l l l r f
`
`i !
`
`
`Effects of the Clozapme Nauonal
`Re’stry System onInadence of
`Deaths Related to Agr
`
` * OCYtOSlS
`
`4‘ Gilbert Honigfeld, PILD.
`
`
`
`’ This material may be protected by Copyright law (Title 17 U.S. Code) I
`
`Obfectioe:Clozapine is the only medication distributedIn the U.5‘. through a
`national patient registry system that provides the medication only ifres‘ults of
`patients' weekly blood tests show no evidence of significant whiteblood cell
`suppression, an effect that can be fated if it progresses to advanced. agranulo-
`cytosis. This study assessed morbidity and mortality related to agrauuibeytu-
`sis during the first five years of the national registry system Metiggrls.‘ Data
`liomthe national registry database maintained by the U..S manufacturer of
`clozapine was used to determine the level of treatingsystems' adherenceto
`the mandated program of weekly white blood cell cau‘nts, number at?In-
`stances in which clozapine treatment was denied because of-prior detenni-
`nation of white blood cell suppression, and number ofcases oFaflr-Inulocyto—
`sis.a-nd'dmldls related to agrauuloeytusis among treated patientsfrom Fehm-
`ary l990, when clorapine was commercially inhoduCed.m- the US, through
`December 1994. The actual numbers of cases of agranulncymsis and related
`deaths were compared with expected outcomes basal on clinical research
`done before the drug became available commercially-Refldts: Approximate—
`1y 97 percent of treating systems had a high overalllevel ofadherenceto the
`registry protocol. In 28 instances, the pretreatment authorization require-
`ment resultedIn denial of clozapine; after additional data were considered
`15 of the patients were cleared for treatment. The actual incidences of-332 ‘
`cases of agranulocytosis and 12 related deaths were lower than theexpec'tc'd -
`995 cases and 149 deaths Mom: The clozapine nationalregistrysystem
`fostered early detection of white blood cell suppression, prevented retreat-
`ment with clozapine of patients who had previously developed white blood
`cell suppression, and brought about lower than expected rates ofagranuloey-
`tosis and associated deaths. (Psychiatric Services 47:52—56,1996)
`
`Dr. Hafigfeld-is asmiate professor In the
`department of psychiatry at the lichen
`Woodjohnwn Medial! School of the Unit
`varsity of Medicine and Dentistry of New
`jersey. 675 Hoes Lane. Pisratmmy, New
`Jersey 08854; He sewed as consultant to
`Samla: thriaceuticuls Corporation at
`theptime ofthe study.
`
`n 1990, approximately 5 million
`persons in the United States .suf-
`feted from severe "IIIeIItal disor-
`ders. Of those, more than half, about
`2.5 million had Schizophrenia '61).
`Among persons with schizophrenia,
`between [0 and 30 percent do not re-
`spond adequately to standard anti-
`psychotic agents, bemuse fliesagents
`have suboptimalfefiicaey nr: intolera-
`ble adverse effects.(2). Thus between
`ammo and mmOIremmehe-esi's-
`[ant persons with schizophrenia re:
`
`sideIn the Um't'ed States They repre—
`sent potential candidates For
`treat-
`ment with clowpino, an atypical 811-
`fipsychoh‘c medication indicated for
`the treatment-resistant patient. Asof
`December 31, 1994. u total'of 99,509.
`patients in the US. had’been exposed
`to clumpine. andmore than half of
`them remained on the medication at
`that time.
`Increased public interest in clum-
`pine and . enhanced Familiarity of
`physicians with the medication make
`itlikely that thempwtic use of claim-
`pine will become more mm-mI-m in
`"the coming yew. However, chim-
`pine use is associated with risk of
`,agrauuloeytosis, a potentially fatal
`blood disotder that is usually to-
`versihle if detected early enough.
`Liuu‘tatI'ons-hr social and medial sup-
`port networks for peIsous with severe
`Intentai
`illness. underscore the need
`forprooedums‘to help saicgumtl [his
`vulnerable patient group From such
`adverse side elfects.
`
`V in keeping with gen-am! principles
`developed by the Food and D mg-Ade
`ministration current procedures lot
`distribution (If clamping stipulate
`that the meditation:5 availableIn the
`U. 5. only through tIezIIment systems
`registered with the national legistry
`developed and maintained by, the -
`US. manufiicturer of clozapine. The
`purposelof the registry is to enhance
`patients-Ida}: by. facilitating early (it?
`.tection. ofpot'entially dangerous white
`blood- cell suppression, dispensing-
`dle mmiicat'ion' only to patients with
`current blood tests, delineating re—
`
`52
`
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`sponsibilities for patient monitoring,
`and eliminating as candidates for
`therapy anyOne with a history of
`clozapine-relatcd white blood cell
`suppression.
`All potential candidates fiir the
`mcdication must be cleared through
`the national registry to identify per-
`sons who have had significant clou—
`pine-relatcd while blood cell sup-
`pression in the past and who should
`not receive the medication again be»
`muse of markedly increased risk of
`agranulocytosis. White blood cell
`counts an: normally 5.000 per cubic
`millimeter or greater. A white blood
`cell count behaw 3,500 per cubic mil-
`limeter itu‘licflles leulmpeuizi, a condi-
`[ion of mild white. blood cell suppres—
`sion that is generally reversible upon
`interruption of clozapine therapy.
`Agrnmrlocytosis, a potentially final
`complication, is-indicated by a white
`blood cell count below 2,000 and de—
`fined by an absolute neutrophil count
`below 500 per cubic millimeter. Dis—
`continuation ofcloupine is mandato-
`ry for patients with agranulocytosis
`luause they are at high risk of death
`secrmdary to a wide range of oppor-
`tunistic infections.
`The registry system requires all pa.-
`ticnts to have a baseline white blood
`cell count and weekly white blood
`cell counts throughout
`treatment
`with clozapinc and for four weeks af-
`ter trenhnmit ends. The meditation is
`
`dispensed weekly only to patienls for
`whom data on current white blood
`cell counts are available. The registry
`system also outlines the rcspousibilh
`ties of physicians, pharmacies, pa—
`tients, and the medication} manufac—
`turer and wholesale distributors in
`
`ensuring proper use of the medica-
`tion. Distribution of the medication is
`
`limited to registered pharmacies,
`Which agree to follmv the “no
`blood—no drug" guidelines.
`Treatment systems that fail to Fulfill
`their obligations to report results of
`Weekly monitoring of patients white
`blood cell counts are contacted by na-
`tional registry staff. who explain the
`risks of clozapine therapy and the re-
`quirements for weekly monitoring.
`Subsequently, national registry stall
`follow up with the physicians and
`pharmacists involved to verify that
`the-problems have been corrected.
`
`This paper discusses clinical prac—
`tice related 'to the clovapine national
`registry system reports on die inci-
`dence of agmoulocytosis and agrono-
`locytmis-related deaths from Febru-
`ary 1990, when clampine was. first
`distributed commercially in the (1.5.,
`In Decemlmr 1994, and compares this
`clinical experience with expectations
`based on pffintlfliflt clinical research
`projedtions.
`This study does not addrassdiroct-
`ly the issue of optimizing the fre—
`quency and patternvol' white blood
`cell
`testing, although the study's
`prospective analyses of rates ol‘agml-
`ulocytosis and related deaths may
`have some hearing on this issue. rIhe
`issue of whcllicr formal alterations in
`
`the current requirement of weekly
`blood tests will result intro iacccpl—
`ublc” increase in risk-is the focus of
`separate. epidemiologio studies and
`will not be considered here. This
`
`study specifically addressed current
`quality assurance functions and
`sought Lo answer» the. question oF
`whether the use oFa single, national
`registry ofall cloZapiuc uScrs in the
`United States" has enhanced patient
`safety and contributed to the saving of
`lives.
`I
`
`Methods
`
`The naliomd registry
`All dataunningsto the clozapinena-
`tional registry are tailored: when in—
`tegrated,
`computerized}, database-
`maintz’unedhy the manufacturer. Pa-
`ticuls’ computer records are estab—
`‘lished during the: initial. phone do
`made by physicians who are seeking
`clearance to-staitaspecific patient on
`clozapine. The records include the
`patients identifying code number
`and initials, the physiciarfs identifica—
`tion,
`the. phannacy’s identifiudion,
`daily dosage of clozupine in mil-
`ligrams, and White blood cell
`test
`dates-and results. ’
`_
`These data are retained perma-
`nentlxnnd odditional data are added
`each Week. As more than- 60,000 pa-
`tients currently receiVe clorapine,
`more than SOC-JEN) separate fields-of
`data-urt- sont tin-"the manufacturer’s
`national registry each-.rymk. Zln. addi-
`tion,‘ separate. databases .arc timin—
`taiued to truck in“ reported adverse
`reactions. Kll-dafii analyzed in tllis‘re-
`
`l'hYUlMTRlCSERVll‘FS O pnuzry [996 M47 No.1
`
`port were drawn. li-om those sources
`and were provided by the manufac—
`turel;
`
`We used these data to examine two
`primess variables related to functions
`of the national registry system over
`the first five years ofc'ommemjal dis-
`tribution of‘the mediation: level of
`adherence to the. mighty protocol
`and denial of clinically iqupmpriate
`retreatment. We also examined 'two
`outcome varial'ilcs—ratc of agronulo-
`cylosis and rate of deaths related to
`ngmnnlocytosis—zmd curupnrcd those
`rates with [he rates that were. predict—
`ed in zumlysr-s nonrhicted before the
`medication was cununcrcially distrib-
`ulcd in the. U.S.
`
`Results and discussion
`Adherence to registry protocol
`The manufiicturer's educational and
`servicing- activiti‘es, plusthe potential
`threat of disciplinary action such- as
`dercgistmfion as a clozapirle treat—
`ment system,,app‘nnr to have resulted
`in generally high levels of adherence
`to weekly monitoring. Over the first
`five years of commercial distribution
`oliclompine, more than 97 percent of
`treating physicians and pharmacists
`mzmaged their patients on clozapiuc
`at high overalllovclsol~ adherence to
`the requirements'of the product la-
`beling. The remaining 3 percent have
`been characterized- by “trying. levels
`of protocol compliance. National rog—
`istry data Show that a small percent:
`age oftreatment systems periodirnlly
`relax adherence to monitoring guide-
`lines.
`0f themore'than 10,000 physicians
`and plumuacists currently involved» in
`dispensing clozapine, about 700 are
`contacted annually because of poor
`compliance in reporting data to the
`nalimml
`registry. National registry
`stall institute corrective actions. in-
`cluding cdumtion, clinical manage-
`ment training, and intensified-review
`As new treatment systems an: added,
`and older one; may become large or
`complacent.
`this iterative process
`continues.
`
`Between 1990 and 1992, analyses
`were perfmmed to determine il’cor-
`motive actions by national registry
`stnll were associated with unproved
`reporting of white blood cell count.
`In March 1992 registry staff identi-
`53
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`
`Figwrc 1
`
`Cumulative number of actual and predicted (ases of agmnulocytosis muong'pa:
`tieuts receiViug clorapiue. 1990—49941 ‘
`
`1.000
`
`Npatients
`
`
`
`
`
`
`’ 19st.
`i993
`1992
`' Cumulative mlmbPrs [if—putter": receiving clam were 9607In 199]. 24.1.1.2In 1991. 412-15in 1991
`7-1;:13'm “Mi. mall 99,502In 1994. Pralimd number ofcaseswas ulmlaled using a mmcrvuh've (sti-
`III-atI: flfl l mutant nth. ntagrannlocytesu, basalon pmmarlcc! climad-Itsarch
`
`1990
`
`1991
`
`cent of the required records of white
`blood cell counts. One year later, in
`Aprfl 1993, despite the addition of
`more than 400 patients to the cage.
`loads of these 100 physicians, lbr a to—
`tal $2,767 patients, the percentage of
`acceptable reports ofwhite hlood nell
`counts by these physiciansbatl im—
`proved-to 61 percent
`
`Denial of mzmmmenz
`Patients who have dismntinued use
`of clompiue due to agranulocytesis
`are at increased Iislt ofdevelbping the
`rcacticui again, generally earlier in
`therapy and in a more aggressive
`lbrm; if Cln7apine is minstituted (3).
`The national registry clears each p0-
`téntial candidate. for chompine them—
`py to reduce the chances of rmxpo—
`sure. to the mcclicatiun by persons at
`increased risk of developing ag'mnu-
`locytosis.
`Between February 1990 and Dc-
`oember 1994, there were 28 instances
`in which potential Landidates lbr the
`medication weredenied retreatanent.
`Ninc inst-tunes involved eight pa-
`tients who hadcontinued histories of
`white blood cell counts below 2,000
`or absolute oculmphil counts below
`L000. The nine instances included’
`two attempts to obtain retreatment
`clearance for one patient In'four olh-
`er instances the regisby was tested-by
`the mml'acturcr using identification
`numbers of non-retreamhle patients
`to assure that the systcnr'fimctioned
`appropriately. [n the other 15 in-
`stances, retreat-meat was denied until
`closer-inslmtion revealed errors in
`data; these patients were Subsequent
`lycle-arcd for retreatmcnt.
`
`Rae ofagmnulocytosis
`Between Februaiy 1990:1216 Decem-
`ber 1399—51, a total of 99,502 patients
`were exposed to clompine in. the [1-5.
`and had wards of more than OllC
`white blood cell count. During the
`first Lalcndaryca: in the-study period
`(February thmugh December 1990)
`9,807 patients were exposed to clou-
`pine. The cumulative total had m-
`creased to 24,112 patients by the end
`ofcalendar year 1991-, to 47246 atthe
`end or. 1992, to 74,345 at the end of
`1993, and to 99,5“)2 by the end of
`1.994.
`'
`'
`
`'
`
`.
`
`'
`
`.
`
`l
`
`l
`
`l
`
`Among the total of 99,502 patients
`
`fled physidans who had mare-than six
`patients 'fiir whom more thanlt) ger-
`oent of the required teportsol’white.
`blood cell counts in the latest three
`months were IIIissiIIg. 'me.‘tbis list,
`the mo physicians with the highest
`percentage of patients for Whom
`
`more than 1.0 percent of the reports
`were missing were identified. At that
`time, these 100’ physicians. welt, re<
`spoflsihléfor 2343 patients;
`Before- ‘the interventiOn by national
`registry stat}; 58 percent (if-those pa-
`tients-were missingmore than, 10 per—
`
`
`
`figural
`
`Cumulative number of actual and predided-deaths ze’lated‘to complications of
`
`agmnuloeytosis among patients receiving clumping 1990—1994' 7
` 169
`
`Npatients
`
`I40
`
`
`
`
`
`1992”
`
`1993
`
`'
`
`m.
`
`‘ Cumulative qunbcn‘s oflnticuls Imdviugclimlpinemm: 9897 in1990-.24.11271". 1991 47,246to £992..
`74.33““IIT [993. and 99,502m 1991Miami hiimher“deaths.was calculated using comcrvalive' esti-
`mates via 1{rural mic ufngm'nulm-ymsis and a 15. 90min]: rate ofass'ociatedmortalitybased on pre-
`markct.clinical (Win
`
`54
`
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`'W—_—__—~—_—~——'—.————_
`Table:
`Effects ofactual and hywthctical rates ofcornpliauee. in'rersnting ofwhiteblood
`all counts on incidence ofagranulncytnsis and related deaths among patients rc-
`ceivillg clampine
`Agrmruhqtosis
`Darth
`
`Rule of coruplim use (‘3?!)
`
`Bale (%)1
`
`N use:
`
`Rate (‘21-)2
`
`. N cases
`
`N pre-
`veritable
`deaths"
`
`,w-wl
`90 to 100‘
`30:50 455 -
`Hmmlhctlcal
`75 to 90 v
`mm 75
`113 to 60
`
`38
`on
`
`.60
`fill
`L0)
`
`382
`[G
`
`59?
`796
`995
`
`ill
`50:0
`
`5.0
`10.9
`l5.0
`
`1?.
`8
`
`an
`so
`I49
`
`_
`—
`
`m
`68
`137
`
`7‘;.
`
`L _\: (m among 99502 mic-um [ha mmulativc number ofpnrimrrs iminrlul'in the national registry from
`Flu-nary 1990 through December 1994
`"Ndcnlhs amongN cases: of agranuloq-tosi:
`5 (hmanud'with N deaths 3:90 to 1m percent rumpI-ianue imparting
`4 [hula mic-599.502 cases ims'hsdud in the xnfiml'mgish? fi-um'Fcfimzy 19511 through 1mm: 199-1
`3 Jim: urn-011g patients treated when doupiru: was first (fistxibuled commercially in Finland in 1975
`
`duringthn. study: period, there were
`2,931 cases of-leukopenia (crude inci-
`dence mte-of2;95porcnnt), 382 cases
`of agraxmlocytos‘is(.38 percent), and
`K2 dcadrs associated‘with agranulocy-
`losis (1)1552 primer“). The rate ,of'
`leukrperria ctmfiirmsqnilc closely to
`predictions based: on pramarket clini-
`cal researchufapproximately 2.5 to 3
`pen-cut of all persons exposed to
`clovapine.
`I
`However, the- crudc rate of agrauu-
`loeytosis during the shldy'parinrl [.38
`percent) waslass than half-that antic-
`ipalcd from premarkct rasearch (l to
`2 poi-cant);_ [figure 1: shows the tumual-
`uumher of axpeckztl and actual cases
`of agranulocymsis-ovar the study pea
`rind; The expected number of cases
`
`was calculated conservatively using
`the l'oWar percentage estimate of l
`pement'basadon the premarlcet clin—
`ical rcscarch. Because the lute of
`leuko'pen'ia-wns «insistent in the pre-
`aud'postruarkct data, theuwrc favor-
`able posunurléet: findings on agranulo-
`cytosis appear to bathe result Of Sys-
`tcrualic monitoring. early detection of
`aboommlifins in white blood cell
`counts, prompt reporting of those
`counts to the national regisoy. and
`prompt discontinuation of al'omgiine
`among. ancuLs' who-wcrc'at risk for
`agrianu-locytosis.
`
`Beam-rate
`
`lk-spita intense monitoring. [fl-per-
`sons diodas a result ofag’ruoulocytd
`
`
`121th 2.
`
`PmSpcctivc armlys'is-of diets of rates of wrrqiliauw in rig-wrung of white blood
`cell counts on incidence ofagmnulocytosis and related deathsamong 20,000 new
`patients meaiving dompine over a. one-year period
`
`
` Optunistic sccnario‘ 'Ilealistic scenario3
`
`
`Rate. of
`Agrmmlnrryrmis
`comuhl
`.
`'
`anon (‘31:)-
`Rate3(%)
`N
`9011.100
`.38
`76
`75 moo.
`.60
`120
`60m 25
`, .80
`lfifl
`
`45 mm _
`' 100'
`200
`
`‘
`
`'
`
`N
`darths
`2
`4
`5
`5
`
`N pre—
`ventzhle
`deaths!”
`0
`:1
`3
`’l
`
`flats: of
`(loath (‘31)
`3.1
`5.0
`lilo
`(5.0
`
`N
`deaths
`2
`6
`16
`30
`
`N pra-
`veritable
`deaths“ '
`0
`4
`I4
`2.8
`
`‘ Assam“ :3 Gill-nascent ratt- trident]: among tam ofagranulrxytusis, mmllrm nf'thrrnumlxzr ufwsm a].
`“(rims lends o‘eorupliama
`:4‘m-m fife JMM mags ol'agtanuloqotcsis‘inamnsz‘s as'nnmhrrnf msns virruuzsus will: (in?
`creased levels: ofcamplim
`J‘bnrjn‘radiwidr “wideaths #50 to .1th compliance in wrong
`
`mmmcfluwm"q janmry I996 “147 No.1
`
`sis-related complications between
`bbhnrary 1990 and December .1994.
`Figure 2 shaws the cumulative ex-
`pected and neural numbers of deaths
`related to agranulocytosis each calen—
`dar year during the study period. The
`mpecta‘rl death rate assumes a l per-
`cent mm ofagmuulocytosis and an as-
`sociated mortality rate of 15 percent.
`This rate is consistent with muscrvav
`tive estimates based on experience.-
`abroad with .cloztapiue and on pub-
`lishcd research on miauscrin, an anti-
`depressant thnt has lenknpenia as a
`potential adverse effect (4,5).
`The dilfcrcnoc between the pre-
`dicted and actual cumulative death
`rates—149 predicted deaths com-
`pared with 12 actual deaths—sug-
`gests the benefits ofv rigorous patient
`monitoring. Those data show that cur—
`rent medical practice and monitoring
`procedures have contributed sub—
`stantially toward saving the lives of
`many patients who require clumpinc
`therapy.
`Table. 1 shows how patientsurv‘ival
`might have been afi'ectcd over the
`study period if mrmitOring had linen
`less rigorous. Actual clinical experi-
`ence in the US. from February 1990
`through December 1994 showed 90
`to no percent compliance with re—
`porting of white blood cell counts; in
`that context, patiean with agranulo—
`Cytosis had an overall risk of Ertal
`complications of 3.1 percent (ISL
`deaths among 382 asses of agranuki-
`cytosis).
`At the other extreme are the initial
`findings on this topic from thmd-in
`19??)4976, where a 50' percent rate
`of mortality emerged among paficnt's
`who developed agmnulocytosis (eight
`deaths among 16 cases of agranulocy-.
`tons). Rates ofWhitc thod cull moni-
`toring were estimated tube 30 to 45
`percent. The outdated medical and
`monitoring conditions existing at that
`tiara-clearly no longer apply, given
`the heightaned awareness of (damp-
`inc and» its tlrerqyeutic and adveise
`effects. However. hean the cur;
`.rent US. ctpcrience, representing
`the highest level of monitoring. and
`the early Finnish experience, once-an
`interpolate intemrcdiale-sccnarios of
`adequate, em, or poor levels‘of moni—
`toring and the associated risks oliliital
`complications of agranulocyiosis.
`
`55
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`1;.
`
`l l l l l ' l l 5
`
`For example, a rate of compliance
`with white blood cell monitoring of
`75 to 90 percent would be associated
`with a risk of fatal complications bfan
`'estiulaled 5 percenl among patients-
`who developed agrannlocytosis,‘ a
`monitoring rate of 60 to 75..pcrccnt
`with an- estimated 10 percent rate of
`fatal complications, and a umnitnring
`rate of 45m 60 percent with an csti—
`mated 1-5 percent rate of filial compli—
`cations.
`the level recently reported
`for dwths related to agnmulocyl‘osis
`associated with mianserin (4). Thus if
`V monitoring stantlards in the US. had
`been less stringent between 1990 and
`1994, between 30 and 149 deaths
`might have occurred. instead of tin;
`12 deaths that actually attuned.
`
`Prospa‘tiw analyses
`Based on memlive projections of
`current-rates ol'acccss to clamping at
`least 2&000 Americans per year are.
`likely to be newly exposed to cloza—
`pine in the-coming years. If these pa-
`tients are. treated under current mnn~
`iton‘u-g conditions. about 76 patients
`(.38 percent) are likely to develop
`'agmuulocytosis, and two patients are
`likely‘tQ-die‘ofcomplications of again-—
`ulocytosis- (3. L percent among agranu—
`loeytosis cases) in each annual whorl.
`(Even. those rates, what would hap—
`pen ifstandards for monitoring were
`lowered? Two principal scenarios,
`whose rates are shown in 'l‘ahle 2, can
`
`be cansidercd. An optimistic scenario
`presumes that medical pfmtice has ad-
`vanced. enough that most cases of
`agranulocytosis;
`including sympto-
`nuitic cases, can he arrested without
`Eital' complimmnsl Thus if one as—
`sume-s that mleqimcy ofmonitoring has
`no hem-mg on fatal outcomes.
`two
`deaths mold he anticipated 'anmug the
`next 20,000 new clmapine patients if
`monitoring compliance remains at
`current levels. IF the rate of compli—
`ance drops. one will likely see an in—
`crease in the mte ol' agxmmlocytnsis
`and an additional. two in four deaths.
`The second, more malistic scenario
`assumes that early detecticm and cow
`tinue‘d vigilanw exert a favorable im-
`pact on the rate of agnmulocytosis
`andthe rate of Fdhllll‘les. In this sce—
`
`nario, a wider Imageof outcomes can
`he pmjecterl, and substantially poorer
`outcomes are likely. Phr example, the
`estiimzted risk of agrgnulucylusis
`would range Horn .38 to l percent and
`the rate of fatalities finm Stu 15 per—
`cent. The projectidns shown in Tnblc
`2 sugest that if monitoring deterio-
`rates from current levels, between
`film and 28 additional deaths may oc-
`cur aulong each annual cohort of new
`patients.
`
`Conclusions
`In the first five years of commercial
`distribution of clozapine in the [125.
`the national clumpine registry system
`
`appears to have contributed to reduc—
`ing momllity related to. mmplimtions
`ofagnmulowtosis substantially. hel0w
`projected rates- derived from premar-
`lret data. The rigorous safeguards} in
`place to maximize the opportunities
`for early detection of white blood coll
`suppression have been associated
`with livorablc outcomes in rates of
`both agranulocytosis and final compli—
`cations. Decreased vigilance wooltl
`likely be assimilated with an increase
`in otherwise preventable deaths. 9
`
`Acknowledgments
`The author thanks Felix Arvllzino, Ml),
`and Sheila Waiter, M.D., of the thug reg-
`islluliun and regulatory aliilim
`—
`ment and Anthony Biuuulliui u
`the
`Clozaril national mgish-y.at Sandal Phar-
`maceutimls Corporation.
`
`Rderences
`1. Health can; rclbnn I‘m-Americans with se-
`ven: llltflllill illmmm-r tripod uftln: Notional
`Advisory Mental Health Counml. Amalia“
`Jam-ml of Psychiatry 131144721465. 19%
`
`la
`
`Kane JM. llrmigfeltl G, Singer ,1,- etval; Clo-
`mplnc for the h-cutnwntareaismntjdflm-
`phrenic. Archives" of (Tamil Byrzhiiilry
`45:789—196. 1938
`
`.‘5. Pisciultn AV: :‘tgrunulucytoris lnducc'd by
`wrtaiu lihenullliaziim almiwliwm- [AMA
`205:1562—1558. “369
`
`4. Ari-nus PC: Mimsedn—imhmedugumihqr—
`tosis. British,-.\Ied1ml]zimnal985:208—209.
`[.933
`'
`
`3‘."
`
`Coultcr DM, Edm‘cls IR: .Mianserin and
`mgmnubcytoris in New Zealand. 13ml;
`Illi'i'fifi—THT, Ill“!
`
`Peer Reviewers Sought by Journal
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`Psychiatric SW3 seeks expert reviewers in the following areas:
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`OOutcome research, particularly in the area of psychopharmaoolngical treatment
`of mental disorders
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`QBating scales for symptoms, outcome, and other aspects of treatment
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`Reviewers should be familiar. with-the literature in,thci_r arc-as of expertise,
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`content andfocus of Psychiatric Services.
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`Prospective reviewers should send a curriculum vitae, spécilying areas of in—
`teimt, to-Jolm A. Talbott, Ml), Editor, figchiafic Services, EPA, I400 K Street,
`N.W,-Washington, 11C. 20005.
`
`Manama . 1111112171996 Vol.4“! No.1
`
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`» JWY1996'V0147 No. 1—
`
`
` .
`
`. Ajoumal of the
`
`.Amctimn Psychiatric
`.
`Association
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`
`fimii‘lniy Hofipifni and Cumminiity Psychiatry
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`Takinglssue
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`7 How’rc WcDoing? jobuATalbi-iu. MD.
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`Articles
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`35 Confméionsofaamcumzmkcvicwcr PaulCMobl. MD.
`
`41 Magma-mm ofGonpinc andPsydio'sodal Tm on Psydflauic
`Symptoms andCognic‘ive Fimctioning Iéfiry 6mm, MD, Stephen 3391615,
`pita, Michael I. Raidirz, ma, minim [.Hc'rz, M-JL Barbara I. Plies;
`RN, mmrBrenne); MA, Ken}: Donnell}. PhD. Pam'da Smitb, KN, MS,
`and 511541: 610111. EN
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`46 Efiecdmofaozapine and a Sochl-Ifimfilgl’mgtamforcheiely Disabled
`Psychiatric inpatients Anthony Menditto, pan; Niels .23ch 1421)., paid
`Slime, 1’b.l)..jmtid1=A. Fisher, 00, Mark Staggnu, Mary Beth Logue, MA,
`and Ixchala'wiu, 111.81
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`32 Effects of the Clouplnc. Nationalllagis‘uySyswm on Incidence-of Baum-Related
`to-Agmnulocytosis ’ Cilbefl 110:2:ng PhD.-
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`5-7 Chm-actedsticsznd Sci-vice UseoiSetiousinenuuy “Famous Livingin. Rumi
`Aims Greer sum-awn. MM, MSRIZ, Gamma Afademn, PhD, and Karen
`1.5mm; ILA.
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`62 Quality (flit: dflong—Stayl’aflmm DiSdm‘ged Frbm-‘Pwo Psychiatric Insti-
`tutions
`julidn 147: Ma, Eliminate Dautzmagmn, MRCPtycb. Cliffs-
`fopber Goat-:13,» M512, Graham ”JawliaoflfiLSE, MR'CPSthb., and Walter
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`68- Outcomes ofllmidcnflal Truancm'ofSubstahoc Abuseinfiospiml» and
`Communky-Based PAW Rating"H5100; PhD, Mch‘ssafKing, ALRH,
`and MidmelAi-Patterson, BA.
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`75 Seven:Wu andlldawd-Condinl’mblcms Among lhunway and
`HomdessAdolesamm Robert £30011), Hm, aidez‘mMg Zbai‘zg, Ms
`23 Dampoims: Electromvulsivc'l'hmpy 1min MKonm, MD.
`25 Managed CamiAlenMg'GAGCinStfot Establishii’m rune-limited Fsydiothelapy
`Gtmps Greg mm;- MA, LDC, andjanuts {€54an MD.
`
`27 [awstl’aydliany MamgedCamandtthancna-«fiau omeul Hahhlaw
`Paul S. Appelbaum, M1).
`
`32 autumnal (‘zicRefomr mime: oiContiacfingon thc'COstofPuhlic Mam-n
`Hcah‘hSavices in (Bilifmnia Teb-wez' Hu; PhD. RimlfCuJeL 1.27.1)" and
`Mary c tuasland, MSEH.
`'
`Issucsin-Managcharc: Highflghtsofflic 1995,mech
`
`Is
`
`SpecialRepm-t
`
`
`Psychiatric seniees (m 'lbfiz-riioi, Is: magnum monthly- by uie.metiiznh;cnimiqnssmm,ediiotal and-decent: cities. i-ioa x Sum, NV.
`Wumfi¢2mfmw© 1996b: inmate-tan radiance-swam minted in lJiAficeond‘dzm muse-mid mswiwxuud :Ii additional mailr
`iguh‘uxstmamsmmrrss Chaim lu'l‘sychlllflc Seflifls. Hm K Smr.N.V/..Wx1iingmi.1111301105.
`-
`
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`
`
` Ajourml of the
`American Psychiatric
`Association
`Formerly Hospital and
`Community Psychiatry
`
`
`
`HEALTH SCIENCE LIBRARY
`University 0! Wisconsin
`
`Madison. WI 53706
`
`JAN 1 fl 1996
`
`1305 Linden Drive
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`.
`.’ P3:
`-|;1Lr.
`
`-
`,:
`
`SC. of Services by
`ntally Ill Persons
`Ving in Rural Areas
`
`V A Concurrent Reviewcr’s
`Guide to Coping With thc
`Demands of Managed Care
`
`O Combining Clo‘mpine and
`Psychosocial Approachcs
`in Treatmg Schizophrenia
`
`
`
`
`
`__..'.<
`
`
`
`PAR1011
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