PREFEITURA MUNICIPAL DE JAHU DEPARTAMENTO DE LICITAÇÕES ATA DE REGISTRO DE PREÇO Nº 003/07 PREGÃO ELETRÔNICO N.º 045/07 – PROCESSO Nº 1668/2007 VALIDADE: 29 DE NOVEMBRO DE 2008 Aos 29 dias do mês de novembro do ano de 2007, presente de um lado o Município de Jaú, pessoa jurídica de direito público, com a Rua Paissandú, 444, nesta cidade de Jaú (SP), ins
Suomen sivusto, jossa voit ostaa halvalla ja laadukas Viagra http://osta-apteekki.com/ toimitus kaikkialle maailmaan.
Yritti äskettäin viagra, se toimii erittäin tehokkaasti)) Ostaa Internetin kautta täällä priligy Myös ostaa levitra oikeudenkäynti, vaikutus on silmiinpistävää.
Genetic and clinical predictors of sexual dysfunction in citalopram-treated depressed patientsNeuropsychopharmacology (2009) 34, 1819–1828& 2009 Nature Publishing Group All rights reserved 0893-133X/09 $32.00 Genetic and Clinical Predictors of Sexual Dysfunction inCitalopram-Treated Depressed Patients Roy H Perlis*,1,2, Gonzalo Laje3, Jordan W Smoller1,2, Maurizio Fava1, A John Rush4 and Francis J McMahon3 Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA; 2Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA; 3Intramural Research Program, National Institute of Mental Health, Bethesda, MD, USA; 4Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA Sexual dysfunction is a major contributor to treatment discontinuation and nonadherence among patients treated with selective serotonin reuptake inhibitors (SSRIs). The mechanisms by which depressive symptoms in general, as well as SSRI exposure in particular, may worsen sexual function are not known. We examined genetic polymorphisms, including those of the serotonin and glutamate systems, for association with erectile dysfunction, anorgasmia, and decreased libido during citalopram treatment. Clinical data were drawn from a nested case–control cohort derived from the STAR*D study, a multicenter, prospective, effectiveness trial in outpatients with nonpsychotic major depressive disorder (MDD). Self-reports of erectile dysfunction, decreased libido, or difficulty achieving orgasm based on the Patient-Rated Inventory of Side Effects were examined among Caucasian subjects (n effect measures were available, and who were treated openly with citalopram for up to 14 weeks. Of 1473 participants, 799 (54%) reported decreased libido; 525 (36%) reported difficulty achieving orgasm. Of 574 men, 211 (37%) reported erectile dysfunction. Using a set-based test for association, single nucleotide polymorphisms in glutamatergic genes were associated with decreased libido (GRIA3; GRIK2), difficulty achieving orgasm (GRIA1), and difficulty achieving erection (GRIN3A) (experiment-wide permuted po0.05 for each).
Evidence of association persisted after adjustment for baseline clinical and sociodemographic differences. Likewise, evidence of association was similar when the cohort was limited to those who did not report a given adverse event at the first post-baseline visit (ie, those whose adverse events were known to be treatment emergent). These hypothesis-generating analyses suggest the potential for glutamatergic treatment targets for sexual dysfunction during major depressive episodes.
Neuropsychopharmacology (2009) 34, 1819–1828; published online 18 March 2009 Keywords: antidepressant; pharmacogenetic; serotonin; glutamate; adverse effect significant SSRI-related adverse event among individualsage 18–40 Sexual dysfunction is common among individuals with The mechanism by which depression itself, or treatments major depressive episodes and may be triggered or such as SSRIs, may induce sexual dysfunction is poorly exacerbated by treatment with the selective serotonin understood. Because the proximal site of action of SSRIs is reuptake inhibitors (SSRIs), with a prevalence of up to believed to be the serotonin transporter, some sexual effects 50–70% in some studies when sexual functioning is have been presumed to relate to serotonergic neurotrans- sexual functioning in general offers some additional decreased libido, difficulty in arousal, and delayed or absent direction about which neurotransmitter systems might be most likely to mediate these symptoms. Specifically, other of life, these effects frequently lead to medication intoler- monoamines, as well as glutamate, appear to have a function in male and female sexual behavior Indeed, sexual dysfunction may be the most clinically Because of their potential importance in antidepressant efficacy, common variations in serotonergic, glutamatergic, *Correspondence: Dr RH Perlis, Department of Psychiatry, Massachu- dopaminergic, and other pathways implicated in antide- setts General Hospital, 185 Cambridge Street, 6th Floor, Boston, MA pressant mechanism of action have been examined recently 02114, USA, Tel: + 1 617 726 7426, Fax: + 1 617 726 6768,E-mail: in a genetic association study in the STAR*D cohort Received 29 July 2008; revised 18 September 2008; accepted 24 to clarify the mechanism by which depression and its treatments may contribute to sexual dysfunction, we MDD with psychotic features, schizophrenia, schizoaffective performed a hypothesis-generating secondary analysis in disorder, or bipolar disorder; a current primary diagnosis of which we examined these genes for association with sexual eating disorder or obsessive-compulsive disorder; presence of severe, unstable concurrent psychiatric conditions likelyto require hospitalization within 6 months (eg severealcohol dependence with recent detoxification admissions); presence of concurrent medical or psychiatric conditions or concomitant medications that contraindicate a protocoltreatment; and pregnancy or intent to conceive within the 9 In the STAR*D trial, all patients were initially treated with the SSRI citalopram. Those who were intolerant ofcitalopram, or who did not achieve remission, could then be randomized to a next-step treatment option. Themethods of the STAR*D study are described in detail The CRC at each study site completed the HRSD17 at baseline to determine eligibility, reviewed other inclusion/ exclusion criteria, and completed the 16-item QuickInventory of Depressive Symptomatology (QIDS-C16) at eachtreatment visitFa clinician-rated scale that assesses nine The STAR*D study, overseen by 14 regional centers (RCs), diagnostic symptoms/domains of MDD. The QIDS-C16 was provided treatment at 41 clinical sites (18 primary care and used to guide treatment implementation and dose adjust- 23 psychiatric care settings) across the United States.
Research outcomes were collected by telephone inter- selected as the primary outcome measure for STAR*D views conducted by a small team of trained research genetics reports. The CRC also completed the 14-item outcome assessors (ROAs) masked to treatment. ROAs received extensive training in the administration of efficacy that quantifies the severity/morbidity of general measures, with interrater reliability assessed periodically.
medical conditions relevant to different organ systems. Eachof the 14 illness categories was scored 0 (no problem) to 4 (extremely severe/immediate treatment required/end organfailure/severe impairment in function). The present analysis The STAR*D clinical cohort consisted of 4041 subjects, of examined total severity summed over all categories except whom 1953 provided blood samples for extraction of DNA and 1910 were genotyped, including 1499 (78.5%) Cauca- The ROA conducted a telephone interview with study sians. This report presents data from the 1473 Caucasians participants within 72 h of the baseline and subsequent from this pool who returned for at least one follow-up visit visits to complete the baseline blinded HRSD17 and the 30- (ie, a modified intent-to-treat cohort). As the study was item Inventory of Depressive Symptomatology, Clinician- designed to represent real-world clinical practice, only individuals who sought treatment at the clinical sites were Individual adverse events were identified at each post- recruited, and advertising was not permitted. Participants baseline clinical visit using the Patient-Rated Inventory of were informed of all risks, benefits, and adverse events Side Effects (PRISE) a nine-item patient- associated with each study treatment and they provided rated assessment of presence or absence of side effects in written informed consent before study entry at each level, as domains including gastrointestinal, cardiac, skin, nervous well as for the genetic study. Participants could decline system, sensory organs, genital/urinary, sleep, sexual participation in the genetic protocol, which was initiated functioning, and other. In each domain, multiple symptoms about 12 months after the clinical study initiation. The may be endorsed. No standardized assessment of patient study protocol was approved by institutional review boards adherence to treatment was collected.
at all participating RCs, the National Coordinating Center,and the Data Coordinating Center. The study was overseen Participants met broadly inclusive and minimal exclusive Details of the STAR*D measurement-based care approach criteria to enroll a representative sample. Male and female outpatients, age 18–75, with a DSM-IV diagnosis of Following citalopram treatment at doses up to 60 mg per nonpsychotic major depressive disorder (MDD), a baseline day for up to 14 weeks, participants who did not achieve score X14 on the 17-item Hamilton Rating Scale for citalopram were encouraged to proceed to next-step research coordinator (CRC), and for whom the treating treatments. Participants could discontinue citalopram and clinician had determined that outpatient antidepressant proceed to next-step treatment at any point in the event of treatment was safe and appropriate were enrolled. Exclusion intolerable side effects requiring change in medication, criteria included a well-documented history of nonresponse inability to increase to an optimal dose because of side or intolerability in the current major depressive episode to effects or patient preference, or presence of significant adequate doses of one or more medications depressive symptoms (defined as QIDS-C16 score X9) after used in the first two treatment steps; lifetime diagnosis of Sexual dysfunction with SSRI treatmentRH Perlis et al Concomitant treatments for current general medical in terms of maximal citalopram dose, amount of decrease in conditions, for associated symptoms of depression includ- QIDS-C16 from baseline to end point, achieving remission ing insomnia, anxiety, and agitation, and for antidepre- ssant-associated side effects were permitted based on medication tolerability (using an algorithm previously clinical judgment. However, stimulants, anticonvulsants, anti- described), and presence or absence of sedative/hypnotic psychotics, alprazolam, nonprotocol antidepressants other than trazodone p200 mg at bedtime for insomnia, andpsychotherapies targeted at depressive symptoms were not association studies, we considered the unit of analysis inthis study to be the single gene rather than SNP; that is, we The process for selecting candidate genes based on evidence were screening for association of a gene (understood as a of involvement in antidepressant mechanism of action, and SNP or set of SNPs) with the phenotype of interest using a selection of single nucleotide polymorphisms (SNPs) to set-based test (here, the ‘set’ in question includes the SNPs capture common variation, has been described elsewhere in a given gene). The set-based test provides a simple means of accounting for linkage disequilibrium between SNPs genes were selected in serotonergic (n ¼ 20), glutamatergic within a gene, and also will generally have greater power to (n ¼ 16), dopaminergic (n ¼ 3), adrenergic (n ¼ 4), and detect associations if multiple SNPs within a gene are neurotrophic (n ¼ 4) systems, as well as other genes associated with the phenotype of interest. In brief, this test, (n ¼ 21). The full list of genes is available in of computes the test statistic (w2 for dichotomous outcomes) for each individual SNP within a gene, then calculates the Illumina BeadArray platform and genotypic data were average test statistic for the best single SNP per region, for cleaned using methods previously described.
the best two SNPs per region, and for the best three SNPsper region. The significance of these set statistics is then estimat by permuting (swapping) individual identifiers togenerate a ‘new’ data set. This method allows an estimate of Decreased libido, difficulty achieving orgasm, and difficulty how often, if no ‘true’ association exists, a set statistic this with erections are three correlated but nonidentical large or larger would be observed by chance. It allows a phenomena assessed by the PRISE. Therefore, three sets determination of gene-wise significance, allowing for of primary analyses were performed examining each of correlation between SNPs and tests, while controlling type these individually. Each symptom of sexual dysfunction was defined as report of that category of adverse event on the Primary analysis screened for association using the set- PRISE on at least one post-baseline visit. For follow-up analyses, we also defined ‘emergent’ symptoms (putative each gene. Significance of SNP combinations including adverse events) as those that were absent at the initial post- between one and three SNPs was estimated, using 20 000 baseline (ie the week 2) visit, but present on at least one permutations. To further control type 1 error, the same approach to permutation was also used to account for all Primary analysis pooled men and women, which would tests in all genes (experiment-wise p-values)Fhere, how maximize power to detect associations provided effects were often would test statistics this extreme, or more extreme, be similar within these two groups. For SNPs with nominal observed in the ‘permuted’ data sets. Where experiment- po0.05 in any genes identified in the primary test of wise po0.05 for a gene was observed, all single SNP association described below, follow-up analysis examined associations in that gene were then examined. For the set- heterogeneity between odds ratios within strata (men and based tests, where pairs of SNPs were in linkage disequili- women) using the Breslow–Day test. This approach was brium with r240.8, only one of the two, selected arbitrarily, guided by the recommendations of a recent structured was included in analysis, but all SNPs in a gene were review of methodological constraints in detecting sex- included when follow-up analyses were conducted. Epistatic effects were not examined due to limited power to detectsuch associations.
To address the potential for confounding by associations with baseline clinical features or longitudinal outcomes, we Degree of overlap between the three categories of also performed a series of planned follow-up analyses for sexual symptoms was examined using cross-tabulation any SNPs in genes with nominal evidence of association.
and Spearman’s r. Individuals with and without each sexual First, we repeated single SNP association analyses with symptom were compared on baseline sociodemographic adjustment for individual baseline clinical and sociodemo- and clinical features using w2-test or unpaired t-test.
graphic features, or longitudinal outcomes that were Multiple logistic regression was then used to determine associated with a given sexual symptom. Efficacy and which of these to include in the multivariate models tolerability can be strongly correlated in clinical trials and described below; any feature with po0.05 in the multi- can therefore confound observed associations. For example, variate regression model was included as a covariate in the individuals who derive less benefit from an intervention association analyses. Symptom groups were also compared might receive greater dosing or longer trials, leading to greater emergence of dose-dependent symptoms or adverse events. A particular concern was confounding by sympto- Erectile dysfunction in men. Supplementary Table 2 shows matic worsening, which led us to examine in a post hoc results from the set-based test for association between the analysis SNPs with nominal evidence of association. In Cox regression, with emergence of a sexual symptom as the with difficulty achieving erection (experiment-wise per- event of interest, we examined models including bothgenotype and visit-to-visit symptom change, the latter as a muted po0.05 for rs1323427, rs1323423, and rs2050641)and met the threshold for further examination. Among serotonergic genes, greatest evidence of association was We further addressed the possibility of population admixture as previously reported, generating probabilities HTR2A (rs6314, rs2770296, rs594242; gene-wise of ethnic group membership using the program STRUC- p ¼ 0.05, experiment-wise p ¼ 0.95). includes all tion. Odds ratios for ED ranged from 1.51 to 1.56 for the cluster individuals based on ancestry-informative markers.
three SNPs with greatest evidence of association, indicating Single SNP analyses were repeated with adjustment for overall risk B50–60% greater among individuals carrying factor loadings assuming a three-population (k ¼ 3) solu- these individual risk alleles. To address the possibility that tion, previously found to represent the optimal number ofpopulations in this cohort the association was confounded by sociodemographic orclinical features, we repeated the single SNP analyses withadjustment for any variables significant in univariateanalyses, yielding no evidence of confounding in terms of change in odds ratios Likewise, to examine thepossibility of confounding by efficacy (eg patients with Comparisons of the genetic cohort to the total clinical poorer response receiving greater citalopram doses), we cohort in terms of baseline sociodemographic features have repeated single SNP analyses with adjustment for maximum citalopram dose, again with little change in strength of genotyped subjects, we excluded 36 subjects who failed to association (Supplementary Table 5). In particular, incor- return for at least one post-baseline visit and therefore did porating a term for symptom change vs prior visit did not not provide adverse event data, yielding a ‘modified intent- change any observed hazard ratios by greater than 10%, to-treat’ sample; a further 401 non-Caucasian subjects were suggesting these associations are not confounded by excluded from primary analyses because allele frequencies symptom change (results not shown). Most, but not all, for many of the genes in question differ across populations, associations remained significant (po0.05) following ad- resulting in 1473 evaluable Caucasian subjects.
justment for population substructure (Finally,when the cohort was limited to those individuals withoutED at the first post-baseline visit (N ¼ 446), 87 (20%) reported new onset of ED Effect sizes, in terms of Sexual Symptoms and Clinical Associations odds ratios, were similar to those observed in the fullcohort.
Of 1473 participants, 799 (54%) reported decrease in libido,and 525 (36%) reported difficulty achieving orgasm;correlation Changes in libido. We examined changes in libido in a r ¼ 0.33). In all, 400 of 1473 (27%) reported both symptoms, similar manner. Two genes, GRIA3 (rs2285127, rs2269551, and 524 of 1473 (36%) reported one symptom. Of 574 men, rs550640) and GRIK2 (rs9404130, rs2518302, rs513216) 211 (37%) reported erectile dysfunction (ED); Spearman’s showed experiment-wise evidence of association (permuted r ¼ 0.32 between ED and libido and 0.44 between ED and po0.05; Supplementary Table 3). Single SNP tests are orgasm. Of 574, 133 (23%) reported two of three sexual shown in For the three top SNPs in GRIK2, risk of symptoms, and 118 (21%) reported. compares those decreased libido was 30–40% greater among those with the who did or did not report each of the three sexual risk allele, and for GRIA3, risk was 20–30% greater. No symptoms in terms of baseline clinical and sociodemo- serotonergic genes were significantly associated with libido; graphic features. For ED, greater age, duration of illness, the gene showing greatest evidence of association was severity of depression at study entry, severity of general medical comorbidity, and presence of an anxiety disorder p ¼ 0.02, experiment-wise p ¼ 0.69). Once again, there was were associated with greater risk. For decreased libido, little change in odds ratios for association with decreased earlier onset of illness, greater severity of depression, being libido when analyses were adjusted for sociodemographic married, and being male were associated with greater risk.
and clinical differences or features of longitudinal For difficulty with orgasm, younger age and earlier age at outcome (Supplementary Table 6). As above, in no case did onset, greater severity of general medical comorbidity, as adjustment for symptom change yield a change in hazard well as being married, male, and treated in a specialty rather ratio of greater than 10% (results not shown). After than primary care setting, were associated with greater risk adjustment for population substructure, most but not all (features of longitudinal course, including number of SNPs remained significantly associated When the follow-up visits, symptomatic improvement or remission, phenotype was restricted to those without the adverse event medication tolerability, and use of concomitant sedative/ at the first post-baseline visit (N ¼ 937) who subsequently hypnotic medication are similarly compared in Supplemen- developed decrease in libido (272 of 937; 29%), effect sizes were similar to those observed in the cohort as a whole.
Sexual dysfunction with SSRI treatmentRH Perlis et al Table 1 Baseline sociodemographic and clinical features of the STAR*D genetics/sexual dysfunction Caucasian cohort (n ¼ 1473) The table shows the baseline sociodemographic and clinical features of genotyped citalopram-treated subjects and association with erectile dysfunction (a), decreasedlibido (b), and difficulty achieving orgasm (c) following treatment. Bold values indicates pp0.05.
Table 2 Single SNP associations with ED (po0.05) among 574 men treated with citalopram for up to 14 weeks Column headings refer to unadjusted association, association adjusted for baseline clinical features, association adjusted for ancestry-informative markers, andassociation with only confirmed emergent symptoms (ie those not present at initial follow-up visit).
Table 3 Single SNP associations with decreased libido (po0.05) among 1473 individuals with MDD treated with citalopram for up to 14weeks 4.65 0.0311 0.82 0.6843, 0.9823 0.0363 0.82 0.0322 0.82 4.30 0.0382 0.79 0.6278, 0.9875 0.0254 0.76 0.0407 0.79 11.29 0.0008 0.75 0.6372, 0.8883 0.0009 0.75 0.0009 0.75 3.95 0.0469 0.84 0.7106, 0.9977 0.0697 0.85 0.0431 0.84 Column headings refer to unadjusted association, association adjusted for baseline clinical features, association adjusted for ancestry-informative markers, test forheterogeneity between men and women, and association with only confirmed emergent symptoms (ie those not present at initial follow-up visit).
Difficulty with orgasm. One gene, GRIA1 (rs1994862, ment for ancestry-informative markers. Limiting the rs10515697, rs1864205), showed evidence of association analysis to the subset without decreased orgasm at baseline with difficulty with orgasm (Supplementary Table 4).
(N ¼ 1153) also yielded similar results Among serotonergic genes, strongest association was againobserved in the same SNPs in SLC6A4 (rs2054847,rs7224199, rs2020942; gene-wise p ¼ 0.003, experiment-wise p ¼ 0.162). Results from individual SNPs in this gene with nominal po0.05 are given in Overall, odds of This secondary analysis of data from a large-scale candidate difficulty with orgasm were B40–50% greater among those gene study of antidepressant response found multiple genes with the risk allele. Adjusting these association analyses for of the glutamatergic system, but none from the serotonergic potential baseline or longitudinal (Supplementary system, to be significantly associated with sexual dysfunc- Table 7) confounders yielded little change in odds ratios.
tion of three correlated but nonidentical types. Follow-up Again, adjustment for symptom change did not change clinical analyses suggest that these associations are not observed hazard ratios for single SNPs by 10% or greater confounded by clinical features that are independently (results not shown). The two top SNPs remained signifi- associated with such symptoms, including general medical cantly associated with difficulty with orgasm after adjust- comorbidity, or by overall symptomatic worsening. This Sexual dysfunction with SSRI treatmentRH Perlis et al Table 4 Single SNP associations with decreased orgasm (po0.05) among 1473 individuals with MDD treated with citalopram for up to 14weeks Column headings refer to unadjusted association, association adjusted for baseline clinical features, association adjusted for ancestry-informative markers, test forheterogeneity between men and women, and association with only confirmed emergent symptoms (ie those not present at initial follow-up visit).
latter finding is notable in light of a prior STAR*D report To our knowledge, only one prior pharmacogenetic study that also identified association between glutamate genes and examined SSRI-associated sexual dysfunction ; in that study of 89 outpatients, a noncoding Although glutamate has not been studied as a mechanism of polymorphism in the HTR2A gene (À1438GA; rs6311) was depression, or antidepressant-associated sexual dysfunction, associated with sexual dysfunction in general, as well as rodent studies highlight its importance in sexual function. In difficulty with arousal. Although we did not directly genotype males, the medial preoptic area (MPOA), which integrates and this polymorphism, for purposes of comparison we did examine rs1928040 in HTR2A which is reported to be in receives glutamatergic input from the medial amygdala and strong linkage disequilibrium with it (r240.8 in the Interna- bed nucleus of the stria terminalis, and in turn (acting through tional Haplotype Map Phase II data), and a two-SNP nitric oxide (NO)) increases dopamine release in the MPOA.
combination which is reported to be in perfect linkage Injecting dopamine antagonists will interfere with copulation disequilibrium with it (rs1928040, rs985933), but found no among male rats, whereas agonists have the opposite evidence of association either in the cohort as a whole, or among male or female cohorts (results not shown; nominal with glutamate agonists and antagonists has analogous effects p40.05 for all three sexual adverse effects). We likewise found no significant evidence of association on a gene-based test for The MPOA projects widely, including the paraventricular association of HTR2A with any of these phenotypes (Supple- nucleus of the hypothalamus (PVN), which appears to mentary Tables 1–3); although ED was nominally associated mediate directly erection through oxytocinogenic neurons.
with some SNPs in HTR2A, these modest effects did not Glutamate agonists induce erections when injected into the survive correction for multiple comparisons. We note that our PVN; erections are blocked by injecting glutamate antago- phenotype differs from that previously examined because of the lack of baseline symptom assessment or sensitive measures also been implicated in animal models of female sexual of sexual function, so cannot exclude the possibility that a behavior. For example, glutamate antagonists infused into larger cohort or more detailed phenotyping might have the ventromedial hypothalamus increase lordosis among detected a significant association. Alternatively, although modulation of postsynaptic 5HT2A may be clinically relevant Far less is known about the neurobiology underlying , there may simply not be a genetic basis for the libido per se, which may be difficult to distinguish from observable pharmacodynamic variation.
sexual activity in animal models. Notably, however, at least A limitation of the present report is that no detailed and one case report associates lamotrigine, which decreases validated assessment of sexual function, such as the glutamatergic neurotransmission, with spontaneous hyper- Changes in Sexual Functioning Questionnaire sexuality or improvement in sexual function or interest ), was used. Therefore, our sensitivity to sexual symptoms and ability to dissect individual components affected is limited. On the other hand, this would tend to In humans, a recent report using magnetic resonance bias our results toward the null, so it does not diminish spectroscopy demonstrated that citalopram administration confidence in the positive findings. In addition, details of increases a composite measure of glutamate and glutamine medical comorbidity or their treatment are not available to us, although adjustment for summary measures of such models or in vitro systems suggests that SSRIs may comorbidity yields no evidence of confounding. Another influence glutamatergic neurotransmission, though the caveat is that, because there is no PRISE completed at baseline, our findings do not necessarily indicate that these symptoms are treatment emergent. Rather, they may example, an in vitro model of neurogenesis suggests synergy indicate risk for sexual dysfunction regardless of treatment.
between SSRIs and glutamate receptor (mGluR2 and 3) We nonetheless relied on this assessment as our primary phenotype because it allowed us to examine the largest possible cohort, we expected that most such reported Advisory/Consulting: AstraZeneca, Bristol-Myers Squibb, symptoms would actually be treatment emergent, and we reasoned that any association detected, regardless ofspecificity, would be of interest. However, a secondary Speaking: AstraZeneca, Bristol-Myers Squibb Eli Lilly and analysis examining only those symptoms clearly absent at Company, GlaxoSmithKline, Pfizer Inc.
initial post-baseline visit, and thus more likely to be trulytreatment emergent, yielded similar results.
A further limitation is our inability to exclude fully the potential confounding effects of population stratification despite adjustment using ancestry-informative markers, andinability to exclude type I error in the absence of a replication cohort Conversely, it is possible Research support: Abbott Laboratories, Alkermes, Aspect that pooling men and women obscured true sex-specific Medical Systems, AstraZeneca, Bristol-Myers Squibb, Ce- associations, resulting in type II error. We did not detect phalon, Eli Lilly and Company, Forest Pharmaceuticals Inc., sex-specific effects for the genes showing main effects and GlaxoSmithKline, J and J Pharmaceuticals, Lichtwer Pharma therefore did not pursue within-sex analyses except for the GmbH, Lorex Pharmaceuticals, Novartis, Organon Inc., SNP in HTR2A previously associated with sexual symptoms.
Pamlab LLC, Pfizer Inc., Pharmavite, Roche, Sanofi/ Finally, in the absence of a placebo or active comparator, Synthelabo, Solvay Pharmaceuticals Inc., Wyeth-Ayerst we cannot address the specificity of the observed associa- tions. The observed associations might indicate pronenessto report sexual symptoms, regardless of treatment, or Advisory/Consulting: Aspect Medical Systems, AstraZeneca, might be limited to SSRIs such as citalopram.
Bayer AG, Biovail Pharmaceuticals Inc., BrainCells Inc.
In sum, in this large-scale candidate gene-based study, we Bristol-Myers Squibb, Cephalon, Compellis, Cypress Phar- find preliminary evidence for association of glutamatergic maceuticals, Dov Pharmaceuticals, Eli Lilly and Company, but not serotonergic genes with sexual dysfunction among EPIX Pharmaceuticals, Fabre-Kramer Pharmaceuticals Inc., individuals with MDD treated with the SSRI citalopram. In Forest Pharmaceuticals Inc., GlaxoSmithKline, Grunenthal all cases, the SNPs identified do not lie in known coding or GmBH, Janssen Pharmaceutica, Jazz Pharmaceuticals, J and regulatory regions. Still, these results suggest that glutama- J Pharmaceuticals, Knoll Pharmaceutical Company, Lund- tergic strategies may merit further consideration for the beck, MedAvante Inc., Neuronetics, Novartis, Nutrition 21, management of SSRI-associated sexual dysfunction. By Organon Inc., Pamlab LLC, Pfizer Inc., PharmaStar, considering variation in glutamatergic genes, as well as Pharmavite, Roche, Sanofi/Synthelabo, Sepracor, Solvay clinical features associated with differential risk, it may be Pharmaceuticals Inc., Somaxon, Somerset Pharmaceuticals, possible to identify individuals at greater risk for experien- cing sexual dysfunction during depressive episodes.
Speaking: AstraZeneca, Boehringer Ingelheim, Bristol- Myers Squibb, Cephalon, Eli Lilly and Company, Forest Pharmaceuticals Inc., GlaxoSmithKline, Novartis, OrganonInc., Pfizer Inc., PharmaStar, Wyeth-Ayerst Laboratories.
The Sequenced Treatment Alternatives to Relieve Depression(STAR*D) study is supported by federal funds from NIMH Equity Holdings: Compellis, MedAvante.
under contract N01 MH-90003 to the University of TexasSouthwestern Medical Center at Dallas (AJ Rush, principal investigator). Dr Perlis is supported by NIMH K23MH67060,a NARSAD Young Investigator/Sidney R Baer Jr Foundation Award, and a Bowman Family Foundation award. Additional Research Support: Bristol-Myers Squibb; Cephalon Inc.; support provided by NIMH Intramural program. We thank Corcept Therapeutics Inc.; Cyberonics Inc.; Eli Lilly and Rutgers Cell and DNA Repository for extracting DNA and Company; Forest Pharmaceuticals; GlaxoSmithKline; Jans- providing samples. We appreciate the support of Forest sen Pharmaceutica; Merck; National Institute of Mental Laboratories for providing citalopram at no cost to the Health; National Alliance for Research in Schizophrenia and STAR*D study. We thank Stephen Wisniewski and Heather Depression; Novartis; Pfizer Inc.; Predix Pharmaceuticals; Eng for providing the clinical data. We thank the STAR*D Research Team for conducting the clinical study and obtainingclinical data and the blood samples for these analyses. Finally, Advisory/Consulting: Abbott Laboratories Inc.; Akzo (Or- we thank the study participants without whom this study ganon Inc.); Bayer; Bristol-Myers Squibb; Cyberonics Inc.; Forest Pharmaceuticals; GlaxoSmithKline; Janssen Pharma-ceutica; Johnson & Johnson PRD; Eli Lilly & Company; Meade Johnson; Parke-Davis Pharmaceuticals, Inc.; Pfizer,Inc.; Pharmacia & Upjohn; Sepracor; Solvay Pharmaceuti- cals Inc.; Wyeth-Ayerst Laboratories.
Research support: Eli Lilly and Company, Elan/Eisai, National Institute of Mental Health, NARSAD, Bowman Speaking: Akzo (Organon Inc.); Bristol-Myers Squibb; Cy- Family Foundation, American Philosophical Society.
beronics Inc.; Forest Pharmaceuticals; Janssen Pharmaceutica Sexual dysfunction with SSRI treatmentRH Perlis et al Products, LP; Eli Lilly and Company; Pharmacia and Clayton AH, Montejo AL (2006). Major depressive disorder, antidepressants, and sexual dysfunction. J Clin Psychiatry Dominguez JM, Gil M, Hull EM (2006). Preoptic glutamate Equity Holdings: None (exclude mutual funds/blinded facilitates male sexual behavior. J Neurosci 26: 1699–1703.
Dominguez JM, Hull EM (2005). Dopamine, the medial preoptic area, and male sexual behavior. Physiol Behav 86:356–368.
Dominguez JM, Muschamp JW, Schmich JM, Hull EM (2004).
Nitric oxide mediates glutamate-evoked dopamine release in the medial preoptic area. Neuroscience 125: 203–210.
Speaker’s Bureau: Cyberonics Inc.; Forest Pharmaceuticals Fava M (2003). Diagnosis and definition of treatment-resistant depression. Biol Psychiatry 53: 649–659.
Fava M, Rankin M (2002). Sexual functioning and SSRIs. J Clin Advisory Boards/Consultant: Advanced Neuromodulation Psychiatry 63(Suppl 5): 13–16; discussion 23–5.
Systems Inc.; Best Practice Project Management Inc.; Fava M, Rush AJ, Trivedi MH, Nierenberg AA, Thase ME, Sackeim Bristol-Myers Squibb; Cyberonics Inc.; Eli Lilly and HA et al (2003). Background and rationale for the sequencedtreatment alternatives to relieve depression (STAR*D) study.
Company; Forest Pharmaceuticals Inc.; Gerson Lehman Psychiatr Clin North Am 26: 457–494, x.
Group; GlaxoSmithKline; Healthcare Technology Systems; Georgescu M, Pfaus JG (2006). Role of glutamate receptors in the Jazz Pharmaceuticals; Merck; Neuronetics; Ono Pharma- ventromedial hypothalamus in the regulation of female rat ceuticals; Organon Inc.; Personality Disorder Research sexual behaviors. II. Behavioral effects of selective glutamate Corp.; Urban Institute; Wyeth-Ayerst Laboratories.
receptor antagonists AP-5, CNQX, and DNQX. PharmacolBiochem Behav 83: 333–341.
Research Support: Robert Wood Johnson Foundation, Gil-Nagel A, Lopez-Munoz F, Serratosa JM, Moncada I, Garcia- National Institute of Mental Health, Stanley Medical Garcia P, Alamo C (2006). Effect of lamotrigine on sexual function in patients with epilepsy. Seizure 15: 142–149.
Grabowska-Grzyb A, Naganska E, Wolanczyk T (2006). Hyper- sexuality in two patients with epilepsy treated with lamotrigine.
Royalties: Guilford Publications, Healthcare Technology Hamilton M (1960). A rating scale for depression. J Neurol Hull EM, Dominguez JM (2006). Getting his act together: roles of glutamate, nitric oxide, and dopamine in the medial preoptic Dr Smoller has received honoraria from Hoffman-La Roche Laje G, Paddock S, Manji H, Rush AJ, Wilson AF, Charney D et al Inc. and has served on an advisory board for Roche (2007). Genetic markers of suicidal ideation emerging during Diagnostics Corporation. He has received research funding citalopram treatment of major depression. Am J Psychiatry 164: from the National Institute of Mental Health and the Langman NJ, Smith CG, Whitehead KJ (2006). Selective serotonin National Alliance for Research in Schizophrenia and re-uptake inhibition attenuates evoked glutamate release in the dorsal horn of the anaesthetised rat in vivo. Pharmacol Res 53:149–155.
The other authors have no financial competing interests to Linn BS, Linn MW, Gurel L (1968). Cumulative Illness Rating Scale. J Am Geriatr Soc 16: 622–626.
Matrisciano F, Zusso M, Panaccione I, Turriziani B, Caruso A, Iacovelli L et al (2008). Synergism between fluoxetine and the mGlu2/3 receptor agonist, LY379268, in an in vitro model forantidepressant drug-induced neurogenesis. Neuropharmacology Angst F, Stassen HH, Clayton PJ, Angst J (2002). Mortality of patients with mood disorders: follow-up over 34–38 years.
McMahon FJ, Buervenich S, Charney D, Lipsky R, Rush AJ, Wilson AF et al (2006). Variation in the gene encoding the serotonin 2A Bishop JR, Moline J, Ellingrod VL, Schultz SK, Clayton AH (2006).
receptor is associated with outcome of antidepressant treatment.
C825T polymorphisms in patients with depression and SSRI- Melis MR, Succu S, Spano MS, Argiolas A (2000). Effect of associated sexual side-effects. Neuropsychopharmacology 31: excitatory amino acid, dopamine, and oxytocin receptor antagonists on noncontact penile erections and paraventricular Bull SA, Hunkeler EM, Lee JY, Rowland CR, Williamson TE, nitric oxide production in male rats. Behav Neurosci 114: Schwab JR et al (2002). Discontinuing or switching selective serotonin-reuptake inhibitors. Ann Pharmacother 36: 578–584.
Miller MD, Paradis CF, Houck PR, Mazumdar S, Stack JA, Rifai AH Clayton AH (2001). Recognition and assessment of sexual et al (1992). Rating chronic medical illness burden in dysfunction associated with depression. J Clin Psychiatry geropsychiatric practice and research: application of the Cumulative Illness Rating Scale. Psychiatry Res 41: 237–248.
Clayton AH (2003). Sexual function and dysfunction in women.
Montejo AL, Llorca G, Izquierdo JA, Rico-Villademoros F (2001).
Psychiatr Clin North Am 26: 673–682.
Incidence of sexual dysfunction associated with antidepressant Clayton AH, McGarvey EL, Clavet GJ (1997). The Changes in agents: a prospective multicenter study of 1022 outpatients.
Sexual Functioning Questionnaire (CSFQ): development, relia- Spanish Working Group for the Study of Psychotropic-Related bility, and validity. Psychopharmacol Bull 33: 731–745.
Sexual Dysfunction. J Clin Psychiatry 62(Suppl 3): 10–21.
Murray JB (1998). Physiological mechanisms of sexual dysfunction Rush AJ, Trivedi MH, Ibrahim HM, Carmody TJ, Arnow B, side effects associated with antidepressant medication. J Psychol Klein DN et al (2003). The 16-Item Quick Inventory of Depressive Symptomatology (QIDS), Clinician Rating (QIDS- Neale BM, Sham PC (2004). The future of association studies: gene- C), and Self-Report (QIDS-SR): a psychometric evaluation based analysis and replication. Am J Hum Genet 75: 353–362.
in patients with chronic major depression. Biol Psychiatry 54: Ott J, Hoh J (2003). Set association analysis of SNP case–control and microarray data. J Comput Biol 10: 569–574.
Rush AJ, Trivedi MH, Wisniewski SR, Stewart JW, Nierenberg AA, Paddock S, Laje G, Charney D, Rush AJ, Wilson AF, Sorant AJ et al Thase ME et al (2006b). Bupropion-SR, sertraline, or venlafax- (2007). Association of GRIK4 with outcome of antidepressant ine-XR after failure of SSRIs for depression. N Engl J Med 354: treatment in the STAR*D cohort. Am J Psychiatry 164: 1181– Shioda K, Nisijima K, Yoshino T, Kato S (2004). Extracellular Patsopoulos NA, Tatsioni A, Ioannidis JP (2007). Claims of sex serotonin, dopamine and glutamate levels are elevated in the differences: an empirical assessment in genetic associations.
hypothalamus in a serotonin syndrome animal model induced by tranylcypromine and fluoxetine. Prog Neuropsychopharmacol Powell WS, Dominguez JM, Hull EM (2003). An NMDA antagonist impairs copulation and the experience-induced enhancement of Sullivan PF (2007). Spurious genetic associations. Biol Psychiatry male sexual behavior in the rat. Behav Neurosci 117: 69–75.
Pritchard JK, Stephens M, Donnelly P (2000). Inference of Svenningsson P, Bateup H, Qi H, Takamiya K, Huganir RL, population structure using multilocus genotype data. Genetics Spedding M et al (2007). Involvement of AMPA receptor phosphorylation in antidepressant actions with special reference Purcell S, Neale BM, Todd-Brown K, Thomas L, Ferreira MAR, to tianeptine. Eur J Neurosci 26: 3509–3517.
Bender D et al (2007). PLINK: a toolset for whole genome Taylor M, Murphy SE, Selvaraj S, Wylezinkska M, Jezzard P, association and population-based linkage analyses. Am J Hum Cowen PJ et al (2008). Differential effects of citalopram and reboxetine on cortical Glx measured with proton MR spectro- Rush A, Carmody T, Reimitz P (2000). The Inventory of Depressive scopy. J Psychopharmacol 22: 473–476.
Symptomatology (IDS): Clinician (IDS-C) and Self-Report Trivedi MH, Fava M, Wisniewski SR, Thase ME, Quitkin F, (IDS-SR) ratings of depressive symptoms. Int J Methods Warden D et al (2006a). Medication augmentation after the failure of SSRIs for depression. N Engl J Med 354: Rush AJ, Bernstein IH, Trivedi MH, Carmody TJ, Wisniewski S, Mundt JC et al (2006a). An evaluation of the Quick Inventory of Trivedi MH, Rush AJ, Ibrahim HM, Carmody TJ, Biggs MM, Depressive Symptomatology and the Hamilton Rating Scale for Suppes T et al (2004). The Inventory of Depressive Symptoma- Depression: a Sequenced Treatment Alternatives to Relieve tology, Clinician Rating (IDS-C) and Self-Report (IDS-SR), and Depression trial report. Biol Psychiatry 59: 493–501.
the Quick Inventory of Depressive Symptomatology, Clinician Rush AJ, Fava M, Wisniewski SR, Lavori PW, Trivedi MH, Sackeim Rating (QIDS-C) and Self-Report (QIDS-SR) in public sector HA et al (2004). Sequenced Treatment Alternatives to Relieve patients with mood disorders: a psychometric evaluation.
Depression (STAR*D): rationale and design. Control Clin Trials Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Rush AJ, Gullion CM, Basco MR, Jarrett RB, Trivedi MH (1996).
Ritz L et al (2006b). Evaluation of outcomes with citalopram for The Inventory of Depressive Symptomatology (IDS): psycho- depression using measurement-based care in STAR*D: implica- metric properties. Psychol Med 26: 477–486.
tions for clinical practice. Am J Psychiatry 163: 28–40.
Supplementary Information accompanies the paper on the Neuropsychopharmacology website )
Via della Libertà, 5 - 51018 PIEVE A NIEVOLE– Tel. 0572/80445 Fax 0572/950110 – www.comprensivo-pieveanievole.it C.F. 81003550472 - C.M. PTIC807009 – e-mail: email@example.com BANDO DI GARA PER LA CONCESSIONE DEL SERVIZIO DI DISTRIBUZIONE DI BEVANDE CALDE E FREDDE CON INSTALLAZIONE DI MACCHINARI AUTOMATICI PER GLI ANNI 2012/13- 2013/14-2014/2015. Oggetto: gestione, per la