SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs) FOR MAJOR DEPRESSION

Transcription

1 SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs) FOR MAJOR DEPRESSION PART II THE COST-EFFECTIVENESS OF SSRIs IN TREATMENT OF DEPRESSION CCOHTA Report 1997: 4E

2 The (CCOHTA) is a non-profit organization, funded by the federal, provincial and territorial governments. It was established to encourage the appropriate use of health technology by influencing decision-makers through the scientific evaluation of medical procedures, devices and drugs. The effectiveness and cost of technology and its impact on health are examined. This report should be cited as:. Selective serotonin reuptake inhibitors (SSRIs) for major depression. Part II. The cost-effectiveness of SSRIs in treatment of depression. Ottawa: ; Additional copies are available from CCOHTA Green Valley Crescent Ottawa, Ontario, Canada K2C 3V4 Telephone (613) Facsimile (613) Internet pubs@ccohta.ca Vous pouvez aussi vous procurer la version française à l OCCETS.

3 Reproduction of this document for non-commercial purposes is permitted provided appropriate credit is given to CCOHTA. Legal Deposit National Library of Canada ISBN X

4 SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs) FOR MAJOR DEPRESSION PART II THE COST-EFFECTIVENESS OF SSRIs IN TREATMENT OF DEPRESSION PROJECT DIRECTOR: Jean-François Baladi AUGUST 1997

5 REVIEWERS External Reviewers Dr. Sten Thelander Psychiatrist, Swedish Council on Technology Assessment in Health Care Stockholm, Sweden Dr. Gilbert Pinard Director, Department of Psychology McGill University Montreal, Quebec SmithKline Beecham Inc. Oakville, Ontario This report was reviewed by external reviewers and by members of a subcommittee of CCOHTA s Scientific Advisory Panel. These individuals kindly provided comments on drafts of this report. This final document incorporates most of the Reviewers comments, however, the authors take sole responsibility for its form and content. Eli Lilly Canada Inc. Scarborough, Ontario Pfizer Canada Inc. Pointe-Claire, Dorval, Quebec Solvay Pharma Inc. Scarborough, Ontario Subcommittee Members Dr. Bernie O Brien Associate Professor, McMaster University Centre for Evaluation of Medicines St. Joseph s Hospital Hamilton, Ontario Dr. Murray Krahn Staff Physician Division of General Internal Medicine & Clinical Epidemiology The Toronto Hospital Toronto, Ontario Dr. Ingrid Sketris College of Pharmacy, Dalhousie University Halifax, Nova Scotia

6 EXECUTIVE SUMMARY Recent years have witnessed large increases in expenditures on antidepressants. This has coincided with the introduction and the widespread use of a new class of antidepressants, the selective serotonin reuptake inhibitors (SSRIs). SSRIs are substantially more expensive than the older tricyclic antidepressants (TCAs), but have a different adverse effect profile and are better tolerated. This study examines the cost-effectiveness of this new class of antidepressants as compared to TCAs in the outpatient treatment of depression. It assesses whether SSRIs, with their higher price, have the ability to enhance the success of antidepressive treatments, can lead to savings in other health care expenditures and can improve quality of life for patients. A decision model is built in order to compare three different strategies. The first strategy consists of an SSRI followed by a TCA in case of failure, the second strategy consists of a TCA followed by an SSRI in case of failure, and the third strategy consists of TCA only. The decision model incorporates the possibility of dropping out of therapy or a relapse or recurrence of depressive symptoms. Success is defined simply as having stayed on treatment without dropping out of it. Clinical data concerning treatment efficacy is obtained from a meta-analysis of randomized controlled trials. Resource use is estimated by the research team from the literature and from discussions held with a number of practitioners. Costs of resources are obtained from a variety of Canadian sources. The cost of SSRIs and TCAs used, generic fluoxetine and generic imipramine, respectively, is the cost of the cheapest drug in each class. Health related quality of life is introduced into the model with the incorporation of utility values. Utility values taken from the literature are varied within the sensitivity analysis. The analysis is carried out from a Ministry of Health perspective and extended over a nine month time horizon. Although simple in construct, the decision model allows the derivation of some interesting conclusions regarding the cost, success rate, and utility of the different strategies examined. The model indicates that the success rate of a short term treatment with an SSRI is higher than one with a TCA, but is also more expensive. However, as maintenance therapy is initiated, and the switch of medications is allowed for those who drop out of a treatment, the cumulative success rate of the SSRI first strategy becomes very similar to that of the TCA first strategy, but the cost of the SSRI first strategy increases over time. In comparison, when estimates of drop-out rates taken from studies conducted in naturalistic environments are substituted for clinical trial rates, this additional cost becomes increasingly small. When the cost of a more expensive TCA is used (such as desipramine), the difference in the expected costs of treatment tend to disappear. If quality of life is considered, the SSRI first strategy offers improved quality of life over the TCA first strategy. In other words, an SSRI first-line strategy is dominant over a TCA only strategy, and an SSRI first-line strategy compared to a SSRI second-line strategy produces QALYs at an acceptable cost by current standards. Sensitivity analysis shows that these results are robust. This analysis allows us to conclude that a treatment strategy which can rely on SSRIs leads to higher success rate than one which relies on TCAs alone. When both drug classes are considered as part of a treatment, the SSRI first strategy has similar success rate as a TCA first therapy and is more costly. However, this cost may likely be offset by improved quality of life of patients.

7 TABLE OF CONTENTS 1. INTRODUCTION Background Therapeutic Classification Indications for which Economic Evaluation is being done Objectives of the Study OVERVIEW OF PREVIOUS WORK METHODS Type of analysis Target Audience Viewpoint Comparator Time Horizon The Decision Model Utilities Resource Measurement and Cost Valuation Uncertainty RESULTS Cost-Minimization Analysis Cost-Effectiveness and Cost-Utility Analyses Sensitivity Analysis Equity Issues DISCUSSION CONCLUSIONS REFERENCES APPENDIX

8 TABLES Table 1: Major Determinants of Cost-Effectiveness... 4 Table 2: Probabilities Used and Sources of Information... 9 Table 3: Comparison of Drop Out Rates Obtained by Different Meta-Analyses Table 4: Utility Values Used in This Model Table 5: Resource Use Table 6: Cost Estimates Table 7: Price Comparison of Selected SSRIs Table 8: Baseline Case Results Table 9: Sensitivity Analysis Results Around Estimates Table 10: Sensitivity Analysis Results Around Assumptions FIGURES Figure 1a: The Treatment Path with SSRI as a First Line Therapy... 8 Figure 1b: The Treatment Path with TCA as a First Line Therapy... 8 Figure 1c: The Treatment Path with TCA as the Only Therapy... 8 ABBREVIATIONS AHCPR CIHI CMG GP HMO HRQOL ICES QALY QOL MT NIH RCT SSRI ST TCA Agency for Health Care Policy and Research Canadian Institute for Health Information Case Mix Group General practitioner Health Maintenance Organization Health related quality of life Institute for Clinical Evaluative Sciences in Ontario Quality Adjusted Life Years Quality of Life Medium term National Institute of Health (U.S.) Randomized controlled trial Selective serotonin reuptake inhibitors Short term Tricyclic Antidepressants

9 1. INTRODUCTION 1.1 Background Recent years have witnessed a substantial growth in the expenditures for antidepressants. For example, the Institute for Clinical Evaluative Sciences in Ontario (ICES) reported that the amount spent on antidepressants per elderly resident of Ontario increased by 120%, from $6.00 to $13.25 per person, between and In themselves, increased expenditures for antidepressants are not necessarily undesirable. Effective treatment of depression can dramatically improve quality of life and social function. In addition, it can affect the burden of illness by reducing direct and indirect costs associated with depression. In other words, there may be economic reasons as well as social benefits behind a society s decision to accept increased expenditures on antidepressants. This growing expenditure has been the result of two factors; a rise in the quantity of antidepressants used and an increase in the average cost per dose of antidepressant prescribed. The utilization of antidepressants could have expanded as a result of the availability of SSRIs. Indications for SSRIs are slightly different than those for TCAs since SSRIs may be used for psychiatric disorders other than depression. Also, conditions which were previously untreated are being treated more often with SSRIs (possibly because of improved recognition of mental illness). Adverse effect profiles of SSRIs differ from those of TCAs thereby making them suitable for a greater number of patients. As a result, prescribers could be more at ease with SSRIs than with TCAs. The increased expenditures on antidepressants may also be due to the switch from the use of tricyclic antidepressants (TCA) to the more expensive selective serotonin reuptake inhibitors (SSRI). The per capita expenditure on TCAs declined in Ontario from $3.40 to $3.13 from the period to the period (by - 8%), and the per capita expenditure on SSRIs increased by nearly 5 fold (by +488%) in the same period from $1.52 to $ Many studies have shown that the use of SSRIs is as, or even more, cost effective than the use of TCAs (see Section 2. Overview of Previous Work). If this is true, this means that although medication costs have increased over time due to the switch from TCAs to SSRIs, the overall direct cost of treatments (including expenditures such as physicians, laboratory, monitoring costs and hospitalization), may not necessarily have increased. Therefore, a switch from TCAs to SSRIs cannot be regarded as the sole reason for increases in expenditures. In all likelihood, the utilization of antidepressants has expanded as a result of the availability of SSRIs. Ideally, therefore, an investigation into the cost effectiveness of SSRIs should be undertaken both in those situations where SSRIs are used as an alternative to TCAs, and in those situations where SSRIs are replacing no treatment at all. The cost-effectiveness of SSRIs depends on their use in actual practice, and the consequences of this use on quality of life and the burden of illness of depression. As a first step in an analysis of the cost-effectiveness of SSRIs, this study focuses on an analysis of the cost-effectiveness of SSRIs when they are used as an alternative to TCAs. This study has not been designed to investigate the use of SSRIs. Part 1 2 of this project investigated the efficacy, adverse effect profiles and drop-out rates of SSRIs. The present study employs a decision-analytic model. Estimates of probabilities for the decision tree branches were obtained from the meta-analyses presented in Part 1, 2 as well as from other sources. Costs are estimated using a variety of Canadian sources. 1.2 Therapeutic Classification 1

10 Selective serotonin reuptake inhibitors are classified as antidepressants. Some of them may also be used as anti-obsessional, antibulimic and antipanic agents. 1.3 Indications for which Economic Evaluation is being done The present analysis examines the cost-effectiveness of SSRIs in the treatment of major depression. However, since this study is a comparative analysis of two treatments, its conclusions apply only in cases where these treatments (SSRIs and their comparators) are indeed options. There may be patients for whom one of the treatments considered is not a valid option due to co-morbidity or drug interactions. For these individuals, results of this evaluation are not applicable. For example, SSRIs are generally preferred in patients at particular risk from some TCA adverse effects, e.g patients at risk of heart disease or urinary retention, or patients unable to tolerate orthostatic hypotension. Also, this analysis does not differentiate between mild, moderate or severe forms of depression even though randomized controlled trials (RCTs), upon which many estimates of this analysis are based, have a tendency to preferentially enroll patients with severe forms of depression. 1.4 Objectives of the Study This study is undertaken primarily to help Canadian Provincial drug plan managers in their formulary decisions. This study attempts to determine: (a) whether SSRIs are a cost-effective alternative to TCAs in the treatment of depression (as outlined in 1.3 above) (b) and whether their use as a first line therapy, or second line treatment influences their costeffectiveness. The least costly SSRI is also determined. 2

11 2. OVERVIEW OF PREVIOUS WORK A number of economic studies have been performed comparing SSRIs to TCAs. Some studies were costminimization, for example, the Sclar et al 3 study, in which fluoxetine was compared to amitryptiline, nortriptyline or desipramine. Some studies were cost-effectiveness studies, for example, Lapierre et al, 4 and Jönsson and Bebbington, 5 compared paroxetine and imipramine. Some studies were cost-utility in which patient preferences were taken into account. 6, 7 Some studies were cost-benefit analyses in which cost and outcomes were measured in pecuniary terms. 8 Researchers have used different techniques such as decision modeling 4, 9 or Markov chains 7 in which probability estimates were obtained from the literature. In other studies, there was retrospective analysis of patient charts in health maintenance organization (HMO) and regression analysis was used to assess whether total expenditures were related to the type of drug used as first line therapy. 10, 3 One study prospectively analyzed resource use and outcomes for HMO patients randomly allocated to fluoxetine, imipramine or desipramine. 11 Researchers accounted for and measured different types of resources; especially with respect to the cost of treatment failures, the cost of the treatment of adverse events, and indirect costs. The inclusion of these costs in the published analyses was variable. The time horizon for these studies has also been diverse, ranging from episodic treatment 5 maintenance or prophylactic therapy over a life-time. 7 to In general, authors concluded that SSRIs are equally, or more, cost-effective than TCAs, their higher drug cost being counterbalanced by a reduction in the consumption of other health care resources such as physician visits or hospitalization. Cost-utility ratios are within the range of acceptable cost per Quality- Adjusted-Life Years (QALY) figures. 12 However, these conclusions were not unanimous or fully robust and were based on different qualities of evidence. Sensitivity analyses conducted in the various studies have shown that there are some variables which are crucially important for the conclusions. They are: drop out and relapse/recurrence rates, as well as resource use and the cost of treatment failures. In Table 1, we try to summarize what is known about the determinants of the cost-effectiveness of SSRI treatment compared with TCA treatment. With this background, we have built a decision model to examine the impact of variables that have been shown to be critical to the cost-effectiveness conclusions, i.e. drop out and relapse/recurrence rates and resource use. 3

12 Table 1: Major Determinants of Cost-Effectiveness Determinant of Costeffectiveness Present State of Knowledge Favor SSRI or TCA Drug efficacy Adverse events profile Drug acceptability and compliance Relapse and recurrence rates Health related quality of life (HRQOL) and patient preferences Drug acquisition costs Resource use during treatment Safety in overdose Indirect costs It is generally agreed that no one antidepressant is clearly more effective than another. This has been confirmed in RCTs as well as retrospective studies RCTs as well as retrospective studies have generally concluded that TCAs and SSRIs have different adverse events profiles. Compared to TCAs, SSRIs have fewer anticholinergic, sedative and cardiovascular adverse effects but have more gastro-intestinal side effects. RCTs have found that drop out due to adverse effects is more important with TCAs, but differences in total drop out have not always been statistically significant. Studies conducted in naturalistic environments generally agree that compliance is higher with SSRIs, but it is not known whether these differences are sustained in the long term. Although there are some doubts regarding the long-term efficacy of TCAs in the prevention of relapse, there is no strong evidence regarding which of SSRIs or TCAs is more effective in this respect. The fact that adverse event profile is different between the two classes of drug does not imply that one is preferred to another. However, the apparent higher acceptability of SSRIs suggests that SSRIs are preferable on average. Also, studies have found that SSRIs are associated with improved HRQOL. SSRIs are generally more expensive than TCAs, but large price differences exist among TCAs Generally the same for SSRIs and TCAs. However, depending on patient conditions, TCAs may require more physician visits and laboratory tests for dosage adjustment and close follow-up. Hospitalization is not believed to be related to treatment with one or another class of drug unless the treatment results in failure. Although SSRIs are regarded as safer in overdose and in case of overdose may require shorter length of stay, the view that completed suicide depends on the willingness to commit suicide rather than on the drug cannot be ruled out. Long-term studies are lacking. To the extent that indirect costs are related to the prevalence of depression, indirect costs will be less important the more a treatment is efficacious and adhered to. Both equally Depends on preferences. Adverse events profile is different SSRIs Still unknown Tends towards SSRIs TCAs Tends towards SSRIs SSRIs Both equally. (Faced with no better evidence) 4

13 3. METHODS 3.1 Type of Analysis Cost-Minimization Among SSRIs The meta-analysis presented in Part 1 2 of this study established that there are no statistical significant differences among SSRIs in terms of efficacy, adverse effect profiles or compliance. Accordingly, a costminimization analysis among SSRIs is presented first. Whether these non-significant statistical differences reflect a lack of clinically important differences among SSRIs is debatable. However, all SSRIs are generally considered equally efficacious, although their pharmacodynamic and pharmacokinetic properties differ. Health related quality of life may also differ for patients on these drugs. This analysis is conducted for the sole purpose of selecting the least costly drug among the SSRIs at a defined daily dose, so that this drug price can be used in the subsequent cost-effectiveness analysis. Cost-Effectiveness of SSRIs Compared to TCAs After the brief review of the current evidence in the preceding section, general considerations regarding decision analytic models are presented. Next, a cost-effectiveness model is built in order to compare the cost-effectiveness of SSRIs to that of TCAs, and to highlight the main determinants of cost-effectiveness. Incorporating Patient Preferences - Cost-Utility Analysis Health related quality of life (HRQOL) and patient preferences are incorporated into the decision model. They are included principally because the side effect profiles of the two classes of drugs are different, although the total drop out rate due to these side effects may not be very different. 3.2 Target Audience The results of this analysis are intended primarily for decision makers within Canadian provincial drug plans, and secondarily for decision makers in institutions and third party payers. However, most aspects of this analysis would also be of interest to practitioners as well. 3.3 Viewpoint In view of the target audience of this analysis, the perspective taken is that of a provincial payer. Costs are measured from a health care system viewpoint. However, patient preferences are incorporated at a later stage in the analysis and the impact of taking a societal perspective is discussed. 3.4 Comparator This study compared SSRIs to TCAs. TCA is a common treatment option for patients with depression. It is also the treatment option for which medication costs are currently the least expensive. More specifically, the model outlined below compares a treatment strategy which consists of SSRI first followed by TCA, with one which consists of TCA first and SSRI second. The third strategy consists of TCA only. Therefore, there are two comparator strategies to the SSRI first strategy. 5

14 The rationale for using strategies that consist of more than one drug is to reflect actual practice in which patients are switched from one drug to another when the first drug fails. This design more closely approaches the purpose of cost-effectiveness analysis which is to investigate the cost-effectiveness of treatment strategies. The third comparative strategy, which consists of TCA alone, is examined in order to investigate the incremental cost-effectiveness of a treatment which includes SSRIs over a treatment in which SSRIs would not be available. 3.5 Time Horizon The decision model extends over a nine month period, mainly because current treatment guidelines 13, 14 recommend maintenance therapy for patients who respond favourably. However, the decision model is also run with a short term time horizon of three months. The short term time horizon of three months analyzes the episodic treatment of depression with either an SSRI or a TCA. By extending the length of treatment by six additional months, the cost-effectiveness of short term treatment plus maintenance treatment is then captured. In the longer term analysis drug substitution, relapses and recurrences were allowed. Splitting the decision model into two time periods allows us to investigate the effect of the length of the treatment period upon cost-effectiveness. Therefore, inferences can be made about the impact of extending treatments by six month intervals. 3.6 The Decision Model Description of the Model As outlined in Section 3.4 above, the model compares three treatment paths; one in which the first-line treatment is an SSRI, and two others where it is a TCA. The model compares these three alternative treatment options, and calculates the cumulative success, expected costs and cost-effectiveness of each alternative over the specified time period. This decision model was formulated by the research team following consultation with four psychiatrists, statisticians, and reviewers. It was run using Data 2-6 and calculations were performed using an Excel spreadsheet. The decision model is depicted in Figures 1a, 1b and 1c. It focuses on specific elements which are believed to influence the cost-effectiveness of SSRIs and TCAs, namely; drop-out rates and relapse/recurrence rates. 1 The probabilities that appear in these figures are explained below. The model simulates patients who might follow one of three treatment arms. The first, the SSRI-TCA case, depicts a treatment strategy which starts with an SSRI and then switches to a TCA in the case of a drop out. Relapses while on maintenance therapy could occur. The second arm, the TCA-SSRI option, depicts a strategy of starting with a TCA and then switching to an SSRI in the event of a drop out. Relapses are also possible while on maintenance therapy. The third arm, the TCA only strategy, depicts a strategy in which only TCAs are available. The possibility for spontaneous remission or recurrence of symptoms under all three arms is also incorporated. 1 The model is built around drop out rates, but in actual life non-compliance may take many different forms, such as patients renewing their refulls more slowly. 6

15 Switchovers that are allowed in two treatment arms give some rigidity in the model since the cumulative probabilities of success and failures will be very similar (see for example the results of the sensitivity analysis below). This may be considered a limitation of the model, but the alternative of not allowing for such switchovers would, in our opinion, reduce the validity of the model. Another simplification is that switches from one SSRI (TCA) to another SSRI (TCA) are not considered. Outcome Measures In this analysis, outcomes are measured first as successes or failures, and second as quality adjusted life years. Success means that a patient did not drop out at the end of the time horizon, and failure means that a patient dropped out of the sequence of treatments. This definition of success assumes that patients who stay for the course of their therapy experience an effect, do not experience bothersome side effects that cause them to drop out (reported drop out rates usually encompass drop out due to adverse events as well as drop out because of a lack of efficacy), and do not relapse. It is acknowledged that some patients could remain on the drug without deriving any benefit from it. However, building a model that assumes this situation to be prevalent would be difficult. The model is extended to include health-relatedquality-of-life and patient preferences by incorporating utility values found in the literature. In the cost-utility analysis, outcome is expressed in terms of quality adjusted life years (QALY). 7

16 Figure 1a. The Treatment Path with SSRI as a First Line Therapy Figure 1b. The Treatment Path with TCA as a First Line Therapy No relapse - success Do not drop # # Relapse - inc. dose 0.13 Do not drop - success # Drop - failure TCA No relapse - success Drop Switch to SSRI Do not drop SSRI # # Relapse - inc. dose 0.13 No recurrence Do not drop - success # Drop - failure Drop SSRI # Recurrence - failure 0.38 Figure 1c. The Treatment Path with TCA as the Only Therapy 8

17 Characteristics of Treatment Arms The model has the following characteristics: i. Once a patients is put on a drug, he/she may drop out or not. ii. If the patient does not drop out, he/she may either relapse or stay on the drug for the nine month period. A relapse is defined as a reported worsening of symptoms while on medication. iii. If the patient relapses while on the first line drug, the dose of the drug is increased. iv. Following the increased dose, the patient again may either drop out or stay on the drug. v. If a patient drops out, therapy is switched, except in the TCA only arm. vi. After a switch of therapy, a patient either drops out or continues treatment. vii. Those who drop out following a switch of therapy may experience a recurrence of symptoms, otherwise their symptoms remit. A recurrence is defined in this study as a worsening of symptoms while not on medication. viii. In the TCA only arm also, those patients who drop out may or may not experience a recurrence. ix. Those patients who have dropped out are considered failures, otherwise the treatment is considered a success. x. The short-term analysis extends over the first three months during which neither a relapse nor a switch of medication occurs. Probabilities and Sources of Information The probabilities of the events included in the decision model as well as the sources are indicated in Table 2. Table 2: Probabilities Used and Sources of Information Estimate Confidence Interval Source SSRI drop out 32.9% Meta analysis in Part 1, Section SSRI relapse 13.0% n.a. Doogan & Caillard, TCA drop out 38.5% Meta analysis in Part 1*, Section TCA relapse 13.0% n.a. Assumed to be equal to that of SSRIs Recurrence 38.0% n.a. Mueller 1996, 16 Keller 1982, 17 n.a.: not available * Part 1 has selected for the purpose of meta-analysis, only a subset of published studies of TCAs (which included all head-to-head studies between SSRIs and TCAs) versus a more complete set of studies involving SSRIs. However, it is assumed that this subset of TCA studies is representative of the larger set of TCA studies. The results of other metaanalyses are tested within the sensitivity analysis. 9

18 Assumption The major assumption made in this model is that drop out rates of TCAs and SSRIs do not depend on previous therapy. However, we are not aware of any other evidence, and Part 1, Section suggested this assumption. The impact of relaxing this assumption will be discussed below. Also, since the drop out rates used in the decision model are those that prevailed at 12 weeks in RCTs, the model approaches a cost-efficacy analysis rather than a cost effectiveness analysis. However, in an attempt to more closely represent real life situations, a number of special cases that rely on estimates coming from naturalistic studies are modeled within the sensitivity analyses. In this decision model, the probability of drop out plays a central role. For comparison Table 3 compares the drop out rates obtained by other meta-analyses. Table 3: SSRI TCA Comparison of Drop Out Rates Obtained by Different Meta-Analyses Study Drop Out Rate Montgomery et al (1994) 18 19% Song et al (1993) 19 32% Dunbar et al (1991) 20 42% Anderson & Tomenson (1995) 21 31% Part % Montgomery et al (1994) 18 27% Song et al (1993) 19 33% Dunbar et al (1991) 20 54% Anderson & Tomenson (1995) 21 33% Part % Difference between SSRI and TCA Montgomery et al (1994) 18-8% Song et al (1993) 19-1% Dunbar et al (1991) 20-12% Anderson & Tomenson (1995) 21-2% Part 1 2-6% 3.7 Utilities Utilities used in this model were derived from published literature. In a recent article, Revicki et al (1995) 7 used utility values obtained by applying standard gamble scaling methods to 70 patients with major depressive disorders. The following utility values were taken from that article and used in this analysis (Table 4). It should, however, be noted that these utility values were derived from a single study with a limited number of patients. Despite the increasing acceptance of utility values, there is still debate about the methods used to elicit such values and the equity assumptions on which they rest. 10

19 Table 4: Utility Values Used in This Model Health state in Revicki et al (1995) 7 Utility Values Health states in our model for which Revicki et al values are applied Utility values used in sensitivity analysis Acute episode, fluoxetine treatment a st 3 months on SSRI months treatment, fluoxetine b nd 3 months on SSRI Prophylaxis, fluoxetine c rd 3 months on SSRI Acute episode, imipramine treatment a st 3 months on TCA months treatment, imipramine b nd 3 months on TCA Prophylaxis, imipramine c rd 3 months on TCA Untreated depression Therapy failure No recurrence a b c Utility after 1 month of treatment. Utility after 3 months of treatment. Utility after 6 months of prophylaxis. 3.8 Resource Measurement and Cost Valuation Resource Use Estimates of resource consumption were determined following consultation with the clinical experts mentioned above. They are based on the following assumptions: i. When neither a drop out nor a relapse occurs, four general practitioner (GP) visits and one set of laboratory tests are required during the nine month period in addition to the cost of medication. ii. TCA treatment requires one additional GP visit for dose adjustment. iii. Following a relapse or a drop out, a patient is treated by a psychiatrist instead of a GP. iv. When there is a switch of medication, one psychiatric consultation is added. v. If the switch is to a TCA, one set of laboratory tests is added. vi. Treatment failures are assumed to require hospitalization. In view of the primary audience of this analysis and the controversy regarding the net loss to society of productivity losses related to morbidity, only direct health care costs to the health care system are considered. However, the impact of patient costs and indirect costs (time and productivity losses) will be discussed. For example, all failures are assumed to require hospitalization. This simplification is made in order to account for the diverse costs of treatment failures. There is indeed some evidence that shows that depressed patients who are not treated, consume more health care resources and are less productive than those who are treated. 11, 22 No cost is attributed to the management and treatment of adverse effects except within sensitivity analysis. Adverse effects are assumed to lead to drop out only. Table 5 lists the estimates of resource used for each treatment arm possibility. 11

20 Table 5: Resource Use End Nodes from Top to Bottom on the Tree SSRI-TCA No. of GP visits No. of psychiatrist visits No. of lab test sets Months on 1 st SSRI Months on increased SSRI dose Months on TCA Months on increased TCA dose Days hospitalized * * 0 20* TCA-SSRI No. of GP visits No. of psychiatrist visits No. of lab test sets Months on 1 st TCA Months on increased TCA dose Months on SSRI Months on increased SSRI dose Days hospitalized * * 0 20* TCA only No. of GP visits No. of psychiatrists visits No. of Lab test sets Months on 1 st TCA Months on increased TCA Months on SSRI Months on increased SSRI dose Days hospitalized * 0 20* * 20 days hospital stay: Case Mix Group (CMG) Cost Valuation Table 6 indicates the dollar values of the resources necessary for the decision analysis. Table 6: Cost Estimates Estimate Source SSRI daily dose: 20 mg generic fluoxetine $ Quebec formulary* 24 SSRI increased daily dose: 40 mg generic fluoxetine $ Quebec formulary* 24 TCA daily dose: 50 mg tid generic imipramine $ Quebec formulary* 24 TCA increased daily dose: 100mg tid generic imipramine $ Quebec formulary* 24 Hospital day: daily cost of 1 hospital day for standard CMG 765 (Depressive mood disorders, no ECT W AX3)H 23 $380 CIHI (personal communication) - Cost estimated by case costing General practitioner visit $58.90 Quebec rate ** Psychiatrist consultation $75.00 Quebec rate ** Laboratory tests $25 Author s estimate * Formulary prices of generic drugs are very similar across Canada ** Provincial fee schedule provided by CIHI Fluoxetine and imipramine costs are used since they have the lowest cost within their class. Other product prices are used within the sensitivity analysis. Quebec rates for GP and psychiatric visits are chosen because they are neither the highest nor the lowest in Canada, and also to be consistent with the drug prices. 12

21 The same cost is attributed to GP and psychiatric visits and consultation. This reflects the present Canadian health care system in which a single fee is attached to a physician visit. In reality, some visits consume less physician time than others, thus freeing up more time for the physician to treat other patients. From the point of view of society s opportunity cost, the two visits are different. Ideally, a more detailed costing method should be used. However, considering the perspective from which costs are measured in this study, this case mix bias 25 is acceptable, since all these physician fees will result in the same cost to the Ministry of Health. 3.9 Uncertainty Uncertainty in this model derives from the use of estimates as well as from the use of assumptions. The uncertainty surrounding each of the estimates and assumptions used in this model is addressed by sensitivity analysis. Sensitivity analysis is performed using the upper and lower bounds of the 95% confidence interval of estimates when available, or from values derived from other sources. Uncertainty about assumptions is handled by running the model with different assumptions. Sensitivity Analysis Around Estimates The following variables are changed within the sensitivity analysis, and the values used are: i. Drop out rates: 95% confidence interval used (Table 2), as well as drop out rates obtained in two other meta-analyses ( SSRI: 42%, TCA 54%, Dunbar 20 and SSRI: 32.3%, TCA: 33.4%, Song 19 ). These two meta-analyses are chosen because the differences in reported rates between SSRIs and TCAs are at different extremes. ii. Relapse rates: +/- 50% iii. Physician and psychiatric costs: Newfoundland fees are used instead of Quebec fees: GP $34.50, psychiatrist $ (Newfoundland has the lowest GP rate, and one of the highest psychiatrist rates, whereas Quebec has the highest GP rate)* iv. Drug costs: the cost of 150 mg of desipramine and 50 mg of sertraline, respectively $ and $1.5364, are used instead of the costs of imipramine and fluoxetine v. Hospitalization: length of stay is increased from 20 days to 60 days (length of stay for elderly patients in psychiatric hospitals) vi. Utility values: utility values are increased by half the difference between the utility value and 1 (to raise the utility values and reduce the impact of quality of life) * (Source: provincial fee schedule costs provided by CIHI) Sensitivity Analysis Around Assumptions In addition to the sensitivity analysis described above, the following scenarios are considered in order to integrate additional evidence regarding actual real life performance of antidepressant therapies. Special Case 1: The prescription of TCA in subtherapeutic doses. It has been argued that TCAs are often prescribed in subtherapeutic doses in general practice with the result that they become less efficacious. 26 For example, in a study on the cost implication of treatment failures, McCombs et al 27, 26 excluded 45% of patient charts from further analysis because of subtherapeutic levels. To account for this, we use the relapse rate obtained for placebo (45.7%) 15 in the TCA arm. Special Case 2: Different drop out rates than those observed in RCTs. It is often argued that the discontinuation rates of SSRIs, and especially TCAs, are higher in actual life than those observed 13

22 in controlled trials. To address this issue, we use drop out rates taken from the review article by Revicki and Luce 28 ; TCA 69.5% and SSRI 50%. Special Case 3: An increased use of resources for patients treated with TCAs. Patients using TCAs are often said to consume more health care resources due to dose adjustment and to management of adverse effects. One physician visit and one lab test are added in this special case. 14

23 4. RESULTS 4.1 Cost-Minimization Analysis Table 7 shows the lowest price per daily dose of each SSRI reimbursed by Canadian drug plans. Note that these dosages may not reflect actual clinical practice and should therefore be interpreted with care. A comparison based on actual clinical practice dosages may yield different results. Note also that pharmacist dispensing fees are not included. Generic fluoxetine appears to be the cheapest alternative among the different SSRIs. This comparison holds only for the present time in Canada, since the table compares prices of generic versions with prices of brand name versions. Table 7: Price Comparison of Selected SSRIs Generic Name Brand Name Daily Dose 29 Generic Version Price 24 Brand Name Price 24 Fluoxetine Prozac 20 mg $ $ Fluvoxamine Luvox 100 mg n.a. $ Paroxetine Paxil 20 mg n.a. $ Sertraline Zoloft 50 mg n.a. $ n.a.: not available Studies comparing the cost of treatments with different SSRIs have been published. An econometric model by Sclar et al 30 compared direct costs of treatment of HMO patients treated with fluoxetine, paroxetine or sertraline (taking into account medication costs, physician visits, laboratory testing, and hospitalization) and concluded that fluoxetine was associated with lower total costs than the other SSRIs examined. However, another study found that the total direct costs per patient were lower for sertraline relative to fluoxetine. 31 Similarly, a retrospective study in 1997 by Singletary et al, 32 which compared the medication costs to a medical centre for fluoxetine, sertraline, and paroxetine revealed that the average daily medication cost with sertraline was lower than that of fluoxetine and paroxetine. Undoubtedly, these findings reflect in large part differences in the unit price of the drugs in the different settings. For example, generic fluoxetine may not be available in other countries. As far as the present Canadian situation is concerned generic fluoxetine appears to have the least acquisition cost among the SSRIs. 4.2 Cost-Effectiveness and Cost-Utility Analyses The Baseline Case Baseline case results are obtained by using the decision model represented in Figures 1a, 1b, and 1c with the assumptions, probability estimates, and costs described in Section 3. The cumulative expected probability of success for a patient started either on SSRI or on TCA therapy is calculated. The expected cost of treating each patient over the defined time period and expected utility of each treatment arm is also estimated. The results of the baseline case analysis (i.e. the short and medium term expected probabilities of success as well as the expected utility and cost) are presented in Table 8. Although an incremental cost per successfully treated patient can be calculated, this result is not displayed due to its high imprecision. The 15

24 denominator of such an incremental cost per successfully treated patient would be the difference between the expected probabilities of success at the end of treatment arms in the two branches. In our case, these probabilities are very similar and have large variances. Therefore the precise number is practically meaningless. Sufficient information can be obtained by considering the similarity between the success rates, on one hand, and cost and utility differences between the treatment branches on the other hand. Table 8: Baseline Case Results SSRI-TCA vs TCA-SSRI SSRI-TCA vs TCA only Probability of success ST incremental success 5.6% 5.6% MT incremental success 0.3% 9% Expected cost ST incremental cost $44 $44 MT incremental cost $110 -$406 Expected incremental utility (MT) Expected cost per QALY gained (MT) $2,818 Dominant ST: Short term, MT: Medium term The short-term analysis reveals that the probability of success of an SSRI therapy is greater than that of a TCA therapy (as expected from the meta analysis of drop out rates presented in Part 1 of this study) 2 and its expected cost is slightly higher. However, when extended over an additional six months, during which relapses, recurrences, and switch of therapies are allowed, the probability of success of an SSRI- TCA therapy is very close to that of a TCA-SSRI therapy, but higher than a TCA only therapy by 9%. In terms of costs, the short-term SSRI first therapy has a slightly higher expected cost than the TCA first therapy ($44), and this cost differential increases as the time horizon is increased to nine months ($110). However, compared to the TCA only therapy, the SSRI first therapy is less costly due to the built-in cost of treatment failures. These incremental costs of $44 and $110 are NOT the incremental costs of successfully treating one more patient with an SSRI instead of a TCA. They are the expected incremental costs of treating one patient with an SSRI rather than a TCA over a period of three and nine months, knowing that the probability of success is similar with the two drugs. When patient preferences are incorporated into the analysis via the use of utility values, the SSRI first therapy provides, on average, increased health related quality of life over the TCA first therapy, and even more quality of life benefits over the TCA only therapy. The cost per QALY is estimated at $3,000. In summary, the SSRI-TCA treatment yields the same success rate as the TCA-SSRI treatment option (0.3% difference), offers improved health related quality of life to patients, but is slightly more costly. This cost tends to increase over time as treatment is maintained. However, compared to a TCA-only therapy, the SSRI-TCA treatment is a dominant strategy. It is both more successful and less costly, and offers increased health related quality of life. The detailed results (expected costs and probabilities) are displayed in Figure A1a, A1b and A1c in Appendix 1. 16

25 4.3 Sensitivity Analysis The robustness of the above conclusions to different probability estimates and to changes in assumptions is examined by using one-way sensitivity analyses as detailed in section 3.9 above. Sensitivity Analysis Around Estimates The results of the one-way sensitivity analyses are presented in Table 9. Sensitivity analysis results show the following: i. Short term success rates: except in the case where the drop out rate for TCA is at its lowest value, the expected short term success rate of the SSRI therapy is higher than that of TCA. ii. Medium term success rate: In all cases, the success rates achieved by the SSRI-TCA treatment are not significantly different than that of the TCA-SSRI strategy. Compared to the TCA only strategy, the SSRI-TCA strategy always has a higher expected probability of success varying between 7% and 11%, depending on the case. iii. Short term cost: In all cases, the short term expected cost of the SSRI-TCA strategy is higher than that of the TCA-SSRI strategy except when sertraline and desipramine costs are used. In this case, the SSRI-TCA strategy is less expensive. iv. Medium term cost: In all cases, the medium term expected cost of the SSRI-TCA strategy is higher than that of the TCA-SSRI strategy. However, in the cases where either the drop out rate for TCA is at its upper bound, Dunbar 20 values are used, the length of hospital stay is high, or where sertraline and desipramine costs are used; the increase in cost, between the short and the medium term, is less than proportional to the increase in length of time (i.e. in these cases, incremental costs would tend to fade as treatment extends over time, other things remaining equal). v. Utility gained and cost-utility ratios: In all cases, the SSRI-TCA strategy leads to increased health related quality of life over the TCA-SSRI case. In all cases also, it leads to even greater increases over the TCA only case, except when higher utility values are used for all health states examined. Costs per QALY gained range between $1,500 and $6,000. In the case where sertraline and desipramine costs are used, the QALY gained is accompanied by reduced cost. It may therefore be argued that the conclusions reached in the baseline case are robust. 17

26 Table 9: Sensitivity Analysis Results Around Estimates SSRI-TCA v/s SSRI-TCA v/s TCA only TCA-SSRI TCA high drop out rate ST increased success rate MT increased success rate ST increased cost $44 MT increased cost $72 -$536 Utility gained Increased cost per QALY gained $1,476 Dominant TCA low drop out rate ST increased success rate MT increased success rate ST increased cost $44 MT increased cost $150 -$284 Utility gained Increased cost per QALY gained $4,922 Dominant SSRI high drop out rate ST increased success rate MT increased success rate ST increased cost $44 MT increased cost $123 -$342 Utility gained Increased cost per QALY gained $4,140 Dominant SSRI low drop out rate ST increased success rate MT increased success rate ST increased cost $44 MT increased cost $96 -$469 Utility gained Increased cost per QALY gained $2,006 Dominant Dunbar 20 values TCA drop 54%, SSRI drop: 42% ST increased success rate 0.12 MT increased success rate ST increased cost $44 MT increased cost $55 -$525 Utility gained Increased cost per QALY gained $1,297 Dominant Song 19 Values TCA drop: 33.4% SSRI drop 32.3% ST increased success rate MT increased success rate ST increased cost $44 MT increased cost $141 -$313 Utility gained Increased cost per QALY gained $4,254 Dominant 18

27 SSRI-TCA v/s TCA-SSRI SSRI-TCA v/s TCA only Low relapse rate ST increased success rate MT increased success rate ST increased cost $44 MT increased cost $115 -$447 Utility gained Increased cost per QALY gained $2,918 Dominant High relapse rate ST increased success rate MT increased success rate ST increased cost $44 MT increased cost $106 -$365 Utility gained Increased cost per QALY gained $2,717 Dominant Newfoundland rate ST increased success rate MT increased success rate ST increased cost $69 MT increased cost $126 -$356 Utility gained Increased cost per QALY gained $3,210 Dominant Desipramine and sertraline costs ST increased success rate MT increased success rate ST increased cost -$35 MT increased cost -$34 -$530 Utility gained Increased cost per QALY gained -$873 Dominant Lengthy hospitalization ST increased success rate MT increased success rate ST increased cost $44 MT increased cost $65 -$1,776 Utility gained Increased cost per QALY gained $1,653 Dominant Higher utilities ST increased success rate MT increased success rate ST increased cost $44 MT increased cost $110 -$406 Utility gained Increased cost per QALY gained $5,636 Dominant ST: Short term MT: Medium term 19

28 Sensitivity Analysis Around Assumptions Results of varying assumptions under special cases are displayed in Table 10. Table 10: Sensitivity Analysis Results Around Assumptions SSRI-TCA v/s SSRI-TCA v/s TCA only TCA-SSRI1 st Subtherapeutic doses of TCA ST increased success rate MT increased success rate ST increased cost $44 MT increased cost -$291 -$807 Utility gained Increased cost per QALY gained Dominant Dominant Real life drop out: TCA 69.5%, SSRI 50% ST increased success rate MT increased success rate ST increased cost $44 MT increased cost $13 -$577 Utility gained Increased cost per QALY gained $276 Dominant More resource use for TCA ST increased success rate MT increased success rate ST increased cost $15 MT increased cost $52 -$465 Utility gained Increased cost per QALY gained $1,316 -$11,859 In all these cases, results are more favorable to the SSRI-TCA strategy than in the baseline case. Conclusions regarding the similarity of success rates between the SSRI first and the TCA first strategy remain unchanged but the medium term expected cost of the SSRI-TCA strategy is in these cases, much lower than the baseline case. When TCA is administered in subtherapeutic doses, the expected cost of the SSRI-TCA strategy is even less than that of TCA-SSRI. Similarly, costs per QALY gained are within the ranges obtained in the sensitivity analyses outlined above. When TCA is administered in subtherapeutic doses increased health related quality of life is obtained at lower cost. Therefore, under these special cases, conclusions are more favorable to the SSRI-TCA strategy than the baseline case. The baseline case assumes that prescribers use the appropriate dose for each drug. Here too, when different assumptions are used, the baseline case yields results that are more favorable to the SSRI first strategy. 4.4 Equity Issues Equity considerations should be borne in mind when tradeoffs between health care interventions are examined. In this study, one of the most important equity issues results from the fact that the adverse effect profiles of SSRIs and TCAs are different, even though the difference in the total drop out rates associated with these drugs, upon which this decision analysis rests, is not statistically significant at a certain level of significance. The equity issue that would arise if these two classes of drugs are considered equivalent on the basis of efficacy and drop out rates cannot be disregarded. Performing a cost minimization analysis between the two classes, while at the same time acknowledging that the adverse effects that lead to drop out are different between the two classes of drugs, is problematic. Such an analysis would favor those who might suffer from the adverse effects associated with the least expensive drug while penalizing those who might suffer from the adverse effects of the most expensive drug. 20

29 5. DISCUSSION General This economic evaluation of SSRIs in comparison to TCAs uses decision modeling to derive conclusions regarding the cost-effectiveness of SSRIs when used as a first or second line therapy in the treatment of depression. The comparators are TCAs, used either alone or supplemented by SSRIs whenever the TCAs failed. The decision model is derived after discussions with practitioners and reviewers. Health related quality of life is incorporated by using published utility values derived from actual patients using standard gamble techniques. Conclusions apply only to instances where SSRIs and TCAs are valid options for the treatment of depression. Due to co-morbidities, drug interactions, or possible adverse effects, either TCAs or SSRIs may not be valid options. Based on this model, it is concluded that the success rate of an episodic treatment with an SSRI (as defined by the non-drop out) is higher than one with a TCA, but is also more expensive. However, as maintenance therapy is initiated, and switch of medications is allowed for those who drop out of a treatment, the cumulative success rate of the SSRI first strategy becomes very similar to that of the TCA first strategy, but its cost increases over time. Compared to a therapy using only TCAs, the SSRI-TCA strategy is dominant since it has a higher probability of success and costs less. The model reveals that the aggregate cumulative probability of success with the different therapies is very similar. This is not surprising given the construct of the model. The fact that patients are modeled to switch between one therapy and another when the first therapy fails, combined with the fact that the success of therapies does not depend on the previous therapies, and that relapses are not a function of the therapies, causes this rigidity. This feature can be desirable, since repeated trials have shown that SSRIs and TCAs are equally efficacious, as measured for example by the Hamilton Depression Rating Scale. A recent study that traced a cohort of patients has indeed found that a number of patients switched therapies, and that the overall success rates were not statistically different between those who were started on an SSRI or on a TCA. 11 The expected incremental cost of SSRI-TCA versus TCA-SSRI increases as the time horizon is increased. This indicates that maintaining responsive patients on an SSRI therapy adds to the expected cost of a treatment (if we assume the above relapse, recurrence and drop out rates as well as therapy switches that might occur during a six month interval). Compared to the TCA only therapy, the SSRI first therapy is less costly due to the built-in cost of treatment failures. This is acceptable given the cost of depression and if one assumes that the availability of SSRIs will enable the treatment of an increased number of patients. Many studies have documented the direct and the indirect cost of depression. Depressed individuals tend to consume more health care resources 26, 33 and are less productive than patients without depression (burden of illness studies). This issue is partially addressed by our assumption that all failures are hospitalized. Although highly simplifying, this assumption is made to capture the cost of treatment failures. In the comparison between the SSRI-TCA and the TCA-SSRI strategies, this assumption has little impact since the probability of hospitalization will be very similar between these two treatment branches. Compared to other cost-effectiveness studies, the baseline analysis of this study is somewhat less favorable to SSRIs. Other cost-effectiveness studies have found that the cost of treatment success is less 4, 5, 7 costly with SSRIs than with TCA. These studies use a different decision model, different estimates, include the cost of managing adverse effects or suicide costs - items which are not accounted for in this 21

30 study. The use of different drug costs could also explain dissimilar results. Sensitivity analysis reveals that drug costs are an important determinant of the incremental cost of treatments in this analysis. The conclusions of these previously published cost-effectiveness studies are also slightly different than those reached in the Simon et al 11 study in which HMO patients were randomized to receive either fluoxetine, imipramine or desipramine. When patients were allowed to switch drugs if one drug failed, the study showed that at the end of six months the total health care costs were similar between the three groups, as was quality of life measured by the SF-36. But those patients originally on fluoxetine were less likely to switch medication. Studies which investigated health-related quality of life have generally concluded that SSRIs offer improved quality of life over TCAs. As many meta-analyses have demonstrated, SSRIs have different adverse effect profiles and overall, patients seem to rate adverse effects associated with SSRIs less unfavorably than those associated with TCAs. This is reflected by the higher utility values obtained from patients and by opinions of psychiatrists. This improved quality of life comes at a cost; a cost which is nevertheless low compared to other health interventions (approximately $3,000 per QALY gained). These values are very close to those obtained by other studies. For example, Hatziandreu et al 6 obtained a value of $US3,692 for the cost-utility of sertraline versus dothiepin, and Revicki et al s 7 cost-utility ratios range between negative amounts to $17,326 for nefazodone compared to imipramine. In the Simon study 11 which followed two cohorts of patients, there was no statistical differences in quality of life between the two cohorts as measured by the SF-36 questionnaire. However, more patients who had started with TCAs switched therapies than those who started on SSRIs. One could conclude from the results presented above that an SSRI first-line strategy is dominant over a TCA only strategy, and that an SSRI first-line strategy compared to a SSRI second-line strategy produces QALYs at an acceptable cost compared with other interventions. It should, however, be noted that the utility values that were used in this study were taken from a single study which relied on a limited number of patients. 7 Despite the increasing acceptance of utility values in economic analyses, the methods used to elicit them are still subjects of research and debate, and controversy still remains as to the equity assumptions on which they rest. Conclusions derived from the use of such values should therefore be taken with caution. In this case, the basic message behind using utility values is not the precise cost per QALY figure that was obtained, it is the fact that the existing (although limited) evidence points to the fact that quality of life seems higher with SSRIs than with TCAs. This being the case, SSRIs tend to look more advantageous than TCAs whenever quality of life considerations are introduced into the analysis. The stronger the belief that SSRI improves health related quality of life compared to TCAs, the lower the incremental cost-utility ratio between the two drugs. Limitations As in any cost-effectiveness analysis that uses modeling, this study has limitations. Sensitivity analysis is used to test the validity of our conclusions with respect to changes in estimates and assumptions. The conclusions appear robust. The following is a brief discussion of the limitations of the study that should be borne in mind when looking at the conclusions and possibly acting upon them. The major limitation relates to the structure of the decision tree itself and its assumptions. In actual life treatment paths and outcomes are not so stylized. The decision model used in this study is very simple and does not allow for differences in success rates to occur over time, especially for the comparison between the SSRI-TCA and the TCA-SSRI strategy. This is because, first, the efficacy of SSRIs and TCAs are not significantly different from each other. Second, the model assumes that the efficacy of the different drugs are not altered by prior treatment (i.e. the efficacies of SSRIs and TCAs are not affected by a prior treatment with a TCA or an SSRI). Third, it is assumed that all drop outs are switched to the other therapy 22

31 and all patients who relapse are put on another course of the same therapy. Had any of these assumptions been relaxed, the conclusions would have tended to be more favorable to the SSRIs because they are associated with fewer drop outs. This analysis is actually a cost-efficacy study. Clinical information on the success of therapies and dropout has been taken, in the baseline case, from RCTs. RCTs do not fully mirror the real world environment. In addition, RCTs eliminate many types of patients such as those with psychotic disorders, concurrent symptoms, or suicidal tendencies; in other words they eliminate many psychiatrists regular patients. Compliance also may not be adequately estimated by RCT drop out rates. The measure of acceptability used might not reflect actual life. This is why sensitivity analyses examine the case where drop out rates are derived from actual follow up of patients. Results in such a case are more favorable to the SSRI first strategy than the baseline case. The baseline case also assumes that prescribers use the appropriate dose for each drug. Here too, when different assumptions are used in the decision model, the baseline case yields more favorable results than the SSRI first strategy. The long term efficacy, and also effectiveness, of the different drugs is unknown. This is also true for the long-term drop out rates and relapse rates (which contribute to the effectiveness of the drug). RCTs usually extend over a maximum period of 12 weeks. The true cost effectiveness of treatments for depression depends on the success of a treatment in the long run: whether it will prevent patient relapse or recurrences, whether it will reduce resource use or increase the quality of life of patients. While studies have shed some light on the impact of different treatments on resource use, quality of life, and to a lesser degree on relapses while on treatment, we still do not know whether one treatment rather than another will reduce recurrence in the future (whether the recurrence is related or not to an earlier episode of depression). This analysis has taken a limited Ministry of Health perspective 2 instead of the broader, and presumably more appropriate, societal perspective. This means that direct costs borne by patients, time costs borne by patients and society s indirect costs in terms of lost production and lost productivity (all of which in the case of depression can be substantial) have been excluded. If these costs are more important with the use of TCAs, then their inclusion would show results more favorable towards SSRIs. This trend is indicated in the sensitivity analysis when the resource use associated with TCAs is increased. Our model also excludes the possibility of suicide and the associated costs. Here again, this possibility is more readily attributable to TCA due to its safety profile in overdose, and the inclusion of these costs in the analysis would have favored SSRIs. The model incorporates estimates of relapse and recurrence rates that were derived from different sources. These rates could include relapse and recurrences which may not be attributable to the first depressive episode or its treatment. Although, in a strict sense, some would argue that a decision model should only consider those relapses that are consequent to the first depressive episode, this is not possible here, since estimates are lacking and possibly empirically impossible to determine (and perhaps meaningless in view of the recurrent nature of depression). Finally, the model does not take into consideration time to symptom improvement. 6. CONCLUSIONS 2 Pharmacy mark-ups and dispensing fees are ignored. 23

32 Our analysis indicates that the strategy of starting a treatment for depression with an SSRI is as successful as, but more costlier than, a strategy which starts with a TCA; success being measured as not having terminated treatment due to adverse events or other causes. However, it is more efficacious and less costly than a strategy in which SSRIs cannot be relied upon as a second line treatment. This result is dependent upon various estimates most of which are derived from clinical trials. When information derived from naturalistic environments or health related QOL considerations are incorporated, conclusions tend to be more favorable towards SSRIs. When a more comprehensive perspective than the Ministry of Health is taken, the SSRI first option tends to be less costly. In short, this study concludes that an SSRI first-line strategy is dominant over a TCA only strategy, and that an SSRI first-line strategy compared to a SSRI second-line strategy produces QALYs at an acceptable cost by current standards. If only direct costs to the Ministry of Health are considered, then TCA first appears to be the cheapest alternative with SSRIs playing the role of a fall back strategy. However, when quality of life considerations and costs borne by patients are taken into account, then SSRIs would be the choice of patients and practitioners. This will likely come at a cost to a Ministry of Health which might increase over time as maintenance therapy becomes more prevalent. However, this cost may be balanced by the improved quality of life and productivity of the individuals concerned. 24

33 REFERENCES 1. Goel V, Williams JI, Anderson GM, Blackstien-Hirsch P, Fooks C, Naylor CD, editors. Patterns of health care in Ontario: the ICES practice atlas. 2nd ed. Ottawa: Canadian Medical Association; Selective serotonin reuptake inhibitors (SSRIs) for major depression. Part 1. Evaluation of the clinical literature. Ottawa: ; Sclar DA, Robison LM, Skaer TL, Legg RF, Nemec NL, Galin, RS, et al. Antidepressant pharmacotherapy: economic outcomes in a health maintenance organization. Clinical Therapeutics 1994;16(4): Lapierre Y, Bentkover J, Schainbaum S, Manners S. Direct cost of depression: analysis of treatment costs of paroxetine versus imipramine in Canada. Canadian Journal of Psychiatry 1995;40: Jönsson B, Bebbington P. Economic studies of the treatment of depressive illness. In: Jönsson B, Rosenbaum J, editors. Health economics of depression. Chichester, UK: John Wiley & Sons; p (Perspectives in psychiatry; vol. 4). 6. Hatziandreu EJ, Brown RE, Revicki DA, Turner R, Martindale J, Levine S, et al. Cost utility of maintenance treatment of recurrent depression with sertraline versus episodic treatment with dothiepin. Pharmacoeconomics 1994;5(3): Revicki DA, Brown RE, Palmer W, Bakish D, Rosser WW, Anton SF, et al. Modelling the cost effectiveness of antidepressant treatment in primary care. Pharmacoeconomics 1995;8(6): Le-Pen C, Levy E, Ravily V, Beuzen JN, Meurgey F. The cost of treatment dropout in depression: A cost-benefit analysis of fluoxetine vs. tricyclics. Journal of Affective Disorders 1994;31(1 May): Stewart A. Revisiting the relative cost-effectiveness of selective serotonin re-uptake inhibitors and tricyclic antidepressants: what price inflation and subtherapeutic dosages? British Journal of Medical Economics 1996;10: Skaer TL, Sclar DA, Robison LM, Legg RF, Galin RS, Nemec NL. Antidepressant pharmacotherapy: effect on women's resource utilization within a health maintenance organization. Journal of Applied Therapeutics 1996;1(1): Simon GE, VonKorff M, Heiligenstein JH, Revicki DA, Grothaus L, Katon W, et al. Initial antidepressant choice in primary care: effectiveness and cost of fluoxetine vs tricyclic antidepressants. JAMA 1996;275(24): Crott R, Gilis P. Economic aspects of pharmacotherapy of depression: an overview. Acta Psychiatrica Scandinavica. In press United States. Agency for Health Care Policy and Research. Depression in primary care. Volume 2. Treatment of major depression. Rockville, MD: Agency for Health Care Policy and Research; 25

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36 APPENDIX A1a 28

37 APPENDIX A1b 29

38 APPENDIX A1c TCA Do not drop $1,624 No relapse $723 Relapse - inc. dose $335; P=0.535 Efficacious $3,319 Failure $393; P=0.049 $7,993; P=0.031 Drop No recurrence $3,065 Recurrence - failure $148; P=0.239 $7,823; P=0.l46 30

39 Green Valley Crescent Ottawa, Ontario, Canada K2C 3V4