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    SS Clozapine Treatment for Suicidality in Schizophrenia International Suicide Prevention Trial (InterSePT) Herbert ¥. Meltzer, MD; Larry Alpks, MD, PhD: Alan I. Green, MD: A. Carlo Altamura, MD; Ravi Anand, MD; Alberto Bertoldi, MD; Mare Bourgeois, MD; Guy Chouinard, MD; M. Zahur Islam, PhD; John Kane, MD; Ranga Krishnan, MD; JP. Lindenmayer, MD; Steven Pothin, MD; for the InterSePT Study Group Background: Approximately 50% of patients with, schizophrenia or schizoaffective disorder attempt suicide, and approximately 10% die of suicide. Study results suggest that clozapine therapy significantly reduces suicidal behavior in these patients, ed, international, 2-year stl comparing the risk for suledal behavior in patients treated with clozapine vs olanzapine was con- ducted in 980 patients with schizophrenia oF schizoal- fective disorder, 26.8% of whom were refractory to pre- Vious treatment, who were considered at high risk for suicide because of previous suicide attempts or current ‘suicidal ideation, To equalize clinical contact across teat ments, all patients were seen weekly for 6 months and then biweekly for 18 months. Subsequent to randomiza- tion, unmasked clinicians at each site could make any interventions necessary to prevent the occurrence of sui- ‘ide attempts, Suicidal behavior was assessed at each Vis Primary end points included suicide attempts (includ- ing those that led to death), hospitalizations to prevent suicide, and a rating of “much worsening of suicidality” from baseline. Masked raters, including an independent suicide monitoring board, determined when end point criteria were achieved. Results: Suicidal behavior was significantly less in pa- tients treated with clozapine vs olanzapine (hazard ra- tio, 0.76; 05% confidence interval, 0.58-0.97; P=.03) Fewer clozapine-ireated patients attempted suicide (34 vs 55; P=.03), required hospitalizations (82 vs 107; P=.05) or rescue interventions (118 vs 155; P=.01) to prevent suicide, oF required concomitant treatment with antide- pressants (221 vs 258; P=.01) or anxiolytics or soporif- les (301 vs 351; P=.03). Overall, few of these high-risk patients died of suicide during the study (5 elozapine- vvs 3 olanzapine-treated patients; P=.73) Conelustons: Clozapine therapy demonstrated supe ority to olanzapine therapy in preventing suicide at- templs in patients with schizophrenia and schizoalfec- Live disorder at high risk for suicide, Use of clozapine in this population should lead to a significant reduction in suicidal behavior Arch Gen Psychiatry. 2003;60:82-91 UICIDE Is the leading cause of premature death among pa- 0.5 to 7.0 years and evaluated for changes {n suicidal behavior, the percentage with Author afiitions. ‘atthe end of this a ‘complete listo the are listed ticle. A members ofthe InersePT Study Group ‘appears inthe box on page 90, Downloaded From: on 11/27/2018 (aepnanteD) TECH tients with schizophrenia. (Overall, patients with schizo- phrenia have approximately 506 hfetime risk for suicide attempts and 4 9% to, 13% lifetime tsk for completed Suicide’ In comparison, the feime risk for suicide in the gencral population of the United Sates is approximately 1%" and in persons with mood disorders, 9% 10 15%" studies examining the ellects of typical antipsychotic medications on su cide and suicidal ideation have not iden fied a change in incidence of suicide with their use. However, several studies sug- gest that using clozapine, an atypical an- Upsychotie drug, may reduce seidal be- havior in schizophrenia. Melizer and Okaylfound that among 88 neuroleptic- resistant palicnts treated with clozapine for (©2003 American Med no suicidality of any type increased from 53% 088%. Inanother study (which used the Clozaril National Registry to identity 57000 curren, recent and past clozapine- teeated patients, followed by linkage of these data with the National Death Index and Social Security Administration Death Master Files to identify cause of death) Walker and colleagies" found that mor. tality from suicide was markedly de- creased in current clozapine users com pared with past users. Analyses!" of Clozapine registry data from the United States and England support the view that the suicide completion rate in treated pa- tients with schizophrenia is substantially reduced. Similsey, a retrospective study!* of 295 treatment-resistant outpatients (ainly African Americans) found that 1 Association, All rights reserved. clozapine treatment reduced the expected rate of suicid- ality during continuous drug administration. In con- trast to these findings, a study"? of the effect of cloza- pine treatment on completed suicides in the Veterans Administration system did not demonstrate a signili- ‘cant effect of clozapine therapy on the suicide rate, How- ever, despite failure to match the comparison group on variables related to risk of suicide and follow-up that in some cases extended for prolonged periods alter pa- tients discontinued clozapine treatment, this study dem- onstrated a trend toward lowering the suicide rate for clozapine compared with nonelozapine treatment Taken together, these studies provide evidence for the ability of clozapine therapy to reduce suicidal behav- lors"; however, they were retrospective and did not con- tuol for possible differences in the risk for suicide be- tween the clozapine and comparison groups, relative differences in the dosage of clozapine vs the compari son antipsychotic drug, differences in the use of con- comitant medications, or differences in the frequency of teat tents, Because managing patients at high rik or sce ina year, double-blind study was not considered clinically fea sible or acceptable and because treatment with clozapine lof ten asociated with a variety of unique, clinically obvious ad terse elles the IntersePT was conducted ae a randomized, open-label rial with masked ratings After discussing the pro- tocoland other treatment options in cet with he patent t= ten informed consent wat obained. Serened patents meet ing inclusion criteria were assigned to weatment with ithe clocapine or olanzapine. For ndomition, patients were blocked by country and medial enter The iresment groups were allocated randomly n'a :1 rato within blocks of pa tients in each medical enter. Recognizing the inert problmsassoclated with an open- Inbe ral extensive efforts were made to ensure masking of the raters All aspects of the primary end points were lined torraings from | of 2 groups of masked raters, A 3-member sulcide monitoring board (GMB) determined whether poten tal end points met th eiteia fora suicide atempt ora hor pitalzalon to prevent suicide. The SMB was nominated bythe Sud sponsor, Novartis Pharmaceutical Corp, Est Hanover, Nand approvedby an academic tering comaltee. The SMB was chaired by one of us (RK) and included Hanna Hela, MD, from the National Public Health Insitute in Helen, Fi Inn and sac Sakincfsy, PAD, fromthe University of Toronto Toronto, Ontario, Each member had extensive experience work ig with suicidal patents Thitcam remained constant through out the sti Every type 1 end point (ee the “Outcome Definitions” suib- section) was reviewed by all ofthe members ofthe SMB, and Consensus was obained A the onset ofthe study, the SMU de ‘eloped the specific procedures for which data and how data wrotld be reviewed and guldelines for how ease evaluations swould acu, Potenal end point packages were reviewed and Cdted if eceseary to eliminate aty indication ofthe anipy- otic drug used for example, adverse effects andblood on- toring, Matking ofthe SMB was monitored by Kevin Cox from Ingenix Pharmaceutical Services, San Diego, Calf, who en sured tit al ofthe data eccved by the SM was macked e- fore delivery tothe SMB, The inslions for which members ofthe SMB worked were not included as participant sts in the study 1 Association, All rights reserved. ‘Table 1. Clinical Global impression {or Severity of Sucidallty Considering al ofthe informaton Tot ata eual ‘alae to you, what asthe 2 Mil sual roe ever ol of suilty 3 Moder suicidal ‘peronced yh pat inthe 4 Several sisal pas ene? 5 tempted suid Considering al oh informaton 1 Vary much improved ‘alah you, pow much as 2 uch improved tho patent icity changed Minimal improved amped vith his oc ht condion Na change tbaelne? $5 Minimal worsened E Much were 7 Vary much worse For purposes of end point assesment, sicde attempts were defined actos commited bya patient, either with wll Tul intent or as responce to ineral compulsions or disor dleved thinking that put him o her at high isk for death, Po- tential end pots were dented by investigators and by sty tnonitore who reviewed medical records and adverse event dala for potential end points The SMB determined whether these tential end polnts met predefined criteria of intent and se- Fowsness to qualify ae study end poi. Tnadliton to these ratings by the SMB, masked psychia- triste at each participating ste aed the plbal assesment of sicidalty fo type & events (eee the “Outcome Definitions” Subsection). Because these were ratings ofan individual pa- tents sucldalty compared with baseline, they could not be assested by the independent SMB, These ste rales interac- thos with patent inthis sty were limited to these aings and the had no other clinical contact with them, Raters were Tequlred to vey thelr masking atthe ume of each ating, and they were regularly monitored by Ingenix Pharmaceutical Ser- ‘esto ensue that they had remained masked to the patients “The weekly or biweekly linia contact required to moni- tor for clozapine associated agranulocytosis wae matched with {Camila vit schedule for olaneapine-treated patients daring ‘which vial signe were obtained. To ensure the safety of par tents during is ral clinicians weresllowed tomake any in tervenions necessary to prevent the occurrence of suicide at tempts, including changing dosages, adding other medications switching medications, and increasing surveillance. In add tion, patfents were queried at each vist about suicdalty fand they were refered to their treating physician i full valuation was indicated. Rescue interventions required to prevent suiciderlated events were analysed as secondary end points he ist patient was enrolled inthe InerSePT on Match 2, 1908, andthe ast patent was enrolled on February 14,1009, “helas patent completed his last vst on February 14,2001 OUTCOME DEFINITIONS las recognized atthe outset that use of suicide deaths alone as an end point would require approximately 20000 patients if the study were powered to detect a decreased relative risk with clozapine therapy by 20%. Furthermore, because failure lo intervene to prevent suicide during the follow-up care of pat tients i this study was considered ethically unacceptable, ex- ceryelfort was made o prevent this outcome, Ths, suicide deaths alone were not regarded asthe primary end point but were in- ‘luded asa subset of much larger group of suicidal behaviors that might occur during the stay. (aepnanteD) TET (©2003 American Med Downloaded From: on 11/27/2018 EN TSVCHATUOL aD, AN DO After consultation with external clinkcal experts in pey- chiaiy, statistical experts, andthe Neuropharinacology Bi sion of the US FDA, 2 types of primary end points were pre specified for this tial /& type'l event was defined as the tecurence of significant suicide attempt (which nce com pleted suicides ae subset) or hospitalization beease of fhinent suicide risk (which included increased levels of sur teilane) that was confined by an external masked group (he SMB). A ype 2event was defined aratings from amasked py chiatist onthe Clinical Global Impression of Sucide Severity (CLS) of "much worse" or "very much worse rom hace line fable 1). Because patients with potential type 2 evens were not always observed by masked peychiassty criteria for 2 significant level of worsening from baseline were also de- fined to have been met whenever a ype Levent occured Other objective measures of suicidality included the in- dividual components ofthe man outcome varable—the spe- tice oan sB-dtermined suicide ater (including death by suicide) or horpltalization to prevent suicide or the num ber ofsulide atempis, the numberof hospitalizations to pre vent sulci, and the numberof interventions to prevents tide, respective of SMB validation. Patients were enrolled for 2 years of follow-up. Attempls were made to continue to collect basic end point information ven the patent discontinued study partcpation early. This information was included inthe intent-to-treat analyse. in addition to these measures, the change in sulide risk ras asessed clinically using the CGLSS as an addional ele tent of the combined end point. Information for rating this scale was collected during a semistructured interview de- signed to let the necessary information for ratings. Valid tion ofthis standardized clinical assessment demonsirats that this instrument fe relable and valid fr asessing current st cidal thinking in patients with schizophrenia and schizoalfe tive disorder by clinicians and reseachers. Additional infor- tation about the the validation ofthis insirument i avalable cleewhere” This 2-tem scale measured severity of suicidality and change in suicidality from baseline (Table 1). Individuals were assessed on the CGL-SS by masked raters at cach site a Brschine and at study weeks 8 16,24, 32,40, 48,52, 00, 08 80,92, and 104 ‘Safa the investigational sites were rained om interSePT procedures and scales and were cert by study moors {alle raters before being permited to parciate All new faters inthe study were ane lo meet prespecified criteria, ‘Additional taining was provided during the study to ensure that reliablty was maintained over ie STATISTICAL ANALYSIS ter the primary data wer lacked and vere static nay ses were condactcdby Ingen Pharmaceutical eves and sup pli touslorexamiaton checking and reprting There were fointerim analyses of data other than a masked review of saty dita Every elf was made to follow all patents to comple tion ofthe 2year evaluation ll data obtained were used in the intent-to-treat nals “The mull hypothess for this study state thatthe relative hazard fortype | and type events ding eatnet wh clea pine compared wih lnsapineweatment would not dle fom "ter consltation withthe EDA, the predefined main aly sis totes this nal hypothesis used the method of Wei et a= foranalysisofmuliple events Inthis analysis the factor coun- try wasters ob reedanizd eaten group waste asthe only covariate Supplementary supportveanalyssofthe SMt-determined end pots were completed using the Cox proportional has- ards reresion model "> Patatve explanatory variables, hat 1 Association, All rights reserved. ‘Table 2. Demographic Characteristics ofthe Treatment Groups at Baseline ‘clozapine croup Ota P vale" characte (a= 400) (Clozapine ve Olanzapine) ‘ge, mean 80, y ara 103 302103 aia103 74 Male ex, No. (%) 301 (6.4) 301 61.4) 02 61.) 98 ace, No.) “9 386 727) 387 (688) 093,707) 5 (133) 36178) soi (154) 6) 714) 13(13) tee 63129) 60 (122) 125 (128) Dgnoi, No) 0 Schizophrenic 300 612) 300 63.) 9 (621) Schostectie 400 (388) 181 (289) snr) Lime sie atemptst No. (6}¢ 413 (843) 3 (822) 210,633) 58 No, maan «$0 36475 32045 24262 20 Sud tongs in te yas 36 ma, No. (8) 307 (627) 311 635) 018 631) 76 Continous variables were analyzed using an ana of vainca model (0, del ge = eaten + pooled cout) Categorical varios wer aralyed using the Cora Mate Hensal method sai by pol country. "Henitewere nae using the leon tat ‘Plumber of pants wha mace 1 sue atmpt beorebacene is factors that may have contributed to the primary end point patients (27%) were rated as treatment resistant. OF the inthis model, included treatment, number of previous suicide total population studied, 477 patients received olanza attempts, active substance or alcohol abuse, country, medical pine, 479 received elozapine, and 24 were never treated center, sex, and age group (18-32, 33-44, and =45 years) at baseline. The hazard ratio, a measure ofthe relative risk be- twveen groups, and its 05% confidence interval (C1), were com- puted on the basis of the fited model. In addition, Kaplan- for various administrative reasons. Eighty-three percent of patients had attempted suicide at least once during their lifetime, and 84% had been hospitalized to prevent a sui Kier estimates of survival probaites were calculated The ckde tempt Sixty-thtee percent of patients had at- average numberof paients needed to ato showa benefit tempted sticide in the previous 36 months. Patients tfclorapineuse ove olanzapine se egarding the prinaryend rested with olanzapine or clozapine did not sigif- point wa computed using the method of Amat” Anmusl- cantly difer in age, sex, race, dlagnoss, treatment fea ates ofauicidestemptewereeaeuated asthe numberof tance, numberof previous sulide tempi, or baseline total suc attempts Gnduding suicide) among the rndom-_ Concrmitant medications Gtaile 2). ized patients divided by the total number of patient-years in the study. For this ealeulation, the total number of patient- years included the dime during follow-up after dropout from the study. Compliance was estimated by dividing the nummber ‘of study drug pills returned by the numberof study drug pills TREATMENT AND EVENTS The means SD prescribed dosages of study drugs were Aispensed stbtractng from @ and mulpying by 400. 16.0464 mg daly for olanzapine and 274.24155.0 mg Because the CGHSS was assessed retvely infrequently daily for clozapine. Compliance was 94.4% forthe cloza- during the study. based onan ageeement wine FDATanin. —plne-treated group and 95.8% for the olanzapine. fered atingofinuch woreeningfrom seine was assumed treated group. Overalldropout rates for patents teated fnihissele ifs patent atempledsuicideor was hospitalized with elasapiae ve olanzapine were not different Rea- to prevent suicide The number ofpatiens with "math wors- sone for dropout are suiminarzed in Fable 3.4 total of ‘ening from baseline CGL-SS" was analyzed using the Fisher ex- fact test. Time to the °much worsening of CGI-SS” was ana- lyzed with the methods sed forthe primary ellicacy variable 380 patients (39%) discontinued taking the study drug carly: 99 (10%) withdrew consent, 74 (8%) for adverse Event rates were computed for other eficacy and safety SveT#S, and 72 (746) were lost to follow-up. The rates of assesunte and the tate sigificanee were pefonmed ae, discontinuation for other reasons were infrequent and ing the Fisher exact eat All Pualuce were bad on Dsided diel not differ between treatment groups, except for dis alternative hypotheses continuations for unsatisfactory antisuieidal effect (6 olan- zapine-treated patients [1%] and 0 clozapine-treated pa- nn cents: 203), very etfort was made to follow patients for suidy end points for the full 2 years of evaluation, even PATIENTS: after they formally discontinued using the study drug. (0F 1005 patients screened for participation in thisstudy, Such information from “retrieved dropouts” was in- ‘980 (92%; 490 per group) met the inclusion criteriaand cluded in the intent-to-treat analyses. More discontinu- {gave written informed consent, They were then ran- ations occurred early in the course of clozapine treat- domly assigned to treatment with either clozapine or olan- ment (usually for adverse events), whereas there tended zapine. Of the total sample, 609 patients (62%) were di-__to be more olanzapine dropouts later in the study agnosed as having schizophrenia and 371 (38%) as having Of the 577 cases sent to the SMB for review (repre schizoaffective disorder. At the time of enrollment, 263 senting 443 unique patients), 483 were determined to (aepnanteD) TECH (©2003 American Med 1 Association, All rights reserved. Downloaded From: on 11/27/2018 ‘Table 3, Patient Study Discontinuations* easont 0) ‘verse overt) 7a) 36) 778) Ty ‘Abnormal laboratory vals) 2104) 0 2(02) 50 ‘Abnormal test procdura resus) 1102) o 4101) > Unsastactor therapeutic econ psychosis 50) 918) wait) 2 Unsatisfactory therapautc fet for lonring suicide risk a 6112) (08) 35 Dette B18) 510) 13113) 2 Protocol valation 2069) z0id1) 1950) 28 Consent withdrawal 50102) 4910) (103) > Lat allaw-up 3367) 30180) 73) 54 Administrative problems 247) 25,63) «960, 7 ‘a 182,392) 187 (382) 37988) 79 a a numba (petcntage) of patents | Batad by ening pry, ‘Bisor atest, Suns sigitar diteronce ‘Table 4, SMB-Cortitied and Other Measures of Sulcdalty* Pvaiey Dlanzapie ory (23% Lathe Dterence) 90) {Olanzapine cerapine) SiB-deemined ed pois Patents with nd points, ttt Patients with signtfeant suicide atest Patents wth hospitalizations o prevent suit ASM determined en points, tal. Patt showing “much worsening ram basin” on the LSS Dscomiruatons for unsatstacor ants elects Coneamsant medestions Aniepressants) vcs oper verse events Patients epaincng “suid atom" Patents expaincng “sia ideation Suid date ‘Al restus interventions to prevnt suid 102208) 141 288) 005 (0810.13) 34169) 55(112) 103011 08) e267 107 218) 105 (0010) 217 266 120245) 161 329) 005 (0810.14) 0 eit) as 235,491) 258,65.) 01 (02 14) 237602) 31 (604) 105 (0113) 707) 65,138) 012 (0216.10) 125261) 158821) 105 (00 12) 5(10) 308) 73(-020 01) 118241) 155(818) 01 (02 13) ‘Abbravaion: CGS, lal Goal impression of Sie Sever Cl. conden tra, SMB, Sui Monitoring Board ‘Nalues are gue a numba pteatga) f pans unless obervise nesta Epes nate nol ppicble fisor attest [Intenton t-rex popuston (al andomied patient) laine, {ange bya msied peta Icluces mpd worsening patient as [satay population al ardomizd patets who tok the study dug): corapne inde ied deaths anda events ing to death by sui. meet end point criteria; ofthese, 111 (clozapine, 43; olan- ~zapine, 68) were considered suicide attempts and 372 (clozapine, 174; olanzapine, 198) were hospitalizations to prevent suicide. MAIN OUTCOME VARIABLES Primary Analysis The results of the main analysis for primary efficacy, based fon the method of Wel et al! demonstrate a significant difference (P=.03) between the clozapine group and the ‘olanzapine group in reducing suicidality as measured by SMB-determined suicide attempts or hospitalizations to prevent suicide and much or very much worsening in the CGI-SS from baseline as assessed by the masked psychia- (aepnu\ TED) ARCTGEN NCHNTRIOL SD, NT (©2003 American Medical Ass Downloaded From: on 11/27/2018 00 anzapna, n= 490, eepiize to prevent suid tempt or atempted sue, 79; anapre, = 477, sist, Results from the individual components of this end point indicate that compared with olanzapine therapy’ clozapine use had hazard ratios of 0.76 (95% CI, 0.58" 0.97) for type 1 events (suicide attempts or hospltaliz: tions to prevent suicide) (P=.03) and 0.78 (95% C1, 0.61- 0.00) for type 2 events (worsening on the CGLSS oF implicit worsening of suicidality severity as demon- strated by occurrence of a type 1 event) (P=.04), indi cating 24% and a 22% advantage, respectively, for cloza- pine therapy. Other efficacy results are summarized in Table 3 and Table Because patients may have ex} rienced more than 1 end point that met SMB criteria dur- ing the 2 years of observation, the absolute number of end points in each treatment group was also dete mined, There were more SMB-determined end points in the olanzapine-treated group than in the clozapine: lation, All rights reserved. ‘nape Group = canaes rap TTT Ha Tim. ¢ Day om mem Te Coxgine Cumin 0 Te tet Ne aeeele 0 MBS ozmarine Cums 0 SBT tre Ne Meola 400s Xapla ir astinaes ote probability ofa suid tempt or hesptalzaion a preven suede. treated group (266 vs 217 events). Of the prognostic fac- tors examined using the Cox proportional hazards re- _gression model as potential predictors of suicide events, fonly the number of lifetime suicide attempts at baseline (hazard ratio, 1.03; 05% Cl, 1.01-1.04; P<001) and cur- rent of previous history of alcohol of other drug abuse at baseline (hazard ratio, 148; 95% Cl, 1.11-1.99; P=.008) predicted the SMB-determined suicide events. The re- sults were largely consistent across countri regions, and diagnoses. Treatment resistance did not predict dif ferential response to clozapine or olanzapine regarding suicidality (data not shown) Secondary Analysis for Primary End Points During the InterSePT, the percentage of patients expe- Fencing at least 1 significant suicide attempt or hospi- talization to prevent suicide that met criteria estab- lished by the masked SMB was greater in the olanzapine: treated group than in the clozapine-treated group (28.8% vs 20.8%; P=.005) (Table 4). The olanzapine-treated ‘group experienced significantly more SMB-determined suicide attempts (11.2% vs 6.9%; P=.03) and SMB- determined hospitalizations to prevent suicide (21.8% vs, 16.7%; P=.05). In the analyses ofthe changes from base line in CGLSS scores, there was a significant difference in the percentage of patients who experienced “much 32.9% vs eloza- worsening from baseline” (olanzapin« pine, 24.5%; P=.005) ‘Overall, there were fewer deaths from suicide than ex- pected, particularly considering that only individuals at high Fisk for suicide were included in this study. Three suicide altempts in the olanzapine-treated group (0.6%) and 5 in the clozapine-treated group (1.0%) resulted in death (05% CC, 0.40%-7.04%; P=.73). On the other hand, when sui- cide attempts were rated for probability of success by the SMB, a “high probability for success” of a completed sui- ‘ide was found for 8 events in the clozapine group and 14 ‘events in the olanzapine group. The later group included (aepnanteD) TECH (©2003 American Med Downloaded From: on 11/27/2018 Table 5. Summary Statistes for Individuals, Who Recelved Rescue Interventions” ‘Gonapine olanzapine ‘Group Group Renese tervention_(n=40e)_n=ete)_ Pvanet Hospinaaionforminent 100(204)128(251)_—_—08 rekot ie Increass inl of sey sm) tt ‘vllanes Aiton ofan andepressant 15(831) 3367) ot et Aditentorchageinan —15(81) 29,59) antipychte agen Ineeaseindseetswdy —37(75) 3469) st mmadaton Aditonlamood sabi 612) 149) tt Aiton of ober 69 as) mabe isin to prt 20 3005) >a spit program Increase in edison sap oy menting ists Inston fpsyeotapy 6 (12) 408) 75 Increase in tequncy of 102) 71) oF eyhaterapy its Eragon) éeparmentvsts 34/69) 43(88) 3 Crs team vi 71408) 5 Becrocomulsietheapy 510) 06 Increase in equncy of 403) © e908 ‘ne te tee 1900 5663) 36 Teta rig2tt) 1550816) ot “lus are gn a amber peeeage) of pans ‘Fister octet the 6 patients discontinued from olanzapine therapy for un- satisfactory control of suicidality. None of the clezapine- treated patients were discontinued for this reason, The supportive analysis using the Cox propor tional hazards regression model with treatment, mum- ber of previous suicide atlempts, active substance or al- cohol abuse, country, sex, and age group at baseline in the model demonstrated a 26% reduced risk for suicide attempt or hospitalization to prevent suicide (type I event) for patients randomized to clozapine treatment com- pared with olanzapine treatment (P = 02; hazards ratio, 0.74;05% Cl, 0.57-0.96). Kaplan-Meierestimates for prob” ability of an event were estimated for the 2 treatment groups (Figure). The time in days to observe the frst 70 type 1 events was 185 days for the clozapine-treated patients and 126 days for the olanzapine-treated pa- ents, A significant reduction in the 2-year event rate at the end of the study (olanzapine, 24.0%; 95% CI of the difference, 0.02-0.14; number needed to treat, 12) and a delay in time 10 event were demonstrated for clozapine-treated patients. The num- ber needed to teat of 13 indicates that under similar treat ment conditions, on average, for every 13 high-risk pa- tients treated, suicidal events, as defined herein, would be observed in | less patient ifthey were treated with eloza- pine rather than olanzapine. The overall annualized rate for attempted suicides (including suicide deaths) was 7.19%, with arate of 8.5% for olanzapine-ireated patients and 5.6% for clozapine-treated patients, 1 Association, All rights reserved. ‘Table 6, Adverse Evens of Interest in the Safely Population ‘olanzapine ‘roe var Bret (ns47r _ Pratot ‘i eon T5e51) 11) OS Suicide atop s(n) 66(t88) one Lacan 2d) 1940) < oot Depression NEC 137285) 173(353) ot oo ateraton Sil) en Mood disorder ° ain one Ineomnia EC 9600) 155(325) <001 Samoans 0159) Mae?)

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