Predictors of a medical-offset effect among patients receiving antidepressant therapy.

OBJECTIVE: Characteristics of patients receiving antidepressant therapy were examined to identify factors that may be associated with a medical-offset effect. METHOD: In a retrospective study, the authors analyzed claims data from a large health insurer in New England. The study subjects included 1,661 persons initiating treatment for depression with selective serotonin reuptake inhibitors or tricyclic antidepressants between July 1991 and June 1993. RESULTS: Patients with anxiety disorders, coronary heart disease, cancer, and chronic fatigue syndrome and those remaining on their initial regimens of antidepressant therapy for at least 6 months were more likely to experience significant reductions in the costs of medical care services. The number of visits to mental health providers had no effect on the costs of medical services. CONCLUSIONS: Specific comorbid conditions and sustained use of antidepressant drugs may be associated with a medical-offset effect for patients receiving treatment for depression.

Randomized database studies: a new method to assess drugs' effectiveness?

The need to evaluate drugs' effects in real clinical practice is increasingly important. Randomized clinical trials (RCTs) and database analyses (DBA) are the two main methods to assess treatments effectiveness. RCTs remain the "gold standard" for comparing alternative treatments. However, they are conducted under strict, protocol-driven conditions that may limit their generalizability. Advantages of new high quality clinical databases, on the other hand, include the simple and economic access to large number and range of cases, and the ability to capture all aspects of actual medical practice. The main potential limitation of DBA is the potential for comparison bias due to the lack of randomization. Despite the efforts to design naturalistic trials and to use sophisticated statistical techniques to minimize selection bias, the inherent limitations of both methods (problems of external and internal validity, respectively) have not been completely solved. Thus, the actual challenge is the development of some new strategy capable of generating results with an acceptable balance between internal and external validity. As randomization is essential to minimize comparison bias, we point out the possibility to include randomization modules in computer-based patient records. The theoretical foundation of these "randomized database studies" is the simultaneous use of both experimental and observational methods in the assessment of drugs' effectiveness. The progressive standardization of clinical practice and the development and adoption of improved computer-based patient records could facilitate the use of this new research strategy.

A review of methodologies for assessing drug effectiveness and a new proposal: randomized database studies.

The need to evaluate the effects of health technologies in clinical practice is increasingly important. In this article, we review the advantages and limitations of naturalistic randomized clinical trials (RCTs) and database analyses, the two primary methods for evaluating treatment effectiveness. Also, we comment on a newer research strategy, cross-design synthesis, which proposes the complementary use of both experimental RCTs and observational database methodologies to avoid the main weaknesses of each: respectively, the lack of external and internal validity. Finally, we propose a new strategy--randomized database studies--capable of generating results with an acceptable balance between internal and external validity. This strategy consists of the simultaneous use of both experimental and observational tools in the assessment of drugs' effectiveness. Randomization is essential to minimize comparison bias, and one possibility for such studies is that randomization modules could be included in computer-based patient records. Although we identify some of the difficulties in implementing the process, the progressive standardization of clinical practice and the development and widespread adoption of improved computer-based patient records could facilitate the use of randomized database studies as a new method of research.

Prescribing of selective serotonin reuptake inhibitors, anxiolytics, and sedative-hypnotics by general practitioners in The Netherlands: a multivariate analysis.

A study of the prescribing of anxiolytics and sedative-hypnotics and the occurrence of anxiety or sleep disorders before and after the initiation of selective serotonin reuptake inhibitor (SSRI) therapy may provide insight into differences in individual SSRIs. The purpose of our study was to evaluate whether and in what way the likelihood of being prescribed an anxiolytic or sedative-hypnotic or receiving a diagnosis of an anxiety or sleep disorder differed in patients prescribed either fluoxetine or paroxetine by a general practitioner (GP) in the Netherlands, where these two agents are the most commonly prescribed SSRIs. Episodes of SSRI treatment were constructed from a recently available GP database in the Netherlands. Logistic regression analysis was used to determine whether, after controlling for other observable factors, the receipt of paroxetine or fluoxetine was a statistically significant determinant for receipt of an anxiolytic or sedative-hypnotic or a diagnosis of an anxiety or sleep disorder. We found that patients who were prescribed fluoxetine as their index drug were less likely to receive a concomitant sedative-hypnotic on their index date compared with patients receiving paroxetine. After controlling for other observable factors, such as use of anxiolytics and sedative-hypnotics before SSRI therapy or on the index date or the existence of comorbid anxiety or sleep disorders, patients starting fluoxetine therapy were no more likely than patients starting paroxetine therapy to receive an anxiolytic or sedative-hypnotic or a diagnosis of an anxiety or sleep disorder during the 60-day post period. The likelihood of a patient's being diagnosed with or receiving a prescription for an anxiety or sleep disorder does not appear to be a differentiating factor between the prescribing of fluoxetine or paroxetine by GPs in the Netherlands.

Economic consequences of selective serotonin reuptake inhibitor use with drugs also metabolized by the cytochrome P-450 system.

Administration of selective serotonin reuptake inhibitors (SSRIs) may increase plasma concentrations of concomitant medications that are also metabolized by the cytochrome P-450 system (CYP-450), in particular by the 2D6 and 3A4 isoenzymes. This may lead to side effects or other clinical events that might be expected to incur higher health-care expenditures. The purpose of this study was to assess whether there was a difference in expenditures during the first 90 days of SSRI therapy with paroxetine or sertraline versus fluoxetine in patients who were also receiving a stable dosage of a nonpsychiatric drug also metabolized by the CYP-450 2D6 or 3A4 isoenzyme systems. A sample of 2445 patients who initiated therapy with an SSRI while receiving a stable dosage of a nonpsychiatric drug was obtained from a private insurance claims database. Multivariate regression techniques were used to estimate total health-care expenditures in the first 90 days after receiving a prescription for an SSRI. After adjusting for nonrandom SSRI prescription patterns and controlling for observable and unobservable characteristics that might correlate with SSRI selection, total health-care expenditures were 95% higher for patients initiating SSRI therapy with sertraline or paroxetine compared with fluoxetine. Results suggest that there are cost differences between SSRIs during concomitant therapy with drugs also metabolized by the CYP-450 system. To determine whether there are additional differences in expenditures across SSRIs, future research should focus on (1) simultaneous initiation of SSRI therapy and a nonpsychiatric drug also metabolized by the CYP-450 enzyme system, and (2) addition of nonpsychiatric drug therapy to stable SSRI therapy. Relationships between additional expenditures, drug interactions, and clinical outcomes should also be assessed directly using medical records and patient interview data that are not available in claims-based files.

SSRI antidepressant use patterns and their relation to clinical global impression scores: a naturalistic study.

BACKGROUND: A cascade of events follows initial antidepressant selection which includes the subsequent antidepressant use pattern, resultant clinical outcomes, and associated health care expenditures. PURPOSE: The purpose of this study using data from a clinical practice setting was to test whether the pattern of antidepressant use was correlated with patients' treatment response as measured by the score on the Clinical Global Impression-Improvement scale. DATA AND METHODS: A retrospective dataset of patients who initiated therapy on fluoxetine, fluvoxamine, paroxetine, or sertraline in a primary care setting in Spain was used. A Cox proportional hazard analysis was used to predict the likelihood of treatment response based upon the pattern of initial antidepressant use, while minimizing the influence of other factors. RESULTS: After controlling for other observed baseline characteristics including initial disease severity, (a) patients who remained on their initial antidepressant therapy for at least 2 months with no switching, augmentation, or upward dose titration were 1.63 times more likely to experience a treatment response than patients who had an adjustment to therapy; and (b) patients who initiated therapy on sertraline were 0.46 times as likely to experience a treatment response as patients who initiated therapy on the most common study antidepressant, fluoxetine. CONCLUSION: The pattern of antidepressant use is an important determinant of treatment response among patients initiating therapy on the newer antidepressants in clinical practice.

Tricyclic antidepressant and selective serotonin reuptake inhibitors antidepressant selection and health care costs in the naturalistic setting: a multivariate analysis.

BACKGROUND: Providers and payers have an interest in the total health care costs following the initiation of antidepressant treatment in the real world of clinical practice. Analyses of these costs can help evaluate the economic consequences of patient management decisions associated with initial antidepressant selection. OBJECTIVE: The purpose of this study was to assess the 1-year total direct health care costs for patients initiating therapy with one of the available tricyclic antidepressants (TCAs) or one of the three most often prescribed selective serotonin reuptake inhibitors (SSRIs) - paroxetine, sertraline, or fluoxetine. METHOD: A two-stage multivariate econometric model and data from fee-for-service private insurance claims between 1990 and 1994 were used to estimate the total direct health care costs following initial antidepressant drug selection for 2693 patients with a 'new' episode of antidepressant treatment. After controlling for both observed and unobserved characteristics, the 1-year total direct health care costs were found to be (1) statistically significantly lower for patients initiating therapy on fluoxetine than for patients initiating therapy on a TCA; (2) statistically significantly lower for patients who initiated therapy on fluoxetine than for patients initiating therapy on sertraline. CONCLUSIONS: Broadly considered, the findings in this study suggest that total direct health care costs differ across initial antidepressant selection after controlling for both observed and unobserved characteristics.

Recovery from depression, work productivity, and health care costs among primary care patients.

We describe a secondary analysis of data from a randomized trial conducted at seven primary care clinics of a Seattle area HMO. Adults with major depression (n=290) beginning antidepressant treatment completed structured interviews at baseline, 1, 3, 6, 9, 12, 18, and 24 months. Interviews examined clinical outcomes (Hamilton Depression Rating Scale and depression module of the Structured Clinical Interview for DSM-IIIR), employment status, and work days missed due to illness. Medical comorbidity was assessed using computerized pharmacy data, and medical costs were assessed using the HMO's computerized accounting data. Using data from the 12-month assessment, patients were classified as remitted (41%), improved but not remitted (47%), and persistently depressed (12%). After adjustment for depression severity and medical comorbidity at baseline, patients with greater clinical improvement were more likely to maintain paid employment (P=.007) and reported fewer days missed from work due to illness (P<.001). Patients with better 12-month clinical outcomes had marginally lower health care costs during the second year of follow-up (P=.06). We conclude that recovery from depression is associated with significant reductions in work disability and possible reductions in health care costs. Although observational data cannot definitively prove any causal relationships, these longitudinal results strengthen previous findings regarding the economic burden of depression on employers and health insurers.

Longitudinal patterns of antidepressant prescribing in primary care in the UK: comparison with treatment guidelines.

The objective of this study was to determine whether patients beginning therapy on the most common tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) differed in their likelihood of having antidepressant treatment that was consistent with recommended treatment guidelines in the UK. An analytical file constructed from a large general practitioner medical records database (DIN-LINK) from the UK for the years 1992-97 was constructed. A total of 16,204 patients with a new episode of antidepressant therapy who initiated therapy on one of the most often prescribed TCAs (amitriptyline, dothiepin, imipramine and lofepramine) or SSRIs (fluoxetine, paroxetine and sertraline) were analysed. A dichotomous measure was defined to indicate whether subjects were prescribed at least 120 days of antidepressant therapy at an adequate average daily dose within the first 6 months after initiation of therapy. Only 6.0% of patients initiating therapy on aTCA and 32.9% of patients initiating therapy on a SSRI were prescribed antidepressant treatment that was consistent with treatment guidelines. After controlling for observable characteristics, patients who initiated therapy on a SSRI were much more likely (odds ratio=7.473, p<0.001) to have a prescribed average daily dose and duration consistent with recommended treatment guidelines within the first 6 months of initiating therapy than were patients who initiated therapy on a TCA. These findings suggest that initial antidepressant selection is an important determinant of whether the subsequent course of treatment is consistent with current national guidelines for the treatment of depression in the UK.

Antidepressant selection and use and healthcare expenditures. An empirical approach.

The purpose of this study was to evaluate whether 1-year total healthcare expenditures differed between patients who initiated therapy on a tricyclic antidepressant (TCA) or a selective serotonin reuptake inhibitor (SSRI) after controlling for initial antidepressant selection and antidepressant use pattern. A retrospective claims database covering a privately insured population in the US was used. Patients who initiated therapy in the outpatient setting (primary care or psychiatrist) were considered. Two-stage sample selection models were estimated that included controls for initial antidepressant selection and use pattern. The analyses indicated that: (i) self-selection due to initial antidepressant selection was a statistically significant determinant of expenditures for patients who initiated therapy on a TCA but not an SSRI; (ii) after controlling for initial antidepressant selection, antidepressant use pattern was a statistically significant and positive determinant of expenditures for both TCA and SSRI patients; and (iii) after controlling for initial antidepressant selection and use pattern, 1-year total direct healthcare expenditures were significantly lower for patients who initiated therapy on an SSRI than for patients who initiated therapy on a TCA.

Initial treatment choice in depression: impact on medical expenditures.

OBJECTIVE: The purpose of this study was to examine the economic outcomes associated with initial treatment choice following a diagnosis of depression. METHODS: Insurance claims data were used to classify patients into one of 4 treatment cohorts: no therapy, psychotherapy, drug therapy and combination therapy. Potential sample selection bias was accounted for by using a 2-stage econometric estimation procedure where initial treatment choice was estimated using a multinomial logistic regression model in the first stage, and total and mental healthcare costs were estimated in ordinary least squares regression models in the second stage. Log predicted costs from the second stage were compared to determine the relative costs associated with each cohort. RESULTS: Significant differences (p < 0.008) in total costs were found between the combination therapy (log predicted cost = 9.526) and psychotherapy cohorts (log predicted cost = 8.120) in the analysis that included all observations (n = 9110). In the analysis that included patients who initiated therapy with a non-mental health provider (n = 2673), the drug therapy cohort (log predicted cost = 8.238) was found to be significantly more costly as compared to the no therapy cohort (log predicted cost = 7.788). CONCLUSIONS: These results indicate that after controlling for both observed and unobserved factors, total healthcare costs may be higher in patients who initiate therapy with drug therapy and combination therapy as opposed to no therapy or psychotherapy. In addition, the finding that patients initially receiving psychotherapy alone tend to have higher mental healthcare costs but lower total healthcare costs than other patients may indicate that psychotherapy has an impact on comorbid illness and may subsequently reduce total healthcare costs.

Gaps in antidepressant prescribing in primary care in the United Kingdom.

An important determinant for achieving efficacy results in clinical practice comparable to those demonstrated in clinical trials is whether or not patients take their medication as prescribed. Recent studies have shown that 30-60% of patients do not take their medications as prescribed. Gaps between antidepressant prescriptions raise questions about the possibility of periods of nonadherence to medication in clinical practice. The purpose of conducting this study was to assess the likelihood of experiencing a gap of > 15 days between antidepressant prescriptions for patients with a depression-related diagnosis and to assess whether this likelihood varied across different antidepressants with tricyclic antidepressants and selective serotonin reuptake inhibitors. Episodes of antidepressant treatment were constructed using the Doctors' Independent Network general practitioner medical records database. For all antidepressant agents considered, approximately 50% of patients had a gap between prescriptions and 15-25% of patients had a gap of > 15 days between prescriptions. A significant proportion of patients in a general practitioner setting in the UK have gaps recorded of > 15 days between antidepressant prescriptions. Gaps between prescriptions raise the question of whether patients may be at risk for clinical consequences associated with nonadherence to therapy, such as reduced effectiveness or treatment interruption symptomatology.

Outpatient antidepressant utilization in a Dutch sick fund.

OBJECTIVE: To identify quality improvement opportunities in the management of depression by evaluating patterns of antidepressant use and concurrent use of anxiolytics or sedative/hypnotics among patients who initiated therapy with amitriptyline, fluoxetine, fluvoxamine, or paroxetine. DESIGN: A longitudinal, retrospective study using electronic prescription data from a Dutch sick fund, ZAO Zorgverzekeringen. PATIENTS AND METHODS: The study patients (n = 2,554) initiated therapy between October 1, 1994 and December 31, 1995. Follow-up periods were 6 months (antidepressant use) and 60 days (concurrent anxiolytic and sedative/hypnotic use). RESULTS: The three key findings were as follows: (1) the majority of patients received less than 4 months of therapy (more common for patients receiving amitriptyline); (2) the average daily doses for initial prescriptions for all four study drugs were below the recommended therapeutic minimums for depression (overall and final amitriptyline doses also were consistently low); and (3) the incidence of concurrent anxiolytic and sedative/hypnotic use during days 2-60 after antidepressant therapy initiation was 18.2%. CONCLUSION: The study suggests that patients in this Dutch sick fund were not likely to receive either adequate antidepressant doses or adequate durations of therapy relative to Dutch guidelines for the treatment of depression. These findings are consistent with findings in other Dutch, European, and US studies and may present opportunities for quality improvement.

Antidepressant use in clinical practice: efficacy v. effectiveness.

BACKGROUND: Although the efficacy of antidepressants has been demonstrated in randomised, controlled clinical trials, it is how an antidepressant is used in clinical practice that determines its clinical effectiveness, or real-world efficacy. AIMS: To explore the frequency with which antidepressants are used at adequate dose and duration to obtain remission of symptoms and prevent relapse in clinical practice and discuss potential implications for clinical outcomes. METHOD: Studies of antidepressant prescribing were reviewed and comparisons made between antidepressant classes and individual compounds within those classes. RESULTS: Naturalistic studies show that patients who begin therapy on tricyclic antidepressants often receive sub-therapeutic doses for inadequate duration; conversely, patients who begin therapy on selective serotonin reuptake inhibitors more often receive an adequate dose of therapy for a longer duration. CONCLUSIONS; How antidepressants are used in clinical practice can determine the clinical outcomes that are achieved. Antidepressants that are more forgiving of sub-optimal prescribing and use patterns by providers and patients, respectively, may help to improve real-world efficacy.

Health economic evaluations of antidepressants: a review.

In an era of constrained health care financing, clinicians are increasingly faced with considering the economic consequences in addition to the clinical outcomes associated with initiating a patient on antidepressant therapy. This has increased the demand for health economic studies comparing antidepressant use and associated health care expenditures in clinical practice. These health economics studies have used methods ranging from clinical trials to other types of analyses including prospective naturalistic trials or retrospective studies which may be less familiar to clinicians. Prospective and retrospective health economics studies performed in clinical practice complement the experience gained from clinical trials in assessing antidepressant use and economic outcomes in light of patient and provider behavior within the usual care environment of a complex health care system. Broadly considered, health economic studies of antidepressants have consistently found differences in clinical practice between the tricyclic antidepressants (TCAs) and the selective serotonin reuptake inhibitors (SSRIs) as well as among the SSRIs. These differences relate to the pattern and duration of antidepressant use as well as total direct health care expenditures. Future health economic research studies in clinical practice should focus on the economic consequences of long-term antidepressant use as well as the impact of antidepressant use on indirect costs such as productivity and absenteeism.

The impact of premenstrual symptomatology on functioning and treatment-seeking behavior: experience from the United States, United Kingdom, and France.

Up to 80% of women experience mood and physical symptoms associated with the menstrual cycle. This study assessed the impact of premenstrual symptomatology on functioning and treatment-seeking behavior for a community-based sample of women in the United States, United Kingdom, and France. A sample of 1045 menstruating women (aged 18-49) completed a telephone questionnaire that measured, at a point in time, premenstrual symptoms, impact on functioning, and treatment-seeking behavior. Results were generally consistent across the three countries. Irritability/anger, fatigue, and physical swelling/bloating, or weight gain were among the most commonly reported symptoms (approximately 80%). Functional impairment tended to be highest at home, followed by social, school, and occupational situations. Among working women, over 50% reported at least somewhat affected occupational functioning. Of women who ever missed work because of symptoms, 1-7 days were missed in the past year. Almost three fourths of the women had never sought treatment, and symptom severity was an important factor in treatment-seeking behavior. Treatment with selective serotonin reuptake inhibitors (SSRIs), which have demonstrated efficacy in this population, occurred with surprisingly low frequency. The functional impairment of premenstrual symptomatology (home, social, and occupational) and treatment-seeking behavior is consistent across countries. Women who experience more impairment are more likely to have severe symptoms and are more likely to believe, relative to women with less severe symptoms, that no treatment is available. This suggests significant unmet medical need in this more severely affected population. Improved clinical identification of these women and increasing awareness of the efficacy of SSRIs in treating premenstrual symptomatology may be of benefit.

A framework for drug utilization evaluation in depression: insights from outcomes research.

BACKGROUND: Drug utilization evaluation (DUE) offers the prospect of improving the quality of care in depression by focusing on drug-related problems (DRPs). Outcomes research in depression can provide a basis on which to address difficulties in implementing DUE programs in the outpatient environment of managed care. OBJECTIVE: The purpose of this paper is to facilitate the development of a drug utilization evaluation program for depressed patients receiving care in an outpatient environment. METHODS: The literature was reviewed in the area of depression treatment, drug-related problems, and current outcomes research. This information was synthesized into a framework with potential DUE criteria. CONCLUSION: The quality of care for depression can be improved if these efforts are focused on solving DRPs. Outcomes research findings may be used as the basis for developing DUE criteria and as a first step in selecting and targeting interventions.

[Pattern of usage of new antidepressants in clinical practice]. / Patrón de uso de los nuevos antidepresivos en la práctica clínica.

INTRODUCTION: Data from naturalistic studies have reported differences in the clinical use of antidepressants referring to the need for adjusting doses, treatment duration, tolerability and use of concomitant medication. These differences could be considered as an indicator of the effectiveness of antidepressants in clinical practice settings. OBJECTIVES: It is a naturalistic, retrospective, observational study which objective is to evaluate and compare the pattern of antidepressant use (fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine) and to establish if there is a relation between the different pattern of use and the effectiveness of them. DATA AND METHODS: A retrospective dataset of patients who initiated therapy on fluoxetine, fluvoxamine, paroxetine, sertraline, or venlafaxine with a follow-up period of 6 months was used. Information about clinical characteristics of patients and antidepressant pattern of use were collected. Pattern of antidepressant use were defined as: "initial doses", "upward dose titration", "augmentation strategy", "switching" and "early interruption of treatment". The efficacy of the therapy was assessed by the CGI-improvement. RESULTS: Fluoxetine was the antidepressant more associated with a statistical significance (p = 0.001) to an stable pattern of use (initial doses without upward dose titration, switching or augmentation). After controlling for other observed baseline characteristics, patients who remained on their initial antidepressant therapy, with a stable pattern of use were 1.61 times more likely than patients who had an adjustment to therapy to experience a treatment response. Patients who initiated treatment with sertraline or venlafaxine were 2.155 and 4.831 times less likely, respectively, to experience a response relative to patients who initiated therapy on fluoxetine. CONCLUSIONS: The need to upward dose titration, switching or augmentation in the treatment could be indicated a worse therapeutic control of the symptoms. Patients treated with fluoxetine are in a stable pattern of use more likely than patients in the other antidepressants, this fact is related with better global therapeutic results.

Antidepressant use and resource utilization in the general practitioner setting in The Netherlands.

OBJECTIVE: To assess antidepressant use and resource utilization in the general practitioner (GP) setting in the Netherlands following initiation of antidepressant therapy. DESIGN: Longitudinal study in a retrospective database. PARTICIPANTS: Sample of 869 patients from a new database in the Netherlands who initiated therapy on a selective serotonin re-uptake inhibitor (SSRI) or a tricyclic antidepressant (TCA). MAIN OUTCOME MEASURES: Mean length of antidepressant therapy within the first 90 days and resource utilization in the GP setting in the first 180 days following therapy initiation. RESULTS: (1) patients who initiated therapy on an SSRI were younger (48.6 years old versus 54.1 years old, p<0.01) and more likely to have a depression diagnosis (58% versus 30%, p<0.01) than patients who initiated therapy on a TCA; (2) patients who initiated therapy on an SSRI were more likely than patients who initiated therapy on a TCA (65% versus 52%, p<0.01) to have more than 30 days of therapy within the first 90 days and to receive antidepressant doses consistent with Dutch guidelines; (3) patients with greater than 30 days of antidepressant therapy within the first 90 days had more general practitioner visits than patients with 30 days of therapy or less (TCA patients: 9.6 versus 7.0; SSRI patients: 8.8 versus 6.9, p<0.01). CONCLUSIONS: Patients in the GP setting in the Netherlands who initiate therapy on SSRIs are more likely than patients who initiate therapy on TCAs to receive recommended doses and duration of therapy consistent with Dutch antidepressant treatment guidelines.