- Email: [email protected]
Is premature ejaculation an impulse control disorder?
Medical Hypotheses 79 (2012) 59–62
Contents lists available at SciVerse ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Is premature ejaculation an impulse control disorder? Osman Özdemir ⇑ Department of Psychiatry, Ipekyolu Public Hospital, Van 65200, Turkey
a r t i c l e
i n f o
Article history: Received 17 January 2012 Accepted 30 March 2012
a b s t r a c t Premature ejaculation (PE) is defined as persistent or recurrent ejaculation with minimal sexual stimulation that occurs before the participant wishes to ejaculate and is associated with marked distress or interpersonal difficulty. Impulse control disorders (ICDs) are grouped as a heterogeneous cluster of disorders linked by a ‘‘failure to resist’’ impulses to engage in harmful, disturbing or distressing behaviours. I hypothesise that premature ejaculation is an impulse control disorder. ICDs share features with PE aspects of impaired control, rapid responses to stimuli and hypersensitivity. These disorders often occur with subjective and social distress for patients. In addition to these features, the neurotransmitter systems have been similarly implicated in ICDs and PE. The same treatment options further support a relationship between ICDs and PE. The behaviours likely exist on a spectrum. Ó 2012 Elsevier Ltd. All rights reserved.
Introduction Premature ejaculation (PE) is defined by the American Psychiatric Association as persistent or recurrent ejaculation with minimal sexual stimulation that occurs before the participant wishes to ejaculate and is associated with marked distress or interpersonal difficulty [1]. The condition has been classified as either primary (lifelong), beginning when a man first becomes capable of functioning sexually, or secondary (acquired), meaning that a man has previously experienced an acceptable level of ejaculatory control but, for unknown reasons, develops the condition later in life [2,3]. A new definition of lifelong PE was proposed by the International Society for Sexual Medicine in 2007, which states that lifelong PE is a male sexual dysfunction that is characterised by ejaculation, which occurs or nearly always occurs prior to or within about a minute of vaginal penetration, and the inability to delay ejaculation on all or nearly all vaginal penetrations and includes negative personal consequences, such as distress, bother, frustration and/or the avoidance of sexual intimacy [4]. It has been reported as the most common sexual problem in men, with prevalence rates ranging from 9% to 31% [5,6]. Despite its high prevalence, there are currently no US Food and Drug Administration (FDA)-approved treatments and only recently has there been a focus on investigating and developing new therapeutic strategies for its management. This disturbance could have profound effects on the psychosexual relationship of a couple, and in its most severe form can lead to secondary impotence or even to male infertility [7].
⇑ Tel.: +90 04322179398; fax: +90 04322176370. E-mail address: [email protected] 0306-9877/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mehy.2012.03.034
In most cases, the aetiology of PE is unknown; however, a combination of organic and psychogenic factors is the most probable cause. Different treatment modalities including local anaesthetic creams, selective serotonin reuptake inhibitors (SSRIs), clomipramine, posphodiesterase type 5 inhibitors, adrenergic a1-antagonists and a centrally acting analgesic (tramadol) have been used for treatment of PE [8]. In the Diagnostic and Statistical Manual of Mental Disorders – Fourth Edition, Text Revision (DSM-IV-TR), Impulse control disorders (ICDs) are grouped as a heterogeneous cluster of disorders linked by a ‘‘failure to resist’’ impulses to engage in harmful, disturbing or distressing behaviours. The formal group of ICDs Not Elsewhere Classified include pathological gambling, intermittent explosive disorder, kleptomania, pyromania, trichotillomania and ICDs not otherwise specified. Criteria for other ICDs have been proposed including compulsive sexual behaviour, compulsive shopping and compulsive computer use [1]. ICDs are characterised by repetitive behaviours and their _ impaired inhibition. Important defining criteria for these disorders include: (1) the failure to resist an impulse to perform acts that are harmful to the individual or others, (2) an increasing sense of arousal or tension before committing or engaging in the act and (3) an experience of either gratification, pleasure or release of tension, while committing the act. Furthermore, there is usually a pattern of engaging in the abnormal behaviour in spite of adverse consequences [9]. Disordered monoamine neurotransmission has been implicated in the pathophysiology of ICDs. Abnormalities in dopamine, serotonin and noradrenergic neurotransmitter activity have been reported: (1) serotonin (5-HT) function in the initiation and cessation of the problematic behaviour [10,11]; (2) abnormal dopamine (DA) function contributing to modulation of reward and
60
O. Özdemir / Medical Hypotheses 79 (2012) 59–62
reinforcement pathways, particularly with regard to aggressive and other impulsive behaviours [12]; (3) norepinephrine (NE) dysfunction associated with arousal and excitement [12]. ICDs are prevalent and disabling conditions still poorly understood in terms of diagnosis, in spite of the relatively high prevalence of some of them, in particular sexual behaviours. Moreover, accumulating data on ‘classical’ and more recently characterised ICDs, such as internet addiction, skin picking, shopping and sexual behaviour, suggest that they would currently represent one of the most frequent and impairing class of mental conditions worldwide [9]. The hypothesis I hypothesise that premature ejaculation is an impulse control disorder. Impulsivity is defined as a tendency to perform prompt unplanned responses to provoking external and internal stimuli regardless of the undesirable consequences of these responses. The definition of PE is the occurrence of persistent or recurrent ejaculation with minimal sexual stimulation before, upon or shortly after penetration and before the person wishes it. Poor delay of gratification and disinhibition are key features of impulsivity and PE. Delay of gratification is the ability to wait for a delayed larger reward over an immediate small reward. Disinhibition is the inability to suppress behaviour in a way that is expected to be appropriate in view of social norms and constraints. By definition, both PE and impulsivity are closely interrelated, as they involve a behavioural pattern in which one often acts on impulses that may yield negative consequences. Evaluation of the hypothesis The following issues can be considered to support this hypothesis. PE as an impulsıve sexual behaviour Multiple factors, including behavioural initiation, arousal, reward and reinforcement and behavioural disinhibition, have been implicated in ICDs [13]. I use the term impulsive sexual behaviour for PE because it involves an impulsive component such as pleasure, arousal or gratification. These behaviours include an inability to inhibit inappropriate behaviours, an inability to wait, an alteration in time perception or a relative insensitivity to negative consequences, particularly delayed or uncertain negative consequences or rewards [14,15]. PE and ICDs are characterised by loss of control over the behaviours PE is primarily a problem of voluntary control over timing of ejaculation and ICDs are typically characterised by loss of control
Table 1 The intersections between PE and ICDs. Key feature of disease a The inability to control ejaculation b Loss of control over the behaviour Pathophysiology of disease The monoamines are known to play a crucial role b Disordered monoamine neurotransmission a
Pharmacological therapies SSRIs have shown benefit in delaying ejaculation The pharmacologic first-line treatment is a range of serotonergic antidepressants
a
b
a b
PE. ICDs.
over the behaviour. ICDs have the following features in common: (1) repetitive or compulsive engagement in a behaviour despite adverse consequences; (2) diminished control over the problematic behaviour; (3) an appetitive urge or craving state prior to engagement in the problematic behaviour; (4) a hedonic quality during the performance of the problematic behaviour [12]. PE presents with three components: a short time interval between penetration and ejaculation, the inability to control ejaculation and distress for the man or for the couple. A common core of clinical features of ICDs is difficulty resisting urges to engage in behaviours that are excessive and/or ultimately harmful to oneself or others [1]. There are phenomenological similarities between PE and ICDs. There are many overlapping theories on the aetiology of PE and ICDs The aetiology of premature ejaculation is unclear: both organic and psychosocial mechanisms have been suggested. The clinical, genetic, phenomenological and biological characteristics of ICDs are not completely understood. There are many overlapping theories on the aetiology of PE and ICDs. Abnormalities in dopamine, serotonin and noradrenergic neurotransmitter activity have been reported in ICDs [16]. The monoamines are known to play a crucial role in normal human sexual functioning [17]. Indirect evidence for involvement of these neurotransmitter systems is derived from diagnostic and pharmacological treatment considerations. Disordered monoamine neurotransmission has been implicated in the pathophysiology of PE and ICDs. Serotonin (the 5-HT system) Central serotonin (5-hydroxytryptamine, 5-HT) function is an important component of normal behavioural inhibition that controls impulsive responding [18,19]. A role for 5-HT in ICDs is supported from results of studies in which reduced 5-HT neurotransmission has been associated with increased impulsivity in people and that chronically inhibiting the 5-HT system led to behavioural disinhibition in animals [12,20,21]. Lesions to the 5HT system significantly increase premature responding [22,23]. It has been postulated that PE might have a sensory/neural component involving perturbations in the 5-HT system [24]. Because individual variability in 5-HT neurotransmission might determine individual ejaculatory thresholds, such alterations could theoretically contribute to the pathogenesis of PE [25]. 5-HT appears to be a key mediator and is considered the main inhibitory neurotransmitter in the central control of ejaculation [26–29]. Activation of postsynaptic 5-HT receptors prolongs ejaculatory latency, whereas activation of presynaptic 5-HT autoreceptors, which inhibits 5-HT release, decreases ejaculatory latency [30,31]. It was suggested that PE might be associated with the presence of low synaptic levels of 5-HT in regions of the CNS that modulate ejaculation, possibly because of variations in 5-HT receptor sensitivity [24]. Thus, abnormal 5-HT function may be central to the development of these conditions. Dopamine (the DA system) The dopamine (DA) system is associated with reward, reinforcement behaviours, loss of self-control and impulsivity [12,21]. Dysfunction within the DA system has been hypothesised to play a major role in psychiatric disorders such as attention deficit hyperactivity disorder (ADHD) [32], pathological gambling (PG) [33] and drug addiction [34], in which impulsivity is high. ICDs may occur with dopamine agonist treatment. Dopamine replacement therapy in the treatment of Parkinson’s disease (PD) has frequently been reported to induce compulsive gambling, pathologic hypersexuality, binge eating and compulsive shopping [12].
O. Özdemir / Medical Hypotheses 79 (2012) 59–62
61
Administration of the DA precursor L-DOPA increases impulsive choice in human volunteers [35]. Dopamine has a fundamental role in the mediation of erectile function. Regarding the mechanism by which this drug might work, we could hypothesise a close relationship with the ‘DA (Dopamine) theory’ of the control of human sexual function. DA seems to have a role in facilitating sexual arousal and in lowering the ejaculatory threshold; accordingly, DA antagonists are likely to have an inhibitory function [36]. These data suggest that 5-HT and DA play a role during impulsive decision-making and ejaculation.
ological gambling, compulsive shopping, hypersexuality and binge eating [53]. Levosulpiride, an anti-dopaminergic drug, is commonly used in some dyspeptic syndromes in anxious patients and to treat some types of hemicrania. The authors observed its effect on premature ejaculation accidentally, after prescribing the drug for its usual purpose to three patients. It was only by chance that all of them were suffering from premature ejaculation. During the following visit, after 20–30 days, they were surprised to hear of a wonderful improvement in the patients’ sexual life [36]. The intersections between the two disorders are tabulated for easy access (see Table 1).
Hypersensitivity
Conclusion
One of the initial theories concerning the cause of this disorder was that the patient’s penis was ‘‘very sensitive’’, triggering the ejaculatory response before the patient or his partner wished [37]. To investigate the correlation between penile hypersensitivity and premature ejaculation (PE), it was determined men with PE have a greater cortical representation of the sensory stimuli from the glans penis [38,39], and have a lower tactile threshold [40], therefore indicating these individuals’ higher sensitivity compared with others [41]. Patients who suffer from impulse control disorders often experience a heightened sense of tension or arousal before performing the act. Poor impulse control has been associated with drug-seeking behaviour and an enhanced risk of relapse, suggesting that impulsivity is causally related to reward hypersensitivity [42]. One possibility is that impulsivity confers hypersensitivity to drug reinforcement. This claim is supported by the finding that impulsivity in rats, quantified by a preference for small immediate reward over a delayed larger reward (delay discounting) is associated with higher rates of cocaine [43,44], alcohol [45] and methylphenidate self-administration [46]. I think that these findings suggest that PE is associated with impulsivity and the aetiologies of these disorders may be mediated by hypersensitivity to stimulus, which is tactile or drug related.
ICDs share features with PE, specifically, aspects of impaired control, rapid responses to stimuli and hypersensitivity. These disorders often occur with subjective distress and are frequently hidden by patients. In addition to these features, the neurotransmitter systems have been similarly implicated in ICDs and PE. The same treatment options further support a relationship between ICDs and PE. The behaviours likely exist on a spectrum and may be idiosyncratic to an individual’s susceptibility, hence complicating any phenomenological classification. There is much disagreement surrounding the classification of these behaviours. Classification within psychiatric categories, which include obsessive–compulsive behaviours, impulse control and addiction processes, is further confounded given the overlapping cognitive processes underlying these behaviours. Further research is needed to understand the biochemical factors underlying the behavioural features. Thus, clinical advances in the identification, prevention and treatment of PE and ICDs need to be facilitated. Conflict of interest statement None declared. Funding
ICDs and PE can often be treated with behavioural and pharmacological therapies Despite the high prevalence rates of ICDs in the general population and in psychiatric cohorts [47,48], pharmacological treatments have been relatively understudied. There are no FDAapproved medications for any ICD. ICDs can often be treated with behavioural and pharmacological therapies. Forms of psychotherapy described in case reports as demonstrating success include psychoanalytic, insight-oriented and behavioural techniques. It is well established that the pharmacologic first-line treatment for ICDs are a range of serotonergic antidepressants (selective serotonin reuptake inhibitors, SSRIs; e.g., fluvoxamine, fluoxetine or paroxetine, clomipramine) [49]. Treatment of PE includes behavioural, psychological and pharmacological therapies. However, an approved treatment regime does not exist. The most studied neurotransmitter in the physiology of ejaculation is 5-HT, which is an inhibitor of ejaculation acting via decreasing serotonin-induced dopamine. The SSRIs inhibit presynaptic reuptake of 5-HT in the central nervous system. The effect of SSRI on PE has been demonstrated in studies [50,51]. SSRIs are currently indicated as antidepressants, but citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline have also shown benefit in delaying ejaculation. A range of impulse control behaviours have been reported following the use of dopamine agonists (DAs) and levodopa in patients with Parkinson’s disease [52]. DAs are particularly associated with path-
The author received no financial support for the research and/or authorship of this article. References [1] American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. [Text Revision]. Washington, DC: American Psychiatric Association Press; 2000. [2] Godpodinoff ML. PE: clinical subgroups and etiology. J Sex Marital Ther 1989;15:130–4. [3] Cooper AJ, Cernovsky ZZ, Colussi K. Some clinical and psychometric characteristics of primary and secondary premature ejaculators. J Sex Marital Ther 1993;19:276–88. [4] McMahon CG, Althof S, Waldinger MD, et al. An evidence-based definition of premature ejaculation: report of the International Society for Sexual Medicine Ad Hoc committee for the definition of premature ejaculation. BJU Int 2008;102:338–50. [5] Goldstein I. Premature to early ejaculation: a sampling of manuscripts regarding the most common male sexual dysfunction published in the IJIR: the journal of sexual medicine. Int J Impot Res 2003;15:307–8. [6] Rosen RC. The premature ejaculation prevalence and attitudes (PEPA) survey: a multi-national survey. J Sex Med 2004;1(Suppl. 1):57–8. [7] Dell’osso B, Marazziti D, Hollander E, Almatura C. Traditional and newer impulse control disorders: a clinical update. Clin Neuropsychiatry 2007;4(1):30–8. [8] Rıley A, Segraves RT. Treatment of premature ejaculation. Int J Clin Pract 2006;60(6):694–7. [9] Hollander E, Buchalter A, DeCaria C. Pathological gambling. Psychiatr Clin North Am 2000;23(3):629–42. [10] Potenza MN. Pathological gambling: clinical aspects and neurobiology. In: Soares J, Gershon S, editors. Handbook of medical psychiatry. New York: Marcel Dekker; 2002. p. 683–99. [11] Potenza MN, Hollander E. Pathologic gambling and impulse control disorders. In: Davis KL, Charney D, Coyle JT, Nemeroff C, editors. Neuropsycho-
62
[12] [13] [14] [15] [16] [17] [18] [19]
[20] [21]
[22]
[23]
[24]
[25] [26] [27] [28] [29] [30]
[31] [32]
O. Özdemir / Medical Hypotheses 79 (2012) 59–62 pharmacology: the fifth generation of progress. Philadelphia, PA: Lippincott Williams & Wilkins. p. 1425–43. Grant JE, Potenza MN. Pathological gambling: a clinical guide to treatment. Washington, DC: American Psychiatric Publishing Inc.; 2004. Grant JE, Brewer JA, Potenza MN. The neurobiology of substance and behavioral addictions. CNS Spectr 2006;11(12):924–30. Barkley RA. ADHD and the nature of self-control. New York: The Guildford Press; 1997. Meck WH. Neuropharmacology of timing and time perception. Brain Res Cogn Brain Res 1996;3:227–42. Wendol AW, Potenza MN. The neurobiology of impulse control disorders. Rev Bras Psiquiatr 2008;30(Suppl. I):S24–30. Bradford JM. The paraphilas, obsessive compulsive spectrum disorder and the treatment of sexually deviant behaviour. Psychiatr Q 1999;70:209–19. Evenden JL. Varieties of impulsivity. Psychopharmacology 1999;146:348–61. Winstanley CA, Eagle DM, Robbins TW. Behavioral models of impulsivity in relation to ADHD: translation between clinical and preclinical studies. Clin Psychol Rev 2006;26:379–95. Soubrie´ P. Reconciling the role of central serotonin neurons in human and animal behavior. Behav Brain Sci 1986;9:319–64. Winstanley C, Theobald D, Dalley J, Cardinal R, Robbins T. Double dissociation between serotonergic and dopaminergic modulation of medial prefrontal and orbitofrontal cortex during a test of impulsive choice. Cereb Cortex 2006;16(1):106–14. Winstanley CA, Theobald DE, Dalley JW, Glennon JC. 5-HT2A and 5-HT2C receptor antagonists have opposing effects on a measure of impulsivity: interactions with global 5-HT depletion. Psychopharmacology 2004;176: 376–385. Harrison AA, Everitt BJ, Robbins TW. Central 5-HT depletion enhances impulsive responding without affecting the accuracy of attentional performance. Interactions with dopaminergic mechanisms. Psychopharmacology 1997;133: 329–342. Waldinger MD, Rietschel M, Nothen MM, Hengeveld MW, Olivier B. Familial occurrence of primary premature ejaculation. Psychiatr Genet 1998;8:37– 40. Waldinger MD. The neurobiological approach to premature ejaculation. J Urol 2002;168:2359–67. Waldinger MD. Premature ejaculation: state of the art. Urol Clin N Am 2007;34:591–9. Coolen LM, Allard J, Truitt WA, McKenna KE. Central regulation of ejaculation. Physiol Behav 2004;83:203–15. Giuliano F, Clément P. Serotonin and premature ejaculation: from physiology to patient management. Eur Urol 2006;50(3):454–66. Giuliano F. 5-Hydroxytryptamine in premature ejaculation: opportunities for therapeutic intervention. Trends Neurosci 2007;30(2):79–84. Hillegaart V, Ahlenius S. Facilitation and inhibition of male rat ejaculatory behaviour by the respective 5-HT1A and 5-HT1B receptor agonists 8-OH-DPAT and anpirtoline, as evidenced by use of the corresponding new and selective receptor antagonists NAD-299 and NAS-181. Br J Pharmacol 1998;125: 1733–1743. Ahlenius S, Larsson K. Specific involvement of central 5-HT1A receptors in the mediation of male rat ejaculatory behavior. Neurochem Res 1997;22:1065–70. Dougherty DD, Bonab AA, Spencer TJ, Rauch SL, Madras BK, Fischman AJ. Dopamine transporter density in patients with attention deficit hyperactivity disorder. Lancet 1999;354:2132–3.
[33] Goudriaan AE, Oosterlaan J, de Beurs E, Van den Brink W. Pathological gambling: a comprehensive review of biobehavioral findings. Neurosci Biobehav Rev 2004;28:123–41. [34] Jentsch JD, Taylor JR. Impulsivity resulting from frontostriatal dysfunction in drug abuse: implications for the control of behavior by reward-related stimuli. Psychopharmacology 1999;146:373–90. [35] Pine A, Shiner T, Seymour B, Dolan RJ. Dopamine, time, and impulsivity in humans. J Neurosci 2010;30:8888–96. [36] Greco E, Polonio-Balbi P, Speranza JC. Levosulpiride: a new solution for premature ejaculation? Int J Impot Res 2002;14:308–9. [37] Choi HK, Xin ZC, Choi YD, et al. Safety and efficacy study with various doses of SS-cream in patients with premature ejaculation in a double-blind, randomized, placebo controlled clinical study. Int J Impot Res 1999;11:261–4. [38] Fanciullacci F, Colpi GM, Beretta G, Zanollo A. Cortical evoked potentials in subjects with true premature ejaculation. Andrologia 1988;20:326–30. [39] Xin ZC, Choi YD, Rha KH, Choi HK. Somatosensory evoked potentials in patients with primary premature ejaculation. J Urol 1997;158:451–5. [40] Eardley I, Sethia K. Erectile dysfunction – current investigation and management. London: Mosby; 1998. [41] Astbury-Ward E. From kama sutra to dot.com: the history, myths and management of premature ejaculation. Sex Relat Ther 2002;17:367–79. [42] Diergaarde L, Pattij T, Nawijn L, Schoffelmeer AN, De Vries TJ. Trait impulsivity predicts escalation of sucrose seeking and hypersensitivity to sucroseassociated stimuli. Behav Neurosci 2009;123(4):794–803. [43] Anker JJ, Perry JL, Gliddon LA, Carroll ME. Impulsivity predicts the escalation of cocaine self-administration in rats. Pharmacol Biochem Behav 2009;93:343–8. [44] Perry JL, Nelson SE, Carroll ME. Impulsive choice as a predictor of acquisition of IV cocaine self-administration and reinstatement of cocaine-seeking behavior in male and female rats. Exp Clin Psychopharmacol 2008;16:165–77. [45] Poulos CX, Le AD, Parker JL. Impulsivity predicts individual susceptibility to high levels of alcohol self-administration. Behav Pharmacol 1995;6:810–4. [46] Marusich JA, Bardo MT. Differences in impulsivity on a delay-discounting task predict self-administration of a low unit dose of methylphenidate in rats. Behav Pharmacol 2009;20:447–54. [47] Kessler RC, Berglund P, Demler O, Jin R, Merikangas K, Walters EE. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 2005;62:593–602. [48] Grant JE, Levine L, Kim D, Potenza MN. Impulse control disorders in adult psychiatric inpatients. Am J Psychiatry 2005;162:2184–8. [49] Schreiber L, Odlaug BL, Grant JE. Impulse control disorders: updated review of clinical characteristics and pharmacological management. Front Psychiatry 2011;2:1–11. [50] Atmaca M, Kuloglu M, Tezcan E, Semercioz A. The efficacy of citalopram in the treatment of premature ejaculation: a placebo-controlled study. Int J Impot Res 2002;14:502–5. [51] Waldinger MD, Zwinderman AH, Schweitzer DH, Olivier B. Relevance of methodological design for the interpretation of efficacy of drug treatment of premature ejaculation: a systematic review and metaanalysis. Int J Impot Res 2004;16:369–81. [52] Weintraub D, Siderowf AD, Potenza MN, Goveas J, Morales KH, Duda JE, et al. Association of dopamine agonist use with impulse control disorders in Parkinson disease. Arch Neurol 2006;63:969–73. [53] Voon V, Hassan K, Zurowski M, de Souza M, Thomsen T, Fox S, et al. Prevalence of repetitive and reward-seeking behaviors in Parkinson disease. Neurology 2006;67:1254–7.
Contents lists available at SciVerse ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Is premature ejaculation an impulse control disorder? Osman Özdemir ⇑ Department of Psychiatry, Ipekyolu Public Hospital, Van 65200, Turkey
a r t i c l e
i n f o
Article history: Received 17 January 2012 Accepted 30 March 2012
a b s t r a c t Premature ejaculation (PE) is defined as persistent or recurrent ejaculation with minimal sexual stimulation that occurs before the participant wishes to ejaculate and is associated with marked distress or interpersonal difficulty. Impulse control disorders (ICDs) are grouped as a heterogeneous cluster of disorders linked by a ‘‘failure to resist’’ impulses to engage in harmful, disturbing or distressing behaviours. I hypothesise that premature ejaculation is an impulse control disorder. ICDs share features with PE aspects of impaired control, rapid responses to stimuli and hypersensitivity. These disorders often occur with subjective and social distress for patients. In addition to these features, the neurotransmitter systems have been similarly implicated in ICDs and PE. The same treatment options further support a relationship between ICDs and PE. The behaviours likely exist on a spectrum. Ó 2012 Elsevier Ltd. All rights reserved.
Introduction Premature ejaculation (PE) is defined by the American Psychiatric Association as persistent or recurrent ejaculation with minimal sexual stimulation that occurs before the participant wishes to ejaculate and is associated with marked distress or interpersonal difficulty [1]. The condition has been classified as either primary (lifelong), beginning when a man first becomes capable of functioning sexually, or secondary (acquired), meaning that a man has previously experienced an acceptable level of ejaculatory control but, for unknown reasons, develops the condition later in life [2,3]. A new definition of lifelong PE was proposed by the International Society for Sexual Medicine in 2007, which states that lifelong PE is a male sexual dysfunction that is characterised by ejaculation, which occurs or nearly always occurs prior to or within about a minute of vaginal penetration, and the inability to delay ejaculation on all or nearly all vaginal penetrations and includes negative personal consequences, such as distress, bother, frustration and/or the avoidance of sexual intimacy [4]. It has been reported as the most common sexual problem in men, with prevalence rates ranging from 9% to 31% [5,6]. Despite its high prevalence, there are currently no US Food and Drug Administration (FDA)-approved treatments and only recently has there been a focus on investigating and developing new therapeutic strategies for its management. This disturbance could have profound effects on the psychosexual relationship of a couple, and in its most severe form can lead to secondary impotence or even to male infertility [7].
⇑ Tel.: +90 04322179398; fax: +90 04322176370. E-mail address: [email protected] 0306-9877/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mehy.2012.03.034
In most cases, the aetiology of PE is unknown; however, a combination of organic and psychogenic factors is the most probable cause. Different treatment modalities including local anaesthetic creams, selective serotonin reuptake inhibitors (SSRIs), clomipramine, posphodiesterase type 5 inhibitors, adrenergic a1-antagonists and a centrally acting analgesic (tramadol) have been used for treatment of PE [8]. In the Diagnostic and Statistical Manual of Mental Disorders – Fourth Edition, Text Revision (DSM-IV-TR), Impulse control disorders (ICDs) are grouped as a heterogeneous cluster of disorders linked by a ‘‘failure to resist’’ impulses to engage in harmful, disturbing or distressing behaviours. The formal group of ICDs Not Elsewhere Classified include pathological gambling, intermittent explosive disorder, kleptomania, pyromania, trichotillomania and ICDs not otherwise specified. Criteria for other ICDs have been proposed including compulsive sexual behaviour, compulsive shopping and compulsive computer use [1]. ICDs are characterised by repetitive behaviours and their _ impaired inhibition. Important defining criteria for these disorders include: (1) the failure to resist an impulse to perform acts that are harmful to the individual or others, (2) an increasing sense of arousal or tension before committing or engaging in the act and (3) an experience of either gratification, pleasure or release of tension, while committing the act. Furthermore, there is usually a pattern of engaging in the abnormal behaviour in spite of adverse consequences [9]. Disordered monoamine neurotransmission has been implicated in the pathophysiology of ICDs. Abnormalities in dopamine, serotonin and noradrenergic neurotransmitter activity have been reported: (1) serotonin (5-HT) function in the initiation and cessation of the problematic behaviour [10,11]; (2) abnormal dopamine (DA) function contributing to modulation of reward and
60
O. Özdemir / Medical Hypotheses 79 (2012) 59–62
reinforcement pathways, particularly with regard to aggressive and other impulsive behaviours [12]; (3) norepinephrine (NE) dysfunction associated with arousal and excitement [12]. ICDs are prevalent and disabling conditions still poorly understood in terms of diagnosis, in spite of the relatively high prevalence of some of them, in particular sexual behaviours. Moreover, accumulating data on ‘classical’ and more recently characterised ICDs, such as internet addiction, skin picking, shopping and sexual behaviour, suggest that they would currently represent one of the most frequent and impairing class of mental conditions worldwide [9]. The hypothesis I hypothesise that premature ejaculation is an impulse control disorder. Impulsivity is defined as a tendency to perform prompt unplanned responses to provoking external and internal stimuli regardless of the undesirable consequences of these responses. The definition of PE is the occurrence of persistent or recurrent ejaculation with minimal sexual stimulation before, upon or shortly after penetration and before the person wishes it. Poor delay of gratification and disinhibition are key features of impulsivity and PE. Delay of gratification is the ability to wait for a delayed larger reward over an immediate small reward. Disinhibition is the inability to suppress behaviour in a way that is expected to be appropriate in view of social norms and constraints. By definition, both PE and impulsivity are closely interrelated, as they involve a behavioural pattern in which one often acts on impulses that may yield negative consequences. Evaluation of the hypothesis The following issues can be considered to support this hypothesis. PE as an impulsıve sexual behaviour Multiple factors, including behavioural initiation, arousal, reward and reinforcement and behavioural disinhibition, have been implicated in ICDs [13]. I use the term impulsive sexual behaviour for PE because it involves an impulsive component such as pleasure, arousal or gratification. These behaviours include an inability to inhibit inappropriate behaviours, an inability to wait, an alteration in time perception or a relative insensitivity to negative consequences, particularly delayed or uncertain negative consequences or rewards [14,15]. PE and ICDs are characterised by loss of control over the behaviours PE is primarily a problem of voluntary control over timing of ejaculation and ICDs are typically characterised by loss of control
Table 1 The intersections between PE and ICDs. Key feature of disease a The inability to control ejaculation b Loss of control over the behaviour Pathophysiology of disease The monoamines are known to play a crucial role b Disordered monoamine neurotransmission a
Pharmacological therapies SSRIs have shown benefit in delaying ejaculation The pharmacologic first-line treatment is a range of serotonergic antidepressants
a
b
a b
PE. ICDs.
over the behaviour. ICDs have the following features in common: (1) repetitive or compulsive engagement in a behaviour despite adverse consequences; (2) diminished control over the problematic behaviour; (3) an appetitive urge or craving state prior to engagement in the problematic behaviour; (4) a hedonic quality during the performance of the problematic behaviour [12]. PE presents with three components: a short time interval between penetration and ejaculation, the inability to control ejaculation and distress for the man or for the couple. A common core of clinical features of ICDs is difficulty resisting urges to engage in behaviours that are excessive and/or ultimately harmful to oneself or others [1]. There are phenomenological similarities between PE and ICDs. There are many overlapping theories on the aetiology of PE and ICDs The aetiology of premature ejaculation is unclear: both organic and psychosocial mechanisms have been suggested. The clinical, genetic, phenomenological and biological characteristics of ICDs are not completely understood. There are many overlapping theories on the aetiology of PE and ICDs. Abnormalities in dopamine, serotonin and noradrenergic neurotransmitter activity have been reported in ICDs [16]. The monoamines are known to play a crucial role in normal human sexual functioning [17]. Indirect evidence for involvement of these neurotransmitter systems is derived from diagnostic and pharmacological treatment considerations. Disordered monoamine neurotransmission has been implicated in the pathophysiology of PE and ICDs. Serotonin (the 5-HT system) Central serotonin (5-hydroxytryptamine, 5-HT) function is an important component of normal behavioural inhibition that controls impulsive responding [18,19]. A role for 5-HT in ICDs is supported from results of studies in which reduced 5-HT neurotransmission has been associated with increased impulsivity in people and that chronically inhibiting the 5-HT system led to behavioural disinhibition in animals [12,20,21]. Lesions to the 5HT system significantly increase premature responding [22,23]. It has been postulated that PE might have a sensory/neural component involving perturbations in the 5-HT system [24]. Because individual variability in 5-HT neurotransmission might determine individual ejaculatory thresholds, such alterations could theoretically contribute to the pathogenesis of PE [25]. 5-HT appears to be a key mediator and is considered the main inhibitory neurotransmitter in the central control of ejaculation [26–29]. Activation of postsynaptic 5-HT receptors prolongs ejaculatory latency, whereas activation of presynaptic 5-HT autoreceptors, which inhibits 5-HT release, decreases ejaculatory latency [30,31]. It was suggested that PE might be associated with the presence of low synaptic levels of 5-HT in regions of the CNS that modulate ejaculation, possibly because of variations in 5-HT receptor sensitivity [24]. Thus, abnormal 5-HT function may be central to the development of these conditions. Dopamine (the DA system) The dopamine (DA) system is associated with reward, reinforcement behaviours, loss of self-control and impulsivity [12,21]. Dysfunction within the DA system has been hypothesised to play a major role in psychiatric disorders such as attention deficit hyperactivity disorder (ADHD) [32], pathological gambling (PG) [33] and drug addiction [34], in which impulsivity is high. ICDs may occur with dopamine agonist treatment. Dopamine replacement therapy in the treatment of Parkinson’s disease (PD) has frequently been reported to induce compulsive gambling, pathologic hypersexuality, binge eating and compulsive shopping [12].
O. Özdemir / Medical Hypotheses 79 (2012) 59–62
61
Administration of the DA precursor L-DOPA increases impulsive choice in human volunteers [35]. Dopamine has a fundamental role in the mediation of erectile function. Regarding the mechanism by which this drug might work, we could hypothesise a close relationship with the ‘DA (Dopamine) theory’ of the control of human sexual function. DA seems to have a role in facilitating sexual arousal and in lowering the ejaculatory threshold; accordingly, DA antagonists are likely to have an inhibitory function [36]. These data suggest that 5-HT and DA play a role during impulsive decision-making and ejaculation.
ological gambling, compulsive shopping, hypersexuality and binge eating [53]. Levosulpiride, an anti-dopaminergic drug, is commonly used in some dyspeptic syndromes in anxious patients and to treat some types of hemicrania. The authors observed its effect on premature ejaculation accidentally, after prescribing the drug for its usual purpose to three patients. It was only by chance that all of them were suffering from premature ejaculation. During the following visit, after 20–30 days, they were surprised to hear of a wonderful improvement in the patients’ sexual life [36]. The intersections between the two disorders are tabulated for easy access (see Table 1).
Hypersensitivity
Conclusion
One of the initial theories concerning the cause of this disorder was that the patient’s penis was ‘‘very sensitive’’, triggering the ejaculatory response before the patient or his partner wished [37]. To investigate the correlation between penile hypersensitivity and premature ejaculation (PE), it was determined men with PE have a greater cortical representation of the sensory stimuli from the glans penis [38,39], and have a lower tactile threshold [40], therefore indicating these individuals’ higher sensitivity compared with others [41]. Patients who suffer from impulse control disorders often experience a heightened sense of tension or arousal before performing the act. Poor impulse control has been associated with drug-seeking behaviour and an enhanced risk of relapse, suggesting that impulsivity is causally related to reward hypersensitivity [42]. One possibility is that impulsivity confers hypersensitivity to drug reinforcement. This claim is supported by the finding that impulsivity in rats, quantified by a preference for small immediate reward over a delayed larger reward (delay discounting) is associated with higher rates of cocaine [43,44], alcohol [45] and methylphenidate self-administration [46]. I think that these findings suggest that PE is associated with impulsivity and the aetiologies of these disorders may be mediated by hypersensitivity to stimulus, which is tactile or drug related.
ICDs share features with PE, specifically, aspects of impaired control, rapid responses to stimuli and hypersensitivity. These disorders often occur with subjective distress and are frequently hidden by patients. In addition to these features, the neurotransmitter systems have been similarly implicated in ICDs and PE. The same treatment options further support a relationship between ICDs and PE. The behaviours likely exist on a spectrum and may be idiosyncratic to an individual’s susceptibility, hence complicating any phenomenological classification. There is much disagreement surrounding the classification of these behaviours. Classification within psychiatric categories, which include obsessive–compulsive behaviours, impulse control and addiction processes, is further confounded given the overlapping cognitive processes underlying these behaviours. Further research is needed to understand the biochemical factors underlying the behavioural features. Thus, clinical advances in the identification, prevention and treatment of PE and ICDs need to be facilitated. Conflict of interest statement None declared. Funding
ICDs and PE can often be treated with behavioural and pharmacological therapies Despite the high prevalence rates of ICDs in the general population and in psychiatric cohorts [47,48], pharmacological treatments have been relatively understudied. There are no FDAapproved medications for any ICD. ICDs can often be treated with behavioural and pharmacological therapies. Forms of psychotherapy described in case reports as demonstrating success include psychoanalytic, insight-oriented and behavioural techniques. It is well established that the pharmacologic first-line treatment for ICDs are a range of serotonergic antidepressants (selective serotonin reuptake inhibitors, SSRIs; e.g., fluvoxamine, fluoxetine or paroxetine, clomipramine) [49]. Treatment of PE includes behavioural, psychological and pharmacological therapies. However, an approved treatment regime does not exist. The most studied neurotransmitter in the physiology of ejaculation is 5-HT, which is an inhibitor of ejaculation acting via decreasing serotonin-induced dopamine. The SSRIs inhibit presynaptic reuptake of 5-HT in the central nervous system. The effect of SSRI on PE has been demonstrated in studies [50,51]. SSRIs are currently indicated as antidepressants, but citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline have also shown benefit in delaying ejaculation. A range of impulse control behaviours have been reported following the use of dopamine agonists (DAs) and levodopa in patients with Parkinson’s disease [52]. DAs are particularly associated with path-
The author received no financial support for the research and/or authorship of this article. References [1] American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. [Text Revision]. Washington, DC: American Psychiatric Association Press; 2000. [2] Godpodinoff ML. PE: clinical subgroups and etiology. J Sex Marital Ther 1989;15:130–4. [3] Cooper AJ, Cernovsky ZZ, Colussi K. Some clinical and psychometric characteristics of primary and secondary premature ejaculators. J Sex Marital Ther 1993;19:276–88. [4] McMahon CG, Althof S, Waldinger MD, et al. An evidence-based definition of premature ejaculation: report of the International Society for Sexual Medicine Ad Hoc committee for the definition of premature ejaculation. BJU Int 2008;102:338–50. [5] Goldstein I. Premature to early ejaculation: a sampling of manuscripts regarding the most common male sexual dysfunction published in the IJIR: the journal of sexual medicine. Int J Impot Res 2003;15:307–8. [6] Rosen RC. The premature ejaculation prevalence and attitudes (PEPA) survey: a multi-national survey. J Sex Med 2004;1(Suppl. 1):57–8. [7] Dell’osso B, Marazziti D, Hollander E, Almatura C. Traditional and newer impulse control disorders: a clinical update. Clin Neuropsychiatry 2007;4(1):30–8. [8] Rıley A, Segraves RT. Treatment of premature ejaculation. Int J Clin Pract 2006;60(6):694–7. [9] Hollander E, Buchalter A, DeCaria C. Pathological gambling. Psychiatr Clin North Am 2000;23(3):629–42. [10] Potenza MN. Pathological gambling: clinical aspects and neurobiology. In: Soares J, Gershon S, editors. Handbook of medical psychiatry. New York: Marcel Dekker; 2002. p. 683–99. [11] Potenza MN, Hollander E. Pathologic gambling and impulse control disorders. In: Davis KL, Charney D, Coyle JT, Nemeroff C, editors. Neuropsycho-
62
[12] [13] [14] [15] [16] [17] [18] [19]
[20] [21]
[22]
[23]
[24]
[25] [26] [27] [28] [29] [30]
[31] [32]
O. Özdemir / Medical Hypotheses 79 (2012) 59–62 pharmacology: the fifth generation of progress. Philadelphia, PA: Lippincott Williams & Wilkins. p. 1425–43. Grant JE, Potenza MN. Pathological gambling: a clinical guide to treatment. Washington, DC: American Psychiatric Publishing Inc.; 2004. Grant JE, Brewer JA, Potenza MN. The neurobiology of substance and behavioral addictions. CNS Spectr 2006;11(12):924–30. Barkley RA. ADHD and the nature of self-control. New York: The Guildford Press; 1997. Meck WH. Neuropharmacology of timing and time perception. Brain Res Cogn Brain Res 1996;3:227–42. Wendol AW, Potenza MN. The neurobiology of impulse control disorders. Rev Bras Psiquiatr 2008;30(Suppl. I):S24–30. Bradford JM. The paraphilas, obsessive compulsive spectrum disorder and the treatment of sexually deviant behaviour. Psychiatr Q 1999;70:209–19. Evenden JL. Varieties of impulsivity. Psychopharmacology 1999;146:348–61. Winstanley CA, Eagle DM, Robbins TW. Behavioral models of impulsivity in relation to ADHD: translation between clinical and preclinical studies. Clin Psychol Rev 2006;26:379–95. Soubrie´ P. Reconciling the role of central serotonin neurons in human and animal behavior. Behav Brain Sci 1986;9:319–64. Winstanley C, Theobald D, Dalley J, Cardinal R, Robbins T. Double dissociation between serotonergic and dopaminergic modulation of medial prefrontal and orbitofrontal cortex during a test of impulsive choice. Cereb Cortex 2006;16(1):106–14. Winstanley CA, Theobald DE, Dalley JW, Glennon JC. 5-HT2A and 5-HT2C receptor antagonists have opposing effects on a measure of impulsivity: interactions with global 5-HT depletion. Psychopharmacology 2004;176: 376–385. Harrison AA, Everitt BJ, Robbins TW. Central 5-HT depletion enhances impulsive responding without affecting the accuracy of attentional performance. Interactions with dopaminergic mechanisms. Psychopharmacology 1997;133: 329–342. Waldinger MD, Rietschel M, Nothen MM, Hengeveld MW, Olivier B. Familial occurrence of primary premature ejaculation. Psychiatr Genet 1998;8:37– 40. Waldinger MD. The neurobiological approach to premature ejaculation. J Urol 2002;168:2359–67. Waldinger MD. Premature ejaculation: state of the art. Urol Clin N Am 2007;34:591–9. Coolen LM, Allard J, Truitt WA, McKenna KE. Central regulation of ejaculation. Physiol Behav 2004;83:203–15. Giuliano F, Clément P. Serotonin and premature ejaculation: from physiology to patient management. Eur Urol 2006;50(3):454–66. Giuliano F. 5-Hydroxytryptamine in premature ejaculation: opportunities for therapeutic intervention. Trends Neurosci 2007;30(2):79–84. Hillegaart V, Ahlenius S. Facilitation and inhibition of male rat ejaculatory behaviour by the respective 5-HT1A and 5-HT1B receptor agonists 8-OH-DPAT and anpirtoline, as evidenced by use of the corresponding new and selective receptor antagonists NAD-299 and NAS-181. Br J Pharmacol 1998;125: 1733–1743. Ahlenius S, Larsson K. Specific involvement of central 5-HT1A receptors in the mediation of male rat ejaculatory behavior. Neurochem Res 1997;22:1065–70. Dougherty DD, Bonab AA, Spencer TJ, Rauch SL, Madras BK, Fischman AJ. Dopamine transporter density in patients with attention deficit hyperactivity disorder. Lancet 1999;354:2132–3.
[33] Goudriaan AE, Oosterlaan J, de Beurs E, Van den Brink W. Pathological gambling: a comprehensive review of biobehavioral findings. Neurosci Biobehav Rev 2004;28:123–41. [34] Jentsch JD, Taylor JR. Impulsivity resulting from frontostriatal dysfunction in drug abuse: implications for the control of behavior by reward-related stimuli. Psychopharmacology 1999;146:373–90. [35] Pine A, Shiner T, Seymour B, Dolan RJ. Dopamine, time, and impulsivity in humans. J Neurosci 2010;30:8888–96. [36] Greco E, Polonio-Balbi P, Speranza JC. Levosulpiride: a new solution for premature ejaculation? Int J Impot Res 2002;14:308–9. [37] Choi HK, Xin ZC, Choi YD, et al. Safety and efficacy study with various doses of SS-cream in patients with premature ejaculation in a double-blind, randomized, placebo controlled clinical study. Int J Impot Res 1999;11:261–4. [38] Fanciullacci F, Colpi GM, Beretta G, Zanollo A. Cortical evoked potentials in subjects with true premature ejaculation. Andrologia 1988;20:326–30. [39] Xin ZC, Choi YD, Rha KH, Choi HK. Somatosensory evoked potentials in patients with primary premature ejaculation. J Urol 1997;158:451–5. [40] Eardley I, Sethia K. Erectile dysfunction – current investigation and management. London: Mosby; 1998. [41] Astbury-Ward E. From kama sutra to dot.com: the history, myths and management of premature ejaculation. Sex Relat Ther 2002;17:367–79. [42] Diergaarde L, Pattij T, Nawijn L, Schoffelmeer AN, De Vries TJ. Trait impulsivity predicts escalation of sucrose seeking and hypersensitivity to sucroseassociated stimuli. Behav Neurosci 2009;123(4):794–803. [43] Anker JJ, Perry JL, Gliddon LA, Carroll ME. Impulsivity predicts the escalation of cocaine self-administration in rats. Pharmacol Biochem Behav 2009;93:343–8. [44] Perry JL, Nelson SE, Carroll ME. Impulsive choice as a predictor of acquisition of IV cocaine self-administration and reinstatement of cocaine-seeking behavior in male and female rats. Exp Clin Psychopharmacol 2008;16:165–77. [45] Poulos CX, Le AD, Parker JL. Impulsivity predicts individual susceptibility to high levels of alcohol self-administration. Behav Pharmacol 1995;6:810–4. [46] Marusich JA, Bardo MT. Differences in impulsivity on a delay-discounting task predict self-administration of a low unit dose of methylphenidate in rats. Behav Pharmacol 2009;20:447–54. [47] Kessler RC, Berglund P, Demler O, Jin R, Merikangas K, Walters EE. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 2005;62:593–602. [48] Grant JE, Levine L, Kim D, Potenza MN. Impulse control disorders in adult psychiatric inpatients. Am J Psychiatry 2005;162:2184–8. [49] Schreiber L, Odlaug BL, Grant JE. Impulse control disorders: updated review of clinical characteristics and pharmacological management. Front Psychiatry 2011;2:1–11. [50] Atmaca M, Kuloglu M, Tezcan E, Semercioz A. The efficacy of citalopram in the treatment of premature ejaculation: a placebo-controlled study. Int J Impot Res 2002;14:502–5. [51] Waldinger MD, Zwinderman AH, Schweitzer DH, Olivier B. Relevance of methodological design for the interpretation of efficacy of drug treatment of premature ejaculation: a systematic review and metaanalysis. Int J Impot Res 2004;16:369–81. [52] Weintraub D, Siderowf AD, Potenza MN, Goveas J, Morales KH, Duda JE, et al. Association of dopamine agonist use with impulse control disorders in Parkinson disease. Arch Neurol 2006;63:969–73. [53] Voon V, Hassan K, Zurowski M, de Souza M, Thomsen T, Fox S, et al. Prevalence of repetitive and reward-seeking behaviors in Parkinson disease. Neurology 2006;67:1254–7.