Psychotic and behavioral disturbances such as hallucinations,

Transcription

1 Article Comprison of Citloprm, Perphenzine, nd Plcebo for the Acute Tretment of Psychosis nd Behviorl Disturbnces in Hospitlized, Demented Ptients Bruce G. Pollock, M.D., Ph.D. Benoit H. Mulsnt, M.D. Jules Rosen, M.D. Robert A. Sweet, M.D. Sti Mzumdr, Ph.D. Ashok Bhruch, M.D. Robert Mrin, M.D. N.J. Jcob, M.D. Kimberly A. Huber, B.A. Kri B. Kstngo, M.S. Mrci L. Chew, B.S. Objective: Until recently, conventionl ntipsychotics were the stndrd phrmcotherpy for psychosis nd behviorl disturbnces ssocited with dementi. This double-blind, plcebo-controlled study compred the cute efficcy of the selective serotonin reuptke inhibitor citloprm nd the neuroleptic perphenzine with plcebo for the tretment of psychosis nd behviorl disturbnces in nondepressed ptients with dementi. Method: Eighty-five hospitlized ptients with t lest one moderte to severe trget symptom (ggression, gittion, hostility, suspiciousness, hllucintions, or delusions) were rndomly ssigned to receive either citloprm, perphenzine, or plcebo under double-blind conditions for up to 17 dys. Results: Ptients treted with citloprm or perphenzine showed sttisticlly significnt improvement on severl Neurobehviorl Rting Scle fctor scores. Compred to those receiving plcebo, only ptients treted with citloprm showed significntly greter improvement in their totl Neurobehviorl Rting Scle score s well s in the scores for the gittion/ggression nd lbility/tension fctors. Side effect scores were similr mong the three tretment groups. Conclusions: Citloprm ws found to be more efficcious thn plcebo in the short-term hospitl tretment of psychotic symptoms nd behviorl disturbnces in nondepressed, demented ptients. (Am J Psychitry 2002; 159: ) Psychotic nd behviorl disturbnces such s hllucintions, delusions, restlessness, disruptive vocliztions, nd physicl ggression re mong the most distressing mnifesttions of Alzheimer s disese. They occur with substntil prevlence nd hve been ssocited with excess disbility, incresed cregiver burden, nd premture institutionliztion (1, 2). Behviorl disturbnces in dementi re heterogeneous, encompssing both gittion occurring in the context of specific delusions or hllucintions nd gittion ssocited with nonspecific fctors. Idel mngement of these behviors includes the serch for modifible environmentl or physicl precipitnt; nevertheless, phrmcotherpy is frequently necessry (3). Until recently, conventionl ntipsychotics were the most frequently prescribed phrmcotherpy for psychosis nd behviorl disturbnces ssocited with dementi (4). Despite the potentil dvntges of typicl ntipsychotics, conventionl neuroleptics re still frequently utilized nd rgubly remin the best-studied medictions (5). A met-nlysis of seven trils tht used doubleblind, plcebo-controlled, prllel-group design reveled tht neuroleptics hve modest overll effect size of 0.18 (6). Previously, perphenzine ws extensively used in our hospitl to tret behviorl disturbnces ssocited with dementi. Our experience with this conventionl neuroleptic suggested tht low fixed doses re effective nd well tolerted in ptients who were not poor metbolizers of the cytochrome P-450 enzyme CYP2D6 (7, 8). Specific biochemicl dt hve suggested tht serotonergic deficits in Alzheimer s disese contribute to ggressive verbl nd physicl outbursts, sleep disturbnce, depression, nd psychosis (5, 9). Over the pst decde, reports on the use of serotonergic medictions for the tretment of the behviorl disturbnces of dementi hve been published (5). Severl cse series nd one rndomized tril (10) suggested tht trzodone is effective. In more recent study (11), however, the efficcy of trzodone ws not better thn tht of plcebo. In two erly plcebo-controlled trils, the selective serotonin reuptke inhibitors (SSRIs) lproclte (12) nd fluvoxmine (13) were lso not found to be more efficcious thn plcebo. However, the numbers of subjects in these trils were smll. In lrger rndomized, plcebo-controlled tril involving ptients with Alzheimer s disese, 31 ptients treted with citloprm showed significnt improvement in emotionl bluntness, irritbility, nxiety, nd restlessness (14). Nonetheless, the subjects in this study were included without regrd to possible depressive symptoms. Moreover, behviorl symptoms in this community-bsed study tended to be mild. The men pretretment scores for symptoms of irritbility, nxiety, nd restlessness were ll less thn 1.5 on scle from 0 (bsent) to 5 (most se- 460 Am J Psychitry 159:3, Mrch 2002

2 POLLOCK, MULSANT, ROSEN, ET AL. vere). In n open pilot study of citloprm, we treted 16 demented ptients with delusions or severe gittion who were dmitted to geropsychitric units (15). Citloprm ws well tolerted, nd the ptients experienced significnt reduction in gittion, hostility, nd suspicion. On the bsis of these preliminry findings nd our erlier experience with perphenzine (8), we conducted doubleblind, plcebo-controlled comprison of citloprm nd perphenzine in older ptients exhibiting moderte to severe psychosis or behviorl disturbnces ssocited with dementi. Method Study Group All ptients with dementi nd psychotic or behviorl disturbnces who were dmitted between October 1995 nd Jnury 2000 to the geritric inptient units t the Western Psychitric Institute nd Clinic were considered for inclusion in the tril. To be eligible for the tril, ptients hd to meet the DSM-IV criteri for dignosis of dementi of the Alzheimer s type, vsculr dementi, mixed dementi of the Alzheimer s type nd vsculr dementi, or dementi not otherwise specified nd not meet the DSM-IV criteri for delirium, schizophreni, bipolr disorder, or mjor depressive disorder. The presence of t lest one cler trget symptom, s demonstrted by score of 3 or more (i.e., moderte to severe) on the Neurobehviorl Rting Scle (16) gittion items (ggression, gittion, hostility) or psychosis items (delusions, hllucintions, suspiciousness) ws lso required. Subjects were excluded if there ws evidence of cliniclly significnt depression, s demonstrted by score of 3 or more on the Neurobehviorl Rting Scle depression item. Subjects with unstble physicl illness or neurologicl illness other thn dementi were lso excluded. In ddition, subjects were required not to hve been treted with fluoxetine within the pst 4 weeks or with monomine oxidse inhibitor within the pst 2 weeks. Cognitive enhncers were permitted if the subject hd been receiving stble dose for minimum of 6 weeks. During the recruitment period, 239 ptients were considered for prticiption. In ccordnce with the policy of the University of Pittsburgh institutionl review bord, before pproching potentil subjects for consent, the tretment tem ws consulted to ensure tht the reserch procedures would not be unduly burdensome or disruptive to impending clinicl procedures. After the reserch stff nd physicin-investigtor hd explined the study procedures, gols, nd risks to the ptient nd his or her uthorized representtive, written informed consent ws obtined from the ptient s representtive. The ptient s ssent ws lso obtined. Informed consent ws obtined for 92 ptients, seven of whom were excluded before medictions were strted. Thus, 85 ptients were rndomly ssigned to tretment groups, took t lest one dose of study mediction, completed t lest one follow-up ssessment, nd were included in the nlysis. Study Design The study ws rndomized, double-blind, plcebo-controlled tril lsting for the durtion of inptient hospitliztion, up to 17 dys. For better evlution of the subjects behviors nd symptoms, the subjects first completed 3 5-dy observtion period nd wshout of ll current psychotropic medictions (i.e., ntipsychotics, ntidepressnts, ntiepileptics nd other mood stbilizers, ntiprkinsonin medictions, nd benzodizepines) except for lorzepm, which ptients could receive during the wshout nd throughout the study t the lowest possible dose, not to exceed 1 mg/dy. Upon completion of the wshout, the subjects were rndomly ssigned to double-blind tretment with 10 mg/dy of citloprm for 3 dys followed by 20 mg/dy for 14 dys or 0.05 mg/kg per dy of perphenzine for 3 dys followed by 0.1 mg/kg per dy for 14 dys. Medictions were dministered ccording to the double-dummy technique, twice dily, with citloprm given t 1:00 p.m. nd perphenzine t 8:30 p.m. Ptients were rndomly ssigned to receive either citloprm, perphenzine, or plcebo ccording to 3:3:2 rtio. Erly discontinution from the study ws considered in the event of the onset of new symptoms tht endngered the sfety or helth of the ptient (e.g., delirium or serious dverse rection possibly relted to study mediction), significnt worsening of psychosis or gittion, n dministrtive reson (e.g., dischrge from the hospitl), or when consent ws withdrwn. At the conclusion of the study the blind ws broken, nd the ptients were treted by their ttending physicins s cliniclly indicted. Assessments On the ptients dmission to the inptient units, full dignostic nd lbortory ssessment ws completed by the clinicl tem to evlute for potentilly tretble cuses of dementi. The ptients were lso ssessed by trined reserch rters t study enrollment, t the study bseline (i.e., t rndom ssignment), nd fter receiving study mediction for 3, 10, nd 17 dys (or t discontinution from the study). Informtion ws obtined from direct observtion of the ptients, interviews with the ptients nd nursing stff, nd chrt review of ll notes for the 3 dys preceding the rting. Instruments included the Neurobehviorl Rting Scle, Udvlg for Kliniske Undersøgelser (UKU) Side Effect Rting Scle (17), nd the Mini-Mentl Stte Exmintion (MMSE) (18). The Neurobehviorl Rting Scle is 28-item observer-rted instrument derived from the Brief Psychitric Rting Scle (BPRS) tht ssesses multiple types of psychopthology. It combines coverge of the bredth of psychopthology ddressed in the BPRS with more comprehensive ssessment of impirments seen in dementi. Scoring for the Neurobehviorl Rting Scle is bsed on 7-point scle of incresing severity (i.e., 0=not present, 1=very mild, 2=mild, 3=moderte, 4=modertely severe, 5=severe, 6=extremely severe). Although the subjects were entered into the study fter meeting severity criteri on individul gittion or psychosis trget symptoms, we hve found tht first-order seven-fctor model of the Neurobehviorl Rting Scle provides the best fit for correltions mong Neurobehviorl Rting Scle items (19, 20). Consequently, the seven Neurobehviorl Rting Scle fctor-bsed scores (for cognition, gittion/ggression, retrdtion, depression, pthy, psychosis, nd lbility/tension) nd their sum, yielding totl Neurobehviorl Rting Scle score, were used s our primry efficcy mesures. Rters prticipted in initil trining sessions nd in retrining sessions yerly. In ddition, interrter relibility of the reserch rters ws estblished nd monitored by clculting intrclss correltion coefficients (ICCs) for the Neurobehviorl Rting Scle, UKU Side Effect Rting Scle, nd MMSE. Throughout the study, interrter relibility ws good to excellent, with ICCs >0.70. Dignoses were estblished ccording to the DSM-IV criteri, fter considering ll vilble informtion, during weekly reserch consensus conference ttended by t lest three investigtor geropsychitrists nd by the reserch stff. In ddition, the criteri for probble or possible Alzheimer s disese of the Ntionl Institute of Neurologicl nd Communictive Disorders nd Stroke nd the Alzheimer s Disese nd Relted Disorders Assocition (21) were used for confirmtory review. Ptients were lso clssified during consensus meetings ccording to the criteri for the dignosis of dementi with Lewy bodies (22). Medicl problems were coded on xis III ccording to the ICD-9-CM clssifiction system. Am J Psychitry 159:3, Mrch

3 CITALOPRAM FOR DEMENTED PATIENTS TABLE 1. Bseline Chrcteristics of Ptients in Rndomized, Double-Blind, Plcebo-Controlled Tril of Citloprm nd Perphenzine for Tretment of Behviorl nd Psychotic Disturbnces Associted With Dementi Chrcteristic Ptients Receiving Citloprm (N=31) Ptients Receiving Perphenzine (N=33) Ptients Receiving Plcebo (N=21) Men SD Men SD Men SD Age (yers) Mini-Mentl Stte Exmintion score N % N % N % Femle White Dementi dignosis Alzheimer s type Vsculr Alzheimer s type nd vsculr Not otherwise specified Dementi with Lewy bodies Possible Probble No sttisticlly significnt differences between groups. Sttisticl Methods Absolute chnge in the seven Neurobehviorl Rting Scle fctor-bsed scores ws the primry outcome mesure. The number of side effects s ssessed with the UKU Side Effect Rting Scle, including extrpyrmidl symptoms, nd use of lorzepm were lso compred mong tretment groups. Anlyses were done on n intent-to-tret bsis with the lst observtion crried forwrd. Thus, ptients who were rndomly ssigned to tretment group, received t lest one dose of study mediction, nd completed the bseline nd t lest one postbseline evlution were included in the nlyses. All sttisticl tests were two-tiled. The test for normlity (Shpiro-Wilk sttistic) indicted tht the fctor-bsed scores were not distributed normlly. Therefore, differences mong the tretment groups in the seven fctor-bsed scores nd the percentge chnge in totl, utonomic, nd extrpyrmidl UKU Side Effect Rting Scle scores were ssessed by using the Kruskl-Wllis test. Pirwise comprisons with the Wilcoxon rnk-sum test were done when deemed necessry. For totl Neurobehviorl Rting Scle scores, which were normlly distributed, we performed n nlysis of covrince with bseline totl scores s covrites. In ddition, chnges from bseline in the totl Neurobehviorl Rting Scle scores were nlyzed by using two-wy cross-clssifiction nlysis of vrince with fctors for tretment group nd lorzepm use. Results Subjects Of the 85 subjects, 61 met the DSM-IV criteri for dementi of the Alzheimer s type, six for vsculr dementi, two for dementi of the Alzheimer s type nd vsculr dementi, nd 16 for dementi not otherwise specified. Nine of the 85 ptients lso met the criteri for probble dementi with Lewy bodies nd nother 23 for possible dementi with Lewy bodies. Thirty-one ptients were rndomly ssigned to receive citloprm (36%), 33 to receive perphenzine (39%), nd 21 to receive plcebo (25%). One ptient who ws ssigned to receive perphenzine ws found on subsequent review to hve hd Neurobehviorl Rting Scle depression rting of moderte. The results of nlyses both including nd excluding dt for this subject did not differ. Thus ll results presented include the dt for this subject. The demogrphic nd clinicl chrcteristics of the three tretment groups re presented in Tble 1. The groups did not differ significntly on ny mesure t bseline. Ptient Disposition All 31 subjects (100%) ssigned to receive citloprm received 20 mg/dy; subjects ssigned to receive perphenzine received men dily dose of 6.5 mg/dy (SD=1.7). Thirty-nine ptients (46%) completed 17 dys of tretment or plcebo in the hospitl, nd 46 (54%) did not. Resons for discontinution included possible side effects (N=14), lck of efficcy (N=23), dministrtive reson (e.g., dischrge due to rpid improvement) (N=7), nd mediction noncomplince (N=2). The three tretment groups did not differ significntly in the overll proportion of ptients who discontinued the tril erly (citloprm: 16 ptients, 52%; perphenzine: 18 ptients, 55%; plcebo: 12 ptients, 57%) (χ 2 =0.17, df=2, p=0.92) nor in the distribution of resons for discontinution (χ 2 =1.27, df=2, p=0.53). Efficcy nd Sfety Before the strt of tretment, the men totl Neurobehviorl Rting Scle scores were 53.5 (SD=10.2), 57.1 (SD=14.0), nd 58.3 (SD=11.9) for the citloprm, perphenzine, nd plcebo groups, respectively. The finl men totl Neurobehviorl Rting Scle scores were 43.5 (SD=12.1), 49.9 (SD=14.2), nd 56.0 (SD=15.2) for the three respective groups. With the bseline totl Neurobehviorl Rting Scle score s covrite, there ws significnt difference in the finl totl Neurobehviorl Rting Scle scores mong the three tretment groups (F=30.8, df=3, 81, p<0.0001). Pirwise comprisons indicted tht the finl totl score of the citloprm group ws significntly different from tht of the plcebo group (t=3.3, df= 50, p=0.002), but the finl totl score of the perphenzine group ws not (t=1.5, df=52, p=0.14). On the bsis of the 462 Am J Psychitry 159:3, Mrch 2002

4 POLLOCK, MULSANT, ROSEN, ET AL. totl Neurobehviorl Rting Scle scores, the tretment effect sizes for citloprm nd perphenzine were 0.64 nd 0.36, respectively. Both the citloprm nd perphenzine groups showed significnt improvement from bseline with respect to the gittion/ggression, psychosis, nd lbility/tension fctors. The citloprm group lso showed significnt improvement in the cognition nd retrdtion fctors. Those receiving plcebo did not demonstrte significnt chnge on ny fctor (Figure 1). The bsolute chnges in gittion/ggression nd lbility/tension fctor-bsed scores were significntly different in the three tretment groups (Kruskl-Wllis test χ 2 =6.7, df=2, p<0.04, nd χ 2 =9.2, df=2, p=0.01, respectively). Pirwise comprisons were significnt only for citloprm versus plcebo (gittion/ggression fctor: χ 2 =5.0, df=1, p<0.03; lbility/tension fctor: χ 2 =9.23, df=1, p=0.002). With regrd to side effects, no significnt chnge in totl UKU Side Effect Rting Scle score ws detected in ny of the three tretment groups (F=1.49, df=2, 81, p=0.23). Also, there were no significnt differences between groups in utonomic nd extrpyrmidl symptom subscores (F=0.57, df=2, 61, p=0.57; nd F=1.84, df=2, 78, p=0.16, respectively). Concomitnt Medictions Twelve ptients who hd received stble dose of donepezil before the current episode of behviorl disturbnce continued to receive this mediction. Four of these ptients were rndomly ssigned to receive plcebo, two to receive perphenzine, nd six to receive citloprm. The three tretment groups did not differ significntly with respect to the proportion of ptients who required lorzepm for 5 dys or more during the tril (citloprm: eight ptients, 26%; perphenzine: 11 ptients, 33%; plcebo: seven ptients, 33%) (χ 2 =0.58, df=2, p=0.83). A two-wy cross-clssifiction nlysis of vrince ws performed to determine whether chnges in the men totl Neurobehviorl Rting Scle score were ssocited with the use of lorzepm or tretment ssignment nd whether there ws interction between lorzepm use nd drug or plcebo ssignment. A tretment ssignment effect (F=4.5, df=2, 79, p<0.02) ws seen but no effect of lorzepm use (F=0.53, df=1, 79, p=0.46) nd no interction effect (F=1.9, df=2, 79, p=0.16) were noted. Discussion In Alzheimer s disese ptients, psychotic nd nonpsychotic behviorl disturbnces improved cutely with both citloprm nd perphenzine. However, only citloprm demonstrted cute efficcy superior to plcebo. At the doses used, both drugs were well tolerted. The min strengths of this study were the prllel tretment design, the inclusion of plcebo group, nd the dignostic nd symptomtic chrcteriztion of the subjects, s well s the prospectively defined hypotheses nd FIGURE 1. Chnge in Neurobehviorl Fctor Scores From Bseline to Study Termintion ( 17 Dys) in Ptients With Dementi in Rndomized, Double-Blind, Plcebo-Controlled Tril of Citloprm nd Perphenzine Men Improvement From Bseline Score Cognition,b Agittion Citloprm (N=31) Retrdtion Depression Perphenzine (N=33) Apthy Psychosis Neurobehviorl Rting Scle Fctor Plcebo (N=21) Lbility Significnt difference within group between bseline nd termintion scores (Wilcoxon signed-rnk test, p<0.05). b Significnt difference between the citloprm nd plcebo groups (Kruskl-Wllis test, p<0.05). dt nlyticl pln. It should lso be pprecited tht the study ptients were hospitlized becuse of the severity of their symptoms, which most likely explins the high ttrition rte we observed. Severity of symptoms nd the inptient setting lso necessitted brief tril, the min limittion of the study. The severity of symptoms nd brief durtion of the tril probbly lso resulted in plcebo response rte tht ws considerbly lower thn tht reported in studies with outptients (11) or long-term cre residents (23). Nonetheless, for severely ffected, hospitlized ptients the gol of tretment is to control symptoms rpidly, t lest to n extent sufficient to permit dischrge, rther thn to chieve full response. Therefore, tril of dys firly represents wht cn be ccomplished during n cute hospitliztion, nd its results re generlizble to ctul prctice. Although perphenzine s effect ws modest nd not significnt reltive to plcebo, the effect size we observed (0.36) ws similr to those reported in other plcebo-controlled trils of conventionl neuroleptics conducted for longer durtions (6). Given the brief period of tretment nd the severity of symptoms t bseline, the improvement in both overll gittion nd specific psychotic symptoms in nondepressed ptients with citloprm is notble. There is need, however, to exercise cution in scribing n ntipsychotic effect to n SSRI. Ptients were entered into the study if they hd symptoms of either psychosis or gittion. Agittion frequently ccompnies psychosis, which reduces our cpcity to determine the specificity of citloprm for these symptoms. Moreover, psychotic symptoms in Alzheimer s disese re clerly distinct from those typi-,b Am J Psychitry 159:3, Mrch

5 CITALOPRAM FOR DEMENTED PATIENTS cl of schizophreni (24). For exmple, of the 23 ptients experiencing hllucintions in our study, 14 (61%) hd only visul hllucintions. Delusions in demented ptients my lso result from more generlized impirment, such s misperceptions nd impired judgment in the context of nxiety. Significnt reltionships hve been reported between delusions in Alzheimer s disese nd life events (25), including mritl discord (26). Therefore, it is possible tht delusions in Alzheimer s disese my be ttenuted by the nxiolytic effect of n SSRI. Nyth nd Gottfries (14) referred to this ction of citloprm s behviorl stbiliztion. Nonetheless, SSRIs my lso hve neuroleptic effects by reducing dopminergic outflow (27), nd dysregultion in serotonergic neurotrnsmission my ply n etiologiclly importnt role for psychotic symptoms in Alzheimer s disese ptients (5). For exmple, common serotonin 5-HT 2A nd 5-HT 2C receptor polymorphisms hve been ssocited with visul hllucintions in Alzheimer s disese subjects (28), nd recently we hve found tht ggression nd psychosis in Alzheimer s disese subjects were ssocited with serotonin trnsporter gene promoter region polymorphisms (29, 30). Finlly, SSRIs differ in their potency nd selectivity for serotonin reuptke inhibition, with citloprm being the most selective with moderte potency nd high biovilbility (31). Therefore, future studies should ddress the reltive effectiveness of other SSRIs s well s cross-clss comprisons with typicl ntipsychotics. Presented in prt t the 153rd nnul meeting of the Americn Psychitric Assocition, Chicgo, My 13 18, 2000, nd the 14th nnul meeting of the Americn Assocition for Geritric Psychitry, Sn Frncisco, Feb. 26, Received Mrch 6, 2001; revision received Aug. 17, 2001; ccepted Sept. 13, From the Geritric Psychophrmcology Progrm, Acdemic Division of Geritrics nd Neuropsychitry, Deprtment of Psychitry, University of Pittsburgh School of Medicine; nd the Geritric Reserch, Eduction, nd Clinicl Center, VA Pittsburgh Helth System. Address reprint requests to Dr. Pollock, Geritric Psychophrmcology Progrm, Western Psychitric Institute nd Clinic, 3811 O Hr St., Pittsburgh, PA 15213; pollockbg@msx.upmc.edu (e-mil). Supported in prt by NIMH grnts MH-55106, MH-59666, MH , MH-01613, nd MH nd grnt RR from the Division of Reserch Resources, NIH. References 1. 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