revisi aksus di jiwa

7/24/2019 revisi aksus di jiwa

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Efectiveness o PaliperidonePalmitate vs Haloperidol

Decanoate or MaintenanceTreatment o SchizophreniaA Randomized Clinical TrialFREEJoseph P. McEvoy, MD1; Matthew Byerly, MD2; Robert M. Hamer, PhD3;

Rosalie Domii!, DrPH3; Marvi ". "wart#, MD$; Robert %. Rosehec!&; 'eepa Ray, M"3; J.

"teve (amberti, MD); Peter *. B+c!ley, MD1; aia M. -il!is, M"3; . "cott "tro+p, MD,

MPH,/

0 %+thor %liatios

JAMA. 241$;3115167816/916/. :oi814.1441 %RA(E'*CRM%C'> RE*ERE'AE"

!mportance (o@9acti@ i


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ha#ar: ratio, 4.6/; 6& A, 4.)&91.$7. he +mber o participats whoe=periece: ecacy ail+re was $6 533./7 i the paliperi:oe palmitate @ro+pa: $ 532.$7 i the haloperi:ol :ecaoate @ro+p. C avera@e, participats ithe paliperi:oe palmitate @ro+p @aie: wei@ht a: those i the haloperi:ol:ecaoate @ro+p lost wei@ht; ater ) moths, the least9s+ares mea wei@ht

cha@e or those ta!i@ paliperi:oe palmitate was icrease: by 2.1 !@ 56&A, 1.2&93.467 a: was :ecrease: or those ta!i@ haloperi:ol :ecaoate 5N4.6)!@; 6& A, N1.// to N4.4$7. Patiets ta!i@ paliperi:oe palmitate ha:si@iIcatly hi@her ma=im+m mea levels o ser+m prolacti 5me, 3$.&) O@(06& A, 26.&936.3 vs 1&.$1 O@( 06& A, 14.3924.4/; P.441, a: orwome, &.16 06& A, )3.439/.3) vs 2)./$ 06& A, 13.269$4.$4; P.4417.Patiets ta!i@ haloperi:ol :ecaoate ha: si@iIcatly lar@er icreases i @lobalrati@s o a!athisia 54.3 06& A, 4.&694./ vs 4.$& 06& A, 4.3194.&6; P.44)7.Concl'sions and Relevance a:+lts with schi#ophreia or schi#oaFective:isor:er, +se o paliperi:oe palmitate vs haloperi:ol :ecaoate :i: ot res+lt ia statistically si@iIcat :iFerece i ecacy ail+re, b+t was associate: with

more wei@ht @ai a: @reater icreases i ser+m prolacti, whereas haloperi:ol:ecaoate was associate: with more a!athisia. However, the As :o ot r+le o+tthe possibility o a cliically meai@+l a:vata@e with paliperi:oe palmitate.Trial Re%istration cliicaltrials.@ov :etiIer8 'A4113)2

Long-acting injectable antipsychotic medications are prescribed to reduce nonadherence andrelapse in people diagnosed with a schizophrenia-spectrum disorder. Long-acting injectableversions of older antipsychotic medications have been available for decades but their use hasbeen limited in part due to their propensity to cause extrapyramidal symptoms, includingtardive dyskinesia. Beginning in !"!, oral forms of newer antipsychotic medications,considered to entail lower risk of extrapyramidal symptoms, were introduced. #ue to rapidacceptance of the newer oral antipsychotics, long-acting injectable versions of these

medications were anticipated to gain widespread use. $he first of these, risperidonemicrospheres, was introduced in %&&'. (isperidone microspheres, however, must berefrigerated before use, reconstituted with a diluent provided by the manufacturer, andadministered biweekly. )n %&&!, a long-acting version of risperidone*s active metabolite,paliperidone palmitate, was brought to market. +aliperidone palmitate can be administeredmonthly and does not reuire refrigeration or reconstitution. Because of these logisticaladvantages, paliperidone palmitate was considered to be an important advance in long-acting injectable antipsychotic medications, although its high acuisition cost made its roleuncertain.1

)n recent years, head-to-head trials and meta-analyses have called into uestion theadvantages of using atypical antipsychotic medications over older antipsychotics.29 &$he$)/ schizophrenia trial 0linical ntipsychotic $rials of )ntervention /ffectiveness1showed that when an older drug 0perphenazine1 was used at moderate doses, several newerones were not superior in safety or effectiveness.3 recent secondary analysis providedevidence that perphenazine is not inferior to olanzapine, uetiapine, and risperidone withrespect to symptom scores.)2oreover, some newer antipsychotic medications were shownto cause significant weight gain and to be associated with dyslipidemias and diabetesmellitus.,/

$his investigation compared the effects of long-acting injectable paliperidone palmitate andhaloperidol decanoate, an older, widely used long-acting injectable antipsychotic. Based onan earlier comparison of oral risperidone to oral haloperidol decanoate,6we hypothesizedthat paliperidone palmitate would be associated with lower rates of efficacy failure andextrapyramidal symptoms than haloperidol decanoate, but that haloperidol decanoate would

cause less weight gain and less increase in serum prolactin levels.
http://clinicaltrials.gov/show/NCT01136772http://jama.jamanetwork.com/article.aspx?articleid=1872816#joi140053r1http://jama.jamanetwork.com/article.aspx?articleid=1872816#joi140053r2http://jama.jamanetwork.com/article.aspx?articleid=1872816#joi140053r2http://jama.jamanetwork.com/article.aspx?articleid=1872816#joi140053r2http://jama.jamanetwork.com/article.aspx?articleid=1872816#joi140053r2http://jama.jamanetwork.com/article.aspx?articleid=1872816#joi140053r3http://jama.jamanetwork.com/article.aspx?articleid=1872816#joi140053r6http://jama.jamanetwork.com/article.aspx?articleid=1872816#joi140053r6http://jama.jamanetwork.com/article.aspx?articleid=1872816#joi140053r7http://jama.jamanetwork.com/article.aspx?articleid=1872816#joi140053r7http://jama.jamanetwork.com/article.aspx?articleid=1872816#joi140053r8http://jama.jamanetwork.com/article.aspx?articleid=1872816#joi140053r9http://jama.jamanetwork.com/article.aspx?articleid=1872816#joi140053r9http://clinicaltrials.gov/show/NCT01136772http://jama.jamanetwork.com/article.aspx?articleid=1872816#joi140053r1http://jama.jamanetwork.com/article.aspx?articleid=1872816#joi140053r2http://jama.jamanetwork.com/article.aspx?articleid=1872816#joi140053r2http://jama.jamanetwork.com/article.aspx?articleid=1872816#joi140053r3http://jama.jamanetwork.com/article.aspx?articleid=1872816#joi140053r6http://jama.jamanetwork.com/article.aspx?articleid=1872816#joi140053r7http://jama.jamanetwork.com/article.aspx?articleid=1872816#joi140053r8http://jama.jamanetwork.com/article.aspx?articleid=1872816#joi140053r9


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METH"D%B"R%A> MEHCD> RE"("> D"A""C'> AC'A("C'"> %RA(E'*CRM%C'> RE*ERE'AE"

St'd( Settin% and Desi%n

L)23 0 omparison of Long-acting )njectable 2edications for 3chizophrenia1 was amultisite, parallel-group, double-blinded randomized clinical trial. $he study was conductedat %% 43 clinical sites affiliated with the 5ational )nstitute of 2ental 6ealth7supported3chizophrenia $rials 5etwork. /ach site obtained institutional review board approval toconduct the study.

Patients

+atients were adults aged " to 89 years with a diagnosis of schizophrenia or schizoaffectivedisorder as defined by criteria from theDiagnostic and Stastical Manual of MentalDisorders 0:ourth /dition, $ext (evision; DSM-IV-TR1 and confirmed by the 3tructuredlinical )nterview for DSM-IV. +atients were eligible if judged by their clinician and studypsychiatrist as likely to benefit from treatment with paliperidone palmitate or haloperidol

decanoate and to be at risk of efficacy failure based on a history of medicationnoncompliance, significant substance abuse, or both. ll patients demonstrated adeuatedecisional capacity to participate and provided written informed consent.

+atients with the following characteristics were excluded< currently stable and doing wellusing an antipsychotic regimen; not expected to benefit from the study medications due topast experience with risperidone, haloperidol, or paliperidone due to adverse effects or noimprovement of severe symptoms in spite of an adeuate treatment trial of at least 8 weeks*duration; moderate or severe tardive dyskinesia; presence of any medical condition thatmight preclude safe completion of the study; or intellectual disability. =omen who werepregnant or breastfeeding were also excluded.

+atients attended a screening visit. )f potentially eligible, a baseline visit was scheduled

within % days. )f determined eligible at the baseline visit, patients were then randomized ona " mg, > mg, 98 mg, and %'? mg; and injectable haloperidoldecanoate supplied in vials of 9& mg@mL or && mg@mL. /ach participant received a blindedtrial of the oral version of the assigned medication prior to receiving an injection. )n the caseof paliperidone palmitate, the oral trial was with risperidone in accordance with the productlabel. $he oral trial lasted from ? to > days, with each patient recommended to receive % mg

of either haloperidol or risperidone on days and % and ? mg thereafter. 6aloperidol, % mg,and risperidone, % mg, were supplied in identical-appearing capsules. Aral benztropine, mg, was supplied to treat extrapyramidal symptoms if needed. +atients who demonstratedallergy, extrapyramidal symptoms not relieved by benztropine, or other intolerability to theoral trial were dropped from the trial. 3eventeen randomized patients never received theassigned long-acting injectable antipsychotic; only % of these were due to intolerability to theoral medication trial. $he first injection was given ? to > days after the baseline visit.3ubseuent visits were at weeks , %, ?, 8, ", &, and %, then monthly 0every ? weeks1 for upto %? months.

$reatment condition was blinded from study physicians and all other personnel. 3tudyphysicians wrote orders for both of the potential long-acting injectable antipsychoticmedications 0eg, if haloperidol decanoate, administer 9& mg intramuscularly; if paliperidonepalmitate, administer > mg intramuscularly1. /ach patient was then injected with only the
http://jama.jamanetwork.com/article.aspx?articleid=1872816#Abstracthttp://jama.jamanetwork.com/article.aspx?articleid=1872816#Methodhttp://jama.jamanetwork.com/article.aspx?articleid=1872816#Resultshttp://jama.jamanetwork.com/article.aspx?articleid=1872816#Discussionhttp://jama.jamanetwork.com/article.aspx?articleid=1872816#Conclusionshttp://jama.jamanetwork.com/article.aspx?articleid=1872816#ArticleInformationhttp://jama.jamanetwork.com/article.aspx?articleid=1872816#ArticleInformationhttp://jama.jamanetwork.com/article.aspx?articleid=1872816#Referenceshttp://jama.jamanetwork.com/article.aspx?articleid=1872816#Abstracthttp://jama.jamanetwork.com/article.aspx?articleid=1872816#Methodhttp://jama.jamanetwork.com/article.aspx?articleid=1872816#Resultshttp://jama.jamanetwork.com/article.aspx?articleid=1872816#Discussionhttp://jama.jamanetwork.com/article.aspx?articleid=1872816#Conclusionshttp://jama.jamanetwork.com/article.aspx?articleid=1872816#ArticleInformationhttp://jama.jamanetwork.com/article.aspx?articleid=1872816#ArticleInformationhttp://jama.jamanetwork.com/article.aspx?articleid=1872816#References


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randomly assigned drug. clinician not otherwise involved in the trial administered theinjection and concealed the identity of the medication from the patient and study personnel.

$he loading strategy schedule described in the paliperidone palmitate prescribinginformation was recommended for both drugs. $he recommended starting dose ofpaliperidone palmitate was %'? mg intramuscularly on day followed on day " with 98 mg

intramuscularly. $he recommended standard monthly dose of paliperidone palmitate was> mg intramuscularly. $he recommended starting dose of haloperidol decanoate was 9&mg intramuscularly on day followed on day " with 9& mg intramuscularly. An day %", therecommended dose of haloperidol decanoate was >9 mg intramuscularly, to be followed onday 98, and on subseuent monthly visits with 9& mg intramuscularly. $he first % injectionswere given in the deltoid 0day and day "1. 3ubseuent monthly injections were given in thedeltoid or gluteal muscle. $he recommended injection schedules were adjusted according tothe clinical situation. :or the first " weeks, clinicians were allowed to supplement the long-acting injectable with any oral antipsychotic as needed.

)f there were a desire to continue providing the study treatment drug to the patient when thefollowing criteria were met< new-onset diabetes mellitus, weight gain of at least 9 pounds,increase in low-density lipoprotein 0L#L1 cholesterol of at least %& mg@dL, worsening tardivedyskinesia, hospitalization, clinical worsening as indicated by the linical lobal)mpressions scale, or any serious adverse event, investigators were reuired to consult withthe project*s safety officer 0a physician from whom treatment assignment was blinded1. fterthe safety officer reviewed the case, study medication was continued if the clinicianconsidered it in the best interest of the patient to continue and the patient and safety officerconcurred.

"'tcome Meas'res

$he primary outcome was efficacy failure, which reflected inadeuate control of thepsychopathology of schizophrenia or schizoaffective disorder. /fficacy failure wasdetermined for each study participant by an outcome adjudication committee consisting of 'research psychiatrists who were blind to treatment assignment and not otherwise involved in

the study. majority vote of the committee determined whether and when a participantexperienced efficacy failure. $he criteria considered for efficacy failure included psychiatrichospitalization; a need for crisis stabilization; a clinically meaningful increase in freuency ofoutpatient visits; a clinician*s decision that oral antipsychotic medication could not bediscontinued within " weeks after starting the long-acting injectable; a clinician*s decision todiscontinue the assigned long-acting injectable due to inadeuate therapeutic benefit; or, forpatients successfully transitioned to receive a study long-acting injectable drug within "weeks, ongoing or repeated need for adjunctive oral antipsychotic medication.

3econdary outcome measures included change in weight from baseline and worst changes infasting blood glucose, glycated hemoglobin, cholesterol, and triglycerides. $he worst changes0eg, highest recorded level of triglycerides, lowest recorded levels of high-density lipoprotein

C6#LD1 were used for these laboratory-measured outcomes because interventions to treatabnormalities were allowed. :or prolactin, the highest recorded level after baseline was theoutcome. Ather important secondary outcomes included measures of abnormal involuntarymovements, akathisia, parkinsonism, and sexual functioning. =eight and measures ofneurologic adverse effects were obtained at all study visits. Laboratory blood tests wereobtained at screening, months ' and 8, and then every 8 months. +atients weresystematically ueried about % adverse effects commonly associated with antipsychoticmedications at each visit. 3ymptoms were measured using the +ositive and 5egative3yndrome 3cale 0+5331 at baseline and then every ' months. $he scoring range for +533is '& to %&, with higher scores reflecting greater severity of psychopathology.

Statistical Methods

$he primary analysis was conducted among the modified intent-to-treat population, whichconsisted of all patients who received at least injection and at least postbaselineassessment. $he Eaplan-2eier method was used to estimate the proportion without efficacy


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failure by assessing time since first injection and using a site-stratified 0%-sided1 log-rank testfor the primary comparison of time until efficacy failure. )n the primary analysis, patientswere censored !& days after their last injection to account for the time most likely affected bythe long-acting study medications. +lanned supporting and sensitivity analyses includedestimating the hazard ratio 06(1 and !9F ) using a ox proportional hazards model0controlling for baseline +533 score and site1; repeating the site stratified log-rank testwithout censoring !& days after last injection; and conducting an unstratified log-rank test.$he ox model was expanded to test for site by treatment interaction and to test whether the6( for treatment was eual across ' predefined time intervals< months to ', months ? to%, and months ' to %?.14$he site-stratified log-rank test was repeated for one subgroupdefined a priori; participants who were not in an exacerbated state 0ie, not hospitalized1 atrandomization. ll main effects of treatment and treatment-by-site interactions for safetyanalyses were tested at the %-sided G H.&9 level. :or efficacy, interactions were tested at theG H.& level.

3afety analyses excluded data collected more than 8 weeks after a participant*s last injection.2ixed-effect linear models 0with spatial power covariance structure1 were used to compareweight change over time. :ixed effects were included for assigned treatment, clinical site,

baseline weight, time 0months since first injection1 and treatment-by-time interaction. $heproportion of patients whose weight increased at least 9 pounds from baseline wascompared using a 2antel-6aenszel I2test. nalysis of covariance 05AJ1 was used formetabolic analyses, with the worst-case change as the outcome and treatment, site, andbaseline value as covariates.

$he same 5AJ approach was used for comparisons of worst bnormal )nvoluntary2ovement 3cale 0)231 global score, Barnes kathisia 3cale 0B31 global score, and3impson-ngus /xtrapyramidal 3cale 0331 score. )ncidence of clinically significant scoreson ' different assessments 0ie, )23 global score K%, B3 global score K', and 33 scoreK111were compared between treatment groups using 2antel-6aenszel I2tests, excludingpatients who had a clinically significant score at baseline. s a posthoc analysis, the

proportions meeting 3chooler-Eane criteria for tardive dyskinesia 0at least moderatedyskinetic movements in body area or mild dyskinetic movements in % body areas112werecompared using 2antel-6aenszel I2tests, excluding patients who met criteria at baseline.

:or prolactin and associated adverse effects, separate analyses were planned for men andwomen. $he key comparisons used analysis of variance 05AJ1 to compare the highestrecorded prolactin level as the response, with treatment and site as covariates. 3upportinganalyses compared incidence of associated abnormalities 0eg, gynecomastia or galactorrhea1between treatment groups using a 2antel-6aenszel I2test or the Barnard exact test 0if &events were observed1 and highest rizona 3exual /xperiences 03/M1 scale score using5AJ.

$he original plan to randomize a total of '8& patients and follow-up for % years was modified

due to resource constraints. $he recruitment period was 2arch %&-Nuly %&%; follow-upended in Nuly %&'. 4ltimately, ' individuals were randomized. $he earliest enrollees werefollowed-up for as many as %? months and the last enrollees for as many as % months. $heplanned sample size was expected to provide at least "&F power to detect a difference insurvival curves 0%-sided log-rank test, G H.&91, assuming efficacy failure rates of &.98 and&.?& for the haloperidol decanoate and paliperidone palmitate groups, respectively 0ie, an6( of .81. nalyses were performed using 33 statistical software version !.' 033 )nstitute)nc1.

RES)*TS%B"R%A> MEHCD> RE"("> D"A""C'> AC'A("C'"> %RA(E'*CRM%C'> RE*ERE'AE"
http://jama.jamanetwork.com/article.aspx?articleid=1872816#joi140053r10http://jama.jamanetwork.com/article.aspx?articleid=1872816#joi140053r11http://jama.jamanetwork.com/article.aspx?articleid=1872816#joi140053r12http://jama.jamanetwork.com/article.aspx?articleid=1872816#Abstracthttp://jama.jamanetwork.com/article.aspx?articleid=1872816#Methodhttp://jama.jamanetwork.com/article.aspx?articleid=1872816#Resultshttp://jama.jamanetwork.com/article.aspx?articleid=1872816#Discussionhttp://jama.jamanetwork.com/article.aspx?articleid=1872816#Conclusionshttp://jama.jamanetwork.com/article.aspx?articleid=1872816#ArticleInformationhttp://jama.jamanetwork.com/article.aspx?articleid=1872816#ArticleInformationhttp://jama.jamanetwork.com/article.aspx?articleid=1872816#Referenceshttp://jama.jamanetwork.com/article.aspx?articleid=1872816#joi140053r10http://jama.jamanetwork.com/article.aspx?articleid=1872816#joi140053r11http://jama.jamanetwork.com/article.aspx?articleid=1872816#joi140053r12http://jama.jamanetwork.com/article.aspx?articleid=1872816#Abstracthttp://jama.jamanetwork.com/article.aspx?articleid=1872816#Methodhttp://jama.jamanetwork.com/article.aspx?articleid=1872816#Resultshttp://jama.jamanetwork.com/article.aspx?articleid=1872816#Discussionhttp://jama.jamanetwork.com/article.aspx?articleid=1872816#Conclusionshttp://jama.jamanetwork.com/article.aspx?articleid=1872816#ArticleInformationhttp://jama.jamanetwork.com/article.aspx?articleid=1872816#ArticleInformationhttp://jama.jamanetwork.com/article.aspx?articleid=1872816#References


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*i@+re 1summarizes the progress of patients who were screened and randomly assigned toeach group. Baseline demographic and clinical characteristics of the ?9 paliperidonepalmitate and ?9 haloperidol decanoate patients in the primary analysis are inable 1.+atients were followed-up for a median of ?"" days 0%9th->9th percentile, %%9-8?91.

Fi%'re +,

Participant Enrollment and Follow-up

a3ubsets may not sum because some participants were counted among those who withdrew prematurely and also among

those who discontinued treatment. )ntent was to provide follow-up even after participants discontinued receivinginjections, whether they withdrew from the study or not.

?iew (ar@e > "ave *i@+re > Dowloa: "li:e 5.ppt7
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Ta#le +, Baselie Demo@raphic a: Aliical Aharacteristics o Patiets i the

Mo:iIe: tet9to9reat Pop+latio


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?iew (ar@e > "ave able > Dowloa: "li:e 5.ppt7

Dose

)n the initial month of long-acting injectable treatment, which included doses on day andday ", the mean dose of paliperidone palmitate was '%9 mg and of haloperidol decanoate !?mg. 3ubseuently the mean monthly dose of paliperidone palmitate ranged from %! to 8!mg and the mean monthly dose of haloperidol decanoate ranged from 8> to "' mg.

E-cac( Fail're
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)n the primary analysis, there was no statistically significant difference in the rate of efficacyfailure for patients in the paliperidone palmitate group 0?! C''."FD1 vs those in thehaloperidol decanoate group 0?> C'%.?FD; site-stratified log-rank PH.!&; site and baseline+533 adjusted 6(, &.!" C!9F ), &.89-.?>D1 0*i@+re 21. (esults of all preplannedsensitivity and supporting analyses led to similar conclusions 0e$able in 3upplement1.(easons for efficacy failure are in e$able % 0in 3upplement1. $he most common reasons forefficacy failure noted by the outcome ajudication committee were psychiatric hospitalization0?? C"!."FD of paliperidone palmitate events and '? C>%.'FD of haloperidol decanoate ones1and clinician discontinuation of study medication due to inadeuate therapeutic effect 0'?C8!.?FD paliperidone palmitate events and %" C9!.8FD haloperidol decanoate ones1.

Fi%'re .,

Time to Efficacy Failure

djusted hazard ratio for paliperidone palmitate vs haloperidol decanoate, &.!" 0!9F ), &.89-.?>1. /fficacy failure,determined by an outcome adjudication committee, reflected inadeuate control of psychopathology.

?iew (ar@e > "ave *i@+re > Dowloa: "li:e 5.ppt7

Secondar( "'tcomes

An average, participants taking paliperidone palmitate gained weight progressively overtime, while those taking haloperidol decanoate lost weight. :or example, at month 8, the

least-suares mean weight change for participants in the paliperidone palmitate group wasincreased %.> kg 0!9F ), .%9 to '.&!1 and for the haloperidol decanoate group was
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decreased O&.!8 kg 0O."" to O&.&?1 0able 21. $he test of time-by-treatment interactionshowed statistically significant treatment group differences 0P.&&&1. 3even patientstaking paliperidone palmitate 0?."F1 compared with % 0.?F1 in the haloperidol decanoategroup discontinued treatment due to weight gain.

Ta#le ., C+tcome Meas+res o "aety i the Mo:iIe: tet9to9reat Pop+latio

$here were no statistically significant differences between those treated with paliperidonepalmitate and haloperidol decanoate in mean change to the highest recorded levels ofglycated hemoglobin 06b1c1, glucose, total cholesterol, L#L cholesterol, and triglycerides;or in the lowest recorded levels of 6#L cholesterol.
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$here were no statistically significant differences in changes in ratings of abnormalinvoluntary movements as indicated by change from baseline score in the )23 global score0&.?' C!9F ), &.'-&.99D for paliperidone vs &.9& C!9F ), &.'"-&.8%D for haloperidoldecanoate; PH.'!;able 21. $here was no statistically significant difference in the incidenceof probable tardive dyskinesia 09 in the paliperidone palmitate group C&.8FD and % in thehaloperidol decanoate group C9.?FD, PH.%?1. +articipants taking haloperidol decanoateexperienced greater increases in B3 global scores 0&.?9 C!9F ), &.'-&.9!D for those in thepaliperidone palmitate group vs &.>' C!9F ), &.9!-&.">D for the haloperidol decanoategroup; PH.&&81. $here was no statistically significant difference in changes in ratings ofparkinsonism, as measured by the mean 33 score 0&.% C!9F ), &.8-&.%>D for thepaliperidone palmitate group vs &.%9 C!9F ), &.%&-&.'&D for the haloperidol decanoategroup; PH.'?1. :ewer patients taking paliperidone palmitate than haloperidol decanoatestarted a medication to treat parkinsonism 0" C9."FD vs %> C%!.'FD; PH.&&>1 and akathisia09 C'.8FD vs 8 C.&FD; PH.&'1.

$reatment discontinuations due to neurologic adverse effects according to clinicianjudgment were as follows< % patients 0.?F1 in the haloperidol decanoate group vs 0&.>F1 inthe paliperidone palmitate group due to akathisia; ' 0%.&F1 in haloperidol decanoate group

vs 0&.>F1 in the paliperidone palmitate group due to parkinsonism; and ? 0%.>F1 in thehaloperidol decanoate group vs 0&.>F1 in the paliperidone palmitate group due to tardivedyskinesia.

mong men, the highest mean prolactin level 03) unit conversion factor, multiply by ?'.?>"for pmol@L1 was higher for paliperidone palmitate 0'?.98 Pg@L; !9F ), %!.>9 to '!.'>1 thanhaloperidol decanoate 09.? Pg@L; !9F ), &.>' to %&.&"1 0P.&&1 and in women, thehighest mean prolactin level was higher for the paliperidone palmitate group 0>9.! Pg@L;!9F ), 8'.&' to ">.'81 than haloperidol decanoate 0%8."? Pg@L; !9F ), '.%! to ?&.?&1 0P.&&1. $here were no statistically significant differences in the proportions takingpaliperidone palmitate or haloperidol decanoate who had a score on the rizona 3exual/xperiences scale of at least !, which indicates sexual dysfunction for men or women. $here

were no significant differences in the incidence of gynecomastia or galactorrhea for men orwomen.

Averall, 8".&F of patients in the paliperidone palmitate group, compared with 9!.!F ofthose in the haloperidol decanoate group, reported at least adverse effect rated as moderateor severe 0able 31. mong the individual event types, 8.'F of patients taking paliperidonepalmitate compared with &.!F in the haloperidol decanoate group developed sialorrhea.$his is the only adverse event with a difference of 9F or more between the groups. 3eventy-six 09.>F1 of patients in the paliperidone palmitate group experienced serious adverseevents compared with 88 0??.!F1 in the haloperidol decanoate group. Ane male participantin his sixties died of unknown causes approximately 8 weeks after his last haloperidoldecanoate injection.

Ta#le /, %:verse Evets i the tet9to9reat Pop+latio
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#ecreases in +533 total scores from baseline were similar for both groups at each timepoint 0see e:igure in 3upplement1. :or example, at month 8, the least-suares mean+533 change was O8."> 0!9F ), O".>! to O?.!?1 for paliperidone palmitate and O8.?&0!9F ), O".'% to O?.?"1 for haloperidol decanoate. )n addition, as seen in *i@+re 1,rates oftreatment discontinuation due to any cause 0&?@?> C>&.>FD for the paliperidone palmitategroup and &@?> C8".>FD for the haloperidol decanoate group1 and due to unacceptableadverse effects 09@?> C&.%FD for the paliperidone palmitate group and ?@?> C!.9FD forthe haloperidol decanoate group1 were similar.

D!SC)SS!"0%B"R%A> MEHCD> RE"("> D"A""C'> AC'A("C'"> %RA(E'*CRM%C'> RE*ERE'AE"

$his randomized clinical trial found no evidence that long-acting injectable paliperidonepalmitate was superior to haloperidol decanoate with respect to prevention of efficacyfailure. 6owever, based on the !9F )s for the event rates, the results cannot rule out aclinically meaningful difference favoring one of the drugs.

ontrary to expectations, there was no statistically significant advantage for paliperidonepalmitate when compared with haloperidol decanoate in ratings of the severity of abnormalinvoluntary movements and parkinsonism, or in the incidence of tardive dyskinesia.6owever, ratings of the severity of akathisia increased more for haloperidol decanoate, andmore medications to manage akathisia and parkinsonism were started for patients in thehaloperidol decanoate group, partially confirming that paliperidone palmitate has a lower

propensity to cause extrapyramidal symptoms than haloperidol decanoate. $he current studywas informed by studies from the !"&s that compared standard doses of typical long-actinginjectable antipsychotic medication with lower doses and found that patients* symptoms
http://jama.jamanetwork.com/article.aspx?articleid=1872816#joi140053f1http://jama.jamanetwork.com/article.aspx?articleid=1872816#joi140053f1http://jama.jamanetwork.com/article.aspx?articleid=1872816#Abstracthttp://jama.jamanetwork.com/article.aspx?articleid=1872816#Methodhttp://jama.jamanetwork.com/article.aspx?articleid=1872816#Resultshttp://jama.jamanetwork.com/article.aspx?articleid=1872816#Discussionhttp://jama.jamanetwork.com/article.aspx?articleid=1872816#Conclusionshttp://jama.jamanetwork.com/article.aspx?articleid=1872816#ArticleInformationhttp://jama.jamanetwork.com/article.aspx?articleid=1872816#ArticleInformationhttp://jama.jamanetwork.com/article.aspx?articleid=1872816#Referenceshttp://jama.jamanetwork.com/article.aspx?articleid=1872816#joi140053f1http://jama.jamanetwork.com/article.aspx?articleid=1872816#Abstracthttp://jama.jamanetwork.com/article.aspx?articleid=1872816#Methodhttp://jama.jamanetwork.com/article.aspx?articleid=1872816#Resultshttp://jama.jamanetwork.com/article.aspx?articleid=1872816#Discussionhttp://jama.jamanetwork.com/article.aspx?articleid=1872816#Conclusionshttp://jama.jamanetwork.com/article.aspx?articleid=1872816#ArticleInformationhttp://jama.jamanetwork.com/article.aspx?articleid=1872816#ArticleInformationhttp://jama.jamanetwork.com/article.aspx?articleid=1872816#References


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could be successfully controlled at these lower doses without relapse and withoutextrapyramidal toxicities.139 1&3imilarly, the $)/ schizophrenia trial found that modestdoses of typical oral antipsychotic medication could be used effectively without excessiveextrapyramidal symptoms.3$he modest dose of haloperidol decanoate used here,approximately >9 mg intramuscularly per month, is lower than the euivalent oral dosageused in a trial that found an advantage of oral risperidone over oral haloperidol.6)n thatstudy, the mean 03#1 daily dose of haloperidol decanoate was .> 09.&1 mg, whereas in thisstudy, using a standard conversion from oral haloperidol to haloperidol decanoate of & to 9times the daily dose, the corresponding daily dose is approximately 9.& to >.9 mg. $hemodest dosing of haloperidol decanoate in this study is consistent with currentrecommendations and may help to account for its better-than-expected comparativetolerability. )t was unexpected that the relapse rate was similar to that in the earlier study,comparing oral risperidone with oral haloperidol, considering that the current study enrolledpeople at increased risk of nonadherence and relapse. Ane reason may be that the outcomein the oral trial, which was relapse, was somewhat broader than the definition of efficacyfailure used here. nother possible reason is that long-acting injectable antipsychoticmedications are more useful than oral ones in preventing relapse, but this uestion was notaddressed in our study. $he higher doses of haloperidol in the prior study may have had anegative effect on its tolerability and, conseuentially, its effectiveness.

/arly termination of the study*s follow-up period, which meant that patients enrolled duringthe second year of the study were followed-up for at least year but less than the planned %years, had little effect on statistical power for the primary outcome because the risk ofefficacy failure during the second treatment year was low. 6owever, the early terminationmay have resulted in less reliable estimates of weight change at later time points.

$he study did not include a comparison with an oral antipsychotic medication. t the timethis study was begun, % randomized clinical trials comparing oral and long-acting injectableantipsychotic medications were underway. 5either of these studies found an advantage oflong-acting injectable antipsychotics over oral ones in reducing hospitalizations.1),1$he

only of these to be published to date had rates of hospitalization 0?9F for oral medicationand '!F for long-acting injectable over % years1 that are similar to the current study.1)

5evertheless, the use of long-acting injectable antipsychotic medications is supported bysome systematic reviews1/,16and expert panels24,21for outpatients at increased risk ofrelapse. limitation is that the study did not include subjective measures of medicationsatisfaction or global well-being. )n addition, this study did not address current costdifferences for payers, which may be substantial as paliperidone palmitate is still on patentwhile haloperidol decanoate is available as a generic drug.

C"0C*)S!"0S%B"R%A> MEHCD> RE"("> D"A""C'> AC'A("C'"> %RA(E

'*CRM%C'> RE*ERE'AE"mong adults with schizophrenia or schizoaffective disorder, treatment with paliperidonepalmitate, compared with haloperidol decanoate, did not result in a statistically significantdifference in efficacy failure, but the results do not rule out the possibility of a clinicallymeaningful difference. $he results are consistent with previous research that has not foundlarge differences in the effectiveness of newer and older antipsychotic medications.

ART!C*E !0F"RMAT!"0%B"R%A> MEHCD> RE"("> D"A""C'> AC'A("C'"> %RA(E'*CRM%C'> RE*ERE'AE"

Correspondin% A'thor1$. 3cott 3troup, 2#, 2+6, olumbia 4niversity ollege of+hysicians and 3urgeons, 5ew Qork 3tate +sychiatric )nstitute, (oom %>&', Box &&, &9(iverside #r, 5ew Qork, 5Q &&'% 0stro+psQyspi.col+mbia.e:+1.
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A'thor Contri#'tions1#r 3troup had full access to all of the data in the study andtakes responsibility for the integrity of the data and the accuracy of the data analysis.Study concept and design:2c/voy, Byerly, 6amer, 3wartz, (osenheck, 3troup.

Acquisition analysis or interpretation of data:2c/voy, Byerly, 6amer, #ominik,3wartz, (osenheck, (ay, Buckley, Lamberti, =ilkins, 3troup.Drafting of t!e "anuscript:

2c/voy, Byerly, 6amer, #ominik, 3wartz, 3troup.#ritical re$ision of t!e "anuscript for i"portant intellectual content:2c/voy,Byerly, 6amer, #ominik, 3wartz, (osenheck, (ay, Buckley, Lamberti, =ilkins, 3troup.Statistical analysis:6amer, #ominik, (ay, =ilkins.%&tained funding:2c/voy, Byerly, 6amer, 3wartz, 3troup.

Ad"inistrati$e tec!nical or "aterial support:2c/voy, 3wartz, (osenheck, 3troup.Study super$ision:2c/voy, 6amer, #ominik, 3wartz, =ilkins, 3troup.Con2ict o !nterest Disclos'res1ll authors have completed and submitted the)2N/ :orm for #isclosure of +otential onflicts of )nterest. #rs 2c/voy, Byerly, 6amer,and 3troup report receipt of a grant from the 5ational )nstitute of 2ental 6ealth 05)261.#r 2c/voy reports receipt of a grant from 2erck, 3unovion, (oche@enentech,laxo3mithEline 0outside submitted work1, and +sychogenics 0outside submitted work1; and

personal fees 0speaking honoraria1 from Lilly, 2erck, and 3unovion; and personal fees forconsulting from Atsuka, (oche@enentech, /nvivo, and lkermes. #r Byerly reports receiptof research support from Atsuka; a grant from 3unovion 0outside the submitted work1; andpersonal fees from Nanssen, 2erck, 5ovartis, Atsuka, and Bristol-2yers 3uibb. #r 6amerreports receipt of personal fees 0data safety and monitoring board1 from 5ovartis, (oche,+rotein 3ciences, lkermes, llergan, bbot@bvie, Bioline, and olumbia 4niversity,0clinical trials consulting1 from Lilly, straReneca, #uke 4niversity,enerx, and 5ational4niversity of 3ingapore@#uke, 0expert witness1 from =inston and 3trawn, 3heppard 2ullin,(akoczy 2olino 2azzochi 3iwik, and oldberg 3egalla, 0grant review panel1 from Jeteransdministration, and 0mock advisory panel1 from $itan, and 5eurogex outside the submittedwork. #r 3wartz reports receipt of personal fees for consulting from 2ed-)S outside thesubmitted work. #r (osenheck reports receipt of personal fees 0expert witness1 in Nones ex

rel the 3tate of ttorney enera of $exas in Te'as $ Janssen P!a"aceutica et al, and0consultant1 from Atsuka outside the submitted work. #r Buckley reports receipt of grantsand personal fees 0#32B and federal reviews1 from 5)26, and grants from meritox and+osit 3cience outside the submitted work. #r 3troup reports participation in 2/ activitiesfunded by enentech outside the submitted work. #rs #ominik and Lamberti and 2ss (ayand =ilkins report no disclosures.The ollowin% investi%ators cond'cted the st'd(1Lawrence dler, lenBurnie, 2#; +eter Buckley, ugusta, ; 2atthew Byerly, #allas, $M; 3tanley aroff,+hiladelphia, +; herilyn #e3ouza, Eansas ity, 2A; #ale #*2ello, Lansing, 2); #eepak#*3ouza, 5ew 6aven, $; :red Narskog, hapel 6ill, 5; Jenkata Nasty, #etroit, 2); /ricEonicki, leveland, A6; 2atthew 2acaluso, =ichita, E3; N. 3teven Lamberti, (ochester, 5Q;Noshua Eantrowitz, 5ew Qork, 5Q; Noseph 2c/voy, Butner, 5; #el 2iller, )owa ity, );

(obert 2illet, #urham, 5; 2ax 3chubert, =aco, $M; 2artin 3trassnig, 2iami, :L; 3riram(amaswamy, Amaha, 5/; ndre $app, $acoma, =; 3arah Qasmin, +alo lto, .F'ndin%3S'pport1$he study was funded by grants from 5)26 to #rs 2c/voy and3troup.Role o the Sponsors15)26 had no role in the design and conduct of the study, inthe collection, analysis, and interpretation of the data, and in the preparation, review, orapproval of the manuscript. $he funder had no role in the decision to submit the manuscriptfor publication. #32B convened by 5)26 monitored the study. 5)26 grant funds paidfor all study medications.Additional Contri#'tions1$he authors thank dam 6aim, +h#, and Noanne 3evere,23, of 5)26 for their support during the project. 5either individual received additionalcompensation in association with work on this article.Correction1 $his article was corrected on 2ay %&, %&?, to fix a denominator in the3econdary Autcomes section, and corrected on Nuly ', %&?, to fix a typographical error.


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REFERE0CES%B"R%A> MEHCD> RE"("> D"A""C'> AC'A("C'"> %RA(E'*CRM%C'> RE*ERE'AE"

+itrome L. +aliperidone palmitateTreview of the efficacy, safety and cost of a new second-generation depot antipsychotic medication. Int J #lin Pract. %&&;8?0%1'0!89>1


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+:A*Suigley N, +essione :. 3core tests for homogeneity of regression effect in the proportionalhazards model. io"etrics. !"!;?901 Link to Article

+.3chooler 5(, Eane N2. (esearch diagnoses for tardive dyskinesia.Arc! *en Psyc!iatry.!"%;'!0?1


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2oore $, Buchanan (=, Buckley +:, et al. $he $exas 2edication lgorithm +rojectantipsychotic algorithm for schizophrenia< %&&8 update.J #lin Psyc!iatry.%&&>;8"019->8%.

PubMed > Link to Article

.+Buchanan (=, Ereyenbuhl N, Eelly #L, et al; 3chizophrenia +atient Autcomes (esearch$eam 0+A($1. $he %&&! schizophrenia +A($ psychopharmacological treatmentrecommendations and summary statements. Sc!i)op!r ull. %&&;'801-!'.

PubMed > Link to Article
http://www.ncbi.nlm.nih.gov/pubmed/18052569http://dx.doi.org/10.4088/JCP.v68n1115http://www.ncbi.nlm.nih.gov/pubmed/19955390http://dx.doi.org/10.1093/schbul/sbp116http://www.ncbi.nlm.nih.gov/pubmed/18052569http://dx.doi.org/10.4088/JCP.v68n1115http://www.ncbi.nlm.nih.gov/pubmed/19955390http://dx.doi.org/10.1093/schbul/sbp116

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