- SSRIs as a Class
Smith and Sherrill found that cost of treatment of depressed patients in TennCare with SSRIs or with TCAs did not differ substantially.63 This retrospective 12-month analysis of claims from a U.S. Medicaid agency (TennCare) compared total costs incurred 76 patients treated with an SSRI (fluoxetine, paroxetine, or sertraline) and 76 patients treated with a TCA. All patients had a confirmed diagnosis of major depressive disorder (ICD-9 code 296.2, 296.3) or depression not elsewhere classified (ICD-9, 311). The total cost for depression-related treatment for a patient treated with an SSRI was $54,164, whereas for those treated with a TCA this cost was $55,838. Because this difference did not achieve statistical significance, the authors concluded that the cost of treating depression was identical between the two treatment groups. It is worth noting that patients covered by the Medicaid agency whose claims were used had been required to experience two treatment failures prior to initiating SSRI therapy. It is therefore possible that the SSRI patients in this study were inherently more difficult to treat than were the TCA patients.
Boyer and Feigner found that treatment of depressed patients with an SSRI led to substantially lower costs than treatment with a TCA when both short-term and maintenance costs were considered.64 Total costs were lower even though total pharmaceutical costs were much higher for the SSRI group. Their model compared direct costs over a six-month period of initial treatment with an SSRI (fluoxetine, paroxetine, or fluvoxamine) versus initial treatment with a TCA. The model assumed that 10% of patients with acute depression would require maintenance treatment, and that 10% would withdraw. The model also assumed that 65% of those who withdrew and 25% of those who were compliant would experience relapse. Based upon these assumptions, the investigators concluded that initial treatment with TCAs would be $1,374 less than with SSRIs. However, when both short-term and maintenance therapy costs were considered, SSRIs were less expensive than TCAs. Per 1000 patients, direct costs of starting treatment with an SSRI, costs of hospitalization, and costs of outpatient visits were estimated to be $47,257, $67,188, and $11,546 less, respectively, than with TCAs. Drug costs were estimated to be $31,476 per 1000 patients more for SSRIs than for TCAs.
In pharmacoeconomic studies comparing an SSRI to TCAs, fluoxetine has been the most frequently studied antidepressant. Some of these studies also have arms comparing fluoxetine to other SSRIs. Only one of these studies is a randomized prospective trial conducted in a naturalistic setting.46
Taken together, this set of studies suggests that treatment with fluoxetine may yield lower costs than treatment with TCAs -- particularly for post-initiation therapy. Most studies conclude there is no difference between the total costs for treating a patient with fluoxetine and the total costs for treating a patient with a TCA, although a few claim economic superiority for fluoxetine over TCAs. Stronger evidence exists, however, for greater compliance with fluoxetine than with TCAs.
Simon and Fishman46 conducted the only prospective, randomized economic clinical trial comparing the cost of treating depressed patients with fluoxetine first-line versus the cost of treating with desipramine or imipramine in a primary care HMO setting. In an intent-to-treat analysis of the six-month trial, the investigators observed no significant difference among drug groups for symptom reduction, Quality of Life, or total healthcare cost endpoints. Patients initiating on fluoxetine were more likely to continue the originally prescribed antidepressant and were also more likely to refill prescriptions than were patients initiating on a TCA. Furthermore, the dropout rate during the first month of treatment was higher in the TCA groups than in the fluoxetine groups. Dropouts were largely driven by unacceptable adverse effects.
Croghan et al. conducted a retrospective database study using 2-stage econometric modeling to estimate healthcare costs of primary care patients receiving one year of initial therapy with fluoxetine (n=799), trazadone (n=89), or one of two classes of TCAs (amitriptyline/imipramine (n=104) or desipramine/nortriptyline (n=250)). Overall, the results suggest that fluoxetine is at least as cost-effective as trazadone or the TCAs.65 Total direct healthcare costs per patient (including hospitalizations, labs, radiology, physician visits, other outpatient services and drugs costs) were no different between the four treatment groups, although total mental healthcare costs were less for the trazadone cohort than for fluoxetine or the TCAs. However, the percentage of patients continuing medication continuously for at least six months was substantially greater with fluoxetine than with trazadone and the TCAs. Likewise, the percentage of patients switching from initial therapy was lowest with fluoxetine. Although the study is limited by its homogenous population, it did control for observed and unobserved characteristics in the econometric modeling, adding credence to the results.
Sclar et al. conducted a retrospective database study coupled with a multivariate regression analysis to compare the total one-year direct medical costs accumulated by patients prescribed either fluoxetine or one of three TCAs (amitriptyline, nortriptyline, desipramine).66 The researchers concluded that use of a TCA was associated with greater per patient post-initiation total healthcare costs ($366) compared to treatment with fluoxetine. The drivers of this increased cost included increases in physician visits, hospital visits, and laboratory costs. Although this study included no direct measure of treatment outcomes, it did show that patients were more likely to continue treatment on fluoxetine than they were on a TCA. The 701 patients in the study were representative of private sector depressed patients. The average age was over 40 and approximately 75% were women. This study, however, did not control for unobserved differences across patients.
In a later study, Sclar, et al. compared claims of patients treated with fluoxetine (n=180) to those treated with amitriptyline (n=211) and nortriptyline (n=159).67 This study tracked costs over a 3.5-year period immediately subsequent to the launch of fluoxetine in the U.S. (1988-1991). The authors concluded that patients treated with fluoxetine had nearly 26% less depression-related health care expenditures than those treated with amitriptyline and over 28% less than those treated with nortriptyline. Again, no direct measure of effectiveness was included. However, patients initiating on amitriptyline were more than three times as likely to require a change in antidepressant pharmacotherapy, while patients initially prescribed nortriptyline were nearly four times more likely to change medication relative to patients initially prescribed fluoxetine. Similarly, 64% of patients initiating on fluoxetine received at least 180 days supply, whereas only 52% of patients on amitriptyline and 48% of patients on nortriptyline received at least this amount. The patients in this study were similar to those in the previous analysis.
In the largest retrospective study conducted to date, Simon et al. compared overall mean total six-month health service costs for patients treated with fluoxetine (n=2,180) versus those for patients treated with imipramine (n=1,721) or desipramine (n=1,268).46 This study, based on HMO medical claims, concluded that although treatment with fluoxetine increased total costs, the increase was not significant statistically. This study included no direct measure of treatment effectiveness.
In a retrospective database study using 2-stage econometric modeling, Hylan et al. (1998) compared the costs of one year of treatment with fluoxetine (n=1,251) with those of treatment with TCAs (n=698).68An intent-to-treat, multivariate analysis showed that patients who initiated therapy with fluoxetine had significantly lower total direct health care costs than patients initiating with TCAs. Treatment costs included costs of hospitalizations, ER, lab and physician visits, other outpatient services, and drugs. The patient claims included in this study were restricted to those for patients with a new episode of depression who were receiving initial therapy, selected from U.S. fee-for-service private insurance claims (MarketScan 1990 to 1994). These investigators controlled for observed and unobserved differences between treatment groups more explicitly than in the previous study by using 2-stage econometric modeling.
Obenchain et al. (1997) conducted a retrospective bootstrap analysis to compare total annual charges incurred by patients taking fluoxetine, TCAs or trazadone for a new episode of depression.69 On average, treatment with fluoxetine (n=799), relative to treatment with trazadone or TCAs (n=443), resulted in a negative incremental cost-effectiveness ratio (ICER). Specifically, fluoxetine realized a reduction in annual charges by $16.48 (0.2%) per patient for each percentage increase in effectiveness. However, the 95% upper confidence limit on the ICER was positive, implying that fluoxetine may actually increase annual per patient charges. The authors stated that any such increase was no more than $130 per patient (1.8%) for each percentage increase in the proportion of patients remaining stable on initial pharmacotherapy for at least 6 months.
Data for this study were collected from the MarketScan database (1990-92) for a period of 12 months proceeding the index event of a diagnosis for depression and a prescription for antidepressant medication. A new episode was identified as a treatment-free period of four months prior to the index event. Patients participated in either fee-for-service or managed care health insurance plans for employed individuals and families. The principal measure of effectiveness was the proportion of patients remaining stable on the antidepressant for at least six consecutive months.
While this study may provide a more reliable and widely applicable approach to statistical analyses of the cost-effectiveness of competing treatments, it has several limitations. For example, sufficient data were not available at the time of the study to make comparisons among SSRIs or to evaluate trazadone and TCAs in separate cohorts. Furthermore, the study relied on effectiveness measures from medical claims data, which do not provide detailed clinical outcomes, such as symptom scores.
Several decision-analytic models have been developed which compare treatment with paroxetine to that with a TCA, namely imipramine. The models estimate that direct medical costs incurred with first-line treatment with paroxetine are no more--if not less--than costs for first-line treatment with imipramine. Several of these studies demonstrate that higher continuation rates (and lower dropout rates) of paroxetine contribute to its superior cost-effectiveness over TCAs. The models described here use results from randomized clinical trials to estimate treatment costs in the clinical practice setting. As a result, external validity of the studies is questionable. Comparative studies based in a naturalistic setting would be more useful in assessing the cost-effectiveness of paroxetine compared to TCAs.
In 1995, Bentkover and Feighner designed a clinical decision analytic model to estimate the annual direct medical costs of treatment with paroxetine or imipramine. 70 Efficacy and effectiveness probabilities were taken from a six-week clinical trial in 717 patients with major depression. The authors concluded that first-line treatment with paroxetine costs no more--if not less--than treatment with imipramine, due to reduced rates of relapse and fewer hospitalizations. Average annual direct medical costs were estimated to be $100 less for paroxetine than imipramine ($2,348 and $2,448, respectively). Sensitivity analysis reveals that the model is robust to changes in major parameters including hospitalization costs and relapse rates. However, it is sensitive to short-term dropout rates (total direct medical costs remain lower for paroxetine than for imipramine when the continuation rate is greater than 47% for paroxetine and constant at 46% for imipramine). It should be noted that this model potentially underestimates the total costs of treatment because it excludes indirect costs and treatment costs due to adverse events.
The clinical trial data used in the above model were used to power two other decision-analytic models that estimate the costs of successful versus failed therapy with paroxetine and imipramine in the UK 71 and Canada.72 As with the Bentkover study, the models estimated treatment patterns from focus groups and obtained costs from health database claims (private and public for the UK and Canada, respectively). In the UK model, when the costs of successful treatment and dropouts were considered separately, successful treatment with paroxetine was associated with lower costs than with imipramine, indicating that poorer tolerance and higher dropout rate increased treatment costs. However, no difference in total costs between the two medications was found. One limitation of the UK study is that it assumes medication discontinuation rates differ by 20% between paroxetine and imipramine, a value greater than that used in other studies. The Canadian model demonstrated cost savings of $96 CAN per patient for the paroxetine group compared to imipramine.
In all three models, sensitivity analysis revealed that continuation rates and dropout rates, rather than drug costs and relapse rates, are the most important predictors of the overall costs of care. For example, in the Canadian model, Paroxetine was cost effective only if the daily costs of medication were less than $4 CAN and the continuation rate was greater than 47%.72Although the UK and Canadian models support the findings of the U.S. model, they are not necessarily generalizable to the US.
Studies comparing treatment with sertraline to that with TCAs are limited in methodology. Both of the studies reviewed below suggest that treatment with sertraline results in lower costs than treatment with TCAs. One study also asserts that sertraline is also more effective than TCAs. Taken together, it is reasonable to conclude that treatment with sertraline is more cost-effective than treatment with TCAs.
Skaer et al. conducted a retrospective database analysis comparing direct health service expenditures for treatment with sertraline to that with TCAs (amitriptyline, desipramine and nortriptyline) in a U.S. managed care setting.73 Multivariate regression analysis revealed that sertraline use resulted in significantly lower direct medical costs than TCAs for one year of treatment following initiation of therapy ($168 per patient, or 21% less than TCAs). Costs associated with depression-related physician visits and general and psychiatric hospitalizations were significantly lower for sertraline than for TCAs, while prescriptions costs were significantly higher and psychiatric costs were similar for sertraline and TCAs. The mean number of prescriptions (for a 30-day supply) was higher for the sertraline group than for TCA recipients (7.5 vs. 4.8) suggesting a more favorable tolerability profile with sertraline compared to TCAs. The study included 823 patients diagnosed with depression who were taking the study medications and for whom 18 months of health service data were available (6 months prior to and 12 months after receiving the initial prescription). Authors noted that this study is limited by its retrospective design, a lack of indirect cost data and the fact that HMO patients tend to be younger than the general population of patients with depression.
Forder et al. used a retrospective quasi-experimental design to compare treatment costs and cost-effectiveness in patients who received sertraline (n=190) or TCAs (n=188) during a large clinical trial in the UK.74 This model showed no significant differences in utilization of generic healthcare and social care services between the sertraline and TCA groups. However, mean costs associated with the use of inpatient and outpatient hospital care and community psychiatric nursing care were significantly lower in the sertraline group in both intent-to-treat and completer analyses. Overall mean costs were significantly lower for the sertraline group than for the TCA group as determined using some statistical tests, but not others. A significantly higher proportion of patients in both the intent-to-treat and completer analysis were rated by GPs as "somewhat improved" or "very much improved" for sertraline than for the TCA group. Resulting cost-effectiveness ratios favored sertraline for all definitions of costs and outcomes except for the acquisition costs of drugs alone.
This study has been criticized for failing to include costs associated with work absence and/or reduced productivity into indirect costs and for the lack of an incremental cost-effectiveness analysis. In addition, opportunity costs, which are not easily validated, accounted for a rather high percentage of total costs. However, no significant differences were found between opportunity costs in the two groups.
Einarson et al. (1995) conducted a meta-analysis of randomized control trials to power a decision analytic model comparing the cost-effectiveness of treatment with venlafaxine to that of treatment with TCAs and trazadone.75 Total inpatient depression-related medical costs were greater for patients treated with TCAs ($12,513), than for patients treated with venlafaxine ($12,201), or trazodone ($11,492). Total outpatient depression-related costs were again greatest for TCAs ($3,061), followed by venlafaxine ($2,401) and trazadone ($1,896). Medical care costs included costs of hospitalization, all physician visits, lab tests, radiology and medications. Venlafaxine patients experienced greater improvements in diagnostic test scores (62% reduction in HAM-D scores) than did patients treated with either TCAs (51%) or trazadone (49%).
Cost-effectiveness ratios that calculated costs per symptom-free day in the inpatient setting were lowest for the venlafaxine group ($93), followed by trazadone ($108), and TCAs ($124). In the outpatient setting, trazadone was the most cost-effective agent at $20 per symptom free day, followed by venlafaxine ($23), and TCAs ($29). Although meta-analysis of randomized clinical trials is a powerful tool to obtain good probability estimates, the external validity of the RCT is questionable, especially when estimating outpatient costs.
Using a similar framework as the U.S. model, Einarson et al. evaluated the cost-effectiveness of venlafaxine and TCAs from the perspective of the Canadian healthcare system.76 In this analysis, venlafaxine was more cost-effective in terms of expected costs per success and per symptom free day (SFD) than TCAs both in the inpatient and outpatient setting. Venlafaxine was also dominant for all incremental pharmacoeconomic analyses. This model was robust for outpatients, but somewhat sensitive to changes in parameters for inpatients. In the worst case inpatient scenario, TCAs were superior to venlafaxine; in the worst case outpatient scenario, venlafaxine remained more cost-effective than TCAs.
Griffiths et al. (1999) conducted a retrospective database analysis of nine U.S. managed healthcare plans to compare treatment with venlafaxine to treatment with TCAs77. Patients were included who had switched from an SSRI after at least two consecutive months of therapy followed by at least two consecutive months of a TCA (n=172) or venlafaxine (n=188). Total direct healthcare costs were not significantly different between the two treatment groups. Further analysis by prescriber specialty and diagnosis code showed cost differences between the groups. While mean depression-coded costs were significantly greater for the venlafaxine group than for the TCA group ($1,948 vs. $1,396), mean non-depression coded costs were significantly lower. When psychiatrists were the initial prescribers of second-line therapy, significant cost differences were observed, but not with primary care physicians. In addition, patients receiving TCAs were more likely to visit an outpatient medical facility and a medical specialist other than a psychiatrist and were also more likely to receive anti-anxiety medications. The study suggests that the greater costs of pharmacotherapy with venlafaxine may be offset by a reduction in costs due to other medical services. The model is strengthened by considering observed and unobserved differences across patients. Limitations of this study include the lack of detailed clinical data on the severity of depression or the patients' complete history of antidepressant therapy. In addition, submitted charges were used as a proxy for costs. Overall the model suggests that venlafaxine is as cost-effective as TCAs for second-line therapy.
The evidence on venlafaxine suggests that treatment with venlafaxine is more cost-effective than treatment with either TCAs or trazadone. Comparison of cost-effectiveness relative to SSRIs will be discussed later in the text.
Four models compare nefazodone to TCAs. Two of these include fluoxetine in the comparison and are discussed later in this section. Although the studies discussed below differ on the relative costs of treatment with nefazodone, they do suggest that treatment with nefazodone is more cost-effective than treatment with imipramine.
Using a Markov state-transition decision analytic model, Revicki et al. compared the lifetime costs and utility outcomes for three groups in a typical US managed care setting:78
- Treatment with nefazodone;
- Treatment with imipramine; and
- Step care with imipramine followed by nefazodone.
Results of the base case analysis estimated lifetime medical costs (discounted at 5%) to be lower for imipramine and step care than for nefazodone ($15,348, $16,061, and $16,669, respectively). However, QALYs were greater for nefazodone treatment than for imipramine or the step approach (14.64, 14.32, and 14.40, respectively). The resulting cost-effectiveness ratio comparing nefazodone with imipramine was $4,065/QALY. This cost falls within the suggested criteria to be adopted into the Canadian healthcare system and may be equally, if not more acceptable in the U.S.
The model was robust to adjustments in key parameters such as compliance rates, discount rates and maintenance treatment probabilities. Sensitivity analyses demonstrated that cost-effectiveness ratios for nefazodone compared with imipramine ranged from $2,572 to $5,841 per QALY gained. Comparing nefazodone to the step approach, cost-effectiveness ratios ranged from $1,436 to $6,764 per QALY gained. Limitations of the study include the omission of indirect costs, the assumption that the target patient population was 30-year old women, and the general limitations of economic models which rely on clinical trial data and expert opinion. The study is also limited in its applicability to the managed care setting. Overall, the study demonstrates that nefazodone is cost-effective compared to imipramine or step care with imipramine and nefazodone.
Unlike the U.S. model, an earlier Canadian model estimates medical costs for nefazodone to be lower than those for imipramine. These differences are explained by differences in model parameters such as hospitalization, compliance rates and depression recurrence rates.78