Studying SSRIs

Studies on SSRIs


Evidence that serotonin affects female sexual functioning via peripheral mechanisms. 2000

Antidepressant-elicited changes in gene expression: remodeling of neuronal circuits as a new hypothesis for drug efficacy. 2005

Effects of chronic treatment with fluvoxamine and paroxetine during adolescence on serotonin-related behavior in adult male rats. 2006

Neonatal Antidepressant Exposure has Lasting Effects on Behavior and Serotonin Circuitry. 2006

Long-term adaptive changes induced by serotonergic antidepressant drugs. 2006

Serotonin 2A -1438 G/A and G-protein Beta3 subunit C825T polymorphisms in patients with depression and SSRI-associated sexual side-effects. 2006

Chromatin remodeling: a novel mechanism of psychotropic drug action. 2006

Evidence that the deficit in sexual behavior in adult rats neonatally exposed to citalopram is a consequence of 5-HT1 receptor stimulation during development. 2006

Neonatal citalopram exposure produces lasting changes in behavior which are reversed by adult imipramine treatment. 2006

Maternal exposure to the antidepressant fluoxetine impairs sexual motivation in adult male mice. 2008

Serotonin inhibits GABA synaptic transmission in presympathetic paraventricular nucleus neurons. 2008

Effects of SNS activation on SSRI-induced sexual side effects differ by SSRI. 2009

Genetic and clinical predictors of sexual dysfunction in citalopram-treated depressed patients. 2009

Epigenetic side-effects of common pharmaceuticals: a potential new field in medicine and pharmacology. 2009

SSRIs act as selective brain steroidogenic stimulants (SBSSs) at low doses that are inactive on 5-HT reuptake 2009

Biochemical and behavioral effects of long-term citalopram administration and discontinuation in rats: role of serotonin synthesis. 2010

Pharmacogenetics of SSRIs and Sexual Dysfunction. 2010

Dose-dependent effects of neonatal SSRI exposure on adult behavior in the rat. 2011

A genome-wide association study of female sexual dysfunction. 2012

Pharmacogenetics of glutamate system genes and SSRI-associated sexual dysfunction. 2012

Patient online report of selective serotonin reuptake inhibitor-induced persistent postwithdrawal anxiety and mood disorders. 2012

PHARMACOLOGY OF SEROTONIN AND FEMALE SEXUAL BEHAVIOR 2015

[Discontinuation syndrome after SSRI antidepressants.] 2014

Hormone replacement with 17β-estradiol plus dihydrotestosterone restores male sexual behavior in rats treated neonatally with clomipramine. 2014

Rational use of antidepressant drugs. 2014

Sexual side effects of serotonergic antidepressants: mediated by inhibition of serotonin on central dopamine release? 2014

Comparison of the effect of sertraline with behavioral therapy on semen parameters in men with primary premature ejaculation. 2014

Serotonergic Modulation of Intrinsic Functional Connectivity. 2014

Dimorphic changes of some features of loving relationships during long-term use of antidepressants in depressed outpatients. 2014

Maternal treatment with fluoxetine promotes testicular alteration in male rat pups. 2015

Withdrawal Symptoms after Selective Serotonin Reuptake Inhibitor Discontinuation: A Systematic Review. 2015

Assessing Sexual Symptoms and Side Effects in Adolescents. 2015

Low-dose paroxetine exposure causes lifetime declines in male mouse body weight, reproduction and competitive ability as measured by the novel organismal performance assay. 2015

Is serotonin an upper or a downer? The evolution of the serotonergic system and its role in depression and the antidepressant response. 2015

A Case of SSRI Induced Irreversible Parkinsonism. 2015

Neuroanatomical dichotomy of sexual behaviors in rodents: a special emphasis on brain serotonin 2015

Estrogenic/antiestrogenic activity of selected selective serotonin reuptake inhibitors 2015

Long-term changes in observed behaviour after exposure to psychiatric drugs: A systematic review of animal studies. 2017

Chronic Treatment with Fluoxetine Induces Sex-Dependent Analgesic Effects and Modulates HDAC2 and mGlu2 Expression in Female Mice. 2017

The Diagnostic clinical Interview for Drug Withdrawal 1 (DID-W1) – New Symptoms of Selective Serotonin Reuptake Inhibitors (SSRI) or Serotonin Norepinephrine Reuptake Inhibitors (SNRI): inter-rater reliability. 2018

Sertraline Suppresses Testis and Adrenal Steroid Production and Steroidogenic Gene Expression While Increasing LH in Plasma of Male Rats Resulting in Compensatory Hypogonadism. 2018

A Real-World Study on Antidepressant-Associated Sexual Dysfunction in 2144 Outpatients: The SALSEX I Study. 2019

Serotonergic, Dopaminergic, and Noradrenergic Modulation of Erotic Stimulus Processing in the Male Human Brain. 2019

Transcriptomic changes following chronic administration of selective serotonin reuptake inhibitors: a review of animal studies. 2019

Physiol Behav. 2000 Nov 1-15;71(3-4):383-93.

Evidence that serotonin affects female sexual functioning via peripheral mechanisms.

Frohlich PF1, Meston CM.

Author information

1

Department of Psychology, University of Texas at Austin, 78712, Austin, TX, USA.

Abstract

A review of the literature indicates that serotonin is active in several peripheral mechanisms that are likely to affect female sexual functioning. Serotonin has been found in several regions of the female genital tract in both animals and humans. In the central nervous system (CNS), serotonin acts primarily as a neurotransmitter, but in the periphery, serotonin acts primarily as a vasoconstrictor and vasodilator. Since, in the periphery, the principal component of sexual arousal is vasocongestion of the genital tissue, it is likely that serotonin participates in producing normal sexual arousal. In addition, serotonin administration produces contraction of the smooth muscles of the genito-urinary system and is found in nerves innervating the sexual organs. Taken together, this evidence suggests that peripheral serotonergic activity may be involved in the normal sexual response cycle. In addition, exogenous substances that alter serotonin activity, such as selective serotonin uptake inhibitors (SSRIs) and the atypical antipsychotics, can produce sexual dysfunction. It is possible that sexual side effects seen with these drugs may result, at least in part, from their action on peripheral mechanisms.

PMID:

 

11150571

Prog Neuropsychopharmacol Biol Psychiatry. 2005 Jul;29(6):999-1009.

Antidepressant-elicited changes in gene expression: remodeling of neuronal circuits as a new hypothesis for drug efficacy.

Yamada M1, Yamada M, Higuchi T.

Author information

1

Department of Psychogeriatrics, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo 187-8553, Japan. mitsu@ncnp-k.go.jp

Abstract

Although antidepressants have been used clinically for more than 50 years, no consensus has been reached concerning their precise molecular mechanism of action. Pharmacogenomics is a powerful tool that can be used to identify genes affected by antidepressants or by other effective therapeutic manipulations. Using this tool, others and we have identified as candidate molecular targets several genes or expressed sequence tags (ESTs) that are induced by chronic antidepressant treatment. In this article, we review antidepressant-elicited changes in gene expression, focusing especially on the remodeling of neuronal circuits that results. This refocusing motivates our hypothesis that this plasticity represents the mechanism for drug efficacy, and thus a causal event for clinical improvement. Defining the roles of these molecules in drug-induced neural plasticity is likely to transform the course of research on the biological basis of antidepressants. Such detailed knowledge will have profound effects on the diagnosis, prevention, and treatment of depression. Consideration of novel biological approaches beyond the "monoamine hypothesis" of depression is expected to evoke paradigm shifts in the future of antidepressant research.

PMID:

 

15975701

 

DOI:

 

10.1016/j.pnpbp.2005.03.022

Eur Neuropsychopharmacol. 2006 Jan;16(1):39-48. Epub 2005 Aug 16.

Effects of chronic treatment with fluvoxamine and paroxetine during adolescence on serotonin-related behavior in adult male rats.

de Jong TR1, Snaphaan LJ, Pattij T, Veening JG, Waldinger MD, Cools AR, Olivier B.

Author information

1

Department of Anatomy, Radboud University Nijmegen Medical Centre, (Intern Mail Nr. 230) Postbus 9101 6500 HB, Nijmegen, The Netherlands. t.dejong@pnf.umcn.nl

Abstract

Selective Serotonin Reuptake Inhibitors (SSRIs) are designed to treat adults, but are increasingly prescribed for adolescents. SSRIs might cause permanent changes in serotonin-related behavior in adolescents, since their serotonergic system is still developing. Male Wistar rats were treated with paroxetine (15 mg/kg p.o.) or fluvoxamine (30 mg/kg p.o.) throughout adolescence. After a washout period their behavior in the elevated plus-maze, prepulse inhibition test, Forced swimming test and elevated T-maze were studied. In addition, the effects of the 5-HT(1A) receptor agonist 8-OH-DPAT on sexual behavior and lower lip retraction were measured. Paroxetine mildly inhibited weight gain during treatment. Both SSRIs caused a reduction in ejaculation frequency and in time spent on the open arm of the elevated plus-maze in adult rats. Fluvoxamine slightly increased avoidance latency in the elevated T-maze compared to paroxetine. No differences between the groups were found in the other tests. Apparently, chronic treatment with SSRIs during adolescence may cause mild changes in adult behavior.

PMID:

 

16107310

 

DOI:

 

10.1016/j.euroneuro.2005.06.004

Go to:

Abstract

A significant fraction of infants born to mothers taking selective serotonin reuptake inhibitors (SSRIs) during late pregnancy display clear signs of antidepressant withdrawal indicating that these drugs can penetrate fetal brain in utero at biologically significant levels. Previous studies in rodents have demonstrated that early exposure to some antidepressants can result in persistent abnormalities in adult behavior and indices of monoaminergic activity. Here, we show that chronic neonatal (postnatal days 8–21) exposure to citalopram (5 mg/kg, twice daily, s.c.), a potent and highly selective SSRI, results in profound reductions in both the rate-limiting serotonin synthetic enzyme (tryptophan hydroxylase) in dorsal raphe and in serotonin transporter expression in cortex that persist into adulthood. Furthermore, neonatal exposure to citalopram produces selective changes in behavior in adult rats including increased locomotor activity and decreased sexual behavior similar to that previously reported for antidepressants that are nonselective monoamine transport inhibitors. These data indicate that the previously reported neurobehavioral effects of antidepressants are a consequence of their effects on the serotonin transporter. Moreover, these data argue that exposure to SSRIs at an early age can disrupt the normal maturation of the serotonin system and alter serotonin-dependent neuronal processes. It is not known whether this effect of SSRIs is paralleled in humans; however, these data suggest that in utero, exposure to SSRIs may have unforeseen long-term neurobehavioral consequences.

Keywords: 

Neuropsychopharmacology. Author manuscript; available in PMC 2011 Jun 20.

Published in final edited form as:

Neuropsychopharmacology. 2006 Jan; 31(1): 47–57.

doi: 10.1038/sj.npp.1300823

PMCID: PMC3118509

NIHMSID: NIHMS297028

PMID: 16012532

Neonatal Antidepressant Exposure has Lasting Effects on Behavior and Serotonin Circuitry

Dorota Maciag,^1,4 Kimberly L Simpson,^2,4 David Coppinger,³ Yuefeng Lu,² Yue Wang,² Rick CS Lin,² andIan A Paul^*,1,3

1 Department of Psychiatry & Human Behavior, University of Mississippi Medical Center, Jackson, MS, USA

2 Department of Anatomy, University of Mississippi Medical Center, Jackson, MS, USA

3 Department of Pharmacology & Toxicology, University of Mississippi Medical Center, Jackson, MS, USA

*Correspondence: Dr IA Paul, Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, 2500 North State St, Jackson, MS 39216-4505, USA, Tel: 601 984 5883, Fax: 601 984 5884, ude.demsmu.yrtaihcysp@luapi

4These authors contributed equally to this work.

Abstract

A significant fraction of infants born to mothers taking selective serotonin reuptake inhibitors (SSRIs) during late pregnancy display clear signs of antidepressant withdrawal indicating that these drugs can penetrate fetal brain in utero at biologically significant levels. Previous studies in rodents have demonstrated that early exposure to some antidepressants can result in persistent abnormalities in adult behavior and indices of monoaminergic activity. Here, we show that chronic neonatal (postnatal days 8–21) exposure to citalopram (5 mg/kg, twice daily, s.c.), a potent and highly selective SSRI, results in profound reductions in both the rate-limiting serotonin synthetic enzyme (tryptophan hydroxylase) in dorsal raphe and in serotonin transporter expression in cortex that persist into adulthood. Furthermore, neonatal exposure to citalopram produces selective changes in behavior in adult rats including increased locomotor activity and decreased sexual behavior similar to that previously reported for antidepressants that are nonselective monoamine transport inhibitors. These data indicate that the previously reported neurobehavioral effects of antidepressants are a consequence of their effects on the serotonin transporter. Moreover, these data argue that exposure to SSRIs at an early age can disrupt the normal maturation of the serotonin system and alter serotonin-dependent neuronal processes. It is not known whether this effect of SSRIs is paralleled in humans; however, these data suggest that in utero, exposure to SSRIs may have unforeseen long-term neurobehavioral consequences.

Keywords: neonatal exposure, citalopram, clomipramine, tryptophan hydroxylase, serotonin transporter, behavior

Expert Rev Neurother. 2006 Feb;6(2):235-45.

Long-term adaptive changes induced by serotonergic antidepressant drugs.

Faure C1, Mnie-Filali O, Haddjeri N.

Author information

1

Laboratoire de Neuropharmacologie et Neurochimie, Faculté de Pharmacie, Université Claude Bernard, Lyon 1, EA-512, 8, Avenue Rockefeller, 69373 Lyon Cedex 08, France. cfaure@sante.univ-lyon1.fr

Abstract

The development of conventional antidepressants has been largely based on the hypothesis of monoaminergic dysfunctions and focuses particularly on the serotonin 5-hydroxytryptamine (5-HT) system. Hence, various classes of antidepressant treatments enhance 5-HT neurotransmission with a time course consistent with their delayed therapeutic effect. This delayed onset appears to be associated with the gradual development of specific adaptive changes of functional 5-HT receptors. However, recent theories suggest that major depressive disorders may be associated with impairments of functional plasticity and cellular flexibility. This review discusses several physiological mechanisms by which 5-HT function and hippocampal neuroplasticity are regulated. Knowledge of these long-term adaptations will increase not only our understanding of pathological processes underlying affective disorders, but could also lead to the development of new strategies to treat these devastating illnesses.

PMID:

 

16466303

 

DOI:

 

10.1586/14737175.6.2.235

Mol Pharmacol. 2006 Aug;70(2):440-3. Epub 2006 May 25.

Chromatin remodeling: a novel mechanism of psychotropic drug action.

Newton SS1, Duman RS.

Author information

1

Laboratory of Molecular Psychiatry, Departments of Psychiatry and Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06508, USA.

Abstract

Regulation of gene expression is known to contribute to the long-term adaptations underlying the effects of psychotropic drugs, including the actions of antidepressants and drugs of abuse in behavioral models. However, the precise molecular events that are required for modification of chromatin and that underlie gene repression or activation have not been elucidated. Recent reports, including the article by Cassel et al. in this issue of Molecular Pharmacology, address this question and demonstrate that psychotropic drugs modify specific methyl-CpG-binding proteins that control histone acetylation and gene expression.

Comment on

• Fluoxetine and cocaine induce the epigenetic factors MeCP2 and MBD1 in adult rat brain. [Mol Pharmacol. 2006]

PMID:

 

16728645

 

DOI:

 

10.1124/mol.106.027078

Brain Res. 2006 Dec 13;1125(1):171-5. Epub 2006 Nov 13.

Evidence that the deficit in sexual behavior in adult rats neonatally exposed to citalopram is a consequence of 5-HT1 receptor stimulation during development.

Maciag D1, Coppinger D, Paul IA.

Author information

1

Departments of Psychiatry and Human Behavior, University of Mississippi Medical Center, 2500 North State St., Jackson, MS 39216-4505, USA.

Abstract

Neonatal (postnatal days 8-21) exposure of rats to the selective serotonin reuptake inhibitor (SSRI), citalopram, results in persistent changes in behavior including decreased sexual activity in adult animals. We hypothesized that this effect was a consequence of abnormal stimulation of 5-HT(1A) and/or 5-HT(1B) receptors as a result of increased synaptic availability of serotonin during a critical period of development. We examined whether neonatal exposure to a 5-HT(1A) (8OH-DPAT) or a 5-HT(1B) (CGS 12066B) receptor agonist can mimic the effect of neonatal exposure to citalopram on adult sexual behavior. Results showed that neonatal treatment with 5-HT(1B) receptor agonist robustly impaired sexual behavior similar to the effect of citalopram, whereas exposure to 5-HT(1A) receptor agonist only moderately influenced male sexual activity in adult animals. These data support the hypothesis that stimulation of serotonin autoreceptors during development contributes to the adult sexual deficit in rats neonatally exposed to citalopram.

PMID:

 

17101120

 

PMCID:

 

PMC1762094

 

DOI:

 

10.1016/j.brainres.2006.10.009

Neonatal citalopram exposure produces lasting changes in behavior which are reversed by adult imipramine treatment.

Maciag D, et al. Eur J Pharmacol. 2006.

Authors

Maciag D¹, Williams L, Coppinger D, Paul IA.

Author information

1

Department of Psychiatry & Human Behavior, University of Mississippi Medical Center, Jackson, MS 39216-4505, USA.

Citation

Eur J Pharmacol. 2006 Feb 27;532(3):265-9. Epub 2006 Feb 14.

Abstract

Neonatal exposure to antidepressants, including selective serotonin reuptake inhibitors such as citalopram, induces behavioral disturbances which persist in mature rats. These disturbances have been proposed to model the symptoms of endogenous depression. However, to date there is scant evidence for the predictive validity of any of these behaviors in response to adult antidepressant treatments. In order to directly assess the predictive validity of the early antidepressant exposure paradigm, the present study examined whether the behavioral abnormalities observed in adult animals exposed as neonates to citalopram can be reversed by adult antidepressant treatment with the prototypic antidepressant, imipramine. As noted earlier, neonatal citalopram exposure robustly increased locomotor activity and impaired male sexual behavior in adult rats. These behavioral changes were reversed following chronic adult imipramine treatment. No such reversal was observed in handled, saline treated rats. The present data support the hypothesis that some of the lasting behavioral abnormalities induced by early antidepressant exposure are sensitive to clinically relevant antidepressant treatments thus adding a measure of predictive validity to this paradigm as a model of these depressive symptoms.

Pharmacol Biochem Behav. 2008 Sep;90(3):416-9. doi: 10.1016/j.pbb.2008.03.025. Epub 2008 Apr 4.

Maternal exposure to the antidepressant fluoxetine impairs sexual motivation in adult male mice.

Gouvêa TS1, Morimoto HK, de Faria MJ, Moreira EG, Gerardin DC.

Author information

1

Department of Physiological Sciences, State University of Londrina, Londrina, Brazil.

Abstract

Depressive disorders have a worldwide high prevalence. Fluoxetine (FLX), a selective serotonin reuptake inhibitor (SSRI) antidepressant, has been widely prescribed for depression during pregnancy and/or lactation. Since serotonin is a neurotrophic factor, the use of FLX by mothers could disrupt brain development resulting in behavioral alterations in their progeny. The aim of the present study was to evaluate the effects of developmental FLX exposure on sexual behavior, as well as on endocrine parameters, of male mice. Swiss dams were treated daily, by gavage, with 7.5 mg/kg of FLX during pregnancy and lactation. Male pups were tested for copulatory behavior and sexual incentive motivation. Male pups also had their anogenital distance, plasmatic testosterone concentration and testis, epididymis, seminal vesicle and pituitary wet weights assessed. Copulatory behavior, anogenital distance, plasmatic testosterone concentration and organs wet weights were not affected by FLX exposure. However, this exposure eliminated preference for a sexual incentive on the sexual incentive motivation test, which indicates reduced sexual motivation, a classic side effect of SSRIs in humans who take these antidepressants.

PMID:

 

18457868

 

DOI:

 

10.1016/j.pbb.2008.03.025

Neurosci Lett. 2008 Jul 11;439(2):138-42. doi: 10.1016/j.neulet.2008.05.012. Epub 2008 May 10.

Serotonin inhibits GABA synaptic transmission in presympathetic paraventricular nucleus neurons.

Lee KS1, Han TH, Jo JY, Kang G, Lee SY, Ryu PD, Im JH, Jeon BH, Park JB.

Author information

1

Research Institute of Medical Sciences, Department of Physiology, College of Medicine, Chungnam National University, 6 Munhwa-dong, Joong-gu, Daejeon, 301-131, Republic of Korea.

Abstract

Activation of serotonin (5-hydroxytryptamine, 5-HT) receptors produces various autonomic and neuroendocrine responses in the hypothalamic paraventricular nucleus (PVN), including increased blood pressure and heart rate. However, the role(s) of 5-HT on the local GABA synaptic circuit have not been well understood in the PVN, where the inhibitory neurotransmitter GABA plays a key role in the modulation of sympathoexcitatory outflow. In the present study, we examined the effects of 5-HT on GABA synaptic transmission in presympathetic PVN neurons projecting to spinal cord using patch-clamp electrophysiology combined with tract-tracing techniques. Bath application of 5-HT (0.01-100 microM) reversibly decreased the frequency of spontaneous GABAergic inhibitory postsynaptic currents (sIPSC) in a concentration dependent manner (IC50, 0.07 microM), with no significant changes in the amplitudes and decay kinetics of sIPSC. The sIPSC inhibition of 5-HT was mimicked by 5-HT1A agonist, 8-OH-DPAT (8-hydroxy-2(di-n-propylamino)tetralin, 10 microM), and blocked by 5-HT1A antagonist WAY-100635 but not by 5-HT1B antagonist SB224289. 5-HT also reduced the frequency of miniature IPSC (mIPSC) (2.59+/-0.51 Hz, control vs. 1.25+/-0.31 Hz, 5-HT, n=16) in similar extent with 5-HT induced reduction of sIPSC frequency (sIPSCs, 55.8+/-6.2%, n=11 vs. mIPSCs, 52.30+/-5.85%, n=16; p>0.5). All together, our results indicate that 5-HT can inhibit presynaptic GABA release via presynaptic 5-HT1A receptors in presympathetic PVN neurons projecting to spinal cord.

PMID:

 

18524490

 

DOI:

 

10.1016/j.neulet.2008.05.012

J Sex Marital Ther. 2009;35(4):311-9. doi: 10.1080/00926230902851322.

Effects of SNS activation on SSRI-induced sexual side effects differ by SSRI.

Ahrold TK1, Meston CM.

Author information

1

Department of Psychology, University of Texas at Austin, Austin, Texas 78712, USA.

Abstract

Selective serotonin reuptake inhibitors (SSRIs) are associated with significant sexual side effects. By definition, all SSRIs increase overall serotonin (5HT) by binding to serotonin autoreceptors (5HT(IA)); however, each SSRI has a unique portfolio of secondary binding properties to other neurotransmitters such as norepinephrine (NE). As 5HT(IA) receptors mediate NE neurotransmission, SSRIs that are highly selective for 5HT(IA) are more likely to reduce NE efficiency; however, in SSRIs that are less selective for 5HT(IA), this could be counteracted by secondary binding to NE. Norepinephrine is the major neurotransmitter of the sympathetic nervous system (SNS), which has been shown to mediate genital arousal in women; thus, it is possible that increasing SNS activity in women taking SSRIs that are highly selective for 5HT(IA) may counteract sexual side effects in those women. To test this hypothesis, we conducted a reanalysis of Meston (2004)'s 8-week, double-blind, cross-over, placebo-controlled study of the effects of ephedrine (50 mg taken 1 h prior to sexual activity) on self-reported sexual functioning of women taking paroxetine (N = 5), sertraline (N = 7), or fluoxetine (N = 7). As predicted, women taking SSRIs, which are highly selective for 5HT(IA) (sertraline, paroxetine), showed improvement in sexual arousal and orgasm. By contrast, women taking SSRIs, which are less selective for 5HT(IA) relative to NE (fluoxetine), showed no change or decrease in sexual functioning. These findings have implications for treating certain SSRI-induced sexual side effects.

PMID:

 

19466669

 

PMCID:

 

PMC4426856

 

DOI:

 

10.1080/00926230902851322

Neuropsychopharmacology. 2009 Jun;34(7):1819-28. doi: 10.1038/npp.2009.4. Epub 2009 Mar 18.

Genetic and clinical predictors of sexual dysfunction in citalopram-treated depressed patients.

Perlis RH1, Laje G, Smoller JW, Fava M, Rush AJ, McMahon FJ.

Author information

1

Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA. rperlis@partners.org

Abstract

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=1473) for whom DNA and adverse 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 p<0.05 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.

PMID:

 

19295509

 

DOI:

 

10.1038/npp.2009.4

Med Hypotheses. 2009 Nov;73(5):770-80. doi: 10.1016/j.mehy.2008.10.039. Epub 2009 Jun 5.

Epigenetic side-effects of common pharmaceuticals: a potential new field in medicine and pharmacology.

Csoka AB1, Szyf M.

Author information

1

Division of Geriatrics, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA 15260, USA. Antonei@Csoka.us

Abstract

The term "Epigenetics" refers to DNA and chromatin modifications that persist from one cell division to the next, despite a lack of change in the underlying DNA sequence. The "epigenome" refers to the overall epigenetic state of a cell, and serves as an interface between the environment and the genome. The epigenome is dynamic and responsive to environmental signals not only during development, but also throughout life; and it is becoming increasingly apparent that chemicals can cause changes in gene expression that persist long after exposure has ceased. Here we present the hypothesis that commonly-used pharmaceutical drugs can cause such persistent epigenetic changes. Drugs may alter epigenetic homeostasis by direct or indirect mechanisms. Direct effects may be caused by drugs which affect chromatin architecture or DNA methylation. For example the antihypertensive hydralazine inhibits DNA methylation. An example of an indirectly acting drug is isotretinoin, which has transcription factor activity. A two-tier mechanism is postulated for indirect effects in which acute exposure to a drug influences signaling pathways that may lead to an alteration of transcription factor activity at gene promoters. This stimulation results in the altered expression of receptors, signaling molecules, and other proteins necessary to alter genetic regulatory circuits. With more chronic exposure, cells adapt by an unknown hypothetical process that results in more permanent modifications to DNA methylation and chromatin structure, leading to enduring alteration of a given epigenetic network. Therefore, any epigenetic side-effect caused by a drug may persist after the drug is discontinued. It is further proposed that some iatrogenic diseases such as tardive dyskinesia and drug-induced SLE are epigenetic in nature. If this hypothesis is correct the consequences for modern medicine are profound, since it would imply that our current understanding of pharmacology is an oversimplification. We propose that epigenetic side-effects of pharmaceuticals may be involved in the etiology of heart disease, cancer, neurological and cognitive disorders, obesity, diabetes, infertility, and sexual dysfunction. It is suggested that a systems biology approach employing microarray analyses of gene expression and methylation patterns can lead to a better understanding of long-term side-effects of drugs, and that in the future, epigenetic assays should be incorporated into the safety assessment of all pharmaceutical drugs. This new approach to pharmacology has been termed "phamacoepigenomics", the impact of which may be equal to or greater than that of pharmacogenetics. We provide here an overview of this potentially major new field in pharmacology and medicine.

PMID:

 

19501473

 

DOI:

 

10.1016/j.mehy.2008.10.039

Go to:

Summary

Brain principal glutamatergic neurons synthesize 3α-hydroxy-5α-pregnan-20-one (Allo), a neurosteroid that potently, positively, and allosterically modulates GABA action at GABA_A receptors. Cerebrospinal fluid (CSF) Allo levels are decreased in patients with posttraumatic stress disorder (PTSD) and major depression. This decrease is corrected by fluoxetine in doses that improve depressive symptoms. Depression-like behavioral dysfunctions (aggression, fear, and anxiety) associated with a decrease of corticolimbic Allo content can be induced in mice by social isolation. In socially isolated mice, fluoxetine and analogs stereospecifically normalize the decrease of Allo biosynthesis and improve behavioral dysfunctions by a mechanism independent from 5-HT reuptake inhibition. Thus, fluoxetine and related congeners facilitate GABA_A receptor neurotransmission and effectively ameliorate emotional and anxiety disorders and depression by acting as selective brain steroidogenic stimulants (SBSSs).

Keywords: allopregnanolone, aggressive behavior, contextual fear conditioning, depression, PTSD, GABA_A 

Curr Opin Pharmacol. Author manuscript; available in PMC 2010 Feb 1.

Published in final edited form as:

Curr Opin Pharmacol. 2009 Feb; 9(1): 24–30.

Published online 2009 Jan 20. doi: 10.1016/j.coph.2008.12.006

PMCID: PMC2670606

NIHMSID: NIHMS97007

PMID: 19157982

SSRIs act as selective brain steroidogenic stimulants (SBSSs) at low doses that are inactive on 5-HT reuptake

Graziano Pinna, Erminio Costa, and Alessandro Guidotti

Author information Copyright and License information Disclaimer

Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612

Corresponding author: ude.ciu.hcysp@annipg

Summary

Brain principal glutamatergic neurons synthesize 3α-hydroxy-5α-pregnan-20-one (Allo), a neurosteroid that potently, positively, and allosterically modulates GABA action at GABAA receptors. Cerebrospinal fluid (CSF) Allo levels are decreased in patients with posttraumatic stress disorder (PTSD) and major depression. This decrease is corrected by fluoxetine in doses that improve depressive symptoms. Depression-like behavioral dysfunctions (aggression, fear, and anxiety) associated with a decrease of corticolimbic Allo content can be induced in mice by social isolation. In socially isolated mice, fluoxetine and analogs stereospecifically normalize the decrease of Allo biosynthesis and improve behavioral dysfunctions by a mechanism independent from 5-HT reuptake inhibition. Thus, fluoxetine and related congeners facilitate GABAA receptor neurotransmission and effectively ameliorate emotional and anxiety disorders and depression by acting as selective brain steroidogenic stimulants (SBSSs).

Keywords: allopregnanolone, aggressive behavior, contextual fear conditioning, depression, PTSD, GABAA receptors, selective brain steroidogenic stimulants (SBSSs)

Neurochem Int. 2010 Dec;57(8):948-57. doi: 10.1016/j.neuint.2010.10.001. Epub 2010 Oct 12.

Biochemical and behavioral effects of long-term citalopram administration and discontinuation in rats: role of serotonin synthesis.

Bosker FJ1, Tanke MA, Jongsma ME, Cremers TI, Jagtman E, Pietersen CY, van der Hart MG, Gladkevich AV, Kema IP, Westerink BH, Korf J, den Boer JA.

Author information

1

University Centre of Psychiatry, University Medical Centre Groningen, University of Groningen, The Netherlands. f.j.bosker@psy.umcg.nl

Abstract

We have investigated effects of continuous SSRI administration and abrupt discontinuation on biochemical and behavioral indices of rat brain serotonin function, and attempted to identify underlying mechanisms. Biochemistry of serotonin was assessed with brain tissue assays and microdialysis; behavior was assessed as the acoustic startle reflex. Long-term SSRI administration to rats reduced the content of 5-HT and its main metabolite shortly after inhibition of 5-HT synthesis in many brain areas with more than 50%. Turnover was not appreciably decreased, but significantly increased within 48h of drug discontinuation. The microdialysis experiments indicate that neuronal release of 5-HT depends strongly on new synthesis and emphasize the role of 5-HT(1B) receptors in the regulation of these processes. Discontinuation of the SSRI rapidly increased behavioral reactivity to the external stimulus. Additional startle experiments suggest that the increased reactivity is more likely related to the reduced extracellular 5-HT levels than to impaired synthesis. The combination of the marked reduction of serotonin content and limited synthesis may destabilize brain serotonin transmission during long-term SSRI treatment. These combined effects may compromise the efficacy of an SSRI therapy and facilitate behavioral changes following non-compliance.

PMID:

 

20946930

 

DOI:

 

10.1016/j.neuint.2010.10.001

Pharmaceuticals 2010, 3(12), 3614-3628; doi:10.3390/ph3123614

Review

Pharmacogenetics of SSRIs and Sexual Dysfunction

Liana Osis andJeffrey R. Bishop * 

Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, 833 S. Wood St. Rm. 164 (M/C886), Chicago, IL 60612, USA

*

Author to whom correspondence should be addressed.

Received: 1 November 2010; in revised form: 30 November 2010 / Accepted: 9 December 2010 / Published: 15 December 2010

Abstract

: Sexual dysfunction (SD) is a common and disconcerting side effect of selective serotonin reuptake inhibitors (SSRIs) that often influences a patient’s desire to continue long-term antidepressant treatment. Studies specifically assessing changes in sexual well-being over time illustrate that the incidence of sexual side effects from SSRIs ranges from 20% to 70%, depending on the characteristics of the study sample assessed. Developing strategies to predict who may be at the highest risk for adverse changes in their sexual well-being is an important step in improving the quality of life and treatment of patients who require antidepressant therapy. Pharmacogenetic studies of SSRI-associated SD have identified associations between serotonin and glutamate system genes with aspects of SD. The results of studies investigating genetic variations in drug metabolism enzymes and their relationships to antidepressant-associated adverse effects have been mixed. Continued efforts to characterize the relationships between genetic markers and antidepressant outcomes, and to translate this knowledge to patient care, have the potential to significantly improve the empiric selection of antidepressant agents and to minimize the risk for intolerable side effects.

Keywords:

 SSRI; sexual dysfunction; polymorphism; serotonin; glutamate; drug metabolism; depression

Brain Res. 2012 Jan 6;1429:52-60. doi: 10.1016/j.brainres.2011.10.025. Epub 2011 Oct 20.

Dose-dependent effects of neonatal SSRI exposure on adult behavior in the rat.

Harris SS1, Maciag D, Simpson KL, Lin RC, Paul IA.

Author information

1

Department of Pharmacology and Toxicology, University of Mississippi Medical Center Jackson, MS, USA.

Abstract

Neonatal exposure to antidepressants produces lasting impairments in male sexual behavior. Although perturbation of the serotonin system during neonatal life has been implicated in the long-term behavioral effects of neonatal antidepressant exposure, dose-response studies were necessary to confirm that inhibition of the serotonin transporter during the neonatal period is sufficient to produce impairments in sexual behavior. Therefore, the present study examined the dose-response effects of neonatal citalopram exposure on sexual behavior. In addition, the effects of exposure on anxiety-related behavior were examined since alterations in this behavioral measure could affect sexual behavior. Male Long-Evans rats were injected subcutaneously with citalopram (CTM) in one of three doses (5, 10 or 20mg/kg/d), or saline (SAL) in a volume of 0.1 ml twice daily (07:00 and 14:00 h) from PD8 to PD21. The rats were tested as adults (>PD90) for anxiety-like behavior and exploration in the elevated plus maze test and sexual behavior. Neonatal citalopram exposure produced persistent reductions in male sexual behavior characterized by significant dose-dependent reductions in the percentage of male rats displaying mounting as well as dose-dependent reductions in the number of mounts and mount latency. Neonatal citalopram exposure also produced significant dose-dependent linear trends for reductions in intromission and ejaculation behavior. However, neonatal SSRI exposure was not found to produce any effects on exploration or anxiety-like behavior in the elevated plus maze test. The present findings support the hypothesis that inhibition of the serotonin transporter during neonatal life by an SSRI is directly responsible for the long-term effects on male sexual behavior.

PMID:

 

22079319

 

PMCID:

 

PMC3228278

 

DOI:

 

10.1016/j.brainres.2011.10.025

PLoS One. 2012;7(4):e35041. doi: 10.1371/journal.pone.0035041. Epub 2012 Apr 11.

A genome-wide association study of female sexual dysfunction.

Burri A1, Hysi P, Clop A, Rahman Q, Spector TD.

Author information

1

Biological and Experimental Psychology Group, School of Biological and Chemical Sciences, Queen Mary University of London, London, United Kingdom. andrea.burri@kcl.ac.uk

Abstract

BACKGROUND:

Female sexual dysfunction (FSD) is an important but controversial problem with serious negative impact on women's quality of life. Data from twin studies have shown a genetic contribution to the development and maintenance of FSD.

METHODOLOGY/PRINCIPAL FINDINGS:

We performed a genome-wide association study (GWAS) on 2.5 million single-nucleotide polymorphisms (SNPs) in 1,104 female twins (25-81 years of age) in a population-based register and phenotypic data on lifelong sexual functioning. Although none reached conventional genome-wide level of significance (10 × -8), we found strongly suggestive associations with the phenotypic dimension of arousal (rs13202860, P = 1.2 × 10(-7); rs1876525, P = 1.2 × 10(-7); and rs13209281 P = 8.3 × 10(-7)) on chromosome 6, around 500 kb upstream of the locus HTR1E (5-hydroxytryptamine receptor 1E) locus, related to the serotonin brain pathways. We could not replicate previously reported candidate SNPs associated with FSD in the DRD4, 5HT2A and IL-1B loci.

CONCLUSIONS/SIGNIFICANCE:

We report the first GWAS of FSD symptoms in humans. This has pointed to several "risk alleles" and the implication of the serotonin and GABA pathways. Ultimately, understanding key mechanisms via this research may lead to new FSD treatments and inform clinical practice and developments in psychiatric nosology.

PMID:

 

22509378

 

PMCID:

 

PMC3324410

 

DOI:

 

10.1371/journal.pone.0035041

Psychother Psychosom. 2012;81(6):386-8. doi: 10.1159/000341178. Epub 2012 Sep 6.

Patient online report of selective serotonin reuptake inhibitor-induced persistent postwithdrawal anxiety and mood disorders.

Belaise C, Gatti A, Chouinard VA, Chouinard G.

PMID:

 

22964821

 

DOI:

 

10.1159/000341178

Pharmacol Biochem Behav. Author manuscript; available in PMC 2015 Jun 1.

Published in final edited form as:

Pharmacol Biochem Behav. 2014 Jun; 0: 31–42.

Published online 2013 Nov 15. doi: 10.1016/j.pbb.2013.11.008

PMCID: PMC4022722

NIHMSID: NIHMS547017

PMID: 24239784

PHARMACOLOGY OF SEROTONIN AND FEMALE SEXUAL BEHAVIOR

Lynda Uphouse

Author information Copyright and License information Disclaimer

Lynda Uphouse, Department of Biology, Texas Woman’s University, Denton, Texas, 76204;

Corresponding Author: Dr. Lynda Uphouse, Department of Biology, Texas Woman’s University, Denton, Texas 76204, Phone: 940-898-2356, Fax: 940-898-2382, ude.uwt@esuohpUL

Abstract

In this review, first a historical perspective of serotonin’s (5-HT) involvement in female sexual behavior is presented. Then an overview of studies implicating 5-HT is presented. The effect of drugs that increase or decrease CNS levels of 5-HT is reviewed. Evidence is presented that drugs which increase 5-HT have negative effects on female sexual behavior while a decrease in 5-HT is associated with facilitation of sexual behavior. Studies with compounds that act on 5-HT1, 5-HT2 or 5-HT3 receptors are discussed. Most evidence indicates that 5-HT1A receptor agonists inhibit sexual behavior while 5-HT2 or 5-HT3 receptors may exert a positive influence. There is substantial evidence to support a role for 5-HT in the modulation of female consummatory sexual behavior, but studies on the role of 5-HT in other elements of female sexual behavior (e.g. desire, motivation, sexual appetite) are few. Future studies should be directed at determining if these additional components of female sexual behavior are also modulated by 5-HT.

Keywords: review, sexual receptivity, proceptivity, SSRIs, sexual motivation, 5-HT receptors

Ugeskr Laeger. 2014 Feb 3;176(3):231-5.

[Discontinuation syndrome after SSRI antidepressants].

[Article in Danish]

Lykkegaard LA1, Videbech P.

Author information

1

Jægerspris Lægecenter, Parkvej 3A, 3630 Jægerspris. lotteakn@hotmail.com.

Abstract

Discontinuation symptoms are described for almost all major groups of antidepressants. Crucial differences between discontinuation symptoms and symptoms after withdrawal of benzodiazepines are pointed out. Furthermore, it is important to discern from relapse of depression in order to manage the symptoms in primary care where the use of selective serotonin re-uptake inhibitors (SSRI) is substantial. In this paper we inform of the key symptoms after SSRI, present tools for understanding and recognizing the condition and suggest initiatives to manage it rationally.

PMID:

 

24629750

Hormone replacement with 17β-estradiol plus dihydrotestosterone restores male sexual behavior in rats treated neonatally with clomipramine.

Limón-Morales O, et al. Horm Behav. 2014.

Authors

Limón-Morales O¹, Soria-Fregozo C², Arteaga-Silva M³, González MH⁴, Vázquez-Palacios G⁵, Bonilla-Jaime H⁶.

Author information

1

Posgrado en Biología Experimental, Universidad Autónoma Metropolitana-Iztapalapa. Apartado, Postal 55 535, C.P. 09340, D.F. México.

2

Laboratorio de Psicobiologia, Centro Universitario de los Lagos, Universidad de Guadalajara, México.

3

Departamento de Biología de la Reproducción, Universidad Autónoma Metropolitana-Iztapalapa. Apartado Postal 55 535, C.P. 09340, D.F. México.

4

Instituto de Neurociencias, Universidad de Guadalajara, Francisco de Quevedo 180, Col. Arcos de Vallarta, CP 44130, Guadalajara, Jalisco, México.

5

Colegio De Ciencia y Tecnología, Universidad Autónoma de la Ciudad de México-San Lorenzo Tezonco, Av. Prolongación San Isidro 151, Col. San Lorenzo Tezonco, Deleg, Iztapalapa CP 09790, México.

6

Departamento de Biología de la Reproducción, Universidad Autónoma Metropolitana-Iztapalapa. Apartado Postal 55 535, C.P. 09340, D.F. México. Electronic address: bjh@xanum.uam.mx.

Citation

Horm Behav. 2014 Nov;66(5):820-7. doi: 10.1016/j.yhbeh.2014.09.014. Epub 2014 Nov 11.

Abstract

Male sexual behavior (MSB) in rodents, in both its consummatory and motivational components, is regulated by hormones such as testosterone, 17β-estradiol and 5-α-dihydrotestosterone. In experiments, neonatal treatment with clomipramine (CMI; a serotonin reuptake inhibitor) reproduces some of the signs of depression in adult age, including reduced sexual behavior manifested in a lower percentage of subjects that mount, intromit and ejaculate, although their testosterone levels were not altered. However, the effect of this treatment on estrogen levels and the consequences of hormone substitution using 17β-estradiol and 5-α-dihydrotestosterone on the expression of male sexual behavior are still unknown. Therefore, the objective of the present study was to analyze the effect of neonatal treatment with CMI on plasma testosterone and 17β-estradiol levels, and the role of testosterone, 17β-estradiol and 5-α-dihydrotestosterone in altering the consummatory and motivational components of sexual behavior in male rats. To this end, it analyzed the copulatory parameters and sexual incentive motivation (SIM) of rats treated with CMI under two conditions: basal and post-hormone replacements. Neonatal treatment with CMI did not affect plasma testosterone or 17β-estradiol concentrations, but did decrease both the consummatory component and sexual motivation according to the results of the SIM test. These aspects were recovered after administering 17β-estradiol +5-α-dihydrotestosterone, but not testosterone.

PMID

 25449595 [Indexed for MEDLINE]

Psychother Psychosom. 2014;83(4):197-204. doi: 10.1159/000362803. Epub 2014 Jun 19.

Rational use of antidepressant drugs.

Fava GA1.

Author information

1

Affective Disorders Program, Department of Psychology, University of Bologna, Bologna, Italy.

PMID:

 

24969962

 

DOI:

 

10.1159/000362803

Pharmacol Biochem Behav. 2014 Jun;121:88-101. doi: 10.1016/j.pbb.2013.10.004. Epub 2013 Oct 12.

Sexual side effects of serotonergic antidepressants: mediated by inhibition of serotonin on central dopamine release?

Bijlsma EY1, Chan JS1, Olivier B1, Veening JG2, Millan MJ3, Waldinger MD1, Oosting RS1.

Author information

1

Utrecht Institute for Pharmaceutical Sciences and Rudolf Magnus Institute of Neuroscience, Utrecht University, Universiteitsweg 99, 3584 CGUtrecht, The Netherlands.

2

Utrecht Institute for Pharmaceutical Sciences and Rudolf Magnus Institute of Neuroscience, Utrecht University, Universiteitsweg 99, 3584 CGUtrecht, The Netherlands; Department of Anatomy, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.

3

Institut de Recherches Servier, Psychopharmacology Department, 125 Chemin de Ronde, 78290 Croissy-sur-Seine, France.

Abstract

Antidepressant-induced sexual dysfunction adversely affects the quality of life of antidepressant users and reduces compliance with treatment. Animal models provide an instructive approach for examining potential sexual side effects of novel drugs. This review discusses the stability and reproducibility of our standardized test procedure that assesses the acute, subchronic and chronic effects of psychoactive compounds in a 30 minute mating test. In addition, we present an overview of the effects of several different (putative) antidepressants on male rat sexual behavior, as tested in our standardized test procedure. By comparing the effects of these mechanistically distinct antidepressants (paroxetine, venlafaxine, bupropion, buspirone, DOV 216,303 and S32006), this review discusses the putative mechanism underlying sexual side effects of antidepressants and their normalization. This review shows that sexual behavior is mainly inhibited by antidepressants that increase serotonin neurotransmission via blockade of serotonin transporters, while those that mainly increase the levels of dopamine and noradrenaline are devoid of sexual side effects. Those sexual disturbances cannot be normalized by simultaneously increasing noradrenaline neurotransmission, but are normalized by increasing both noradrenaline and dopamine neurotransmission. Therefore, it is hypothesized that the sexual side effects of selective serotonin reuptake inhibitors may be mediated by their inhibitory effects on dopamine signaling in sex brain circuits. Clinical development of novel antidepressants should therefore focus on compounds that simultaneously increase both serotonin and dopamine signaling.

KEYWORDS:

Animal model; Antidepressants; Drug-induced; Ejaculation; Sexual behavior; Sexual dysfunction

PMID:

 

24128918

 

DOI:

 

10.1016/j.pbb.2013.10.004

Urology. 2014 Apr;83(4):800-4. doi: 10.1016/j.urology.2013.12.004. Epub 2014 Feb 12.

Comparison of the effect of sertraline with behavioral therapy on semen parameters in men with primary premature ejaculation.

Akasheh G1, Sirati L1, Noshad Kamran AR2, Sepehrmanesh Z3.

Author information

1

Kashan University of Medical Sciences, Kashan, Iran.

2

Arak University of Medical Sciences, Arak, Iran.

3

Kashan University of Medical Sciences, Kashan, Iran. Electronic address: z.sepehrmanesh@gmail.com.

Abstract

OBJECTIVE:

To investigate the effects of sertraline on semen parameters and comparison of its effect with behavioral therapy (BT) in men with primary premature ejaculation.

METHODS:

In this single-blinded clinical trial, a total of 60 married men with primary premature ejaculation were randomly divided into 2 groups: the sertraline group (n = 30, sertraline 25 mg/day for 1 week followed by 50 mg/day for 3 months) and the BT group (n = 30, using BT technique for 3 months). Semen analysis was applied, and the results were compared between groups before and 3 months after intervention.

RESULTS:

The significant reduction in sperm concentration (10(5)/mL) and percentage of normal morphology was reported in sertraline group (P <.05). The percentage of sperm deoxyribonucleic acid fragmentation after intervention in sertraline group was significantly higher than BT group (P = .004). There was no significant change in semen parameters in patients treated using BT.

CONCLUSION:

Our study revealed detrimental effects of sertraline on some semen parameters. It should particularly be considered in patients who are trying to conceive. It seems BT is a safe method without any side effect on semen analysis parameters.

Copyright © 2014 Elsevier Inc. All rights reserved.

PMID:

 

24529582

 

DOI:

 

10.1016/j.urology.2013.12.004

Curr Biol. 2014 Oct 6;24(19):2314-8. doi: 10.1016/j.cub.2014.08.024. Epub 2014 Sep 18.

Serotonergic modulation of intrinsic functional connectivity.

Schaefer A1, Burmann I2, Regenthal R3, Arélin K4, Barth C2, Pampel A5, Villringer A6, Margulies DS7, Sacher J8.

Author information

1

Department of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, 04103 Leipzig, Germany; Department of Electrical and Computer Engineering, Clinical Imaging Research Centre & Singapore Insitute for Neurotechnology, National University of Singapore, 117583 Singapore, Singapore.

2

Department of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, 04103 Leipzig, Germany.

3

Division of Clinical Pharmacology, Rudolf-Boehm-Institute of Pharmacology and Toxicology, University of Leipzig, 04107 Leipzig, Germany.

4

Department of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, 04103 Leipzig, Germany; Clinic of Cognitive Neurology, University Hospital Leipzig, 04103 Leipzig, Germany; Leipzig Research Center for Civilization Diseases, University of Leipzig, 04103 Leipzig, Germany.

5

Nuclear Magnetic Resonance Unit, Max Planck Institute for Human Cognitive and Brain Sciences, 04103 Leipzig, Germany.

6

Department of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, 04103 Leipzig, Germany; Clinic of Cognitive Neurology, University Hospital Leipzig, 04103 Leipzig, Germany; Leipzig Research Center for Civilization Diseases, University of Leipzig, 04103 Leipzig, Germany; Integrated Research and Treatment Center Adiposity Diseases, University of Leipzig, 04103 Leipzig, Germany; Berlin School of Mind and Brain, Mind and Brain Institute, Charité and Humboldt University, 10099 Berlin, Germany.

7

Berlin School of Mind and Brain, Mind and Brain Institute, Charité and Humboldt University, 10099 Berlin, Germany; Max Planck Research Group for Neuroanatomy & Connectivity, Max Planck Institute for Human Cognitive and Brain Sciences, 04103 Leipzig, Germany.

8

Department of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, 04103 Leipzig, Germany; Clinic of Cognitive Neurology, University Hospital Leipzig, 04103 Leipzig, Germany; Berlin School of Mind and Brain, Mind and Brain Institute, Charité and Humboldt University, 10099 Berlin, Germany. Electronic address: sacher@cbs.mpg.de.

Abstract

Serotonin functions as an essential neuromodulator that serves a multitude of roles, most prominently balancing mood. Serotonergic challenge has been observed to reduce intrinsic functional connectivity in brain regions implicated in mood regulation. However, the full scope of serotonergic action on functional connectivity in the human brain has not been explored. Here, we show evidence that a single dose of a serotonin reuptake inhibitor dramatically alters functional connectivity throughout the whole brain in healthy subjects (n = 22). Our network-centrality analysis reveals a widespread decrease in connectivity in most cortical and subcortical areas. In the cerebellum and thalamus, however, we find localized increases. These rapid and brain-encompassing connectivity changes linked to acute serotonin transporter blockade suggest a key role for the serotonin transporter in the modulation of the functional macroscale connectome.

PMID:

 

25242032

 

DOI:

 

10.1016/j.cub.2014.08.024

Dimorphic changes of some features of loving relationships during long-term use of antidepressants in depressed outpatients

Author links open overlay panelDonatellaMarazzitiaHagop S.AkiskalabMiekoUdobMichelaPicchettiaStefanoBaroniaGabrieleMassimettiaFrancescoAlbaneseaLilianaDell׳Ossoa

a

Dipartimento di Medicina Clinica e Sperimentale, University of Pisa, Italy

b

International Mood Center, San Diego Veterans Administration Medical Center, San Diego, CA, USA

Received 9 December 2013, Revised 17 April 2014, Accepted 17 April 2014, Available online 2 May 2014.

Abstract

The present study aimed at investigating the possible changes of some features of loving relationships during long-term treatment of depression with both selective serotonin reuptake inhibitors (SSRIs) and tricyclics (TCAs), by means of a specifically designed test, the so-called “Sex, Attachment, Love” (SALT) questionnaire.

The sample was composed by 192 outpatients (123 women and 69 men, mean age±SD: 41.2±10.2 years), suffering from mild or moderate depression, according to DSM-IV-TR criteria, that were selected if they were treated with one antidepressant only for at least six months and were involved in a loving relationship.

The results showed that SSRIs had a significant impact on the feelings of love and attachment towards the partner especially in men, while women taking TCAs complained of more sexual side effects than men. These data were supported also by the detection of a significant interaction between drug and sex on the “Love” and “Sex” domains.

The present findings, while demonstrating a dimorphic effect of antidepressants on some component of loving relationships, need to be deepened in future studies.

Reprod Fertil Dev. 2015 Jan 13. doi: 10.1071/RD14199. [Epub ahead of print]

Maternal treatment with fluoxetine promotes testicular alteration in male rat pups.

Ramos AC, H Dos Santos A, Silveira KM, Kiss AC, Mesquita SF, Gerardin DC.

Abstract

Fluoxetine (FLX) is a selective serotonin reuptake inhibitor (SSRI) antidepressant commonly prescribed during pregnancy and lactation. Pre- and post-partum depression, as well as SSRI treatment during these periods, may change maternal care, interfering with offspring development. Moreover, it is known that SSRIs may alter testes structure and function in offspring. The present study investigated the effects of maternal FLX exposure on maternal behaviour and testes function in offspring. Female Wistar rats were treated with 7.5mgkg-1 FLX or tap water (control group) by gavage from the Day 1 of pregnancy until 21 days after birth (postnatal Day (PND) 21). Maternal behaviour was evaluated and morphofunctional analyses of offspring testes were conducted on PND 21 and 50. There were no significant differences between the FLX-treated and control groups regarding maternal behaviour. Nor did maternal treatment with FLX have any effect on bodyweight gain, anogenital distance, day of preputial separation, testis weight and the gonadosomatic index in male offspring. However, there was a decreased number of Sertoli cells at both PND 21 and 50 in FLX-exposed male offspring. The findings of the present study demonstrate that maternal exposure to FLX can impair testicular function in weanling and pubertal animals.

PMID:

 

25582582

 

DOI:

 

10.1071/RD14199

Psychother Psychosom. 2015;84(2):72-81. Epub 2015 Feb 21.

Withdrawal Symptoms after Selective Serotonin Reuptake Inhibitor Discontinuation: A Systematic Review.

Fava GA1, Gatti A, Belaise C, Guidi J, Offidani E.

Author information

1

Affective Disorders Program, Department of Psychology, University of Bologna, Bologna, Italy.

Abstract

BACKGROUND:

Selective serotonin reuptake inhibitors (SSRI) are widely used in medical practice. They have been associated with a broad range of symptoms, whose clinical meaning has not been fully appreciated.

METHODS:

The PRISMA guidelines were followed to conduct a systematic review of the literature. Titles, abstracts, and topics were searched using the following terms: 'withdrawal symptoms' OR 'withdrawal syndrome' OR 'discontinuation syndrome' OR 'discontinuation symptoms', AND 'SSRI' OR 'serotonin' OR 'antidepressant' OR 'paroxetine' OR 'fluoxetine' OR 'sertraline' OR 'fluvoxamine' OR 'citalopram' OR 'escitalopram'. The electronic research literature databases included CINAHL, the Cochrane Library, PubMed and Web-of-Science from inception of each database to July 2014.

RESULTS:

There were 15 randomized controlled studies, 4 open trials, 4 retrospective investigations, and 38 case reports. The prevalence of the syndrome was variable, and its estimation was hindered by a lack of case identification in many studies. Symptoms typically occur within a few days from drug discontinuation and last a few weeks, also with gradual tapering. However, many variations are possible, including late onset and/or longer persistence of disturbances. Symptoms may be easily misidentified as signs of impending relapse.

CONCLUSIONS:

Clinicians need to add SSRI to the list of drugs potentially inducing withdrawal symptoms upon discontinuation, together with benzodiazepines, barbiturates, and other psychotropic drugs. The term 'discontinuation syndrome' that is currently used minimizes the potential vulnerabilities induced by SSRI and should be replaced by 'withdrawal syndrome'. © 2015 S. Karger AG, Basel.

PMID:

 

25721705

 

DOI:

 

10.1159/000370338

Pediatrics. 2015 Apr;135(4):e815-7. doi: 10.1542/peds.2014-3003.

Assessing sexual symptoms and side effects in adolescents.

Levine A1, McGlinchey E2.

Author information

1

Division of Child and Adolescent Psychiatry, Department of Psychiatry, College of Physicians and Surgeons, Columbia University, and New York State Psychiatric Institute, New York, New York ama146@columbia.edu.

2

Division of Child and Adolescent Psychiatry, Department of Psychiatry, College of Physicians and Surgeons, Columbia University, and New York State Psychiatric Institute, New York, New York.

KEYWORDS:

CAMS; SSRI; TADS; adolescence; sexual side effects; sexual symptoms

PMID:

 

25802347

 

DOI:

 

10.1542/peds.2014-3003

Neurotoxicol Teratol. 2015 Jan-Feb;47:46-53. doi: 10.1016/j.ntt.2014.11.002. Epub 2014 Nov 12.

Low-dose paroxetine exposure causes lifetime declines in male mouse body weight, reproduction and competitive ability as measured by the novel organismal performance assay.

Gaukler SM1, Ruff JS2, Galland T2, Kandaris KA2, Underwood TK2, Liu NM2, Young EL2, Morrison LC2, Yost GS3, Potts WK2.

Author information

1

Department of Biology, University of Utah, 257 South 1400 East, Salt Lake City, UT 84112, USA. Electronic address: Shannon.Gaukler@gmail.com.

2

Department of Biology, University of Utah, 257 South 1400 East, Salt Lake City, UT 84112, USA.

3

Department of Pharmacology and Toxicology, University of Utah, 30 South 2000 East, Salt Lake City, UT 84112, USA.

Abstract

Paroxetine is a selective serotonin reuptake inhibitor (SSRI) that is currently available on the market and is suspected of causing congenital malformations in babies born to mothers who take the drug during the first trimester of pregnancy. We utilized organismal performance assays (OPAs), a novel toxicity assessment method, to assess the safety of paroxetine during pregnancy in a rodent model. OPAs utilize genetically diverse wild mice (Mus musculus) to evaluate competitive performance between experimental and control animals as they compete among each other for limited resources in semi-natural enclosures. Performance measures included reproductive success, male competitive ability and survivorship. Paroxetine-exposed males weighed 13% less, had 44% fewer offspring, dominated 53% fewer territories and experienced a 2.5-fold increased trend in mortality, when compared with controls. Paroxetine-exposed females had 65% fewer offspring early in the study, but rebounded at later time points, presumably, because they were no longer exposed to paroxetine. In cages, paroxetine-exposed breeders took 2.3 times longer to produce their first litter and pups of both sexes experienced reduced weight when compared with controls. Low-dose paroxetine-induced health declines detected in this study that were undetected in preclinical trials with doses 2.5-8 times higher than human therapeutic doses. These data indicate that OPAs detect phenotypic adversity and provide unique information that could be useful towards safety testing during pharmaceutical development.

KEYWORDS:

Intraspecific competition; Pharmacodynamics; Reproductive success; SSRI; Semi-natural enclosures; Toxicity assessment

PMID:

 

25446017

 

PMCID:

 

PMC4416947

 

DOI:

 

10.1016/j.ntt.2014.11.002

Neurosci Biobehav Rev. 2015 Apr;51:164-88. doi: 10.1016/j.neubiorev.2015.01.018. Epub 2015 Jan 24.

Is serotonin an upper or a downer? The evolution of the serotonergic system and its role in depression and the antidepressant response.

Andrews PW1, Bharwani A2, Lee KR2, Fox M3, Thomson JA Jr4.

Author information

1

Department of Psychology, Neuroscience and Behaviour, McMaster University, 1280 Main Street West, Hamilton, Ontario L8S 4K1, Canada. Electronic address: pandrews@mcmaster.ca.

2

Department of Psychology, Neuroscience and Behaviour, McMaster University, 1280 Main Street West, Hamilton, Ontario L8S 4K1, Canada.

3

Department of Psychiatry and Human Behavior, University of California Irvine, Orange, CA, USA.

4

Counseling and Psychological Services, University of Virginia Student Health, Charlottesville, VA, USA; Institute of Law, Psychiatry, and Public Policy, University of Virginia, Charlottesville, VA, USA.

Abstract

The role of serotonin in depression and antidepressant treatment remains unresolved despite decades of research. In this paper, we make three major claims. First, serotonin transmission is elevated in multiple depressive phenotypes, including melancholia, a subtype associated with sustained cognition. The primary challenge to this first claim is that the direct pharmacological effect of most symptom-reducing medications, such as the selective serotonin reuptake inhibitors (SSRIs), is to increase synaptic serotonin. The second claim, which is crucial to resolving this paradox, is that the serotonergic system evolved to regulate energy. By increasing extracellular serotonin, SSRIs disrupt energy homeostasis and often worsen symptoms during acute treatment. Our third claim is that symptom reduction is not achieved by the direct pharmacological properties of SSRIs, but by the brain's compensatory responses that attempt to restore energy homeostasis. These responses take several weeks to develop, which explains why SSRIs have a therapeutic delay. We demonstrate the utility of our claims by examining what happens in animal models of melancholia and during acute and chronic SSRI treatment.

KEYWORDS:

Analysis; Depression; Distraction; Energy regulation; Hippocampus; Hypothalamus; Learning; Plasticity; Prefrontal cortex; Serotonin; Working memory

PMID:

 

25625874

 

DOI:

 

10.1016/j.neubiorev.2015.01.018

J Clin Diagn Res. 2015 Feb;9(2):VD01-VD02. doi: 10.7860/JCDR/2015/11394.5583. Epub 2015 Feb 1.

A Case of SSRI Induced Irreversible Parkinsonism.

Dixit S1, Khan SA1, Azad S2.

Author information

1

Classified Specialist, Department of Psychiatry, Base Hospital Delhi Cantt , New Delhi, India .

2

Resident, Department of Psychiatry, Base Hospital Delhi Cantt , New Delhi, India .

Abstract

Serotonin specific reuptake inhibitors (SSRI) are widely used antidepressants for variety of clinical conditions and have found popularity. They are sometimes associated with extrapyramidal side effects including Parkinsonism. We report a case of generalized anxiety disorder on treatment with SSRI (fluoxetine / sertraline) who developed irreversible Parkinsonism. SSRI are known to cause reversible or irreversible motor disturbances through pathophysiological changes in basal ganglion motor system by altering the dopamine receptors postsynaptically. Clinician should keep risk benefit ratio in mind and change of antidepressant of different class may be considered. Case is reported to alert physicians to possibility of motor system damage while treating with SSRI.

KEYWORDS:

Drug induced parkinsonism; Epidemiology; Fluoxetine; Sertraline

PMID:

 

25859504

 

PMCID:

 

PMC4378786

 

DOI:

 

10.7860/JCDR/2015/11394.5583

Behav Pharmacol. Author manuscript; available in PMC 2016 Mar 3.

Published in final edited form as:

Behav Pharmacol. 2015 Sep; 26(6): 595–606.

doi: 10.1097/FBP.0000000000000157

PMCID: PMC4777293

NIHMSID: NIHMS763338

PMID: 26110223

Neuroanatomical dichotomy of sexual behaviors in rodents: a special emphasis on brain serotonin

Mariana Angoa-Pérez1,2 and Donald M. Kuhn1,2

Author information Copyright and License information Disclaimer

1Research & Development Service, John D. Dingell VA Medical Center, Detroit, MI 48201, USA

2

Abstract

Much of the social behavior in which rodents engage is related to reproduction, such as maintaining a breeding territory, seeking mates, mating, and caring for young. Rodents belong to the internally fertilizing species that require sexual behavior for reproduction. The dyadic, heterosexual patterns of most mammalian species are sexually dimorphic, but they also share mutual components in both sexes: sexual attraction is reciprocal, sexual initiative is assumed, appetitive behavior is engaged in and mating involves consummatory and postconsummatory phases in females as well as in males. Serotonin, a phylogenetically ancient molecule, is the most widely distributed neurotransmitter in the brain and its signaling pathways are essential for numerous functions including sexual behavior. Since the late 1960’s, brain serotonergic neurotransmission has been considered to exert an inhibitory influence on the neural mechanisms mediating sexual behavior. This contention was based mainly on the observations that a decrease in central serotonergic activity facilitated the elicitation of sexual behavior while an increase in central serotonergic activity attenuated it. However, the discovery of over 14 types of serotonin receptors has added numerous layers of complexity to the study of serotonin and sexual behavior. Evidence shows that upon activation, certain receptor subtypes facilitate while some others suppress sexual behavior as well as sexual arousal and motivation. Furthermore, the role of these receptors has been shown to be differential in males versus females. The use of serotonergic pharmacological interventions, mouse strains with genetic polymorphisms causing alterations in the levels of brain serotonin as well as animal models with genetic manipulations of various serotonin effectors has helped delineate the fundamental role of this neurotransmitter in the regulation of sexual behavior. This review aims to examine the basics of the components of female and male sexual behavior and the participation of the serotonin system in the modulation of these behaviors with emphasis on rodents.

Keywords: serotonin, sexual behavior, copulation, female receptivity, mounting

Clujul Med. 2015; 88(3): 381–385.

Published online 2015 Jul 1. doi: 10.15386/cjmed-474

PMCID: PMC4632899

PMID: 26609273

Estrogenic/antiestrogenic activity of selected selective serotonin reuptake inhibitors

ANCA POP, DIANA IOANA LUPU, JULIEN CHERFAN, BELA KISS, and FELICIA LOGHIN

Author information Article notes Copyright and License information Disclaimer

Department of Toxicology, Faculty of Pharmacy, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania

Address for correspondence: moc.liamg@78anaidupul

Abstract

Background and aims

Selective serotonin reuptake inhibitors (SSRIs) are one of the most prescribed classes of psychotropics. Even though the SSRI class consists of 6 molecules (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine and sertraline), only fluoxetine was intensively studied for endocrine disruptive effects, while the other SSRIs received less attention. This study was designed to evaluate the estrogenic/antiestrogenic effect of fluoxetine, sertraline and paroxetine.

Methods

The in vitro (anti)estrogenic activity was assessed using a firefly luciferase reporter construct in the T47D-KBluc breast cancer cell line. These cells express nuclear estrogen receptors that can activate the transcription of the luciferase reporter gene upon binding of estrogen receptor agonists.

Results

All three compounds were found to interact with the estrogen receptor. Fluoxetine had dual properties, weak estrogenic at lower concentrations and antiestrogenic effect at higher concentrations. Sertraline shared the same properties with fluoxetine, but also increased the estradiol-mediated transcriptional activity. Paroxetine presented only one type of effect, the ability to increase the estradiol-mediated transcriptional activity.

Conclusions

Overall, our results indicate a possible interaction of SSRIs with the estrogen receptor. As SSRIs are being used by all categories of population, including pregnant women or children, establishing whether they can affect the endocrine mediated mechanisms should be a priority.

Keywords: fluoxetine, sertraline, paroxetine, luciferase assay

Long-term changes in observed behaviour after exposure to psychiatric drugs: A systematic review of animal studies 

Pia Brandt Danborg, Anders Lykkemark Simonsen, Asbjørn Hróbjartsson, Peter C. Gøtzsche

Abstract:

Many patients are taking psychiatric drugs for years despite little knowledge about their long-term harms. Here, we summarise the findings of whether psychiatric drug exposure causes long-term harms in mammals after a drug-free period. We searched PubMed, Biosis and Embase for controlled animal studies (no behavioural priming; behavioural assessments performed after a 90 day drug-free period). Data was extracted by two assessors for animal characteristics, study design, funding and behavioural outcomes: sleep, addiction, pain, anxiety, depression, locomotion, cognition and social (sexual) behaviour. Meta-analysis was performed when two or more studies were eligible. We included 33 studies in mice, rats, hamsters, cats and monkeys. The quality of the studies was poor or poorly reported and heterogeneity was high. Antidepressants caused impaired sexual behaviour; benzodiazepines, antidepressants and methyl-phenidate caused statistically significant but variable effects on anxiety. Cognition was unaffected by haloperidol, olanzapine decreased learning in one test and diazepam impaired cognition on all cognitive outcomes. Antipsychotics increased vacuous chewing movements. Animal research on long-term outcomes is sparse and dominated by poor methodology. Still, impaired sexual behaviour, cognition and locomotion were seen. Action should be taken to improve reporting and reduce bias. We suggest that psychiatric drug research follow the animals after end of the intervention to assess long-term harms.

Neuropsychopharmacology. 2006 Oct;31(10):2281-8. Epub 2006 May 10.

Serotonin 2A -1438 G/A and G-protein Beta3 subunit C825T polymorphisms in patients with depression and SSRI-associated sexual side-effects.

Bishop JR1, Moline J, Ellingrod VL, Schultz SK, Clayton AH.

Author information

1

University of Illinois at Chicago College of Pharmacy, Chicago, IL, USA.

Abstract

The occurrence of sexual side-effects from antidepressants is thought to be mediated through serotonin 2A (5HT2A) receptors. It is currently unknown if functional polymorphisms in the 5HT2A receptor or its G-protein second messenger complex are related to sexual dysfunction in patients taking an selective serotonin reuptake inhibitor (SSRI) for depression. The purpose of this study was to determine the relationship of the 5HT2A -1438 G/A and GNB3 C825T single nucleotide polymorphisms with overall sexual well-being and individual components of sexual health as measured by the Changes in Sexual Functioning Questionnaire (CSFQ). We evaluated 89 outpatients (18-40 years of age) at low risk for other causes of sexual dysfunction who were being treated for depression with an SSRI and did not have sexual difficulties before taking the antidepressant. Outcome measures were stratified by 5HT2A and GNB3 genotypes. After controlling for age, gender, anxiety scale scores, and depression scale scores, persons with a GG genotype of the 5HT2A -1438 single nucleotide polymorphisms (SNP) were significantly more likely to be categorized as having sexual dysfunction than persons with a GA or AA genotype (OR=3.6; 95% CI 1.03, 12.6; p=0.046). Furthermore, the 5HT2A -1438 GG genotype was a significant predictor of lower arousal scores (p=0.022) after accounting for other measures. There was no significant relationship between any outcome measure and GNB3 genotype.

PMID:

 

16710319

 

DOI:

 

10.1038/sj.npp.1301090

Front Pharmacol. 2017 Oct 20;8:743. doi: 10.3389/fphar.2017.00743. eCollection 2017.

Chronic Treatment with Fluoxetine Induces Sex-Dependent Analgesic Effects and Modulates HDAC2 and mGlu2 Expression in Female Mice.

Zammataro M1, Merlo S2, Barresi M3, Parenti C1, Hu H4, Sortino MA2, Chiechio S1.

Author information

1

Department of Drug Sciences, University of Catania, Catania, Italy.

2

Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.

3

Institut des Maladie Neurodégénératives, Bordeaux, France.

4

Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, United States.

Abstract

Gender and sex differences in pain recognition and drug responses have been reported in clinical trials and experimental models of pain. Among antidepressants, contradictory results have been observed in patients treated with selective serotonin reuptake inhibitors (SSRIs). This study evaluated sex differences in response to the SSRI fluoxetine after chronic administration in the mouse formalin test. Adult male and female CD1 mice were intraperitoneally injected with fluoxetine (10 mg/kg) for 21 days and subjected to pain assessment. Fluoxetine treatment reduced the second phase of the formalin test only in female mice without producing behavioral changes in males. We also observed that fluoxetine was able to specifically increase the expression of metabotropic glutamate receptor type-2 (mGlu2) in females. Also a reduced expression of the epigenetic modifying enzyme, histone deacetylase 2 (HDAC2), in dorsal root ganglia (DRG) and dorsal horn (DH) together with an increase histone 3 acetylation (H3) level was observed in females but not in males. With this study we provide evidence that fluoxetine induces sex specific changes in HDAC2 and mGlu2 expression in the DH of the spinal cord and in DRGs and suggests a molecular explanation for the analgesic effects in female mice.

KEYWORDS:

HDAC2; fluoxetine; metabotropic glutamate 2 receptor; pain; sex differences

PMID:

 

29104538

 

PMCID:

 

PMC5654865

 

DOI:

 

10.3389/fphar.2017.00743

Riv Psichiatr. 2018 Mar-Apr;53(2):95-99. doi: 10.1708/2891.29158.

The Diagnostic clinical Interview for Drug Withdrawal 1 (DID-W1) – New Symptoms of Selective Serotonin Reuptake Inhibitors (SSRI) or Serotonin Norepinephrine Reuptake Inhibitors (SNRI): inter-rater reliability

Cosci F1, Chouinard G2, Chouinard VA3, Fava GA4.

Author information

1

Department of Health Sciences, University of Florence, Italy - Department of Psychiatry & Neuropsychology, Maastricht University, The Netherlands.

2

Clinical Psychopharmacology and Therapeutics Unit, Montréal, Québec, Canada - University Mental Health Institute of Montreal, Research Center Fernand Seguin, University of Montréal, Québec, Canada.

3

Psychotic Disorders Division, McLean Hospital, Harvard Medical School, Belmont, USA.

4

Department of Psychology, University of Bologna, Italy - State University of New York at Buffalo, Buffalo, New York, USA.

Abstract

AIM:

A wide range of clinical phenomena have been reported with dose reduction or drug discontinuation of Selective Serotonin Reuptake Inhibitors (SSRIs) or Serotonin Norepinephrine Reuptake Inhibitors (SNRIs). In 2015, a new classification of SRIs/SNRIs withdrawal (i.e., new withdrawal symptoms, rebound symptoms withdrawal, persistent post-withdrawal disorders) was outlined on the basis of the literature and clinical observations. A semistructured clinical interview, the Diagnostic clinical Interview for Drug Withdrawal 1 - New Symptoms of SSRI and SNRI (DID-W1), was developed for identifying and differentiating such syndromes. Its inter-rater reliability has been tested.

METHODS:

Seventeen consecutive outpatients with a history of SSRI or SNRI dose reduction or discontinuation were assessed independently by 2 clinicians at different times during the same day. Percent agreement, Cohen’s kappa, and the squared correlation coefficient were used to measure inter-rater reliability.

RESULTS:

The percent agreement for the whole interview was 97.06%, the Cohen’s kappa 0.85 (95% CI of 0.61-1.08), the squared correlation coefficient 0.72.

DISCUSSION AND CONCLUSIONS:

The kappa values indicated excellent inter-rater agreement. Validity evaluation and comparison with other instruments need to be performed. The DID-W1 may help diagnosing the clinical phenomena related to SSRI and SNRI discontinuation, their differentiation from relapse, and the potential iatrogenic origin of psychiatric symptoms in clinical practice.

PMID:

 

29674777

 

DOI:

 

10.1708/2891.29158

Toxicol Sci. 2018 Jun 1;163(2):609-619. doi: 10.1093/toxsci/kfy059.

Sertraline Suppresses Testis and Adrenal Steroid Production and Steroidogenic Gene Expression While Increasing LH in Plasma of Male Rats Resulting in Compensatory Hypogonadism.

Munkboel CH1, Larsen LW1, Weisser JJ1, Møbjerg Kristensen D2,3, Styrishave B1.

Author information

1

Toxicology Laboratory, Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen OE, Denmark.

2

Danish Headache Center, Department of Neurology, Rigshospitalet, University of Copenhagen, 1165 Copenhagen, Denmark.

3

Inserm (Institut National de la Santé et de la Recherche Médicale), Irset - Inserm UMR 1085, 35000 Rennes, France.

Abstract

Selective serotonin reuptake inhibitors are used as first line treatment in major depressive disorder. However, selective serotonin reuptake inhibitors have also been associated with sexual disorders, abnormalities, and sexual dysfunction, although mechanisms are unclear. The aim of this project was to investigate the possible endocrine disrupting effect of sertraline (SER) on sex steroid production in male rats exposed to 3 therapeutically realistic doses of SER 1.25, 5, and 20 mg/kg/day. To achieve this, we analyzed all the major steroids in testis, adrenals, brain, and plasma using Liquid chromatography tandem mass spectrometry. Furthermore, we investigated the potential effects on gene expression on the major genes involved in testicular, adrenal and brain steroidogenesis using quantitative PCR. Moreover, plasma luteinizing hormone (LH) levels were analyzed. We observed significant reduction in steroid production, in particular on the testicular Δ-4 axis and on the adrenal CYP17-hydroxylase axis. Effects in brain and plasma were less pronounced. Testicular gene transcription was also significantly down-regulated except for the CYP19 (aromatase) gene. In contrast, no effects on the adrenal gene expression were observed, except for an up-regulation of the CYP17. Plasma LH and LH/TS were increased, in particular in the lowest exposure group, indicating some degree of compensatory hypogonadism. In conclusion, this study demonstrates extensive endocrine disruption during SER exposure in male rats, both directly on steroid production in major endocrine tissues, but also indirectly by affecting gene expression. Furthermore, increased LH levels may augment decreased sex steroid production, in particular testosterone production, inducing a state of compensatory hypogonadism.

PMID:

  

29850907

  

DOI:

  

10.1093/toxsci/kfy059

Arch Sex Behav. 2019 Apr;48(3):923-933. doi: 10.1007/s10508-018-1365-6. Epub 2019 Feb 21.

A Real-World Study on Antidepressant-Associated Sexual Dysfunction in 2144 Outpatients: The SALSEX I Study.

Montejo AL1,2, Calama J3,4, Rico-Villademoros F5, Montejo L6, González-García N3,7, Pérez J8; SALSEX Working Study Group.

Collaborators (96)

Mañas JAA, Agüero JA, Aldabatreku M, de La Torre ÁA, Quintanilla PA, Lobato PÁ, Paz MTA, Antón JA, González JA, Simón JA, Chomón AA, Rodríguez CB, Herrero LB, Pérez EB, Bonaechea BB, González JB, García JC, Calvo P, Campos M, Dono CC, Iglesias JMC, Del Valle JCD, Feliz FD, Alfonso AE, Izquierdo JRE, Barrio JAE, Álvarez ME, Atienzar CF, Cuesta JMF, Torre ÓF, Vivanco EF, Freire I, De Dios MTG, Mahia MCG, Mellado JAG, Nicolás MG, Sánchez FG, Ullán LG, Usieto EG, Robina FG, Bardanca SG, De María VG, Izquierdo PG, Marín EG, Martínez RG, Pablos EG, Vázquez AIG, Zinnmerman LG, de Las Heras MÁH, González MJH, González MH, Abella FI, Lorenzo GI, Iraizoz I, Ochoa JL, Borrajo JML, Ilundain JL, Pérez MM, Van Son JM, Medina MÁ, Merino CM, Eguiluz BM, García MJM, Zugazabeitia BM, Justel AM, Morera B, Munarriz I, García JM, León SO, Otaño M, Yañez LP, Pastor M, Terán JMP, López MP, Nievas FP, Portilla JAP, Mestre NP, Yañez PQ, Fernández FR, Pérez VR, García MS, Iglesias SS, de Santiago Iaz A, de Santiago Sastre J, de La Garza CS, Granado OS, López JMS, Biddle DS, Arribas JS, Loza AS, Ablanedo LS, Prieto AT, Vega PT, Ventoso CV, Boyero JLV, Merayo YZ.

Author information

1

Neurosciences Area, Instituto de Investigación Biomédica de Salamanca, University of Salamanca, Salamanca, Spain. amontejo@usal.es.

2

Psychiatry Department, University Hospital of Salamanca, Paseo de San Vicente, 58-182, 37007, Salamanca, Spain. amontejo@usal.es.

3

Neurosciences Area, Instituto de Investigación Biomédica de Salamanca, University of Salamanca, Salamanca, Spain.

4

Psychiatry Department, University Hospital of Salamanca, Paseo de San Vicente, 58-182, 37007, Salamanca, Spain.

5

Neurosciences Institute, University of Granada, Granada, Spain.

6

Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Centro de Investigación Biomédica en Red de Salud Mental, Barcelona, Spain.

7

Department of Statistics, School of Medicine, University of Salamanca, Salamanca, Spain.

8

Department of Psychiatry, University of Cambridge, Cambridge, UK.

Abstract

The objective of this cross-sectional study was to evaluate the frequency, impact, and management of sexual dysfunction associated with commonly prescribed antidepressants available in psychiatry outpatient clinics in Spain. We recruited 2163 adult patients who had undergone treatment with antidepressants for at least 8 weeks and had a history of normal sexual functioning before the prescription of the antidepressant, except for mildly impaired libido. We used the Psychotropic-Related Sexual Dysfunction Questionnaire (PRSexDQ-SALSEX) for evaluating the frequency and tolerance of sexual dysfunction and whether this side effect was spontaneously reported. Overall, 79% patients showed sexual dysfunction, as indicated by a total score ≥ 3 on the PRSexDQ-SALSEX; 64% showed moderate-severe sexual dysfunction, with no differences between men and women on these outcomes. In the multivariate logistic regression analysis, treatment with a serotonergic antidepressant and having a severe clinical state of psychiatric illness were the factors associated with the highest likelihood of presenting with sexual dysfunction. Sexual dysfunction was spontaneously reported by 838 (41%) of the 2066 evaluable patients for this outcome. Among patients with sexual dysfunction, this condition was poorly tolerated by 22% of the patients, with these frequencies being significantly higher in men than in women. The most frequently used strategies employed by the psychiatrists in our study for dealing with sexual dysfunction were switching to another antidepressant (34%) and waiting for spontaneous resolution (33%). In conclusion, our results indicate that despite being a well-known, long-standing side effect of antidepressants, sexual dysfunction continues to be extremely common in patients receiving antidepressants, especially serotonergic ones, potentially jeopardizing treatment success in a substantial proportion of patients. There are important sex differences in the reporting and tolerance of sexual dysfunction that require further investigation.

KEYWORDS:

Antidepressant; Psychotropic; Sex differences; Sexual dysfunction; Sexual functioning

PMID:

 

30790204

 

DOI:

 

10.1007/s10508-018-1365-6

J Clin Med. 2019 Mar 14;8(3). pii: E363. doi: 10.3390/jcm8030363.

Serotonergic, Dopaminergic, and Noradrenergic Modulation of Erotic Stimulus Processing in the Male Human Brain.

Graf H1, Malejko K2, Metzger CD3,4,5, Walter M6,7, Grön G8, Abler B9.

Author information

1

Department of Psychiatry and Psychotherapy III, Ulm University, 89075 Ulm, Germany. heiko.graf@uni-ulm.de.

2

Department of Psychiatry and Psychotherapy III, Ulm University, 89075 Ulm, Germany. kathrin.malejko@uni-ulm.de.

3

Department of Psychiatry, Otto von Guericke University, 39120 Magdeburg, Germany. coraline.metzger@med.ovgu.de.

4

Institute of Cognitive Neurology and Dementia Research (IKND), Otto von Guericke University, 39106 Magdeburg, Germany. coraline.metzger@med.ovgu.de.

5

German Center for Neurodegenerative Diseases (DZNE), 39120 Magdeburg, Germany. coraline.metzger@med.ovgu.de.

6

Department of Psychiatry, Eberhard Karls University, 72074 Tuebingen, Germany. martin.walter@uni-tuebingen.de.

7

Leibniz Institute for Neurobiology, 39120 Magdeburg, Germany. martin.walter@uni-tuebingen.de.

8

Department of Psychiatry and Psychotherapy III, Ulm University, 89075 Ulm, Germany. georg.groen@uni-ulm.de.

9

Department of Psychiatry and Psychotherapy III, Ulm University, 89075 Ulm, Germany. birgit.abler@uni-ulm.de.

Abstract

Human sexual behavior is mediated by a complex interplay of cerebral and spinal centers, as well as hormonal, peripheral, and autonomic functions. Neuroimaging studies identified central neural signatures of human sexual responses comprising neural emotional, motivational, autonomic, and cognitive components. However, empirical evidence regarding the neuromodulation of these neural signatures of human sexual responses was scarce for decades. Pharmacological functional magnetic resonance imaging (fMRI) provides a valuable tool to examine the interaction between neuromodulator systems and functional network anatomy relevant for human sexual behavior. In addition, this approach enables the examination of potential neural mechanisms regarding treatment-related sexual dysfunction under psychopharmacological agents. In this article, we introduce common neurobiological concepts regarding cerebral sexual responses based on neuroimaging findings and we discuss challenges and findings regarding investigating the neuromodulation of neural sexual stimulus processing. In particular, we summarize findings from our research program investigating how neural correlates of sexual stimulus processing are modulated by serotonergic, dopaminergic, and noradrenergic antidepressant medication in healthy males.

KEYWORDS:

dopamine; erotic stimulus processing; fMRI; healthy; human; noradrenaline; serotonin

PMID:

 

30875818

 

DOI:

 

10.3390/jcm8030363

Neuropsychopharmacol Hung. 2019 Mar;21(1):26-35.

Transcriptomic changes following chronic administration of selective serotonin reuptake inhibitors: a review of animal studies.

Kumar S1, Gal Z, Gonda X, Huse RJ, Juhasz G, Bagdy G, Petschner P.

Author information

1

Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary. petschner.peter@pharma.semmelweis-univ.hu.

Abstract

The review focuses on transcriptomic changes following treatment with serotonin reuptake inhibitor (SSRI) antidepressants. We aimed to overview results of the most established methods for the investigation of the gene expression alterations including northern blotting, in situ hybridization, quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), microarray and RNAseq in various brain regions and after chronic treatment protocols. In spite of some measurable changes in serotonin system mRNA expression, serotonin transporter levels remained mostly unaltered following various treatment protocols. In contrast, tryptophan hydroxylase 2 appeared to be downregulated in serotonergic nuclei, and upregulated in the midbrain regions. Alterations in serotonin receptors lack clear conclusions and changes probably reflect animal strain/substance related- and brain region dependent effects. Brain derived neurotrophic factor was upregulated following many, but not all chronic treatment regimens. GABA and glutamate genes also showed heterogeneous changes, with a surprising NMDA receptor downregulation in areas including the striatum and amygdala, known to be involved in depressive states and stress reactions. The review of the above studies suggests alterations in multiple processes, reflecting the heterogeneity of the action depending on brain area and type of SSRI, and raises the possibility of a novel grouping of antidepressant medications based on their chronic molecular profile rather than on their initial actions.

PMID:

 

30962407