Disparities in antidepressant treatment in medicaid elderly diagnosed with depression.

Strothers HS 3rd, Rust G, Minor P, Fresh E, Druss B, Satcher D.

Department of Family Medicine, Morehouse School of Medicine, East Point and Atlanta, Georgia, USA. Strothh msm.edu

OBJECTIVES: To determine whether there were racial or ethnic disparities in the use of antidepressants in low-income elderly patients insured by Medicaid. DESIGN: Examination of 1998 Medicaid claims data. SETTING: Centers for Medicare and Medicaid Services Medicaid claims data for five U.S. states. PARTICIPANTS: All Medicaid recipients aged 65 to 84 with a diagnosis of depression. MEASUREMENTS: Treatment versus no treatment; in those treated, treatment with drugs was classified as old- or new-generation antidepressants. RESULTS: In 1998, 7,339 unique individuals aged 65 to 84 had at least one outpatient encounter with depression as the primary diagnosis. Nearly one in four (24.2%) received no antidepressant drug therapy, and 22% received neither psychotherapy nor an antidepressant. African-American individuals were substantially more likely to be untreated (37.1%) than Hispanic (23.6%), white (22.4%), or Asian (13.8%) individuals. In logistic regression models adjusting for sex, state, long-term care status, and age group, African Americans with a primary diagnosis of depression were almost twice as likely as whites not to receive an antidepressant within the study period (odds ratio=1.91, 95% confidence interval=1.62-2.24). Patients in long-term care facilities and those aged 65 to 74 were less likely to receive treatment. CONCLUSION: Substantial numbers of elderly Medicaid enrollees with a primary diagnosis of depression did not receive antidepressants or behavioral therapy. This gap in care disproportionately affected African-American patients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15743289&dopt=Abstract antidepressant




Assessment of the contributions of CYP3A4 and CYP3A5 in the metabolism of the antipsychotic agent haloperidol to its potentially neurotoxic pyridinium metabolite and effect of antidepressants on the bioactivation pathway.

Kalgutkar AS, Taylor TJ, Venkatakrishnan K, Isin EM.

Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Global Research and Development, Groton, Connecticut 06340, USA. amit_kalgutkar groton.pfizer.com

As a plausible explanation for the large interindividual variability in the pharmacokinetics of the neuroleptic agent haloperidol, the contributions of CYP3A isozymes (CYP3A4 and the polymorphic CYP3A5) predominantly involved in haloperidol bioactivation to the neurotoxic pyridinium species 4-(4-Chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-pyridinium (HPP(+)) were assessed in human liver microsomes and heterologously expressed enzymes. Based on recent reports on drug-drug interactions between haloperidol and antidepressants including selective serotonin reuptake inhibitors, the inhibitory effects of antidepressants on the CYP3A4/5-mediated haloperidol bioactivation were also evaluated. HPP(+) formation followed Michaelis-Menten kinetics in microsomes, recombinant CYP3A4, and CYP3A5 with K(m) values of 24.4 +/- 8.9 microM, 18.3 +/- 4.9 microM, and 200.2 +/- 47.6 microM, respectively, and V(max) values of 157.6 +/- 13.2 pmol/min/mg of protein, 10.4 +/- 0.6 pmol/min/pmol P450, and 5.16 +/- 0.6 pmol/min/pmol P450, respectively. The similarity in K(m) values between human liver microsomal and recombinant CYP3A4 incubations suggests that polymorphic CYP3A5 may not be an important genetic contributor to the interindividual variability in CYP3A-mediated haloperidol clearance pathways. Besides HPP(+), a novel 4-fluorophenyl-ring-hydroxylated metabolite of haloperidol in microsomes/CYP3A enzymes was also detected. Its formation was consistent with previous reports on the detection of O-sulfate and -glucuronide conjugates of a fluorophenyl ring-hydroxylated metabolite of haloperidol in human urine. Finally, all antidepressants except buspirone inhibited the CYP3A4/5-catalyzed oxidation of haloperidol to HPP(+) in a concentration-dependent manner. Based on the estimated IC(50) values for inhibition of HPP(+) formation in microsomes, the antidepressants were ranked in the following order: fluoxetine, nefazodone, norfluoxetine, trazodone, and fluvoxamine. These inhibition results suggest that clinically observed drug-drug interactions between haloperidol and antidepressants may arise via the attenuation of CYP3A4/5-mediated 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-4-piperidinol biotransformation pathways.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12584149&dopt=Abstract antidepressant




The role of sigma receptors in depression.

Bermack JE, Debonnel G.

Department of Psychiatry, McGill University, Montreal, Quebec, Canada.

Behavioral models used to test potential antidepressants have shown that ligands that bind to sigma receptors possess "antidepressant-like" properties. The focus of this review is to discuss the literature concerning sigma receptors and their ligands, with respect to their antidepressants properties. In addition to the behavioral data, we discuss electrophysiological and biochemical models demonstrating sigma receptors' ability to modulate important factors in the pathophysiology of depression and/or the mechanisms of action of antidepressants such as the serotonergic neurotransmission in the dorsal raphe nucleus (DRN) and the glutamatergic transmission in the hippocampus. We also discuss the significance of these two systems in the mechanism of action of antidepressants. Sigma ligands have potential as antidepressant medications with a fast onset of action as they produce a rapid modulation of the serotonergic system in the DRN and the glutamatergic transmission in the hippocampus. As these effects of sigma ligands may produce antidepressant properties by completely novel mechanisms of action, they may provide an alternative to the antidepressants currently available and may prove to be beneficial for treatment-resistant depressed patients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15750289&dopt=Abstract antidepressant




Neurobiology of mood, anxiety, and emotions as revealed by studies of a unique antidepressant: tianeptine.

McEwen BS, Olie JP.

1Harold & Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY, USA.

Recent studies have provided evidence that structural remodeling of certain brain regions is a feature of depressive illness, and the postulated underlying mechanisms contribute to the idea that there is more to antidepressant actions that can be explained exclusively by a monoaminergic hypothesis. This review summarizes recent neurobiological studies on the antidepressant, tianeptine (S-1574, [3-chloro-6-methyl-5,5-dioxo-6,11-dihydro-(c,f)-dibenzo-(1,2-thiazepine)-11-yl) amino]-7 heptanoic acid, sodium salt), a compound with structural similarities to the tricyclic antidepressant agents, the efficacy and good tolerance of which have been clearly established. These studies have revealed that the neurobiological properties of tianeptine involve the dynamic interplay between numerous neurotransmitter systems, as well as a critical role of structural and functional plasticity in the brain regions that permit the full expression of emotional learning. Although the story is far from complete, the schema underlying the effect of tianeptine on central plasticity is the most thoroughly studied of any antidepressants. Effects of tianeptine on neuronal excitability, neuroprotection, anxiety, and memory have also been found. Together with clinical data on the efficacy of tianeptine as an antidepressant, these actions offer insights into how compounds like tianeptine may be useful in the treatment of neurobiological features of depressive disorders.Molecular Psychiatry advance online publication, 8 March 2005; doi:10.1038/sj.mp.4001648.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15753957&dopt=Abstract antidepressant




Relationship of total health care charges to selective serotonin reuptake inhibitor utilization patterns including the length of antidepressant therapy--results from a managed care administrative claims database.

Eaddy MT, Druss BG, Sarnes MW, Regan TS, Frankum LE.

Applied Health Outcomes, 3488 East Lake Rd., Suite 201, Palm Harbor, FL 34685, USA. meaddy applied-outcomes.com

OBJECTIVE: Administrative claims data analysis performed in the early 1990s found lower total medical costs for patients with depression who remained on antidepressant therapy with selective serotonin reuptake inhibitors (SSRIs) for at least 90 days compared with patients who discontinued therapy prior to 60 days. Over the past decade, many changes in the health care system have occurred that might impact the reproducibility of these findings. The purpose of this study was to investigate the association between SSRI utilization patterns and the use of health care services in the managed care environment. METHODS: A large managed care claims database was used to identify patients receiving 2 or more SSRI prescriptions between June 2001 and December 2002. In order to ensure that patients were newly started on SSRI therapy, patients were required to have 6 months of enrollment data prior to their index date, without evidence of antidepressant therapy. Continuous enrollment for 12 months following their index prescription was also required. Patients with schizophrenia, bipolar disorder, or who received antipsychotic medications were excluded from this analysis. Patients were placed into 1 of 5 mutually exclusive antidepressant utilization cohorts: (1) <90 days, (2) e 90 days, (3) titration, (4) partial compliance, and (5) therapy change. Total medical costs, with and without pharmacy costs, were then compared between antidepressant utilization cohorts for 12 months of claims data. RESULTS: There were 65,753 patients included in the study. Medical charges without pharmacy charges were lowest in the e 90-day cohort ($5,143) compared with the partial compliance ($5,909, P<0.05), <90-day ($6,289, P<0.001), titration ($6,375, P<0.001), and therapy change ($7,858, P<0.001) cohorts. Differences in total medical charges without pharmacy charges were primarily influenced by inpatient charges. The addition of pharmacy charges, including the charges for antidepressants, resulted in total medical charges that were not statistically different for the e 90-day cohort compared with the <90-day cohort, $7,454 and $7,829, respectively, P=0.606. CONCLUSION: Medical charges without pharmacy charges were lower for patients remaining on antidepressant drug therapy for at least 90 continuous days compared with patients who used antidepressants for less than 90 continuous days, but total health care charges, including pharmacy charges, were not different between the 2 groups.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15766321&dopt=Abstract antidepressant




Expression of Ndrg2 in the rat frontal cortex after antidepressant and electroconvulsive treatment.

Takahashi K, Yamada M, Ohata H, Momose K, Higuchi T, Honda K, Yamada M.

Department of Pharmacology, Showa University School of Pharmaceutical Sciences, Tokyo, Japan.

Although the therapeutic action of antidepressants most likely involves the regulation of serotonergic and noradrenergic signal transduction, no consensus has been reached concerning their precise molecular or cellular mechanisms of action. In the present study, we demonstrated that chronic treatment with a tricyclic antidepressant (imipramine) and a selective serotonin reuptake inhibitor (sertraline) reduced the expression of Ndrg2 mRNA and protein in the rat frontal cortex. Ndrg2 is a member of the N-Myc downstream-regulated genes. Interestingly, repeated ECT also significantly decreased Ndrg2 expression in this region of the brain. These data suggest that Ndrg2 may be a common functional molecule that is decreased after antidepressant treatment and ECT. Although, the functional role of Ndrg2 in the central nervous system remains unclear, our findings suggest that Ndrg2 may be associated with treatment-induced adaptive neural plasticity in the brain, a chronic target of antidepressant action. In conclusion, we have identified Ndrg2 as a candidate target molecule of antidepressants and ECT.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15769300&dopt=Abstract antidepressant




The antidepressant effect of running is associated with increased hippocampal cell proliferation.

Bjornebekk A, Mathe AA, Brene S.

Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.

A common trait of antidepressant drugs, electroconvulsive treatment and physical exercise is that they relieve depression and up-regulate neurotrophic factors as well as cell proliferation and neurogenesis in the hippocampus. In order to identify possible biological underpinnings of depression and the antidepressant effect of running, we analysed cell proliferation, the level of the neurotrophic factor BDNF in hippocampus and dynorphin in striatum/accumbens in 'depressed' Flinders Sensitive Line rats (FSL) and Flinders Resistant Line (FRL) rats with and without access to running-wheels. The FRL strain exhibited a higher daily running activity than the FSL strain. Wheel-running had an antidepressant effect in the 'depressed' FSL rats, as indicated by the forced swim test. In the hippocampus, cell proliferation was lower in the 'depressed' rats compared to the control FRL rats but there was no difference in BDNF or dynorphin levels in striatum/accumbens. After 5 wk of running, cell proliferation increased in FSL but not in FRL rats. BDNF and dynorphin mRNA levels were increased in FRL but not to the same extent in the in FSL rats; thus, increased BDNF and dynorphin levels were correlated to the running activity but not to the antidepressant effect of running. The only parameter that was associated to basal level of 'depression' and to the antidepressant effect was cell proliferation in the hippocampus. Thus, suppression of cell proliferation in the hippocampus could constitute one of the mechanisms that underlie depression, and physical activity might be an efficient antidepressant.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15769301&dopt=Abstract antidepressant




Efficacy of antidepressants in substance use disorders with and without comorbid depression A systematic review and meta-analysis.

Torrens M, Fonseca F, Mateu G, Farre M.

Psychiatric and Drug Abuse Department, Hospital del Mar-IAPs, Passeig Maritim 25-29, E-08003 Barcelona, Spain.

Antidepressants are commonly used in substance abusers due to the potential effect on some underlying mechanisms involved in drug use disorders and to treat comorbid depression. A systematic review of the literature of the efficacy of antidepressant drugs in subjects with drug abuse disorders, including alcohol, cocaine, nicotine and opioid, with and without comorbid depression was performed. Only randomised, double-blind, controlled trials have been evaluated. A meta-analysis was done with the included studies that used common evaluation procedures in alcohol, cocaine and opioid dependence. Based on the present review some recommendations may be proposed. The prescription of antidepressants for drug abuse seems only clear for nicotine dependence with or without previous comorbid depression (bupropion and nortryptiline). In alcohol dependence without comorbid depression, the use of any antidepressant seems not justified, while in cocaine dependence has to be clarified. The use of antidepressants in alcohol, cocaine or opioid dependence with comorbid depression needs more studies in well-defined samples, adequate doses and duration of treatment to be really conclusive. Interestingly, SSRIs do not seem to offer significant advantages compared with tricyclic drugs in substance abuse disorders. Differences both related to individual characteristics and specific antidepressant drugs need to be clarified in future studies.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15769553&dopt=Abstract antidepressant