schulz exhibit 2

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Name:----

2nd BiennialSchizophrenia Treatment:Bridging Science to Clinical Care

April 6-7, 2006

Hyatt RegencyRegency Ballroom1300 Nicollet Mall

Minneapolis, Minnesota

This Continuing Medical Education conference is presented by:

International Congress on Schizophrenia Research;

Department of PsychiatryUniversity of Minnesota;

&

Office of Continuing Medical EducationUniversity of Minnesota

The Office of Continuing Medical Education at the University of Minnesota is committed to providing

the highest quality educational programs for physicians and other health care providers. Our goal is to

improve the health of the public through provision of local, regional, national and international educational

programs and to share the excellence and innovation of the University of Minnesota Medical School. Our

educational courses are designed to promote a lifetime of outstanding professional practice.

For information on CME offerings through the University of Minnesota, contact:

Office of Continuing Medical Education

University of Minnesota

Phone: 612-626-7600 or 800-776-8636

E-mail: [email protected]

www.cme.umn.edu

CME Medical SchoolUNIVERSITY OF MINNESOTA

Continuing Medical Education

mailto:[email protected]

http://www.cme.umn.edu/

http://www.cme.umn.edu/

mailto:[email protected]



Abstract

PI/geNu.

1

10

14

21

29

,AG-ENDA

2 ' 1 1 1 B ien nia! S ch iZ f!Pliren ia T reatm en t: B rid gin g S den ce to C lln ica! C are

Thursda! f ' . t J p r i ( 6, .2006

7:00 a.m. Registration and Continental Breakfast

8:15 Introduction

S . C ha rle s S ch ulz a nd C aro l A . T amm in ga

CAnE & CAFE: Treatment Implications from Multicentered Trials

Chair: Stephen Olson

/1-,\( 8:30) Do CATIE Results Impact Pharmacologic\_,_,,~'

Treatment of Schizophrenia? .

9:15 The First Steps - CAFE Results .

10:00 Break

10:30 What Does All This Mean? ..

11:15 Panel Discussion

12:00 p.m. Lunch

Schizophrenia I Bipolar Continuum

Chair: Carol A. Tamminga

1:30 Human Brain Imaging: Clinical Uses in Psychiatry ..

2:15 Are There Overlapping Genes and Endophenotypes? ..

3:00 Break

3:30 Treatment Implications Across the Diagnostic Continuum:

The Role of Antlpsychotics ..

4:15 Panel Discussion

5 : 0 0 Adjourn

-1-

John G . Csernansky

S te ph en CO ls on

Peter F . Buckley

C aro l A . T amm in ga

Irving l Gottesma.n

a nd D an ie l R . H an so n

Ph ilip G . J anic ak



Page 2 of 2

. - A b s t r a c tP ag e N o.

38

43

49

AJENDA, con t .

2 1 1 1 iB ien nia! S ch izo yliren ia T rea tm en t: B titfgin g S den c« to C lln icaf C a re

Frir!a! f l L j J r i f T, 20Q6

7:30 a .m. Registration and Continental Breakfast

Early Stages of Schizophrenia: The Prodrome and First Episode

Chair: Tonya White

8:30 The Biological Underpinning of First Episode Schizophrenia Robert B. Zipursky

9:15 Research in Childhood and Adolescent Onset Psychosis... Tonya White

10:00 Break

10:30 Antipsychotics in Teens .,................................................. S. Charles Schulz

11: 15 Panel Discussion

12:00 Course Adjourns

T lian f !fo ufir atten din g tliis co urse. W e li'!J 'e it wa s e du ca tio n af a nd i'! fo n na tiv e.

_TL



COURSEFKULTY

S cliiz oy lir en ia T r ea tm e n t: B r id g in g Sdenc« to C /ln ic a! C a re

Peter F. Buckley, MD, C ha irm an an d P ro fe sso r, D ep artm ent o f P sych ia try a nd H ea lth B eh avio r,

M e dic al C olle ge o f G eo rg ia , G eo rg ia

John G. Csernansky, MD, G re go ry B . C ou ch P ro fe ss or o f P sy ch ia try , Wa sh in gto n U niv ers ity S ch oo l o f M e dic in e,

Missouri

Irving I. Gottesman, PhD, Hon FRCPsych,B ern ste in P ro fe ss or in A du lt P sy ch ia try , S en io r F ello w in P sy ch olo gy ,

U niv ers ity o f M in ne so ta Me dic al S ch oo l, M in ne so ta

Daniel R. Hanson, MD, PhD, Ass is ta nt P ro fe ss or , V et er an s A ffa ir s Medic al Ce nt er , M in ne ap olis , M in ne so ta

Philip G. Janicak, MD, P ro fe ss or o f P sy ch ia tr y, Ru sh Un iv er sity Medic al Ce nt er ; Medic al D ir ec to r, P sy ch ia tr y C lin ic al

Resea rch Cen te r, I ll in o is

Stephen C. Olson, MD, D ire cto r o f S ch iz op hre nia P ro gram a nd A ss oc ia te P ro fe ss or o f P sy ch ia try , University of

M in ne so ta ; A tte nd in g P sy ch ia tris t, U niv ers ity o f M in ne so ta Me dic al C en te r, M in ne so ta

S. Charles Schulz, MD, P ro fe ss or a nd H ea d, D ep artm en t o f P sy ch ia try , U niv ers ity o f M in ne so ta Me dic al S ch oo l,

Minnesota

Carol A. Tamminga, MD, P ro fe ss or o f P sy ch ia try , U niv ers ity o f T ex as , S ou th we ste rn Me dic al C en te r, T ex as

Tonya White, MDj A ss is ta nt P ro fe ss or o f P sy ch ia try , U niv ers ity o f M in ne so ta Me dic al S ch oo l, M in ne so ta

Robert B. Zipursky, MD, FRCP(C), P ro fe ss or a nd Tap sc ott C h air in S ch iz op hr en ia S tu die s; V ic e-Ch air , R e se ar ch ,

D ep artm e nt o f P sy ch ia try , U niv ers ity o f T oro nto ; C lin ic al D ire cto r, S ch iz op hre nia P ro gram , C en tre fo r A dd ic tio n a nd

M ental H ea lth , T oron to , O nta rio, C an ada



EDUCAT IONAL OBJECI'lVES

The overall goal of the Second Schizophrenia Treatment: Bridging Science to Clinical Care is to review and discuss

psychopharmacology, the schizophrenia/bipolar continuum, and the prodrome and early stages of schizophrenia.

Fo{ fow in !J t li is c 0' !l cr cnce, jJ ar ti cj pan ts s li ou fr l b e a 6 f e to :

• Analyze and discuss the recent multicentered trials reporting comparisons of atypical antipsychotic medications in

patients with schizophrenia who have had the illness for some time (CATIE) and those at the outset of the illness

(CAFE).

• Describe the latest studies that have explored the relationship of schizophrenia to bipolar disorder - from a vantage

point of the underlying biology to the new pharmacological options for treatment.

• Identify the recent advances in the study of first episode schizophrenia and its prodrome. Attention will focus on

assessment and intervention.

CREDIT STATEMENTS

American Medical Association/PRA

The University of Minnesota designates this educational activity for a maximum of 9.0 AMA PRA Category 1 Credits™.

Physicians should only claim credit commensurate with the extent of their participation in the activity.

The University of Minnesota is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide

continuinq medical education for physicians.

Minnesota Board of Psychology

This activity has been approved by the Minnesota Board of Psychology (Board Log #0604-7520) for 4/6=7; 4/7=3;

Total 10 continuing education hours.

Minnesota Board of Social Work

This activity has been reviewed and is acceptable for up to 9.0 prescribed credits by the Minnesota Board of Social Work.

Minnesota Board of Nursing

This activity has been designed to meet the Minnesota Board of Nursing continuinq education requirements. However, the nurse

is responsible for determining whether this activity meets the requirements for acceptable continuing education.

If you intend to claim fewer than the maximum number of hours for this activity,

please sign your name and number of hours on the sheet at the registration desk before you leave.

-IV-



F .A C lJ LT Y ADDENDUM

CO'!ftlct ifIn te r e st I '! f onna tion

T he Univ ers ity o f M in ne so ta O ffic e o f C on tin uin g Me dic al E du ca tio n h as a c on flic t o f in te re st p olic y th at re qu ire s c ou rs e

fa cu lty to d is clo se w he th er o r n ot th ey h av e fin an cia l in te re sts o r a ffilia tio ns w ith o rg an iz atio ns w ith ad ire ct a nd s ub sta ntia l in te re st in th e s ub je ct ma tte r o f th eir p re senta tio ns .

T he fo llo win g in fo rm atio n w as re ce iv ed from c ou rs e fa cu lty fo r

Schizophrenia Treatment: Bridging Science to Clinical Care ,

It is n ot a ss um ed th at th es e fin an cia l in te re sts o r a ffilia tio ns w ill h av e a n a dv ers e im pa ct o n fa cu lty p re se nta tio ns .T he y s im ply a re n ote d h ere to fu lly in fo rm c ou rs e p artic ip an ts .

Peter F. Buckley, MD: Consul tant : Abb ott, A lamo Pha rm ac eu tic als , A stra Ze ne ca , B ris to l-M ye rs S qu ib b, E li L illy ,

J an ss en P ha rm ac eu tic a, M e rc k, P fiz er; G ra nt/R e se arc h S up po rt (P rin cip al In ve stig ato r o r w o rk in g d ire ctly fo r

c ompsny /c ompeny's a gen t): Astr aZ eneca, B ris to l-Myer s Squib b, E li L illy , J an ss en Pharmaceutic a, P fiz er , S o lv ay ;

Honorar ia : Abb ott, A lamo Pha rm ac eu tic als , A stra Ze ne ca , B ris to l-M ye rs S qu ib b, E li L illy , J an ss en P ha rm ac eu tic a,

Pfizer

John G. Csernansky, MD: Consul tant : El i L il ly , Sanofi -Aven ti s; Sp ea ke rs B ure au : Janssen , B r is to l-Mye rs Squ ibb ;G ra nt/R e se arc h S up po rt (P rin cip al In ve stig ato r o r w ork in g d ire ctly fo r c omp en y/c omp en y's a ge nt): Pfizer;Honorar ia : Janssen, Bristo l-Myers Squibb .

Irving I. Gottesman, PhD, Hon FRCPsych: in dic ate d no fin an cia l in te re sts o r a ffilia tio ns

Daniel R . Hanson, MD, PhD: in dic ate d no fin an cia l in te re sts o r a ffilia tio ns

Philip G. Janicak, MD: Consul tant : B ris to l-Mye rs Squib b, J an ss en , P fiz er , S h ire ; Sp ea ke rs B ure au : Abbott,

B ris to l-Myers Squib b, A str aZ eneca, J an ss en , P fiz er , S h ir e; G ra nt/R e se arc h S up po rt (P rin cip al In ve stig ato r o r w ork in g

d ire ctly fo r c omp an y/c omp an y's a ge nt): B ris to l-Myer s Squib b, A str aZ eneca, So lv ay , J an ss en , Neuro ne tic s;

Honorar ia : A bb ott, B ris tol-M ye rs S qu ib b, A stra Ze ne ca , Ja ns se n, P fiz er, S hire . I d o in te nd to d isc us s o ff

la be l/in ve stig ativ e u se (s ) o f th e fo llo win g c ommerc ia l p ro du ct(s )/d ev ic e(s ): A ntip sy ch otic s fo r m oo d d is ord ers ;

a ntic onv ulsa nts a nd lith iu m fo r p sy ch otic d iso rd ers ; d evice -b ase d th era pie s fo r m oo d a nd p sy ch otic d is ord ers .

Stephen C. Olson, MD: Consul tant : As traZene ca , B ris to l-Myer s Squib b, P fiz er ; Sp ea ke rs B ure au : El i L i ll y,

B ris to l-Myers Squib b, J an ss en ; G ra nt/R e se arc h S up po rt (P rin cip al In ve stig ato r o r w o rk in g d ire ctly fo r

c omp sn y/c orn pe ny s a ge nt): A straZeneca, E li L illy, S olvay, M erck, P fizer. I do intend to discuss off

la be l/in ve stig ative u se (s) o f th e fo llo win g comm ercia l p ro du ct(s)/d evic e(s): T re atm en t o f p sy ch osis p ro drome w ith

ant i psychot ics.

S. Charles Schulz, MD: Consul tant : El i L il ly , As traZeneca ; Speake r's Bu reau: El i L i ll y, As traZeneca ;

G ra nt/R e se arc h S up po rt (P rin C ip al In ve stig ato r o r w o rk in g d ire ctly fo r c omp en y/c omp sn y's a ge nt): Abbo tt, E li L illy ;

Honorar ia : A stra Ze ne ca . I d o in te nd to d is cu ss o ff-la be l/in ve stig ative u se (s) o f th e fo llo win g c omme rcia l

p ro du ct(s )/d ev ic e(s ): o la nz ap en e, ris pe rid on e, q ue tia pin e, z ip ra sid on e, a rip ira zo le in te en ag ers .

Carol A. Tamminga, MD: Consul tant : A ve ra (d ru g d eve lo pm en t); N eu ro ge n (d ru g d eve lo pm en t); A ca dia (d ru gd eve lo pm en t); In tra ce llu la r T he ra pie s (d ru g d eve lo pm en t); N up ath e (d ru g d ev elo pm en t); P atte rso n, B elk na p,

Webb & T yle r (fo r Jo hn so n & Johnson on a legal case); O rganon (ad hoc consultant); Abbott (ad hoc

consultant); Spe ak ers B ure au : AstraZeneca; G ra nt/R e se arc h S up po rt (P rin cip al In ve stig ato r o r w ork in g d ire ctly fo r

c ompsn y/c ompeny's a gen t): Natio na l In stitu te o f M e nta l H ea lth (N IMH ), S ta nle y Me dic al R es ea rc h In stitu te ;

Honorar ia : Univ ers ity o f C olo ra do Me dic al S ch oo l, U niv ers ity o f A rk an sa s fo r M e dic al SC ie nc es , U niv ers ity o f T ex as

M ed ic al B ra nch , U niv ers ity o f P en nsy lva nia S ch ool o f M ed ic in e, In stitute o f L ivin g/H artfo rd H osp ital, B eth Isra el

D ea co ne ss Me dic al C en te r/H arv ard , L un db ec k USA , In c., W rig ht S ta te U niv ers ity , Y ale U niv ers ity , C orn ell U niv ers ity ,

J ou rn al o f C lin ic al P s yc hia tr y; Fu ll -t ime /par t- time Emp loyee : Americ an J ou rn al o f P sy ch ia try

Tonya White, MD: in dic ate d no fin an cia l in te re sts o r a ffilia tio ns

Robert B. Zipursky, MD, FRCP(C): Honorar ia : El i L i ll y



KKNOWLEDGMENT

S tg;yo rt Jo r tlie zuiBienniai S cfriz oy fire nia T rea tme nt c o'! ier en ce

has 6 een_p roPitfedftom tliifo {! ow in !f c om j Ja nie s:

. . Gold Level

AstraZeneca

Br is to l-Mye rs Squ ibb

E li L illy a nd C ompa ny

Janssen Pha rmaceu tica

Exhibitor Level ' .

E li L illy a nd C ompa ny

Forest Pharmaceutica ls

We g ra te fu lly a ck nowle dg e th eir s up po rt

S eve ral of th e compa nies ha ve e ducatio na l d isp la ys at this con fere nce w hich a tte nd ee s m ay visit

to le arn m ore ab ou t p rod uct lin es or info rm ation rela ted to S ch izop hre nia T re atm ent.

-VI-



Do CATIE Results ImpactPharmacologic Treatment of

Schizophrenia?

John G. Csernansky, M.D.

Washington University School of Medicine

t ? - : CATIE

CATIE Trial Organization

Sponsor:National Institute of Mental Health

Contract Organization:University of North Carolina

Collaborating Universities:Duke University. Yale University. Columbia University

Contract Research Organization:Quintiles Incorporated

Sites:

57 schizophrenia trial sites

I~ (;A'l'TE

CATIE Schizophrenia Trial DesignPhaso1- Phase2 Phase3

DoubI~Ind. nadOI'll

tna,,"-"tnslgnment.

o t.A.NZ.APlNE

PartlclpantswhodlaeontllWt P.tir~pc1t1·Whod~

PM"'I<t!.2.2H.Ilthft'ttnI ~.2m22it0tl.td~c :laupiM or thezlp ,..tI daM ~I ~"g ~~tbel

fVldomlutJon~thwly1i .~';;=~~ E H A z m EDECAHOATE

oQ1.AHZAP~E

. .~~

QUE'TlAPINE

RtsPERlOONE

ZJPRAS ICOHE

dZlPRASJOOHS

~ OlNaAPJHE.QUETlAP INE or

ruSl 'ERlDOHE

o fUSPEfUDONE

PERPHENAZJNE

"1"IWG lA:~withTt)rN"'211100notgotr.mdortUod'loporpllon;u:ine:pI'Ia$&tB:p;utir;;ip.3nl3wMJd

patphona:rino'rilbe~ndon'i;tod'lo;matypical(~.QI.IfIIi;1pine,Of~lbafon:IoligibililylO'~2.

ATI E Stroup TS et a t Sch izophr Buf l .2003;29:15-31

-1-

Primary Questions Addressed

by CATIE Schizophrenia Trial

• How do the second generation anti psychotics

compare with a representat ive f irst generat ion

antipsychotic?

What is the comparative effectiveness of the

second generat ion antipsychotic drugs?

• Are the second generation antipsychotics cost·,

effective?

f): CATIE S tro up TS e t at Schizophr Bull. 2003;29:15-31.

CATIE Schizophrenia Trial: Overview

Participants

1460 people with schizophrenia

• Trial duration

Subjects participate for 18 months

• Design

Pragmatic trial that is a hybrid of efficacy

and effect iveness trial designs

t ? - : CATIF. s tro up TS e t e t Sch izophr Buf l .2003;29:15·31.

CATIE Phase 1:

Double-Blinded and Randomized

Olanzapina7.5-30 mgJday

Perphenazine8 -3 2 mg Jd ay

QueUapine201}-S00 mgJday

Risperidone1.5-6 mgJday

Ziprasidone

'P- . -",-on-s-w-;th-TO-n-o-I-as-s;-gn-.-d-IO-P-.rp-C-h.-naz-;n- ' . '4 0- 1 60 mg /d ay '

~Z lp ra s id one added a f te r 40% sample en ro l le d

TIE Str oup TS et aI Sch izophr Bu l / ..2003;29;15-31



Primary Outcome Measure:

All-Cause Treatment Discontinuation

Efficacy Tolerability

~All-Cause

Discontinuation

~Clinician Input Patient Input

-7:.CATIE

Primary Treatment Comparisons

Primary Phase 1 Treatment Comparisons

Secon@ySIOfl2B

Eac h ,&JypiQIvs.. Po~HodlborvMultiple~MfUS\I\'IQni

" " ' ~ I

Power for Pairwise Comparisons

of Discontinuation Rate

• 85% power to identify a 12% difference betweentwo atypicals (olanzapine, quetiapine, risperidone)

• 76% power to identify a 12% difference between

perphenazine and an atypical (olanzapine,quetiapine, risperidone)

• 58% power to identify a 12% difference betweenziprasidone and another antipsychotic medication

• Power is based on actual count of 1460randomized patients

l ? : : f ~ATIE 11

-2-

Hypotheses for Primary Outcome:

All-cause Discontinuation1. There are overall differences among antipsychoticmedications (olanzapine, quetiapine, rispendone,and perphenazine)

2a. There are differences between second generationantipsychotic medications (olanzapine, quetiapine,and risperidone)

2b. There are differences between the first generationantipsychotic (perphenazine) and secondgeneration antipsychotic medications (olanzapine,quetiapine, and risperidone)

3. There are differences between ziprasidone andthe other antipsychotic medications (olanzapine,quetiapine, risperidone, and perphenazine)

-7:CATIE

Primary Treatment Comparisons(Ziprasidone is excluded from all primary comparisons)

1. Overall treatment differences in Phase 1?

Inc luding perphenaz ine, exc luding TD pat ients

If yes (pSO.()5), proceed t() 2I \. and28: .

2a.Overali atypical differences in Phase 1/1A?

Exc luding perphenaz ine, inc luding TD pat ients

I f yes (p:sD.05), proceed to pairwise atypica l comparisons

3 comparisons, each eva luated at p :sD..05

2b.Pairwise atypical vs perphenazine differences in Phase 1?

Excluding TD patients

3 Pairwise comparisons Hochberg Adjus tment: smalles t p-vaiueeva luated at 0 .0513=0 ..0167

-7 :CATIE

CATIE Schizophrenia Trial:

Phase I Results

1 7 - : CATIE Uebe rma n JA e t at. NElM. 2005;353:'209-1223.

10



Demographic & Clinical Characteristics

Assessment I n = ; : . ~ 1DomoaraohicsA e mean SO 40.6 11.1

Gender1080174%Male

Race

0 While 874 (60%)

0 Black IAf r ican-Amer ican 513 (35%)

0 A ll o t he r ra ce QfOUPS 7'{5%

Soan ish /Hispan ic! La t ino e thn ic itv 17012%

Education (veats 12. 1 2 .3

Marital Status

0 Married 167 (11%)

0 Previousty Married 42529%)

0 Never Married 86~59%

Unemp lo e d 1217 85%

Exacerbat ion InPast 3 Mon lhs 402 2B%

PANSS Tot al S co re 3 0· 21 0 75. 7 1 7. 6

C finiclan Rated CGI Sever it y Score ( 1~7) 40 (O.9)CG- s o f 4 = • moderateJ ~r

Phase I Randomization and TreatmentOLZ DUET RISP PER" ZPR p;.vaJue

""336 n=337 0=341 ""'-'261 n=185

jotent-to-ueat patients 330 3 2 . 333 257 183

Average modal dose (mg) 20.1 543.' 3.s 20.B 112.8

Patients teaching malilTllll dose '''' ,,% 40% '0% 48% <0.001

Time to Discontinuation for Any Reason

OvenlI~·O.OO4'

0.'

0 .e -

o.

01P<O.OOlloro£ilnmpino V$ quatlapine

P:::O.0Q2ror~vs~

-Q.,dll","" -ZlF1olido'". . . . .-ct.

1 ~ 1 . " " . . . . ZPR

tnool:SO) t"-nl, ,. . . '" (n-tll)

21°1&,('1'.) 2&.l(!2%1 2~(74'!fo1 tll2{~"L1 I . c S I 7 1M i o )

01P.:,~.5) 1

., 5. ' as16.9,1211 1 '.0 ,6 .1 1 I • .5. 6.3 1 p.1 .S, .,

. . g : ~ t . J e rs'"

0."0.002' 0.021 O.02e

?c:CATIE

Demographic & Clinical Characteristics

Psvch ia tl ic H is to rv

Age of First Treatment for Any Behavioral or 240 (B.9)

Emotional Problem

Basel ine Ant ipsv chot ic Med ic at ions

O lanzap lne Alane . 322 (22'(0)

Que tiap ine A lone 95 (7'(0)

Risperidone Alone 275 (19%)

Combinations with 0,0, or R 125 (9'(0)

A ll O th er s ( no l O,a,R) 229 (16%)

None 414 28%,

B asenne Med ical D iagnoses

Diabetes Type I o r " 154 11%

I jy p~ rl i idemia 204 14%

Hvoertension 289 20%

Obese 8MI >=30 611 42%

13 14

Overall Rates of Discontinuation by

Reason in ITT Population

(n=1432)

Reason for'Discontinuation n %

All-cause 1061 74.1

Lack of eff icacy 340 23.7

tntolerablnty 213 14.9

Patient's Decision 428 29.9

(No te : admin is tr at iv e is induded in a ll -c ause , bul no! in any o f the o ther categor ies)

ATIE15 16

Time to Discontinuation for Lack of Efficacy

!. ~ o.. .Gr.)D~"'O.ool '' - - _i

0.& -ce-

-.j

~ 0.'a

.i0.'

J P<O.OOllar(l~V5Q\IC\i;lpine.~andpe~

0 ~. .1, 15 .r~lo~forUadtofErr~!mo)

-OtiIn1:l~ . . . . . . . . . Dpr.dcf<1".

. " '. . . . . . . . Rbp"1dono.

ou: QUIIT RJSp PER ZPR

(0-130, !notl2:9) (n"3ll1 ,='" In·,11l1

Ois<::ominuad .a { 15%J 92f2S"4) ; , ( 27%) 65(Z5%) «f2 .%)

1K;pbn-t.4eief25Ih'%UIe{1TOS 6.0 '.0 • . . 6•I I I S ' . 4 C l J 118 .0 ,-1 , . , 5 .11 .0) foI·4,9.0I '4.5,9.1\ f J.2.f2.11

tHa:.o!rdr.l tb:s l~ - 0.4' 0 .. 0.47 0.59<O.(XW .. 0.001' <0.001' 0.026

~ CATIE 1.17

-3-



Time to Discontinuation Owing to

!

, -Patient Decision

"-_Ovot; ; lfp-¥i:It..oe:: ;O.O:W

~ 0.'

f~.

E 0.'

!0.'. .• 0>

}0 3 '. 9 2 , I,

TIlT1I:!IOOi$.CO!1bnl).llho!\o..-ngIOPalionrsO&m.ion{rro)

-.,...,.. . . . . . _ . Q ! .I I It b pi . .. . _ . D _,- Rl'~M

OLZ OUEr IUSP PE R ZPR(nIKlJO) (n-l29l ,,,,,W) (n·:lS1) (n.1!l)

Oiso;l:nIitwed 78f2_".) 109(33%) 101130%) n<""" 6J{3A%)

I Kapbn-Mltior 2 . 5 1 t 1 %tile (rRJs) '".,"

.. ,3.'

( 95%cq [ B . O . 1 7 · 1 t J Il.l,7.(J] (l.1,8.61 (H.B.II 1 3 . . 0 . 6 . 1 1

I Ha:I:: lIrd~Iic)$'orOtal1t3p1ne - 0.56 0.ti7 or n 0.63<0.001' 0.008' 0.036 0.018

~ rA'l'IF. 19

CATIESchi:z:ophrenia Trial:

Phase II Results

CATIE Phase II: Treatment

Comparisons

23

- 4 -

PANSS Total Score

Interaction of t im e • treatment inditates s ign if i cant var i at i on in t re at me n t e R ee ls o ve r l im e

h n pr ov em e ru w a s Inftiany g r eal e sl w i th o i an z api n e but i ts a d va n ta g e d im in is ha d a v er t ime.

The number 01 p a ti en ts d e cl in e s o ve r a s se ss m en t l im e s. L ea s t - sc u ar e m e en e st im a te s a re f ro m a

rn i xet i model . which assumes t ha t data a re m is si ng a t r a nd om . v et oe s a t t at er l im e p oi nt s a re based on

the cuservec data f or c :o n ti rw in g p a ti en ts a s w e ll a s e st im a te d data f o r d i s c or l li n ued pa ti e nt s

~'CATIE

CATIE Phase II: Preference Pathways(for people who discontinue Phase 1)

Olanzapine, Quetiapine, orRisperidone-one of these

not taken in Phase 1

I Randomization withinchosen pathways

ATIE S lr O Up T S et at. Schizophr BUll. 2003;29:15-31.

CATIE Phase II: Treatment Comparisons

Same Strategy for liT and liE

1.0verall treatment difference?

3 d f. test

If yes (pgj.OS). proceed to 2A and 26:

za, Pairwise test treatment vs. atypical (0. a. R)differences?

3 Pai rw ise cornpar tsons Hochberg Adjus tmen t sma ll es t p -value

evaluated at 0.OS13=0..0167

2b. Atypical differences (o.o, R)?

2d. f. t es t

I f yes (pgj.05). proceed to pai rwise atypical comparisons

3 comparisons, each evaluated at p~105

~ CATIE

20

22

24



Phase liT: Baseline DemographicsTotal

(n=444)

Demographics

Ace at chase 2 baseline. mean SD 40.8 11.0

Gender

Male 308 (69%)

Race

o While 291 (66%)

0 Black IAfrican-American 132(30%)

o All a lher race orouos 20(4%)

SaanishlHisoanici Latino elhnicilv 56 13%

Educalion (veers 12.1 2 .3

ATIE


08'. . . . . . ,.

Overall P-value=O 004·

0,6

04

-02

oL-----~----~----~----~--o 4 6 12 16

TIme 1. 0 Q is c: on ti nu a Uo n f or A n y C a us e ( m o)

--OIBr1Z3plne

Oueliapine

Risperidone

• Z ipras1dOl " l! !

~ CATIE


tt

"--, Ovor . lJIP . . . . .akJu"G.D44·

ae ..."-~----

I

"-.

OA . ~"" " .... -

'2

.. , . . tz

" "T""",m~bLado.ofElraocy!.,..,)

-""",""", - -Ouetbp;,.,. , . . . .. . . .OLZ RISP QUET ZP R

n=fiG n=69 n=<;3 n=135

tsconunued 1 3';' 826% 35% 42 1%

i(aplan-MeJer 25%ilo 9.1 8.3 4.2

"~1hn(3.5.-J (29.1301 (3.0.5.9) 12.4.5.8J

Hazard Ratios for 082 050 0.49

Ofanzapine10~'s.i;541

10.28.0.96} (O.27.0.8910.038 O . Q 1 B

p\ CP TIE 29

25

27

Phase liT: Reason for Discontinuation

from Phase I

0,039

OLI RlSP QUET ZPR TotalIn0:101l) (n=1tJ.4) (11=95) fn=131J (n.:.UC) p-vawe

Inadequate Thetapeutic Elfed 54 I SO"!.) 39 ( 38%) 37 f 39~.) 54 ( 39%) 18414"".) 0221

Unao: :eplab loSideEffec ts 29(27'Y.) 46 (<<%) 39( 41%) 54 (3 9%) T58(3 8%1

OLZpairwiset~ 0.008 0.032

TIE


Overall P-value=0004'

aun=6G

44 67%

RISP

n=G9

4464%

cuar,. .,

53 84%

Z J > R

nl::'135

104 %K ap la n- Mei er Med ia n

(mas)

95%CI

.3

135.97]7.0

[41.10.0J

•. 0

(31,04BI

Z8

{2A.4.4]

Hazard Ratios (or

Olanzapine

0.65

1°.43.0.97J

0.034'

1.02

10.67,1 .551

0.939

0.S1

10.43.0.87J

0.006'

Hazard Rat io s f or

Risperidone0.54

1043,0.951

0.027"

O . S O

10.42.0.'5,0.005'

Haz:ard Rat io s f or

Queliapine

0.94

10~;d ;31 '

TIE

Time to Discontinuation Due to Patient's Decision

0.'

c. S

• . .

"

TIE

0.048

ae

2'

30



Time to Discontinuation Due to Intolerability

0.6

0.'

02

4 a 12 16rmo '0 ~!ion Owing 10 1n1ol1lf2bility l m o J

I OLI I RlSP I(n=S61 ( n=69)

QUET I ZPR I(n=63) (n=135)

Discontinued 13(20%) 7(10%) 11 1m, , ) 19 (14%)

Phase liE: Baseline Characteristics

Assessment Tota l

0=99

39.7 10.4e mean SO

~:~~~~ ,.- -.--,--'--"-- . ".. _ 80 81%

Race

o Whi t ec Black IAfr ican-Amer ican

c All o th e r r a ce c rc u es

6 3 ( 64 % .)

33(33%)

33%

S p an is h /H is p an ic / L a ti no e t hn ic it y 14114 '10)

Edu ca ti on e ar s 12.6 2.0Married 99%

lJnemployed 64 (86%)

Time to pis,continuation for Any Cause

I 0.e ) "

J 0.6- " l~ ~---------,

J 1 5 tI 17 15

T""tI~iQtMy~!IRIJ

_ =N-..t5) Ouft;a,*,,(N<I!~!

~ O f ~fJ ~ :N f n 11 f I . G

I=:m~1 , 2 . r ' ~ fl2.~

0.57 0.39 0,42

HaurtfRilt0kwCbupl'lcl 1O~~;'61 to I~!~ec] (1l*~I~~6'1

aes 0.73

H&utd R l l t i o J IooOantDpi'oa 1 O ' : ' : ii , ' :; ' 1 I C t f ; J , . ti T l

'"H&DnlFbliolllooO\lortDpiw f O - : ~

t;k CATIE

33

35

-6-

~~eIlT:Most P'r,r' '1matic Side Effects

r>.du RlSP OUEr ZPR' P,.,;;lut

(nort08) 1n:1(4) (n..-ss) In"137)

D!scontinuedDuelo 19" ""19%

""0,478

SideElleds(Total)

WeighVMctaboli(; 8% ' ' I . I " " . " "0.004

Extr .1pyr . ;1midaJ ,' . ""J ,% " . om

" " " ' ' ' ' ' ' 0% ", " , 1% 0.797

0""' 8% 8% '''I ''''' 0.591

\J

ATIE

Demographic & Clinical Characteristics:Reason for Discontinuation from Phase I

"-"- ."- " : ~ " - - " ."-~""_.""-" ""-- .. "- ..

Assessment ClOZ aLI aUET RISP Tom l p-vaiue

" " " . n=19 0"'15 n=16 0=99

I n adequa te T he rapeu ti c 4.4(90%) 16(84%) 12(80%) 13(61%) 85(86%) 0.712Err"",

U n ac ce p ta b le S id e 3(6%) o (O"k ) 1(7%) 1 {6%} 5 (5%) 0773Elfects

Patient Decision 24% :3 16% 213% 1 S% 8 B% 0.290Adminlslr.l!ive 00% 00% o 0 '10 16% 11% NT


,~:'\"L __

o-r;a p-'r. lhro" 0.010"

1 , , " 15T~lD~b'l-'O.glEIFgq>(mG)

~fN""$l ~("",.,-~!N.'n ~ 'N'=")

CLOZ OU QUET

",,",5 n=17 1'1"14

NlJITIbor 6iscontinul'ld 5 11% 635% 6 .3%

f ? ; : "CATIE

HalOIttIFQtioslorClot;Ipine 0.2" 0.16

10.01,0.78\ 10.04.0.5410.019" O.()(),C"

0 .16(0.05.0.50410.003'

HazartlFQliosfor~ 0_66

1 0 2 D . 2 . . 2 2 J0"505

0."{O,21.2.231

0.5181.03

{O.3:1, l .2S!0.957

32

34



Relapse Versus Discontinuation as

Outcome Measures100

90

~ 8070

:i s60. .

.c50e

c. 40. .30>

~ 20

" 10U)

R.isperidone

- Haloperidol

100 200 300 400 500 600 700 800

Time In··study (days)

Mean time to relapse 452 (rlsper idone] vs 391 (haloper idol) days· p < .001

7 :: CATIE C sem an sk y J G e t a I . NEJM. 2002;346:1f5.22.

Conclusions

• In Phase I.only olanzapine had an outcome that wassuperior to the other antipsychotic treatments

In Phase liT. both olanzapine and risperidone had superioroutcomes as compared to other antipsychotic treatments

In Phase liE. clozapine was superior to other treatments

Discontinuation was a common outcome across alltreatments - lack of efficacy and patient decision weremore common than poor tolerability

Judgments about relative effectiveness of differentantipsychotics are dependent~ tcome measure

ATIE

Relapse Versus Discontinuation as

Outcome Measures

Rol.llp:H

In: IdequOlllr

. . . . . . . . .Po o rcomplia~

A d " " " ".... nts

Chou tocUseonUnue. . . . . . .

foUow-up

All oU...r

10 15 20

Pationts roportJng (~.)

44.1" '_ of nspertdcne- and S2.7·A. of hatcpertdct-treated s u b Joc t s d i s con t in u od

t he : s tudy for roasons unrelated t o re lapse (not s lgn ff i can t Jydi f f e ren t ,

p : : ' .CATIE Csemansky JG et aI. NEJM. 2002;346:16-22.

25



\VHAT DOES ALL THIS MEAN? .

Peter F. Buckley, MD

Professor and Chairman

Department of Psychiatry

Medical College of Georgia

Augusta Georgia

WHAT DOES ALL THIS ~AJ.,\1= ..Outline of Presentation

1. lrriporiarice andcontext 6fCATIE and CAfE

2, Why this design

s. Dosing and design really matter

4.Switcning/ stopping mcds are the expectation, not the exception

5 "w e i g ht g a in a n d m e t ab o li c d is tu r ba n ce s r ea ll y m a t te r

6. There is :1 lot more to this than medicationsC o~ vr i: :: bl ~ r8u l :' ; 'I ( > 'o ' 2006

Cumulative Relapse Rates in First Episode

Schiz~hrenia (~'!zsggod as ! ! . % c ; : : e t s = -· ' _ t _ ' ) _

Typical antipsyc:hotics algorithm

Patients Remaining

Relapse Lower Upper at Risk at

Year Rate(%) 95% Limit 95% Limit End of Year

16.2 8.9 23,4 80

2 53.7 43.4 64.0 39

3 63,1 52.7 73.4 22

4 74.7 64.2 85.2 9

5 81.9 70.6 93.2 4

-10-

Learning Objectives

• Appreciate the design of effectiveness/pragmatic trials

• Appreciate the methodology of the CAIIE and CAFE

trials

• Explain the findings of the CAIIE and CAFE trials

and their impact on th e clinical treatment ofpatients

with SChizophrenia

• Appreciate the context of evolving use of

antipsychotics in patients with schizophrenia

Why Did We Need to Conduct the CATIE Trial?

• Issues of comparative efficacy of first generationantipsychotics vs second generation agents

·NeedforindcEcrl_~ent evaluation of comparativemerits of each second generationantipsychot£

• Complexity of clinician decision utilizing secondgeneration antipsychotics in light of adverseeffects

• Cost and formulary considerations

• Effectiveness studies may be more revealing for

clinical practice than registration clinical b;ls

Data Sources for Evaluating antipsychotics



Pros and Cons of Registration Clinical Trials_ .._-------_._._ ... _ ..---- ----..------Pro

• FDA registration

• Placebo-controlled

Double-blind

Strict criteria

• Prove efficacy

• Detect adverse events

Co n

• No optimal patient

representation

Short-term duration

Most other meds not

allowed

• Limited dosinginformation -

~b.:lSti.1:n C$, Cl:a:OI"W.Sucll.loyPF,,20~:11::~lQ.

Factors Contributing to Antipsychotic

_ _ _ . _. . E J f ~ ~ 1 i y .e _ I J _ e .~ s '_ _ _ _

Compared to ri~r:!done at a dose of 4_I!!g/day-_.theequivalent dose of quetiapilze is ..•

p _ B : - - - -

SOOm~ j . . ( . , . . y

A!x)vc 800m:

bJ~ = = = = = - = - = =JO :::D JO sc

% ot respondents (N=2S6)

Buckley. oJ C!i:: Psyc.~oph:;)rm200S

-11-

/

Eff e ct iv e n e ss

Efficacy

Effectiveness = +

Tolerability

Dosing With First-Generation Antipsychotics

"In general clinical practice, the dosage of

an antipsychotic drug used in the treatment

of patients with schizophrenia is determined

at best on a pragmatic 'trial-and-error'

basis some doctors prefer high doses

and others prefer low doses; what dosecomparison studies there are do not offermuch of a guide in the usual patient:'

.V;ln v".~<:!1 T. C ' : _ : . . S a o rv : (\ 'l :i c- P 4 \l f \. \ ! . .. e vd ~ In': t eal l f ' l l ."Ol !· ·kC"OuJ.i lnt$c!\~".Uph.mli.;I';r.t 'CIt!\. .0: I\,..;."'>! a. 5 . : .h . .!r.SC ,;0.:\ li,.- ,\'n..n"'f1'1!r-,"~""'''''''"w I'wi,""' ('fwnll:1,""j,,-,J/uHI woJ T I' nJ I . .. . , ,,, ,) A ~ ro"Ctl,;llr;c,l'I'l:!"~"" 1',"Xl

Dosing of Second-Generation Antipsychotics

During Maintenance Therapy: Art or Science·?

• Dosing of second-generation antipsychotic

medications in the maintenance treatment of

schizophrenia is currently "more art than science"

• Study information on long-term use of second-generation antipsychotics is now emerging to inform

dosing decisions

There is a conspicuous absence of fixed-dose studies

• The dosing profiles differ between second-

generation agents



Reasons to Switch Antipsychotic Medication

Persistent symptoms

- Positive

- Negative

- Cognitive

- Affective

Side effects

- Extrapyramidal symptoms (EPS)

- Subjective dysphoria

- Weight gain

- Metabol ic

- Sexual dysfunction

- Sedat ion or insomnia

- Anticholinergic

We are not yet measuring health consistently enough

Frequency of B:z.seJineAssessrnent for Weight andMetabolic

Parameters Prior to Iniciat:ing Treatment with a SG.,A.

p.~.n. '& ..m'~~••!5~~~~:!iiiiiiir--r-~lH.lght .. blJdy W.li1h~

w.I•••, ~ u m " ~ · ~ ~ ' g l : DBlood p..... u...

F•• tlng btood gluco ••

F•• tlng lipid prom.

W ~ ro M ~

Evidenced-Based Practices in

Mental Health

Prac t ice Level o f E v id en ce Extent of

Imp l emen ta t iDn

concerted TMAP lmptementatinn, Med MAP var-iable

medlcatlcn APAfPORT/exPf:n consensus

management guidelines

muUisystemacic randomized control trial:s limited

family therapy demonstration projects 'partbl fidelity'

assertive randomized conlroltriab variable

commonity demonstration projects

treatment

ADA Consensus on Antipsychotic Drugs and

Obesity and Diabetes: Monitoring Protocol

Stan 1 2 w ks12

wks wks mos. mos. yrs.

Per sona l / fami ly Hx X X

Weight (EMI) X X X X X

Wais l circumference X X

B l o o d p r es s ur e X X X

Fa st i n g g l uco s e X X X

F a st in g l ip id p ro f il e X X X

Dbbtlts cere. 27:596-601. 2004

Advocacy, Recovery, And The Challenges of

Consumerism For Schizophrenia

« ..... One o[tlt~_t;Q!!§e_qu_e!1£~s_oL11t()te

effective treatments is that aspersons

improve, they will have an increasing

ability to express their views and

identify what they see as barriers totheir recovery. »

Frese, 1998

Schizophrenia PORT

Adherence rates generally <50%

• Correct maintenance dose of antipsychotic: 29%

• Adjunctive antidepressant: 46%

• Adherence lower for psychosocial treatments than for

pharmacotherapies

• Family psycho education: 10%

• Vocational rehabi litat ion: 22%



Human Brain lmaging: ClinicalUses in Psychiatry

Carol A. Tamminga M.D.

UT Southwestern Medical School

Dallas, TX

Brain Imaging Techniques

Positron EmissionTomography (PET)

Magnetic Resonance(MR)

• PET-neurochemistry • MRI (structure)(with receptor l igands; • MRS (chemistry)

ego1,C-NMSP) • fMRI (function)

• PET-function (with • Dil (pathways)metabolic ligands; egFDG or 150-water)

The Human Brain: The Organ of

Psychiatry

H U M AN B RA IN

:::':,:

RAO!OACTiVE



D-2 Dopamine Receptor Occupancy,Long-acting Risperidone

Peak and Trough Levels

so mg 12 weexsP C . : J k Ptasma :"el(c~

75 % Occupancy

50 ",g f 2 wook:

Tro;.;gn p : n S l " : " ' . . t I Level

65%Oec:.:;>ancy

Rcminc:~o:'lat ~I. A . - - r . J ?sVCf ' l i : lt rv 2006

Alzheimers Disease:

Flurodeoxyglucose/PET

A.l.;:hoimorBr.:IinNo rm~16r . l i n

'Seeing' Medication Effects

in Schizophrenia

O r u g . F I ' C < > Haloperido l C i C C J p i n e

0-2 Dopamine Receptor Occupancy,Long-acting Risperidone

Peak and Trough levels

I

" " 1 5 . . .~ . . . I m ~ : ;

I I JRC:T1ing!on c t a t. Am J ? s yc h e: .' )' 2 0 06



PHARMACO-IMAGING

Pharmacokinetics, Detection and Likeability:

DA T Occunancv of r~-Methvnhenidate

versus OROS-Methvphenidate

Spencer, Biederman, Ciccone, et a l.

SponSOiCU by 7'v1c7'c ilPharmaceut ica ls

Average::SEM d-MPH Concentration-Time Profi les:

4() rno !R-MPH :iQ mg OROS MPH

c0' _._._" -----v-." c:

::. c'!":.o- ,...- ~ t::

'j tc, •• ~ " ). ........ ",,.v,:,"

ccupancy- lime ro lies:

90 mg OROS-MPH

S pe nc er . e t a t, A M J ?svch .2C06

-16-

Rate of Drug Uptake Into the Brain

- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - ~iv cocaine ivM?H ora! MPH

i..1m~(tfA"

~ ~ 'A 1.:

; " ; A r ;$ ' 0_

! . " . . ~

~_ ,. ., ... w. ""' .... "t ~;;" _ .' ... _ ....

l'_l_i n.-(_I

. '• ,Rapid

'.

• • • j Slow 1

"_ '~)f " * " , . - . • " . . . " ' Qoo

n.-I_I

1----------------,----------• Cocaine ( iv) and meL~y lphe~idate ( iv ) produce a ·high·bet me thy lphenidate (oral ) does no t

• The slow brain uptake of orai methy.phenicate per rn :: se f fec ti ve t rea tmen t w . t. l- : ou t a ' "h igh"

Volkow..: ~:.A l ' c h Cell P = o y c l J 1 ! 1 ' 9 5 : 5:' J N f l f J f ' O , $ . C / 2 O Q 1 ,

Average:l :SEM d·MPH Concentration-Time Profi les:

4Q mg iR-MPH 9Qm g OROS MPH

--



Listening Task in Schizophrenia

Normal Bra in

Schizophren ia Bra in

A modern MRI scanner.

-17-

OAT Occupancy vs._Detection

:R·~1?H

c o rrel auon . . 0 J!-

o

"

o oC) 0 0

% OccupancySccncor. t!: : 1 : . A . \ A J ?svch.2006

Decision-Making in Schizophrenia

Normal Bra in

Schizophren ia Brain

LAUTERBURG AND MANSFIELD:NOBEL PRIZE IN MEOICINE. 2003. MAGNETIC RESONANCE IMAGING

o OROS·\1r;~C~: J. ll on - OJ) )



Making an MR Signal

Contrast and contrast-to-noise in MR

images.'. \: ;r~:

Memory for a New Picture

~ ~ ! " " ' /

: : 1sceeaeuee: S0rm. .31 minu:; Sehi::ophroni:a

Overview

Images of Brain Activation

MovingFinger

Rest Motor Cortical

Activation

CLINICAL APPLICATIONS:

Functional Brain Imaging

• Alzheimer's disease (reduce parietal and

frontal neuronal activity).

• Epilepsy (interictal reduction in neuronal

activity and ictal excitation).

• Brain tumors (metabolically active=fast

growing; metabolically inactive=benign),

• Receptor occcupancy in drug developmentfor DA, 5HT, opioid drugs for CNS activity.

-18-



NORMAL HUMAN: SEX DIFFERENCE PROGRESS IN NEUROIMAGING

1890 2005



SCHIZOPHRENINBIPOLAR

CONTINUUM

ARE THERE OVERLAPPING GENES &ENDOPHENOTYPES ?

II. Gottesman & D.R HansonUniversity of Minnesota Med. School

Historical Roots of Dilemma

All in all it may be concluded that there is no strong1- , empirical evidence invalidatinglhe dichotomy along-

Kraepelinian lines if only the existence of someadditional nosological entities is taken into

consideration. But this is, of course, not a proof,only a suggestion that the dichotomy is still, in

general, a valid hypothesis. (1990/1994)

Erik Slrt)mgren (1909-1993)

His v iew after d iscussin9 Gries inger's (1845) Einheitspsychose andUrs te in (1912 ), C r. C loninger (1994 ) & Crow (1994 ),

0degaard Revisited

Table ij" O i ~ gn o ni c u i lt r iu u ti o n 0 1 NO~ 9 i~ n inJu patient] ;nd ( n f ir p s ydu :ni e r e l a ti v es t

f't1tt1'lU9'e0lj!JYthot;enlninl;

No"o l di" 11 lOl.n!nMring:

PlIlb,ndd..,.,OIlI P'JYdlcric

fd.:i'ft~ Sdll.laplll~"Q; Rucu., . Allfal"

PtythOlu IIfycham

_._--,Smit09!trtnQ.Jtntfd,lK1

'"78. 7.l

'"Sdljlllllhrtn4,d~ldlltd na ,,.1 5 ' : ; ' IlJ

Sd!i.lOPIlf"lt>U,l\Qcltffd

hehIlGlllretht_C'tt.l

'" " . '" ",RUC: IW tP1 l ' ch01<I

" ". H ..5 Z . . . .

AlYpial~ftl<:1inplrdloul

" ca s ,8 1 iss

Mttlic-drprenin'plythlml . ,ra.t 10.6 '0 2

-- British Concepts

--- New York Concept of Schizophrenia

Z u bi n. K r ame r.WHO,Cooper

'60s

From Farmer et al, 1987

DSM-lli Categories and MZ/DZ Concordance

Ratio in the Maudsley Twin Series

Reanalysis

MZ/DZ Concordance Ratio8,

" 1 1 1 1 1 1 1OSM-III Categories



Multifactorial Model

( a.....-.w.bUl~ I, , , , t . ,.2L, ...:u. , . .. ..L. ,.IIl. ., . .IIL,

5p00c:itk.-u.cJW>iI~

f .. L 1+21.! .. 3L! ..... L! ... aL I .eL I

~ ... ...uc.I~

I +L !.2L'.aL' .....b'.aL, ...IIL'c;;;..--.I ..... uJ lI..blllq

• _ L I _ 2'L I _ llL t - . . L ! - Ill.. I - aL I

"-""-1 -1.. t_2L,_IILI_41..,_at.t_lJLt. ._ -

Gottesman, Shields. Hanson 1982

F in al D ia gn os es (R DC ) o f T arg ets a nd

S ib lin gs , B oth S amp le s (K im lin g 2 0 05 )

HRSz HRA f f Ne--."

S ch iz O ji li re n li He fa te d - -

P sy ch o si s ( SR P )- - Z O - u , rr % ) ' 5- (4.2%) -1- (M%)-_

A ff e ct iv e P s yc hot ic s13 (9.1%) 8 (6]%) 2 (0.8%)

(S M, SP , M 1DP )

B i po l ar D i so r de r6 (4.2%) 10 (8.3%) 9 (3.9%)

-NonPsyc:notic

A f fe c ti ve D i so r de r46 (32.4%) 48 (40.1%) 74 (32.1%)

-NonPsyc:notic

Anxi e ty D is o rde rs &19 (13.4%) 19 (15.8%) S5 (24.0%)

S ub st an ce A b us e

N o A xis I D is or de r 38 (26.8%) 30 (25.0%) 89 (38.7%)

--.·."""TttU"1::l..rx:u.r:,~

--- -'''1.'or(l.!-~

Fltll-f""'"\IOl.,1I·ll_! -:;V''''1«.,U.J-w..,IW'.-~

:!1:~'=~~r:~:i!--. . "UI_~t..-I.'

Prediction of SRP: (%) Sensitivityand False Positives

Erlenmeyer·Kimling et al, 2000

HRSz HRAff

False FalseMeasure Sensitivi ty Positive Sensitivity Positive

~Attenti!lll 58.3 17.9 0. .0 0/-Verbal Memory 83.3 28.4 25 ..0 11.3

Gross Motor Skill 75.0 26.9 50.0 5.7

All 3 Together 50.0 10.4 0.0 00

- - - - - - - - -HRSz = Highrisk tor ~phlllniaHRA f l = H i g h r i sk for affedive diso rders

NC = No rma l t . on ' II l 3r i son S \ l bi e c ts ( a n se n s i t iv i ty & false positives r ol es . . 0 % )

.ccncress-wneuer.aracct,

Convergencebetweenpooled linkage results of schizophrenia

and genes relatedto glial growth or synaptic strength

1 2 3! ~ ~,? 8~ ~ ! O ~1 12_

ht j · r ; : - ~ ~ : r ~ ; r t ·r ; u , r r! ' r ~: ~';' :.~t ; ~ ,- = ~ ~ I tU

PI I L . ~ - : u• . _ . .: lNX' 1-. . !! ., : ~- - r - - s., ru:u..i II f" '· "" '- _ _ ~~ -. I r - u.. ~p-J Pt"",c:i!!' -~ •.. - .-- ... - m '

~ WtSI~ ~I!: D - ~ I r Q U n I ~ ~~~._.::- -'-";;..n--~ !!". ;: ..,~!.!~~ :::- ~ l.M'U~UC U

U ,,1-U



Weight o f avai lable ev idonce for genes impl ica ted in the

pathogenesis of

schizophrenia. bipolar disorder. and mixed bipolar-psychosis

Simplified Hypoth!>si::od Relationship 6ctwoon Specific Suscoptibil ity

Genes (above :.~eblack lino) and Clinical Phonotype (below the line)

S:J~"cptib,:,ty _'~:;:;"_;,\",

qc~(,~.

EnCOP!1cnoty;>csi~~

" '...... )'. );

~~

'_.'''_~l_---,,,.--,..~,' ..•.'.'.'"" --.~.-,.~"--,., - - .. .~.. - . , -

Cr;":'Jo.Xj,.C'o.~"",'l.C-::c.N.U;tph ..... l l ..u.t>n , .;'OOI'

~t : ' : , : ' : . . ~ ; , ; , . ~ . . . . . . . .1 0 . : : 0 ' . . . . .. c-.~\Y1'~ ~~~~

o ~;

'5 on

'"IIJ :;7

'0

h' = " - ~

~~

,g

1 ! ! " "Co :

u, . . c::

~ii:

c ~;e

~ : :: i ~

0- c ce,

Number or Inc!ependerlt RIsk Factor.;

Contributing to the Syndrome

Multifactorial Model

: "L t-::JL,.:" .. , • .u.,.IIl,.,-lILl~,-- ,\M.WJ. . . ,.

I_I .-n.t~.-N..'-""!

Gottesman, Sh i el d s, H a n son ~9S2

-23-

Behavioral Dysfunctions in

Sc/BP Psychoses are Pervasive

Thought disorder

E Affective dysregulation

Memory impairment

Attention deficits

t Perceptual disturbances

c Motor abnormalities/co-ordination/balance

f Autonomic/homeostasis dysfunction



"If we come to examine the smallest

ramifications of the cerebral arteries in

microscopical sections of the brains oflunatics, I believe it is exceptional to f ind

-----t} le-vessels---~a--- perfectly----healthy-- -1-

state ... the innermost coat of the artery

may show a variable amount of

proliferation, by which the calibre is much

diminished ... "

Brain Changes in Sc/BP

Psychoses

~ Diminished brain tissue (?maller brains.larger ventricles)

: Abnormalities of hippocampus/disruption

of pyramidal cell layer

r Variable and non-specific findings

: Gliosis is debated

,

1j

1j

0, s . s . Kc~~!M.D~R .& W l ' o J f l1 r J . ) tD ..~ti-t:~rm\!L~tD..F..A . . . F~"-.r.J!i.M.D..

K . £ . A ; ;" < : . M . D . . ,~JU . S c h m , J " ~ \ . D .

Brain Changes in Sc/BP

Psychoses

.- For many patients, no obvious8Onormality

r Imaging studies variably show decreased

metabolic activity in frontal lobes, temporal

lobes, various other regions

s Alterations in cerebral blood blow

"' would suggest, therefore, that the., .degeneration of the nerve-cells is

possibly often a secondary result of the

want of proper nourishment of the cell,-due--to-the cuttmg off Of rl:LeJJ:1 Qo d$t!:ppk _

by - di~~L_.Qr occluded _arteries.

Beadles, JMentsCiencA

~

-24-



In"!,' t •• ,~I"(). . . . . '.;, . . . - . . .

, ". ...:

": /. -

. - /_"''''''''\IH'";''''''!I'''

t'l.....·,l·.••('."H."

Realities We May Encounter

~ There are no "Schizophrenia" or "Bipolar" genes

t'- The genetic factors for SelBe are o . o t . 1 o the

brai~

IT The genetic factors in Sc/BP are not "abnormal"

r Biological & environmental factors may be

common in well & i ll (nul li fy null Ho design)

'---------------.---- -!

-25-

-;0 1~ 2

c;

i

.

2

iil

~ ~'.,Ii'

~:.~.!:

2219 20 21 x- ~ " ,5 -r s 17 'j3

,'" - . ,L,

• x ~ •- J..::; " ..

I~ .• I : . I

I - . ,.~..I

~. I

r... .. . ~ 7

Hansen & Go::csrn::m 2005

" '. "· .· . .. .. "" . .. I .: ~ . .. . ~ . . 'I . .. .. .. .. .. . t...·."(_,,~_...:"",'..,..., ....,,..

~2CC5 O,R,

Hanson &I.L

Go:tcs."nan

" /)

Reality: Psychotic symptoms in____ disease can be Sc-like or

BP-like

E Huntington

LWilson

t Demyelinating

r Inflammatory eNS/vascular

L Parkinson

s: Paraneoplastic

r Seizure



Conclusion

r There must be at least some overlap inbiological and environmental factors in the

development of both Sc and BP given:

- Causal/contributing factors are very common

- Neurobiology does not separate affect fromthought (e.g. basal ganglia disease)

( A multitude of common environmental

agents may playa role in the...----developmentofpsychoses-but-the speclflc-> ---

nature of the 'trauma' may have little

relevance---it is the body's response,

shaped by genetic factors, that determine

whether the reaction is curative or

damaging

Implications

When the facts change, I change

ny mind. And what do you do,

.•.?

John Maynard Keynes [1883-1946]

British economist & monetary exper

-26-

Implications

f Reformulating our concepts regarding

- Pathophysiology-g lia, vascular supply, & neurons

- Imaging technology

- Psychopharmacology

I Treatment--e.g. anti-inflammatory agents

I Prevention- immunization, prophylactic anti-

infectives, anti-inflammatory agents, prenatalnutrition, etc.

What next?

( To define the areas of overlap and

uniqueness, we should discourage

researchthatstudiesschizop hrenia .and,

bipolar illness separately1-- .



Disclosure Information

2nd Biennial Schizophrenia Treatment 2006Phillip G. Janicak, M.D.

I have the following financial relationships to disclose:• Consultant for: Bristol Myers Squibb(BMS); Janssen; Pfizer; Shire

• Speaker Bureau for: Abbot; BMSiAstre-zenece: Janssen; Pfizer;Shire

• Grant/Research support from: BMS; Astra-Zeneca; Solvay;Janssen; Neuronetlcs

• Honorar ia from: As a speaker for the above companies

I will discuss the following off label use and/orinvestigational usein my presentation:• Antipsychotics for mood disorders• Anticonvulsants and lithium for psychotic disorders• Device-based therapies for mood and psychotic disorders

Objectives

o To review the interplay of psychotic

and mood symptoms across the.cHagriostiC contim.ium---

o To focus on the role of antipsychoticsfor both schizophrenia and mood

disorders

o To review relevant safety and

tolerability issues

Schizophrenia and Related

Psychotic Disorders: Core Sym

Affective natteningAlogia

Avotltton

AnhedoniaSodal inattentiveness

-scnnetcerten First Rank Symptoms

Treatment Implications Across

the Diagnostic Continuum: TheRole of Antipsychotics

Phillip G. Janicak, M.D.

Professor of Psychiatry

Rush University Medical Center

Chicago,IL

International Congress on Schizophrenia Research

April 6, 2006

Antipsychotics: Indications

o Schizophrenia

o Schizoaffective disorder

-~ O~Bipolar-disordef---

o Major depression

-29-

o Psychosisdue to other medical disordero Developmental disability (psychosis/aggression)

o Tourette's disorder

n - , ~

; tchizoaffective Disorder: CoreSymptoms

o Presence of a ful l mood syndrome plusconcurrent prominent delusions orhallucinations

o Presence of psychotic symptoms for at

least 2 weeks without prominent moodsymptoms

o Mood symptoms are present during asubstant ia l proportion of an episode

o Subtypes:

• Bipol¥,.manic,depressed,ormixedtype• Depr~ive type

- - - - - - - - - - - - - - - - - - - - - - - - - - - -



First Episode: Schizophrenia

Proportion of Remission

·0. . .·•!~

c·S 10

· 12f. . 26

39

· 52Ej::

Chlorpromazine

Clozapine

P=.033·

60 6020 40

% Patients With Remitted Symptoms

-8'1 GE E logistic regression for eeceetec measvres, cxmtrol led tor gender, duntjon, and weeks of

t re atment , T he fe w as a ls o I I ! > Ig ni fi ca .n t g en du e ff ec t (pc.Ol60, ....I th m al e CD feml li e o dd s ! '; ,t Ic 01remission bSing 1.89' I but no tIonJrignt intmCllgn with drug

uecerrran JA er II. Heurops'ftnophllmlllcololl'l 2003;28:995-'1003

Acute Treatment: Schizophrenia

Risperidone vs Haloperidol:

PANSSTotal and Factor Scores (LOCF Analysis)

Fadors

UncontrolledDiso rganized Hosti li ty Anx iety lThough t E xd tem~l Dep resSIon

TotalPAHSS

~---~·--O

J-2

e-4

3 -6

Ul -6e- -to0

~ -12

~ -14

U wiG

-16

-20

S Risper idone 6 mg/d (n=255)

Haloperidol 20mg/d (n=85)

lOCF . . last Observation carried forward.·P<O,Ol risperidOntllShalooertdol' '1'$:0.05

Marder er"I,.J ClJ"Psychiatry. 1997;58:538


Clozapine Response Rates

Treatment-Refractory Schizophrenia

Duration Responders

N (wk) ("10)

Kane, 1988 126 6 30

Meltzer, 1990 51 26 61

Pickar, 1992 21 16 38

Conley, 199? 25 52 60

Breier,19~:'~ 30 52 60

Marder, 1995 54 29 54

Buchanan, 1998 61 ,';2 49

Rosenheck, 1999 205 52 60

"

100

IJ

rs

-31-

First Episode: Schizophrenia

First Principal Component

Neurocognitive Improvement

0.4

0.32*OlZ

• HAL

1: .0.3.'"E 1 iOJ:

0.2> ue cc.~E •_:I:

0.1

Composite

Keefe RSEet "I, Am) P$yd'I.iarry 2004;161:965-995, Data provided courtesy orDr ]A Ueberrnan 14


Schizophrenia Symptom Improvement:

PANSS Total Score

Baseline Study week

Analysis by last: observation camed fu rward ( lOCF ) a nd I nd ud ed s dl lU lp tv -e n\ c a nd s ct ti zo .aReat ve

patient$.

·Statlstically significant P<D.OSforIIrtplprarole, rtsperidone vs placebo (trt1ll4),Sahli AR.er ill Blo/ PsychlJtTy .. 2001;2{suppl 1):3055

______~~.v~.~·~I~_f~b~'~'~(~A-~~

Maintenance Treatment: Schizophrenia

Long-Acting Antipsychotics:

Potential Advantages

o Maybenefit treatment-refractory patientson oral preparations

o Mayimprove adherence

o Bioavailability approaches 100%

o Lower and more predictable plasma druglevels with clinically equivalent doses of oralpreparations

o Longer duration of action

o Possiblyfewer side effects, especiallywithhaloperidol decanoate; risperidonemicrospheres

18

\ tI Ja ni Ca k 2 00 6




Goals of Long-Term Management

o Prevent relapse

o Improve long-term functional

outcomes

o Minimize residual psychopathology and

cognitive deficits

o Prevent or reduce suicidality and

violence

o Improve treatment adherence


Risperidone vs Haloperidol:

Relapse Prevention in Stable Patients

100 - Ri sp er idone (mean dose: :4.9mgi n: :177)

- Ha lop erid ol (mea n dos e=11.7mg; n=188)

P=0.001

o ~o 100 200 300 400 500 600 700 800

Days

Csemansky et a t N E ro gl J />led 2002;346:16

Clozapine in the Treatment of MoodDisorders

30 40 50 60 70

Response rates (O/o)

8010 20

Frye er at, J Affea Oisort l. 1998:48:91·104: Suppes et er. Am) Psycttioltry 1999;156:1164'1169 23

19

21

90 100

-32-


Relapse in Schizophrenia

100

" 90

~ SO0-m70. .

" 60l;

SOZ~40c

~ 30

•0. 2010

0

0

ConventionalAntipsychotic

•' "I'" -I '-

•Hogarty et a l (N=374)

Placebo Prien et al (N-630)

~,J CaffeV et iII l (N=2S9)

_'r--.--'~ -r---,---.,3 6 9 U ~ U II ~ D ~

Months

B al de ss ar in l F U. T ar di ve D ys kJ ne sJ a A PA T as k F of 'c e Report 16; 1 9$ 0


Risperidone vs Haloperidol ( I-Year Study)Mean Change in PANSS Total and Cluster Scores

~ JRis:peridone H<lloperidol

-- -__. "L.

" IT\In

Tz . _ " 1 _ ' : "<. .1 1.5 ·1 .L .l

!1 * * *·2

*·3

1" ·4e.. ·5 Uncontrolled:t

*Positive HCI1JaUni otsofljanb:ed HostlUty/ Amdety/

Tolal SymPWmI Symptoms Thoughts Exdt.ment ~pre:ulon

• ~OS r ta!~ridone V$ ha1 o eendo t .Csemansj, ;y J e r " , WW S naves . 2000

Olanzapine in the Treatment of Mood

Disorders

o Superior to placebo for mania (Tehan, 1999, 2000)o Augmentat ion o f VPA or lithium for mania improves

efficacy (Tohen, 2000)o Superior/comparable to VPAfor mania (Tohen, 2000;

Zajecka, 2001)o Comparable to haloperidol for bipolar mania (Tohen, 2001)

o ra~r:~f:~~~~a~~~fa~~:~Fai~~~~~~~ig~~(~~~~~n~e~8Bho Superior to neuroleptlcs In decreasing BPRS/PANSS

anxiety/depression factor scores (Davis and Chen, 2001)

o :~ja~:~~.:'~~~~ed~p=~~~(~~elrg~,bTo"Jt)

o gro1;'~~2b'W:!,)onseto placebo for bipolar depression

Olke and lanlak., r oT N, 2 00 2

Cllantcak 2006

2 .

~-~



Acute Mania

Similar YMRS Improvement in

Nonpsychotic and Psychotic Subjects _

Study Ithree weeks

29.58 27.56

Study IIfour weeks

30.8 25.5aasenee:

. . . . -5v

~Q

'" -10

~J:u

-IS

~z

Acute Mania

Risperidone* vs Placebo

• ! ' o !" , , , , '. 1 T 'QC.e :t ~IXC .. "-,~ ~r;Jt!tt.,

__._.}t~~~.,-~,J:..~.." ' . '. ; I _( "~ ' I. _ _ ,

M,.-••C1\t.'!;(! eo : ~t :!oo:!

Acute Mania

Improvement in YMRSTotal Score,. .

e l Stu<ty: . .. . l

.:: :

c; :: ; rs. ."

I t O l ~ ' " "';; ~2 .. ....QTP <"_lQ8)

:c 0.- ....,.PBO(n_195)

.714::1 13 41 ~ 70 ...

0 .,

CI~1Study 3 ...<4

e 1~'

:l~

i: J~...j

~~4-~

: :~ +QTP + ru Of' OV?) (n.:'B5)

:r : o.::(LJ orOVP) +PBO (n-18S)

o 14::1

Doy

- e-c c o: .-s euo ~p.:~ 0;. vo; ~C. '::"C.OC: ~!"nO ·~·'O,Oo:."o;::...; c.I' OW) .. Pt:O.-" - _., - - _ , ,- ..- .. . _ .._ .. ,.." . . -_

C':'"P-~o.t:I.~; rt\O-~!.Io:~; ~""UI:"'<T!; 0Vf' ..c. .1!"~,

~:.> 1 ; 1 < \ '<If:, ...~~.....~"'~ Ph4"""KNt.u..'!; .,fi', Wi!,... c ; r . O I " I . or;

Risperidone in the Treatment of

Mood Disorders

::;Monotr.<:r.JPYsuperier to pteeebe for acute t':'l.1~iJ (Vu:!:~2002:H\r-_.c,:',Cld,2002)

:: CompOlmble to lithium Zlnd h31operidol :o~-n...U:"')(Scg;,t e: lll.1995)

C Augment4J tion effec tive rn !>ipo!a:- ;Jnd:-;C'h:o.lr,'ed:ivcdisorder (Toncnct .)!, :'996; Yath.)r."I, 2000; Vict,) et 031,200:,

c : LonO~3ctjn~ fOMnubtion m.:ty :'\J:VC a -e'c {~c.."'~ et aI, 2000)

:::scceeer to ncufo:c:ltiC in C::CC"C')::;. i !" l9 BPR$ 3nxiety/depresslon

f:J:ctor scores (MJ:fC:cr, O;'V!$. C~Ol:Ir\Jrc:, 1997)

: : A c . :Gmc ! 1 t .a : ;o ~ e ! :c : c. :i v < ; i:'l m.oJ:jor depN: ss io n W :: l' 1 o r W)thOl.!t ~chQ!;.l:;

( O: :; :ro :" :' " ne : N e! :: on . : '9 99 ; s ee n. 2 000; ; ;: sn tQ k c t at, :;'l.ibmittc::d)

C Monothcr,,::>yerrecave in s.chj:z:~ff~ve di$Order (J.."In:C.)i(e t " I.200~)

r-t Two double..blind, controlled trials ~oracute mania(n=604) ~si"g iithium or haloperidol asactivecomparators found quetiapine superior to placebo.

I~·_····_~~·· C_Two_double.blind-controlled-trials·found-<luetiapine-·~· ---'~-'---'--~~--combined wi th li th ium or divalproex super ior toplacebo.

Dot.:bie-blind,placebo-controlied trial of quetiapine(450 mg!day) combined with divalproex (20mg/kg)tor 6 weexs in ~Omanic or mixed bipolar I .adolescents, Su~erior to DVPXalone andwelt-tolerated,

-33-

Quetiapine in the Treatment of Mood

Disorders

CJ Two double-blind, plecebo-contrctted trials of quetiapinemonotherapy (300 or 600 mq/dav) superior to placebo

for bipolar depression (BOLO:R !and I!studies),

Ziprasidone in the Treatment of

Mood Disorders

o Ziprasidone superior to placebo on 6PRS manicitems in schizoaffective disorder (Keck et ai,2001)

o Ziprasidone superior to placebo in acutebipolar manic/mixed episodes (Keck et al,2003; Potkin et ai, 2004)

o Ziprasidone superior to placebo in redudngmean MAORS and BPRS depression clusterscores in schizophrenia and schizoaffectivedisorder (Keck et ai, 1998; Daniel et al, 1999)

:.



-.- PI .ceb o (n=122 ; Mean 8 ,.el1ne, 2'.7) 0 Convincing monotherapy evidence for

o -0-Ariplpr.owle (n=123, Me.n 8ase l lner 2B.2) efficacy in acute treatment of mania; onset

'e--L-j\"\"--'-·,·-·--------:---··,·, ._I .__...-=~o~f-a-ct-io-n~w_:it-h-in""'":2-:-4-d-a~Y~s--__:__:"::---c~

~~ 0 Strong evidence for or augmentation or

g > ; combination in maniame

~~ ·6 0 Future studies need to focus on subtype

: III ·7 * response patterns::E -8

-9 • e.g., mixed, rapid cycling, substance-10 J_~~ __ ~ ~________ abuse comorbidity

Acute Mania

Ziprasidone vs Placebo:

Mean Change from Baseline in MRS" 14 21

·2

· ·4

'"c -s·""e -a··:t '10

-12

-14Placebo (n:::66)

-a- Ziprasldone ("=131)

(80-160 mg/dav)

p<O.Ol.

p<O.DDl vs placebo,

ICed.et')l Am} Psych/arty 2003

·P<O,OI v5plecebo,t..OCf Inaly!>ls:

KeeXeti\l" Am)PsydJJ.)rry 2003

Acute Mania

Aripiprazole vs Placebo: Mean

Change from Baseline in YMRS

Day4 Week1 Day10 Week 2. Week 3

Acute Bipolar Depression

Olanzapine-Fluoxetine Combination(OFC)

• P lacebo (n : :: 355)

.6. Olanupine (n:::: 351)

o Qlaru:apine-nuoxetine combination

(n:::: a2)

.P< .05'1$ placebo.

Tonen MFJr. et II An:h Get'!Psych/dtry" 2003;60:1079"1088. Erntum In:Arttl Gert PSyct lio lt ry 3S2004;6:176

Jl

JJ

t*

-34-

Acute Mania

Arieiprazole

AripiprazoleDuration Mean

Study (wk) Comparator Dose (mg) Response11 3 Placebo 28 40%/19%"

2 3 Placebo 15,30 41«¥o,4solo/38%-

Placebo 28 510f0/31%"

4 12 Haloperidol 22 500f0/28%'

IKetk, er ill. Am J Psydll",try. lOOJ;HHl:1651.

Data on file. Bristol·Hyers SQuibb Company and Otsuka Americ:DFhlrm<aceutlcal. lrn;; 2003

Summary

SGAs in Acute Bipolar Manic/Mixed

Episodes

Acute Bipolar Depression

Mood Stabilizer Plus Risperidone

and/or Paroxetine

f8III

Q

:E. .::: 8

6

. . Risper idonC! (n; :: 10)

,o.'Pilroxetine (n ....lQ)

- e - - Risperidone + p.;lto'ICetinti (n = 10)

0123456789101112

Week

Sheltcn R. Stahl S J ClIftPsydIIatry 2004;65:1115--1719

32

J'



Bipolar Maintanence

The Role of SGAs

o Studies of maintenance ant ipsychotic therapy in

bipolar disorder are sparse

• Only studies to date are for olanzapine andaripiprazole

• Some lonqer-terrn acute trials (eg, 12 weeks)

provide indirect data (quetiapine, aripiprazole)

o Role of SGAs in bipolar maintenance is st il l being

refined

• Long-term tolerability is a critical factorsince pat ients wi ll not take drugs they cannot

tolerate

Strakowsk i SM, eea t El tf J Op Pharmllcofner 20DJ:~(5l:751~760

Adverse Effects

Adverse Effects

H.aloper ldof Cblaplne Risper idone Olart t.apine OUetiapine Zlprasidone Aripiprazol~ ,

Objectives

EPS· 0/. 0/' 0/'

We i gh t g a in 0/.

AIltichol ioergic 0/' +/++ 0/' 0/'

HemalDlOgical

Cardiovascular

Endocrinological 0/. ",. ",. 0/.

SedatiOn ./ -0A! a p pr o pr ia t e d o se s ; o e ncoe: • "'mild; -=mode ra! .e : : + +- + '" Substantial

Adapted f rom Masand PSee if H .Jndoaok o f P : ;y eh i. 6t ry I n Priml Jry c "r r. 1996

o To review the interplay of psychotic

and mood symptoms across the----I--.----dia~gn-o·stic-continuum----··--·------·- --- ..-._--.---

o To focus on the role of antipsychoticsfor both schizophrenia and mood

disorders

o To review relevant safety andtolerability issues

CJaric:lk2000

-36-



The Biological Underpinning ofFirst Episode Schizophrenia

Robert Zipursky. MO.FRCPCProfossor of Psychi:>try

Tapscot t Cha ir in Schizophren ia Studies

University of Toronto

The Dopamine Hypothes isof Schizophrenia

• Drugs that block dopamine O2receptors resolve psychosis

Relat ionship Between Base line Dopamine Levels

and the Decrease in Posit ive Symptoms Measured

After 6 Weeks of Ant ipsychot ic Treatment

0

SOI 0.5r'= 0.58. P = 0.001

~ !!X l I

" "40,

0

~j

30 !~ 00

~ 20 0 00<:

0 00

101

0 0

I , 0

0:: o~~-----·-o~ -60 -s o -40 -30 -20 -10 0

C h .. .1 n go i n P o si !l vo S y m pt om s

Fol low ing 6 Wool u o f An:Ij)~yc:hOtie TroJtmGnt {.":')

B iology and Illn ess Ou tcome

• What is the nature of the disease weare treating?

+ Is schizophrenia a neurodevelopmentalor a neurodegenerative disease?

• How does our understanding of biologyinform our expectations about clinicaloutcomes?

.. .

Haloperidol and D 2 Occupancy

How Quickly Do Antipsychotics Work?

! Immediate onset ,

~;]I

I

Time (weeks)

k : o < : : O. K.l:wr S, AIenovWt ':'.~--ky RJl kr:It Con P: : yr ;h imry . :ZOCZ;( ;O:~ZU!.-~Z::

-38-



I~~~~" '- - - - - - - - - - - -. .- - I ~ ~ ~ ~ . = - - - - ~ - - - · - - - - i . ~. .- . -

~ .. . . . . _ . . .. .

Perc en t Im pro vemen t Over T ime(Core Psycho ti c Symptoms)*

WC'Ckso! Treatment

.p < C ~ . PV~ I. OC~ ~~(e:;cn: the m..'ldl C~t.'d 0: ~me_Ef':'Of ! : m r - : . tt'prC"~: SE,

MCOr.I::I1 /.If:J'lGoI7nP:;yctu;ay :::lC:.GC:~:'Z~~~

Gra y Ma tte r Volume Defic itsin Sch izophren ia

+ When are thei_evident?-"------

+ Do the deficits increase over time?

+ Is outcome a function of the magnitudeand distribution of gray matter deficits?

+ Is the course of illness determined byongoing loss of gray matter volume?

B ra in A bn ormalitie s a nd Outcome

F :f !" '. J:' C 1. C o ro na l S ec ti on . .. . of t he B ra in . .~ o f:! P ati en t W i:. .. "Schizophrenia Wi3 1

Poor Outcome, !lPatient W~:'hGood Outceme. and :lHC':l l thy Comparison Sl:ojec.

Staa l et al, Am J P s yc h ", :r y 1 5 S :1 1 4 0 .1 1 4 2, Ju l y 2 0 01

-39-

BPRS "Psy cho sis " F a cto r Shows Imp ro vemen t

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Gray Matter Volumes Change with Age



t-yr Change in B ra in Volumes

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Cabn . W,d r:1 (1001) ~rch G t 1 I Ps.vcAi f l l ty .59.IOOloIOIO

If the bra in a bnormalities fou nd in

.- __ schizophrenla.are. notprogressiv.e,---then why are the long-term cou rse

and outcom e so poor?

Berkson 's Fa llacy

~ . - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - ~

. .. t h ose who have o ther d isab iliti es th at a re notcausa ll y connected to the condi tion being inves tiga teda re more lik el y to ente r t he fo rmal tr ea tmen t s ys tem

.. . th ese e tio lo gicall y unrel ate d condi tio ns may have apernic io us i nflu en ce on the cou rse o f t he il ln ess.

P . C o h en . J C o he n. A rc h G e ne ra l P s yc 11 ia tt y 1 98 4; 41 :1 1 71 1 -1 1 82

Whole Brain

Volumo

(co,

- -_tIIIcIb_

pelleU

'~I

Z i p u r sk y e t ;1 1 , S c h iz o p h r en i a R e s ea r c h 2 0 04 ; 71 : 5 15 . 5 1 6

The Clinic ian's I llusionP . C o he n, J. Cohen, Arch Gene ra l Psych i a try 1984;41 ;1118- 1182

--

. .. t he a tt ribu tion o f the cha racter is ti c and cou rse o f those_..p_atLellis__w_ho_are_currentlyJllJoJruu:mfire.pop_ulatiQocontracting the i llness.

... t he c lin ic ia n's sample is b ia sed towa rd cases o f l ongd ura tio n s inc e the prob ab ility tha t a c as e w ill ap pe ar in ap reva lence sample is p ropo rt iona l to i ts durat ion.

Time to Remission in F irs t Episode Sch izophren ia

Lieberman J, et al AIr:h Gen Psych i a tt y . 1993;511(5):369-376.

-40 -


http://slidepdf.com/reader/full/schulz-exhibit-2 41/90-41-

R ecovery from psychotic illness:a 15- and 2 5-year internati?~al fo llow -up study

G .Ha rr is on c t 0 1 ; ,

B r it is h ~ou " 'o l o ! P s y ch i o tr y ( 2 00 1 ) . 1 7S .5 0 s. .S ~7

+ 14 inc idence coho r. .s /4p reva lencecoho r ts (N = 1633)

+ % t im e p sy ch ot ic in f ir st 2 y rs b es t p re dic to r o f o ut com e

+ - 5 0% o f t ho se w i th s chi zophr en ia r at ed a s " re cove red "

• - 4 0% h ad n ot b ee n p sy ch otic in p as t 2 y ea rs

• 5 6- 74%we re wo rk in g f or m o st o f t h e p as t 2 y ea rs

Wha t det ermines t he ou tcome f rom sch izoph ren ia?

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G~:;,~~:.~e~~::;~r.t;;~,~ c e ; ~ s : r . ~ m . ~ : i~~I protocol

Why do so m any patients do poorly?

+ Premorbid deficits

• l imited access to needed interventions

• Non-adherence with resulting relapses

• Downhill spiral due to stigma, poverty.homelessness, unemployment



Research in Childhood and

Adolescent Onset Psychosis

Tonya In, i/e, M.D., Assistant Pro fe ssor

Division o/Child and Adolescent Psychiatry

Unt'versitv Afflliations:

Departmen t o f Ped ia tric s, Insti tu te o f Child Development , Cen te r for

Neurohehavioral Development, 'Center for Magnetic Resonance Research, Center

for Excel lence in Children' s Men ta l Heo .l th

Communin, Affiliations:

Board Member: Minneso ta Assoc ia tion for Children' s Men ta l Hea lth,

Educational Network of Minnesota

The Team

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Schizophrenia - The etiologic puzzle

ra re .

M al es ha ve ea rl ie r a ge o f o nse t

B o th g en et ic a nd e nv ir on m en ta l

c om po ne nt s i nv ol ve d

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s ym p to m s o f s ch iz op hr en ia

I mp ro ve me nt o f p os it iv e

symptoms wi th typ ic a l

neu ro lep t ics

Im pro vem en t o f sy mpt om s an d

c og ni ti on w it h a ty pi ca l

neu ro lep t ics

Phases of Schizophrenia

Pre-l lIness

Subtle Neurocognit ive

& Social Defici t s

• M ot or f un ct io n

• A t t e nt i cn

Symptoms o f

Schizopbrenia

• H a l l u c in a t io n s• W o r k in g memory

• D ef ic it s i n s oc ia l

cognit ion

• D e l u si o n s

• D i so rg an iz ed t ho ug hl

• D is or ga ni ze d s pe ec h

• N e g at i ve SymPtoM

Relationship between the Onset of Psychosis and a

History of Cognitive Decline and Social Withdrawal

A T im e u e e Approadl

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-44-



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statisrical parametr ic map

o f gr;lY m : : : u c ! ' reductions

(Zvscorc =,,5),

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Working Hypotheses

• Research is directed to test one or severalworking hypotheses

- The information gained through research ei ther

supports or disproves the working hypothesis

- .Working' refers to the possibility that newinformation m ay r esu lt in a ch an ge in th e

hypothesis

• 'Our Working Hypothesis

: - Schizophrenia involves a developmental

. disrupt ion in the communicat ion between di fferent]

bra in regions.--~=------,----...c....---M

-45-



Testing the Hypothesis: How?

• If there is a problem with the connectivity

between brain regions. how do you measure that

in living people'?

- Diffusion Tensor I rr '& l lg ing

- F un ctio na l M ag ne tic Resonance l rnaging

- Elcctroenccpholography

- Magnctocnccphalography

B r o li n I n 1: 1 : :i n ;: : in Childhood :InC Adolescent Pxychiarric Disorders

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-46-

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Alterations in Patterns of Gyrification in

Development and Schizophrenia

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Antipsychotics in Teens

International Congress on Schizophrenia Research

Schizophrenia Treatment: Bridging Science to

Clinical Care

S. Charles Schulz, M.D.

Professor and Head

Department of Psychiatry

University of Minnesota Medical School

Disclosure Information2nd Biennial Schizophrenia Treatment 2006

S. Charles Schulz, M.D.

I h av e t he f o ll o wi ng f in an ci al r el at io n sh ip s t o d is cl o se :- C o ns ul ta nt f o r E l i L il ly , A st ra Z en ec a

- S pe ak er 's B u re au f o r E li L il ly , A st ra Z en eC 2

- G r an V Re se an :b S u pp or t f ro m A b bo tt , E li L il ly , A st ra Z en ec a

- S to ck ho ld er in N on e

- H o no r ar ia f ro m A st ra Z eo ec a

- E mplo ye e o f N o ne

I w il l d is cu ss t he f ol lo w in g o ff l ab el u se a nd /o ri nv e st ig a ti o na l u s e i n my p r es en t at io n : An t ip sy ch o t icm edica tio ns, a s n one a re a pp ro ve d f or u se in p atie ntsu nder 1 8

• To describe diagnostic and epidemiologiccharacteristics of schizophrenia when it occurs in • Psychotic symptoms of p eople who developteenagers schizophrenia frequently begin during teenage

___ .1__._" To sample neuropsychiatric studies of adoles.c~llts._.__ .I I._._ ...) 'ears - maybe as many as40%of cases in lJI.J!kL--.I ....------··--·with schizophrenia that illustrate a similar (Loranger, 1984)pathophysiology compared to adult subjects • The diagnosis of schizophrenia is generally stable

• To review studies of pharmacological treatment in in the first episode after 6 months from indexadolescent schizophrenic patients interview (Carlson, 1994)

• To conclude with a synthesis of the use of • Outcome may be poorer in earlier onsetantipsychotic medication approaches to schizophrenia; however, large scale studies haveadolescents with schizophrenia. not been performed (Ropcke, 2005)

Objectives

Early-onset Schizophrenia: A IS-Year Follow-up

Rdpcke. B and Eggers , C: Eu r Ch i ld Adolesc. P s yc h ia tr y 2 0 05

In tr od uc tio n: T he o bje ct iv e o f t he s tu dy w as t o a sse sso u tc ome i n a do l es ce nt s w it h s ch iz o ph re ni a 1 5 y ea rs a ft eri n it i al t r e atmen t

M et ho ds : G l ob al sy mp to m s a nd G l ob al A sse ss me nt o f

S o ci al F un ct io n w e re t he m a in m e as ur es

R esu lts: O f th e 55 su bje cts, 8 5% w ere fo und a nd 71 %in te rv ie we d. F ul l r em iss io n w as o bse rv ed in 8 % , m o de ra teo utco me in 56% , and po or o utco me in 36% . S ev ere o rv er y se ve re im pa ir me nt ( G AS F ) w as n ot ed f or 5 1 % .D ia gn osis w as st ab le o v er t im e f or 7 0% o f t he sa m pl e.

Conc lus ions : In t hi s s am p le t he re w e re m a ny s im i la ri ti es t oa du lt s ch iz o ph re ni a a nd s om e d if fe re nc es f ro m YEOS ,

-49-

Diagnosis and Epidemiology of Schizophrenia

When ItOccurs in Adolescents

Brain Imaging Studies Reveal Morphometric

Differences Between Adolescent

Schizophrenia Patients and Controls

• MR1 studies reveal differences in ventricular and

cortical areas (Rapoport, 1997; Friedman, 1999;

Kumra, 2000)

• Imaging studies suggest possibility of

"progression" of imaging measures during

adolescence (Rapoport, 1999), but not in all

studies (James, 1999)

• Functional imaging studies also show differences

between patients and controls (Jacobsen, 1997)



An MRl Study of Adolescent Patients with

Either Schizophrenia or Bipolar Disorder as

Compared to Healthy Control Subject,

F r i C \ .l : n ;t r . L ct c!.. B _ i £ l J . 0 : :i ~ ! P ~ ' . ! !. c . 1 i. : .1 ! ! Y .: ' ) ( } ( '

Alterations in Patterns of Gyrification in Children

and Adolescents with Schizophrenia

Cognitive Impairment in Adolescents

with SchizophreniaKenny ct al.. Am.l P~}:c..hl~!r.Y.1997

Q l J l r ; _ C J 1 V C : To assess adolescent subjects wi~h schizophrenicl ! S i n g en objective neuropsychological battery

~-;; Adole sc ent patie nts (N~ 17)were compa re d 10controls (N~~17)utilizing en age-appropriate neuropsychological

battery

R~lJlf$: P a th : :l ts w e r e impaired o n n e ar ly all measures v...i:h

th eir g re ate st d iffic uh y se en in working memory a.,d attention.

C o nc lu sio ns : T he subjects h : Jd a generelized cogni tive

dysfunction with g r ea te s t d i f f ic u l t ie s i n a !! C !1 :: o n z n d. w o rk i ng .

memo r y

(The authors have t.•tilized t he se f in di ng s t o p la n clinicaltreatments in day hcspital !t.~dcutpcticnt cl inic)

-50-

An MRI Study of Adolescent Patients with

Either Schizophrenia or Bipolar Disorder as

Compared to Healthy Control SubjectsF riedm an :._ tlal., RiQ!o ~·;~~ .?Lf2;; .~..r .J:!!!: .y~: QQ< )

Progressive Cortical Change During Adolescence

in Childhood-Onset SchizophreniaRapopo r t JL c: al.• 8!:£h.Q_~~Qj:1;"'. 1999

Neuropsychology Battery

• Employed a comprehensive neuropsychologic

battery of tests including

- Atten tion (St roop. Digi t Span Dist ract ion, Paced

Auditory Seria l Addition test)

- Working memory (trigram recall)

- Verba l memory (lis; l earning, logic al memory. word

g c " . .neration)

- Exe cutive func tion (Wisconsin Card Sorting Test,

maze test)

- IQ (informati on. similarities a nd block design tests of

the Wechsler intelligence scale for children



WORKING ME:'>IORY

"V('ch~cr Tower o r London BRrEF Workin:,:

Workin;: ;\tem. Test :\1cmory Sc",1('

Figuro 1_EXJmplc of !i"..::lbloworxi~ memory c c r l e i : : : : . in

a do le sc en t p C) ~ ic n~ with sc.'11zophrcniorS?<!CO.r.Jrr.eo~cmlo i ' . s


Schizophrenia Treatment: Bridging Science

to Clinical Care

Neuropsychiatric Measures

• Studies illustrate the similarity of adolescent

to adult forms of the illness and point to the

need for engaging treatment

• The neuropsychological tests also illustrate

the pathophysiology of the illness and may

be carefully used in treatment planning

-51-

Neurocognitive functioning and clinical status

during the first year of treatment in

adolescent-onset psychosis.Wozn~k_'; r:t, W!"Jto. ;,J . Jensen ••L . 61oc:k. . E . . Guim; )r .}C! ;. A . Loi ::cn , w,. So

Sc:.'utz. S C (2006c Fcbr.:ary).

Overview

• Males ::md1crr~lc~. 3SCSi2 - ,7• S chi zo p hr cni fO t r. " l. S c ." ' I. : ;o ;:m ro nt ; l_ & SChlZoOlH'Cct!VC

• Exc l~ : ;i o :, :s : iQ < 7 0 . n cu ro lo gi c: :1 d ls -o re c r o r i nj ur y" c o ne it io n 3 ~CC " J: 1g or ai n.

POD, oeO. suestaocc ceosc• W ' .. :J jo r it yo f p .: lt ie n ts w e re o n a ty pi co l o :m u ps yc ", ot ic m e ci cn e s

• E nro l:cC , n = 3 0; T we lv e m o nt !' : f o! :o w . .u p, n = ~C

M:lin finding:!; wore:

h C og ni tiv c d ofi cits o f o b ov t , S O w er e e vid en t a t b as elin e i n m a rr y ~ or n. Jln s

. . A ! !. ~ouSh symp tom! ; ! lu c " '. . .. :. a t( . oCo ve r 1 0i lo w. .y p o ne , g on er al ly . i mp ro ve d ~ y o ne

yC3~wi!.~ t . " 'Oat rnc r. : . , cogni tivc func tioning wa s Quite sbblco

• T he re w as n o s :. ;b s: an ti al c V. .c !o :" '. eoo t e : cC : !' ~ nCY .imt> ro vcmc :\ ! i n mos : O:"COS

o ! cogn i ti ve ! u :" IC "j o nin 9o

Prt:!.CnUJc 0. : me $J'cr.nutlltlir.:or W o rk :; ho p o n S ch i: op hf 'C fl iu R C :; l' Jl Jf Ch , D :w o :: .

SwrlZI) I'1:, r , (J,

P RO CES SJ :- 1G S PEED

W<'dnJC'rPrO(~, SlroopColor COWAl"f luctJ(y

Spc:1:'d fl ldcx Naminc

Figure 2. Examplo o!s t. :J b :C d e f ic it s i n p ro c es s in g s pe e d I n

adole scen t ~ t icn ts w i t. ~ se .~ l ;: !O i 'h ron ia~s ;: >o c: r tom condi ti o ns

{b::lSCli r:o :md 12 mont: l (tT..l shO'Nn)

Duration of Psychosis and Outcome

in First-Episode Schizophrenia

• Severity of'first-episode patients was followed for

three years to examine the impact of length of

illness on outcome

• Duration of psychotic symptoms was related to

time of remission (p=0.03) and level of remission

(1'=0.0])" Prodrome was also related to level of

remission ( ; r O c O O O } ) .



C linica l R espo nse to R isperido ne

Trea tmen t

Pretreatment Postt reatment

Variable Score Score p Value

BPRS Total 48,88 ± 745 30.06 ± 6.35 -7J7 p<MOOI

BPRS

Negative

Symptoms 1138 ± 4..62 V5±3,72 -4.26 p<O,OOI

COl

Severity of

Symptoms 556 ± L03 338 ± L03 -5..35 p<0.0001

[hw;uemeans;tSDs

BrRS" Bri c: rp sy th ia tr ic Rat ing S ca le [Over af and Gcrbam. 1982)

CGI" Clinic:J! Glohallmpress ion [Rapoport, 1985)

G rcev ieh S e t al , J Child Adolesc Psvchoph:mn, 1996

Childhood-Onset Schizophrenia: A Double-

blind Clozapine-Haloperidol ComparisonKumra Set at, Arch Goo Psychiatry 53:1090-1097, 1996

B ac kg ro un d: T he sa fe ty a nd e ff ic ac y o f c lo za pin ew as a sse sse d in a t re at m en t-re fra ct ory g ro up o n

COS

• M et ho ds: A six -w ee k, d ou bl e-b lin d c om p ariso nw as pe rfo rm ed w ith 21 su bje cts (m ea n a ge 1 4,0)

R esu lt s: C lo za pin e w as su pe rio r t o h al op erid ol intre atm ent o f psycho sis. T he a utho rs no te tha t the

n eu tro pe nia a nd se iz ure s w ere o f c on ce rn

• C onclu sio ns: C lo za pine w as su pe rio r to

h al op erid ol in t his d if fic ul t t o t re at p op ul at io n, b utc ar ef ul m o n it o ri ng i s n ee de d.

A Com para tiv e S tudy o f A typica l T he E ff icacy and Safe ty o f O lanzapine in

A ntipsycho tic T rea tm ent o f P sycho sis inA do le sce nts w ith S chizo phre nia : T he R esu lts

Adolescen tsfro m a D ouble-b lind, P lacebo -co ntro lled T ria l

Je nse n J et at, Schizophr Bull 31:488, 2005 Ludmi l laK ryzhanovskaya ,M.D . ,Ph ,D . I ;S . Char lesSchu lz ,M .D .2 ;Clu i s topher r, McDoug l e ,M .D . ) ; J e anA .

· I nt ro d u ct io n : F ew s tu d ie s h a ve e x am in e d a t yp ic a lF r a zi e r,M .D . ', Ra l fW . D i t tmann,Ph .D .,M .D . 5 ;Ca ro lRQb.er tson:Elo_u(;h,j ) .YM~;J1Jl: r_esa_Bau,et,J l,S.~;W ~ I 1__ _

antipsychotics in - t een age r s, E v en f ewe r h av e- -- -- -· Xu , P h .D .I, W e i v . .W ang ,M .S .I , J a ni c eCa r l son , P h .D .I ,c omp ar ed c omp o un ds Mau r ic i oToh en ,M .D . , P h .D . '

·Me t ho d s: P a t ie n ts w i th a n o n- af fe c ti v e p sy ch o si s w e re I Lil ly R e se n n: h 1 . .c l l~ I n di a na p ol is ., I N

r an dom i z ed t o o p e n t re a tm e n t w i th e it he r r is pe ri do n e ,2- U n iv , o r M in n es o ta M e di ca l S c ho o l. , M in n c: tp O li ~ . M N

J I nd ia nf l U n iv e rs it y S ch oo l o r M e di ci ne . l nd ia na po li s. . T N

o l a nz a pi ne o r q u et ia p in e a t FDA - ap pr o v ed d o se s, C ll tt lb r id g e H e al th A l li an c e, M c Le an H a s: pi ~ ~ H l I J " V a r o M c rJ ic al S c ho o l, B o st o n, M A

s l.illy D e ut sc hl an d M e di ca ! D e pa nm a u. G=y a nd D tp .l lr tm en l o f C & A Psydloromalic

· R e su lt s: T h e s tu dy i s i n p ro g re ss ; h owe v er , t he M e di ci ne , U n iv e rs it y o ( H am b ur g. G e rm a ny

• M cL C 2I l H o sp it aL H a rv ar d M ed ic al S ch oo l. B el mc ru , M A

me di ca ti on s a pp ea r t o b e o f s im i la r e ff ic ac y a nd

tolerabi li ty Prc'U'Oled U. pester-at Ibe Wiluuworlubop all Scbizophrmls. DIVOt. .Swlturlud. 2006

Mean Change in BPRS-C Score (from Baseline 10Endpoint

LOCF)

i

,. J · 91 N=35

E f fe ct s iz e = 0 6 3; p= 003

, t _ _ ~'IM! r " , , , , T~IM"" 5 ." ,, :: 1 ~" '" _ . .." " 01 ',,,,,,,",,,,,,,r.tK!'JJ., ''''''''~ ~"~ . ' " ' ie.W' ' ' ' 'Incr 1:n '~~""" ;n ; ." ,c. , ,ICI ' I In<wu"l5 I.letn,I.._1 '''''.If?1.mU'n

Visitwise Mean Change in BPRS-C Score (MMRM)

_O"'"'~r'''I' I~~~""

-.. . . . . . . . . , _p=004 -~

IF 023 '__..___

p=010 -..p= ors

,>..:I~:IlmIId!""" ~t n : > " " I I Y . l < k t " " I . ' I ' , . . . . . . Co! · .o.=~"a,' :;. .IICrJI.'''':. M e tI e< ' n., .~!"", lim:. !», CD.~~'[V<:, !ll:"",op,. 11::11

lootl.mu. ""u;rlrncodo."1'~~~'r~

-52-



Mean Changes in Secondary Efficacy Measures (from Baselineto Endpoint, LOCF)

Efficacy MeasureOlanz..apinc Placebo

(n=721 (n=35)PANSS·

Total" ·213 -8.6

Pcs luve ' -65 ·27

Negative~ ·38 ·18

CG1-S . " ·05

CGt·I~· 27 38

OAS

Tolal ., 0 ·01

Verbal Aggression ·05 ·02

Physical Aggress ion Toward-03 -02

Objects

Physica l Aggress ion Towards Sel l 01 01

Physical Aggress ion Toward Others ·0.2 01

005

002

08,

004

< 001

OS,

163

256

053

.019


Schizophrenia Treatment: Bridging Science

to Clinical CareMedication Treatment

Studies are beginning to emerge about medication

treatment in adolescent schizophrenia patients, but isstill amazingly thin considering the magnitude of the

problem

Comparison studies that may inform management arejust now being reported

Questions sti ll to be addressed include: I) What is the

best dosing strategy? 2) Are side-effects different in

teenagers? 3) What is a reasonable algorithm to

manage treatment resistance?

Family Issues in Programmatic Treatment of

Adolescent Schizophrenia Schizophrenia

• Confusion in early attempts to help• As more patients are treated in an ambulatory

setting, a multidisciplinary team approach is

useful-_...

• Shock and denial during early treatment ..··Proven psych-o'soci1l1itl1erventiCfrfs-to-forestall

relapse include

- Family psychoeducation

• Concern about medication and side effects - Social Skills Training Program

• Proven psychosocial programs that improve

• Special needs in psychoeducation andoutcomes and further reduce symptoms

- Cognitive Rehabilitationsupport

._ Cognitive Behavior Therapy

TrP« II! S",.,ol s.""" ....""~, ...., ...1eo-.;,:",nc..c I..NC~VI.r: IAo:It.1. C,M'J:tt n""JIITtLonw.Of

~ .1 ' : 0 ' > 1 - 1 )Q~'M:; WII!\t:cll'. b 'n !. .t . .. ~ " ,, :" :! J: .ooc ln : ~~u", . .

. " ' ' ' '' ' '~1.:nr l~ '' ' ' ''

-53-



AstraZeneca

Resu lts Upda te

David Brennan

August 3rd, 2005

Overview of 1H Resulis

US Market Update

Seroquel®

Crestor®

Nexium®

Future

;/';

2 ,AE~traZt:::neca(2

1



AstraZeneca

S econd Q u arter and H alf Y earResults

In order to utilize the 'Sat e Harbor' prov isions ct the United States Private

Securit ies Lit igation Ref onn / let ct1995, AstraZena:;a is providing the

f allowing cautionary steternert. This presentation contains forward-looking

statements with respect to thef inancial condit ion, resul ts o f operations and

businesses o f AstraZeneca By their nature, forward-looking statemerts and

f orecasts irv oive risk and uncertainty because they relate to e-; ents and

depend on circumstances that will occur in the future. There are a number o f

fectors that could cause ectual results and developrnerts to differ materialty

f rom that expressed or implied by thesef orward-Iooking statements. These

f octo IS include, among other things, the loss or expiration o f patents,

marketing exclusivity or trade manes: exchange ratef luctuations; the risk that

R&D will not yield new products that achieve commercial success; the impact

of competition; price cortrcls and prce reductions; taxation risks; the risk ctsubstartial product liabil ity claims; the impsct o f any failure by third parties to

supply materials or services; the risk ct delay to new product launches; the

difficutties o f obtaining and maintaining gov ernmental approv as for products;

and the risk o f erwironmentalliabilities.

2



2005 2004 Actua l CER

___jm_-~ $m growth growth

Sales 6,132 5,288 +16% +13%

Opera ting pro fit 1,718 1,052 +63% +53%

EPS $0.75 $0.48 +55% +400/0

2005 2004 Actua l CER$m $m growth growth

Sales 11,875 10,362 +15% +12%

Operating profit 3,171 2,104 +51% +44%

EPS $1.38 $0.95 +45% +37%

Dividends $0.38 $0.295 +29%

Share repurchase $1,182m $968m

I'

6 AstraZenec.;{.2

3



Actualgrowth

+15%

CERgrowth

+12%Sales

2005

$m

11,875

2004

$m

10,362

-----,--,-----'"----,-~-- .. --~--~-,--North America 5,731 5,016 +'14% +13%

Europe 4,362 3,803 +15% +8'/0

Japan 736 666 +11% +9%

Rest of World 1,046 877 + 1 g o lo +'15%,.

i),

7 l\straZenec.:{";?

i/O:;

8 ,AstraZe:neca'_Z

4



o n c ~ o I : o g yIIIF'--Arimid

ex

Qi1Statins Crestot'"'

Atacand"

P at en t p ro te de d P P S Nexium®

Seroquel'fl1

F ix ed c on b B -a go n + st er oi ds Symbicort®

Analgesics

o 500 1000 1500 2000 2500 3000 3500 4000

Absolute gro v.th USD C ER

MAT/01 /2005 vs MAT/01/2004

Sales CER

$m % growth

Nexium® 2,259 +22%

Crestor" 590 +72%

Symbicort® 502 +21%

Arirnidex" 553 +50%

Seroquel® 1,300 +37%

Total 5,204 +32%

I~

10 AstraZeTlec.:{2

5



Launch ofCrestor®

:; ;20%

'"> -(;

" 15%a,

~.c;

" § :Ie 10%C J

f-

~5%

------

------------,--,~-----------------------------

" ,~PnIQseClli·· .

Expiry

-- Total Sales - M I l . T Growth - R&D/ SG&A - M I l . T Growth

'S t rong ea rn ings growth : +37% CER

'M a r gin : 2 6.7% o f s ale s; f - ~

12 , . o , s t r a Z e i f l e c , : : : t J r

6



AstraZeneca

Results Update

David Brennan

August 3rd, 2005

AstraZeneca

US Business Update

Tony Zook

August 3rd, 2005

7



2004 US Pharma Mcrket Exceeded $2358

$250Market Value +7%

4.0

3.8

$200_ _ _ _ - - -

3.6

~$ ~pre,aiPIIO"' 3.4 ~

$150 +4% 3.2 ' I i . -

~ B ~3.0 Cl e :

ID TRx 0 :: \9 .

O J $100 2.8 !

2.6e

$50Dollar market growth for

2.4

2005 forecasted to be2.2

7.5% to 8.5%$0 2.0

2000 2001 2002 2003 2004 2005

Com petition for Share of Voice greater than ever

Medicare Prescription Benefit: $270 billion over 10 years

Renewed emphasis on safety

Challenges with approvals timing

Clinical trials expense

Increasing managed care influence on patients/co-pays

Pharma reputation crisis

OTCs and generics playing a greater role

,t)'

16 /lstraZeneca .2

------------------------, ..~--8



CustomerIn fo r ma t i on

AZPhmrnceuti:al

Sales Speciaists

·1 1 miilioo detaHSffnonth

-650,000 calls/month

• I nt eg r a t ed sales

r ep or t s up p or ti n g

Operations,P e rf or m a ne e &

Communicat ions

• S tr at eg ic T ar ge ti ng P la n• Co ll ab o ra ti o n & Pre-Call

P I an ni n g t oo l s

a AZ ranks 6th in sales force size but 5th in

total sales

37% increase in Sales per Rep

AZ was ranked 1st or 2rd for all activities

with GEs

AZ improved with Cardiologists, moving

from 6th to 3rd in rating rank for

Traditional Details and Samples,

remained at 3rdfor Meetings and

Events, and improved from 511 to 3rdforDisease-State Management Programs

2004 2002

Detail

AZ Effe ctivenes s

O""'all < I 5

Anesth esiology 6 7

Cardiology 3 ii

GE 1 1

GPIFPlOO 5 6

GS i 5 5

1M 4 -stoeu,ology - . .Oncology 2 6

Pediatrics 10 7

Psychiatry 6 -7

Pulmonology 7 4

10



Pfizer Pfizer

GSK GSK2

Merck3 Sancf i .Aventis

4 Sanoti-Avents

hJovartis PfizerForest

l?

21 r,,"straZe.'1en:/k

11



Market

~ US Sales Grov.th Share Cap SBili

Total Mar l<et"""$24"3' ~% -roo%

Pfizer$30 -2% 12% $205

2 GSK $19 2% 8% $136

3J&J $16 3% 7% $193

4 Merck $15 0% 6% $68

5 $12 15~ti 5° 1 $68AstraZ ene ca '0

6 Novartis$11 9% 5% $111

7 Sanoti-Avantls $11 13% 4% $114

8

Arrqsn

$11 26% 4% $75

9 BMS $9 -10% 4% $49

10 W)-€th $8 6% 3% $60

lr

25 l 'l,straZel1ec.::{ ..I2 '

5.6% 176%

+3.7 $2.3827.0% 25%

$379M31.6% +8.4 41%

28.5% +2.3 $4.18 12%

$1.3828.5% +1.3 15%

13



Nexium'": 1H sales $2,259m, up 22%

US sales$1,514m, up 18%

Other markets $745m, up 28%

Crestor": 1H sales $590m, up 72%

US sales $338m, up 83%


Sercquel": 1H sales $1 ,300m, up 37%

US sales $933m, up 34%


Tamox ifen con tin ues to dec lin e80%

70% -------_________ Strong volume growth60% _____ - - _50% ~amOxifen47.2%

40%

Arlmldex" 31.6%

~~~~

2 0 " / . , ' " " t 1 T . . 'e-,1".t.-t:£r"-at"'-a; I I< ' --

~ -~--,--'--..-10% ---

1-------

30%

0%

~ MM M

C 0 0 0- c

;~

c." 0<

M

ogo

o

l:o

.,-;It. A r i mi c e x Aromasin _,_ F em ara ._. ..- - NolvadexlT amoxf fen ,.28 ,Jl.straZeneca',E

14



40%

30Cl/o

@

J 'lif)

K

20%~~I-

10%

Atenolol = 34.4%

1 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - , - - - -

-4- Topro ~XL

-- Propanolol

M3top rolo I Tenormin _. Atenolo I

Coreg -- Innopran X L ,_ An Others

Drive key brand growth

Foster deeper customer relationships

Continued focus on execution and marketing excellence

Continuation of cost containment initiatives and rigorousevaluation of investment decisions

;1.';

30 ..-"straZerrec.:{E

15



Tony Zook

August 3rd, 2005

AstraZeneca

US Business Update

Johan Hoegstedt

August 3rd, 2005

AstraZeneca

16



6.0% -e-vro Actual

3.5%

5.3%

il!

\\ 2 %, ~ ~ %

5.3%

/ - s :4.10

Market growth opportunities:

·PCP education on diagnosingBipolar Mania

·Increasing patient corrplianceon prescriptions

5.5%

5.0%

4.5%

4.0%

3.0% +---r---,.--...----r---.---.----...---..---,.---.--.---,----.

Jan Feb Mar Apr May Jun Jul ALg Sep Oct Nov Dec

2004 = 82%i-I

35 l'l,straZe:teca'~k

35%

30%

25%

> 20%0(/)

~ 15%

10%

5%

0%

~SEFOalEL

_" Z YP REX A'Z YD to

-GEODON

--- SY MB YAX -- R ts PE RD ALIM ·T AB tC ON STA

CLOZARIL - AB IUFY

- ALLOTHEA

/~'c36 ,l\straZenecaZ

18



70

60

.;J> 500C/) 40~0

a. 30Ua. ~.-20

10

0

.+..Seroquel Zyprexa - Symbyax - Ability - Risperdal Geodon

pcp is cafmd e s : E rn O 'g :l n: y M o :I ci re . F ami ~' Placito, ( ?a mr a! M wc ir e, G mc ra ! P nc tc e. Ge la uc s , lntena! ~.-bdche,md one

Expand the market & grow share by driving successfulbipolar patient outcomes

Leverage Seroquel's differentiated profile to grow share intargeted patient populations within sdlizophrenia

"";

38 , A s t r a Z e l 1 E ' c . : : r / . 1 ?

19



CAFE: Results presented at the 8th World Congress of Biological

Psychiatry (WCBP) in Vienna, Austria

QUAI=tIZ; ..Re suits presented in May at American Psychiatric

Association convention (APA)

BOLDER: Results presented in May at American Psychiatric

Association convention (APA) and Bolder I study published in JulyAmerican Journal of Psychiatry

Bolder II studyin bipolar depression has finishedrecrui1ment

US submission around year end

Sustained Release for schizophrenia - on track for 1H 06global submission

Other brand enhancing LCM opportunities

/-'{

40 AstraZenecaZ

20



Large and Grow ing Class Best in Class Profile

LCM

AstraZeneca

Johan Hoegstedt

August 3rd, 2005

21



AstraZeneca

Adele Gulfo

August 3rd, 2005

Statin Market Overview

Crestor" Performance & Strategic Positioning

Recent Events/Efforts

22



$16.0$16.5

$16.0

$14.0 fp,~

~ $120

a~ $10.0

'"en:: ? $6.0

s

' "$6.0

en

$4.0

$20

$0.0

MATJune01 MAT June02 MATJune03 MATJune04 MAT June05

/1

47 ,.'I,straZel1eca l:i

Drug Company Launch P5:!l~nt ExRiry

Mevacor Merck 1987 Expired

Pravachol Bristol-Myers Squibb 1991 2006

Zocor Merck 1992 2006

Lipitor Pfizer 1997 2010

Generic Lovastatin Mylan 2000 NlA

Crestor® AstraZeneca 2003 2016

Vytorin Merck/Schering-Plough 2004 2015

2 4



60,0%

40,0%

e<1 l.<:C/) 3O,!)'%.xa:z

20,0%

10,.0%

6,2%

0.0%'__ "M"_'", ..._" ..,~ ..__ . . . .------

M0

M M

~ ~ -e ~q q

~q q q q

~ ~ ~ ~ ~ ~ ~s 0 0 :;; s :; : :; : s :; : : ; ; : ; : 0 0 0 : ; ; : ;: ~ : ; ; : ; : s'" '" '" '" '" '"~ ~ ~ § S li ~ !1 ~ s s s :; ; ~ ~ § S li ~ :; :;; s

- Crestor .- Lipitor - Lovastatin -" •. Pr ava:;hoi - Zooor - Vytorin

;t i

49 A s t r a Z r ; :n e c . ; {1 ?

FD A Re~cts PC P e t it i o n

9%VloniSt'f'llrteHeOf~

B% -..- ~x Share

7%

Q)

~ 6%

s:

~ 5%

oI ii 4%

W

~ 3%

C re sb ' 2 00 0

. . . . . .,--.._..~M M M M . . . . ~

~. . . .~~ . . . . . . . . . . . . . . . .

:i l s :; ; s :i l : ; : s : i l : i l s s :i i:;; 2 i S li S li ~ :; :;; s s :i s :;; a- , f , : "

50 . A s t r a Z r : : n e c a " k

---------------------_._--------------

25



Label Update

Labeling rev isiors are a normal cccur rerce

3 minor changes to the prescribing informat ion

FDA Petition response

Renal prof ile can parable to other other marketed stat ins

Muscle toxici ty can parable to other marketed stat ins

Greater LDL-C effk:acy at lower doses increases the risk- benefit o f

Crestor"

3rd party

NLA review

Other independent safety reviews & real world effectiveness studies

51 .AstraZeneca

Hones t and s tra ightfo rwa rd tona lity

R isk inform ation as prom inent a s thebenefits

Educa tiona l condition in format ion

/~

52 .AstraZeneca ;;;f

26



9 Studies

Completed

15 Studies

Ongoing

>46,000

Patients

45

Countries

Statin market offers tremendous opportunity

Crestor" has experienced setbacks and weathered storms

The weight of evidence will continue to show a favorablebenefit-risk profile for Crestor"

Our commitment to Crestor? is undiminished

j';~

54 , ' '\straZcon€'ca'p

27



Adele Gulfo,

VP Primary Care

August 3rd, 2005

AstraZeneca

Linda Palczuk

Executive DirectorAugust 3rd, 2005

ASTraZeneca

US Nexiurrr'Update

28



Strong performance in 1H

us Sales up 18% to $1,514 million

US: positive share gains across all metrics

YTD June Total Rx + 13%'

YTD June Extended UnITs + 16%'

Nexium® passes Prevacid for #1 TRx spot*

NSAID opportunity

PPls represent $13 billion in sales**

~'~J

S7 AstraZem:ca',.B'

.i 30% ---------...-.

(f)

.~§

~ 20% _~-----------

~ ._.-~w

i{ 3 ! . 10%

40%

~ ~ ~ - - - ~ - - - - - - - - - - - - - - - - - - - - - - - - - --e -o

o

~o

~o

I~o

I-- Oneprazole

._ .- Z eg er id

- Prevacd Family_ ." Acipb e x

Prilosec

4t". Ne x u m

_ . . .. _ . P r ot o n ix F am ll y

!_'::

58 ,AstraZeneca{l?

29



40.0%

a :"-~ 30.0%

i' 5]Ili;

'" 20.0%

Nexium® = 28.54%

co

_-_~

_-.1It" __ G I II ;-~

Prell acid Family = 28.46%~ ----_._._._. _ _ •._ - _ . f

+ O . o s

%

+67

%

§~m

c: 10 .0~/"

'"'"

0.0%

~

2 ? 9-c ra

a. u rom mif) Cl

'"

a

a.mif)

, t ¥ _

59 ,'I,straZe:neca'.Je

:~E-' :::rRx:urut-l; t,i ies:==

::::::::==:::O.6t.05:=::.3:2::6'2t:::::===:40'/~

,,,~~,~,- . . . . ""'''- . . . .-,,.,"''----

~ ~ § ~ il ~ ~ ~ ~ ij I ~ ~ ~ ~ j ~ 5 ~ s; :8~~ ~ e 1 5

~ ~ ~;; ; 6 " is 5 ~ ~ ~

;; ~ ~ ~ S • ~0 s"s s s

" " " "-9-Nexium@ Omep r azo le P rev ac id F am il y

~ Pro ton ix Fami ly - Zeger t J

30 '10

20X

-"'--~~-lQ'/"

.. . _ ." " - • • • . _ . lO r .

" ' I .

~ ~ ~ ~ ~ ~Il ~ ~ to ~ ~E s s ~ ~ s

Aci""ex

Prilosec

t~

60 ,l\straZe;neca',k'

30



0303 0403 0104 0204 0304 0404 0105 0205

'.ll!1..Al;.t 'i lIl.A.cJ.

46%c:f'! l.eo

50%PPI ex-Ornep 11 ..2% 8.7

40% Nexium® 19.4% 15JP/o

30%

< t- 20%.c:

i 10%0

c !i 0%:::J

w -10%><

[f -20%

-30%··33%

·35%-40% ·40% -40%

-50%PPI 1I0meprazoie IIPPI ex-omep II Nexium

/';

61 , A < ; : 4 r a Z e n e c . : : h 8 '

40%

35%

30%

e25%

. ..c:

20%(J)

' < t -15%

10%

5%

0%,"

~ < $ ;> ~ < $ ;> < s > " > rfi' ~ \>

! ' : - 'V , , 0 . , " " , " " , . " " ~ " , , < s >

',j::i . . . . cf' < ! 'V '< ~ ....~< .

-1J- NEXIUM'IV ,,--- PRILOSEC

-PREVACIDFAMILY -ACIPHEX

,,_ .• ZE GER ID

- PROTONIXAV

- OMEPRAZOLE

J'

62 AstraZeneca'?

31



Nexium®I.V. approved March 31st

3rd I.V. entrant

Current Market Environment

Highly cornpetitve prcinq on LV.formulation

Contractuallirk between LV. and oralformulations

Nexium® IV/Hospital Strategy

Superior clinical prd ile of Nexiurr® LV.

Priced crmpettv ey

Capture spillov er benef it in retail segnent

(!

65 ,AstraZe!l€c.:t 2'

AstraZeneca

Linda Palczuk

August 3rd, 2005

33



AstraZeneca

The Road Ahead

Sustainable long-term growth enabled by:

Driving unique in-line brand opportunities

Improving operational effidency

Bring differentiated, superior products to market

Disciplined cost management and focus on productivity

Corporate reputation that speaks to identity

Enable a high performance culture

~;l

68 ,l\straZI:'::1eca'if

34



Symbicorf" pMDI in asthma

us filing on track late 302005

EU submission filed

Sym blcort" Maintenance and Reliever Therapy forasthma:

EU filing on track 402005

New studies support submission: SMILE and COMPASS

On track for regulatory subm issions in 2007

GALLANT programme currently 10 studies ongoing:

2005 2006 20072004

ARMOR

GAL 2 (mono v Pac)

GAL 4 (monov SU)

GAL 5 (mono v Mel)

36



SAINT I first ever positive NeuroprotectantTrial

Significant reduction in disabil ity measured by

Modified Rankin Scale

Effect present

across 6 hour time window

across stroke severities

irrespecttve of r t-PA use

Neurological recovery end point not signif icant onpre-specified analysis

Excellent safety profil e - similar to placebo

~(~

73 AstraZenecaE

Inhibitor of VEGF and EGF signalling

Enters phase II I

Phase II data in NSCLC shows unprecedented anti-tumouractivity

" As monotherapy and in cornbinafion with chemolherapy

Thyroid cancer trials

Activity seen in RET mutated hereditary medullary thyroid cancer

All patients had at least 50% reduction in a key biomarker

(caldtonin)Completion of phase II meeting with FDA

/'~.;74 ,AstraZenec(iI,;;:

37



Pre-clinical Phase I

Phase "

Accelerated dlv elopment

New !l'edical EntitiesPhase tansition since Jan-05Line extensions

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75 AstraZel1eCa'2

Biopharmaceuticals

AZD8593 for haemostasis

Monoclonal antibodies

Abgenix, CaT and AZD31 02

Development and discovery partnerships

Humanised antibodies for oncology, inflammatory andneurosdence disease areas

;I:

76 ,AstraZen€cat'2

38

schulz exhibit 2

Documents