This supplement to The American Journal of Managed Care is based

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1 Decision Mker Forum in Mnged Cre expert consultnts John M. Kne, MD (Co-Chir) Professor, Psychitry, Neurology, nd Neuroscience Albert Einstein College of Medicine Chirmn, Deprtment of Psychitry The Zucker Hillside Hospitl Glen Oks, New York Dougls L. Noordsy, MD (Co-Chir) Associte Professor of Psychitry Drtmouth Medicl School Lebnon, New Hmpshire Lwrence J. Cohen, PhrmD, BCPP, FASHP, FCCP Professor of Phrmcotherpy Wshington Stte University College of Phrmcy Assistnt Director for Psychophrmcology Reserch nd Trining Wshington Institute for Mentl Illness Reserch nd Trining Spokne, Wshington Robert L. Dufresne, PhD, PhD, BCPS, BCPP Professor of Phrmcy University of Rhode Islnd College of Phrmcy Kingston, Rhode Islnd Psychitric Phrmcotherpy Specilist Providence VA Medicl Center Providence, Rhode Islnd Joseph Prks, MD Chief Clinicl Officer nd Division Director Comprehensive Psychitric Services Missouri Deprtment of Mentl Helth Jefferson, Missouri Stephen Skld, PhrmD, BCPP Director, Psychitric Phrmcy Progrm Phrmcotherpy Eduction nd Reserch Center University of Texs Helth Science Center t Sn Antonio Sn Antonio, Texs PUBLISHING STAFF Director of Scientific Content Jeff Prescott, PhrmD, RPh Contributing Editor Amy Lodolce, PhrmD, BCPS Contributing Writer Pmel Musner, MD Mnging Editor Brbr M. Mrino Design Director Chrles Lebed A Supplement to OL54999 Prt 1 of 3-Prt Series DECEMBER 2008 Importnce of Erly nd Effective Phrmcologic Tretment in Schizophreni This supplement to The Americn Journl of Mnged Cre is bsed on presenttions nd discussions from roundtble meeting comprising expert consultnts. This meeting ws sponsored by Eli Lilly nd Compny, held in Detroit, Michign, on July 18, Subsequent newsletters in this 3-prt series will discuss Evidence-Bsed Medicine: Clinicin nd Pyer Perspectives nd Applictions for Schizophreni nd The Appliction of Evidence-Bsed Medicine in Evluting Formulry Options: Pyer Perspectives nd re expected to publish in erly Overview of schizophreni Schizophreni is mjor mentl illness chrcterized by episodes of psychosis, ssocited with disturbnces of orgniztion, motivtion, mood, nd/or cognition tht result in functionl impirment. Epidemiology Approximtely 2.4 million Americn dults, or 1.1% of the popultion ged >18 yers, hve schizophreni. 1 The nnul incidence hs been estimted t 0.2 to 0.4 per The incidence of schizophreni is similr for men nd women, but women tend to hve lter ge of onset typiclly in their 20s nd 30s, compred to teens or erly 20s for men. 1 World Helth Orgniztion dt show similr ptterns of incidence nd prevlence cross mny different popultions nd geogrphic res. 2,3 Symptoms Three mjor ctegories of symptoms occur in schizophreni: positive, negtive, nd cognitive. Positive symptoms (psychotic symptoms) include delusions (flse beliefs) nd hllucintions (perceptul experiences in the bsence of externl stimuli). Common types of delusions include delusions of persecution, delusions of control (eg, the belief tht others re influencing one s thoughts), grndiose delusions, nd somtic delusions (eg, the belief tht one s body is rotting). Hllucintions cn involve ny of the senses, but most often re uditory. 2 Negtive symptoms re emotionl nd behviorl deficits, for exmple, blunted ffect, nhedoni (bsence of plesure), volition (inbility to initite or persist in gol-oriented ctivity), nd logi (diminished speech quntity or content). 2 It is importnt to determine whether negtive symptoms re primry, or whether they re secondry to other cuses such s depression, nxiety, mediction side effects, or environmentl deprivtion. 4 Cognitive symptoms my include difficulty with ttention nd concentrtion, psychomotor slowing, memory nd lerning problems, nd impired executive function (eg, impired problem solving, plnning, orgnizing, bstrct thinking). It should be noted

2 tht cognitive function my be within the norml rnge in schizophreni, lthough it is typiclly impired reltive to the ptient s premorbid stte. 2 Course Schizophreni cn be considered to hve 4 clinicl stges: premorbid, prodroml, progressive, nd residul. Premorbid stge. Mild motor, cognitive, nd/or socil impirments my be present in children who lter develop schizophreni 5 ; however, these impirments re nonspecific nd re not useful predictors. Prodroml stge. Usully beginning in erly dolescence, 5 mnifesttions of the prodroml stge my include ttenuted positive symptoms (eg, illusions, superstitiousness, mgicl thinking, ides of reference), mood chnges (eg, nxiety, irritbility, dysphori), cognitive impirment (eg, distrctibility, concentrtion difficulties), obsessive behvior, socil withdrwl, nd deteriortion in functioning. These mnifesttions re not dignostic becuse they overlp with the rnge of behviors nd experiences in dolescents who do not go on to develop schizophreni. 5 Progressive stge. The emergence of frnk psychosis, typiclly between the ges of 16 nd 30 yers, 2 mrks the forml onset of schizophreni. 5 However, dignosis is ll too often delyed; it is frequently 1 to 2 yers fter the onset of psychotic symptoms before the ptient first receives dequte tretment. 4,5 Most ptients chieve symptomtic remission following the initil episode (no residul positive or negtive symptoms greter thn mild). 5,6 However, despite good response to first-episode tretment, the mjority of ptients go on to hve relpsing/ remitting course often due to mediction discontinution or prtil dherence with drug therpy, 5 nd mny do not recover fully in terms of socil nd voctionl djustment. Compred 2 to the first episode, subsequent episodes re generlly ssocited with decresed tretment response. 6 With ech successive relpse, recovery is more likely to be incomplete, with progressive functionl deteriortion. 5 This process typiclly continues for 5 to 10 yers fter the first episode. 5 Residul stge. Although symptom excerbtions my continue to occur, point is usully reched fter which there is no further functionl decline or increse in residul symptoms. However, some ptients with severe disese my continue to decline through old ge. 5 Cuses nd risk fctors Both genes nd environmentl fctors pper to ply role in schizophreni. Genetic fctors. The risk of developing schizophreni is incresed mong reltives of persons with schizophreni, compred to the generl popultion. Adoption nd twin studies show tht the incresed risk is geneticlly medited. First-degree reltives of ptients hve 10-fold incresed risk of developing schizophreni; person whose prents re both ffected hs nerly 50% risk; nd the monozygotic twin of person with schizophreni hs 60% to 84% risk of developing the disese. 2 Genetic trnsmission ppers to be complex; there re probbly multiple susceptibility genes, ech hving smll effect. 7,8 At lest 7 potentil susceptibility genes hve been described 7,8 ; however, specific susceptibility vrints hve not been identified. 7 Environmentl fctors. A number of environmentl fctors re ssocited with n incresed risk of developing schizophreni. These include: Prentl or birth complictions (eg, infection, toxic exposure, hypoxi). 5 Becuse the mjority of people exposed to these risk fctors do not develop schizophreni, it is believed tht schizophreni my result from the interction between n environmentl insult nd genetic susceptibility. 2 Socioeconomic fctors (eg, poverty, lower socil clss). Two opposing hypotheses hve been proposed to ccount for these ssocitions. The socil custion hypothesis holds tht stressful socioeconomic conditions increse the risk of developing schizophreni. In contrst, the hypothesis of downwrd socil drift holds tht schizophreni, in impiring socil nd occuptionl functioning, increses the risk of poverty nd lower socil clss. Substnce use. The prevlence of substnce use is significntly higher mong ptients with psychosis compred to the generl popultion. 9 Among ptients with schizophreni, the prevlence of comorbid substnce buse my be s high s 65%. 10 A wide vriety of substnces re used most frequently tobcco, lcohol, nd cnnbis nd multiple substnce use is common. 9,10 Possible explntions for the high comorbidity rtes include: (1) substnce use leds to schizophreni, (2) schizophreni leds to substnce use, (3) both hve common origin, nd/or (4) they interct with nd mintin ech other. 9 No single model dequtely explins ll of the dt. 9 Evidence suggests tht, t lest for some geneticlly vulnerble individuls, cnnbis use my increse the risk of developing schizophreni 9 ; however, there is little evidence tht other substnces ply custive role. 9 Neurodevelopmentl schizophreni. A number of bnormlities of brin ntomy, cytorchitecture, nd biochemistry hve been demonstrted in ptients with schizophreni. 11 Multiple lines of evidence suggest tht these chnges rise from bnorml erly brin development, beginning in the prentl period. 5 Although the exct

3 Decision Mker Forum in Mnged Cre reson is uncler, one hypothesis for the delyed onset of psychosis is tht synptic pruning ( norml phenomenon occurring during dolescence nd erly dulthood) my precipitte psychosis when it reches certin threshold in these vulnerble individuls. 2 Neuroimging studies further suggest tht the neuropthology my be progressive, t lest mong ptients who hve poorer outcomes or more severe course 5 ; in other words, schizophreni my be neurodegenertive s well s neurodevelopmentl disorder. Consequences nd burden of schizophreni Schizophreni is one of the most disbling of psychitric disorders. 2 Positive symptoms cuse gret psychologicl suffering for the ptient nd fmily; furthermore, relpses often result in repeted hospitliztion. 12 Negtive symptoms nd cognitive impirment fluctute less thn the positive symptoms but re ssocited with poor psychosocil functioning. 2 The ptient s bility to interct with others, to work, nd to cre for himor herself is impired, 13 resulting in disrupted fmily nd socil life, lost income, nd productivity. Other consequences of schizophreni my include substnce use, homelessness, criminl behvior, suicide, incresed medicl morbidity, nd incresed costs. Substnce use. There is evidence to suggest tht, t lest in some individuls, substnce use my be n ttempt to self-medicte in prticulr, to llevite dysphori. 9 Nevertheless, ptients with schizophreni who re substnce users tend to hve poorer outcomes thn those who re not substnce users. 9 Homelessness. In prospective observtionl study, 263 ptients with schizophreni or schizoffective disorder were ssessed t the time of hospitl dischrge nd gin 3 months lter. 14 More thn 7.5% reported n episode of homelessness during the follow-up period. 14 The risk of becoming homeless ws gretest mong those with recent history of substnce use disorder, persistent symptoms, or impired globl functioning t the time of dischrge. 14 Criminl behvior. In retrospective study, mle ptients with cute or chronic schizophreni were compred with mtched controls from the generl popultion. 15 Ptients with cute schizophreni were nerly 4 times more likely thn controls to hve been convicted of violent crimes, nd more thn twice s likely to hve been convicted of crimes ginst property. In contrst, ptients with chronic schizophreni hd lifetime prevlence of violent nd property crimes similr to those of the generl popultion. 15 Suicide. Bsed on n nlysis of literture, the lifetime risk of suicide mong ptients with schizophreni hs been estimted to be pproximtely 5% to 6%. 16 Most of the risk occurs erly in the course of the illness (ie, during the initil yers fter the onset). 16 Medicl comorbidity. Medicl morbidity nd mortlity rtes re elevted mong ptients with chronic mentl illnesses, prticulrly schizophreni. This my, t lest in prt, be relted to chronic stress in response to symptoms, unhelthy lifestyles, mediction dverse effects, nd/or indequte medicl cre in this popultion. 17 Common medicl comorbidities in schizophreni include: Crdiovsculr disese. Compred with the generl popultion, ptients with schizophreni hve higher prevlence of number of crdiovsculr risk fctors, including cigrette smoking, 17,18 obesity, 17 dibetes, 17,18 hypertension, 18 nd low high-density lipoprotein cholesterol levels. 18 Comprison of dt from ptients with schizophreni enrolled in the Clinicl Antipsychotic Trils of Intervention Effectiveness (CATIE) study versus mtched controls from the Ntionl Helth nd Nu trition Exmintion Survey (NHANES) III showed tht 10-yer crdic risk ws significntly higher in the popultions with schizophreni, even fter controlling for body mss index. 18 ntipsychotic gents my cuse substntil weight gin. Although ptients with schizophreni re generlly t risk for obesity due to poor diet, use of second-genertion ntipsychotics hs been ssocited with n incresed risk of dibetes, which my result indirectly from weight gin nd/ or, possibly, from direct effect on insulin sensitivity. 17 Chronic respirtory disese. Asthm, bronchitis, nd emphysem re significntly more prevlent mong ptients with schizophreni compred to mtched controls from the generl popultion, even fter controlling for smoking. 19 Infectious disese. Incresed rtes of humn immunodeficiency virus infection nd heptitis B nd C hve been reported mong ptients with schizophreni. Ptients with severe mentl illness my more frequently engge in behviors tht increse the risk of trnsmission. 17 Incresed costs. The totl (direct nd indirect) excess cost of schizophreni in the United Sttes in 2002 ws estimted to be pproximtely $62.7 billion. Of tht mount, direct helthcre costs ccounted for $22.7 billion including pproximtely $8.0 billion for long-term cre, $6.9 billion for outptient cre nd professionl fees, $5.0 billion for medictions, nd $2.8 billion for inptient cre. 20 Tretment Schizophreni tretment cn be divided, somewht rbitrrily, into 3 phses. The cute phse extends from the onset of psychotic episode (either first episode or relpse) 3

4 until symptoms re reduced to the ptient s expected bseline level. The stbiliztion phse is the trnsition between the cute nd the stble phse; together, the cute nd stbiliztion phses usully spn bout 6 months. During the stble phse, symptoms re under control nd the focus is on rehbilittion nd recovery. 4 Phrmcologic therpy is the minsty of tretment. 2 Antipsychotic gents re the primry drug therpy used for schizophreni, nd re used in ll 3 tretment phses. They re effective both for reducing psychotic symptoms nd for preventing relpse, but hve only modest effect on negtive nd cognitive symptoms. 2 Adjunctive phrmcologic gents in schizophreni include: Benzodizepines. In the cute phse, benzodizepines re used to tret cttoni, nd to mnge nxiety nd gittion until the ntipsychotic gent tkes effect. 4 During the stble phse, they re helpful for nxiety nd insomni. 4 Mood stbilizers nd bet-blockers. These gents my be given to help reduce hostility nd ggression during the cute phse; however, their efficcy hs not been well estblished. 4 During the stble phse, mood stbilizers re used to reduce mood lbility. 4 Antidepressnts. These re prescribed to tret comorbid mjor depressive disorder nd obsessivecompulsive disorder. 4 However, ctecholmine reuptke inhibitors cn potentilly excerbte psychotic symptoms (lthough this is minly risk when ptients re not tking n dequte dose of ntipsychotic mediction). 4 Antiprkinsonin gents. Anticholinergics nd dopmine gonists cn reduce the severity of prkinsonin symptoms; however, dopmine gonists my excerbte psychosis. 4 In ddition, centrlly cting bet-blockers (eg, 4 proprnolol) nd benzodizepines re effective for kthisi. 4 Electroconvulsive therpy my be considered (in conjunction with ntipsychotic gents) for ptients with severe psychotic symptoms tht do not respond to mediction lone; for cttoni tht does not respond to benzodizepines; nd for tretmentresistnt or life-thretening comorbid depression. 4 Psychosocil interventions re essentil in the tretment of schizophreni. During the cute nd stbiliztion phses, useful interventions include stress reduction, supportive reltionships, nd ptient nd fmily eduction. 4 During the stble phse, community tretment progrms, fmily therpy, supported employment, integrted dul disorders tretment, socil skills trining, nd cognitive behviorl therpy hve demonstrted benefit. 4 Prognosis: with optiml tretment, functionl recovery is possible Some uthors hve suggested tht ntipsychotic gents suppress symptoms of schizophreni but do not lter the deteriorting course of the disese. In contrst, others hve proposed tht ntipsychotic gents not only improve symptoms but lso mitigte disese progression. 5 Emerging evidence supports the ltter, more optimistic, view. One line of evidence comes from cute tretment studies of ptients in their first psychotic episodes. Most first-episode ptients respond well to tretment, with 70% chieving symptom remission within 3 to 4 months, nd 83% within 1 yer. 4 A number of fctors hve been ssocited with poorer tretment response, including the following: (1) greter degree of negtive symptoms t the time of the first psychotic episode, 6 nd (2) longer durtion of psychotic symptoms prior to tretment initition. 5,6,21 A recent review nd met-nlysis of 43 first-episode tretment studies exmined the reltionship between durtion of pretretment psychosis nd subsequent tretment response. 21 Shorter durtion of pretretment psychosis ws ssocited with significntly greter improvement in severl outcomes, including both positive nd negtive symptoms, globl psychopthology, nd functionl sttus. The effect sizes for these outcomes were smll to moderte in mgnitude. In most of the studies, the ssocition persisted fter djustment for confounding fctors. Notbly, studies tht djusted for premorbid functionl sttus nd/or mode of onset (insidious vs cute) both of which my be mrkers of disese severity consistently found tht durtion of pretretment psychosis is n independent predictor of tretment response. In ddition, some (not ll) of the studies found n ssocition between durtion of pretretment psychosis nd subsequent relpse risk. 21 These dt suggest tht erly dignosis nd tretment my improve outcomes. 21 Mintennce tretment studies provide second line of evidence. Even mong ptients who recover completely from first episode, the risk of relpse is high. 21 With ech successive relpse, recovery is more likely to be incomplete, with poorer ntipsychotic response, 4,6 incresing chronic residul symptoms, 4 nd progressive functionl deteriortion. 5 Progressive neurontomicl chnges hve lso been observed. 4 Without ntipsychotic mintennce tretment, 60% to 70% of ptients will relpse within 1 yer, nd lmost 90% within 2 yers; mintennce tretment reduces the risk of relpse to <30% per yer. 4 Furthermore, continuous mintennce ppers to prevent relpse more effectively thn intermittent tretment strtegies, in which ntipsychotics re discontinued fter remission nd restrted when symptoms of impending relpse occur. 4,21,22 In summry, lthough further reserch is needed, these results suggest the possibility tht:

5 Decision Mker Forum in Mnged Cre A neurodegenertive or some other deleterious process occurs during periods of ctive psychosis, which cn impir the potentil for tretment response nd functionl recovery. Durtion of untreted first-episode psychosis nd number of relpses my be modifible risk fctors. Erly nd effective phrmcologic intervention for ll ptients with new or recurrent psychotic symptoms my improve both short- nd long-term outcomes. Erly nd effective phrmcologic tretment In cute-phse schizophreni whether first episode or relpse prompt ntipsychotic tretment is recommended to reduce emotionl distress, minimize disruption to the ptient s life, nd reduce the risk of dngerous behviors. 4 In ddition, s discussed bove, prompt tretment my improve long-term outcomes. However, to relize these benefits, it is importnt to determine s quickly s possible whether the ntipsychotic mediction chosen to initite tretment is going to be effective for the individul ptient. Figure 1 Mjority of Symptom Improvement t 1 Yer Occurred by Week 4 Incrementl Percent of BPRS Improvement BPRS Totl Score BPRS totl OC BPRS totl LOCF Defining tretment effectiveness The efficcy of n ntipsychotic gent represents its bility to meliorte the symptoms of schizophreni. In contrst, the concept of effectiveness encompsses not only efficcy, but lso tolerbility nd sfety. 13 To be effective, n ntipsychotic gent hs to be tken consistently. CATIE n 18-month study involving 1493 ptients with schizophreni used ll-cuse discontinution s mesure of overll effectiveness. 13 In tht study, the overll rte of ll-cuse discontinution of the ssigned gent ws 74%. 23 A decision to stop tretment with prticulr gent or to stop drug therpy ltogether my be mde unilterlly by the ptient, by the physicin, or by both jointly. Resons for drug discontinution include 4,24 : Weeks Mediction-relted resons (eg, lck of efficcy; dverse effects) ie, resons relted to mediction effectiveness. Ptient-relted resons (eg, lck of insight regrding the illness; misconceptions bout the need Psychotic Symptoms Subscore Psychotic subscore OC Psychotic subscore LOCF BPRS indictes Brief Psychitric Rting Scle; LOCF, lst observtion crried forwrd; OC, observed cses. Reprinted with permission from Leucht S, et l. Biol Psychitry. 2005;57(12): Figure 2 for continued tretment; culturl beliefs; cognitive impirment). Environmentl influences (eg, brekdown of the therpeutic llince; lck of fmily support; cost; moving out of town). Recent evidence suggests tht the most importnt reson for discontinution of specific ntipsychotic Proportion of Erly Responders nd Erly Nonresponders Achieving Response t End Point (Mximum 6 Months) Proportion of Responders (%) Erly responders (n = 313) Erly nonresponders (n = 689) 40% Improvement in PANSS Totl Score PANSS indictes Positive nd Negtive Syndrome Scle. Erly response ws defined s >20% improvement in PANSS totl score t 2 weeks. The numbers of ptients per group re slightly lower t end point thn t initition (erly responders, n = 325; erly nonresponders, n = 752) becuse ptients discontinued the study between weeks 2 nd 3. Reprinted with permission from Kinon B, et l. Eur Neuropsycho phrmcol. 2007;17(suppl 4):S447. Presented t: 20th Europen College of Neuro psychophrmcology Con gress; October 13-17, 2007; Vienn, Austri. Lilly Reserch Lbortories. Dt on file. 52% P < % 5

6 Figure 3 Erly Tretment Responders Demonstrted Better Symptom Improvement Thn Erly Nonresponders t All Time Points (Weeks 1-24) Men Chnge in PANSS Totl Score Improvement gent is lck of efficcy. A post-hoc nlysis ws conducted using pooled dt from 4 rndomized, double-blind trils of 24 to 28 weeks in durtion. The 4 studies included 1627 ptients with schizophreni or relted disorders who were treted with second-genertion ntipsychotic gents. Overll, 53% of ptients discontinued tretment erly. Of those who discontinued, 36.4% did so due to either poor response (s evluted by the ptient nd/or clinicin) or worsening psychitric symptoms; 12.2% due to intolerbility of side effects; nd 51.4% for vrious other resons. 24 Thus, lck of efficcy ws the single most frequent cuse of discontinution 3 times more frequent thn dverse effects. In the tretment of schizophreni, nondherence (unilterl discontinution by the ptient) is prticulr concern. Nondherence rtes rnging from 25% to 75% hve been reported in ntipsychotic tretment trils nd my be higher in relworld settings. 24 Dt show tht poor dherence to ntipsychotic therpy is one of the strongest predictors of relpse 12 nd rehospitliztion, 25 nd Erly responders (n = 325) Erly nonresponders (n = 752) P <.001 t every time point Tretment Week PANSS indictes Positive nd Negtive Syndrome Scle. Response ws defined s >20% improvement in PANSS totl score t 2 weeks. Reprinted with permission from Kinon B, et l. Eur Neuropsychophrmcol. 2007;17(suppl 4):S447. Presented t: 20th Europen College of Neuropsycho phrmcology Congress; October 13-17, 2007; Vienn, Austri. Lilly Reserch Lbortories. Dt on file. my ccount for n estimted 37% of rehospitliztion costs. 26 Furthermore, n nlysis of literture suggests tht nondherent ptients hve higher relpse rtes, not only compred to ptients who continue their tretment, but lso compred to ptients whose medictions re withdrwn by their physicins. 26 Evluting tretment effectiveness How long does it tke to determine whether given ntipsychotic gent is effective for n individul ptient? There hve been 2 competing hypotheses regrding the time course of the response to ntipsychotic mediction. According to the delyed-onset hypothesis, there is lg of 2 to 3 weeks between drug initition nd response. 27 In contrst, the erly-onset hypothesis holds tht the response begins s soon s the gent reches therpeutic levels (within the first few dys); the effect then ccumultes over time until it reches plteu. 27 Consistent with the delyed-onset hypothesis, it hs generlly been ccepted tht therpeutic tril requires t lest 3 to 6 weeks. This is reflected in 2003 report of n expert consensus pnel. The pnel considered 3 to 6 weeks n dequte tril but would wit longer (4-10 weeks for the first ntipsychotic gent, 5-11 weeks for the second) if prtil response is observed before mking mjor chnge in therpy (eg, dose increse or drug switch). 28 However, emerging evidence supports the erly-onset hypothesis, suggesting tht determintion cn be mde more quickly. A met-nlysis of 42 studies of ntipsychotic drugs (both first- nd second-genertion), involving 7450 ptients, 27 exmined the time course of response s mesured by the Brief Psychitric Rting Scle (BPRS) nd the Positive nd Negtive Syndrome Scle (PANSS). Percent reduction in BPRS thought disturbnce subscle nd PANSS positive subscle scores (reflecting improvement in core psychotic symptoms) ws more thn 3 times greter during the first 2 weeks of tretment thn during the subsequent 2 weeks (24.4% vs 7.7%; P <.01). 27 The erly-onset hypothesis is further strengthened by n nlysis of pooled dt from 7 rndomized studies, involving 1708 ptients receiving second-genertion ntipsychotic. 29 Two of the studies in this nlysis provided dt extending to 1 yer. 29 Symptom reduction t weeks 1 nd 2 ws significntly greter thn the dditionl reduction observed t week Among 748 ptients with long-term dt, 68% of the men BPRS improvement t 1 yer hd lredy been chieved within the first 4 weeks of tretment (Figure 1). 29 Consistent with the erly-onset hypothesis, current (2004) Americn Psychitric Assocition guidelines recommend 2- to 4-week therpeutic tril before chnging the regimen. If the ptient is not responding within tht time period, it my be helpful to determine whether the lck of improvement is due to nondherence, poor bsorption, or rpid metbolism. 4 6

7 Decision Mker Forum in Mnged Cre Figure 4 Erly Response Predicted Stying on Tretment Men PANSS Totl Score Improvement Completed Discontinued b Weeks Study design 4 clinicl trils; durtion, weeks N = 1627 Dignosis Schizophreni 78.5% Schizoffective 20.84% Schizophreniform 0.6% P <.001. b Erly response predicted study completion: >20% improvement in PANSS totl score by 2 weeks ws ssocited with n ~80% greter likelihood of study completion (odds rtio, 1.76; confidence intervl, ; P <.0001). PANSS indictes Positive nd Negtive Syndrome Scle. Reprinted with permission from Liu-Seifert H, et l. BMC Med. 2005;3:21. The impct of erly nd effective tretment The implictions of n erly tretment response or nonresponse (ie, with in the first 2 weeks) extend beyond the cute phse of tretment. Dt suggest tht n erly response is ssocited with better long-term symptom control, greter tretment dherence, nd lower helthcre costs. even when they chieve subsequent response, do not ctch up with the erly responders. Greter tretment dherence. A pooled nlysis of 4 rndomized trils, involving 1627 ptients receiving vrious second-genertion ntipsychotics, exmined mediction discontinution rtes mong erly responders versus erly nonresponders. An erly response ws defined s >20% reduction in PANSS totl score t 2 weeks. Erly nonresponders were 80% more likely to complete 24 weeks of tretment thn those who did not chieve n erly response (Figure 4). Lower helthcre costs. A post-hoc nlysis ws performed using dt Better long-term symptom control. A pooled nlysis of 5 rndomized trils, involving 1077 ptients receiving second-genertion ntipsychotics, exmined 6-month outcomes of erly responders versus erly nonresponders. An erly response ws defined s >20% reduction in PANSS totl score t 2 weeks; subsequent response ws defined s >40% reduction in PANSS totl score from bseline to 6 months. Erly responders were significntly more likely thn erly nonresponders to chieve subsequent response (52% vs 19%; P <.001) (Figure 2). Furthermore, erly responders hd significntly more improvement in PANSS totl score t ll time points from week 1 to week 24 (Figure 3). 30,31 These dt demonstrte tht erly nonresponders, Figure 5 Erly Responders to Tretment Hd Lower Totl Tretment Costs Thn Erly Nonresponders Over 8 Weeks Cost ($) P <.01 $2102 $4336 Totl Cost Erly responders (n = 98) Erly nonresponders (n = 345) $569 $621 Mediction Cost P <.05 $1533 $3714 Nonmediction Cost PANSS indictes Positive nd Negtive Syndrome Scle. Response ws defined s >20% improvement in PANSS totl score t 2 weeks. Reprinted with permission from Ascher-Svnum H, et l. Schizophr Bull [Epub hed of print]. Lilly Reserch Lbortories. Dt on file. 7

8 from 1-yer, rndomized, openlbel study. The nlysis included 443 chroniclly ill ptients who completed 8 weeks of tretment with ny of severl first- or second-genertion nti psychotics. 32 An erly response ws, gin, defined s >20% reduction in PANSS totl score t 2 weeks; other outcomes, including level of functioning, were lso ssessed. 32 Com pred to erly nonresponders, erly responders were significntly more likely to chieve remission, 32 hd more improvement on multiple functionl domins, 32 nd perceived their mediction s more beneficil. 32 Moreover, erly responders incurred significntly lower totl direct helthcre costs over 8 weeks, primrily due to reduction in nonmediction costs (Figure 5). 32,33 To summrize: Emerging dt suggest tht the initil 1 to 2 weeks of ntipsychotic therpy my be window of opportunity for erly identifiction of ptients unlikely to respond robustly to their mediction. Erly nonresponders hve poorer long-term outcomes, higher rtes of mediction nondherence, nd higher helthcre costs thn erly responders. However, it should be noted tht minority of erly nonresponders do chieve subsequent (lthough not necessrily optiml) response if continued on the sme regimen. In ddition, the dt do not necessrily men tht regimen chnge will increse the likelihood of response. 32 Discussion Topics: Chllenges to Erly nd Effective Tretment of Schizophreni As prt of the meeting, severl questions nd res of discussion were rised. The following summry represents some of the key issues nd comments from the ttendees. How does psychitric tretment differ from medicl tretment? First, there my be differences in tretment strtegy. In cncer tretment, for exmple, the strtegy my be either to strt with the big gun (the highest-efficcy drug) even if it hs high dverse effect burden nd then bck off when the ptient is through the criticl, cute phse of tretment; or, lterntively, to strt with the mediction tht hs the most benign dverse effect profile nd, if the response is indequte, to esclte People with schizophreni hve more chronic medicl illness. They re ctully more likely to die of chronic medicl illness thn they re of suicide or ccidentl deth. They re more likely to be obese, more likely to be dibetic, more likely to hve hert conditions. Some of this is result of the illness itself, it ppers. Some of it is result of the medictions we use to tret, pcking on pounds. And some of it is the ccess to medicl cre nd the stigmtiztion. You go into the ER, nd if you re on Thorzine, they ll cll psychitrist first even though you my be hving crdic event. Joseph Prks quickly to the big gun. In contrst, psychitric tretment usully does not employ the big gun (eg, clozpine in schizophreni) until multiple other medictions hve been tried. Second, there re differences in insurnce coverge. Trditionlly, insurnce provides less coverge for mentl helth thn for physicl helth. Although mentl helth prity hs been relity for government benefits for some time, tht mndte hs only recently been extended to privte insurnce (with number of significnt loopholes). Third, there re differences in societl ttitude; stigm is still n issue, nd cn mke it more difficult for ptients to ccept nd follow through with tretment. Fortuntely, stigm, lthough still considerble, is decresing. This is not so much becuse people re seeing schizophreni s brin disorder (s opposed to mentl illness); people still do 8

9 References 1. Ntionl Institute of Mentl Helth. The numbers count: mentl disorders in Americ. Accessed October 1, Mueser KT, McGurk SR. Schizophreni. Lncet. 2004;363: Jblensky A. The 100-yer epidemiology of schizophreni. Schizophr Res. 1997;28: Lehmn AF, Liebermn JA, Dixon LB, et l. Prctice guideline for the tretment of ptients with schizophreni. Second edition. Am J Psychitry. 2004; 161(2 suppl): com/content.spxid= Accessed September 30, Liebermn JA, Perkins D, Belger A, et l. The erly stges of schizophreni: specultions on pthogenesis, pthophysiology, nd therpeutic pproches [correction ppers in Biol Psychitry. 2002;51:346]. Biol Psychitry. 2001;50: Liebermn JA, Alvir JM, Koreen A, et l. Psychobiologic correltes of tretment response in schizophreni. Neuropsychophrmcology. 1996;14(3 suppl):13s-21s. 7. Norton N, Willims HJ, Owen MJ. An updte on the genetics of schizophreni. Curr Opin Psychitry. 2006;19: Hrrison PJ, Owen MJ. Genes for schizophreni? 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Delyed-onset hypothesis of ntipsychotic ction: hypothesis tested nd rejected. Arch Gen Psychitry. 2003;60(12): Kne JM, Leucht S, Crpenter D, Docherty JP; Expert Consensus Pnel for Optimizing Phrmcologic Tretment of Psychotic Disorders. The expert consensus guideline series. Optimizing phrmcologic tretment of psychotic disorders. Introduction: methods, commentry, nd summry. J Clin Psychitry. 2003;64(suppl 12): Leucht S, Busch R, Hmnn J, Kissling W, Kne JM. Erly-onset hypothesis of ntipsychotic drug ction: hypothesis tested, confirmed nd extended. Biol Psychitry. 2005;57: Kinon B, Chen L, Ascher-Svnum H, Stuffer V, Kollck-Wlker S. Antipsychotic effectiveness bsed on erly response in the tretment of schizophreni. Eur Neuropsychophrmcol. 2007;17(suppl 4):S447. Presented t: 20th ECNP Congress; October 13-17, 2007; Vienn, Austri. 31. Lilly Reserch Lbortories. Dt on file. 32. Ascher-Svnum H, Nyhuis AW, Fries DE, Kinon BJ, Bker RW, Shekhr A. Clinicl, functionl, nd economic rmifictions of erly nonresponse to ntipsychotics in the nturlistic tretment of schizophreni. Schizophr Bull [Epub hed of print]. doi: /schbul/sbm Lilly Reserch Lbortories. Dt on file. DISCLOSURES The fculty report the following disclosures: Lwrence J. Cohen, PhrmD, BCPP, FASHP, FCCP: Consultnt/Advisory bord: AstrZenec, Lilly, Wyeth; Honorri: AstrZenec, Forest, Lilly. Robert L. Dufresne, PhD, PhD, BCPS, BCCP: Advisory bord: Johnson & Johnson, Eli Lilly; Expert testimony: AstrZenec; Lecturer: Johnson & Johnson, Eli Lilly. John M. Kne, MD: Consultnt/Advisory bord: Bristol- Myers Squibb, Jnssen, Lilly, Otsuk, PGxHelth, Wyeth; Lecturer: Bristol- Myers Squibb, Jnssen, Lilly, Otsuk; Stockholder: MedAvnte. Joseph Prks, MD: Consultnt: Eli Lilly, Jnssen, Solvy, Wyeth; Employee: Missouri Deprtment of Mentl Helth; Pending grnts: Ntionl Institute of Mentl Helth; Grnts received: Substnce Abuse & Mentl Helth Services Administrtion; Honorri: Ntionl Allince on Mentl Illness Albm. Dougls L. Noordsy, MD: Consultnt/Advisory bord: Lilly; Grnts: Jnssen; Honorri: AstrZenec, Lilly, Pfizer. Stephen Skld, PhrmD, BCPP: Advisory bord: Lilly Acdemic PhrmD Advisory Bord; Honorri: Drtmouth University; Spekers bureu: Bristol-Myers Squibb, Pfizer. 12