Home About us Contact
|
Home About us Contact | ||
|
|
||
Antidepressant Drugs (antidepressant + drug)
Terms modified by Antidepressant Drugs Selected AbstractsAntidepressant use in a nationally representative sample of community-dwelling US Latinos with and without depressive and anxiety disorders,DEPRESSION AND ANXIETY, Issue 7 2009Hector M. González Ph.D. Abstract Background: Antidepressant drugs are among the most widely prescribed drugs in the United States; however, little is known about their use among major ethnic minority groups. Method: Collaborative Psychiatric Epidemiology Surveys (CPES) data were analyzed to calculate nationally representative estimates of Latino and non-Latino White adults antidepressant use. Setting: The 48 coterminous United States was the setting. Participants: Household residents aged 18 years and older (N=9,250). Main outcome: Past year antidepressant use. Results: Compared to non-Latino Whites, few Latinos, primarily Mexican Americans, with 12-month depressive and/or anxiety disorders reported past year antidepressant use. Mexican Americans (OR=0.48; 95%CI=0.30,0.77) had significantly lower odds of use compared to non-Latino Whites, which were largely unaffected by factors associated with access to care. Over half of antidepressant use was by respondents not meeting 12-month criteria for depressive or anxiety disorders. Lifetime depressive and anxiety disorders explained another 21% of past year antidepressant use, leaving another 31% of drug use unexplained. Discussion: We found a disparity in antidepressant use for Mexican Americans compared to non-Latino Whites that was not accounted for by differences in need and factors associated with access to care. About one third of antidepressant use was by respondents not meeting criteria for depressive or anxiety disorders. Our findings underscore the importance of disaggregating Latino ethnic groups. Additional work is needed to understand the medical and economic value of antidepressant use beyond their primary clinical targets. Depression and Anxiety, 2009. Published 2009 Wiley-Liss, Inc. [source] The role of BDNF and its receptors in depression and antidepressant drug action: Reactivation of developmental plasticityDEVELOPMENTAL NEUROBIOLOGY, Issue 5 2010Eero Castrén Abstract Recent evidence suggests that neuronal plasticity plays an important role in the recovery from depression. Antidepressant drugs and electroconvulsive shock treatment increase the expression of several molecules, which are associated with neuronal plasticity, in particular the neurotrophin BDNF and its receptor TrkB. Furthermore, these treatments increase neurogenesis and synaptic numbers in several brain areas. Conversely, depression, at least in its severe form, is associated with reduced volumes of the hippocampus and prefrontal cortex and in at least some cases these neurodegenerative signs can be attenuated by successful treatment. Such observations suggest a central role for neuronal plasticity in depression and the antidepressant effect, and also implicate BDNF signaling as a mediator of this plasticity. The antidepressant fluoxetine can reactivate developmental-like neuronal plasticity in the adult visual cortex, which, under appropriate environmental guidance, leads to the rewiring of a developmentally dysfunctional neural network. These observations suggest that the simple form of the neurotrophic hypothesis of depression, namely, that deficient levels of neurotrophic support underlies mood disorders and increases in these neurotrophic factors to normal levels brings about mood recovery, may not sufficiently explain the complex process of recovery from depression. This review discusses recent data on the role of BDNF and its receptors in depression and the antidepressant response and suggests a model whereby the effects of antidepressant treatments could be explained by a reactivation of activity-dependent and BDNF-mediated cortical plasticity, which in turn leads to the adjustment of neuronal networks to better adapt to environmental challenges. © 2010 Wiley Periodicals, Inc. Develop Neurobiol 2010 [source] Circadian rhythm disturbances in depression,HUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue 7 2008Anne Germain Abstract Objective The aim of this article is to review progress in understanding the mechanisms that underlie circadian and sleep rhythms, and their role in the pathogenesis and treatment of depression. Methods Literature was selected principally by Medline searches, and additional reports were identified based on ongoing research activities in the authors' laboratory. Results Many physiological processes show circadian rhythms of activity. Sleep and waking are the most obvious circadian rhythms in mammals. There is considerable evidence that circadian and sleep disturbances are important in the pathophysiology of mood disorders. Depressed patients often show altered circadian rhythms, sleep disturbances, and diurnal mood variation. Chronotherapies, including bright light exposure, sleep deprivation, and social rhythm therapies, may be useful adjuncts in non-seasonal and seasonal depression. Antidepressant drugs have marked effects on circadian processes and sleep. Conclusions Recent progress in understanding chronobiological and sleep regulation mechanisms may provide novel insights and avenues into the development of new pharmacological and behavioral treatment strategies for mood disorders. Copyright © 2008 John Wiley & Sons, Ltd. [source] An algorithm to identify antidepressant users with a diagnosis of depression from prescription dataPHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 1 2009Helga Gardarsdottir PharmD Abstract Purpose Antidepressants are used for many indications besides depression. This makes investigating depression treatment outcomes in prescription databases problematic when the indication is unknown. The aim of our study is to develop an algorithm to identify antidepressant drug users from prescription data that suffer from depression. Methods Data for deriving the algorithm were obtained from the Second Dutch National Survey of General Practice, carried out in 2001 by The Netherlands Institute for Health Services Research (NIVEL), and for validation the Integrated Primary Care Information (IPCI) database was used. Both sets included adults receiving their first antidepressant drug in 2001 (n,=,1855 and 3321, respectively). The outcome was a registered diagnosis of depression. Covariates investigated for developing the algorithm were patient and prescribing characteristics, and co-medication. Results The predictive algorithm included age, SSRI prescribed on the index date, prescribed dose, general practitioner as prescriber and the number of antidepressant prescriptions prescribed plus medication for treating acid related disorders, laxatives, cardiac therapy or hypnotics/sedatives prescribed in the 6 months prior to index date. The probability that the algorithm correctly identified an antidepressant drug user as having a depression diagnosis was 79% with a sensitivity of 79.6% and a specificity of 66.9%. Conclusion In conclusion, we developed and validated an algorithm that can be used to compose cohorts of patients treated with antidepressants for depression from prescription databases. Copyright © 2008 John Wiley & Sons, Ltd. [source] Clinical diagnosis and treatment of suspected neuropathic pain in three dogsAUSTRALIAN VETERINARY JOURNAL, Issue 1-2 2009RG Cashmore Three dogs were referred to The Queen's Veterinary School Hospital at University of Cambridge for chronic behavioural or locomotor disorders associated with pain. All three had been unsuccessfully treated with conventional analgesics, including non-steroidal anti-inflammatory drugs, glucocorticoids and opiate agonists, prior to referral, with minimal or no response. They were investigated by neurological examination plus conventional ancillary diagnostic tests and therapeutic drug trials. Ruling out other causes of pain and applying previously well-described criteria, each case was diagnosed as consistent with neuropathic pain, a poorly recognised condition in domestic dogs. Treatment with the tricyclic antidepressant drug, amitriptyline, or the antiepileptic drug, gabapentin, resulted in either a dramatic improvement or full resolution of clinical signs in all cases. [source] Clinical pharmacokinetic studies with INN 00835 (Nemifitide), a novel pentapeptide antidepressantBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 1 2002John P. Feighner Abstract Nemifitide (4-fluoro-L-phenylalanyl-trans-4-hydroxy-L-prolyl-L-arginylglycyl-L-tryptophanamide ditrifluoroacetate) is a novel antidepressant, currently in phase 2/3 clinical trials. The purpose of our phase 1 clinical trials (conducted over a three year period) was to provide safety and pharmacokinetic data to support its clinical development as an antidepressant drug. Single and multiple doses ranging from 18 to 320 mg were administered subcutaneously to healthy volunteers in five phase 1 studies. Plasma concentrations of unchanged parent drug were determined by a validated LC/MS/MS method in blood samples collected at timepoints between 10 min and 72 h after dosing. Nemifitide was rapidly absorbed (Cmax at 10 min) and eliminated (t1/2 15,30 min) in most subjects. Regression and power model analyses were used to evaluate the data. The results indicate that pharmacokinetic parameters: AUC0,t, AUC 0,, and Cmax, were close to dose proportional in the dose range investigated. There was no evidence of systemic accumulation of drug following 5 daily doses. No serious adverse events or clinically significant systemic adverse events occurred at any of the doses investigated in the over 100 subjects dosed in these studies. Drug-related adverse events were limited to local and transient skin reactions (pain and/or erythema) at the injection site, especially at the high doses administered: 240 and 320 mg. Copyright © 2002 John Wiley & Sons, Ltd. [source] Complexes of the copper-containing amine oxidase from Arthrobacter globiformis with the inhibitors benzylhydrazine and tranylcypromineACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 7 2008David B. Langley Complexes of Arthrobacter globiformis amine oxidase (AGAO) with the inhibitors benzylhydrazine and tranylcypromine (an antidepressant drug) have been refined at 1.86 and 1.65,Å resolution, respectively. Both inhibitors form covalent adducts with the TPQ cofactor. A tyrosine residue, proposed to act as a gate to the AGAO active site, is in its open conformation. [source] Mania associated with antidepressant treatment: comprehensive meta-analytic reviewACTA PSYCHIATRICA SCANDINAVICA, Issue 6 2010L. Tondo Tondo L, Vázquez G, Baldessarini RJ. Mania associated with antidepressant treatment: comprehensive meta-analytic review. Objective:, To review available data pertaining to risk of mania,hypomania among bipolar (BPD) and major depressive disorder (MDD) patients with vs. without exposure to antidepressant drugs (ADs) and consider effects of mood stabilizers. Method:, Computerized searching yielded 73 reports (109 trials, 114 521 adult patients); 35 were suitable for random effects meta-analysis, and multivariate-regression modeling included all available trials to test for effects of trial design, AD type, and mood-stabilizer use. Results:, The overall risk of mania with/without ADs averaged 12.5%/7.5%. The AD-associated mania was more frequent in BPD than MDD patients, but increased more in MDD cases. Tricyclic antidepressants were riskier than serotonin-reuptake inhibitors (SRIs); data for other types of ADs were inconclusive. Mood stabilizers had minor effects probably confounded by their preferential use in mania-prone patients. Conclusion:, Use of ADs in adults with BPD or MDD was highly prevalent and moderately increased the risk of mania overall, with little protection by mood stabilizers. [source] Do the old psychostimulant drugs have a role in managing treatment-resistant depression?ACTA PSYCHIATRICA SCANDINAVICA, Issue 4 2010G. Parker Parker G, Brotchie H. Do the old psychostimulant drugs have a role in managing treatment-resistant depression? Objective:, As the authors have observed clinical benefit from the psychostimulants methylphenidate and dexamphetamine for treating resistant melancholic and bipolar depression, those drugs were evaluated in a consecutively recruited sample of 50 such patients. Method:, Patients (27 bipolar, 23 unipolar) received either methylphenidate (n = 44) or dexamphetamine (n = 6), with 30 having it prescribed as an augmenting drug and 20 as monotherapy. At the final review, ranging from 6 weeks to 62 months (mean 57 weeks), 52% were still receiving their psychostimulant. Results:, Thirty-four per cent reported the psychostimulant as distinctly improving their depression, 30% reported some level of improvement and 36% reported no improvement and/or side-effects. For improvers, the modal dose of methylphenidate was 20 mg. Significant side-effects were reported by 18% (including one manic response), switching was rare and limited to the bipolar subjects, and most side-effects were minor. Any positive response occurred rapidly and loss of efficacy was rare. Testing of tricyclic levels in some patients suggested that stimulant drugs may raise tricyclic levels in those who are rapid metabolizers. Conclusion:, Although this study was not controlled, the high success rate in a diagnostically refined sample implies that the psychostimulants may be efficacious for patients with melancholic and bipolar depression who have failed to respond to orthodox antidepressant drugs. [source] Quantified superiority of cognitive behaviour therapy to antidepressant drugs: a challenge to an earlier meta-analysisACTA PSYCHIATRICA SCANDINAVICA, Issue 2 2008G. B. Parker Objective:, The study aimed to review the conclusion of a previously published meta-analysis which quantified distinct superiority of cognitive therapy to antidepressant drug-therapy (P < 0.0001). Method:, We sought to include all studies used in the original meta-analysis. Adopting both that study's inclusion criteria and additional criteria resulted in a reduced set of studies. We analysed both ,completer' and ,intention to treat' data, using effect size and odds ratio quantification. Results:, There was an overall trend for cognitive therapy to be superior to antidepressant drug-therapy, but this was significant for only one of the four meta-analyses (an intention to treat analysis). We demonstrated considerable heterogeneity between studies, and a significantly higher drop-out rate in the antidepressant groups. Conclusion:, The previous interpretation , cognitive therapy being distinctly superior to antidepressant medication , cannot be sustained from the currently analysed data set. [source] Positron emission tomography and its use to image the occupancy of drug binding sitesDRUG DEVELOPMENT RESEARCH, Issue 2 2003S. John Gatley Abstract The development of positron emission tomography (PET) and the ability to synthesize compounds labeled with the short-lived positron emitters 11C and 18F has made possible the imaging and quantification of drug binding sites in the human body. By conducting PET studies with an appropriate radioligand before and after treatment with a drug, the fraction of the total number of binding sites that is occupied by the drug (the "occupancy" of the site) can often be determined. To the extent that occupancy is a good indicator of pharmacological activity, such PET experiments can aid the development of drug dosage regimens. Some of the general issues involved in PET studies of drug occupancy are discussed. There have been many such studies involving antipsychotic drugs and dopamine D2 receptor radioligands. Since neuroleptics have been extensively reviewed elsewhere, only the major findings are discussed here. Other binding sites (and drug classes) in the dopamine system to which this methodology has been applied include: the dopamine transporter (stimulant drugs) and monoamine oxidase A and B (antidepressant drugs). Occupancy studies are also possible for many drug targets beyond the dopamine system. Drug Dev. Res. 59:194,207, 2003. © 2003 Wiley-Liss, Inc. [source] Advances in the enantioseparation of second-generation antidepressant drugs by electrodriven methodsELECTROPHORESIS, Issue 1 2006Roberto Mandrioli Abstract Stereochemistry is steadily increasing in importance in the development of new drugs, and the availability of pure enantiomer drugs can make therapy safer and more efficacious. In particular, almost all second-generation antidepressant drugs possess one or more chiral centres; however, only some of them are administered as single enantiomers. A fundamental part of the quality control of pharmaceutical formulations is the determination of enantiomeric excess and enantiomeric purity; this is also important for the therapeutic drug monitoring of depressed patients. For this purpose, efficient and reliable analytical methods are needed and electrodriven techniques (most of all CE, CEC and MEKC) are very efficient and inexpensive candidates for the role. In this review, the enantioselective electrodriven methods available for the analysis of second-generation antidepressant are presented and discussed. In particular, the following pharmacological classes of antidepressants will be considered: selective serotonin reuptake inhibitors (fluoxetine, citalopram, paroxetine, sertraline); norepinephrine reuptake inhibitors (reboxetine); serotonin and norepinephrine reuptake inhibitors (venlafaxine, milnacipran, duloxetine); and noradrenergic and specific serotonergic antidepressants (mirtazapine). [source] Autonomic symptoms in patients and pre-manifest mutation carriers of Huntington's diseaseEUROPEAN JOURNAL OF NEUROLOGY, Issue 8 2010N. A. Aziz Background and purpose:, Although autonomic function tests have revealed abnormalities of the autonomic nervous system in Huntington's disease (HD), autonomic symptoms and their association with other symptoms and signs of HD have not yet been assessed in large groups of patients or pre-manifest mutation carriers. Therefore, we aimed at delineating the characteristics and correlates of autonomic symptoms in HD. Methods:, Using the scales for outcomes in Parkinson's disease-autonomic symptoms (SCOPA-AUT) and Beck Depression Inventory questionnaires, autonomic symptoms and depressed mood were assessed in 63 patients with HD, 21 pre-manifest mutation carriers, and 85 controls. The Unified Huntington's Disease Rating Scale was used to assess other HD symptoms and signs. Results:, Relative to controls, patients with HD experienced significantly more gastrointestinal, urinary, cardiovascular and, in men, sexual problems. The most prevalent symptoms were swallowing difficulties, erection and ejaculation problems, dysphagia, sialorrhea, early abdominal fullness, straining for defecation, fecal and urinary incontinence, urgency, incomplete bladder emptying, and light-headedness whilst standing. Pre-manifest mutation carriers experienced significantly more swallowing difficulties and light-headedness on standing up compared with controls. In patients with HD, autonomic symptoms were associated with a greater degree of functional disability, more severe depression, and antidepressant drugs use. However, depression was the only independent predictor of autonomic dysfunction. Conclusions:, Autonomic symptoms are highly prevalent in patients with HD and may even precede the onset of motor signs. Moreover, autonomic dysfunction is related to functional disability and depression in HD. [source] Sex hormone-dependent desensitization of 5-HT1A autoreceptors in knockout mice deficient in the 5-HT transporterEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 8 2003Saoussen Bouali Abstract The serotonin transporter (5-HTT) is the target of most antidepressant drugs, whose therapeutic action is related to their facilitatory influence on 5-HT neurotransmission. In this study, we investigated the functional adaptive properties of 5-HT1A autoreceptors, which regulate serotonergic neuronal firing, in knockout mice deficient in 5-HTT. Neurons of the dorsal raphe nucleus (DRN) were recorded extracellularly under chloral hydrate anaesthesia in male and female knockout 5-HTT mice and their wild-type counterparts. The inhibitory response of DRN neurons to intravenous injection of the 5-HT1A agonist 8-OH-DPAT was dramatically reduced in knockout 5-HTT compared with wild-type mice, especially in females. Changes in 8-OH-DPAT-induced hypothermia and autoradiographic labelling of 5-HT1A sites in the DRN confirmed a greater level of desensitization/down-regulation of 5-HT1A autoreceptors in female than in male knockout 5-HTT mice. After gonadectomy, the functional status of 5-HT1A autoreceptors was unchanged in wild-type mice, whereas in knockout 5-HTT, castrated males exhibited a down-regulation, and ovariectomized females an up-regulation of these receptors, as shown by electrophysiological recording and autoradiographic labelling in the DRN, as well as by changes in 8-OH-DPAT-induced hypothermia. Finally, in gonadectomized knockout 5-HTT mice, treatment with testosterone or estradiol restored the DRN neuronal firing sensitivity to 8-OH-DPAT back to sham control level in males or females, respectively. These data indicate that sexual hormones participate in the mechanisms responsible for the desensitization of 5-HT1A autoreceptors in knockout 5-HTT mice. The differential effects of testosterone and estradiol on 5-HT1A -mediated control of 5-HT neurotransmission might be related to the well-established gender differences in the vulnerability to depression. [source] Increased neurogenesis and brain-derived neurotrophic factor in neurokinin-1 receptor gene knockout miceEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 7 2003Sara Morcuende Abstract It has previously been shown that chronic treatment with antidepressant drugs increases neurogenesis and levels of brain-derived neurotrophic factor in the hippocampus. These changes have been correlated with changes in learning and long-term potentiation and may contribute to the therapeutic efficacy of antidepressant drug treatment. Recently, antagonists at the neurokinin-1 receptor, the preferred receptor for the neuropeptide substance P, have been shown to have antidepressant activity. Mice with disruption of the neurokinin-1 receptor gene are remarkably similar both behaviourally and neurochemically to mice maintained chronically on antidepressant drugs. We demonstrate here that there is a significant elevation of neurogenesis but not cell survival in the hippocampus of neurokinin-1 receptor knockout mice. Neurogenesis can be increased in wild-type but not neurokinin-1 receptor knockout mice by chronic treatment with antidepressant drugs which preferentially target noradrenergic and serotonergic pathways. Hippocampal levels of brain-derived neurotrophic factor are also two-fold higher in neurokinin-1 receptor knockout mice, whereas cortical levels are similar. Finally, we examined hippocampus-dependent learning and memory but found no clear enhancement in neurokinin-1 receptor knockout mice. These data argue against a simple correlation between increased levels of neurogenesis or brain-derived neurotrophic factor and mnemonic processes in the absence of increased cell survival. They support the hypothesis that increased neurogenesis, perhaps accompanied by higher levels of brain-derived neurotrophic factor, may contribute to the efficacy of antidepressant drug therapy. [source] Voluntary exercise induces anxiety-like behavior in adult C57BL/6J mice correlating with hippocampal neurogenesisHIPPOCAMPUS, Issue 3 2010Johannes Fuss Abstract Several studies investigated the effect of physical exercise on emotional behaviors in rodents; resulting findings however remain controversial. Despite the accepted notion that voluntary exercise alters behavior in the same manners as antidepressant drugs, several studies reported opposite or no effects at all. In an attempt to evaluate the effect of physical exercise on emotional behaviors and brain plasticity, we individually housed C57BL/6J male mice in cages equipped with a running wheel. Three weeks after continuous voluntary running we assessed their anxiety- and depression-like behaviors. Tests included openfield, dark-light-box, elevated O-maze, learned helplessness, and forced swim test. We measured corticosterone metabolite levels in feces collected over a 24-h period and brain-derived neurotrophic factor (BDNF) in several brain regions. Furthermore, cell proliferation and adult hippocampal neurogenesis were assessed using Ki67 and Doublecortin. Voluntary wheel running induced increased anxiety in the openfield, elevated O-maze, and dark-light-box and higher levels of excreted corticosterone metabolites. We did not observe any antidepressant effect of running despite a significant increase of hippocampal neurogenesis and BDNF. These data are thus far the first to indicate that the effect of physical exercise in mice may be ambiguous. On one hand, the running-induced increase of neurogenesis and BDNF seems to be irrelevant in tests for depression-like behavior, at least in the present model where running activity exceeded previous reports. On the other hand, exercising mice display a more anxious phenotype and are exposed to higher levels of stress hormones such as corticosterone. Intriguingly, numbers of differentiating neurons correlate significantly with anxiety parameters in the openfield and dark-light-box. We therefore conclude that adult hippocampal neurogenesis is a crucial player in the genesis of anxiety. © 2009 Wiley-Liss, Inc. [source] Mirtazapine naturalistic depression study (in Sweden),MINDS(S): clinical efficacy and safetyHUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue 3 2006Jan Wålinder Abstract Objective To study how implementation of a naturalistic trial design for mirtazapine treatment in major depressive disorder for six (up to 12) months could be used and evaluated by means of clinical efficacy and safety. Method An open-labelled, prospective, multicenter, non-comparative trial was conducted during a 2-year period in patients with major depression according to DSM-IV treated in psychiatric departments and primary care in Sweden. Minimal inclusion and exclusion criteria were used in order to diminish the potential patient selection bias. Maximum flexibility of the dosage of mirtazapine was allowed, and clinical assessments included MADRS, CGI, vital signs and spontaneous reporting of adverse events. Results 192 patients were found eligible and enrolled in the study. A significant improvement in depressive symptoms according to MADRS and CGI was observed including particularly marked sleep improvement early in the treatment. Slight increases in body weight and BMI were observed. The investigational drug was well tolerated overall. Conclusion The clinical efficacy and safety of mirtazapine found in this naturalistic setting is in line with previously reported data on mirtazapine in traditional controlled clinical trials. The results confirm that the naturalistic study design facilitated conduct of the trial. The authors suggest that this type of study design should also be applied to other antidepressant drugs that are frequently prescribed in the general population. Copyright © 2006 John Wiley & Sons, Ltd. [source] Enantiomeric antidepressant drugs should be considered on individual meritHUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue S2 2001Pierre Baumann Abstract Many antidepressants have been introduced as racemic drugs, the enantiomers of which may differ in some of their pharmacodynamic and pharmacokinetic properties. This review argues that each enantiomer of a chiral antidepressant should be evaluated according to its individual characteristics rather than by extrapolation from the racemate, or by assumptions based on the stereoselective characteristics of other enantiomeric drugs. For example, in some cases the enantiomers' pharmacodynamic and therapeutic properties can be complementary, which suggests that the racemate should be used clinically. In other cases where enantiomers show qualitatively similar but quantitatively different properties to the racemate, using a single enantiomer might be more appropriate. In yet further cases, a distomer may induce the metabolism of the eutomer, enantiomers may be metabolised by different enzymes, there may be a different profile of drug,drug interactions, and therapeutic drug monitoring may be simpler. Therefore, this review exemplifies the principle that each enantiomer of a chiral antidepressant should be evaluated according to its individual pharmacological, pharmacokinetic and pharmacogenetic characteristics. These factors are discussed in relation to five chiral antidepressants: trimipramine, mianserin, mirtazapine, fluoxetine and citalopram. It is hoped that an appreciation of the stereoselective differences between enantiomers will facilitate improvements in the benefit:risk ratio of drugs used in the management of depression. Copyright © 2001 John Wiley & Sons, Ltd. [source] Corticosteroid use and risk of hip fracture: a population-based case,control study in DenmarkJOURNAL OF INTERNAL MEDICINE, Issue 5 2003P. Vestergaard Abstract. Vestergaard P, Olsen ML, Paaske Johnsen S, Rejnmark L, Toft Sørensen H, Mosekilde L (Aarhus University Hospital, Denmark; and Aarhus and Aalborg University Hospitals; Aarhus, Denmark). Corticosteroid use and risk of hip fracture: a population-based case,control study in Denmark. J Intern Med 2003; 254: 486,493. Background. Corticosteroids (CS) are used in a wide range of conditions but have several possible adverse effects including an increased risk of osteoporotic fractures. Objective. To examine the association between cumulative CS dose and risk of hip fracture. Design. Population-based case,control design. Subjects and methods. A total of 6660 subjects with hip fracture and 33 272 age-matched population controls were identified using the County Hospital Discharge Registry in North Jutland County, Denmark and the Danish Central Personal Registry, respectively. Data on redeemed prescriptions for CS within the last 5 years before the index date were retrieved from a population-based prescription database, and recalculated to prednisolone equivalents. Cases and controls were categorized according to cumulative CS dose: (i) no use; (ii) <130 mg (e.g. equivalent to 30 mg of prednisolone for 4 days given for an acute exacerbation of asthma); (iii) 130,499 mg (e.g. equivalent to a short course of prednisolone of 450 mg for acute asthma); (iv) 500,1499 mg (e.g. equivalent to 7.5 mg prednisolone daily for 6 months or 800 ,g day,1 of inhaled budesonide for 1 year); and (v) ,1500 mg (e.g. equivalent to >4.1 mg day,1 for 1 year, a long-term high dose). Data were analysed using conditional logistic regression adjusted for potential confounders including gender, redeemed prescriptions for hormone replacement therapy, antiosteoporotic, anxiolytic, antipsychotic and antidepressant drugs. Results. Compared with never users, an increased risk of hip fracture was found for CS users, with increasing cumulative doses of any type of CS use during the preceding 5 years [adjusted odds ratio (OR) = 0.96, 95% confidence interval (CI) = 0.89,1.04] for <130 mg prednisolone; OR = 1.17 (CI = 1.01,1.35) for 130,499 mg; OR = 1.36 (CI = 1.19,1.56) for 500,1499 mg; and OR = 1.65 (CI = 1.43,1.92) for ,1500 mg. An increased risk was also found when the study population was stratified according to gender, age and type of CS (systemic or topical). Conclusions. Even a limited daily dose of CS (more than an average dose of approximately 71 ,g prednisolone per day) was associated with an increased risk of hip fracture. [source] Analysis of tricyclic antidepressant drugs in plasma by means of solid-phase microextraction-liquid chromatography-mass spectrometryJOURNAL OF MASS SPECTROMETRY (INCORP BIOLOGICAL MASS SPECTROMETRY), Issue 10 2007Claudete Alves Abstract Solid-phase microextraction coupled to liquid chromatography and mass spectrometry (SPME-LC-MS) was used to analyze tricyclic antidepressant drugs desipramine, imipramine, nortriptyline, amitriptyline, and clomipramine (internal standard) in plasma samples. SPME was performed by direct extraction on a PDMS/DVB (60 µm) coated fiber, employing a stirring rate of 1200 rpm for 30 min, pH 11.0, and temperature of 30 °C. Drug desorption was carried out by exposing the fiber to the liquid chromatography mobile phase for 20 min, using a labmade SPME-LC interface at 50 °C. The main variables experimentally influencing LC-MS response were evaluated and mathematically modeled. A rational optimization with fewer experiments was achieved using a factorial design approach. The constructed empirical models were adjusted with 96,98% of explained deviation allowing an adequate data set comprehension. The chromatographic separation was realized using an RP-18 column (150 mm × 2.1 mm, 5 µm particles) and ammonium acetate buffer (0.01 mol/l, pH 5.50) : acetonitrile (50 : 50 v/v) as mobile phase. Low detection levels were achieved with electrospray interface (0.1 ng/ml). The developed method showed specificity, linearity, precision, and limit of quantification adequate to assay tricyclic antidepressant drugs in plasma. Copyright © 2007 John Wiley & Sons, Ltd. [source] Behavioural Assays to Model Cognitive and Affective Dimensions of Depression and Anxiety in RatsJOURNAL OF NEUROENDOCRINOLOGY, Issue 10 2008M. D. S. Lapiz-Bluhm Animal models have been used extensively to investigate neuropsychiatric disorders, such as depression, and their treatment. However, the aetiology and pathophysiology of many such disorders are largely unknown, which makes validation of animal models particularly challenging. Furthermore, many diagnostic symptoms are difficult to define, operationalise and quantify, especially in experimental animals such as rats. Thus, rather than attempting to model complex human syndromes such as depression in their entirety, it can be more productive to define and model components of the illness that may account for clusters of co-varying symptoms, and that may share common underlying neurobiological mechanisms. In preclinical investigations of the neural regulatory mechanisms linking stress to depression and anxiety disorders, as well as the mechanisms by which chronic treatment with antidepressant drugs may exert their beneficial effects in these conditions, we have employed a number of behavioural tests in rats to model specific cognitive and anxiety-like components of depression and anxiety disorders. In the present study, we review the procedures for conducting four such behavioural assays: the attentional set-shifting test, the elevated-plus maze, the social interaction test and the shock-probe defensive burying test. The purpose is to serve as a guide to the utility and limitations of these tools, and as an aid in optimising their use and productivity. [source] Inhibition and possible induction of rat CYP2D after short- and long-term treatment with antidepressantsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 11 2002Wladys, awa A. Daniel The aim of this study was to investigate the influence of tricyclic antidepressants (imipramine, amitriptyline, clomipramine, desipramine), selective serotonin reuptake inhibitors (SSRIs: fluoxetine, sertraline) and novel antidepressant drugs (mirtazapine, nefazodone) on the activity of CYP2D, measured as a rate of ethylmorphine O -deethylation. The reaction was studied in control liver microsomes in the presence of the antidepressants, as well as in microsomes of rats treated intraperitoneally for one day or two weeks (twice a day) with pharmacological doses of the drugs (imipramine, amitriptyline, clomipramine, nefazodone 10 mg kg,1 i.p.; desipramine, fluoxetine, sertraline 5 mg kg,1 i.p.; mirtazapine 3 mg kg,1 i.p.), in the absence of the antidepressants in-vitro. Antidepressants decreased the activity of the rat CYP2D by competitive inhibition of the enzyme, the potency of their inhibitory effect being as follows: clomipramine (Ki = 14 ,M) > sertraline , fluoxetine (Ki = 17 and 16 ,M, respectively) > imipramine , amitriptyline (Ki = 26 and 25 ,M, respectively) > desipramine (Ki = 44 ,M) > nefazodone (Ki = 55 ,M) > mirtazapine (Ki = 107 ,M). A one-day treatment with antidepressants caused a significant decrease in the CYP2D activity after imipramine, fluoxetine and sertraline. After prolonged administration of antidepressants, the decreased CYP2D activity produced by imipramine, fluoxetine and sertraline was still maintained. Moreover, amitriptyline and nefazodone significantly decreased, while mirtazapine increased the activity of the enzyme. Desipramine and clomipramine did not produce any effect when administered in-vivo. The obtained results indicate three different mechanisms of the antidepressants-CYP2D interaction: firstly, competitive inhibition of CYP2D shown in-vitro, the inhibitory effects of tricyclic antidepressants and SSRIs being stronger than those of novel drugs; secondly, in-vivo inhibition of CYP2D produced by both one-day and chronic treatment with tricyclic antidepressants (except for desipramine and clomipramine) and SSRIs, which suggests inactivation of the enzyme apoprotein by reactive metabolites; and thirdly, in-vivo inhibition by nefazodone and induction by mirtazapine of CYP2D produced only by chronic treatment with the drugs, which suggests their influence on the enzyme regulation. [source] Withdrawing antidepressants: guide to patient managementPRESCRIBER, Issue 1 2006Guy Edwards FRCPsych Our series on stopping drugs provides practical advice on why, when and how to withdraw and change drug therapy. In this article, Dr Edwards discusses the withdrawal of antidepressant drugs and addresses some of the issues this raises with respect to patient management. Copyright © 2006 Wiley Interface Ltd [source] ,2 -adrenoceptors are critical for antidepressant treatment of neuropathic pain,ANNALS OF NEUROLOGY, Issue 2 2009Ipek Yalcin PharmD Objective Tricyclic antidepressants (TCAs) are one of the first-line pharmacological treatments against neuropathic pain. TCAs increase the extracellular concentrations of noradrenaline and serotonin by blocking the reuptake transporters of these amines. However, the precise downstream mechanism leading to the therapeutic action remains identified. In this work, we evaluated the role of adrenergic receptors (ARs) in the action of TCAs. Methods We used pharmacological and genetic approaches in mice to study the role of ARs in the antiallodynic action of the TCA nortriptyline. Peripheral neuropathy was induced by the insertion of a polyethylene cuff around the main branch of the sciatic nerve. The specific role of ,2 -AR was evaluated by studying ,2 -AR,/, mice. We used von Frey filaments to assess mechanical allodynia. Results The antiallodynic action of nortriptyline was not affected by cotreatment with the ,2 -AR antagonist yohimbine, the ,1 -AR antagonists atenolol or metoprolol, or the ,3 -AR antagonist SR 59230A. On the contrary, the ,-AR antagonists propranolol or sotalol, the ,1/,2 -AR antagonists alprenolol or pindolol, or the specific ,2 -AR antagonist ICI 118,551 blocked the action of nortriptyline. The effect of nortriptyline was also totally absent in ,2 -AR,deficient mice. Interpretation Stimulation of ,2 -AR is necessary for nortriptyline to exert its antiallodynic action against neuropathic pain. These findings provide new insight into the mechanism by which antidepressants alleviate neuropathic pain. Our results also raise the question of a potential incompatibility between ,-blockers that affect ,2 -AR and antidepressant drugs in patients treated for neuropathic pain. Ann Neurol 2009;65:218,225 [source] Ef,ciency of antidepressant drugs as monoamine reuptake inhibitors: analysis of the hydrophobicity in,uence using biopartitioning micellar chromatographic dataBIOMEDICAL CHROMATOGRAPHY, Issue 7 2004C. Quiñones-Torrelo Abstract The reuptake blockade of biogenic amines by antidepressants is related not only to their therapeutics effects, but also to their side effects and potential drug,drug interactions. As an alternative to classical quantitative structure,activity relationships studies, in this work we propose different quantitative retention,activity relationships (QRAR) models that are able to describe the monoamine reuptake inhibition by antidepressants. The retention of compounds is measured using a biopartitioning micellar chromatography (BMC) system that can simulate the same hydrophobic, electronic and steric molecular interactions as those that condition drug activity. Since all the compounds considered in this work are structurally related because all of them share the same molecular features as the corresponding basic pharmacophore, the results obtained show that there is a retention range in which antidepressants present the highest monoamine reuptake inhibitor potency. Copyright © 2003 John Wiley & Sons, Ltd. [source] Reduced signal transduction by 5-HT4 receptors after long-term venlafaxine treatment in ratsBRITISH JOURNAL OF PHARMACOLOGY, Issue 3 2010R Vidal BACKGROUND AND PURPOSE The 5-HT4 receptor may be a target for antidepressant drugs. Here we have examined the effects of the dual antidepressant, venlafaxine, on 5-HT4 receptor-mediated signalling events. EXPERIMENTAL APPROACH The effects of 21 days treatment (p.o.) with high (40 mg·kg,1) and low (10 mg·kg,1) doses of venlafaxine, were evaluated at different levels of 5-HT4 receptor-mediated neurotransmission by using in situ hybridization, receptor autoradiography, adenylate cyclase assays and electrophysiological recordings in rat brain. The selective noradrenaline reuptake inhibitor, reboxetine (10 mg·kg,1, 21 days) was also evaluated on 5-HT4 receptor density. KEY RESULTS Treatment with a high dose (40 mg·kg,1) of venlafaxine did not alter 5-HT4 mRNA expression, but decreased the density of 5-HT4 receptors in caudate-putamen (% reduction = 26 ± 6), hippocampus (% reduction = 39 ± 7 and 39 ± 8 for CA1 and CA3 respectively) and substantia nigra (% reduction = 49 ± 5). Zacopride-stimulated adenylate cyclase activation was unaltered following low-dose treatment (10 mg·kg,1) while it was attenuated in rats treated with 40 mg·kg,1 of venlafaxine (% reduction = 51 ± 2). Furthermore, the amplitude of population spike in pyramidal cells of CA1 of hippocampus induced by zacopride was significantly attenuated in rats receiving either dose of venlafaxine. Chronic reboxetine did not modify 5-HT4 receptor density. CONCLUSIONS AND IMPLICATIONS Our data indicate a functional desensitization of 5-HT4 receptors after chronic venlafaxine, similar to that observed after treatment with the classical selective inhibitors of 5-HT reuptake. [source] Open questions in current models of antidepressant actionBRITISH JOURNAL OF PHARMACOLOGY, Issue 6 2010A Tanti Research on depression and antidepressant drugs is necessary, as many patients display poor response to therapy. Different symptomatic and pathophysiological features have been proposed as end points of the depressive phenotype and of the antidepressant action, including anhedonia, depressed mood, alterations in morphology and activity of some brain areas (amygdala, nucleus accumbens, hippocampus, prefrontal cortex and cingulate cortex), modifications in the connectivity between brain structures, changes in neurotransmitters (serotonin, noradrenaline, glutamate and neuropeptides), brain plasticity (neurogenesis, neurotrophins) and abnormal function of the hypothalamic-pituitary adrenal axis. However, few models have been proposed to describe how these end points could induce the depressive phenotype and are involved in the mechanism of action of antidepressants. Here we propose a connectionist-inspired network of depression and antidepressant action, in which the different aetiological factors participating in the release of a depressive episode are represented by input nodes, the different symptomatic as well as pathophysiological end points are represented by an intermediate layer, and the onset of depression or of comorbid disease is represented by the output node. The occurrence of depression and the mechanism of the antidepressant action thus depend upon the weight of the interactions between the different end points, none of them being per se crucial to the onset of a depressive phenotype or to the antidepressant action. This model is heuristic to draw future lines of research concerning new antidepressant therapies, designing new animal models of depression and for a better understanding of the depressive pathology and of its comorbid pathology such as anxiety disorders. [source] Neurotransmitter transporters and their impact on the development of psychopharmacologyBRITISH JOURNAL OF PHARMACOLOGY, Issue S1 2006Leslie Iversen The synaptic actions of most neurotransmitters are inactivated by reuptake into the nerve terminals from which they are released, or by uptake into adjacent cells. A family of more than 20 transporter proteins is involved. In addition to the plasma membrane transporters, vesicular transporters in the membranes of neurotransmitter storage vesicles are responsible for maintaining vesicle stores and facilitating exocytotic neurotransmitter release. The cell membrane monoamine transporters are important targets for CNS drugs. The transporters for noradrenaline and serotonin are key targets for antidepressant drugs. Both noradrenaline-selective and serotonin-selective reuptake inhibitors are effective against major depression and a range of other psychiatric illnesses. As the newer drugs are safer in overdose than the first-generation tricyclic antidepressants, their use has greatly expanded. The dopamine transporter (DAT) is a key target for amphetamine and methylphenidate, used in the treatment of attention deficit hyperactivity disorder. Psychostimulant drugs of abuse (amphetamines and cocaine) also target DAT. The amino-acid neurotransmitters are inactivated by other families of neurotransmitter transporters, mainly located on astrocytes and other non-neural cells. Although there are many different transporters involved (four for GABA; two for glycine/D -serine; five for L -glutamate), pharmacology is less well developed in this area. So far, only one new amino-acid transporter-related drug has become available: the GABA uptake inhibitor tiagabine as a novel antiepileptic agent. British Journal of Pharmacology (2006) 147, S82,S88. doi:10.1038/sj.bjp.0706428 [source] | ||||||||||||||||||||||||||||||||||