SSRI antidepressant drug use patterns in the naturalistic setting: a multivariate analysis.

Hylan TR, Crown WH, Meneades L, Heiligenstein JH, Melfi CA, Croghan TW, Buesching DP.

Global Health Outcomes Research, Eli Lilly and Company, Indianapolis, IN 46285-2128, USA.

BACKGROUND: The study of the duration and pattern of antidepressant use in actual clinical practice can provide important insights into how antidepressant prescribing patterns compare with recommended depression treatment guidelines. OBJECTIVE: The purpose of this study, using data available from depressed outpatients in the United States, is to assess the effects of initial SSRI antidepressant selection on the subsequent pattern and duration of antidepressant use. RESEARCH DESIGN: Multiple logistic regression analysis of data from a large prescription and medical claims database (MarketScan) for the years 1993 and 1994 were used to estimate the determinants of antidepressant drug use patterns for 1,034 patients with a "new" episode of antidepressant therapy who were prescribed one of three most often prescribed selective serotonin reuptake inhibitors (SSRIs), paroxetine, sertraline, or fluoxetine. RESULTS: Patients initiating therapy on sertraline or paroxetine were less likely than patients initiating therapy on fluoxetine to have four or more prescriptions of their initial antidepressant within the first 6 months. CONCLUSIONS: The findings suggest that antidepressant selection is an important determinant of the initial duration and pattern of antidepressant use which is consistent with current recommended depression treatment guidelines.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10217392&dopt=Abstract antidepressant




Baclofen and antidepressant--induced antinociception in formalin test: possible GABA(B) mechanism involvement.

Sabetkasai M, Khansefid N, Yahyavi SH, Zarrindast MR.

Department of Pharmacology, School of Medicine, Shaheed-Beheshti University of Medical Science, Tehran, Iran.

In this study, the influences of GABA(B) agents on antidepressant-induced antinociception in the mouse formalin test have been investigated. The GABA(B) receptor agonist baclofen (2.5, 5 and 10 mg/kg) induced a dose-dependent antinociception in the second phase of the formalin test. This response was inhibited by the GABA(B) receptor antagonist, CGP35348 [P-(3-aminopropyl)-p-diethoxymethyl-phosphinic acid], in a dose-dependent manner. The antagonist by itself also induced antinociception. Single administration of the antidepressants citalopram (10, 20, 40 and 80 mg/kg), desipramine (20, 40, 80 mg/kg) or imipramine (10, 20 and 40 mg/kg) also induced antinociception in both phases of the formalin test. CGP35348 (100 and 200 mg/kg) pretreatment reduced the response induced by the tricyclic antidepressants. A combination of baclofen with the tricyclic antidepressant did not potentiate antinociception induced by antidepressants, but a decrease in the response induced by higher dose of baclofen was shown. It is concluded that GABA mechanism(s) may modulate the antidepressant-induced antinociception.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10229069&dopt=Abstract antidepressant




Regulation of corticosteroid receptor gene expression in depression and antidepressant action.

Barden N.

Laval University Hospital Research Centre, Universite Laval, Ste-Foy, Que.

OBJECTIVE: Major alterations of the hypothalamic-pituitary-adrenocortical (HPA) system are often seen in patients with depression, and can be reversed by successful antidepressant therapy. Persuasive evidence points to the involvement of a dysfunctional glucocorticoid receptor system in these changes. The authors developed a transgenic mouse to determine the mechanism for these changes. DESIGN: In vivo and in vitro animal experiments. ANIMALS: Transgenic mice expressing glucocorticoid receptor antisense RNA and control mice. INTERVENTIONS: In vivo: hormone assays and dexamethasone suppression tests; in vitro: cell transfection, chloramphenicol acetyl transferase assay, Northern blot analysis, binding assays of cytosolic receptor. OUTCOME MEASURES: Indicators of depressive disorder in transgenic mice, effect of antidepressant therapy on dexamethasone binding in transgenic mouse hippocampus, mouse behaviour, and glucocorticoid receptor activity. RESULTS: Transgenic mice showed no suppression of corticosterone with a dose of 2 mg per 100 g body weight dexamethasone. Treatment with amitriptyline reduced levels of corticotropin and corticosterone, increased glucocorticoid receptor mRNA concentrations and glucocorticoid binding capacity of several brain areas, and reversed behavioural changes. In vitro experiments also showed that desipramine increased glucocorticoid receptor mRNA. CONCLUSION: These transgenic mice have numerous neuroendocrine characteristics of human depression as well as altered behaviour. Many of these neuroendocrinologic and behavioural characteristics are reversed by antidepressants. The antidepressant-induced increase in glucocorticoid receptor activity may render the HPA axis more sensitive to glucocorticoid feedback. This new insight into antidepressant drug action suggests a novel approach to the development of new antidepressant drugs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9987205&dopt=Abstract antidepressant




The impact of treatment-resistant depression on health care utilization and costs.

Crown WH, Finkelstein S, Berndt ER, Ling D, Poret AW, Rush AJ, Russell JM.

MEDSTAT Group, Cambridge, Mass, USA.

BACKGROUND: Approximately 50% of patients diagnosed with major depressive disorder will experience a recurrent or chronic course of illness for which long-term treatment is recommended. Moreover, at least 20% of patients diagnosed with depression do not respond satisfactorily to several traditional antidepressant medication treatment trials. Very little is known about the health care costs of patients with treatment-resistant depression. METHOD: Based on medical claims data (MarketScan Research Database, The MEDSTAT Group, Cambridge, Mass.) from January 1, 1995, to June 30, 2000, a naturalistic, retrospective analysis was conducted to study the characteristics and health care utilization of patients with treatment-resistant depression. All patients having an International Classification of Diseases, Ninth Revision (ICD-9), diagnosis code for unipolar or bipolar depression with specified antidepressant dosing and treatment durations were initially selected. Patients were then classified as "treatment resistant" if either they switched from or augmented initial antidepressant medication with other antidepressants at least twice (outpatient treatment-resistant group) or they switched from or augmented their initial antidepressant medication and also had a claim for either a depression-related hospitalization or suicide attempt (hospitalized treatment-resistant group). Those meeting the initial medication and diagnosis selection criteria but not meeting the treatment-resistance criteria constituted the comparison group. Members of the comparison group had comparatively stable antidepressant medication use patterns, consistent with an acceptable response to treatment. Patients were followed for a minimum of 9 months. Resource utilization was calculated from index date to last available claims data point and then annualized. RESULTS: Treatment-resistant patients were more likely to be diagnosed with bipolar disorder or concurrent substance abuse or anxiety disorders than the comparison group (p <.001). Treatment-resistant patients were at least twice as likely to be hospitalized (general medical and depression related) and had at least 12% more outpatient visits (p <.02). Treatment resistance was also associated with use of 1.4 to 3 times more psychotropic medications (including antidepressants) (p <.001). Patients in the hospitalized treatment-resistant group had over 6 times the mean total medical costs of non-treatment-resistant depressed patients ($42,344 vs. $6512) (p <.001) and their total depression-related costs were 19 times greater than those of patients in the comparison group ($28,001 vs. $1455) (p <.001). CONCLUSION: Treatment-resistant depression is costly and associated with extensive use of depression-related and general medical services. These findings underscore the need for early identification and effective long-term maintenance treatment for treatment-resistant depression.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12444808&dopt=Abstract antidepressant




Chronic antidepressant medication attenuates dexamethasone-induced neuronal death and sublethal neuronal damage in the hippocampus and striatum.

Haynes LE, Barber D, Mitchell IJ.

Biomedical Science, Medical School, The University of Nottingham, Queens Medical Centre, E70, Nottingham NG7 2UH, United Kingdom. linda.haynes nottingham.ac.uk

Dexamethasone, a synthetic corticosteroid, which can induce a range of mood disorders including depression and affective psychosis, is toxic to specific hippocampal and striatal neuronal populations. Chronic administration of antidepressants can induce neuroprotective effects, potentially by raising cellular levels of brain-derived neurotrophic factor (BDNF). We accordingly tested the hypothesis that chronic pretreatment of rats (Sprague-Dawley, male) with antidepressants would attenuate dexamethasone-induced neuronal damage as revealed by reductions in the level of neuronal death and in sublethal neuronal damage shown by the increase in the number of MAP-2 immunoreactive neurons. In support of this hypothesis, we demonstrate that chronic treatment with a range of antidepressants prior to dexamethasone administration (0.7 mg/kg, i.p.) attenuated the levels of neuronal death and loss of MAP-2 immunoreactivity in both the hippocampus and striatum. The antidepressants used were: desipramine (8 mg/kg, i.p., tricyclic), fluoxetine (8 mg/kg, i.p., selective serotonin reuptake inhibitor) and tranylcypromine (10 mg/kg, i.p., monoamine oxidase inhibitor) with each drug being injected once per day for 10 days. In contrast, acute injection of none of the antidepressants exerted a protective effect from dexamethasone-associated neuronal damage. Similarly, injection of neither cocaine nor chlordiazepoxide (benzodiazepine) exerted protective effects when injected either chronically or acutely. The observed protection from dexamethasone-induced neuronal damage is in keeping with the potential of chronic antidepressant medication to increase BDNF levels. The potential for dexamethasone to induce disorders of mood by damaging specific neuronal populations in the hippocampus and dorsomedial striatum is discussed.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15488477&dopt=Abstract antidepressant




Research design features and patient characteristics associated with the outcome of antidepressant clinical trials.

Khan A, Kolts RL, Thase ME, Krishnan KR, Brown W.

Northwest Clinical Research Center, Number 112, 1900 116th Avenue NE, Bellevue, WA 98004, USA. akhan nwcrc.net

OBJECTIVE: The authors examined which, if any, research design features and patient characteristics would significantly differ between successful and unsuccessful antidepressant trials. METHOD: Clinical trial data were reviewed for nine antidepressants approved by the Food and Drug Administration between 1985 and 2000. From the antidepressant research programs on these medications, 52 clinical trials were included in the study. The authors evaluated trial design features, patient characteristics, and difference in response between placebo and antidepressant. RESULTS: Nine trial design features and patient characteristics were present in the research programs for all nine of the antidepressants. The severity of depressive symptoms before patient randomization, the dosing schedule (flexible versus fixed), the number of treatment arms, and the percentage of female patients were significantly associated with the difference in response to antidepressant and placebo. The duration of the antidepressant trial, number of patients per treatment arm, number of sites, and mean age of the patients were similar in successful trials (with a greater antidepressant-placebo difference) and less successful trials (with a smaller antidepressant-placebo difference). CONCLUSIONS: These findings may help in the design of future antidepressant trials.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15514405&dopt=Abstract antidepressant




Outcomes of prenatal antidepressant exposure.

Simon GE, Cunningham ML, Davis RL.

Center for Health Studies, Group Health Cooperative, 1730 Minor Avenue #1600, Seattle, WA 98101, USA. simon.g ghc.org

OBJECTIVE: This study evaluated the effects of prenatal antidepressant exposure on perinatal outcomes, congenital malformations, and early growth and development. METHOD: Within a group-model health maintenance organization, all infants with apparent prenatal exposure to tricyclic or selective serotonin reuptake inhibitor (SSRI) antidepressants were frequency matched to an unexposed comparison group by year of birth, maternal age, and mother's lifetime use of antidepressant drugs and mental health care. A structured blind review of mothers' and infants' medical records examined perinatal outcomes, congenital malformations, and developmental delay. RESULTS: Tricyclic antidepressant exposure was not associated with any significant difference in perinatal outcomes. Exposure to SSRIs was associated with a 0.9-week decrease in mean gestational age, a 175-g decrease in mean birth weight, and a 0.29 decrease in mean Apgar score at 5 minutes, but differences in birth weights and Apgar scores were not significant after adjustment for gestational age. Differences in gestational age and birth weights were unrelated to length of exposure, but differences in Apgar scores were limited to those with third-trimester exposure. Neither tricyclic antidepressant nor SSRI exposure was significantly associated with congenital malformations or developmental delay. CONCLUSIONS: The authors found no association between tricyclic antidepressant or SSRI exposure and either congenital malformations or developmental delay. SSRI exposure during pregnancy was associated with earlier delivery and consequent lower birth weight. Third-trimester SSRI exposure was also associated with lower Apgar scores. Women considering taking SSRIs during pregnancy may balance any higher fetal risk against the risk of persistent or recurrent depression.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12450956&dopt=Abstract antidepressant




The impact of antidepressant treatment on population health: synthesis of data from two national data sources in Canada.

Patten SB.

Departments of Community Health Sciences and Epidemiology, University of Calgary, 3300 Hospital Drive NW, Calgary, Alberta, CANADA, T2N 4N1. patten ucalgary.ca.

BACKGROUND: In randomized, controlled trials, antidepressant medications have been shown to reduce the duration of major depressive episodes and to reduce the frequency of relapse during long-term treatment. The epidemiological impact of antidepressant use on episode duration and relapse frequency, however, has not been described. METHODS: Data from two Canadian general health surveys were used in this analysis: the National Population Health Survey (NPHS) and the Canadian Community Health Survey (CCHS). The NPHS is a longitudinal study that collected data between 1994 and 2000. These longitudinal data allowed an approximation of episode incidence to be calculated. The cross-sectional CCHS allowed estimation of episode duration. The surveys used the same sampling frame and both incorporated a Short Form version of the Composite International Diagnostic Interview. RESULTS: Episodes occurring in antidepressant users lasted longer than those in non-users. The apparent incidence of major depressive episodes among those taking antidepressants was higher than that among respondents not taking antidepressants. Changes in duration and incidence over the data collection interval were not observed. CONCLUSIONS: The most probable explanation for these results is confounding by indication and/or severity: members of the general population who are taking antidepressants probably have more highly recurrent and more severe mood disorders. In part, this may have been due to the use of a brief predictive diagnostic interview, which may be prone to detection of sub-clinical cases. Whereas antidepressant use increased considerably over the data-collection period, differences in episode incidence and duration over time were not observed. This suggests that the impact of antidepressant medications on population health may have been less than expected.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15518594&dopt=Abstract antidepressant