from these trials do not show that fluoxetine is associated with an increased risk of suicidal acts or emergence of substantial suicidal thoughts among depressed patients. Introduction Because depression is an important risk factor for suicide'3 there is a need to study the effects of BMJ VOLUME 303 21 SEPTEMBER 1991 685 antidepressants on suicidalitv (suicidal acts and suicidal ideation) in patients with major depressive illnesses. Though it is generally expected that any treatment that improves the depression is also likely to reduce suicidality, one study did not support this view.4 It has not been suggested until fairly recently that, paradoxically, worsening of suicidality might in a small subset of patients be associated with the use of antidepressants. "' Five reports"' (one subsequently retracted") have hypothesised that the use of fltioxetine (a serotonin uptake inhibitor) might lead to the emergence or worsening of suicidal ideation in a very small proportion of patients taking this drug. Patients receiving different classes ofantidepressants, including fluoxetine, have shown no differences in rates of suicidalityv' while greater improvement with respect to suicidalitv has occurred with serotonin uptake inhibitors than with comparative drugs in depressive illnesses."-' Recently Rouillon et al reported that maprotiline (a noradrenaline uptake inhibitor) was associated with a greater incidence of suicidal acts than placebo during long term treatment of depression.'2 To examine any possible relation of fluoxetine to the emergence of suicidality, we carried out a com- prehensive meta-analysis of all relevant clinical trial data. Methods TYPES AND SOURCES OF DATA The meta-analysis was carried out on the United States investigational new drug depression clinical trial database for fluoxetine; this consists of all double blind, randomised trials of fluoxetine in depression controlled against placebo or tricyclic antidepressants. Trials that had been completed and analysed up to the end of December 1989 were included. The exclusions were: depression trials that had not used a comparative drug, trials that had used a comparator other than placebo or a tricyclic antidepressant, non-blind extensions of controlled trials, non-blind compas- sionate trials, trials for other potential indications, and pharmacokinetic trials. For these analyses the clinical trials were organised into five analysis groups: (1) placebo controlled trials (five trials); (2) trials controlled with tricyclic anti- depressants (10 trials); (3) trials controlled with placebos and tricyclic antidepressants (two trials); (4) analysis group 1 and the fluoxetine and placebo arms of analysis group 3; and (5) analysis group 2 and the fluoxetine and tricyclic antidepressant arms of analysis group 3. The specific protocols included in each analysis group and the characteristics of the patients studied are summarised in the Appendix. Potential cases of suicidal acts were first identified electronically by searching two sources: (a) clinical report form data from the trials (for adverse events, reasons for trial discontinuation, Hamilton depression rating scale item 3 scores,'" and free text comments) and (b) data from the drug experience network for. adverse events and outcomes. The drug experience network database contains reports of all serious adverse events (as defined by United States Food and Drug Administration criteria) that have occurred in clinical trials, as well as all adverse events voluntarily reported as part of the manufacturer's (Eli Lilly and Company) post-marketing surveillance. '9 Those clinical com- ments that had not been transferred to computer were examined by the research staff, and all cases in which it was clear that there had been no suicidal act were eliminated. All remaining cases were then reviewed independently by two Eli Lilly and Company psy- chiatrists, who were blind to the drug that had been used, to determine whether or not a suicidal act had occurred. D)EFINITIONS A suicidal act was defined as any behaviour under- taken purposefully from which the outcome was likely to be self harm, and where no explicit data suggested that suicide had not been intended.' Actions that might be described as suicidal gestures were not excluded. A suicidal act had to have occurred before or during the day following the last day of double blind treatment, in compliance with the trial protocol. This time limit was adopted for three reasons: post-discontinuation data had not been collected as part of the trials; the end of participation in the trial or withdrawal of the study treatment, or both, might have influenced an event occurring after discontinuation; and other drugs might have been started after the end of the study treatment. Suicidal ideation was identified by the scores on item 3 of the Hamilton depression rating scale. The scale defines these as: 0=absence of such ideation; 1=doubtful or trivial ideation; 2=mild ideation; 3= active suicidal ideation and suggestive behaviours; and 4= severe ideation, usually involving a suicidal act. Emergence of substantial suicidal ideation was defined as a change in score on item 3 of the Hamilton depression rating scale from 0 or 1 at baseline to 3 or 4 at any time during the double blind treatment. Emergence of substantial suicidal ideation was evaluated only for those patients whose score was 0 or 1 at baseline. Worsening of suicidal ideation was defined as any increase in item 3 score from baseline at any time during double blind treatment. Worsening was evaluated only for those patients who could worsen during double blind treatment-that is, those whose score was less than 4 at baseline. Improvement of suicidal ideation was defined as any decrease in item 3 score from baseline to the last evaluation while the patient was in double blind treatment. Improvement was evaluated only for those patients who could improve during double blind treatment -that is, those whose score was greater than 0 at baseline. DESIGN Data were analysed from 17 single centre and multicentre randomised, double blind trials including 3065 patients (1765 receiving fluoxetine, 731 receiving tricyclic antidepressants (amitriptyline, desipramine, doxepin, imipramine, nortriptyline), and 569 receiving placebo). Five trials compared fluoxetine with placebo, 10 compared fluoxetine with a tricyclic antidepressant, and two compared fluoxetine with a tricyclic anti- depressant and a placebo. Fluoxetine doses ranged from 20 mg to 80 mg a day (except in one trial where the range was 5 mg to 40 mg a day); in 15 trials the fluoxetine doses were individually adjusted, and in two the patients were randomly assigned to one of several fixed doses. Doses of tricyclic antidepressants were adjusted individually within current manufacturers' guidelines. In 16 trials the patients met criteria for non- psychotic major depressive disorder (three trials used Research Diagnostic Criteria,0 nine trials used the Diagnostic and Statistical Manual of Mental Disorders, 3rd edition (DSM-III) criteria for symptoms of one month's duration, and four trials required DSM-III criteria"'). Most patients had a score ¢20 on the 21 item Hamilton depression rating scale (one trial used a score 18 and one trial included a stratum of patients with scores between 14 and 19), and most did not improve their score by 20% or more during the lead in period (approximately one week of single blind placebo treatment). In one trial the patients were diagnosed by DSM-III criteria as having bipolar disorder and being depressed; they had a baseline score :20 on the 21 item Hamilton depression rating scale and failed to BMJ VOLUME 303 21 SEPTEMBER 1991686 show a 20010 or greater improvement in this score during placebo lead in. Written informed consent was given appropriately in all cases. Exclusion criteria included a history of substance misuse within one vear; psychotic or organic mental disorder; serious suicidal risk as clinically assessed by the investigator (suicidal ideation was not a criterion; two inpatient trials did not have an explicit exclusion criterion based on serious suicidal risk); and unstable medical conditions or any medical condition precluding use of one of the drugs used in these studies. Trials lasted five or six weeks with evaluations about once a week, except in one inpatient trial where there were two evaluations a week for the first two weeks of double blind treatment and one outpatient trial where there were two evaluations during the first week and three during the second week of double blind treatment. ANALYTICAL AND STATISTICAL METHODS Descriptive statistics, including the incidence of suicidal acts and the emergence of substantial suicidal ideation (the primary measures) and worsening of suicidal ideation and improvement of suicidal ideation, were conmputed for all individual trials, for analysis groups 4 and 5, and for all trials combined. Inferential statistical analyses were performed for analysis group 4 (fluoxetine z' placebo), analysis group 5 (fluoxetine v tricyclic antidepressants), and all trials combined. All 3065 randomised patients were included in the analysis of suicidal acts. A total of 1999 patients with a baseline score on item 3 of the Hamilton depression rating scale of 0 or 1 and at least one post-baseline score were included in the analysis of emergence of substantial suicidal ideation. The incidence of worsening of suicidal ideation was based on 2995 patients with a baseline score <4 and at least one post-baseline score. The incidence of improvement of suicidal ideation was based on 2053 patients with a baseline score >0 and at least one post-baseline score. The incidence difference and corresponding 95% confidence interval was used to compare the incidence of the four outcome variables (suicidal acts, emergence of substantial suicidal ideation, worsening of suicidal ideation, improvement of suicidal ideation) between treatments for individual clinical trials. The incidence difference22 was defined as the incidence in patients treated with fluoxetine minus the incidence in patients treated with the comparator. An incidence difference greater than 0 implies a numerically higher incidence with fluoxetine than with the comparator; an incidence difference less than 0 implies a numerically higher incidence with the comparator than with fluoxetine; and an incidence difference equal to 0 implies equal incidence. Owing to potential heterogeneity of trials the adjusted incidence difference, which stratifies by trial, was used to compare the incidence of the four outcome variables between treatments in analysis groups 4 and 5. The individual incidence differences TABLE I -Characteristics of patietnts at baselinle MNean (S)) score on Hamilton deprcssion rating scalc MNleni w)romen MNedian ratigei No of patients (years) 21 Itcms Item 3 Analysis group 4: Fluoxetinc 1322 39 (61) 38 (13-70) 23-5 )5.3) (09(099) Placebo 569 41:59) 37(12-70) 25 5 (5 5) 1 1(0 9) Ynalvsis group 5: Fluoxetine 720 34)66) 43 (19-90() 27-2(5-4) 1-3(1-0) Tricvclics 731 36(64) 45 (18-88) 27-2 (5 5) 1-4(1-0 All trials: Fluoxetine 1765 38 62) 40 (13-90) 24 4 (5 6) 1 0 (1 0) Tricyclics 731 36(64) 45(18-88) 27-2)(5-5) 14)(1-0) Placebo 569 41 (59) 37 12-70) 25 5 (5-5) 1.1 )0 9) were combined across the clinical trials to form the adju
本文档为【Fluoxetine and suicide】,请使用软件OFFICE或WPS软件打开。作品中的文字与图均可以修改和编辑, 图片更改请在作品中右键图片并更换,文字修改请直接点击文字进行修改,也可以新增和删除文档中的内容。
该文档来自用户分享,如有侵权行为请发邮件ishare@vip.sina.com联系网站客服,我们会及时删除。
[版权声明] 本站所有资料为用户分享产生,若发现您的权利被侵害,请联系客服邮件isharekefu@iask.cn,我们尽快处理。
本作品所展示的图片、画像、字体、音乐的版权可能需版权方额外授权,请谨慎使用。
网站提供的党政主题相关内容(国旗、国徽、党徽..)目的在于配合国家政策宣传,仅限个人学习分享使用,禁止用于任何广告和商用目的。
下载需要: 免费 已有0 人下载
最新资料
资料动态
专题动态
is_136836
暂无简介~
格式:pdf
大小:1MB
软件:PDF阅读器
页数:0
分类:
上传时间:2013-09-23
浏览量:26