Major depressive disorder is a common disorder in

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1 Artile Effiay of Duloxetine on Cognition,, and Pain in Elderly Patients With Major Depressive Disorder: An 8-Week, Doule-Blind, Plaeo-Controlled Trial Joel Raskin, M.D., F.R.C.P.C. Curtis G. Wiltse, Ph.D. Alan Siegal, M.D., M.B.A. Javaid Sheikh, M.D. Jimmy Xu, Ph.D. James J. Dinkel Benjamin T. Rotz, R.Ph. Rihard C. Mohs, Ph.D. Ojetive: This study ompared the effets of duloxetine, 6 mg/day, versus plaeo on ognition, depression, and pain in elderly patients with reurrent major depressive disorder. Method: Patients were randomly assigned (2:1) to duloxetine, 6 mg/day (N= 27), or plaeo (N=14) for 8 weeks in a doule-lind study. The primary outome measure was a prespeified omposite ognitive sore omposed of four individual tests. Seondary measures inluded the Geriatri Sale, the Hamilton Rating Sale, the Visual Analogue Sale assessing pain, and standard safety and toleraility assessments. Results: Patients had a median age of 72 years (range=65 9). Duloxetine demonstrated signifiantly greater improvement in the omposite ognitive sore versus plaeo (least-squares mean hange from aseline to endpoint: 1.95 versus.76), driven y improved veral learning and memory. Duloxetine treatment showed signifiantly greater aseline-to-endpoint redutions in oth Hamilton depression sale ( 6.49 versus 3.72) and Geriatri Sale (.7 versus 1.34) total sores ompared with plaeo. Hamilton depression sale response (37.3% versus 18.6%) and remission (27.4% versus 14.7%) rates at endpoint were signifiantly higher for duloxetine than for plaeo. Duloxetine signifiantly improved Visual Analogue Sale sores for ak pain and time in pain while awake versus plaeo. Signifiantly fewer patients reeiving duloxetine withdrew from the study eause of lak of effiay (2.9% versus 9.6%); the inidenes of disontinuation due to adverse events were similar for duloxetine and plaeo (9.7% versus 8.7%). Conlusions: Duloxetine improved ognition, depression, and some pain measures and was safe and well tolerated in elderly patients with reurrent major depressive disorder. (Am J Psyhiatry 27; 164:9 99) Major depressive disorder is a ommon disorder in the elderly and is often assoiated with physial disaility and ognitive defiits (1, 2). Studies show that ognitive funtion may return to normal if depression is effetively treated (3, 4). Cognitive impairment is an important linial issue among elderly patients with depression and has a more omplex etiology eause of the variale rate of mild ererovasular and/or Alzheimer s-type neurodegenerative hanges assoiated with depression in the elderly (5). Longitudinal studies of ommunity-dwelling elderly have found that ognitive impairment sometimes preedes the onset of depression (6), and follow-up studies (7) have indiated that some elderly patients with depression may have neurodegenerative hanges that are preursors to dementia. Cognitive funtions, inluding learning, memory, and foused attention, are partiularly suseptile to disruption in patients with depression. Patients with depression perform approximately one half of an SD worse than healthy omparison sujets on veral learning and memory tests (3). Other studies of patients with depression have found defiits most onsistently in ognitive tasks involving foused attention, working memory, and deision making (3, 4). Cognitive impairment should e onsidered as important as other emotional and physial symptoms of major depressive disorder (8). Ideally, an antidepressant for elderly patients with major depressive disorder should improve ognitive funtions while improving mood and physial symptoms. Duloxetine hydrohloride is a reently approved antidepressant mediation that inhiits oth serotonin (5-HT) and norepinephrine reuptake (9). The dual ation of duloxetine makes it partiularly interesting in the treatment of depression with ognitive impairment eause imalane or defiieny in 5-HT and/or norepinephrine systems has een found to ontriute to ognitive defiits (1, 11). Beause the effet of duloxetine on ognitive performane in elderly patients with depression has not een previously evaluated, the primary ojetive of the present study was to ompare the effiay of duloxetine, 6 mg/ day, with plaeo on ognition as assessed y a prespei- 9 ajp.psyhiatryonline.org Am J Psyhiatry 164:6, June 27

2 RASKIN, WILTSE, SIEGAL, ET AL. fied omposite measure in a doule-lind, plaeo-ontrolled trial involving elderly patients with reurrent major depressive disorder. The onventional measures of mood were speified as seondary endpoints in the protool. and pain are ommon omoridities (12). Pain as a physial symptom of depression affets approximately 65% of patients, leading to less favorale outomes and greater health are utilization. Moreover, depression is a ommon feature in patients with hroni pain and an affet pain threshold and tolerane. Several lasses of antidepressants have een used suessfully in the treatment of somati symptoms of depression and for a variety of pain syndromes (12). A diret relationship etween pain severity and depression has een identified in older patients with hroni pain (13). Therefore, it is important to assess pain measures in elderly patients with depression. FIGURE 1. Study Design Week Sreening phase Aute treatment phase No study drug, all patients Random assignment to plaeo Plaeo, all patients Random assignment to duloxetine, 6 mg/day Visit Method Study Design 4 6 This was a multienter, doule-lind, plaeo-ontrolled study of 311 elderly outpatients with reurrent major depressive disorder onduted in the United States. After a 1-week sreening phase and a 1-week plaeo phase, patients were randomly (2:1) assigned to one-daily duloxetine, 6 mg/day (N=27), or plaeo (N=14) for 8 weeks and then entered a 1-week, doulelind disontinuation phase in whih the dosage of duloxetine was redued to 3 mg/day for 4 days, followed y replaement with plaeo (Figure 1). If after visit 2 the patient ould not tolerate the assigned drug, the dose ould e redued to 3 mg/day at the disretion of the investigator, ut the full dose had to e reahed y visit 5 (week 2 of treatment) or the patient was dropped from the study. 8 9 Disontinuation phase Swith to duloxetine, 3 mg/day 7 8 Patients All patients in this study were age 65 years with reurrent major depressive disorder. All patients met diagnosti riteria for major depressive disorder as defined in the DSM-IV. The diagnosis was onfirmed y the Mini International Neuropsyhiatri Interview (14), a standardized diagnosti interview ased on DSM-IV riteria. Baseline disease severity was defined y patients sores on the Hamilton Rating Sale with 17 items (HAM-D) (15). Patients were required to have a HAM-D total sore 18 at visits 1 and 2; a Mini-Mental State Examination (MMSE) (16) sore 2 with or without mild dementia; and at least one previous episode of major depression. Patients with an MMSE sore of 2 to 23 were ategorized as having mild dementia, while those with a sore of 24 were ategorized as having no dementia. Patients were exluded for the following reasons: urrent primary axis I diagnosis other than major depressive disorder or mild dementia (inluding dysthymia or psyhoti depression); previous diagnosis of psyhoti disorder; organi mental disorder, moderate to severe dementia, or mental retardation; serious or unstale medial illness, psyhologial ondition, or linially signifiant laoratory anormality that, in the opinion of the investigator, would ompromise partiipation in this study or e likely to lead to hospitalization during the ourse of the study; or an alanine transaminase, aspartate transaminase, or gamma glutamyl transferase level >1.5 times the upper limit of normal, ased on Eli Lilly and Company s referene ranges (17). Eah patient provided written informed onsent efore any study proedures or administration of study drug, in aordane with the Delaration of Helsinki. Effiay Measures The primary outome measure was a protool-speified omposite ognitive sore ased on four ognitive tests: 1) the Veral Learning and Reall Test, 2) the Symol Digit Sustitution Test, 3) the Two-Digit Canellation Test, and 4) the Letter-Numer Sequening Test. These tests were seleted eause they assess aspets of ognition shown previously to e most impaired in patients with depression, speifially veral learning and memory, attention, exeutive funtion, and working memory (3, 4). Additionally, eah of these tests has een used extensively in linial psyhopharmaology and an e ompleted in a short period of time. Seondary measures inluded the Geriatri Sale, the HAM-D, the Visual Analogue Sale for pain, and the Clinial Gloal Impression (CGI) severity sale. For the Veral Learning and Reall Test, whih was adapted from the Rey Auditory Veral Learning Test (18), the patient was given three trials to learn a list of 15 ommon nouns presented on ards one at a time. The learning sore was the average numer of words realled for the three trials. The delayed reall sore was the numer of words orretly realled after the other ognitive tests had een administered. The Symol Digit Sustitution Test is an attention-demanding omponent of the Wehsler Adult Intelligene Sale, 3rd ed. (WAIS-III) (19). The Symol Digit Sustitution Test sore was the numer of digits oded orretly in a 9-seond test period. The Two-Digit Canellation Test (2) was designed to assess drug effets on visual attention and exeutive funtion in persons with mild ognitive impairment. The patients had 45 seonds to Am J Psyhiatry 164:6, June 27 ajp.psyhiatryonline.org 91

3 DULOXETINE AND ELDERLY DEPRESSED PATIENTS TABLE 1. Baseline Demographi and Psyhiatri Charateristis of Patients With ANOVA or Variale Plaeo Group (N=14) Duloxetine (6 mg/day) Group (N=27) Fisher s Exat Test N % N % p Female Ethniity.82 Cauasian Hispani Afrian desent Other Mean SD Mean SD p Age (years) a Weight (kg) Baseline psyhiatri profile Composite ognitive sore Hamilton Rating Sale (17-item version) (HAM-D) total sore (visit 1) HAM-D total sore (random assignment, visit 3) Geriatri Sale sore Duration of urrent episode (weeks) Numer of previous episodes Visual Analogue Sale overall sore N % N % p Mild dementia a Range: plaeo, 65 89; duloxetine, Defined as a Mini-Mental State Examination sore of 23. searh for two target digits among rows of numers on a page. The Two-Digit Canellation Test sore is the numer of targets hit minus the numer inorretly marked (errors) minus the numer of times the patient had to e reminded of the task. The Letter-Numer Sequening Test is another omponent of the WAIS-III (19) and assesses working memory and exeutive funtioning. The test administrator read aloud a group of numers and letters (e.g., 9-C-3) then asked the patient to repeat them after rearranging them with the numers first, in order from smallest to largest, followed y the letters in alphaetial order. The sequene length (2 8) was inreased until the patient failed three trials of a given length. The sore was the sum of the item sores (1). The omposite ognitive sore, ranging from to 51, was onstruted so that the ontriution of eah test was roughly proportional to the time spent in administering the test. Tests stressing learning and memory were weighted only slightly more than the omination of those stressing attention or exeutive funtion. The omposite ognitive sore was defined as the sum of the following: 1. The average numer of words realled on the three learning trials of the Veral Learning and Reall Test (sore 15) and the numer of words realled on the delayed reall test of the Veral Learning and Reall Test (sore 15) 2. The fration of all possile targets orret on the Symol Digit Sustitution Test (numer orret divided y 133) multiplied y 7 (sore 7) 3. The numer of targets hit minus the numer inorret minus the numer of times the patient had to e reminded of the task divided y the possile numer orret (4) on the Two-Digit Canellation Test multiplied y 7 (sore 7, set to if negative) 4. The total sore on the Letter-Numer Sequening Test ( 21) divided y 3 (sore 7) The Geriatri Sale (21) was developed as a asi sreening measure for depression in older adults. The Visual Analogue Sale (22) for pain onsists of six questions regarding the experiene of overall pain, headahe, ak pain, shoulder pain, pain interferene with daily ativities, and time in pain while awake. The Visual Analogue Sale is used widely in the assessment of pain. Cognitive measures and the MMSE were reorded one efore random assignment and at the last visit of the aute treatment phase. The Geriatri Sale, the HAM-D, the CGI severity sale, and the Visual Analogue Sale were reorded one efore random assignment and at every visit of the aute treatment phase. Response and remission rates were also seondary effiay outome measures, with response defined as a 5% derease in the HAM-D total sore from aseline to endpoint and remission as a HAM-D total sore 7 at endpoint. Safety and Toleraility Measures Safety and toleraility measures reorded at every visit inluded spontaneously reported adverse events, onomitant mediations, weight, and supine and standing lood pressure and heart rate. An ECG, a urine sample, and lood for hemistry and hematology tests were olleted at sreening and at the last visit of the aute treatment phase. Sustained elevation in systoli (diastoli) lood pressure was defined as supine systoli (diastoli) lood pressure 14 (9) mm Hg and an inrease from aseline 1 mm Hg for three or more onseutive visits in the aute treatment phase. Sustained elevation in lood pressure was defined as sustained elevation in either systoli or diastoli lood pressure. Treatment-emergent orthostati hypotension was defined as 1) having the standing diastoli lood pressure at least 1 mm Hg less than the supine diastoli lood pressure or the standing systoli lood pressure at least 2 mm Hg less than the supine systoli lood pressure at any time in the aute treatment phase and 2) not meeting these riteria at any visit in the aseline interval. Values for anormal laoratory tests were ased on Covane (Covane Central Laoratory Servies, Indianapolis) referene limits. Statistial Analysis All analyses were onduted on an intent-to-treat asis. For treatment omparisons, the term signifiant indiates statistial signifiane (two-sided, p.5). No adjustments for multiple omparisons were made. Unless otherwise speified, aseline 92 ajp.psyhiatryonline.org Am J Psyhiatry 164:6, June 27

4 RASKIN, WILTSE, SIEGAL, ET AL. FIGURE 2. Cognitive Sore Changes Among Depressed Patients Randomly Assigned to Duloxetine or Plaeo a Improvement Least-Squares Mean Change Composite Cognitive Sore Individual Cognitive Sore Duloxetine, 6 mg/day N=194 N=165 N=29 N=197 N=195 N=196 N=197 N=197 Plaeo N=98 N=82 N=16 N=98 N=98 N=99 N=99 N=99 e d All randomly assigned patients Patients soring <24 on Hamilton Rating Sale Patients soring 24 on Hamilton Rating Sale Learning trials Delayed reall d Veral Learning and Reall Test Symol Digit Sustitution Test Two-Digit Canellation Test Letter- Numer Sequening Test a Interation (left): p=.82; mean aseline sores (right): learning trials, ~7; delayed reall, ~7; symol digit sustitution, ~36; two-digit anellation, ~22; letter-numer sequening, ~9. p<.2 versus plaeo. p=.13 versus plaeo. d p=.3 versus plaeo. e p=.2 versus plaeo. refers to the last nonmissing oservation efore random assignment. Endpoint refers to the last nonmissing oservation during the aute treatment phase. The aseline used for determination of elevated lood pressure was the maximum oservation efore random assignment. Changes in ontinuous effiay variales from aseline to endpoint were analyzed with a fixed-effets analysis of ovariane (ANCOVA) model that inluded terms for treatment, investigator, and aseline sore. Continuous aseline variales; hanges from aseline to endpoint in vital signs, weight, and ECG intervals; and hanges in laoratory results were evaluated y using a fixed-effets analysis of variane (ANOVA) model that inluded terms for treatment and investigator. Laoratory variales were rank-transformed eause they are often skewed to the right and not normally distriuted. These analyses are referred to as mean hange analyses. Some effiay variales measured over time were analyzed y using a mixed-effets model, likelihood-ased, repeatedmeasures approah. The model inluded the fixed ategorial effets of treatment, investigator, visit, and treatment-y-visit interation, as well as the ontinuous fixed ovariates of aseline sore and aseline sore-y-visit interation. The unstrutured ovariane struture was used to model the within-patient errors. Categorial measures, suh as rates of response and remission, adverse events, and disontinuations, were analyzed with Fisher s exat test. Throughout this artile, mean refers to the raw mean unless the least-squares mean is speified. Sugroup analyses of the omposite ognitive sore and the Geriatri Sale and HAM-D total sores were performed y adding the relevant sugroup and treatment-y-sugroup interation terms to the ANCOVA model. Interation effets were tested at a two-sided,.1 signifiane level. The sugroups were defined a priori in the protool, namely: investigator, age (<75, 75), gender, origin (Cauasian, other), omoridity (yes, no), mild dementia at aseline (yes, no), aseline HAM-D sore (<24, 24), HAM-D anxiety (yes, no), HAM-D insomnia (yes, no), numer of previous episodes of depression (<median, median), Geriatri Sale total sore, CGI severity sale sore, and numer of previous drugs reeived for depression (, 1). Treatment-emergent adverse events were reported using preferred terms for version 7. of the Medial Ditionary for Regulatory Ativities. Path analysis (23) was performed post ho to test the diret treatment effet on the hange in the omposite ognitive sore. In the analysis, prespeified pathways desried the ausal relationships for the testing: the treatment has effet on hange in the omposite ognitive sore (diret effet), and the treatment effet on depressive symptoms (as measured y the Geriatri Sale and HAM-D total sores) has effet on hange in the omposite ognitive sore (indiret). Indiret effets through the two depression measures were evaluated separately. The signifiane of the diret treatment effet was tested y Student s t test in the regression model, in whih hange in the omposite ognitive sore was the dependent variale and treatment, aseline omposite ognitive sore, aseline Geriatri Sale (or HAM-D) total sore, and hange in Geriatri Sale (or HAM-D) total sore were regressors. In addition, with another regression model for hange in Geriatri Sale (or HAM-D) total sore, the indiret treatment effet y means of hange in Geriatri Sale (or HAM-D) total sore was a result of multiplying the treatment oeffiient y the oeffiient of the orresponding hange in the first desried regression model. The perentages of diret and indiret effets on the total treatment effet were omputed. Two hundred duloxetine- and 1 plaeo-treated patients provide 8% power to detet an effet size (differene etween mean hanges in the omposite ognitive sore divided y the ommon SD) of.35 y using a 5% two-sided signifiane level and assuming that 95% of patients have data for the analysis. All analyses were performed using SAS software (SAS Institute, Cary, N.C.). Am J Psyhiatry 164:6, June 27 ajp.psyhiatryonline.org 93

5 DULOXETINE AND ELDERLY DEPRESSED PATIENTS FIGURE 3. Repeated Measures and Mean Change Analyses of Rating Sale Sores Among Depressed Patients Randomly Assigned to Duloxetine or Plaeo a Change From Baseline Sore Geriatri Sale Clinial Gloal Impression Severity Sale Hamilton Rating Sale a Mean aseline Geriatri Sale sore: ~18 (top); mean aseline Hamilton Rating Sale sore: ~19 (middle). p.1 versus plaeo. p<.1 versus plaeo. Results 1 2 Patient Charateristis Least-Squares Mean Change From Mixed-Effets Model Repeated Measures Patient harateristis at aseline are summarized in Tale 1. The duloxetine and plaeo groups did not signifiantly differ in any variale exept for the Geriatri Sale total sore, whih was higher for the duloxetine group than for the plaeo group (p<.1). Effiay in Cognitive Measures Plaeo (N=11) Duloxetine, 6 mg/day (N=198) Plaeo (N=12) Duloxetine, 6 mg/day (N=21) Plaeo (N=12) Duloxetine, 6 mg/day (N=21) 4 8 Weeks Effiay in Measures Results from the repeated measures and mean hange analyses of the depression effiay measures are shown in Figure 3. Patients treated with duloxetine had signifiantly greater improvement in Geriatri Sale total sore than did plaeo-treated patients eginning 1 week after random assignment and ontinuing through the end of treatment (p.1 at weeks 1 and 2 and p.1 at weeks 4 and 8) and at endpoint (p.1) (Figure 3, top). Duloxetine also showed signifiantly greater improvement in HAM-D total sores and CGI severity sale sores starting at week 4 and week 2, respetively, through the end of treatment and at endpoint (Figure 3, middle and ottom). When hanges from aseline to endpoint in Geriatri Sale and HAM-D total sores were analyzed in sugroups y aseline HAM-D sores, there was a signifiant treatment-y-aseline HAM-D interation (p=.9 and p=.3, respetively), with a greater advantage of duloxetine over plaeo in the patients with more se- Least- Squares Mean Change Improvement Improvement Improvement Figure 2 presents the mean hange from aseline to endpoint in the omposite ognitive sore for all randomly assigned patients and y sugroups ased on aseline HAM-D sores (<24 versus 24). Duloxetine signifiantly improved ognitive performane ompared with plaeo in all randomly assigned patients (p<.2). The advantage of duloxetine over plaeo was slightly greater in patients with more severe depression ompared with patients with less depression, ut the treatment-y-aseline HAM-D interation was not signifiant (p=.82). On average, the omposite ognitive sore worsened in patients with more severe depression taking plaeo. For the omposite sore, there was no signifiant interation of treatment with investigator; gender; age; origin; numer of previous drugs for depression; numer of previous episodes of depression; Geriatri Sale total sore; CGI severity sale sore; HAM-D anxiety; HAM-D insomnia; omorid arthritis, diaetes, vasular disease, or any of these; or mild dementia. As Figure 2 also indiates, the mean aseline sores for the individual tests were all near the middle of the range of possile sores, suggesting that all tests had suffiient dynami range to measure oth improvement and deterioration due to drug treatment. Compared with plaeo, patients taking duloxetine had signifiant improvement in oth Veral Learning and Reall Tests (learning trials, p=.3; delayed reall, p=.2), ut not other ognitive tests (Figure 2). Composite ognitive sore improvement in patients treated with duloxetine was driven mainly y veral learning and memory. Least-squares mean hanges from aseline for MMSE sores were similar for duloxetine- and plaeo-treated patients (.29 versus.24, p=.87). Path analysis showed that for improvement of the omposite ognitive sore, there was a 9.9% diret effet (p=.3) and a 9.1% indiret effet through improvement in the Geriatri Sale total sore. There was an 81.3% diret effet (p=.7) and an 18.7% indiret effet through improvement in the HAM-D total sore. 94 ajp.psyhiatryonline.org Am J Psyhiatry 164:6, June 27

6 RASKIN, WILTSE, SIEGAL, ET AL. FIGURE 4. Rating Sale Sore Changes in Duloxetine and Plaeo Groups for All Randomly Assigned Patients and y Baseline Hamilton Rating Sale Sore a Total Sore on Geriatri Sale Total Sore on Hamilton Rating Sale Improvement Least-Squares Mean Change 4 8 Duloxetine, 6 mg/day N=198 N=171 Plaeo N=11 N=86 N=27 N=15 d N=21 N=12 N=172 N=86 N=29 N=16 12 All randomly assigned patients Patients soring <24 on Hamilton Rating Sale Patients soring 24 on Hamilton Rating Sale All randomly assigned patients Patients soring <24 on Hamilton Rating Sale e Patients soring 24 on Hamilton Rating Sale a Interation (left): p<.9; interation (right): p<.3. p<.1 versus plaeo. p<.2 versus plaeo. d p<.8 versus plaeo. e p<.1 versus plaeo. vere depression ompared with those with less severe depression (Figure 4). When hanges from aseline to endpoint in HAM-D total sore were analyzed y aseline Geriatri Sale total sore ( 18 and >18) and CGI severity sale sore ( 4 and >4), no signifiant interations were found. However, for hange in the Geriatri Sale total sore, a signifiant interation was found etween treatment and aseline Geriatri Sale total sore (p=.5), with a greater advantage of duloxetine over plaeo in patients with higher aseline Geriatri Sale total sores ompared with those with lower aseline Geriatri Sale total sores (data not shown). There was no signifiant interation etween treatment and aseline CGI severity sale sores. For hanges in oth Geriatri Sale and HAM-D sores, there were no signifiant treatment-y-mild-dementia sugroup interations. Patients treated with duloxetine also had signifiantly greater HAM-D response (p<.1) and remission (p<.2) rates than did plaeotreated patients (Figure 5). Effiay in Pain Measures Patients treated with duloxetine showed a signifiantly greater improvement in Visual Analogue Sale for ak pain sores (Figure 6, top) and amount of time in pain while awake ompared with plaeo-treated patients (Figure 6, middle). The improvements for other pain measures, inluding overall pain (Figure 6, ottom), headahe, shoulder pain, and pain interferene with daily ativities, were not signifiantly different etween patients treated with duloxetine or given plaeo. FIGURE 5. Hamilton Rating Sale Response and Remission Rates at Endpoint Among Patients With Randomly Assigned to Duloxetine Versus Plaeo Perent of Patients Response a p<.1 versus plaeo. p<.2 versus plaeo. a Safety and Toleraility Measures Duloxetine, 6 mg/day (N=21) Plaeo (N=12) Remission Seventeen (8.3%) of 25 patients treated with duloxetine and one (1.%) of 14 patients treated with plaeo had a susequent dose redution. Overall disontinuation rates for any reason did not signifiantly differ etween the duloxetine and plaeo groups (21.7% versus 23.1%). However, disontinuation eause of lak of effiay was signifiantly less likely in the duloxetine group (2.9%, p<.3) than in the plaeo group (9.6%). Disontinuations due to adverse events were similar for duloxetine-treated patients ompared with plaeo-treated patients (9.7% ver- Am J Psyhiatry 164:6, June 27 ajp.psyhiatryonline.org 95

7 DULOXETINE AND ELDERLY DEPRESSED PATIENTS FIGURE 6. Repeated Measures and Mean Change Analyses of Pain Ratings Among Depressed Patients Randomly Assigned to Duloxetine or Plaeo a Change From Baseline Sore on Visual Analogue Sale Bak Pain Overall Pain Time in Pain While Awake Least-Squares Mean Change From Mixed-Effets Model Repeated Measures d Plaeo (N=12) Duloxetine, 6 mg/day (N=21) Weeks a Mean aseline pain severity: ~26 (top); ~35 (middle), ~32 (ottom). p<.5 versus plaeo. p<.1 versus plaeo. d p<.1 versus plaeo. sus 8.7%, p=.84) (Tale 2). Treatment-emergent adverse events for whih the inidene among duloxetine-treated patients was at least 5.% and twie the plaeo rate are presented in Tale 3. Of these events, those ourring signifiantly more frequently for duloxetine than for plaeo were dry mouth (14.5% versus 1.9%, p<.1), nausea (12.6% versus 3.8%, p<.2), and diarrhea (8.2% versus 1.9%, p<.5). Five patients (one duloxetine-treated patient and four plaeo-treated patients) experiened serious adverse events. No patients died during the study. Blood pressure and pulse hanges were modest and did not differ signifiantly etween duloxetine- and plaeotreated patients. The rates of sustained hypertension were Least- Squares Mean Change Improvement Improvement Improvement.5% for duloxetine and 1.% for plaeo. The rates of treatment-emergent orthostati hypotension were 15.6% for duloxetine and 2.5% for plaeo. There was a signifiant derease in weight for duloxetine- ompared with plaeo-treated patients (.73 versus.13 kg, p=.9). Of the five hepati enzymes, alkaline phosphatase was signifiantly inreased in duloxetine-treated patients ompared with plaeo-treated patients, although mean hanges were not onsidered linially relevant (.41 versus.41 U/liter, p<.2). No signifiant differenes existed etween the duloxetine and the plaeo treatment groups in the inidene of treatment-emergent anormal laoratory values at any time. Disussion Duloxetine treatment for 8 weeks resulted in a signifiant improvement ompared with plaeo on a omposite measure of ognitive funtions previously demonstrated to e impaired in patients with reurrent major depressive disorder (2, 3). Most of the improvement was driven y veral learning and memory, whereas measures of foused attention and exeutive funtioning showed no duloxetine-plaeo differene. Duloxetine also signifiantly improved oth self- and liniian-rated depression measures and lessened the severity of some self-reported pain measures. Although ognitive defiits in patients with major depressive disorder have een demonstrated in many studies (3), antidepressant mediations, suh as paroxetine and nortriptyline, do not routinely improve ognition in these patients (24). Follow-up studies of elderly patients treated for major depressive disorder oexisting with dementia have shown that some patients demonstrate poor performane on ognitive tests after imipramine treatment (25). The effet of duloxetine to augment 5-HT and norepinephrine ativity may make it partiularly enefiial in treating the ognitive defiieny of depression. The preursor to dopamine, L-dopa, was found to improve ognitive funtion, mainly veral learning and longerterm memory, ut had little antidepressant effet in patients with major depressive disorder (26). The effet of duloxetine on ognition may have een more learly shown in the urrent study eause it inluded some patients with mild dementia. Path analysis suggested that the effet of duloxetine on improvement of the omposite ognitive sore was mainly a diret treatment effet rather than an indiret effet through improvement of depression measures. The results from this trial demonstrate that duloxetine, 6 mg/day, may e an effetive treatment for elderly patients with major depressive disorder. The Geriatri Sale total sore was a more sensitive sale than the HAM-D and CGI severity sale for measuring the onset of treatment effet of duloxetine, as indiated y rapid separation from plaeo as early as week 1. The remission rate was also sig- 96 ajp.psyhiatryonline.org Am J Psyhiatry 164:6, June 27

8 RASKIN, WILTSE, SIEGAL, ET AL. TABLE 2. Adverse Events Reported as Reason for Disontinuation in Patients With Plaeo Group (N=14) Duloxetine (6 mg/day) Group (N=27) Fisher s Exat Test Adverse event N % N % p Disontinued due to adverse event Nausea <.5 Dizziness Rash Insomnia Anxiety, onfusional state, diarrhea, eye pruritis, gastroesophageal for eah adverse. 1 for eah adverse.5 1. reflux disease, irritale owel syn- event event drome, lethargy, restlessness, sedation, upper lim frature, vertigo, vomiting Noninsulin-dependent diaetes mellitus (type 2 diaetes), irritaility, pain in extremity, palpitations 1 for eah adverse event 1. for eah adverse event..33 TABLE 3. Treatment-Emergent Adverse Events With an Inidene of 5.% Among Duloxetine-Treated Patients With (and Twie the Rate Among Plaeo-Treated Patients) Plaeo Group (N=14) Duloxetine (6 mg/day) Group (N=27) Fisher s Exat Test Treatment-Emergent Adverse Event N % N % p Patients with at least one treatment-emergent adverse event Dry mouth <.1 Nausea <.2 Constipation Dizziness <.9 Diarrhea <.5 Fatigue Somnolene <.7 nifiantly greater for duloxetine than for plaeo (27.4% versus 14.7%, p<.2), whih is in agreement with a reent report showing that duloxetine, 6 mg/day, was effetive in the treatment of major depressive disorder in patients age 55 years and older (27). The asolute response and remission rates were relatively low, perhaps attriutale to a relatively short 8-week study duration, a fixed dosing shedule, and low plaeo response rates. However, the relative advantages of duloxetine over plaeo in response and remission rates were sustantial, as evidened y the fat that they were twie the plaeo rates. Several plaeo-ontrolled antidepressant trials in elderly patients an e ompared with the present study (28 32). In general, antidepressant trials in the elderly are more diffiult to show positive effiay results for ative treatments over plaeo than trials in general populations (28). In a reent plaeo-ontrolled study of fluoxetine and venlafaxine, there were no signifiant differenes among the three treatment groups in the hange in HAM- D (21-item version), Montgomery-Åserg Rating Sale, or CGI severity sale sores, and there was no statistially signifiant differene in the proportion of remitters at the last on-therapy visit (29). Similarly, in ommunity-dwelling patients over 75 years of age, italopram was no more effetive than plaeo for the treatment of depression (3). However, in two larger studies in patients with depression over 6 years of age, sertraline or fluoxetine were more effetive than plaeo (31, 32). The remission rates in these studies were low in general, and the differenes etween treatment groups were small (2% 35% for ative treatments, 18% 33% for plaeo). The numer needed to treat is elieved y many linial epidemiologists to e the most linially meaningful and useful measure of a treatment effet (33). In this study, the duloxetine versus plaeo numer needed to treat for response was 5.3, and the numer needed to treat for remission was 7.9. For duloxetine registration studies (all adults), the duloxetine versus plaeo numer needed to treat for response ranged from 3.7 to 15.2, and the numer needed to treat for remission ranged from 4.7 to The fat that the numer needed to treat for response and remission in elderly patients lies within these orresponding ranges suggests that duloxetine effiay in the elderly is omparale to that in the general adult population. The numer needed to treat for response was very similar to the mean numer needed to treat of five for triyli/plaeo omparisons in the elderly reported in the metaanalysis y Taylor and Doraiswamy (34). It is etter than the mean numer needed to treat of eight reported for seletive serotonin reuptake inhiitor (SSRI) antidepressant studies (and for antidepressants overall) in that review. Similar results were found in a reent report y Cookson et al. (35). Duloxetine demonstrated statistially signifiant improvement on two pain measures, as evidened y separation from plaeo on the Visual Analogue Sale for time in pain while awake at week 1. However, patients enrolled in this study were not seleted speifially for pain, and the pain reported was generally not severe. It is possile that Am J Psyhiatry 164:6, June 27 ajp.psyhiatryonline.org 97

9 DULOXETINE AND ELDERLY DEPRESSED PATIENTS more or less pain effiay for duloxetine might e oserved in patients with depression with higher initial pain severity. The toleraility of duloxetine in the elderly patients is omparale with the profile oserved in a general population of adult patients with depression (36). The dropout rate of this study an e ompared with the aforementioned other pulished studies of elderly patients with antidepressants (3, 31), although no diret omparisons an e made. In this study, overall disontinuation rates for any reason did not signifiantly differ etween the duloxetine and plaeo groups, similar to what was found in an 8-week study of sertraline in elderly patients (31). The dropout rates were signifiantly higher in elderly patients treated with italopram (21.4%) ompared with patients treated with plaeo (12.2%) (3). In the present study, the rates of adverse events reported as a reason for disontinuation were similar for patients treated with duloxetine and plaeo, exept for the disontinuation rate due to nausea, whih was atually signifiantly higher in patients treated with plaeo than in patients treated with duloxetine (3.8% versus.5%, p<.5). The most frequently reported treatment-emergent adverse events for patients treated with duloxetine in the present study were dry mouth (14.5%) and nausea (12.6%); they were reported at rates omparale to those oserved in several studies onduted with elderly patients treated with SSRIs (37, 38). This study had several limitations, inluding 1) duration of treatment for only 8 weeks; 2) exlusion of patients with serious or unstale medial illnesses, inluding psyhosis; 3) exlusion of first-episode patients and those with signifiant psyhiatri omoridities; and 4) limited dose flexiility during the study. In onlusion, the present results suggest that duloxetine, 6 mg/day, is effetive in improving ognition and depression measures in patients with reurrent major depressive disorder age 65 years. Duloxetine also may e an effetive treatment for some pain symptoms in these patients. The dual ation of duloxetine on 5-HT and norepinephrine reuptake inhiition may explain its effiay in treating the traditional symptoms of depression as well as improving some ognitive and pain symptoms. The study results also suggest that duloxetine, 6 mg/day, is well tolerated in elderly patients. Colletively, the present results indiate that duloxetine, 6 mg/day, may represent a new treatment option for older patients with reurrent major depressive disorder. Presented in part as a poster at the 18th meeting of the Amerian Assoiation for Geriatri Psyhiatry, San Diego, Marh 3 6, 25. From Lilly Researh Laoratories, Eli Lilly Canada; Lilly Researh Laoratories, Eli Lilly and Company, Indianapolis; Geriatri and Adult Psyhiatry, LLC, Hamden, Conn.; and the Department of Psyhiatry and Behavioral Sienes, Stanford University Shool of Mediine, Stanford, Calif. Address orrespondene and reprint requests to Dr. Raskin, Eli Lilly Canada, 365 Danforth Ave., Toronto, Ontario, Canada MIN 2E8; joel.raskin@lilly.om ( ). Dr. Siegal reeives researh support from Eli Lilly, Sanofl, Ono Pharmaeutials, Voyager Pharmaeutials, AstraZenea, GlaxoSmith- Kline, Takeda, and Forest. He is a onsultant for and on the speakers ureaus of Aott, AstraZenea, Forest, Eli Lilly, Novartis, and Sepraor. Dr. Raskin, Dr. Witse, Mr. Dinkel, Mr. Rotz, and Dr. Mohs are employees and stokholders of Eli Lilly. The remaining authors report no ompeting interests. Sponsored y Eli Lilly and Company. Clinial trial registration identifier: NCT The authors thank the Duloxetine-Fluoxetine Produt Team, the patients for their voluntary partiipation, and the prinipal investigators. They also thank Eli Lilly and Company statistial analysts Wenqi You, Steve Gelwiks, Cathy Zhou, Brue Spotts, Lin Yan, John Reese, Russell Newhouse, and Huifang Chen for their assistane; Elizaeth Agostinelli for editorial review; and Jessia Pitrelli and Sharie Sipowiz for formatting assistane. Referenes 1. Steffens DC, Skoog I, Norton MC, Hart AD, Tshanz JT, Plassman BL, Wyse BW, Welsh-Bohmer KA, Breitner JC: Prevalene of depression and its treatment in an elderly population: the Cahe County Study. Arh Gen Psyhiatry 2; 57: Meoi P, Cheruini A, Mariani E, Ruggiero C, Senin U: in the elderly: new onepts and therapeuti approahes. Aging Clin Exp Res 24; 16: Burt DB, Zemar MJ, Niederehe G: and memory impairment: a meta-analysis of the assoiation, its pattern, and speifiity. 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