S-2 Recent advances and conszderam)n~ m the lreatment o f ~'chtzophrenra 165

k n o w n since there is ilttle d 'ec t ev!oer 'ce to suppo ' t the suggested FTlecr/a nism of dopamlne receotor qypersensi t v l ty Surely some of the dysklnes~as are due to the psychosis, as <raepelm and Bleuier noted ~Dhke a o n o r ' ' a movemen ts in sch:zopbrema long before t leurolept ca were available 1 ne chal lenging issue ,s to de te rmme how' muc'- ~s due to drugs and how m.~,c ~ ~s due to the il lness.

Neuro lept ic - induceo EPS and TD have beer" an, impor tant area of practical and heurist ic research These m o v e ~ - e " t d sorde 's have prowded an irnpe tus to ident i fy new and novel c o m # o u n c s w<q equal or greater eff icacy argo f e w or no EPS. Substant ial #rogress qas been made wi th the advent ot im proved ant ipsychot ic compounds hq ade i t i on to c l o z a p n e a r d r i spendone novel c o m p o u n d s in deve demen t SUCh as o anzaolPe ser t indo le seroqsel and ziprasidone all have data to show good eff,cacy and encouragmgly low EPS l iabi l i ty Thus, the t rea tment of psychot ic d ness will surely ~morove tot pat ients, their fami l ies ano menta health p ro fess iona ls

References Casey DE (1989) CIozaplP@ r e ' J r o l e p t l c qdL, L,~£1 ~;~q arqC; ta rd lvP d y s k q e s l a

chopharm 9gs47 $53 Casey DE (1994) Schizophrema Psychooharn-acologv, irl Tqe Psychiatnc Chn~cs {?

North America Annual of DrL.g Therapy Edited by JW Jefferson and JH Gre,:t Philadelphia, WB Saunders. 19!)4, p~ 81 99

Meltzer Hy Matsubara S Lee JC (! 989) Classification oi typical and atypical ant~psychoh: drugs on the bass of dopamine D-" D2 ar, c sero[oriln pK~ values JPET 251 238 24(

I • Health economic considerations in the treatment of schizophrenia

E. S o u e t r e Benefit Research Group Se~m, ev,'//,ers Oance

The purpose of this presenter o r is 1o rev iew eco*~orn c eva bat or- o" d~t~" nat ives ip the t rea tment of sch zcDbrenla This w l l be De ' funned by undo' taking a rapid ove rwew of the contex t o: scRizopnrerTla ( e eplder-~lOlCg~, disabil ity, c q r o n c l t y and lack o ~ stanoarerzed t ' ea :ments irl sch ,zopr ,e nia). the mul t ip le ssues sur rour lcmg t'-e econom c IFTlpacI of ,reuro optics l eg . , assumpt ions and me thodo boy) a rc cur 'ent examples te g , commu ni ty care vs hosp tel care, the ar'wal o; f~ew d~ugs suc ~ as Clozap~ne ar~('. Risper idone)

As Dart of the general fleie of medl::~ne es~::niatry has benef teE] ,.,v~.',t, '. f rom recent advances irl healtq care :e( :hro lo@es Decisions about :h!P use of such techr]o logles ,~ psychiatry used to be made solely on :t'e g rounds of clirrica safety and eff icacy, :h~s led ' - 'any decis ion make,s e r r mos t c l i r ic ians to regare h u b techno logy meal clne as Synonynlous ,~.itr excel lent care. However, the eCOFOR~IC enwronmer / : for t t e provlSlOr ot health care has changed drar'~atlcaliy bye" the last 10 years

Schizophrenia has bee r ShOW'r~ :C nave a cors lderab le ecofiOn/l(: ,!~! pact. In the cur rent chmate of beal thca,e p o l c y strateg c choices new: t~/ be made. Tqe concep t of ecor lemlc evaldatlOl] represents a malof tOOl r' decis ion.making, PnallTly tO assess :he dveral e:l c l en (y {.'i a t "e rapebt r: i n te rven t i on This aporoacb appears t:" rm somewha t ,ele~:~rlr i : pay. ~- i try, espec:ai ly n sChlzooh 'er a whe 'e cn' '~"( : mscrder!~ a'~ :or~7 '~ o" i! ! sospi tal admiss~or" f requem

Consider ing the e p l o e m l e i O g y o,t s : : " , ze [ ] l ' r ~ [ la ~s ',%~el ~s i t s i ] <

charac ters t i cs , there ,s p lenty of ev lce l lce cf :s m*caat OF COS!S a i r : qual i ty of life result ing m econom s bu 'deq D~rec: costs o ~ scmzophre r are mainly due to and mecical serv cos wrl lcr are intens very used ir e r e c t costs are mainly loss of product ivm/an:J tlr~le spent oy ca regwers Quality r" life represents ~*ainlv SOCla professional arid fend,el d mens~orls g r e t a indirect costs ef schizophrenia represeq: nlore than direct costs

There s a large body o # ev,dence Sd;}port nq the ~oea tqat psych a t i l lnesses and tqe r current : reatmer l ts reEireserqt R~ erlorn~aua eccqcF burden to most rr locern sos e:!es A ',',) I d agree that ~octors sn}i~ : refrain f rom proved ng serw::es o r the ; ~1 of [!'e medical curve, e t' ,!r offers no addit ional heal thy suttee, es ;d ~ b a t a r e ai u/crease n coat - ' # d;f f icul ty aqses when there a'e ~.co fev. Iesou 'ees to al ow al ~;sych~at ( pahents to receive all fcrrns cf ca 'e tna: nave a chance cf ~nq~;rovlng me' :a health. ~hJs, t race-of fs mus', be nlade a" ,on. ; services The meas ~reni(!, " of economic eff iciel/ey usIr'g chrs!cal e(:dlerlq£} techr'lQUES s~'o,Iq h ( cl inicians ach eve the goal ) f ac ~, e v u g I?-e g esteat b,~Fel ; ;or : rE ' : : t people, thus, max rn;z~r]g tn~, Utllqy i f m d ::~1 a'e fn' "ear l . rues .~se' a con tex t of rapl@ or-andes ~, the svs:{ t cf ,, e r ta ',ealtr :'are ~ {),n~::+ assessment along these l i res of the~ape ,t~c s: :}fogies seer"s to ee ' ee : l r , {

Cons ideqng the radio anc Sill a rges . ' : : c ~ t~:) ed g r c w v o r hem th : ! , , expend i tu re anc cons denqg the re at lw '" [::nrt~ r cE e! :he ) s t s ,:," , m r " disorders, it seems importa !: to " o c t ; "h~ a * - e r : ) , o f ~)o t ' ? l r l (2 a , ' s i ,t

decision makers )n the nee I :or ;~( ~)t/ ~" r aT : "' a* hE: lb / , r ( : : n

e s Th;s need fo" economic assessment is also dr iven b y t h e deve lopmen t df new irr terver ' t lons that can incur maior health care costs (e .g . clozapine). [he evaluat ion of the relative ef f ic iency of those new strategies may help decision makers and may faci l i tate the acceptance (and the del ivery} of new mterveqhons For instance, a cost -benef i t analysis of c lozapine has recent ly enabled the produc t to earn a place in hospital formular ies in the State of New York

In practical terms, economic assessment should be based on a close col- laborat ion between the medical c o m m u n i t y and the c o m m u n i t y of health econom sts This should lead to the deve lopmen t of methodo log ies that f it the special requ i rements of chronic mental disorders. Ano the r potent ia l ly useful area of research wou ld be into the methods of evaluat ing the effi- c l e n c y o f new lntervent lons ( including new d rugs ) Finally new ins t ruments are r~eeded for assessing the global impact of our therapeut ic decis ions. Among these, qual i ty of life assessments wil l be of great importance.

I S-2-4 i Update on new atypical antipsychotics

Gary D Toliefson L///y Research Laboratozies, Ell L///y and Company, IrTd/anapohs, IN 46285

i~eg nmng w th the mt 'oduct loq of Cn lo rpro~az :ne , the major i ty of ant ipsy- ( :horus have been products of D 2 receptor screening programs. While structural ly dwerse, this fami ly demons t ra ted comparab le p ro f i l es How- ever, ciozapme iCLZ) has cataiyzed a new phase of an t ipsychot ic research

e a search for a typ ica l i ty CLZ's profi le in t roduces a var ie ty of hypothe t - ~:a m e c h a n s m s however, which one or combina t ion media tes its unique r:fflcacy s ur~kqown A broad spec t rum receptor approach includes olanza- [:H'e (OLZ) 'which exhibi ts greater a f f ,n i ty fo r 5-HT 2 than D 2 and D4 than D 2 ecep to r s coupled wtth nanomolar aff inity at 5 HT1c, D 1, and select mus ea'.~lc bindiPg s i tes Al ternat ive efforts to target a subset of CLZ binding , t e s ~pcludes r ,speqdone/serbndole /seroquel (5-HT2/D2). OLZ select ively hrTun:sqes Vie spontaneous f r i rg rate of A1O oopaminerg ic neurons wi th

},Jr dec~eas,ng :be race of Ag neurons on chronic adminis t rat ion. In vivo :~e~av~oral stud es suggest ant ipsychot ic potent ial w i th a low propens i ty to oroduce EPSE OLZ also increases punished respond ing in a conf l ic t tes t

, r , a r tc CL:~Z and subst i tutes for CLPZ in a drug d iscr iminat ion test. in a P~ase II ooL~ble bhnd. p !acebocon t ro l l ed trial. 335 pat ients wi th DSMII I R : cq zopnren,a were randomized to one of the 5 arms; placebo, OLZ- low ( 2 5 7 5 rag) O L Z m e d i u m { 7 6 1 2 6 mg), O L Z h i g h ( 1 2 . 5 - 1 7 5 m g ) a n d haloperidol !HAL: 10-20 m g ) The acute phase of the s tudy lasted 6 weeks ~ t n evaluaborls per fo rmec week ly Patients in both the med ium- ( - 1 2 . 6 p:s !and h g q ( - 1 5 . 2 p t s . ) dose ranges of OLZ achieved basel ine to end i~omt r e d J c l o n s m normal ized BPRS total scores that were stat ist ical ly u [ . e n o r than p lacebo( 31 p t s ) OLZ-high dose reduced mean BPRS to- :el score more ~han ha loper ido l ( 15.2 and 12.9 respect ively). OLZ-high ~lso v elOeo a slgnif cant reduct ion in negat ive symp toms (SANS compos i te ~::ere) versus PAL or p lacebo ( - 1 3 . 6 . 6 6 , and 19). Patients receiv- , ' g O_ZexDeneqced no a c u t e d y s t o q i c reac t ions s~gni f icant ly fewer EPSE eve- ts , a rc mlFimal prolact in elevat on as ccmpared to H A L Discont inu , l ions d~e tc ar~ adverse event were highest in the p lacebo (10.3%) and n a l ) p e r i d o (8 7%) groups

;- s u m m a ' v t"lese results (and two other trials to be presented} prov ide e'weence that OLZ may fulfill criteria as a novel "atypical an t i psycho t i c " ' qese obsewat ions will be contrasted wi th several o ther agents in the later * a ~ e s of d '~g d e v e l o p m e n t

References ~/oore NA lye SIC Ax~op MS, Risius FC (1992); Tne behavioral pharmacology of olan

z I31qe a r s.,el atypica ' antipsychoric agent J Pbarmacol Exp Ther 262(2):545-551

[S-2•-5 Reintecjration strategies in schizophrenia: maximizing outcomes

k b L ittrel Sc'hrzophrenia TreatmentAnd Re,~abi//tat/on, Inc. 208 Church ~trr,et Decatur: Georg/a, 30030, USA

,)u mg :he past decade we have undergone a dramat ic shi f t in the paradigm : dp cernmg SCbLzophreqia increased unders tand ing of brain func t ion ing and ~mproved elf casv of ant ipsychot ic medicat ions have raised t rea tmen t ex- ~)er:tatlor-s at the same t ;me drast ic recoof igurat ions of the heaithcare :~eJ very syste m" have presented enormous chal lenges to cl inicians in the : ' ea tment o" these most ;11 individuals. Professionals w h o had prev ious ly o c u s e d on maintenance and stabditv, are n o w called to imp lemen t inno ,a! ons ir~ :: n,cal pract ice m order to propel pat ients to a h igher level of

166 S-2 Broadening insights into antidepressant mechanisms

funct ion ing It appears evident that rnoroveo patient outcomes I;e w t h m the combined strategies of pharmacetherapy and osychosociai treatments A broad cluster!ng of current ~nterventions include psychotherapy, pay choeducation, psychosoclal/skills training, and medication management The focus of tr~ese tnterventlons :s essentiaily two-fold in nature: first, ef- fectively engage the patient and famdy/caregiver ~n the healthcare delivery system, and second, to provioe a framework fo ~ consistent community relntegratlon. In order to validate these treatment interventions a system of outcome measurements must be interwoven with the actual healthcare delivery Thds analysis of outcomes should be multidimensional in nature and focus not only on psychopathoiogy, but other factors such as social adjustment, role functioning, medication comloliance, family burden, qual ~tyofl i fe, and cost-effectiveness A program model for treating adultsw~th schizophrenia, which combines state-of-the-art antipsychot~c medications and ngorous psvchosocial interventions will be discussed. Throuqh the use of a multidisciplinary treatment team. {amily collaboration, novel ant~psy chotictherapy, and a theoret ica model for reintegration patient outcomes have been measured Data collected in six broadsubsetareasconf i rmsthat patient outcomes are d-amatically improved and well sustained throughout t~me. Case examples are presented t~at illustrate this tandem approach to pharmacological and psychosocial ,nterventions is effective in enhancing iongterm outcomes

References Birchwood M , and Macrmilam F ',1993) Early ~ntervention in schizophrenia Aust~ahar

and New Zealand Journal of Psycmatry, 27{3i 374 378 Fallen, I R, Brooker C and Graham Hole, V (19921 Psychosocial interventions for sch -

zophrema Behavior change 9(4) 238 245 Johnson, C G Littrell, K H , and Magill A M !1994) Starting patients on Clozapine ~n a

partial hospitalization program Hospital aPd Cornrnunitv Psychiatry 45 {3) 264-268 Littrell, K H {1995) Maximizing schizophrenia treatment outcomes a model for -einte

gration Psychosoc~al Rehabilitation Journal (in p,ess}

S-3 Broadening insights into antidepressant mechanisms

S-3-1 I Alpha-2 adrenergic dysfunction in depression: standardization and validation of the clonidine REM suppression test (CREST)

M Scnittecatte ~ Van Gosh Hospita/, Char/ezot~ 6030, Belgium

The elaboration of theCREST(re ~ l ) w a s b a s e d o n (1) one "tool":clon~(:h:'e a specific and potent agonist of the ~ 2 adrenoceDtors (2) one hv~ncthesis clinical depression is linked to a down'egulat lon of those receptors: i31 ore strategy: human polysomnography

In animals and man. clcnldine reduces REM S'eep Recent s t udes r, vwo and in vitro, suggest that clonidine acts by the st;mulatlon of [}patsy naptic ~-2 adrenoceptors located on the cells of the medial pontine re:~cu:ar formation (mPRF). C onidine elicits a hvper polarization of these chol ne-glc cells involved in REM sleep generation and, subsequently, a" i"hiolt or' o f REM sleep production (ref 2)

Standardization of the CREST2 =n a ~ lo t study {ref 1 ) we showed that :on t dine, administrated I V during the second NonREM pe'lod, was slg'qificar tlv less RFM sleep suppressant in 10 depressed patients with pnmarv r~ajer affective =llness (MDD) than =n three crcups of matched subiects 1[) ror real centre!s, 1 0 patients with minor depression !toDD) and ~ 0 patients vv,th generalized anxiety (GAD). To qdantify the REM sleep suppressant effect of clonidine (infused I V over a ten minute period timed to end 30 ~l- 'utes after the completion of the first REM per iod )we calculate an RFM1 ~E%~2 interval which is the t ime elapsed between the end of the first REM oenoo and the onset of the second REM penod or, if no REM sleep further o::curs the end of the recording L, sing a cutoff value of t 80 minutes for the a~tervai between the first and the second RFM period after the infusion of c]on dine we successfully selsarateo ITlajo~ primary dep,esseO patiepts from the three control groups

Va/idation of the CREST In a secone study (ref 3), we compared the efficacy of the CREST to separate ]5 Dat,ents w th onmary malor affeclwe i lness from three control groups I10 normal controls, 15 patients with minordepresslon and 15 patients with generalzed arlxlety) with that o+tqree currently proposed biological markers o fdeoress 'on ,~e the!atencyofraoic eve movement sleep (RL), the dexamethasone sul:)p~esslon test (DST) ant t~qe GH stimulation test (CLO) The four used indices of efficacy {ser~aitwitv specificity, accuracies for positwe ann negatwe predict on), ca!culate:l L~Slng

the "classical" cutoff values described in the literature for the four tests [CREST, RL, DST and CLO). showed that the CREST had the highest efficacy to discnminate the patients with primary major affective illness from the three other groups

Utility of the CREST Studies are now conducted to (1) evaluate the sen- sit~vlty and the specificity of the CREST on larger samples of patients and controls (2) determine if the "blunted" CREST is "state" or "trait" dependant; (3) evaluate if the CREST is of potential practical value in the monitoring of antidepressant treatment.

(1) Untd now, CREST were performed (respective REM1-REM2 intervals between brackets} in four schizophrenic patients (200, 242, 250 and 274 min), one demented patient (208 min), two patients with panic disorder (196 and 318 rain.), one patient with a post traumatic stress disorder (282 m in ) and one woman with a diagnosis of anorexia-bulimia (187 min.}. None of these patients had an abnormal CREST(REM1-REM2 interval of less than 180 min } In a young narcoleptic patient who never received treatment for his oisease and found a typical sleep-onset REM period on the first night and a normal CREST(REM1-REM2 interval - 272 min.)on the second night, suggesting that the shortening of REM latency described in narcolepsy and depressive disorders could not be related to the same mechanisms.

We had also the opportunity to perform a CREST test in a patient with the DSM li]-R, cnteria of a manic episode and found an "abnormal" CREST with an REM1-REM2 interval of 153 minutes.

(2) We are performing CREST in patients meeting DSM-III-R. criteria for maior depression, before and after treatment with various antidepressants. The second CREST are realized after a washout of the antidepressant of at least 15 days in "responder" (i.e. showing at least a 50% reduction of their HRS baseline score at two consecutive visits) patients. Our first results (9 MDD patients treated with fluvoxamine} suggest that a CREST (normal or abnormal before treatment) does not seem to be modified by an SS.R.I. antidepressant treatment in remitted patient.

/n summary our work confirms that at least a subgroup of primary de- pressed patients have an abnormal or "blunted" REM sleep response to clonidine This "blunted" response could be related toadownregu la t ion of ~x-2 receptors. These results add new convincing evidence to the hypothesis that changes in ~-2 adrenoceptor sensitivity play a part in the pathophysi- piggy of depression, maybe as a marker of vulnerability. Siever and Davies (ref 4) have proposed ten years ago that such a decreased responsive- ness of regulatory inhibitory or-2 adrenerglc receptors in depression, could induce an altered noradrenergic system activity in which noradrenergic neu- ronal fidng is increased and erratic while NE released per nerve impulse is decreased, reducing responsiveness to specific stimuli.

The CREST, ~n our opinion, might be in clinical practice of great interest as it has shown in our studies a high efficacy to separate patients with malor depressive disorders and patients with other psychiatric diagnosis. The fact that, contrary to the Growth Hormone response to clonidine {ref 5), the CREST does not seem to be influenced by sex and recent use of an- tidepressants ~s important as a majority of depressed patients are women, frequently around the menopausal period and in recent antidepressant washout

References Schlttecatte M, Charles G, Machowski R, Garcia Valentin J, Mendlewicz J, Wilmotte J

(1992) Reduced clonidine REM sleep suppression in patients with primary major af- fective illness Archives of general psychiatry. 49, 637~642.

Bier M J, Greene BW. McCarley RW (1990) Norepinephrine mediated responses in the pont~ne reticular formation in vitro and in wvo studies 10th congress of the European Sleep Research Society Strasbourg: Abstract Book; 64

Schittecatte M, Garcia-Valentin J, Charles G, Machowski R, Pena-Othaitz M-J, Mendlew~cz J and Wilm otte J (1994) Efficacy of the clonidine R E M suppression test (C R E S T) to separate patients with major depression from controls; a companson with three currently proposed biological markers of depression. Journal of affective d:sorders, 1995 (in press)

Siever L J Davis KL (1985) Overview: towards a dysregulation hypothesis of depression American Journal of Psychiatry; 142:1017-31

Schittecatte M. Charles G, Machowskl R, Dumont E GarcJa-Valentin J, Wilmotte J, Papart £ Pitcher W, Wauthy J, Ansseau M, Hoffman G Pelc I (1994). Effects of Gender and Diagnos~s on Growth Hormone Response to Clonldine for Major Depression: a Large Scale Multicenter Study American journal of psychiatry, 151,2. 216-220