Skip to main content
SpringerLink
Log in

SSRI-Related Modulation of Sexual Functioning is Predicted by Pre-treatment Resting State Functional Connectivity in Healthy Men

  • Original Paper
  • Published:
Archives of Sexual Behavior Aims and scope Submit manuscript

Abstract

Sexual dysfunction related to treatment with selective serotonin reuptake inhibitors (SSRIs) is a common reason for discontinuation of otherwise effective antidepressant treatment regimens. Thus, identification of subjects at risk for this side effect remains a crucial challenge. After demonstrating task-related neural correlates of impaired sexual functioning under treatment with the SSRI paroxetine (Abler et al., 2011), we studied (1) if resting state brain function before treatment predicts subsequent development of treatment-related modulation of sexual function, and (2) which neural circuits relate to different aspects of the impairment. Effects of paroxetine and bupropion administration over 1 week on subjective sexual functioning were investigated in 17 healthy male volunteers in a placebo-controlled, randomized cross-over design using the Massachusetts General Hospital Sexual Function Questionnaire. Data from a 10 min eyes-closed resting state scan were used to analyze functional connectivity under placebo in previously identified brain regions, focussing on the sublenticular extended amygdala (SLEA), dopaminergic midbrain, and anterior cingulate cortex. Resting state functional connectivities of the pregenual anterior cingulate cortex (pgACC), midbrain, and insula to the SLEA sufficiently predicted the development of subjective SSRI-related decreased sexual functioning and distinguished vulnerable from resilient subjects. Furthermore, connectivity with the midbrain particularly predicted orgasm-related deficits, while connectivity with pgACC predicted sexual satisfaction. Linking SSRI-related subjective sexual functioning to pre-treatment resting state connectivities in cortico-subcortical network of sexual processing, we demonstrated the potential of novel, non-invasive and passive brain imaging techniques to guide therapeutic decisions and adjust treatment protocols in psychiatric disorders and sexual medicine.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Abler, B., Grön, G., Hartmann, A., Metzger, C., & Walter, M. (2012). Modulation of frontostriatal interaction aligns with reduced primary reward processing under serotonergic drugs. Journal of Neuroscience, 32, 1329–1335. doi:10.1523/JNEUROSCI.5826-11.2012.

    Article  PubMed  Google Scholar 

  • Abler, B., Seeringer, A., Hartmann, A., Grön, G., Metzger, C., Walter, M., et al. (2011). Neural correlates of antidepressant-related sexual dysfunction: A placebo-controlled FMRI study on healthy males under subchronic paroxetine and bupropion. Neuropsychopharmacology, 36, 1837–1847. doi:10.1038/npp.2011.66.

    Article  PubMed  Google Scholar 

  • Alex, K. D., & Pehek, E. A. (2007). Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission. Pharmacology & Therapeutics, 113, 296–320. doi:10.1016/j.pharmthera.2006.08.004.

    Article  Google Scholar 

  • Arnow, B. A., Desmond, J. E., Banner, L. L., Glover, G. H., Solomon, A., Polan, M. L., … Atlas, S. W. (2002). Brain activation and sexual arousal in healthy, heterosexual males. Brain: A Journal of Neurology, 125, 1014–1023. doi:10.1093/brain/awf108.

  • Azmitia, E. C., & Segal, M. (1978). An autoradiographic analysis of the differential ascending projections of the dorsal and median raphe nuclei in the rat. Journal of Comparative Neurology, 179, 641–668. doi:10.1002/cne.901790311.

    Article  PubMed  Google Scholar 

  • Benedetti, F., Mayberg, H. S., Wager, T. D., Stohler, C. S., & Zubieta, J. K. (2005). Neurobiological mechanisms of the placebo effect. Journal of Neuroscience, 25, 10390–10402. doi:10.1523/JNEUROSCI.3458-05.2005.

    Article  PubMed  Google Scholar 

  • Biswal, B., Yetkin, F. Z., Haughton, V. M., & Hyde, J. S. (1995). Functional connectivity in the motor cortex of resting human brain using echo-planar MRI. Magnetic Resonance in Medicine, 34, 537–541. doi:10.3410/f.714597885.790202808.

    Article  PubMed  Google Scholar 

  • Bocher, M., Chisin, R., Parag, Y., Freedman, N., Meir Weil, Y., Lester, H., … Bonne, O. (2001). Cerebral activation associated with sexual arousal in response to a pornographic clip: A 15O-H2O PET study in heterosexual men. NeuroImage, 14, 105–117. doi:10.1006/nimg.2001.0794.

  • Castellanos, F. X., Margulies, D. S., Kelly, C., Uddin, L. Q., Ghaffari, M., Kirsch, … Milham, M. P. (2008). Cingulate-precuneus interactions: A new locus of dysfunction in adult attention-deficit/hyperactivity disorder. Biological Psychiatry, 63, 332–337. doi:10.1016/j.biopsych.2007.06.025.

  • Chai, X. J., Castanón, A. N., Ongür, D., & Whitfield-Gabrieli, S. (2012). Anticorrelations in resting state networks without global signal regression. NeuroImage, 59, 1420–1428. doi:10.1016/j.neuroimage.2011.08.048.

    Article  PubMed  Google Scholar 

  • Clayton, A., Keller, A., & McGarvey, E. L. (2006). Burden of phase-specific sexual dysfunction with SSRIs. Journal of Affective Disorders, 91, 27–32. doi:10.1016/j.jad.2005.12.007.

    Article  PubMed  Google Scholar 

  • Clayton, A. H., Pradko, J. F., Croft, H. A., Montano, C. B., Leadbetter, R. A., Bolden-Watson, C., … Metz, A. (2002). Prevalence of sexual dysfunction among newer antidepressants. Journal of Clinical Psychiatry, 63, 357–366.

  • Craig, A. D. B. (2011). Significance of the insula for the evolution of human awareness of feelings from the body. Annals of the New York Academy of Sciences, 1225, 72–82. doi:10.1111/j.1749-6632.2011.05990.x.

    Article  PubMed  Google Scholar 

  • Downing, P. E., Jiang, Y., Shuman, M., & Kanwisher, N. (2001). A cortical area selective for visual processing of the human body. Science, 293, 2470–2473. doi:10.1126/science.1063414.

    Article  PubMed  Google Scholar 

  • Dunn, J. A., Arakawa, R., Greist, J. H., & Clayton, A. H. (2007). Assessing the onset of antidepressant-induced sexual dysfunction using interactive voice response technology. Journal of Clinical Psychiatry, 68, 525–532.

    Article  PubMed  Google Scholar 

  • Ferretti, A., Caulo, M., Del Gratta, C., Di Matteo, R., Merla, A., Montorsi, F., … Romani, G. L. (2005). Dynamics of male sexual arousal: Distinct components of brain activation revealed by fMRI. NeuroImage, 26, 1086–1096. doi:10.1016/j.neuroimage.2005.03.025.

  • Fox, M. D., & Greicius, M. (2010). Clinical applications of resting state functional connectivity. Frontiers in Systems Neuroscience, 4, 19. doi:10.3389/fnsys.2010.00019.

    PubMed  Google Scholar 

  • Fox, M. D., Zhang, D., Snyder, A. Z., & Raichle, M. E. (2009). The global signal and observed anticorrelated resting state brain networks. Journal of Neurophysiology, 101, 3270–3283. doi:10.1152/jn.90777.2008.

    Article  PubMed  Google Scholar 

  • Georgiadis, J. R., & Holstege, G. (2005). Human brain activation during sexual stimulation of the penis. Journal of Comparative Neurology, 493, 33–38. doi:10.1002/cne.20735.

    Article  PubMed  Google Scholar 

  • Georgiadis, J. R., Reinders, A. A. T. S., van der Graaf, F. H. C. E., Paans, A. M. J., & Kortekaas, R. (2007). Brain activation during human male ejaculation revisited. NeuroReport, 18, 553–557. doi:10.1097/WNR.0b013e3280b10bfe.

    Article  PubMed  Google Scholar 

  • Graf, H., Abler, B., Hartmann, A., Metzger, C. D., & Walter, M. (2012). Modulation of attention network activation under antidepressant agents in healthy subjects. International Journal of Neuropsychopharmacology. doi:10.1017/S1461145712001368.

  • Gregorian, R. S., Golden, K. A., Bahce, A., Goodman, C., Kwong, W. J., & Khan, Z. M. (2002). Antidepressant-induced sexual dysfunction. Annals of Pharmacotherapy, 36, 1577–1589. doi:10.1345/aph.1A195.

    Article  PubMed  Google Scholar 

  • Hamann, S., Herman, R. A., Nolan, C. L., & Wallen, K. (2004). Men and women differ in amygdala response to visual sexual stimuli. Nature Neuroscience, 7, 411–416. doi:10.1038/nn1208.

    Article  PubMed  Google Scholar 

  • Heimer, L., Harlan, R. E., Alheid, G. F., Garcia, M. M., & Olmos, J. d. (1997). Substantia innominata: A notion which impedes clinical-anatomical correlations in neuropsychiatric disorders. Neuroscience, 76, 957–1006. doi:10.1016/S0306-4522(96)00405-8.

    Article  PubMed  Google Scholar 

  • Hensler, J. G. (2006). Serotonergic modulation of the limbic system. Neuroscience and Biobehavioral Reviews, 30, 203–214. doi:10.1016/j.neubiorev.2005.06.007.

    Article  PubMed  Google Scholar 

  • Holstege, G., Georgiadis, J. R., Paans, A. M. J., Meiners, L. C., van der Graaf, F. H. C. E., & Reinders, A. A. T. S. (2003). Brain activation during human male ejaculation. Journal of Neuroscience, 23, 9185–9193.

    PubMed  Google Scholar 

  • Horn, D. I., Yu, C., Steiner, J., Buchmann, J., Kaufmann, J., Osoba, A., Eckert, U., … Walter, M. (2010). Glutamatergic and resting-state functional connectivity correlates of severity in major depression-the role of pregenual anterior cingulate cortex and anterior insula. Frontiers in Systems Neuroscience, 4. doi:10.3389/fnsys.2010.00033.

  • Karama, S., Lecours, A. R., Leroux, J.-M., Bourgouin, P., Beaudoin, G., Joubert, S., et al. (2002). Areas of brain activation in males and females during viewing of erotic film excerpts. Human Brain Mapping, 16, 1–13. doi:10.1002/hbm.10014.

    Article  PubMed  Google Scholar 

  • Keedwell, P. A., Andrew, C., Williams, S. C. R., Brammer, M. J., & Phillips, M. L. (2005). The neural correlates of anhedonia in major depressive disorder. Biological Psychiatry, 58, 843–853. doi:10.1016/j.biopsych.2005.05.019.

    Article  PubMed  Google Scholar 

  • Kriegeskorte, N., Lindquist, M. A., Nichols, T. E., Poldrack, R. A., & Vul, E. (2010). Everything you never wanted to know about circular analysis, but were afraid to ask. Journal of Cerebral Blood Flow and Metabolism, 30, 1551–1557. doi:10.1038/jcbfm.2010.86.

    Article  PubMed  Google Scholar 

  • Labbate, L. A., & Lare, S. B. (2001). Sexual dysfunction in male psychiatric outpatients: Validity of the Massachusetts General Hospital Sexual Functioning Questionnaire. Psychotherapy and Psychosomatics, 70, 221–225. doi:10.1159/000056257.

    Article  PubMed  Google Scholar 

  • Mayberg, H. S. (1997). Limbic-cortical dysregulation: A proposed model of depression. Journal of Neuropsychiatry and Clinical Neurosciences, 9, 471–481. http://neuro.psychiatryonline.org/data/Journals/NP/3847/471.pdf.

    Google Scholar 

  • McCabe, C., Jones, Q., Nikolopoulou, A., Wathen, C., & Luqmani, R. (2011). Pulmonary–renal syndromes: An update for respiratory physicians. Respiratory Medicine, 105, 1413–1421. doi:10.1016/j.rmed.2011.05.012.

    Article  PubMed  Google Scholar 

  • Meissner, K., Bingel, U., Colloca, L., Wager, T. D., Watson, A., & Flaten, M. A. (2011). The placebo effect: Advances from different methodological approaches. Journal of Neuroscience, 31, 16117–16124. doi:10.1523/JNEUROSCI.4099-11.2011.

    Article  PubMed  Google Scholar 

  • Metzger, C. D., Eckert, U., Steiner, J., Sartorius, A., Buchmann, J. E., Stadler, J., … Walter, M. (2010). High field FMRI reveals thalamocortical integration of segregated cognitive and emotional processing in mediodorsal and intralaminar thalamic nuclei. Frontiers in Neuroanatomy, 4, 138. doi:10.3389/fnana.2010.00138.

  • Meyer, J. H., Wilson, A. A., Sagrati, S., Hussey, D., Carella, A., Potter, W. Z., … Houle, S. (2004). Serotonin transporter occupancy of five selective serotonin reuptake inhibitors at different doses: An [11C]DASB positron emission tomography study. American Journal of Psychiatry, 161, 826–835. doi:10.1176/appi.ajp.161.5.826.

  • Montejo-Gonzáles, A. L., Llorca, G., Izquierdo, J. A., Ledesma, A., Bousono, M., Calcedo, A., … Vicens, E. (1997). SSRI-induced sexual dysfunction: Fluoxetine, paroxetine, sertraline, and fluvoxamine in a prospective, multicenter, and descriptive clinical study of 344 patients. Journal of Sex & Marital Therapy, 23, 176–194. doi:10.1080/00926239708403923.

  • Moulier, V., Mouras, H., Pélégrini-Issac, M., Glutron, D., Rouxel, R., Grandjean, B., … Stoléru, S. (2006). Neuroanatomical correlates of penile erection evoked by photographic stimuli in human males. NeuroImage, 33, 689–699. doi:10.1016/j.neuroimage.2006.06.037.

  • Mouras, H., Stoléru, S., Bittoun, J., Glutron, D., Pélégrini-Issac, M., Paradis, A.-L., et al. (2003). Brain processing of visual sexual stimuli in healthy men: A functional magnetic resonance imaging study. NeuroImage, 20, 855–869. doi:10.1016/S1053-8119(03)00408-7.

    Article  PubMed  Google Scholar 

  • Nieuwenhuys, R. (2008). The human central nervous system (4th ed.). Berlin: Springer.

    Google Scholar 

  • Patel, K., & Hellstrom, W. J. (2009). Central regulation of ejaculation and the therapeutic role of serotonergic agents in premature ejaculation. Current Opinion in Investigational Drugs, 10, 681–690.

    PubMed  Google Scholar 

  • Phan, K. L., Wager, T. D., Taylor, S. F., & Liberzon, I. (2004). Functional neuroimaging studies of human emotions. CNS Spectrums, 9, 258–266.

    PubMed  Google Scholar 

  • Ponseti, J., Bosinski, H. A., Wolff, S., Peller, M., Jansen, O., Mehdorn, H. M., … Siebner, H. R. (2006). A functional endophenotype for sexual orientation in humans. NeuroImage, 33, 825–833. doi:10.1016/j.neuroimage.2006.08.002.

  • Pryor, J. L., Althof, S. E., Steidle, C., Rosen, R. C., Hellstrom, W. J. G., Shabsigh, R., … Kell, S. (2006). Efficacy and tolerability of dapoxetine in treatment of premature ejaculation: An integrated analysis of two double-blind, randomised controlled trials. Lancet, 368, 929–937. doi:10.1016/S0140-6736(06)69373-2.

  • Redouté, J., Stoléru, S., Grégoire, M. C., Costes, N., Cinotti, L., Lavenne, F., … Pujol, J. F. (2000). Brain processing of visual sexual stimuli in human males. Human Brain Mapping, 11, 162–177. doi:10.1002/1097-0193(200011)11:3<162::AID-HBM30>3.0.CO;2-A.

  • Reinecke, A., Schöps, D., & Hoyer, J. (2006). Sexuelle Dysfunktionen bei Patienten einer verhaltenstherapeutischen Hochschulambulanz: Häufigkeit, Erkennen, Behandlung [Sexual dysfunction in patients at a university outpatient department specialized for behavioral therapy: Quantity, detection, treatment]. Verhaltenstherapie, 16, 166–172.

    Article  Google Scholar 

  • Scheidegger, M., Walter, M., Lehmann, M., Metzger, C. D., Grimm, S., Boeker, H., … Seifritz, E. (2012). Ketamine decreases resting state functional connectivity in healthy subjects: Implications for antidepressant drug action. PLoS ONE, 7, e44799. doi:10.1371/journal.pone.0044799.

  • Seidman, S. N., & Roose, S. P. (2001). Sexual dysfunction and depression. Current Psychiatry Reports, 3, 202–208.

    Article  PubMed  Google Scholar 

  • Simmons, A. N., Arce, E., Lovero, K. L., Stein, M. B., & Paulus, M. P. (2009). Subchronic SSRI administration reduces insula response during affective anticipation in healthy volunteers. Journal of Neuropsychopharmacology, 12, 1009–1020. doi:10.1017/S1461145709990149.

    Article  Google Scholar 

  • Song, X.-W., Dong, Z.-Y., Long, X.-Y., Li, S.-F., Zuo, X.-N., Zhu, C.-Z., … Zang, Y.-F. (2011). REST: A toolkit for resting-state functional magnetic resonance imaging data processing. PloS ONE, 6, e25031. doi:10.1371/journal.pone.0025031.

  • Stoléru, S., Grégoire, M. C., Gérard, D., Decety, J., Lafarge, E., Cinotti, L., … Comar, D. (1999). Neuroanatomical correlates of visually evoked sexual arousal in human males. Archives of Sexual Behavior, 28, 1–21.

    Google Scholar 

  • Stoléru, S., Redouté, J., Costes, N., Lavenne, F., Le Bars, D., Dechaud, H., … Pujol, J. F. (2003). Brain processing of visual sexual stimuli in men with hypoactive sexual desire disorder. Psychiatry Research, 124, 67–86. doi:10.1016/S0925-4927(03)00068-4.

  • Veer, I. M., Oei, N. Y. L., Spinhoven, P., van Buchem, M. A., Elzinga, B. M., & Rombouts, S. A. R. B. (2011). Beyond acute social stress: Increased functional connectivity between amygdala and cortical midline structures. NeuroImage, 57, 1534–1541. doi:10.1016/j.neuroimage.2011.05.074.

    Article  PubMed  Google Scholar 

  • von dem Hagen, E. A. H., Passamonti, L., Nutland, S., Sambrook, J., & Calder, A. J. (2011). The serotonin transporter gene polymorphism and the effect of baseline on amygdala response to emotional faces. Neuropsychologia, 49, 674–680. doi:10.1016/j.neuropsychologia.2010.12.013.

    Article  Google Scholar 

  • Walter, M., Bermpohl, F., Mouras, H., Schiltz, K., Tempelmann, C., Rotte, M., … Northoff, G. (2008a). Distinguishing specific sexual and general emotional effects in fMRI-subcortical and cortical arousal during erotic picture viewing. NeuroImage, 40, 1482–1494. doi:10.1016/j.neuroimage.2008.01.040.

  • Walter, M., Henning, A., Grimm, S., Schulte, R. F., Beck, J., Dydak, U., … Northoff, G. (2009). The relationship between aberrant neuronal activation in the pregenual anterior cingulate, altered glutamatergic metabolism, and anhedonia in major depression. Archives of General Psychiatry, 66, 478–486. doi:10.1001/archgenpsychiatry.2009.39.

  • Walter, M., Stadler, J., Tempelmann, C., Speck, O., & Northoff, G. (2008b). High resolution fMRI of subcortical regions during visual erotic stimulation at 7 T. Magnetic Resonance in Medicine, 21, 103–111. doi:10.1007/s10334-007-0103-1.

    Google Scholar 

  • Walter, M., Witzel, J., Wiebking, C., Gubka, U., Rotte, M., Schiltz, K., … Northoff, G. (2007). Pedophilia is linked to reduced activation in hypothalamus and lateral prefrontal cortex during visual erotic stimulation. Biological Psychiatry, 62, 698–701. doi:10.1016/j.biopsych.2006.10.018.

  • Weissenbacher, A., Kasess, C., Gerstl, F., Lanzenberger, R., Moser, E., & Windischberger, C. (2009). Correlations and anticorrelations in resting-state functional connectivity MRI: A quantitative comparison of preprocessing strategies. NeuroImage, 47, 1408–1416. doi:10.1016/j.neuroimage.2009.05.005.

    Article  PubMed  Google Scholar 

  • Yan, C., & Zang, Y. (2010). DPARSF: A MATLAB toolbox for “pipeline” data analysis of resting-state fMRI. Frontiers in Systems Neuroscience, 4, 13. doi:10.3389/fnsys.2010.00013.

    Google Scholar 

  • Yüksel, C., & Öngür, D. (2010). Magnetic resonance spectroscopy studies of glutamate-related abnormalities in mood disorders. Biological Psychiatry, 68, 785–794. doi:10.1016/j.biopsych.2010.06.016.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

Coraline D. Metzger and Martin Walter contributed equally to this publication. This work was supported by the German Research Foundation (DFG), Collaborative Research Centre 779 (SFB 779) (CDM, MW). The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. We thank Prof. Dr. C. Hiemke and his staff at the University of Mainz (Germany), Department of Psychiatry and Psychotherapy, for measurements of drug blood serum levels. In addition, we thank Henrik Dobrowolny, Otto-von-Guericke University Magdeburg (Germany), Department of Psychiatry and Psychotherapy, for his skillful assistance and Marie José van Tol, Leibniz Institute for Neurobiology Magdeburg (Germany), for her help with manuscript correction.

Author information

Authors and Affiliations

  1. Department of Psychiatry and Psychotherapy, Centre for Behavioral Brain Sciences (CBBS), Otto-von-Guericke University, Magdeburg, Germany

    Coraline D. Metzger & Martin Walter

  2. Leibniz Institute for Neurobiology, Brenneckestraße 6, 39118, Magdeburg, Germany

    Coraline D. Metzger & Martin Walter

  3. Department of Psychiatry, Ulm University, Ulm, Germany

    Heiko Graf & Birgit Abler

Authors
  1. Coraline D. Metzger
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Martin Walter
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Heiko Graf
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Birgit Abler
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Martin Walter.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 29 kb)

Supplementary material 2 (DOC 90 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Metzger, C.D., Walter, M., Graf, H. et al. SSRI-Related Modulation of Sexual Functioning is Predicted by Pre-treatment Resting State Functional Connectivity in Healthy Men. Arch Sex Behav 42, 935–947 (2013). https://doi.org/10.1007/s10508-013-0103-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10508-013-0103-3

Keywords

Search

Navigation