Targeting Circuits of Sexual Desire as a Treatment Strategy for Hypoactive Sexual Desire Disorder Stephen M. Stahl, MD, PhD Issue: Hypoactive sexual desire disorder (HSDD) is hypothesized to be a disor- der of the brain’s reward circuitry. Neurotransmitters in reward circuits are thus therapeutic targets for improving sexual desire. Novel treatment strategies are to enhance dopamine (DA) actions, reduce serotonin (5-HT) actions, or both. What Is Wrong in HSDD? No Approved Pharmacologic commercial reasons and lack of consis- The circuits thought to mediate Treatments for HSDD Yet tent, robust efficacy. normal sexual function are the same Estradiol and testosterone both are circuits that mediate reward in the linked to sexual arousal in women.3 The Novel Targets to Enhance brain.1–3 Young women with HSDD ability of erotic visual stimuli to activate Neurotransmitters of Sexual Arousal viewing erotic videoclips appear to limbic and cortical areas is reduced in Since DA is generally considered have less subjective sexual arousal than women after menopause but can be to be the major neurotransmitter that young women without a history of restored by hormone treatment with mediates sexual arousal, due to its ac- sexual problems, and to overly activate estrogens and androgens, as can sexual tions in mesolimbic and hypothalamic brain areas that hypothetically suppress desire and number of sexually satisfying circuits, enhancing dopaminergic ac- emotions and not those brain areas events.3–5 Because of such observations, tions in these brain areas is a logical that hypothetically experience emo- estrogens, testosterone, and synthetic strategy for improving the symptoms tions.3–5 It is as though HSDD patients steroids such as tibolone have all been of HSDD.1–3 In fact, anecdotal evidence are mentalizing erotic images and not administered for HSDD, with improve- suggests that patients who take levodo- enjoying them, sometimes also called ment in the number of satisfying sexual pa or DA agonists (such as drugs given “spectatoring.” These neuroimaging events, especially in postmenopausal for Parkinson’s disease) experience an studies lead to the question: Is HSDD women.3 However, concerns about the increase in sexual drive. Additionally, due to hypofunctional sexual arousal, long-term safety of this approach have some patients who have been taking hyperfunctional sexual inhibition, or largely caused large clinical trials to be antidepressants that lead to increased some combination of the two?” So far, abandoned, and currently no hormone DA release, such as the norepinephrine- imaging studies in HSDD are consistent treatment is approved for women with dopamine reuptake inhibitor (NDRI) with hyperfunctional inhibition of re- HSDD. bupropion, can also experience an in- ward pathways.3–5 If so, it predicts that Other pharmacologic approaches crease in sexual drive.1–3 Testosterone treatments that block inhibitory path- to improve sexual interest, libido, and may actually enhance sexual interest via ways would disinhibit sexual reward arousal in HSDD are largely anecdotal a dopaminergic mechanism, namely by and improve sexual arousal in HSDD. and based in part upon similarly anec- interacting with neurons in the hypo- dotal treatments for sexual dys function thalamus and boosting the ability of DA in patients taking selective serotonin to act in the hypothalamus.3 Animal reuptake inhibitors (SSRIs).2,3 These models of sexual arousal also strongly Brainstorms is a section of The Journal treatments include off-label use of a support the role of DA in mesolimbic of Clinical Psychiatry aimed at providing updates 3 of novel concepts emerging from the neurosciences wide variety of agents that act by en- and hypothalamic circuits. However, that have relevance to the practicing psychiatrist. hancing DA activity (eg, bupropion, agents with robust DA actions are of- From the Neuroscience Education Institute stimulants, DA agonists, amantadine, ten reinforcing, causing the develop- in Carlsbad, California, and the Department of Psychiatry at the University of California San buspirone), or by inhibiting 5-HT activ- ment of addiction, and agents with less Diego, and the Department of Psychiatry at the ity (eg, cyproheptadine, buspirone).2,3 robust DA actions are often ineffective, University of Cambridge, Cambridge, United 2,3 Kingdom. None of these agents is currently be- or wear off over time. Thus, direct For reprint and financial disclosure information, ing tested in large scale clinical trials targeting of DA targets has been largely go to www.psychiatrist.com/brainstorms. doi:10.4088/JCP.10bs06117blu for HSDD, and none will likely ever be abandoned as a treatment strategy for ©Copyright 2010 Physicians Postgraduate Press, Inc. formally approved for the disorder for HSDD. J Clin Psychiatry 71:7, July 2010 821 TAKE -HOME POIN T S ◆ In HSDD, sexual excitation may be reduced, possibly due to reduced actions of the neurotransmitters dopamine (DA), norepinephrine, oxytocin, or melanocortins in reward circuits. ◆ Sexual inhibition may be enhanced, which is possibly the cause of the reduced sexual excitation in HSDD. Sexual inhibition may be mediated by the increased actions of the neurotransmitters serotonin (5-HT), opioids, or endocannabinoids in reward circuits. ◆ Drugs that increase DA directly may enhance sexual excitation in HSDD but risk the development of abuse and addiction due to unwanted actions in reward pathways. ◆ Increasing DA by indirect means such as disinhibition, thus avoiding direct DA actions in reward pathways, is another strategy for treating HSDD. Thus, drugs that increase DA indirectly by blocking 5-HT actions or that promote oxytocin or melanocortins in reward pathways are promising and novel treatment strategies to enhance sexual excitation in patients with HSDD. Melanocortins are neuropeptides actions is flibanserin. This agent not a functional magnetic resonance imaging study. linked to arousal, especially their ac- only increases DA and reduces 5-HT in Neuroscience. 2009;158(2):484–502. doi:10.1016/j.neuroscience.2008.09.044 PubMed 5. Holstege G, Willemsen A, Beers C, et al. 2009. 11 tions at 2 different melanocortin recep- prefrontal cortex, but also is in late- Differences in brain activity in premenopausal tors (MC3 and MC4) in hypothalamus stage clinical development for HSDD, women with hypoactive sexual desire disorder and limbic areas.1,3,6 The intranasal or showing a significant increase in sexu- (HSDD) compared to women without sexual 12 dysfunction. Presented at the 12th Congress subcutaneous administration of the ally satisfying events. of the European Society for Sexual Medicine. neuropeptide bremelanotide, an MC3,4 Theoretically, agents that block opi- November 16, 2009; Lyon, France. agonist, improves sexual dysfunction ates or block endocannabinoids might 6. Hadley ME. Discovery that a melanocortin 7–9 regulates sexual functions in male and female in both men and women. However, also disinhibit sexual inhibitory mech- humans. Peptides. 2005;26(10):1687–1689. doi:10.1016/j.peptides.2005.01.023 PubMed it also raises blood pressure and has anisms in reward pathways,3 but there 7. Diamond LE, Earle DC, Rosen RC, et al. been dropped from further develop- are few trials or agents utilizing this Double-blind, placebo-controlled evaluation of the safety, pharmacokinetic properties and phar- ment. Another neuropeptide, oxytocin, approach yet. macodynamic effects of intranasal PT-141, a well known as the “affinity” neurotrans- melanocortin receptor agonist, in healthy males mitter or the “bonding” hormone, can Summary and patients with mild-to-moderate erectile 3 dysfunction. Int J Impot Res. 2004;16(1):51–59. doi:10.1038/sj.ijir.3901139 PubMed promote sexual arousal, but is difficult HSDD may be linked to overactive 8. Rosen RC, Diamond LE, Earle DC, et al. to administer and, as a natural prod- inhibitory circuits in reward pathways, Evaluation of the safety, pharmacokinetics and uct, is not patentable and thus there is with excessive activity of 5-HT and pharmacodynamic effects of subcutaneously administered PT-141, a melanocortin receptor not commercial incentive for it to be diminished activity of DA. Promising agonist, in healthy male subjects and in patients developed. approaches to the treatment of HSDD with an inadequate response to Viagra. include inhibiting the inhibitory circuits Int J Impot Res. 2004;16(2):135–142. doi:10.1038/sj.ijir.3901200 PubMed 9. Diamond LE, Earle DC, Heiman JR, et al. Blocking Neurotransmitters of (thus disinhibiting them) by blocking An effect on the subjective sexual response Sexual Inhibition Also Disinhibits the overly active 5-HT circuits in order in premenopausal women with sexual Neurotransmitters of Sexual Arousal to indirectly enhance the underactive arousal disorder by bremelanotide (PT-141), a melanocortin receptor agonist. J Sex Med. More promising is the approach DA circuits. Other promising therapeu- 2006;3(4):628–638. doi:10.1111/j.1743-6109.2006.00268.x PubMed of increasing DA by indirect actions, tic targets are enhancing the actions of 10. Bortolozzi A, Díaz-Mataix L, Scorza MC, et al. namely by disinhibiting its release. If melanocortins and oxytocin. The activation of 5-HT receptors in prefrontal cortex enhances dopaminergic activity. sexual dysfunction in HSDD is due to J Neurochem. 2005;95(6):1597–1607. doi:10.1111/j.1471-4159.2005.03485.x PubMed 11. Invernizzi RW, Sacchetti G, Parini S, et al. overly active inhibitory 5-HT circuits in REFE R ENCES reward pathways, DA would be exces- Flibanserin, a potential antidepressant drug, 1. Stahl SM. Circuits of sexual desire in lowers 5-HT and raises dopamine and nora- sively inhibited, both at the brain stem HSDD (hypoactive sexual desire disorder). drenaline in the rat prefrontal cortex dialysate: and via prefrontal cortex circuits.1–3 J Clin Psychiatry. 2010;71(5):518–519. role of 5-HT(1A) receptors. Br J Pharmacol. When such inhibition is blocked, as can 2. Stahl SM. Stahl’s Essential Psychopharmacology. 2003;139(7):1281–1288. doi:10.1038/sj.bjp.0705341 PubMed 3rd ed. New York, NY: Cambridge University 12.