Fluoxetine and imipramine: are there differences in cost-utility for depression in primary care?

RATIONALE: Depressive disorders generate severe personal burden and high economic costs. Cost-utility analyses of the different therapeutical options are crucial to policy-makers and clinicians. Previous cost-utility studies, comparing selective serotonin reuptake inhibitors and tricyclic antidepressants, have used modelling techniques or have not included indirect costs in the economic analyses. OBJECTIVE: To determine the cost-utility of fluoxetine compared with imipramine for treating depressive disorders in primary care. METHODS: A 6-month randomized prospective naturalistic study comparing fluoxetine with imipramine was conducted in three primary care centres in Spain. One hundred and three patients requiring antidepressant treatment for a DSM-IV depressive disorder were included in the study. Patients were randomized either to fluoxetine (53 patients) or to imipramine (50 patients) treatment. Patients were treated with antidepressants according to their general practitioner's usual clinical practice. Outcome measures were the quality of life tariff of the European Quality of Life Questionnaire: EuroQoL-5D (five domains), direct costs, indirect costs and total costs. Subjects were evaluated at the beginning of treatment and after 1, 3 and 6 months. Incremental cost-utility ratios (ICUR) were obtained. To address uncertainty in the ICUR's sampling distribution, non-parametric bootstrapping was carried out. RESULTS: Taking into account adjusted total costs and incremental quality of life gained, imipramine dominated fluoxetine with 81.5% of the bootstrap replications in the dominance quadrant. CONCLUSION: Imipramine seems to be a better cost-utility antidepressant option for treating depressive disorders in primary care.

Cost-efficacy of individual and combined treatments for panic disorder.

OBJECTIVE: The objective of this study was to examine the relative cost-efficacy of empirically supported treatments for panic disorder. As psychosocial, pharmacologic, and combined treatments have all demonstrated efficacy in the treatment of panic disorder, cost-efficacy analysis provides an additional source of information to guide clinical decision making. METHOD: Cost-efficacy was examined based on results from the Multicenter Comparative Treatment Study of Panic Disorder, a randomized controlled trial of treatment for panic disorder (DSM-III-R). The trial was conducted from May 1991 to April 1998. Cost-efficacy ratios representing the cost per 1-unit improvement in Panic Disorder Severity Scale mean item score were calculated for 3 monotherapies (cognitive-behavioral therapy [CBT], imipramine, and paroxetine) and 2 combination treatments (CBT-imipramine and CBT-paroxetine) at the end of acute, maintenance, and follow-up phases. RESULTS: Results demonstrated consistently greater cost-efficacy for individual over combined treatments, with imipramine representing the most cost-efficacious treatment option at the completion of the acute phase (cost-efficacy ratio = $972) and CBT representing the most cost-efficacious option at the end of maintenance treatment (cost efficacy ratio = $1449) and 6 months after treatment termination (cost-efficacy ratio = $1227). CONCLUSION: In the context of similar efficacy for combined treatments, but poorer cost-efficacy, current monotherapies should be considered the first-line treatment of choice for panic disorder. Additionally, CBT emerged as the most durable and cost-effective monotherapy and, hence, should be considered as a particularly valuable treatment from the perspective of cost accountability.

Effectiveness and cost-effectiveness of antidepressant treatment in primary health care: a six-month randomised study comparing fluoxetine to imipramine.

BACKGROUND: Over the past decade, studies of the effectiveness of pharmacological treatment for depression have often been based on research designs intended to measure efficacy, and for this reason the results are of limited generalizability. Research is needed comparing the clinical and economic outcomes of antidepressants in day-to-day clinical practice. METHODS: A six-month randomised prospective naturalistic study comparing fluoxetine to imipramine carried out in three primary care health centres. Outcome measures were the Montgomery Asberg Depression Rating Scale (MADRS), direct costs, indirect costs and total costs. Subjects were evaluated at the beginning of treatment and at one, three and six months thereafter. RESULTS: Of the 103 patients, 38.8% (n = 40) were diagnosed with major depressive disorder, 14.6% (n = 15) with dysthymic disorder, and 46.6% (n = 48) with depressive disorder not otherwise specified. Patients with major depressive disorder or dysthymic disorder achieved similar clinical improvement in both treatment groups (mean MADRS ratings decrease in major depressive disorder from baseline to 6 months of 18.3 for imipramine and 18.8 for fluoxetine). For patients with major depressive disorder and dysthymic disorder, the imipramine group had fewer treatment-associated costs (imipramine 469.66 Euro versus fluoxetine 1,585.93 Euro in major depressive disorder, p < 0.05; imipramine 175.39 Euro versus fluoxetine 2,929.36 Euro in dysthymic disorder, p < 0.05). The group with depressive disorder not otherwise specified did not experience statistically significant differences in clinical and costs outcomes between treatment groups. LIMITATIONS: Exclusion criteria, participating physicians may not represent GPs. CONCLUSIONS: In a primary care context, imipramine may represent a more cost-effective treatment option than fluoxetine for treating major depressive disorder or dysthymic disorder. There were no differences in cost-effectiveness in the treatment of depressive disorder not otherwise specified.

Cost-effectiveness of psychological and pharmacological interventions for generalized anxiety disorder and panic disorder.

OBJECTIVE: To assess from a health sector perspective the incremental cost-effectiveness of interventions for generalized anxiety disorder (cognitive behavioural therapy [CBT] and serotonin and noradrenaline reuptake inhibitors [SNRIs]) and panic disorder (CBT, selective serotonin reuptake inhibitors [SSRIs] and tricyclic antidepressants [TCAs]). METHOD: The health benefit is measured as a reduction in disability-adjusted life years (DALYs), based on effect size calculations from meta-analyses of randomised controlled trials. An assessment on second stage filter criteria ("equity", "strength of evidence", "feasibility" and "acceptability to stakeholders") is also undertaken to incorporate additional factors that impact on resource allocation decisions. Costs and benefits are calculated for a period of one year for the eligible population (prevalent cases of generalized anxiety disorder/panic disorder identified in the National Survey of Mental Health and Wellbeing, extrapolated to the Australian population in the year 2000 for those aged 18 years and older). Simulation modelling techniques are used to present 95% uncertainty intervals (UI) around the incremental cost-effectiveness ratios (ICERs). RESULTS: Compared to current practice, CBT by a psychologist on a public salary is the most cost-effective intervention for both generalized anxiety disorder (A$6900/DALY saved; 95% UI A$4000 to A$12 000) and panic disorder (A$6800/DALY saved; 95% UI A$2900 to A$15 000). Cognitive behavioural therapy results in a greater total health benefit than the drug interventions for both anxiety disorders, although equity and feasibility concerns for CBT interventions are also greater. CONCLUSIONS: Cognitive behavioural therapy is the most effective and cost-effective intervention for generalized anxiety disorder and panic disorder. However, its implementation would require policy change to enable more widespread access to a sufficient number of trained therapists for the treatment of anxiety disorders.

Cost-effectiveness of antidepressant treatment reassessed.

BACKGROUND: A recent simulation concluded that the serotonin-specific reuptake inhibitor (SSRI) paroxetine was more cost-effective than the tricyclic antidepressant (TCA) imipramine, despite substantially higher medication acquisition costs. METHOD: We replicated the previous model and revised key assumptions which drove the results. The revised model was subjected to sensitivity analysis. RESULTS: Most scenarios in the revised model showed that the TCA is equally or more cost-effective than the SSRI. Model revision producing these results were changes in assumptions about switched treatment success rates, treatment length and initial treatment success. The revised model appears sensitive to drug acquisition and delivery costs and costs of treatment failure. CONCLUSIONS: Based on the model, a policy of using TCAs as first-choice antidepressant treatment, with SSRIs reserved for those patients not doing well initially, appears more cost-effective than the reverse sequence. Given limitations in current knowledge about key parameters to include in a simulation model, large prospective random-assignment cost-effectiveness studies are needed.

Cost-effectiveness of newer antidepressants compared with tricyclic antidepressants in managed care settings.

BACKGROUND: Our aim was to determine the cost-effectiveness of newer antidepressants compared with tricyclic antidepressants in managed care organization settings. METHOD: We employed cost-utility analysis based on a clinical decision analysis model derived from published medical literature and physician judgment. The model, which represents ideal primary care practice, compares treatment with nefazodone to treatment with either imipramine or fluoxetine or to a step approach involving initial treatment with imipramine followed by nefazodone for treatment failures. The outcome measures were lifetime medical costs, quality-adjusted life years (QALYs), and costs per QALY gained. RESULTS: The base case analysis found that nefazodone treatment had $16,669 in medical costs, compared with $15,348 for imipramine, $16,061 for the imipramine step approach, and $16,998 for fluoxetine. QALYs were greatest for nefazodone (14.64), compared with 14.32 for imipramine, 14.40 for the step approach, and 14.58 for fluoxetine. The cost-effectiveness ratio comparing nefazodone with imipramine was $4065 per QALY gained. The cost-effectiveness ratio comparing nefazodone with the step approach was $2555 per QALY gained. There were only minor differences in costs and outcomes between nefazodone and fluoxetine, with nefazodone resulting in $329 fewer costs and 0.06 more QALYs. The cost-effectiveness ratios comparing fluoxetine with imipramine and with the step approach were $6346 per QALY gained and $5206 per QALY gained, respectively. In the sensitivity analyses, the cost-effectiveness ratios comparing nefazodone and imipramine ranged from $2572 to $5841 per QALY gained. The model was most sensitive to assumptions about treatment compliance rates. CONCLUSION: The findings suggest that nefazodone is a cost- effective treatment compared with imipramine or fluoxetine treatment for major depression. Fluoxetine is cost-effective compared with imipramine treatment, but is estimated to have slightly more medical costs and less effectiveness compared with nefazodone. The basic findings and conclusions do not change even after modifying key model parameters.

Economic evaluation of paroxetine and imipramine in depressed outpatients.

In this pilot study, we compared the economic impact of paroxetine and imipramine treatment of depressed outpatients from a university teaching hospital and a community mental health center. A 12-month retrospective chart review of patients was performed. Clinical outcomes including clinic usage, death, relapse, function, adverse effects, psychiatrist visits, and drug costs were evaluated. We analyzed drug costs, psychiatrist costs, and total direct costs using the Mann-Whitney U Test. The incidence of clinic usage, death, function, adverse effects, and psychiatrist visits was similar in patients treated with paroxetine (n = 12) and imipramine (n = 13). Two patients in the imipramine group were hospitalized once for a total of 5 days compared with none in the paroxetine group. Paroxetine drug costs were significantly higher than imipramine drug costs. Direct total costs (i.e., drug, psychiatrist visits, blood levels, and hospitalization costs) did not differ significantly between the groups based on actual drug usage (paroxetine: median $1,432.50 per patient per year; imipramine: median $1,425.81 per patient per year). Although the median direct total cost per patient per year for patients who received 12 months of therapy was lower in the paroxetine group ($1,479.90, n = 8) than the imipramine group ($1,503.61, n = 8), the difference was not significant. Our cost minimization analysis revealed no significant difference in the total cost between the two groups. However, the major cost in the paroxetine group was drug cost, whereas the major cost in the imipramine group was hospitalizations. Future large prospective trials are needed to validate these findings.

Economic analysis of treating depression with nefazodone v. imipramine.

BACKGROUND: It is estimated that treating diagnosed depression costs 420 pounds million annually in England and Wales. This economic study analyses treatment of major depression with nefazodone v. imipramine. METHOD: The study updates a previously published model using data obtained from the continuation phase of a double-blind one-year placebo-controlled comparison of nefazodone with imipramine. RESULTS: Annual costs for nefazodone are lower than those for imipramine, 218 pounds compared to 254 pounds; the cost per successfully treated patient is also lower for nefazodone than for imipramine, 242 pounds v. 323 pounds. Varying the resources included in the treatment patterns still results in lower costs for nefazodone treatment. CONCLUSIONS: Based on clinical trial data for patients completing six to eight weeks of depression treatment and followed for at least one year, the model shows that the annual costs of nefazodone are lower than those for the less expensive imipramine.

Initial antidepressant choice in primary care. Effectiveness and cost of fluoxetine vs tricyclic antidepressants.

OBJECTIVE: To compare the clinical, functional, and economic outcomes of initially prescribing fluoxetine with outcomes of initially selecting imipramine or desipramine. DESIGN: Randomized controlled trial. SETTING: Primary care clinics of a Seattle, Wash, area staff-model health maintenance organization from 1992 through 1994. PATIENTS: A total of 536 adults beginning antidepressant treatment for depression. INTERVENTION: Random assignment of initial antidepressant prescription (desipramine, fluoxetine, or imipramine). Subsequent antidepressant treatment (doses, medication changes or discontinuation, specialty referral) was managed by the primary care physician. MAIN OUTCOME MEASURES: Assessments after 1, 3, and 6 months examined clinical outcomes (Hamilton Depression Rating Scale and the depression subscale of the Hopkins Symptom Checklist) and quality-of-life outcomes (Medical Outcomes Study SF-36). Medication use and health care costs were assessed using the health maintenance organization's computerized data. RESULTS: Patients assigned to receive fluoxetine reported fewer adverse effects, were more likely to continue the original medication, and were more likely to reach adequate doses than patients beginning treatment with either tricyclic drug. The fluoxetine group reported marginally better clinical outcomes after 1 month, but these differences were not statistically significant and disappeared by the 3-month assessment. Quality-of-life outcomes in the 3 groups did not differ. Total health care costs over 6 months were approximately equal for the 3 groups, with higher antidepressant costs in the fluoxetine group balanced by lower outpatient visit and inpatient costs. CONCLUSIONS: Clinical outcomes, quality-of-life outcomes, and overall treatment costs provide no clear guidance on initial selection of fluoxetine or tricyclic drugs. Thus, patients' and physicians' preferences are an appropriate basis for treatment selection.

Modelling the cost effectiveness of antidepressant treatment in primary care.

The aim of this study was to estimate the cost effectiveness of nefazodone compared with imipramine or fluoxetine in treating women with major depressive disorder. Clinical decision analysis and a Markov state-transition model were used to estimate the lifetime health outcomes and medical costs of 3 antidepressant treatments. The model, which represents ideal primary care practice, compares treatment with nefazodone to treatment with either imipramine or fluoxetine. The economic analysis was based on the healthcare system of the Canadian province of Ontario, and considered only direct medical costs. Health outcomes were expressed as quality-adjusted life years (QALYs) and costs were in 1993 Canadian dollars ($Can; $Can1 = $US0.75, September 1995). Incremental cost-utility ratios were calculated comparing the relative lifetime discounted medical costs and QALYs associated with nefazodone with those of imipramine or fluoxetine. Data for constructing the model and estimating necessary parameters were derived from the medical literature, clinical trial data, and physician judgement. Data included information on: Ontario primary care physicians' clinical management of major depression; medical resource use and costs; probabilities of recurrence of depression; suicide rates; compliance rates; and health utilities. Estimates of utilities for depression-related hypothetical health states were obtained from patients with major depression (n = 70). Medical costs and QALYs were discounted to present value using a 5% rate. Sensitivity analyses tested the assumptions of the model by varying the discount rate, depression recurrence rates, compliance rates, and the duration of the model. The base case analysis found that nefazodone treatment costs $Can1447 less per patient than imipramine treatment (discounted lifetime medical costs were $Can50,664 vs $Can52,111) and increases the number of QALYs by 0.72 (13.90 vs 13.18). Nefazodone treatment costs $Can14 less than fluoxetine treatment (estimated discounted lifetime medical costs were $Can50,664 vs $Can50,678) and produces slightly more QALYs (13.90 vs 13.79). In the sensitivity analyses, the cost-effectiveness ratios comparing nefazodone with imipramine ranged from cost saving to $Can17,326 per QALY gained. The cost-effectiveness ratios comparing nefazodone with fluoxetine ranged from cost saving to $Can7327 per QALY gained. The model was most sensitive to assumptions about treatment compliance rates and recurrence rates. The findings suggest that nefazodone may be a cost-effective treatment for major depression compared with imipramine or fluoxetine. The basic findings and conclusions do not change even after modifying model parameters within reasonable ranges.

Prediction and decision making using Bayesian hierarchical models.

This paper uses Bayesian hierarchical models to analyse multi-centre clinical trial data where the outcome variable of interest is continuous, but not normally distributed, and where censoring has occurred. The goal of such an analysis is the same as for any subgroup analysis, to provide survival estimates for specific subgroups as well as for the population and to provide estimates of the degree of heterogeneity between subgroups. An analysis of the Collaborative Study of Long-Term Maintenance Drug Therapy in Recurrent Affective Illness, a multi-centre clinical trial funded by the National Institute for Mental Health's Pharmacologic Research Branch, serves to illustrate the proposed methodology. A feature of this data set is that one treatment group was withdrawn from medication at the time of randomization. The paper contains comparison of models, one that accounts for the drug washout period through the use of a changepoint model as well as a comparison of results across several choices of prior parameter values. In addition, the paper considers sensitivity to model choice and priors in a decision theory context.

Direct cost of depression: analysis of treatment costs of paroxetine versus Imipramine in Canada.

OBJECTIVE: To assess the potential economic impact of new and more expensive antidepressants on the overall cost of treatment using cost-effectiveness analysis. METHOD: For this analysis, a computerized decision tree of clinical practice was developed to model the 12-month treatment of moderate to severe depression in Canada. To complete the model, data were obtained from physician panels, the Ontario Ministry of Health, and clinical comparative trials of paroxetine, a selective serotonin reuptake inhibitor, and imipramine, a tricyclic antidepressant. RESULTS: The overall cost of treatment when paroxetine 30 mg per day was used first-line was found to be lower than when generic imipramine was used as the initial therapy ($1697 versus $1793). The higher drug cost of paroxetine ($1.69 per day) versus imipramine ($0.05 per day) was offset by a higher rate of treatment failures with the tricyclic necessitating an alternate therapy, additional physician visits and/or hospitalization. Sensitivity analysis of key variables determined that drug price and relapse rates after discontinuation were relatively insensitive predictors of the overall cost of care. More important was the continuation rate while on different therapies. CONCLUSION: Paroxetine demonstrated a cost-benefit relative to imipramine when the continuation rate was > or = 47%. Clinical trials of paroxetine have reported continuation rates of 41% to 65%, suggesting that paroxetine is a cost-effective alternative to imipramine in the 1-year management of patients with moderate to severe depression.

Cost analysis of paroxetine versus imipramine in major depression.

A simulation decision analytical model was used to compare the annual direct medical costs of treating patients with major depression using the selective serotonin reuptake inhibitor (SSRI) paroxetine or the tricyclic antidepressant (TCA) imipramine. Medical treatment patterns were determined from focus groups of general and family practitioners and psychiatrists in Boston, Dallas and Chicago, US. Direct medical costs included the wholesale drug acquisition costs (based on a 6-month course of drug therapy), psychiatrist and/or general practitioner visits, hospital outpatient visits, hospitalisation and electroconvulsive therapy. Acute phase treatment failure rates were derived from an intention-to-treat analysis of a previously published trial of paroxetine, imipramine and placebo in patients with major depression. Maintenance phase relapse rates were obtained from a 12-month trial of paroxetine, supplemented from the medical literature. The relapse rates for the final 6 months of the year were obtained from medical literature and expert opinion. Direct medical costs were estimated from a health insurance claims database. The estimated total direct medical cost per patient was slightly lower using paroxetine ($US2348) than generic imipramine ($US2448) as first-line therapy. This result was sensitive to short term dropout rates but robust to changes in other major parameters, including hospitalisation costs and relapse rates. The financial benefit of paroxetine, despite its 15-fold higher acquisition cost compared with imipramine, is attributable to a higher rate of completion of the initial course of therapy and consequent reduced hospitalisation rates.

Pharmacoeconomic issues in the treatment of depression.

The goal of pharmacoeconomics is to define the cost and value of different treatment strategies. The cost-effectiveness analysis, one model used in the study of pharmacoeconomics, considers not only the cost of the drug itself, but also the labor costs associated with physician and pharmacy visits, and expenses for laboratory testing. Drugs that require more intensive medical surveillance, either for dose adjustments or overall management of treatment-related side effects, can escalate costs. In the case of antidepressant drugs, various cost-effectiveness analyses have shown that the total cost of disease management is similar for generic tricyclics and the more expensive selective serotonin reuptake inhibitors. This outcome is due to the higher labor costs associated with tricyclics that offset their acquisition cost advantage. The application of cost-effectiveness studies in formulary decision-making and clinical practice guidelines, will maximize the use of health care resources.

Cost utility analysis of maintenance treatment for recurrent depression.

This paper presents a cost-utility analysis of three maintenance treatments for recurrent depression: interpersonal therapy (IPT-M), imipramine drug therapy (Drug), and a combination of the two. We base our analysis on the results of the University of Pittsburgh's Controlled Clinical Trial of Maintenance Therapies for Recurrent Depression. We construct a Markovian state-transition model to incorporate clinical effectiveness into cost and quality-of-life impacts; we assign empirical values to the parameters of this model; and we then use Monte Carlo analysis to compare the relative cost effectiveness of the different maintenance treatments. For the patients who met the eligibility standards for the study, Drug maintenance treatment is cost-effective in the strongest sense of the term compared to either a placebo group or IPT-M: it both improves expected lifetime health (measured in quality-adjusted life years, or QALYs) and reduces direct medical costs. This is true even when relatively severe side effects of the drug are considered. Compared to the placebo group, IPT-M and the combination of IPT-M and Drug each improve expected lifetime health, although in neither case are expected direct medical costs reduced. Still, the cost of the resulting health improvements, under $5000/QALY, are very reasonable. A similar conclusion holds comparing Drug and IPT-M to IPT-M alone. All of the above conclusions are quite robust to sensitivity analyses.