Enhancement of antidepressant potency by a potentiator of AMPA receptors.

Li X, Witkin JM, Need AB, Skolnick P.

Neuroscience Discovery Research, Eli Lilly and Co., Lilly Research Laboratories, Corporate Center, Indianapolis, Indiana, USA. li_xia_x1 lilly.com

1. AMPA receptor potentiators (ARPs) exhibit antidepressant-like activity in preclinical tests (for example, the forced swim test) that are highly predictive of efficacy in humans. Unlike most currently used antidepressants, ARPs do not elevate extracellular levels of biogenic amines (e.g., 5HT, NE) in prefrontal cortex at doses that are active in the forced swim test. 2. The present series of experiments examined the effects of combining the ARP, LY 392098, with biogenic amine-based antidepressants in the forced swim test. Male, NIH Swiss mice were placed in a cylinder of water and observed for attempted escape behaviors and immobility. 3. LY 392098 dose-dependently decreased immobility as did a range of classical antidepressants. At doses of LY 392098 below those that decreased immobility, this compound significantly increased the potency with which fluoxetine and citalopram (SSRI antidepressants), imipramine (tricyclic antidepressant), duoxetine (norepinephrine/serotonin uptake blocker), nisoxetine (norepinephrine uptake inhibitor), and rolipram (PDE4 inhibitor) decreased immobility in the forced swim test with potency shifts upward of 5-fold (fluoxetine, imipramine, and rolipram). Likewise, ineffective doses of the traditional antidepressants potentiated the effects LY 392098 with shifts in the dose-effect functions that were 10-fold or more for citalopram, fluoxetine, imipramine, and duloxetine. 4. Combined with other evidence for a role of AMPA receptors in the efficacy of antidepressants, the current data suggest that the addition of an ARP may augment the activity and perhaps the onset of the therapeutic effects of biogenic amine and second messenger-based antidepressants.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12825836&dopt=Abstract antidepressant




Relative risk of vaginal candidiasis after use of antibiotics compared with antidepressants in women: postmarketing surveillance data in England.

Wilton L, Kollarova M, Heeley E, Shakir S.

Drug Safety Research Unit, Southampton, United KingdomUniversity of Portsmouth, Portsmouth, United Kingdom. linda.wilton dsru.org

BACKGROUND: Vaginal candidiasis is a common infection in women. The microflora of the vagina are influenced by a number of factors, including pregnancy, oral contraceptive use, menses and diabetes mellitus. Previous antibiotic use is generally accepted to be a risk factor for vaginal candidiasis but the published evidence to support this is limited.Aim: To determine the relative risk of vaginal candidiasis following the use of antibiotics compared with antidepressants in prescription-event monitoring (PEM) studies. METHODS: Using data from postmarketing surveillance studies of six antibiotics and six antidepressants, conducted using the observational cohort technique of PEM, the number of reports of vaginal candidiasis was determined in women aged > or =16 years, in each of the first 7 weeks following a prescription for one of these drugs. The relative risks for vaginal candidiasis following the use of these antibiotics and for each of the individual antibiotics compared with antidepressants were calculated for each week and for the overall 7-week period. Women treated with antidepressants were the most suitable comparator group from the PEM database, as they were of a similar age range and the studies were conducted at a similar time period to those of the antibiotics. Also, there was no pharmacological plausibility for vaginal candidiasis being associated with antidepressants. RESULTS: There were 188 reports of vaginal candidiasis in 31 588 women, aged > or =16 years, treated with antibiotics and 70 in the 45 492 treated with antidepressants. The relative risk for vaginal candidiasis (antibiotic/antidepressants), was highest in the second week, 10.70 (95% CI 4.86-23.55) but was also significantly greater in the first and third weeks after the start of treatment. The risk was also higher in each of the 3 weeks after starting the course for five of the antibiotics, compared individually to the group treated with antidepressants, the exception being fosfomycin, which had a much smaller cohort. CONCLUSION: This study shows a significant increase in the risk of developing vaginal candidiasis following the use of the antibiotics studied (ciprofloxacin, ofloxacin, norfloxacin, cefixime, azithromycin and fosfomycin) compared with that after taking the antidepressants fluvoxamine, fluoxetine, paroxetine, sertraline, venlafaxine and nefazodine in these PEM studies.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12825971&dopt=Abstract antidepressant




Impact of antidepressant discontinuation after acute bipolar depression remission on rates of depressive relapse at 1-year follow-up.

Altshuler L, Suppes T, Black D, Nolen WA, Keck PE Jr, Frye MA, McElroy S, Kupka R, Grunze H, Walden J, Leverich G, Denicoff K, Luckenbaugh D, Post R.

Stanley Bipolar Treatment Network, USA. laltshuler mednet.ucla.edu

OBJECTIVE: While guidelines for treating patients with bipolar depression recommend discontinuing antidepressants within 6 months after remission, few studies have assessed the implications of this strategy on the risk for depressive relapse. This study examined the effect of antidepressant discontinuation or continuation on depressive relapse risk among bipolar subjects successfully treated for an acute depressive episode. METHOD: Eighty-four subjects with bipolar disorder who achieved remission from a depressive episode with the addition of an antidepressant to an ongoing mood stabilizer regimen were followed prospectively for 1 year. The risk of depressive relapse among 43 subjects who stopped antidepressant treatment within 6 months after remission ("discontinuation group") was compared with the risk among 41 subjects who continued taking antidepressants beyond 6 months ("continuation group"). RESULTS: A Cox proportional hazards regression analysis indicated that shorter antidepressant exposure time following successful treatment was associated with a significantly shorter time to depressive relapse. Furthermore, patients who discontinued antidepressant treatment within the first 6 months after remission experienced a significantly shorter period of euthymia before depressive relapse over the length of 1-year follow-up. One year after successful antidepressant response, 70% of the antidepressant discontinuation group experienced a depressive relapse compared with 36% of the continuation group. By the 1-year follow-up evaluation, 15 (18%) of the 84 subjects had experienced a manic relapse; only six of these subjects were taking an antidepressant at the time of manic relapse. CONCLUSIONS: The risk of depressive relapse in patients with bipolar illness was significantly associated with discontinuing antidepressants soon after remission. The risk of manic relapse was not significantly associated with continuing use of antidepressant medication and, overall, was substantially less than the risk of depressive relapse. Maintenance of antidepressant treatment in combination with a mood stabilizer may be warranted in some patients with bipolar disorder.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12832239&dopt=Abstract antidepressant




Antidepressant use in psychiatry and medicine: importance for dental practice.

Keene JJ Jr, Galasko GT, Land MF.

Department of Applied Dental Medicine, Southern Illinois University, School of Dental Medicine, Alton 62002, USA. jokeene siue.edu

BACKGROUND: Many dental patients receive antidepressant therapy. However, antidepressants taken with other drugs may increase the risk of complications that require special dental precautions and care. METHODS: The authors conducted a retrospective study of 1,800 randomly selected patient records and evaluated the prevalence of using antidepressants and other medications concurrently. They analyzed antidepressant intake relative to drug classification and mechanism of action, age, sex and associated potential for clinical complications such as xerostomia, orthostatic hypotension and interaction with vasoconstrictors. The potential for additive adverse effects between antidepressants and other medications also was analyzed. RESULTS: Three hundred eighty-one (21 percent) of the 1,800 patient records indicated that patients were being treated with 412 antidepressants. Female subjects out-numbered male subjects by an approximate 2.3:1 ratio. Selective serotonin reuptake inhibitors were most commonly prescribed, followed by tricyclic antidepressants, atypical and third-generation antidepressants, and monoamine oxidase inhibitors. Based on reported medication intake, almost 58 percent of subjects in the antidepressant group were receiving treatment with two or more medications that had the potential for producing xerostomia. Two hundred fifty-seven (67 percent) of the 381 records documented intake of an antidepressant or other medication with orthostatic hypotension potential. CONCLUSIONS: Three hundred eighty-one patients reported that they were receiving antidepressant therapy for psychiatric and other medical reasons. Potential adverse effects and interactions with other medications have direct implications for dental treatment. CLINICAL IMPLICATIONS: Patients receiving antidepressant therapy are at risk of developing xerostomia and orthostatic hypotension, as well as experiencing the adverse effects of interaction with vasoconstrictors. Dentists must take appropriate precautions in treating these patients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12555959&dopt=Abstract antidepressant




Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants.

Shimizu E, Hashimoto K, Okamura N, Koike K, Komatsu N, Kumakiri C, Nakazato M, Watanabe H, Shinoda N, Okada S, Iyo M.

Department of Psychiatry, Graduate School of Medicine, Chiba University, Chiba, Japan.

BACKGROUND: Because researchers have reported that antidepressants increase the expression of brain-derived neurotrophic factor (BDNF) in the rat hippocampus, we investigated whether serum BDNF levels may be used as a putative biological marker for major depressive disorders (MDD). METHODS: We measured serum BDNF in the following three groups: antidepressant-naive patients with MDD (n = 16), antidepressant-treated patients with MDD (n = 17), and normal control subjects (n = 50). Patients were evaluated using the Hamilton Rating Scale for Depression (HAM-D). Serum BDNF was assayed with the sandwich ELISA method. RESULTS: We found that serum BDNF was significantly lower in the antidepressant-naive group (mean, 17.6 ng/mL; SD, 9.6) than in the treated (mean, 30.6 ng/mL; SD, 12.3; p =.001) or in the control group (mean, 27.7 ng/mL; SD, 11.4; p =.002). There was a significant negative correlation (r = -.350, z = -2.003, p =.045) between serum BDNF and HAM-D scores in all patients. In a preliminary examination, reduced BDNF values of three drug-naive patients recovered to basal levels after antidepressant treatment. CONCLUSIONS: Our study suggests that low BDNF levels may play a pivotal role in the pathophysiology of MDD and that antidepressants may increase BDNF in depressed patients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12842310&dopt=Abstract antidepressant




Antidepressant medications and their association with invasive breast cancer and carcinoma in situ of the breast.

Moorman PG, Grubber JM, Millikan RC, Newman B.

Cancer Prevention, Detection, and Control Research Program, Department of Community and Family Medicine, Duke University Medical Center, Durham, NC 27710, USA. patricia.moorman duke.edu

BACKGROUND: Experimental studies in animals have suggested that antidepressants may promote the growth of mammary tumors, but epidemiologic data have not shown consistent associations between antidepressant use and breast cancer. METHODS: We analyzed data from a population-based, case-control study conducted in North Carolina from 1996 to 2000 to examine the association between antidepressant use and breast cancer. Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) separately for invasive breast cancer and carcinoma in situ. RESULTS: Over 20% of both cases and controls reported having ever used antidepressants. Overall, women with invasive breast cancer did not report antidepressant use more frequently than controls (OR = 1.0; CI = 0.7-1.2). There was a suggestion that use of selective serotonin reuptake inhibitor antidepressants for 36 months or more was more common among the breast cancer cases (OR = 2.7; CI = 0.9-7.9). Carcinoma in situ cases reported antidepressant use less frequently than controls (OR = 0.6; CI = 0.4-0.8). No consistent relation was observed between duration of use and carcinoma in situ. CONCLUSIONS: Antidepressant use in general was not related to an increased risk of breast cancer. There may be increased risk associated with long-term use of SSRIs. Continued monitoring of this relation is warranted, given the high prevalence of use of these drugs in the general population.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12859031&dopt=Abstract antidepressant




The influence of Hispanic ethnicity on patients' expression of complaints about and problems with adherence to antidepressant therapy.

Sleath B, Rubin RH, Wurst K.

School of Pharmacy and Cecil G. Sheps Center for Health Services Research, University of North Carolina at Chapel Hill, North Carolina 27599-7360, USA. betsy_sleath unc.edu

BACKGROUND: Although Hispanics constitute the most rapidly growing ethnic group in the United States, few studies have examined the relationship between Hispanic ethnicity and patients' experiences with the use of antidepressant medications. OBJECTIVE: The purpose of this study was to examine the influence of Hispanic ethnicity on patients' expression of complaints about and problems of adherence with antidepressant medications and physicians' reactions to these complaints and adherence problems. METHODS: Data were collected as part of a larger cross-sectional study of physician-patient communication conducted during 1995 in the general medicine and family practice clinics of the University of New Mexico. Between March and December 1995, patients' medical visits were recorded on audiotape, patients were interviewed after each visit, and patients' medical records were reviewed. The present analysis focused on patients who received a prescription for an antidepressant on the day of the audiotaped visit. Because this was a cross-sectional study, only 1 visit was recorded for each patient. RESULTS: Ninety-eight patients were identified who received a new or refill prescription for an antidepressant on the day of the audiotaped visit. Twenty-eight (28.6%) patients expressed a complaint about their antidepressant therapy. Younger patients and non-Hispanic white patients were more likely to express such a complaint than were older patients and Hispanic patients. Ten (10.2%) patients reported an adherence problem. Patients who rated their physical health as better were more likely to express adherence problems with antidepressant therapy than were patients who rated their physical health was worse. Physicians were generally responsive to patients' expression of complaints and adherence problems. CONCLUSIONS: Patients' ethnicity was related to their expression of complaints about antidepressant therapy but not to their expression of adherence problems or to physicians' reactions on patients' expression of either. Because many patients express complaints about and adherence problems with antidepressant therapy, providers should be prepared to educate patients about their prescribed therapy or change the antidepressant regimen.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12860495&dopt=Abstract antidepressant




Role of neuropeptides in antidepressant and memory improving effects of venlafaxine.

Nowakowska E, Kus K, Bobkiewicz-Kozlowska T, Hertmanowska H.

Department of Pharmacology, Karol Marcinkowski University of Medical Sciences, Rokietnicka 5A, PL 60-806 Poznan, Poland.

The aim of this study has been to investigate the effects of vasopressin and oxytocin on antidepressive and memory improving effects of venlafaxine. Male Wistar rats weighing 180-200 g were used in the study. Venlafaxine (20 mg/kg) was administered po 30 min before the test once, and for 7 and 14 days in the chronic experiments. Oxytocin (1 microg/kg) ip and vasopressin (1 microg/kg) sc were administered only once on the test day, 60 min before the tests. The animals were subjected to Porsolt's test for testing antidepressant activity, and their memory functions (working and spatial memory) were evaluated in the maze test and Morris Water Maze test. Antidepressant effects of venlafaxine could be observed already after single drug administration and the effect was maintained during 7 days of drug administration. Oxytocin also exhibited antidepressant activity, and concurrent administration of venlafaxine and oxytocin helped to maintain antidepressant activity of venlafaxine. Vasopressin was devoid of antidepressant action, yet concurrent administration of vasopressin and venlafaxine did not suppress antidepressant activity of the latter. In the chronic experiment, there was no shortening of passive swimming time. Venlafaxine improved memory in the labyrinth test and in the spatial memory test, whereas oxytocin did not affect memory of the tested animals. Joint administration of venlafaxine and oxytocin did not produce memory improving effect observed after administration of venlafaxine only. Vasopressin improved memory and joint administration of venlafaxine and vasopressin maintained the memory improving effect induced by vasopressin. The regulatory role of neuropeptides and new antidepressant drugs, e.g. venlafaxine in mood status and memory functions may depend on the interactions between monoaminergic and neuropeptidergic systems.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12866715&dopt=Abstract antidepressant