Antidepressant medication use for and risk of ovarian cancer.

Moorman PG, Berchuck A, Calingaert B, Halabi S, Schildkraut JM.

Cancer Prevention, Detection, and Control Research Program, Department of Community and Family Medicine, Duke University Medical Center.

OBJECTIVE: It has been hypothesized that antidepressants may enhance cancer growth. Previous studies of antidepressant use and ovarian cancer have been inconsistent and have been limited in their ability to examine the association with selective serotonin reuptake inhibitors (SSRIs), which are currently the antidepressants most commonly prescribed. The objective of this paper was to evaluate whether women with ovarian cancer were more likely to report past use of antidepressants than control women. METHODS: Antidepressant use was assessed in a population-based, case-control study of ovarian cancer (593 cases, 628 controls). Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) associated with antidepressant use overall and by subcategories of antidepressants. RESULTS: Antidepressant use was reported by 18% of cases and 20% of controls. No increased risk was observed for ever use of any type of antidepressant (OR 0.9, 95% CI 0.7-1.2) or for SSRIs (OR 1.0, 95% CI 0.7-1.5). There also was no evidence of increased risk with longer duration of use. Our study had greater than 80% power to detect an OR as small as 1.5. Thus, even a modest increase in risk associated with antidepressant use can be excluded with these data. CONCLUSION: Our study adds to the growing body of evidence suggesting that antidepressants do not have a significant effect on ovarian cancer risk. In particular, the data suggest that SSRIs, which are the most commonly used class of antidepressants, are not associated with an increased risk for ovarian cancer. LEVEL OF EVIDENCE: II-2.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15802397&dopt=Abstract antidepressant




Management of Depression After Stroke. A Systematic Review of Pharmacological Therapies.

Hackett ML, Anderson CS, House AO.

From The George Institute for International Health, Neurological Diseases and Ageing Division, affiliated with the Royal Prince Alfred Hospital and the University of Sydney, Australia; and Academic Unit of Psychiatry and Behavioural Sciences, University of Leeds, United Kingdom.

BACKGROUND AND PURPOSE: Although depression may affect recovery and outcome after stroke, it is often overlooked or inadequately managed, and there is uncertainty regarding the benefits of antidepressant therapy in this setting. We aimed to assess the effectiveness of antidepressants for the treatment and prevention of depression after stroke. METHODS: We undertook a systematic review using Cochrane methods of randomized placebo-controlled trials of antidepressants for the treatment or prevention of depressive illness and "abnormal mood" after stroke. Treatment effects on physical and other outcomes were also examined. RESULTS: Outcome data were available for 7 treatment trials including 615 patients and 9 prevention trials including 479 patients. Because of the considerable variation in research design, trial quality, and method of reporting across studies, we did not pool all the outcome data. In the treatment trials, antidepressants reduced mood symptoms but had no clear effect on producing a remission of diagnosable depressive illness. There was no definitive evidence that antidepressants prevent depression or improve recovery after stroke. CONCLUSIONS: There is insufficient randomized evidence to support the routine use of antidepressants for the prevention of depression or to improve recovery from stroke. Although antidepressants may improve mood in stroke patients with depression, it is unclear how clinically significant such modest effects are in patients other than those with major depression. There is a pressing need for further research to better define the role of antidepressants in stroke management.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15802637&dopt=Abstract antidepressant




Comparison of Alterations in c-fos and Egr-1 (zif268) Expression Throughout the Rat Brain Following Acute Administration of Different Classes of Antidepressant Compounds.

Slattery DA, Morrow JA, Hudson AL, Hill DR, Nutt DJ, Henry B.

[1] 1Psychopharmacology Unit, Dorothy Hodgkin Building, Whitson Street, University of Bristol, Bristol, UK [2] 2Department of Pharmacology, Organon Laboratories Ltd, Newhouse, Lanarkshire, Scotland, UK [3] 3Neuroscience Research, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland.

The majority of immediate-early gene (IEG) studies focus on a few key brain regions associated with the class of psychoactive compound being studied. Recently, using a meta-analysis of the c-fos literature, we demonstrated the utility of c-fos profiling to classify such compounds. The present study examined acute delivery of a range of antidepressant classes; fluoxetine, imipramine, LiCl, and mirtazapine. The dual aims were to study the IEG profiles of these varying classes of antidepressants throughout the rat brain and to compare the utility of c-fos or Egr-1 as IEGs to classify clinically efficacious antidepressants. All antidepressants increased c-fos mRNA in the central amygdala, as previously shown, while c-fos was also increased in the anterior insular cortex and significantly decreased within the septum. Although acute antidepressant administration altered c-fos expression in a number of brain regions, Egr-1 expression was only significantly altered in the central amygdala, suggesting that Egr-1 may not be as useful a marker to investigate acute antidepressant treatment. The fact that these drugs, including the previously unclassified antidepressant mirtazapine, share a number of common loci of activation, which are implicated by human and animal studies in depression, adds further support to the use of IEG mapping to classify psychoactive compounds.Neuropsychopharmacology advance online publication, 6 April 2005; doi:10.1038/sj.npp.1300717.

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Substance p receptor antagonists in psychiatry : rationale for development and therapeutic potential.

Herpfer I, Lieb K.

Department of Psychiatry and Psychotherapy, University of Freiburg Medical School, Freiburg, GermanyDepartment of Pharmacology, University College London, London, UK.

Increasing evidence suggests that substance P (SP) and its receptor (neurokinin [NK]-1 receptor [NK1R]) might play an important role in the modulation of stress-related, affective and/or anxious behaviour. First, SP and NK1R are expressed in brain regions that are involved in stress, fear and affective response (e.g. amygdala, hippocampus, hypothalamus and frontal cortex). Second, the SP content in these areas changes upon application of stressful stimuli. Third, the central administration of SP produces a range of fear-related behaviours. In addition, the SP/NK1R system shows significant spatial overlap with neurotransmitters such as serotonin and noradrenaline (norepinephrine), which are known to be involved in the regulation of stress, mood and anxiety. Therefore, it was hypothesised that blockade of the NK1R might have anxiolytic as well as antidepressant effects.Preclinical studies investigating the effects of genetic or pharmacological NK1R inactivation on animal behaviour in assays relevant to depression and anxiety revealed that the behavioural changes resemble those seen with reference antidepressant or anxiolytic drugs. Furthermore, antagonism or genetic inactivation of the NK1R causes alterations in serotonin and norepinephrine neuronal transmission that are likely to contribute to the antidepressant/anxiolytic activity of NK1R antagonists but that are - at least partially - distinct from those produced by established antidepressant drugs. This underlines the conceivable unique mechanism of action of this new class of compounds. In three independent clinical trials with three different compounds (aprepitant [MK-869], L-759274 and CP-122721), an antidepressant effect of NK1R antagonists could be demonstrated. These results, however, have been challenged by recent failed studies with aprepitant.There are numerous indications from preclinical studies that, in addition to SP and NK1R, other neurokinins and/or neurokinin receptors might also be involved in the modulation of stress-related behaviour and that exclusive blockade of the NK1R might not be sufficient to produce consistent anxiolytic and antidepressant effects. One such candidate is the neurokinin-2 receptor (NK2R), and clinical trials to assess the antidepressant effects of NK2R antagonists are currently underway. Of special interest might also be substances that block more than one receptor type such as NK1/2R antagonists or NK1/2/3R antagonists. These compounds may be more efficacious in antagonising the effects of SP than compounds that only block the NK1R.

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Changes in signaling pathways regulating neuroplasticity induced by neurokinin 1 receptor knockout.

Musazzi L, Perez J, Hunt SP, Racagni G, Popoli M.

Center of Neuropharmacology-Department of Pharmacological Sciences and Center of Excellence on Neurodegenerative Diseases, University of Milan, Via Balzaretti 9-20133 Milano, Italy.

Abstract Neurokinin 1 (NK-1) receptor knockout mice showed behavioral responses similar to animals chronically treated with antidepressants. The aim of this study was to analyse, in NK-1 receptor knockout, the molecular modifications of signaling pathways involved in the pathophysiology of depression and antidepressant mechanism. We found, in total cell cytosol from the prefrontal/frontal cortex, hippocampus and striatum, a marked up-regulation of Ca(2+)-independent enzymatic activity and Thr(286) autophosphorylation of Ca(2+)/calmodulin-dependent protein kinase (CaMK) II. Similar changes in CaMKII regulation were previously observed in rats chronically treated with antidepressants. In striatum, up-regulation of the activity and phosphorylation of CaMKII was also found in the homogenate and synaptosomes. No major changes were observed in the Ca(2+)-dependent kinase activity, with the exception of homogenate from the prefrontal/frontal cortex. We also analysed the expression and phosphorylation of presynaptic proteins, which modulate synaptic vesicle trafficking and exocytosis, and found a marked decrease in synapsin I total expression and basal phosphorylation of Ser(603) (the phosphorylation site for CaMKII) in the prefrontal/frontal cortex. Accordingly, the Ca(2+)/calmodulin-dependent posthoc endogenous phosphorylation of synapsin I in the same area was increased. The knockout of NK-1 receptor had no consequences on the expression or phosphorylation levels of the transcription factor cAMP-responsive element-binding protein and its regulating kinase CaMKIV. However, phosphorylation of ERK1/2-mitogen-activated protein kinases was reduced in the hippocampus and striatum, again resembling an effect previously observed in antidepressant-treated rats. These results show similarities between NK-1 knockouts and animals chronically treated with antidepressants and support the putative antidepressant activity of NK-1 receptor antagonists.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15813946&dopt=Abstract antidepressant




Prescribing rates for psychotropic medication amongst east London general practices: low rates where Asian populations are greatest.

Hull SA, Cornwell J, Harvey C, Eldridge S, Bare PO.

Department of General Practice and Primary Care, Queen Mary and Westfield College, Medical Sciences, Mile End Road, London E1 4NS, UK.

OBJECTIVES: The aim of this study was to examine the contribution of Asian ethnicity to the variation in rates of practice prescribing for antidepressant and anxiolytic medication, taking into account other population and practice organizational factors. METHODS: A practice-based cross-sectional survey was carried out of the prescribing of antidepressants and anxiolytics (daily defined dosages) in 164 general practices. The study was set in East London and the City Health Authority, which includes the multiethnic inner London boroughs of Hackney, Tower Hamlets, Newham and the City of London. The main outcome measures were the annual prescribing rates for each group of drugs, calculated as the total annual daily defined dosages divided by the practice population, and the ratio of antidepressant/ anxiolytic annual prescribing rates. RESULTS: Prescribing rates for antidepressants showed a 25-fold variation between practices; this was greater for anxiolytics. The median annual prescribing rate for all antidepressants combined was 4.13 (interquartile range 2.50-5.88). For all anxiolytics and hypnotics combined the median annual prescribing rate was 3.55 (interquartile range 1.71-6.36). Univariate analysis showed that Asian ethnicity alone accounted for 28% of the variation in antidepressant prescribing and 20.5% of the variation in the anxiolytic prescribing. A backwards multiple regression model using 10 explanatory practice and population variables accounted for 47.7% of the variance in antidepressant prescribing and 34% of the variance in the anxiolytic prescribing. CONCLUSION: In practices where the proportion of Asian patients is high, both antidepressant and anxiolytic prescribing is low. This is important for understanding interpractice prescribing variation and for setting levels of drug budgets. This study confirms that the low rates of non-psychotic disorders presented by Asian populations is not a selective feature of access to secondary care, but is evident in the prescribing behaviour of GPs. Uncertainty remains as to how much this is due to a lower prevalence rate, "culture-bound syndromes" or practical difficulties in diagnosis and management within the general practice setting.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11264267&dopt=Abstract antidepressant




Anti-Inflammatory effects of antidepressants through suppression of the interferon-gamma/interleukin-10 production ratio.

Kubera M, Lin AH, Kenis G, Bosmans E, van Bockstaele D, Maes M.

Clinical Research Center for Mental Health, Antwerp, Belgium.

There is some evidence that major depression--in particular, treatment-resistant depression (TRD)--is accompanied by activation of the inflammatory response system and that proinflammatory cytokines may play a role in the etiology of depression. This study was carried out to examine the effects of antidepressive agents, i.e., imipramine, venlafaxine, L-5-hydroxytryptophan, and fluoxetine on the production of interferon-gamma (IFN-gamma), a proinflammatory cytokine, and interleukin-10 (IL-10), a negative immunoregulatory cytokine. Diluted whole blood of fluoxetine-treated patients with TRD (mean age, 50.6+/-3.9 years) and age-matched healthy controls (mean age, 51.6+/-1.7 years) and younger healthy volunteers (mean age, 35.4+/-9.6 years) was stimulated with phytohemagglutinin (1 microg/mL) and lipopolysaccharide (5 microg/mL) for 48 hours with and without incubation with the antidepressants at 10-6 M and 10(-5) M. IFN-gamma and IL-10 were quantified by means of enzyme-linked immunoassays. The ratio of IFN-gamma to IL-10 production by immunocytes was computed because this ratio is of critical importance in determining the capacity of immunocytes to activate or inhibit monocytic and T-lymphocytic functions. All four antidepressive drugs significantly increased the production of IL-10. Fluoxetine significantly decreased the production of IFN-gamma. All four antidepressants significantly reduced the IFN-gamma/IL-10 ratio. There were no significant differences in the antidepressant-induced changes in IFN-gamma or IL-10 between younger and older healthy volunteers and TRD patients. Tricyclic antidepressants, selective serotonin reuptake inhibitors, and serotonin-noradrenaline reuptake inhibitors, as well as the immediate precursor of serotonin, have a common, negative immunoregulatory effect by suppressing the IFN-gamma/IL-10 production ratio. It is suggested that the therapeutic efficacy of antidepressants may be related to their negative immunoregulatory effects.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11270917&dopt=Abstract antidepressant




Salmon calcitonin potentiates the analgesia induced by antidepressants.

Ormazabal MJ, Goicoechea C, Sanchez E, Martin MI.

Dpto. Farmacologia, Fac. Medicina, Universidad Complutense de Madrid, Avda Complutense s/n, Ciudad Universitaria, 28040 Madrid, Spain.

Antidepressants are used in the treatment of a variety of pain syndromes. Most of them act by blocking noradrenaline (NA) and serotonin (5-HT) reuptake. It is also well known that the serotonergic system is also involved in calcitonin (CT) analgesia. Taking these two evidences into account, the modification of the analgesic effect of nortriptyline, amitriptyline, and paroxetine in the presence of salmon CT (s-CT) was examined in mice. The forced-swimming test was carried out in order to choose doses of each drug that did not induce an antidepressant effect under our experimental conditions (nortriptyline: 0.2-5 mg/kg ip, amitriptyline: 2.5-20 mg/kg ip, and paroxetine: 5-30 mg/kg ip). The analgesic effect of each antidepressant was then evaluated using the acetic acid test. At the doses tested, the antidepressants induced a dose-dependent analgesic effect. When mice were pre-treated with a subanalgesic dose of s-CT (2.5 IU/kg), the analgesic effect of amitriptyline and paroxetine was significantly increased though no modification was found for nortriptyline. In summary, s-CT was able to increase the analgesic effect of the antidepressant drugs that reduce the uptake of 5-HT, suggesting that the joint administration of antidepressants and CT may be an interesting alternative in pain management.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11274717&dopt=Abstract antidepressant