- Email: [email protected]
SAT-5-6 A randomized, naturalistic cost-effectiveness study in a managed health care setting
SAT-5 Lilly." Advancing CNS research into the twenty-first century
256 appropnate responding, wJth sever out of the eight animals selecting the cozapine iever after 1 25 mg/kg, p (Moore et al,, 1992) These data suggest that olanzapine shares many aspects of the pharmacological profile of c:ozaplne. In conclusion, olanzapine is a potent 5HT 2, dopamine D1/D2/D 4 recep tor antagonist with antichoiinergic actwtty. Electrophysiologically, the com pound displays mesolimbic selectivity The behawoural profile of olanzapine ~s very similar to that of the 'atypical' agent, clozapine. On the basis of these findings, ,t would be Dredrcted that olanzapine would be an effectNe antipsychotic and produce fewer extrapyramidal symptoms than existing treatments.
References Benvenga, MJ and Leander, J D (1995) O~anzaplne Increases rates of punlshea re sponding in pigeons. Psychopharmacology m press Bymaster, FP, Calligaro, D O, Falconer J F Marsh. R D, Moore, N A, Tye, N C, See man, R. Wong, D T:(1995) Radioreceptor binding profile of the atypical antlpsychotlc olanzapine Neuropsychopharmacology m press Fuller, R W. and Shoddy. HD: (1992) Neuroendocrine evidence for antagonism of serotonln and dopamlne receptors by olanzaplne, an antlpsychotic drug candidate Res Comm Chem Path Pharmacol 77 87 93 Moore N A , Tye N C , Axton M S and Risius FC (1992) The Behavioural Pharmacology of Olanzapine a novel 'atypical' antipsychotic agent Journal of Pharmacol Exp Ther 262 545 551 Moore, N A , Calligaro, D O , Wong, D T, BymasteE F and Tye N C : (1993) The pharmacology of Olanzapme and other new ant/psychotic agents Curr Opm Invest Drugs 2{4): 281 293 Moore, NA , Rees, G, Sanger, G and Tye. N C : (1994) Effects of olanzaplne and other antipsychotlc agents on responding maintained by a conflict schedule Behawoural Pharmacology 5:196 202 Seem an, P and Van Tol, H M Dopamme receptor pharmacology {1993)Curr Opln Neu rol Neurosurg 6:602 608 Stockton, M E , Bymaster, FR and Rasmussen. K (1995) Electrophysiological effects of olanzapine, a novel atypical aPtipsychotlc, on A9 and A10 dopamine neurons Neu ropsychopharmacology, in press
associated with OLZ. At the highest end of the dose range, the incidence was 1/3 to I/2 the rates observed within a clinically effective range of HAL (10 to 20 mg). Increased serum transaminase was transient, seen early in the course of therapy, dose-related, and was not associated with any clin,cal manifestation The mean elevation of prolactin was also significantly less than that observed with HAL (endpoint and categorical). No agranulocytosis has been observed. Further, in a subset of patients with previous clozapine-associated agranulocytosis, OLZ did not induce a re-emergence. A single global Phase III protocol was conducted in 18 countries involving 178 investigative sites. Over 1996 patients were randomized to either OLZ (5 to 20 mg) or HAL (5 to 20 rag). Statistically significantly more patients completed six weeks of acute pharmacotherapy with OLZ {66%) than with HAL (46%) While comparable reduction in BPRS-positive symptoms (baseline to endpoint) was observed for OLZ and HAL. OLZ was statistically significantly superior on the following efficacy parameters: BPRS total, BPRS negative symptoms, PANSS negative, and CGI severity. Baseline to endpomt improvement in depression (MADRS) also favored OLZ. Furthermore, OLZ was associated with a statistically significantly lower incidence of EPSE. Significantly greater baseline to endpoint reduction in AIMS scores was also observed. rn summary, the substantial clinical data base on OLZ strongly suggests a profile of antipsychotic efficacy with negligible EPSE. Thus. OLZ appears to fulfill key criteria defining atypicality Furthermore, OLZ manifests ther apeut~c benefits in the reduction of negative symptoms, secondary mood disturbance, and overall functional well b e i n g QLZ is on the verge of establishing itself as a major advance in the pharmacotherapy of schizophrenia and other osychosis.
References L~eberman JA Understanding the mechanism of action of atypical antipsychotics Br J Psychiatry 163 {S-22): 7 18, 1993 Meltzer HY The mechanism of action of novel antipsychotic drugs. Schizophrenia Bull 17 263 287, 1991 Nyberg S, Farde L. Halldin C A PET study of 5-HT2 and D2 dopamine receptor occupancy induced by olanzapine in healthy subjects (submitted manuscript).
SAT-5-5 10lanzapine: an exciting atypical ant/psychotic - the clinical experience
G a r y D Tollefsoe, Charles M. Beasley, P i e r r e V T r a r . T Sanger L/fly
Research Laboratories, CNS Drvision, Eli L/fly and Company, LJ//y Corporate Cente4 /ndtanapohs, Indiana 46285 USA Conventional neuroleptic therapy reduces acute psychosis and recurrence rates However, approximately 30% of patients do not respond Convert tional agents also do not exert therapeutic effects against all domains of schizophrenic pathologye g , negative or deficit features (Lieberman, 1993) Equally ~mportant, conventional ant/psychotics carry a side-effect profile that compromises patient compliance. The present search is for antipsychoticagents with an improved risk: benefit ratio Alternative approaches, implicating other neurotransmltter systems, have ted to the development of novel antipsychotic candidates (Meltzer. 1991) A prototype ~s olanzapme Olanzapine (OLZ)is extensive y metabolized; the pnmary pathway is N-glucuronldation. The predominant clinical profile is attributable to the par entmolecuie, lts pharmacokinetrcs are linear and dose-proportional OLZ's half-life ranges from 33 to 51 hours with m,nimal age-related d~fferences In vitro microsomal studies have demonstrated that olanzapine is a weak inhibitor of cytochrome P450 enzymes The pharmacodynamic profile of OLZ has been explored with PET After 10 mg, 5-HT 2 receptor occupancy ranged from 74 to 92% w;th a corresponding D 2 occupancy of 59 to 73% (Farde et al, 1995) This profile resembles the atypical ant/psychotic clazapine and differentiates OLZ from qsperidone and other conventional antipsychotics OLZhas been studied in over 3000 individuals, mcludingover 600 subjects for six months or longer Two placebo-controlled trials have established the efficacy of OLZ { 7 5 to 1 7 5 rag/day) in the treatment of an acute exacerbation of chronic DSM-IIIR-compatibleschizophrenia Increas ~ng doses have been associated with increased improvement in general psychopathology and specifically, negative s y m p t o m s A third multinational trial comparing four fixed-dose ranges of OLZ (1 through 17.5 rag/day) with haloperidol (HAL)(10 to 20 mg/day) suggested an increasing dose-response pattern where OLZ was generally superior to HAL on BPRS and PANSS total/negative scale scores. In summary, the mean change from baseline to endpoint (LOCF) analysis across all three Phase II efficacy studies demon strated that OLZ was effective in the treatment of both positive and negative symptoms of schizophrenia Safety results from these studies revealed that a very low percentage of patients discontinued OLZ due to an adverse event (range 1.6 to 16 1% for OLZ; 0 to 1 9 3 % for placebo; and 8 7 to 14 8% for HAL) Of note was the low rate of acute extrapyramidalsymptoms(EPSE}
ISAT-5-61
A randomized, naturalistic cost-effectiveness study in a managed health care setting
J H . Heiiigenstein, G. Simon. CNS-G/-GU Division, tJT/y Research
Laboratones, /ndianapo#s, IN, 46285, USA," Center for Health Studies, 1730 Minor Avenue, #1600, Seattle, WA, 98101, USA In the United States, 80% of the general population treated for depressive disorders receive their care from general medical providers (Shapiro et al 1984). Studies have shown that depressed primary care patients are often inadequately treated relative to antidepressant dosage and duration of treatment (Katon et al 1992). A recent study found depressed primary care patients experienced significant impairments in their daily functioning ard sense of well-being, equivalent to that seen in patients with chronic lung disease or advanced cardiac disease (Wells et at. 1989). In addition, community resleents with depression have been found to experience more cays lost from work (4 days/month) than those who did not have a mood cisorder (1 day/month in the first year following their diagnosis (Broadhead et al 1990). Fluoxet,ne (fix), a selective serotonergic reuptake inhibitor, can be prescribed once daily, does not require dose titration, and has a more tolerable side-effect profile than tricyclic antidepressants (tcas}. Observational data m a managed health care setting found that fix patients were less likely to discommue treatment due to side effects and more likely to continue treatment for the recommended period of time than tea patients (Simon et al 1993) As a result of increased compliance and because of the higher dally cost for fix as compared to the low cast tcas, a higher pharmacy cost would result W t h an increasing focus on health care cost containment, experimental evidence on effectiveness and cost of newer antidepressants, such as f:x, will determine which antidepressant will be the first choice antidepressant ;n the primary care setting Object/vest In the primary care clinics of a managed health care setting, a randomized clinical trial comparing the effectiveness and cost of three antidepressants was undertaken to: 1. examine and compare the overall effectwenesa of three antidepressants (imi, dmi, fix} as measured by relief of depressive symptoms and change in functional status. 2. compare the direct and indirect costs of depression treatment for each of the three antidepressants, 3 compare intermediate outcomes of depression treatment (side effect seventy and compliance/adherence) for each of the three groups
257
SAT-5 Lilly: Advancing CNS research into the twenty-first centu~' Design and Methodology Patients assessed as depressed by their Dr, mary care physician and who were candidates for a new antidepressant prescription were presented with the option of participating in the study. A study coordinator assessed patients for eligibihty and completed a base line assessment of depression severity and functional ~mpairment. Patients were stratified according to the presence/aosence of current DSM-IIIR major depression by structured interwew and randomized to initial treatment with imi, dml or fix using computer-generated random numbers. All patients received a standard patient education package concerning antidepressant treatment at the time of the initial prescnption fill. Data collection for each patient will continue for t w o years from the time of randomization. The study will conclude in June, 1996 Naturalistpc follow-up care has been provided by the referring physician who has made all decisions concermng antidepressant dosage, duration of treatment, change in antidepressant drug and referral for specialty care A research assistant has conducted or will conduct follow-up evaluations by telephone at intervals of 1,3, 6.9, 12, 18 and 24 months. A t t h e time ol study entry, study participants were informed that follow-up assessments were completely independent of clinical management and that assessment would continue for t w o years regardless of subsequent antidepressant use Follow-up evaluations consists of the SCID depresspon module, the HAMD 17, the SCL-90 depression and anxiet), subscales, the SF-36. an assessment of days of disability and restricted acbvity, an antidepressant quest~onnaqre to assess current antidepressant use/reasons for discontinuation/s~de effect severity, a utilization questionnaire to assess non-managed health care service utilization and an assessment of global improvement. Additlona! data available via automated data systems includes medication use, medlcai service utilization, and direct medical costs Outcomes. The primary clinical outcome is the HAMDI7. The pnmar~,. functional outcome is the SF-36 Emotional Functioning score with sec ondary functional outcomes to include days of d~sability and days of re stricted activity The primary cost outcome is the total direct medical costs with additional analyses of indirect costs and total direct and indirect costs Utilization outcomes include the total number of outpatient visits menta health/substance abuse wslts, total number of inpatient days, and ores ence/absence of any inpatient stay. Intermediate outcomes include the severity of antidepressant treatment and treatment adherence. The presentation will focus on the design of the study ¢ollowee by pre liminary results of 6 month data
References Broadhead WE, Blazer DG. George LKr Tse C 1990 Depression disabdity days and days lost from work in a prospect ve epidemioioglc suwey JAMA 2642524 2528 Katon W Von Korff M, Lin E, Bush T, Ormel J 1992 Adequacy and duration of ant~de pressant treatment in primary care Meal Care 30(1 ):67-76 Shapiro S, Skinner EA, Kessler LG, Von Korff M, German PS, Tlschler GL et al 1984 Utilization of health and mental health services three epldemlologic catchment area sites Arch Gen Psychiat 41 971 978 Simon G, Von Korff M, Wagner EH, Barrow W 1993 Patterns of antidepressant bse ir" commumtv practice Gen Hosp Psychiatry 15:399-408 Wells KB, Stewart A, Harys RD, Burnan MA, Rogers W, Danials M e t a! 1989 The fJnc tioning and well-being of depressed patients Results from the Medical Outcome Study JAMA 262:914-19
I
SAT-5-7 1 Biological
enrichment in the study, of drug: placebo differences of patients with affective disorders
StevenJames, John Heiligenstein Douglas ~anes, GarvTollefson ZJ//y Research Laboratories Lilly Corporate Center Build,'ng 31/2 Drop Code 2128 Indianapolis, IN. 46285 Disruptions in the sleep-wake :ycle are frequently heard complaints re ported by depressed patients To better understand the significance of these problems, an impressive body of knowledge has oeen developed over the past decade examining the association between sleep parameters and clinical presentation of affectlve disorders Despite this heighten recognition that sleep disturbances offer ~m13ortant clues in the identification of underlying affectwe illness, sleep laooratory studies rarely are included in the evaluation of depressed patients Ques lions still remain concerning the clinical significance of disturbed sleep *o" 'normal' sleep in depressed patients) in art ring at the diagnosis of affectlve disorder Also unanswered ~s what p,ognostlc value disturbed sleep car" provide in predicting treatment ou:come with antidepressant medication o" placebo. The sleep laboratory can prov,de obiect ve n;ormation about the physl ological measures of human s l e e p Al:bougn there,s httleagreeme~t ore"
what role these sleep-EEG measures from the sleep laboratory play in affestive disorders, a critical need remains to develop objective methods to ~dentify depressed patients likely to respond to pharmacotherapy. In addition, it is equally important to screen out patients complaining of depression from causes other than affective disorders and to recognize patients likely to respond to placebo To address these needs we have incorporated sleep laboratory assessments into our clinical trials of depressed patients prior to randomization onto recognized antidebressants or investigational comoounds. In developing our protocol for sleep laboratory evaluation we sought to utihze sleep EEG parameters to enrich our population of depressed patients under study We anticipated that w e would identify a group of patients with changes in EEG-sleep parameters associated with affective disorders. By segregatqng these patients with reported biological markers in sleep for malor depression we hoped to recruit a more 'homogeneous' population of depressed patients. We also predicted that patients with changes in sleep revealed through ;)olysomnographic techniques would have a more robust response to antidepressant treatment. Previous studies had already reported this observation with tricyclic antidepressants but the applicability of that earlier work to treatment with newer classes of antidepressants was unknown. Finally, we wanted to investigate whether the presence (or absence) of cnanges in EEG monitored sleep would permit selection of patient populations less likely to respond to placebo. We anticipated that patients with more disturbance in sleep and possible greater severity of overall symptoms would ~mprove with antidepressants and be less likely to respond to placebo To address tnese issues, w e enrolled 160 0argents in a clinical trials program evaluating a novel antidepressant compound. All subjects were screened by a physician experienced in sleep disorders. After one week of maintaining strict sleep hygiene guidelines, all batients were studied for two or three nights in a sleep laboratory. During the first night a complete polysomnogram (PSG) was performed with careful attention to evaluating respiration, motor activity and arousals for evidence of disturbed sleep as a result of sleep apnea, nocturnal myoclonus or other primary sleep disorders. The second and third night were a modified PSG and obtained to evaluate sleep staging only. After the laboratory analysis 105 patients were found to have complaints of depression while maintaining strict sleep hygiene and in the absence of a primary sleep disorden Fifty three patients were identified with REM latencies less than 65 minutes and were grouped in the short REM latency group. The remaining 52 patients all had REM latencies greater than 65 minutes and were grouped into the normal REM latency group. Patients w~thin each group were randomized onto study drug or placebo and results determined by the Hamilton Depression Rating Scale {HDRS). We present the results of this study and compare with earlier work studying the association between sleep parameters and antidepressant response We also will discuss the role of sleep evaluation on identification of individuals likely to respond to placebo conditions
References Nelson, J C and Charney. D S (1980) Primary Affective Disorder criteria and the endogenous reactive distinction Arch Gen Psychiatry 37,787 793 Giles, D G, Roffwarg, HP, Schlesser, MA. and Rush, A J {1986}Which endogenous depressive symptoms relate to REM latency reduction? Biological Psychiatry 21,473482 Spiker. D G . Coble, P, Cofsky, J, Foster, FG and Kupfer, D J (1978) EEG sleep and severity of depresskon. Biological Psychiatry 13, 485~188
ISAT-5-8
i
I
Adaptive randomization in clinical trials: a placebo compromise
1 L/fly Research Centre Ltd, Er/ Wood Manor, Wind/esham, Surrey, GU20 6PH, UK," 2 Eli DTly and Company, L/fly Corporate Centre, Indianapohs, Indiana 46285, LZS.A. A Wood 1, D Faries 2, j. Heiligenstein 2
A number of innovative strategies have been explored in order to minimize the exposure of subjects included in clinical trials to either placebo or ineffectwe novel drug candidates. These strategies are particularly important m the area of psychopharmacology where the morbidity associated with a failure of treatment can be particularly severe T~e so-called adaptive study design, known colloquially as "playing the winner", ~s based on a Bayesian statistical argument and progressively modifies trle randomization schedule based on outcomes from foregoing 0argents ~n the study in order to maximize the chance of subsequent sublects being randomized to efficacious treatments.
256 appropnate responding, wJth sever out of the eight animals selecting the cozapine iever after 1 25 mg/kg, p (Moore et al,, 1992) These data suggest that olanzapine shares many aspects of the pharmacological profile of c:ozaplne. In conclusion, olanzapine is a potent 5HT 2, dopamine D1/D2/D 4 recep tor antagonist with antichoiinergic actwtty. Electrophysiologically, the com pound displays mesolimbic selectivity The behawoural profile of olanzapine ~s very similar to that of the 'atypical' agent, clozapine. On the basis of these findings, ,t would be Dredrcted that olanzapine would be an effectNe antipsychotic and produce fewer extrapyramidal symptoms than existing treatments.
References Benvenga, MJ and Leander, J D (1995) O~anzaplne Increases rates of punlshea re sponding in pigeons. Psychopharmacology m press Bymaster, FP, Calligaro, D O, Falconer J F Marsh. R D, Moore, N A, Tye, N C, See man, R. Wong, D T:(1995) Radioreceptor binding profile of the atypical antlpsychotlc olanzapine Neuropsychopharmacology m press Fuller, R W. and Shoddy. HD: (1992) Neuroendocrine evidence for antagonism of serotonln and dopamlne receptors by olanzaplne, an antlpsychotic drug candidate Res Comm Chem Path Pharmacol 77 87 93 Moore N A , Tye N C , Axton M S and Risius FC (1992) The Behavioural Pharmacology of Olanzapine a novel 'atypical' antipsychotic agent Journal of Pharmacol Exp Ther 262 545 551 Moore, N A , Calligaro, D O , Wong, D T, BymasteE F and Tye N C : (1993) The pharmacology of Olanzapme and other new ant/psychotic agents Curr Opm Invest Drugs 2{4): 281 293 Moore, NA , Rees, G, Sanger, G and Tye. N C : (1994) Effects of olanzaplne and other antipsychotlc agents on responding maintained by a conflict schedule Behawoural Pharmacology 5:196 202 Seem an, P and Van Tol, H M Dopamme receptor pharmacology {1993)Curr Opln Neu rol Neurosurg 6:602 608 Stockton, M E , Bymaster, FR and Rasmussen. K (1995) Electrophysiological effects of olanzapine, a novel atypical aPtipsychotlc, on A9 and A10 dopamine neurons Neu ropsychopharmacology, in press
associated with OLZ. At the highest end of the dose range, the incidence was 1/3 to I/2 the rates observed within a clinically effective range of HAL (10 to 20 mg). Increased serum transaminase was transient, seen early in the course of therapy, dose-related, and was not associated with any clin,cal manifestation The mean elevation of prolactin was also significantly less than that observed with HAL (endpoint and categorical). No agranulocytosis has been observed. Further, in a subset of patients with previous clozapine-associated agranulocytosis, OLZ did not induce a re-emergence. A single global Phase III protocol was conducted in 18 countries involving 178 investigative sites. Over 1996 patients were randomized to either OLZ (5 to 20 mg) or HAL (5 to 20 rag). Statistically significantly more patients completed six weeks of acute pharmacotherapy with OLZ {66%) than with HAL (46%) While comparable reduction in BPRS-positive symptoms (baseline to endpoint) was observed for OLZ and HAL. OLZ was statistically significantly superior on the following efficacy parameters: BPRS total, BPRS negative symptoms, PANSS negative, and CGI severity. Baseline to endpomt improvement in depression (MADRS) also favored OLZ. Furthermore, OLZ was associated with a statistically significantly lower incidence of EPSE. Significantly greater baseline to endpoint reduction in AIMS scores was also observed. rn summary, the substantial clinical data base on OLZ strongly suggests a profile of antipsychotic efficacy with negligible EPSE. Thus. OLZ appears to fulfill key criteria defining atypicality Furthermore, OLZ manifests ther apeut~c benefits in the reduction of negative symptoms, secondary mood disturbance, and overall functional well b e i n g QLZ is on the verge of establishing itself as a major advance in the pharmacotherapy of schizophrenia and other osychosis.
References L~eberman JA Understanding the mechanism of action of atypical antipsychotics Br J Psychiatry 163 {S-22): 7 18, 1993 Meltzer HY The mechanism of action of novel antipsychotic drugs. Schizophrenia Bull 17 263 287, 1991 Nyberg S, Farde L. Halldin C A PET study of 5-HT2 and D2 dopamine receptor occupancy induced by olanzapine in healthy subjects (submitted manuscript).
SAT-5-5 10lanzapine: an exciting atypical ant/psychotic - the clinical experience
G a r y D Tollefsoe, Charles M. Beasley, P i e r r e V T r a r . T Sanger L/fly
Research Laboratories, CNS Drvision, Eli L/fly and Company, LJ//y Corporate Cente4 /ndtanapohs, Indiana 46285 USA Conventional neuroleptic therapy reduces acute psychosis and recurrence rates However, approximately 30% of patients do not respond Convert tional agents also do not exert therapeutic effects against all domains of schizophrenic pathologye g , negative or deficit features (Lieberman, 1993) Equally ~mportant, conventional ant/psychotics carry a side-effect profile that compromises patient compliance. The present search is for antipsychoticagents with an improved risk: benefit ratio Alternative approaches, implicating other neurotransmltter systems, have ted to the development of novel antipsychotic candidates (Meltzer. 1991) A prototype ~s olanzapme Olanzapine (OLZ)is extensive y metabolized; the pnmary pathway is N-glucuronldation. The predominant clinical profile is attributable to the par entmolecuie, lts pharmacokinetrcs are linear and dose-proportional OLZ's half-life ranges from 33 to 51 hours with m,nimal age-related d~fferences In vitro microsomal studies have demonstrated that olanzapine is a weak inhibitor of cytochrome P450 enzymes The pharmacodynamic profile of OLZ has been explored with PET After 10 mg, 5-HT 2 receptor occupancy ranged from 74 to 92% w;th a corresponding D 2 occupancy of 59 to 73% (Farde et al, 1995) This profile resembles the atypical ant/psychotic clazapine and differentiates OLZ from qsperidone and other conventional antipsychotics OLZhas been studied in over 3000 individuals, mcludingover 600 subjects for six months or longer Two placebo-controlled trials have established the efficacy of OLZ { 7 5 to 1 7 5 rag/day) in the treatment of an acute exacerbation of chronic DSM-IIIR-compatibleschizophrenia Increas ~ng doses have been associated with increased improvement in general psychopathology and specifically, negative s y m p t o m s A third multinational trial comparing four fixed-dose ranges of OLZ (1 through 17.5 rag/day) with haloperidol (HAL)(10 to 20 mg/day) suggested an increasing dose-response pattern where OLZ was generally superior to HAL on BPRS and PANSS total/negative scale scores. In summary, the mean change from baseline to endpoint (LOCF) analysis across all three Phase II efficacy studies demon strated that OLZ was effective in the treatment of both positive and negative symptoms of schizophrenia Safety results from these studies revealed that a very low percentage of patients discontinued OLZ due to an adverse event (range 1.6 to 16 1% for OLZ; 0 to 1 9 3 % for placebo; and 8 7 to 14 8% for HAL) Of note was the low rate of acute extrapyramidalsymptoms(EPSE}
ISAT-5-61
A randomized, naturalistic cost-effectiveness study in a managed health care setting
J H . Heiiigenstein, G. Simon. CNS-G/-GU Division, tJT/y Research
Laboratones, /ndianapo#s, IN, 46285, USA," Center for Health Studies, 1730 Minor Avenue, #1600, Seattle, WA, 98101, USA In the United States, 80% of the general population treated for depressive disorders receive their care from general medical providers (Shapiro et al 1984). Studies have shown that depressed primary care patients are often inadequately treated relative to antidepressant dosage and duration of treatment (Katon et al 1992). A recent study found depressed primary care patients experienced significant impairments in their daily functioning ard sense of well-being, equivalent to that seen in patients with chronic lung disease or advanced cardiac disease (Wells et at. 1989). In addition, community resleents with depression have been found to experience more cays lost from work (4 days/month) than those who did not have a mood cisorder (1 day/month in the first year following their diagnosis (Broadhead et al 1990). Fluoxet,ne (fix), a selective serotonergic reuptake inhibitor, can be prescribed once daily, does not require dose titration, and has a more tolerable side-effect profile than tricyclic antidepressants (tcas}. Observational data m a managed health care setting found that fix patients were less likely to discommue treatment due to side effects and more likely to continue treatment for the recommended period of time than tea patients (Simon et al 1993) As a result of increased compliance and because of the higher dally cost for fix as compared to the low cast tcas, a higher pharmacy cost would result W t h an increasing focus on health care cost containment, experimental evidence on effectiveness and cost of newer antidepressants, such as f:x, will determine which antidepressant will be the first choice antidepressant ;n the primary care setting Object/vest In the primary care clinics of a managed health care setting, a randomized clinical trial comparing the effectiveness and cost of three antidepressants was undertaken to: 1. examine and compare the overall effectwenesa of three antidepressants (imi, dmi, fix} as measured by relief of depressive symptoms and change in functional status. 2. compare the direct and indirect costs of depression treatment for each of the three antidepressants, 3 compare intermediate outcomes of depression treatment (side effect seventy and compliance/adherence) for each of the three groups
257
SAT-5 Lilly: Advancing CNS research into the twenty-first centu~' Design and Methodology Patients assessed as depressed by their Dr, mary care physician and who were candidates for a new antidepressant prescription were presented with the option of participating in the study. A study coordinator assessed patients for eligibihty and completed a base line assessment of depression severity and functional ~mpairment. Patients were stratified according to the presence/aosence of current DSM-IIIR major depression by structured interwew and randomized to initial treatment with imi, dml or fix using computer-generated random numbers. All patients received a standard patient education package concerning antidepressant treatment at the time of the initial prescnption fill. Data collection for each patient will continue for t w o years from the time of randomization. The study will conclude in June, 1996 Naturalistpc follow-up care has been provided by the referring physician who has made all decisions concermng antidepressant dosage, duration of treatment, change in antidepressant drug and referral for specialty care A research assistant has conducted or will conduct follow-up evaluations by telephone at intervals of 1,3, 6.9, 12, 18 and 24 months. A t t h e time ol study entry, study participants were informed that follow-up assessments were completely independent of clinical management and that assessment would continue for t w o years regardless of subsequent antidepressant use Follow-up evaluations consists of the SCID depresspon module, the HAMD 17, the SCL-90 depression and anxiet), subscales, the SF-36. an assessment of days of disability and restricted acbvity, an antidepressant quest~onnaqre to assess current antidepressant use/reasons for discontinuation/s~de effect severity, a utilization questionnaire to assess non-managed health care service utilization and an assessment of global improvement. Additlona! data available via automated data systems includes medication use, medlcai service utilization, and direct medical costs Outcomes. The primary clinical outcome is the HAMDI7. The pnmar~,. functional outcome is the SF-36 Emotional Functioning score with sec ondary functional outcomes to include days of d~sability and days of re stricted activity The primary cost outcome is the total direct medical costs with additional analyses of indirect costs and total direct and indirect costs Utilization outcomes include the total number of outpatient visits menta health/substance abuse wslts, total number of inpatient days, and ores ence/absence of any inpatient stay. Intermediate outcomes include the severity of antidepressant treatment and treatment adherence. The presentation will focus on the design of the study ¢ollowee by pre liminary results of 6 month data
References Broadhead WE, Blazer DG. George LKr Tse C 1990 Depression disabdity days and days lost from work in a prospect ve epidemioioglc suwey JAMA 2642524 2528 Katon W Von Korff M, Lin E, Bush T, Ormel J 1992 Adequacy and duration of ant~de pressant treatment in primary care Meal Care 30(1 ):67-76 Shapiro S, Skinner EA, Kessler LG, Von Korff M, German PS, Tlschler GL et al 1984 Utilization of health and mental health services three epldemlologic catchment area sites Arch Gen Psychiat 41 971 978 Simon G, Von Korff M, Wagner EH, Barrow W 1993 Patterns of antidepressant bse ir" commumtv practice Gen Hosp Psychiatry 15:399-408 Wells KB, Stewart A, Harys RD, Burnan MA, Rogers W, Danials M e t a! 1989 The fJnc tioning and well-being of depressed patients Results from the Medical Outcome Study JAMA 262:914-19
I
SAT-5-7 1 Biological
enrichment in the study, of drug: placebo differences of patients with affective disorders
StevenJames, John Heiligenstein Douglas ~anes, GarvTollefson ZJ//y Research Laboratories Lilly Corporate Center Build,'ng 31/2 Drop Code 2128 Indianapolis, IN. 46285 Disruptions in the sleep-wake :ycle are frequently heard complaints re ported by depressed patients To better understand the significance of these problems, an impressive body of knowledge has oeen developed over the past decade examining the association between sleep parameters and clinical presentation of affectlve disorders Despite this heighten recognition that sleep disturbances offer ~m13ortant clues in the identification of underlying affectwe illness, sleep laooratory studies rarely are included in the evaluation of depressed patients Ques lions still remain concerning the clinical significance of disturbed sleep *o" 'normal' sleep in depressed patients) in art ring at the diagnosis of affectlve disorder Also unanswered ~s what p,ognostlc value disturbed sleep car" provide in predicting treatment ou:come with antidepressant medication o" placebo. The sleep laboratory can prov,de obiect ve n;ormation about the physl ological measures of human s l e e p Al:bougn there,s httleagreeme~t ore"
what role these sleep-EEG measures from the sleep laboratory play in affestive disorders, a critical need remains to develop objective methods to ~dentify depressed patients likely to respond to pharmacotherapy. In addition, it is equally important to screen out patients complaining of depression from causes other than affective disorders and to recognize patients likely to respond to placebo To address these needs we have incorporated sleep laboratory assessments into our clinical trials of depressed patients prior to randomization onto recognized antidebressants or investigational comoounds. In developing our protocol for sleep laboratory evaluation we sought to utihze sleep EEG parameters to enrich our population of depressed patients under study We anticipated that w e would identify a group of patients with changes in EEG-sleep parameters associated with affective disorders. By segregatqng these patients with reported biological markers in sleep for malor depression we hoped to recruit a more 'homogeneous' population of depressed patients. We also predicted that patients with changes in sleep revealed through ;)olysomnographic techniques would have a more robust response to antidepressant treatment. Previous studies had already reported this observation with tricyclic antidepressants but the applicability of that earlier work to treatment with newer classes of antidepressants was unknown. Finally, we wanted to investigate whether the presence (or absence) of cnanges in EEG monitored sleep would permit selection of patient populations less likely to respond to placebo. We anticipated that patients with more disturbance in sleep and possible greater severity of overall symptoms would ~mprove with antidepressants and be less likely to respond to placebo To address tnese issues, w e enrolled 160 0argents in a clinical trials program evaluating a novel antidepressant compound. All subjects were screened by a physician experienced in sleep disorders. After one week of maintaining strict sleep hygiene guidelines, all batients were studied for two or three nights in a sleep laboratory. During the first night a complete polysomnogram (PSG) was performed with careful attention to evaluating respiration, motor activity and arousals for evidence of disturbed sleep as a result of sleep apnea, nocturnal myoclonus or other primary sleep disorders. The second and third night were a modified PSG and obtained to evaluate sleep staging only. After the laboratory analysis 105 patients were found to have complaints of depression while maintaining strict sleep hygiene and in the absence of a primary sleep disorden Fifty three patients were identified with REM latencies less than 65 minutes and were grouped in the short REM latency group. The remaining 52 patients all had REM latencies greater than 65 minutes and were grouped into the normal REM latency group. Patients w~thin each group were randomized onto study drug or placebo and results determined by the Hamilton Depression Rating Scale {HDRS). We present the results of this study and compare with earlier work studying the association between sleep parameters and antidepressant response We also will discuss the role of sleep evaluation on identification of individuals likely to respond to placebo conditions
References Nelson, J C and Charney. D S (1980) Primary Affective Disorder criteria and the endogenous reactive distinction Arch Gen Psychiatry 37,787 793 Giles, D G, Roffwarg, HP, Schlesser, MA. and Rush, A J {1986}Which endogenous depressive symptoms relate to REM latency reduction? Biological Psychiatry 21,473482 Spiker. D G . Coble, P, Cofsky, J, Foster, FG and Kupfer, D J (1978) EEG sleep and severity of depresskon. Biological Psychiatry 13, 485~188
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Adaptive randomization in clinical trials: a placebo compromise
1 L/fly Research Centre Ltd, Er/ Wood Manor, Wind/esham, Surrey, GU20 6PH, UK," 2 Eli DTly and Company, L/fly Corporate Centre, Indianapohs, Indiana 46285, LZS.A. A Wood 1, D Faries 2, j. Heiligenstein 2
A number of innovative strategies have been explored in order to minimize the exposure of subjects included in clinical trials to either placebo or ineffectwe novel drug candidates. These strategies are particularly important m the area of psychopharmacology where the morbidity associated with a failure of treatment can be particularly severe T~e so-called adaptive study design, known colloquially as "playing the winner", ~s based on a Bayesian statistical argument and progressively modifies trle randomization schedule based on outcomes from foregoing 0argents ~n the study in order to maximize the chance of subsequent sublects being randomized to efficacious treatments.