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`1 This material may be protected by Copyright law (Title 17 US. Code)
`
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`I
`
`Reducing Clozapine-Related Morbidity andMOrtality:
`5 Years of Experience With the Clozaril National Registry
`
`Gilbert Honigfeld, Ph 0., Felix Arellano, M. D., Jitender Sethi, Ph.0.,
`Anthony Bianchini, and Jeffrey Schein, Dr.P.H., M.-P.-H.
`
`MAR31TESS
`
`1305LinMadlaon,$3?35%.
`
`The Clozaril National Registry (CNR) wascrwted to help protect patients from developing poten-
`tially fatal agranulocytosis secondary-to treatnient with the antipsychotic rtiedicine cloviapiue. The
`CNR. designed and maintained by the moutacturer of the branded Clouril (clozapine),'has'the prin-
`cipal goals of (I) prophylaxis—preventing inappropriate retreannent, and .(2) quality assurance—
`oversec'm adherence to a “no blood, no drug" policy. This article reviews the estimated impact of the
`CNR on clozapine-related morbidity and mortality over the first 5 years of commercial czpen'euce in
`the United States. Method: Completed‘ata on leukopenia and agranulocytosis, gathered from the CNR
`database for the period of 19901994 were reviewed and compared with data from the pre-CNR peti-
`' od. Results: Use of clompine'to 99.502patients according to package labelinngroquirements (distribu-
`tion of the medicine linked to mandated white blood cell count testing) was associated with a total of
`381 cases of agranulocytosis (0.38%) versus an expected cumulative total of 995 cases~(based on the
`pre-CNR rate of l% to 2%). Based on the expected agranurlocytosis rate, upto 149 deems-11113111113113
`been anticipated. Instead, there were only l2. deaths attributed to complications-ofngmnulocytosis.
`Conclusion: The CNR provides .for'universal ‘r‘echallcnge protection as wellas- controlled dispensing
`ofclozapinc. It also servesas an early warning system to promote the safe and ell‘eetive use of cloza—
`pine The CNR includes quality assurance mechanisms designed to enhance compliance. Despite the
`added logistic requirements this system places upon physician. phannacist, and manufacturer the
`CNR has helped to reduce substantially potential fatal outcomes The CNR.reinforcesboth patient and
`treatment system eomplianoe. Based on this fawmble experience concerning .agranulocytosis and as-
`sociated fatalities. the Neuropsyehopharmacology Advisory Committee 11) the US 1‘quand Drug
`Administration has unanimously recommended a reductionIn frequency of the white blood cell count
`testing requirement after 6 months to every 14 days, instead of weekly Fnally, the CNR database
`containing white blood cell count and demogmptnc data on everypatient in the. United States'tvho has
`received the medicinehas ucrved- as a unique epidemiologic database.
`(JClinPsychiatry. 1998,59lsupp1313—7)
`
`About 1 adultto 100m the United States (approxi—
`
`mately [.5 million) suffers from schizophrenia.‘1 At
`least 10% to 20% of these patients are unresponsiveto
`typical unfipsychotic phannacotherapy.” Another group
`of patients may respond to antipsychotics but experience
`dose-limiting extrapyramidal symptoms (El’Slor ‘tardi‘ve
`dyskincsia (TD). A large-scale survey of psychiatric pa-
`tients treated with conventional antipsychotics found an
`
`,
`From the Universily ofMedi:me andDentistry-11wa
`Jersey. Robert WoodJohnsonMedical school, PLantaway (Dr.
`Hanigfeld)andNauartis Pharmaceuticdls Comazafiwt. (first
`Hanover; NJ. {DYS- Amllana. Szlhr',andS'rjmr‘n mad Mr.
`Biandz’ini). 01: Arellano15 currently at Zerzeta
`Phanmceuticals, "filming/Ian, Del.
`Supported by! an unrestricted educuliunal grim! from
`Nouarlis Pharmaceuticals Comoratim
`_
`Reprint requests to: Gilbert Honiofeld, Pita. (hiversity‘ of
`Medicine and Demithy ofNew Jersey. Robert Woodlabnrnn
`MedicalSchool, 675 Hoes Lane, Priscafaway. NJ 08844—56135.
`
`I Ciin Psychiatry 1998;59 (suppl 3)
`
`overall-proportion of TD of 23%.5'The prevalence of TD
`was calculated to be about 5%,per year of cumulative ex-
`posure to the medication for; younger patients for at least
`the first 4 to .5 yearn-this frequency is probably much
`higher in olderpatients.‘ Tardive dyskin'esia is a major
`cause.of successfulmalpructiee litigation against psychia-
`trists.6Thus. in these patients who do not respond to con-
`Iventional antipsyehotic therapy or for whom BPS become
`unacceptable. suchtreatment is often reduced or voluntar-
`tfil
`-
`il-y discontinued by the patien
`Cloeapine_(Cloza1il).' an atypical. dibenzodi-achine an-
`tipsychotic. has been found to offertherapentic benefits
`superior to 'chlorpromazine for a group of hard-to-treat'pa-
`Itients:
`(1-) neuroloptiénonreSponsive patients and (2)
`those potentially sensitive to the adverse effects of neuro-
`_le1’;1ti<:s.3"“.l2 A pivotal. comparative study in 268 treatment—
`resistant patients demonstrated the therapeutic superiority
`of clozapine to chlorpromazine in relieving both positive
`and negative symptoms. Among patients treated with
`
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`Honigfeld et at.
`
`elozrapine alone, within 6 weeks 30% were judged to be
`responders. compared with only. 4% of patients treated
`with chlotpromazine plus benztrbpine (p < 001)} Clout-
`pine has also been associated with a near absence of EPS
`and no documented cases (if TD attributed to clozapirte
`alonc.'3‘”
`
`Despite these benefits. cloza'pine use has been limited
`only to those patients who arortiSistant to or intolerant of
`other antipsychotic medications. This policy is based
`largely on premarketing clinical research and foreign
`postmarketing experience during the 19705 and early
`19805, which showed that apprmtimately 1% to.2.% of
`treated patients developed agrauulocytosis, a potentially
`fatal complication.“ 13 Bringing these data of the 19705
`into closer focus, however, revealed that the condition was
`reversible and that the risk of. death was related to the time
`and clinical conditions under which the diagnosis of
`agranulocytosis was made. When clozapine-related agra-
`nulocytosis was diagnosed after the onset. of infection, as
`many as 50% of the initially aflected patients died. But
`when their condition was detected by blood test. before
`they developed complications, and the medication Was
`promptly discontinued. no patients with agranuIOCytOSis
`died.zz These results suggested that a patient surveillance
`system providing auearly warning of significant decreases
`in whiteblood cell count.(WBC) could helplimitrthe num-
`her and severity of episodes of agranulocytosisf‘us Cloza-
`Pine was apprO‘Ved in' 1989’ for use in the United=States
`contingent on the manufacmrer's implementation of such a
`surveillance system, the ‘Clozaril Natiunalvkegislry (CNR).
`Clazapine and the risk of'agranrtlocytosis. Agranulo-
`cytosis is defined as an absolute neutrophil' count (ANC)
`below SOD/mini.” The onset of clozapineéinduced agraria-
`locytosis is usually marked by a gradual. fall in WBC
`counts. often over several weeks;,rapi‘d WBCdropswithin
`1 week may also occur. but are much less._comtnon.u7
`Most instances of clozapinc-rclatcd. agranulneytusis' oe-
`eur early in. the Course of treatment. In a retrospective
`analysis of 366 agranulocytosis cases between I973 and
`1990, 75% occurred within the-first :18 weeks of treat.—
`trier-1W“?3 The peak period of. risk for agmnulocytosis was >
`found to be during the third monthol"t.rt:atn_tent.18
`When clozztpine therapy isstopped‘upon identification
`of marked leukopeni'a, patients usually recover modieully
`and hematologically within 14 to 24 daysand withom se-
`quelae However rechallenging patients who have experi-
`enced clozapine—induced agmnulocytosis leadsto the rede-
`velopment of: the dyscrasia. Theonset ofthe new episode
`is usually more rapid and more aggressive than the original
`episode. In 9 patients known to have been rechallenged
`the average time to the onset in leukopen'ia (WBC < 3000/
`mm“) or agranulocytosis was 24;4.weeks-for3 the first-cpl
`sode and 14. 6 weeks for the secon d." Such patients should
`not be exposed to cluzapineagain, since the risk of.a fatal
`outcome is apparently increased;71°373°
`
`Itis not possible to predict who will develop agranulo—
`cytosis', and the reaction is not dose-related?“ Although
`some data have suggested the possibility of genetic predisr
`position to clozapine-induced agranulocytosis.“l others
`have not.fl It has been suggested that the presence of the
`alleles HLA—B‘38; DR4, and DQw3 might be associated
`with an increased susceptibility to egg-armIocytosis.Jl How-
`ever, no reliable genetic markers have yet been identified.
`
`ME'HIOD
`
`The Cloud] National Registry: Principles and
`Requirements
`Clozapine is dispensed only through participating treat-
`ment systems registered with the CNR. Each treatment
`system consists of a physician. a pharmacist. and a quality
`assurance chairperson who commit to work together to
`implement the 5 major principles of the CNR: rechallenge
`protectith centralized patient registration, weekly._WBC
`monitoring, limited 7—day distribution of the medicationfi
`and quality assurance. Except for rechallenge ptbtéctinnf ..
`prior to lrcatinan all active clinical decision—nluldng and
`patient» care responsibility occur at the: level of the physi—
`cians and pharmacists and their staffs. who together'com—
`prise each local Clozaril Treatment System, The specifics
`of each of the 5 basic functions are spelled'out below.-
`1. Rechauenge protection; Screening of all patients
`through the CNR database prior to initiating clozapine
`treatment prevents patients from receiving the medicine
`attain if they have a record of ever experiencing clozapine—
`related agranutocytosis or severe leukopenialgranulocyto.
`penia.
`2. Centralized treatment system and patient registra-
`tion. The heart of the CNR is an integrated, computerized.
`confidential database that is maintained by the manufac-
`turer. All physicians and pharmacists who plan to use
`clozapine. for the benefit of speci fie patients must agree to
`abide by the package labeling requirements and register
`with the CNR. Each- patient must be registered with the
`CNR before clozap'ine treatment begins. Patients are idcn~
`ti‘fied only by their initials, Socialhecurity number (SSN),
`gender. anddate of birth.
`'3. Weekly WBC monitoring. All patients taking cloza-
`pint: must. have a baseline complete blood cell count
`(CBC) before starting therapy. In order for patients to be
`gin'elozapinetherapy, their baseline WBC must be above
`35.00/mm“. The WBC is then monitored weekly thereafter
`as long as they stay on the medicine, and for 4 additional
`weeks folloWing treatment termination. Continuation of
`therapy requires that the WBC remain above 3000/mm’. If
`a patient‘s total WBC is found to be below 200011111111de
`or the granulocyte count is below lOOO/rnm’, clozapine
`therapy must be discontinued and never. reinstitutc'd. The
`CBC'and WBC may be conducted by any laboratory of the
`physician's choice.
`
`I Clin Psychiatry 1998;59 (Suppl 3)
`
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`Reducing‘Clozapine—Reialed Morbidity and Mortality
`
`
`Figure I. Clnzaril National Registry “('30 Reporting Fort-n"
`
`National Registry iNBC Count
`]D] CLOZARIL'
`Reporting Farm
`
`
`
`(dozaplne)
`
`DOCTOR: This form islor recording required WHO mm. Disinformation must'be supplied to
`me pharmacist mskly. in advance of dispensing. PIescfrpfla/Is will M11175 filled without a current.
`acceptable WBC count
`
`Pam's
`CLOZARIL Slalus
`
`
`
`Palisrl‘slnilials: LJ Dfist um
`
`“m«%dwv*|
`l
`l IEEIEEED
`“Wanna...
`.
`_
`i 3mm:
`“Sperry: C]: III mg
`uncoupled
`
`ToflWBCwmllpertt-‘n‘jxlm ]_ I
`- [m {103
`Distal-named
`some CoumAeeeptabbtorfisomshg? E] L]NO
`
`PRESCRIBNG-FEMINDEHS:
`O Irma] NBC count L112:
`Q hymn: simian out be 0 H SWIM O ummwac ewnllalin
`below 3000 (10:10]
`counts are betweenm
`umamoaaxton
`‘lw'uled it W3C wail is
`permm". therapy should
`la: titan 3500(35110’)
`(31mm) and .‘h’m (3 Still?)
`‘ per Imi‘. "many shodd
`be dwninued and paint
`pe'r nrn‘.
`per mm" twice midyWBC
`be’tntertuggd and
`should never be comm“
`mm and dlflegutial
`.
`eaten! usuynmilored.
`
`.muslnuldbewrhnmd. wilht‘l OZARIL
`
`
`
`
`
`
`
`Physician's Name (typed'nr prinlud):
`Ll Checklist!) '1 mi: manna-Imus a new address
`Address:
`
`appear. the CNR staff institutes cor-
`rective actions.
`including educa—
`tion, clinical management training,
`and intensified review. These scr—
`vices, combined with the prospect
`of tie-registration for a noncompli-
`unt treatment system. have resulted
`in overall
`levels of adherence to
`weekly monitoring of 97%.24
`
`Assessment of Observed Versus
`Expected Rates
`Both lcukopenia and agranuln-
`cytosis
`incidence rates obtained
`over the 5-year course of this study
`were compared with rates projected
`from the pre-CNR period; Specir
`tically,
`the precormnercialization
`ieukopenia rate was 2.8%, and the
`agranulocytosis rate was estimated
`at 1% to 2%.
`
`RESULTS
`
`
`
`___.___ _____. ' _..
`
`City.State: _ ..
`Phone NLmbst:
`thsician'sleNIDNumbemEL] mfl
`meme. 11:133-
`Today's CLOZARIL Dosage: EEC] Total “lg/day
`Today'sDalaz]
`I [3:] av:
`‘ _
`Pharmacists Name (typed or pr‘nted);,.____—
`Hmmwawmmwrtlrmjjjjj
`
`‘08:! lm 'fll' 11-41!“le DEW 1.an he QUINN.mamWNWmu t-dbylilrytrp'u'urvulafl
`nnmm‘
`nor: "is-ismhmpaz Whoa-tint:
`“Infamy WWDCWNMW'NA7UMLEGISTRVWW
`mwmusmmma
`mmmmmmmm. finds."
`Jeri-[smiths
`met-pap hm mount-mm NY" 9.0. In! mu,- "II-wan MI”M70: Far I: rectum-5551. In m
`mmmmimm
`am
`g In a..- sum-ow.—
`Mlulh USA.
`M;
`"E‘I‘l‘ ‘
`
`
`
`
`mor—
`Agranulocymsts-related
`bidity and mortality: US. postmar-
`[rating experience. For the 5—year
`period between February I990 (first
`day of commercialization) and De—
`cember 1994, a total of 99.502 pa,-
`ticnts were registered with the CNR
`and treated with clozapirte. Of
`these, 2931 (2.95%) developed leu-
`kopenia (WBC<3500/mm3). An
`additional 382 patients (0.38%) de-
`veloped
`agranulocytosis
`(ANC
`< SOOImmJ); 12 (0.012%) of these
`agranulocytosis patients died from
`secondary infections, despite adher»
`cone to bloodmonitoring requirements.24
`These findings contrast with the 1% to 2% cumulative
`incidence of risk of agranulocytosis expected” on the ba-
`sis-of premarketing clinical research data in 1743 U.S. pa—
`tients.” as well as studies carried out in Europe during the
`19705 and 1980539313345 Conservatively assuming a-l%
`cumulative incidence of risk of agranulocytosis.
`the
`99,502- clozapine-treated patients would have resulted in
`approximately 995 cases of agmnulocytosis by the end of
`1994.
`
`*Afler assmsing the patient'5 WBC count. the presenting physician transmit: this fonn tn the
`pharmacist who may than dispense a_ 1-weeksupply of 'clozapine;
`
`4. Lindteddiszribution. Bachprescriptionforclozapine
`must be accompanied by a record of the current WBC and
`identified by the patient’5 initials, SSH, and d'z'tte ofthe
`blood sample. The 3-pan Clozaril National'Registry WBC
`Count Reporting Form (Figure l) is typically used for this
`purpose. Prescriptions may be filled only at participating
`pharmacy service providers registered with the manufac-
`tutor of Clo-writ A 1-week supply of. medication is dis—
`pensed to p‘au‘errt’s, linkedto a current WBC.
`'
`5. @441in assurance. As a means of identifying treat-
`ment systems, physicians, andpharmacists whose adher-
`ence to the CNR protocols may be substandard, a large,
`full-time CNR staff is charged with reviewing data on a
`reuospective basis; Their primary function is to identify
`discrepancies, such as missing data or low WBCs associ-
`ated with continued prescriptions. If such anomalies
`
`1 Clin Psychiatry 1998;59 '(suppl 3)
`
`Concerning anticipated fatalities, the proportion of pa-
`tients who died after developing agranulocytosis when
`treated with the antidepressant medication mianserin was
`approximately 20%.”37 Although this patient cotton is
`unique and different from a schizophrenic population.
`based on this figure, up to 149 deaths would have been
`
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`Honigfeld et a1.
`
`expected inpatients treated with clozapinc over the 5-year
`period 199010 1994. Instead. the actual number of persons
`who died due to complications from clozapine—related
`agranulocytosis was 12."
`Leukemia-occurred in 2931 of these patients (cumu-
`lative incidence. 2.95%). This figure is very similar to that
`obtained during premarlteting clinical research, which was
`2.8% of- all persons exposed to clozapine. This suggests
`that the reducedrisk of agranulocytosis in patients treated
`with clo7apine was not secondary to a reduction in leuko—
`peuia. I Rather. it reinforces one of the major rationales
`of the CNR. that early detection of leukopenia through
`regular WBC monitoring, combined with prompt.- discon-
`tinuation of treatment in patients whose WBCs fall below
`murmur-t will minimize the further progression to
`agranulocytosis and the associated risk of death.”
`The primary goal of the CNR has been to reduce mor—
`bidity and mortality associated with agranulocytosis, but
`additional benefits have also accrued from close patient
`monitoring." For example, the large, and complete, data—
`base of all treated patients facilitates epidemiologic 1111a]y-
`sis. it has allowed researchers to track WBCs in all pa-
`tients over time and to accurately calculate death- ralos and
`causesof death inthis population.
`All-cause rmriality. Schizophrenia is a. disorder with
`an age-related risk of death that isapproximately 2 to 2.5
`times higher than the risk in the general population,“ "3
`largely due to. a high suicide. rate.“"“ This translates into a
`decrease in life expectancy of 21.9% for males and 16.4%
`for femaleslor a net loss of 16.years for males and 13
`years for females}: In a recent epidemiologic analysis of
`all causes of death in 67,072 registered patients '(< 54
`years of age) being. treated with clozapi‘nc at the time of
`death, Walker et 211.25 found an overall'reduction in mortal—
`ity rates compared with non—cloupine-treuted controls.
`The risk of death from all causes was decreased except
`respiratory diseases, pulmonary embolism, and cardiac
`Conducticin disorder, which were rare; These modest in—
`creases Were more thanvcompensated for, however, by a
`majordeciease in the rate of suicide that was large enough
`to rednrerhe overall death rate to a point approaching the
`death rate of the general population.5
`
`DISCUSSION
`
`Despite theserious adverse potential represented by
`agranulocytosis, clozapine is the treatment for patients
`with chronic schizophrenia who fail to respond optimally
`to Other anti-psychotic agents.3“"2Clozapine was approved
`by the U-8; Food and Drug Administrationin 1989 for
`treatment Of these patients, provided the manufacturer
`implemented anearly warning system tominimize the risk
`of' agranulocfiosis. The CNR has served-that function.
`'Aua'lySes of 5 years of patient data comprising all patients
`who have received clozapine in the United States since
`
`commercialization confu‘m that, although the rate of leu-
`kopenia remained unchanged at near 3%. the Clararil Na-
`tional Registry—supported use was associated with far
`lower than expected agrannlocytosis—related morbidity
`and mortality Twelve of 99.502 patients treated with
`clozapine through December 31. 1994. died from infec-
`tions secondary to agranulocytosisf‘ Previous experience,
`based on a 1% cumulative incidence of'agranulocytosis.
`would have predicted as many as 149 deaths?4 0n the ba—'
`sis of this favorable experience concerning agranulocyto-
`sis and associated fatalities. the Neuropsychopharrnacol—
`ogy Advisory Committee to the 'U;S. Food and Drug
`Administration has unanimously recommended a reduc-
`tion in frequency of the white blood cell count testing re—
`quirement after 6 months to every 14 days, instead of
`weekly.
`Suicide, which accounts for up to half of all deaths in
`patients with schizophrenia," decreases dramatically in
`patients receiving clozapine.35‘“’ This finding contrasts
`with earlier studies in patients receiving other antipsy~
`chotics that showedmereases in depression and potential
`suicidality 4““ The specific mechanism of clozapine-
`related suicide reduction is uncertain. but significant. te—
`ductions in both positive and negative symptomatology
`are almost certainly involved. as is the associated benefit
`of clozapinc—induccd euthymia.‘9"l
`The CNR also provides an important mechanism [or ’
`monitoring and optimizing compliance of both patients
`and treatment: systems. Because patients must presentior
`weeldy WBCs before they can receive their medicatiorrit
`has been suggested that this regular contact may he one
`factor that contributes to good outcomes. Weekly contact
`with healthcare professionals might play a preventive role
`as well. because it permits early intervention inpatients
`who evidence suicidal plans or ideation.‘5
`Treatment systems compliance with the CNR protocol
`requirements is crucial to the success of clozapine treat—
`ment. Treatment systems that do not adhere to CNR moni-
`toring standards can be identified through retrospective
`analyses; subsequent interventions have proven'to be of?
`fective in restoring system compliance, thus enhancing:
`patient safety and clinical efficacy. The compliance of
`physician-pharmacist treatment systems duringthe first 5
`years of the CNR was 97%.‘ This contrasts with the situa-
`tion during the 1970:: before thebenefits of close WBC >
`count monitoring were appreciated, when the frequency or
`WBC monitoring was estimated to be 30% to 245% and-
`was assoeialcd initially with agranulocytosis mortality of
`up to 50%. '9’4
`-
`The CNR provides a system for universal rechallen'ge
`protection as well as controlled dispensing of clozapine. .
`The CNR serves as an early warning system to promote
`the safe and ellcclivc use of clozapine. It also includes
`quality assurance mechanisms designed to enhance 0.0m—
`pliance. Despite the logistic requirements that this system V
`
`J Clin Psychiah'y 1998;59 (suppl 3)
`
`PAR1034
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`

`places upon physician, pharmacist, and manufacturer. the
`CNR has helped substantially in reducing fatal outcomes
`related to clozapinc-induccd agranulocytosis. The CNR
`reinforces both patient and Imminent system compliance.
`Finally. the CNR database. containing WBC data on
`every patient in the United States who has. received this
`medicine, serves as 11 unique cpi'dcmiologic database, al~
`lowing this kind of prccisc safety assessment.
`
`Drug namm‘: hennmpinc (Cogentin and others). Chlorpromnzine (Thor-
`nzine zuId othcrs). cloupinc (Clozaril).
`
`nnrnnnncas
`
`l. Kcsalcr KL; McGrInngle KA.'ZIao 5. et 2]. Lifetime 12-month prcvalcnoc
`of DSM-l'fl-R psydtiatrlc disorders in the United States: rrsulls from the
`Nflicmal Comorbidity Survey. Arch Gen Psychiatry 1994;51:3—19
`2. Roscrmcin Ml, Whale-Sayre Ll, Mandcmcheid RW. Carr: of persons
`with schizophrenia: a statistical profile. Schizophr Bull 1989;15:415—58
`3. Kane 1. Honigfcld G. Singcr 1. ct a]. Clnmlpint: fur lite umtmcntmistant
`schizophrenic: ado-able blind unuparison with chlorpmmazinc (Clouril
`thbomivc Study]. Arch Gen Psychiatry 1988;45:789—796
`4'. Stephms P. Amiiew of clampinc: anaulipsychwiu for unatmcnt-rmistant
`.,
`schizophrenia. Lompr 1’3thqu l990.31(4):315—326
`5. [Canon/l WIIunIaI M LidiemIanJ. Tardivc dyskinesia: prevalcncc inci-
`dence. and riskfzxzrors. J Clin Psychophnnnaml 198KXlsuppl 4):5'79563
`6. Mills Ml.EIiIS.Le-iulhnhr1ny with psychotropic drug use: cxtrapyramidal
`syndmm and lardivc dyskincsia. J Clin Psychiatry 1987;48lsuppl91
`23—33
`7. Melucr'HY. Treatment ofthevneumlqnic-nnnmrxmsiw schizophrenic pa-
`tient. Sdiiwphr B‘nll l992;lli:5l5—S4?.
`8. KmIcJM. Hortigfcld 6. Singer 1. a 211. Clampinc forth: lradumu-msislant
`schizophrcuic: rcsuhs of II US rnnllicentnr trial. Psychophannacology
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`'
`
`PAR1034
`
`IPR of US. Patent No. 7,668,730
`Page 5 of 7
`
` PAR1034
`IPR of U.S. Patent No. 7,668,730
` Page 5 of 7
`
`

`

`THE JOURNAL OF
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`CLINICAL PSYCHIATRY
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`VOLUME 59
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`1998
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`SUPPLEMENT 3
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`MAR311998
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