IN REVIEW

The Neurobiology, Neuropharmacology, and Pharmacological Treatment of the Paraphilias and Compulsive Sexual Behaviour
John MW Brad ford, MB, ChB, DPM, FF Psych, FRC Psych, DABPN, DABFP, FRCPC1

There has been in creas ing in ter est in the treat ment of sex ual dis or ders in re cent years. Sex ual dis or ders are clas si fied in DSM-IV as sex ual dysfunctions, paraphilias, and gen der iden tity dis or ders. The sex ual dysfunctions are nondeviant or nonparaphillic. The sex ual dys func tion dis or ders should in clude hy per ac tive sex ual de sire dis or der un der sex ual de sire dis or ders . Fur ther, there should be a speci fier for paraphilias of with hypersexuality or with out hypersexuality. There is still in com plete un derstand ing of the neurobiology of sex ual dis or ders al though func tional neuroanatomy and neoropharmcological re search has exposed the neurotransmitters, receptors, and hormones that are in volved in sex ual de sire. Various pharmacological agents in clud ing se ro to nin reuptake in hib i tors, antiandrogens, LHRH agonists, and oth ers have been doc u mented as re duc ing sex ual de sire. An al go rithm for the use of these drugs in the treat ment of the paraphilias as well nonparaphilic hypersexuality is out lined. The modes of ac tion, dos ages, aims of treat ment, and usual meth ods of pre scrib ing these agent s is re viewed in this ar ti cle. Some fu ture di rec tions of re search in phar ma co log i cal treat ment is also dis cussed. (Can J Psy chi a try 2001;46:26 34) Key Words: sexual desire disorders, paraphilias, hypersexuality, compulsive sexual behaviour, antiandrogens, specific serotonin reuptake inhibitors, LHRH agonists

l though it would be pre ma ture to say that the neurobiology and neuropharmacology of sex ual be haviour is un der stood, there clearly have been ma jor ad vances in re cent years. There has been sig nif i cant re search on the se rotonin receptors and their function in the brain. Serotonin (5-HT) is in volved in the neurobiology of many psy chi at ric dis or ders, par tic u larly mood disorder, and specifically de pres sion, anx i ety, schizo phre nia, eat ing dis or ders, and ob sessivecompulsive dis order (OCD). It also plays a role in mi graines. Al though the eti ol ogy of these dis or ders is not under stood, phar ma co log i cal treat ments that mod u late lev els of 5-HT have shown to be ef fec tive in all of them. Fur ther, sexual disor ders, both paraphilic (sexual devi a tion) and nonparaphilic (com pul sive sex ual dis or der or nonparaphilic hypersexuality), have also responded to pharmacological treat ments mod u lat ing se ro to nin lev els (1). This has led to the spec u la tion that a group of dis or ders could be clas si fied together as obsessivecompulsive spectrum disorders (1,2). This is based not only on the diagnostic characteristics of these dis or ders as out lined in DSM-IV but also on the fact that

they respond to pharmacological treatment af fecting the cen tral ner vous sys tem level of 5-HT (1,2). In gen eral, the as sess ment and treat ment of all types of sex ual dis or ders have been ne glected by psy chi a try. In re cent years, how ever, ad vances in psy chi at ric re search have fo cused gen eral psychiatry on these important clinical entities. OCD spec trum dis or ders in clude OCD, eat ing dis or ders, somatoform dis or ders, im pulse con trol dis or ders, and neu ro psychiatric dis or ders such as Tourette syn drome (TS); they may also in clude the sex ual dis or ders (1,2). There are clin i cal sim i lar i ties be tween OCD and sex ual dis or ders that can be sum ma rized as fol lows (1):
Ob ses sions are sim i lar to sex ual fan ta sies, both paraphilic

and nonparaphilic.
Com pul sions are sim i lar to com pul sive sex ual be hav iour

(CSB), which can be paraphilic or nonparaphilic.

There is a cross over of comorbidity be tween OCD and the

sex ual dis or ders, with de pres sion and anx i ety dis or ders being com mon in both groups.
At a neurobiological and neuropharmacological level,

Manu script re ceived and ac cepted De cem ber, 2000.

1 Pro fes sor and Head, Di vi sion of Fo ren sic Psy chia try, Uni ver sity of Ot tawa;

there is a sig nif i cant over lap be tween these dis or ders. There is no con sensus at this time as to whether the paraphilias and com pul sive sex ual be hav iour (nonparaphilic hypersexuality) should be included in the OCD spectrum disorders.
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Royal Ot tawa Hos pi tal, Ot tawa, On tario. Ad dress for cor re spon dence: Dr JMW Brad ford, Royal Ot tawa Hos pi tal, 1145 Car ling Ave nue, Ot tawa, On tario K1Z 7K4 e- mail: jbrad for@rohcg.on.ca

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There has been con sid er able re cent prog ress in map ping out 5-HT receptor sub types (3). Many phar ma co log i cal treatments act ing on the cen tral 5-HT sys tem, such as se lec tive sero to nin reuptake in hib i tors (SSRIs), an ti de pres sants act ing presynaptically to serotonergic neurons, and 5-HT receptor an tag o nists used in the pro phy laxis of mi graine, have mostly nonselective ef fects on postsynaptic 5-HT re cep tor sub types (3). The ini tial work on 5-HT re cep tor sub types was based on phar ma co log i cal tools. Since that time, re cep tor bind ing profiles, com mon sec ond mes sen ger cou pling, and func tional activity of ligands have iso lated fur ther re cep tor types (3). Based on this work, 4 main sub groups of 5-HT re cep tors have been identified, spe cifically 5-HT1, 5-HT2 , 5-HT 3, and 5-HT4. This clas si fi ca tion has been con firmed by the so phis ticated tech niques of mo lec u lar bi ol ogy, but the lat ter have also led to the iden ti fi ca tion of novel 5-HT re cep tors, spe cif ically 5-HT1F, 5-HT 5, 5-HT6, and 5-HT 7 (3). Var i ous sub types have also been iden ti fied. The 5-HT1 re cep tor has 5-HT 1A, 5-HT1B, 5-HT 1D, 5-HT1E, and 5-HT1F subtypes. The 5-HT 2 sys tem has been shown to have 5-HT A, 5-HT2B , and 5-HT2C 2 sub types. There do not yet ap pear to be any sub types of 5-HT 3 and 5-HT 4 re cep tors, but 5-HT5 has 2 sub types, 5-HT 5A and 5-HT 5B. No sub types have been iden ti fied for the 5-HT and 6 5-HT7 re cep tors (3). All of the 5-HT re cep tors be long to a fam ily of G pro tein-coupled re cep tors (3). Phar ma co log i cal re search is es tab lish ing se lec tive lig ands for the var i ous recep tor sub types, facil i tat ing the de vel op ment of sub type-specific agonists and an tag o nists. This will help elu ci date how 5-HT re cep tor sub types af fect be hav iour, includ ing sex ual dis or ders. It is also pos si ble that other 5-HT recep tor sub types will be iso lated or that fur ther vari a tions in re cep tor sub types will be found. Perhaps mu ta tions of the 5-HT re cep tor or subreceptor struc tures will be found to play a r o l e i n a v a r i e t y of psy c h i a t r i c dis or d e r s ( 3 ) . Neuropharmacological re search into 5-HT re cep tors is likely to con tinue to be of sig nif i cant in ter est to gen eral psy chi a try and to the eval u a tion and treat ment of sex ual dis or ders. There have been several studies on the neurobiology of hypersexuality. Broadly, the re search lit er a ture shows that lesions in cer tain parts of the brain can lead to disinhibition of sex ual be hav iour that may re sult in com pul sive sex ual be haviour (3). In the neu ro log i cal and neu ro psy chi at ric lit er a ture, there are ref er ences to disinhibited sex ual be hav iour as a result of fron tal lobe le sions. The cau tion here is that this is most likely part of a gen eral be hav ioural disinhibition rather than be ing spe cific to sex ual be hav iour. The clin i cal pre sen ta tion of cer tain el derly pa tients with de men tia and disinhibited behav iour in clud ing paraphilic behav iour (ex hi bi tion ism) and nonparaphilic hypersexuality (in ap pro pri ate sex ual ad vances to women) is mostly re ported. A more de tailed clin i cal eval ua tion would usu ally show that this is more clin i cally ob vi ous disinhibited be hav iour among a spec trum of other disinhibited be hav iours (4,5). Paraphilic be hav iour has been reported secondary to a wide variety of neuropsychiatric

dis or ders. These in clude tem po ral lobe ep i lepsy, postencephalitic neu ro psy chi at ric syn dromes, septal le sions, TS, fron tal lobe le sions, tu mours in var i ous sites, bi lat eral temporal lobe les ions, and multiple sclerosis (5). Both nonparaphilic hyposexuality and hypersexuality have been reported in as so ci a tion with var i ous brain le sions. In ter est ingly, OCD has also been ob served sec ond ary to var i ous neu ro log i cal dis or ders, and the sites of the le sions caus ing OCD over lap con sid er ably with the ones that are as so ci ated with sex ual dis or ders (5). There has also been re search show ing that corticostriatal cir cuits are most likely in volved in OCD and TS (4,6,7). It has also been noted that there is comorbidity be tween sex ual dis or ders and TS, in clud ing ex hi bi tion ism, other paraphilias, and nonparaphilic hypersexuality (8). It is interesting that coprolalia and copropraxia in TS clearly have a sex ual be hav iour com po nent (8). Other re search shows that these symp toms are re lated to the de gree of Tourette syn drome gene-loading that is pres ent (7). These sexual symp toms de crease with treat ment us ing SSRIs and dopamine blockers (4,6,7). These observations sup port a re la tion be tween paraphilic be hav iour, com pul sive sex ual behav iour, and a neurobiological ab normality; paraphilia and CSB ap pear to be a be hav ioural re sponse to that ab nor mal ity. At the same time, there is pos si bly an over lap of the neurobiological ab nor mal ity and OCD spec trum dis or ders. The ex act na ture of hypersexuality is dif fi cult to de fine. The to tal sex ual out let (TSO), orig i nally de fined by Kinsey as the num ber of or gasms per week, is one mea sure o f hypersexuality. Kafka has at tempted to ad dress this prob lem in a study of men pre sent ing for treat ment with com pul sive sex ual be hav iour, which he de scribes as paraphilia re lated dis or ders (PRD) (9). In di vid uals with PRD were found in a small study to have 5 or more sex ual out lets (or gasms) per week for long pe ri ods of their adult lives, while the av er age man would have 3 (9). Al though this is sim ple and at trac tive in clin i cal terms, it does not de fine hypersexuality in em pir i cal terms. What is needed is a large study of paraphilic and nonparaphilic men and women in whom typ i cal pat terns of sex ual drive are ex am ined. In ad di tion, in my opin ion, there would have to be some de gree of so cial or oc cu pa tional or other dys func tion cou pled with it, rather than sim ply a quan ti ta tive mea sure of to tal or gasms per week. Var i ous lev els of sex drive could be es tab lished and de fined as hyposexuality, normosexuality, and hypersexality, based on ranges of sex ual out let mea sures. What is im por tant con cep tu ally, how ever, is that there are some men who have hypersexuality, some of whom may be paraphilic and some who are not. Testing for the pres ence or ab sence of paraphilia would be rep li cated at all levels of sexual drive, as men and women who have a paraphilia may be hypersexual, normosexual, or hyposexual. In ad di tion, some in di vid u als ex hibit com pul sive sex ual behav iours (CSB) which are nonparaphilic. These in clude compul sive mas tur ba tion, com pul sive use of por nog ra phy, and

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pro mis cu ity. In di vid uals with CSB may also be hypersexual, normosexual, or hyposexual. As com pul sive sex ual be haviour be comes more de fined con cep tu ally and di ag nos ti cally, a spe cific pharmacological approach to hypersexuality (paraphilic or nonparaphilic), in con trast to normosexuality or hyposexuality, would be developed. Hypersexuality would be rec og nized as dis tinct from CSB and paraphilic behav iour. What is not clear from re search to date is whether hypersexuality is an ag gra vat ing fac tor in paraphilias. A consis tent di ag nos tic for mu la tion for hypersexuality must be de vel oped, and it should be in cluded in DSM-V. Animal re search and clin i cal stud ies have shown that the monoamines 5-HT and dopamine affect sexual behaviour (1,10). Fur ther, ma nip u la tions of 5-HT and do pa mine can either decrease or increase sexual behaviour, depending on which neuropharmacological intervention occurs (1,10). Any dis cus sion of the ef fects of neurobiology on sex ual behav iour has to take into ac count the neuropeptides in the brain that are significantly involved with the regulation of hor mones (10). A neuropeptide, by def i ni tion, is a chain of 2 or more amino ac ids linked by pep tide bonds and dif fers from other pro teins only in the na ture of the pep tide links (10). Over 100 unique, bi o log i cally ac tive pep tides, rang ing in size from 2 to about 40 amino ac ids, have been found, in clud ing go nad o tro pin-releasing hor mone (GRH) and prolactin (10). GRH stim u lates the re lease of fol li cle-stimulating hor mone (FSH) and luteinizing hormone (LH) from the pituitary, which drive the pro duc tion of tes tos ter one in the tes tes and estro gen and other hor mones in the ova ries (11). The be havioural ef fects of neuropeptides have been ob served af ter their injection di rectly into the cen tral ner vous sys temthe pre ferred method of ad min is tra tion be cause most of the pep tides can not pen e trate the blood-brain bar rier in amounts suf fi cient to be ac tive (10). These neuropeptides are simi lar to monoamine neurotransmitters in having receptors on neu rons, which they can ex cite or in hibit (10). One dif fer ence, how ever, is that the rate of ac tiv ity for neuropeptides is slow com pared with that of the monoamine neurotransmitters, and the du ra tion of their ac tiv ity can be ex tended for sub stan tially lon ger pe ri ods of time (10). Neuropeptides are found through out the cen tral ner vous system as well as in pe riph eral or gans such as the gas tro in tes ti nal tract, the pan creas, and the ad re nal glands (10). The hy po thalamic re gions con tain con sid er able amounts of these neuropeptides, in clud ing, a m o n g o t h ers, G R H , corticotropin-releasing hor m o n e (CRH), and thyroid-releasing hor mone (TRH) (10). Clearly, the role of the neuropeptide trans mit ter GRH is crit i cal to an un der stand ing of hu man sex ual be hav iour (11). Al though re search in rats has shown that the ef fects of neuropeptides on sex ual be haviour are me di ated solely through cer tain se ro to nin re cep tor sub types (12), the as sump tion that ei ther 5-HT or do pa mine independently have a dominant neurobiological role in

controlling sexual be hav iour in hu mans is most likely completely in ac cu rate. The sit u a tion in humans is much more com pli cated (11). How ever, both an i mal re search and research on the hu man male have shown that sex ual be hav iour de clines fol low ing sur gi cal cas tra tion and that this oc curs at dif fer ent rates in dif fer ent spe cies. The first el e ment that disappears is ejaculation, followed by intromission, and then mount ing be hav iour (11). These re sponses are re stored in the re verse se quence with an dro gen re place ment (11). The sites of ac tion of an dro gens in the male an i mal are known to a cer tain de gree. These are in the limbic sys tem of the brain, the spi nal cord, and the pe nis (11). In the spi nal cord, the re flexes con trol ling erec tion and ejac u la tion are an dro gen-dependent and in the penis, tactile sen sitivity is androgen-dependent (11). Studies of hor mone re place ment in hypogonadal men as well as stud ies of the ef fects of hor mone lev els in men with sex ual dys func tion have all con trib uted to our knowl edge of the role of an dro gens in male sex ual be hav iour (11). Studies of hyperprolactinemia show that it causes a de cline in sex ual de sire, as seen in cer tain prolactin-producing tu mours (11). The be hav ioural ef fects of the prin ci pal an dro gens in the hu man male, tes tos ter one (T) and dihydrotestosterone (DHT), are me di ated through T re cep tors and DHT re cep tors in the brain, par tic u larly in the septal re gion, the pi tu itary, and the hy po thal a mus (1113). Tes tos ter one can also be aromatized to estradiol. Aromatization oc curs in the hy po thal a mus and else where and is also re lated to sex ual drive in hu mans (11). Thus, the neurobiology of human sexual behaviour is extremely com pli cated and in volves not only the monoamine trans mit ters 5-HT and, to a lesser ex tent, do pa mine but is also reg u lated by neuropeptide neurotransmitters, lo cated prin ci pally in the hy po thal a mus. In ad di tion, cir cu lat ing an dro gens and intracellular DHT and T receptors, specifically in the septal area and hy po thal a mus, also play a very im por tant role. Clearly, com pli cated mech a nisms both fa cil i tate and in hibit sex ual be hav iour and in volve all of these neurobiological systemsand prob a bly oth ers as well. It is ob vi ous that these mechanisms are not fully understood at this time and it is there fore ex tremely pre ma ture to talk about a monoamine hypothesis of compulsive sex ual be hav iour. At the same time, certain pharmacological agents, by their actions on monoamine neurotransmitters and their ef fects on an dro gen re cep tors and cir cu lat ing hor mone lev els, can have very sig nif i cant and last ing ef fects on sex ual be hav iour (1, 1416). A reduction in sexual behaviour, whether nonparaphilic or paraphilic, can be achieved. The etiology of the paraphilias or sex ual de vi a tions is unknown (17,18). Fur ther, the ac tual in ci dence and prev a lence of the paraphilias is un known (18,19). What is known is that the level of vic tim iza tion of males and fe males in the gen eral pop u la tion is fairly con sis tent. As ini tially re ported by Kinsey in the late 1940s, 24% of fe males had been vic tims of sex ual abuse when they were 14 years of age or youn ger (20). A national sur vey in Can ada in 1984 found that 23.5 % of fe males

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and 12.8% of males were vic tims of child hood sex ual abuse (21), which is quite con sis tent with Kinseys data. This may assist in gaug ing the prev a lence of one paraphilia, spe cif ically, pedophilia. For ex am ple, it is known that among iden tified pedophiles, ap prox i mately 35% were vic tims of sex ual abuse as children. The average number of victims per pedophile is also known. It may there fore be pos si ble to es timate the prev a lence of pedophilia in the gen eral pop u la tion through extrapolation. In one study of sexual fantasies, two-thirds of males re ported het ero sex ual pedophilic fan tasies and about one-third of males had rape fan ta sies (22). As the pres ence of de vi ant sex ual fan ta sies is an in di ca tion of the pres ence of a paraphilia at a mild level, this im plies that mild pedophilia is prev a lent at a stag ger ingly high rate in men in the gen eral pop u la tion. Fur ther, as sum ing that the pres ence of rape fantasies indicates the presence of another paraphilia, spe cif i cally sex ual sa dism, then mild sa dism would also be highly prev a lent in the pop u la tion at large. In my opin ion, these are gross overestimates of the prev alence of mild pedophilia and sex ual sa dism. How ever, even if these fig ures were over es ti mated by a fac tor of 10, and the real lev els are 6% and 3%, these dis or ders would still have a vastly higher prevalence than most other psychiatric disorders. At this time, the prev a lence of paraphilias in the gen eral pop u la tion is un known, and the prev a lence of com pul sive sex ual be haviour is also un known. There are a num ber of phar ma co log i cal in ter ven tions that are avail able for the treat ment of CSB and the paraphilias. These agents ap pear to have a di rect im pact on sex ual drive. Sex ual drive con sists of var i ous com po nents, in clud ing a psy cho logi cal com po nent of sub jec tive de sire to en gage in sex ual ac tivity (the sex ual equiv a lent of hun ger); the pres ence of sex ual fan ta sies which may be nonparaphilic or paraphilic; a state of sex ual arousal that pro vides mo ti va tion for seek ing out sex ual ac tiv ity; and fi nally, the ac tual sex ual ac tiv ity it self, which ulti mately re sults in an or gasm (23). Phar ma co log i cal agents have been iden ti fied that can af fect all of the com po nents of sex ual drive. Ideally, how ever, one would want phar ma colog i cal agents that could af fect de vi ant sex ual in ter ests in the case of paraphilias but not af fect nondeviant sex ual be haviour. As dis cussed later in this pa per, there is at least some ev idence that this might occur with the spe cific antiandrogen cyproterone ac e tate and the SSRI sertraline (24). In the case of CSB, the ideal treat ment would re sult in a gen eral re duc tion of sex ual drive with out ex tin guish ing itbut giv ing the in di vid ual more con trol over his or her sex ual be hav iour. The evaluation of sexual behaviour re quires ex per tise and training in sexology and a specialized sexual behaviours clinic. In such a clinic, there is typ i cally a de tailed psy chi at ric and phys i cal ex am i na tion and an as sess ment of sex ual be haviour, us ing var i ous psy cho log i cal and phys i o log i cal tests. As var i ous neu ro psy chi at ric prob lems can have a sig nif i cant effect on sexuality, neuropsychiatric expertise should be

avail able and should be used to com plete the eval u a tion. The eval u a tion in cludes a sex hor mone pro file, con sist ing of free and to tal tes tos ter one, FSH, LH, estradiol, prolactin, and pro gesterone. This sex hormone profile will also provide the base line for any treat ments in volv ing antiandrogens or hormones. In addition, sex drive abnormalities and cer tain high-risk cases for sex ual vi o lence may in volve hor mone ab normalities. Var i ous ques tion naires are used to provide a struc tured sex ual his tory and mea sure the na ture and de gree of sex ual fan ta sies, the na ture and de gree of cog ni tive dis tor tions and how they re late to paraphilias, com po nents of sexual drive and of nonparaphilic sexual behaviour, and the pres ence and ex tent of sub stance abuse. The last com po nent of the eval u a tion is phys i o log i cal test ing of sex ual arousal to establish whether a de vi ant sex ual pref er ence is pres ent or not. This author has recently established an al gorithm for the treatment of paraphilias (24) that is based on an enhanced clas si fi ca tion of paraphilias de scribed in the DSM-III-R (23). The new clas si fi ca tion scheme has 4 cat e go ries (24): 1. Mild 2. Mod er ate 3. Se vere 4. Cat a strophic The last cat e gory, cat a strophic, has been added to the orig i nal 3 de scribed in DSM-III-R. The full ver sion of this clas si fi cation is avail able in a re cent pub li ca tion by this au thor (23). The newly-developed algorithm encompasses 6 levels of treat ment for the 4 cat e go ries of paraphilia. Level 1: Re gard less of the se ver ity of the paraphilia, cog nitive-behavioural treat ment and re lapse-prevention treat ment would al ways be given. Level 2: Phar ma co log i cal treat ment would start with SSRIs. This would be in di cated in all cases of mild paraphilia. Level 3: If the SSRIs were not ef fec tive in 4 to 6 weeks at ad equate dos age lev els, a small dose of an antiandrogen would be added. A typ i cal phar ma co log i cal re gime would be sertraline 200 mg daily with 50 mg of medroxyprogesterone acetate (MPA) or 50 mg of cyproterone ac e tate (CPA). This would be used in mild and mod er ate lev els of paraphilia. Level 4: The full antiandrogen or hor monal treat ment would be given orally. This would in volve 50 to 300 mg of MPA daily or 50 to 300 mg of CPA daily. This reg i men would be used in most mod er ate cases and in some se vere cases. Level 5: The full antiandrogen treat ment or hor monal treat ment would be given intramuscularly (IM). This would

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in volve 300 mg of MPA given IM each week with 200 mg of CPA given IM ev ery 2 weeks. This reg i men would be used in se vere cases and some catastophic cases. Level 6: A com plete sup pres sion of an dro gens and sex drive would be sought by giv ing CPA 200 to 400 mg IM weekly or pro vid ing a luteinizing hor monere leas ing hor mone (LHRH) ag o nist. This reg i men would be used for some se vere cases of paraphilia and would be the treatment of choice in cat astrophic cases. The aims of treat ment us ing this al go rithm would be the suppres sion of de vi ant sex ual fan ta sies, urges, and be hav iours, with a mi nor im pact on sex ual drive at Levels 2 and 3. Suppression of de vi ant sex ual fan ta sies, urges, and behaviour, with a mod er ate re duc tion in sex ual drive, would be seen at Levels 3 and 4, but this would be dose-dependent. Sup pres sion of de vi ant sex ual fan ta sies, urges, and be hav iour, and a se vere re duc tion of sex ual drive (de pend ing on the dose of med i ca tion) would oc cur at Levels 4 and 5. A com plete or near-complete sup pres sion of sex ual drive would be seen at Level 6. In gen eral, the aims of phar ma co log i cal treat ments would be to sup press de vi ant sex ual fan ta sies, to sup press de vi ant sexual urges and be hav iour, and to re duce the risk of re cid i vism and further victimization. With regard to nonparaphilic hypersexuality (NPH), a mild, mod er ate, and se vere clas si fica tion would ap ply fol low ing the out line in DSM-III. Pharmacological Treatment There are 3 main cat e go ries of phar ma co log i cal in ter ven tion in the paraphilias, and to a cer tain de gree, they could also be used for the treat ment of nonparaphilic hypersexuality. These phar ma co log i cal treat ments are (24):
The spe cific se ro to nin reuptake in hib i tors (SSRIs) The antiandrogens and hormonal treatments The LHRH agonists

most com monly used phar ma co log i cal agents for the treatment of the paraphilias and nonparaphilic hypersexuality. Kafka re ported on 4 pa tients treated for NPH with fluoxetine hydrochloride (30). Significant reductions in sexual drive were observed. He also reported on 3 cases of paraphilia treated with fluoxetine hydrochloride, where considerable clin i cal im prove ment was ob served (30). Kafka and Prentky completed an open-label outpatient study on one group of men with paraphilia and an other group suf fer ing from NPH. Both groups were treated over a 12-week pe riod with a mean dose of 30 mg fluoxetine hydrochloride daily. Clinical improvement in all cases was noted (31). Stein and oth ers reported a failure of treat ment of sex ual disor ders with fluoxetine hydrochloride (32). Coleman and others com pleted a study of 13 men with paraphilia treated with fluoxetine hy dro chlo ride and re ported im prove ment in all aspects of de vi ant sex ual be hav iour but, spe cif i cally, a re duction in de vi ant sex ual fan ta sies, urges, and be hav iours (33). Kafka re ported on an open-label clin i cal trial of men suf fering from paraphilia and NPH us ing sertraline (34). The subjects showed a significant reduction in deviant sex ual fan ta sies, urges, mas tur ba tion, and de vi ant and nondeviant sex ual be hav iour. The clin i cal re sponse rate was 50%. The treat ment nonresponders were of fered fluoxetine hy dro chlo ride, and about 60% of this group showed some clin i cal improve ment. The mean dos age of sertraline in Kafkas study was 100 mg daily, and for fluoxetine hy dro chlo ride it was 51.1 mg daily. The mean duration of treatment was 30.5 weeks (SD 16.8 weeks). Brad ford and oth ers re ported on a 12-week open-label dose study of pedophilia treated with sertraline (35). There were 20 sub jects in the study. Two sub jects dropped out. The mean ef fec tive dos age of sertraline was 131 mg daily. None of the patients dis con tin ued the sertraline due to in ad e quate treat ment re sponse. The study looked at var i ous sex ual be hav iours, in clud ing sex ual arousal pat terns. All of the de vi ant sex ual behaviours were reduced by the sertraline and, in addition, het ero sex ual in ter course showed a slight in crease over the course of the study. This indicated some improvement in normophilic behaviour. Physiological measures of sexual arousal showed deviant arousal was reduced, while at the s a m e t i m e , c o m p a r a t i v e lev e l s of normophilic arousalarousal to con sent ing sex with adultswas maintained or in fact in creased. Greenberg and oth ers treated a variety of paraphilias using 3 different SSRIs, specifically sertraline, fluoxetine, and fluvoxamine (36). The fi nal sam ple (n = 58) showed that the 3 SSRIs were equal in their ef fec tiveness in re duc ing de vi ant sex ual fan ta sies, urges, and be hav iour. The principle ef fect was on de vi ant sex ual fan ta sies (36). In a sim i lar study, Greenberg and oth ers looked at a sample ( = 95) of paraphilic men treated with SSRIs com pared n with a control group ( n = 104) who received only

The SSRIs The SSRIs have long been doc u mented as caus ing a re duc tion in sex ual de sire. They have also been an im por tant ad vance in the treat ment of the paraphilias be cause they are well-known to the av er age psy chi a trist (15,25). De creasing brain 5-HT in an i mals re sulted in sex ual drive in creases as mea sured by increased mounting behaviour. In contrast, increasing brain levels of 5-HT reduced sex ual drive and sex ual behaviour. There fore drugs that in crease 5-HT lev els in the brain have been used to treat paraphilias (15, 25). Starting in 1990, treatment suc cesses for var i ous paraphilias, such as ex hi bi tionism, us ing fluoxetine hy dro chlo ride and sertraline, have been reported (2536). Fluoxetine and sertraline have been the

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cognitive-behavioural treat ment (25). Over the initial 12-week pe riod of treat ment, the fre quency and se ver ity of sexually de vi ant fan ta sies and urges were sig nif i cantly reduced in the SSRI-treated group com pared with the con trol group. These stud ies pro vide ev i dence that SSRIs re duce deviant sexual fantasies, urges, and behaviour. This would make them the drug of choice in the treat ment of paraphilias as well as nonparaphilic hypersexuality. The num ber of studies com pleted to date is still small, how ever, and no dou ble blind stud ies have been re ported. Antiandrogens and Hor monal Agents The initial hormonal treatment for the paraphilias used estrogens. The effectiveness of these treatments, however, was re duced be cause of their var i ous side ef fects, spe cif i cally nau sea, vom it ing, weight gain, and feminization (3741). Medroxyprogesterone acetate (Provera) has been the most com mon form of phar ma co log i cal treat ment for sex ual de vi ation in the US. This is partly due to stud ies started at Johns Hopkins, but has also been dic tated by the lack of al ter na tives such as CPA. Sev eral clin i cal stud ies have been com pleted (42-58). MPA is a progestagen and has a mo tive ac tion through the induc tion of tes tos ter one reductase in the liver, thereby de creasing cir cu lat ing lev els of tes tos ter one. In ad di tion, its ac tion as a progestagen blocks the se cre tion of the gon ado tro pins (FSH and LH), al though the mech a nism of ac tion is not fully un derstood (15). Studies have shown that it does not com pete with androgens at the androgen receptor level and therefore by def i ni tion is not a true antiandrogen (15). MPA can be given both orally or IM. A num ber of side ef fects have been de scribed, in clud ing weight gain, de creased sperm pro duc tion, a hyperinsulinic re sponse to a glu cose load, and the po ten tial to ag gra vate or pre cip i tate di a be tes mellitus, head ache, deep vein thrombosis, hot flashes, nau sea or vomiting, and feminization. Clin i cal stud ies show that MPA has a sig nif icant im pact on de vi ant sex ual fan ta sies and de vi ant sex ual urges and be hav iour. MPA has been used pri mar ily in open clinical tri als and most com monly is given IM at a dos age level of 300 to 400 mg weekly as part of an ini tial treat ment, with the re duc tion to 100 mg weekly as part of a main te nance pro gram. MPA can be given orally in dos ages rang ing from 50 to 300 mg daily (15, 24). Two open clin i cal stud ies of note were com pleted in 1981. In the first, Berlin and Mienecke treated 20 paraphilic men (42). They showed that MPA was an ef fec tive treat ment in re duc ing de vi ant sex ual fan ta sies and urges. At the same time, they ob served that there was a significant relapse rate if treat ment were dis con tin ued. The dos age of MPA was 200 to 400 mg IM given weekly. In the sec ond study, Gagne treated 48 pa tients (45) and re ported effects similar to those of Berlin and Mienecke. He also

extensively documented various side effects, as outlined above. Wincze and oth ers com pleted a dou ble-blind study on 3 pedophiles using MPA (58). They noted that sexual arousal, as measured by penile tumescence in a laboratory setting, showed significant reduction in response to erotic stimuli. Self-reported arousal out side of the lab o ra tory setting, however, was unreliable and inconsistent. Nocturnal penile tu mes cence was also mea sured and was re duced in all cases with ac tive treat ment. Meyer and oth ers com pleted a study of 40 men treated with both MPA and group psy chother apy (49). The MPA was given at a dosage of 400 mg weekly by IM in jec tions and the du ra tion of treat ment ranged from 6 months to 12 years. They in cluded a con trol group of treat ment re fus ers who re ceived only group psy cho ther apy over the same pe riod. This study also as sessed treat ment out come. The MPA-treated group had an 18% re cid i vism rate while the treat ment-refuser group had a 35% re cid i vism rate. Gottesman and Schu bert used a low dos age of MPA (60 mg daily) given orally for a pe riod of 15 months in an open-label trial in volv ing 7 sub jects (46). They re ported a sig nif i cant reduc tion in de vi ant sex ual fan ta sies and pos i tive treat ment out come in all of these pa tients. The sig nif i cant fea ture of this study is that it is the only one to ex am ine sys tem at i cally the ef fects of orally ad min is tered MPA. Cyproterone ac e tate is a true antiandrogen as well as hav ing progestinic and antigonadotropic ef fects (15). CPA is by far the most ex ten sively stud ied antiandrogen in terms of its effects as a treat ment for sex ual de vi a tion (15). It was orig i nally used in Ger many in the mid-1960s and since then has been used ex ten sively in var i ous parts of the world (5971; and Ortmann J, 1984, un pub lished ob ser va tions). As a true antiandrogen, CPA is ac tive at an dro gen re cep tors through out the body. It blocks the intracellular mo lec u lar recep tors. The block of an dro gen re cep tors de creases all types of sex ual be hav iour, in clud ing sex ual fan ta sies, de vi ant sex ual be hav iour, mas tur ba tion, and sexual intercourse, and it also has an impact on erections. CPA also has strong progestational ac tiv ity, re duc ing the lev els of FSH and LH. It is the acetate radical that gives it the progestinic effect. Cyproterone with out t h e a c e t a t e rad i cal has no antigonadotropic ef fects. CPA is a com pet i tive in hib i tor of testosterone and dihydrotestosterone at an dro gen re cep tors through out the body (15,24). The first clin i cal stud ies us ing CPA were con ducted in Germany (66,67). In 1971, Laschet and Laschet re ported on more than 100 sex u ally de vi ant men who were treated with CPA. They were mostly ex hi bi tion ists and pedophiles, as well as sex ual sa dists. About 50% of the sub jects were also sex ual of fend ers. This was an open-label clin i cal trial with a treat ment du ra tion of 6 months to 4 years (67). In 80% of cases, CPA

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given orally at 100 mg daily and sig nif i cantly re duced sex ual drive, erec tions, and or gasms. CPA was also ad min is tered IM at levels of 300 mg every second week. With this ap proach, 20% of ex hi bi tion ists had a com plete elim i na tion of all de vi ant sex ual be hav iour and, in some cases, these be haviours did not re turn even af ter the treat ment was dis con tin ued. Side effects of weight gain, depression, and feminization were noted. Laschet and Laschet re ported on a sim i lar study on 300 men treated for up to 8 years with ex cel lent treat ment out come (66). Sev eral other stud ies have since then been completed, all of which show that CPA is gen er ally an ef fec tive treat ment for sex ual de vi a tion. This au thor com pleted 2 stud ies on CPA, one a dou ble-blind study and the other an examination of the sexual arousal patterns of pedophiles (59,60). The dou ble-blind cross over study used 19 sub jects, all of whom met DSM-III-R cri te ria for pedophilia. This sample also in cluded sex ual of fend ers, prin ci pally with high pretreatment re cidivism rates and a mean of 2.5 previ ous con vic tions for sex ual of fences per sub ject. CPA was ad minis tered orally in 3-month ac tive-treatment phases al ter nat ing with 3-month pla cebo phases. There was a re duc tion in sex ual arousal re sponses by ac tive drug treat ment that did not quite reach statistical sig nif i cance. Self-reported urges of sex ual arousal were all reduced, as was psychopathology as mea sured by var i ous writ ing styles. Other mea sures of sex ual behav iour, in clud ing sexual fan ta sies and mas tur ba tion, were all sig nif i cantly re duced by CPA. In the study of CPA ef fects on the sex ual arousal pat terns of pedophiles, it was noted that de vi ant sex ual arousal was af fected differ ently from normophilic arousal in the same sub jects. This dif fer en tial effect on sex ual arousal is a very im por tant clin i cal ob ser va tion that re quires fur ther re search. LHRH Ag o nists Luteinizing hor monere leas ing hor mone agonists have also been used to treat paraphilias. They have the spe cific treatment ef fect of over stim u lat ing the hy po thal a mus. There is ini tially an in crease in GRH se cre tion and then a re duc tion to al most zero. Con se quently, there is no go nad o tro pin se cretion and the cir cu lat ing lev els of T and DHT drop to cas tra tion lev els (15, 24). The LHRH agonists are given IM and have a pro longed ac tion. They were first flagged as po ten tial treat ment by this au thor in 1985 (14). There have been lim ited clinical studies on the use of LHRH agonists (7275). A study by Rous seau and oth ers in 1998 doc u mented changes in sexual behaviour in prostate cancer patients treated with flutamide as well as an LHRH ag o nist. There was a sig nif icant im pact on sex ual func tion ing com pared with a pre treatment phase. Thibaut and oth ers re ported on the treat ment of 6 men who suf fered from a paraphilia, prin ci pally pedophilia. Two of them had pre vi ously been treated with oral CPA at dos ages rang ing from 150 to 300 mg daily, but they did not ap pear to respond; how ever, their com pliance was in

ques tion. The pa tients were treated with triptorelin 3.75 mg IM monthly concurrently with CPA 200 mg daily for 5 months. In 5 out of the 6 pa tients, a marked de crease in sex ual be hav iour was noted (75). A very im por tant study was published by Rosler and Witztum (73). This was an un con trolled open study of 30 men with a mean age of 32 years who were treated with triptorelin. They re ceived monthly in jec tions of 3.75 mg of triptorelin and sup port ive psy cho ther apy for a fol low-up pe riod of be tween 8 and 42 months. Treat ment outcome was measured by questionnaires. All of these men showed a de crease in de vi ant sex ual fan ta sies and de vi ant sexual urges. Plasma testosterone levels fell to castration levels. Conclusion There are sev eral phar ma co log i cal treat ments avail able for the treat ment of the paraphilias and nonparaphilic hypersexuality. These treat ments are based on es tab lished neurobiological prin ci ples. Fu ture re search on se ro to nin recep tors and polypeptidic neurotransmitters is likely to lead to new phar ma co log i cal treat ments. Hypersexuality should be in cluded as a sep a rate sex ual dys func tion (sex ual de sire disor der) in DSM-V. References
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RsumLa neu ro bio lo gie, la neu ro phar ma colo gie et le traite ment phar ma colo gique des paraphil ies et du com por te ment sexuel com pul sif
Ces dernires annes, on constate un intrt accru pour le traitement des troubles sexuels. Les troubles sexuels sont classs dans le Manuel diagnostique et statistique des troubles mentaux (DSM IV) comme tant les dysfonctions sexuelles, les paraphilies et les troubles de lidentit sexuelle. Les dysfonctions sexuelles sont non dviantes ou non paraphiliques. Les dysfonctions sexuelles devraient inclure le trouble du dsir sexuel hyperactif , dans la catgorie des troubles du dsir sexuel. En outre, on devrait spcifier si les paraphilies sont avec hypersexualit ou sans hypersexualit . On ne comprend pas encore compltement la neurobiologie des troubles sexuels, bien que la neuroanatomie fonctionnelle et la recherche neuropharmacologique aient expos les neurotransmetteurs, les rcepteurs et les hormones responsables du dsir sexuel. Les tudes indiquent que divers agents pharmacologiques, y compris les inhibiteurs de recaptage de la srotonine (IRS), les antiandrognes, les agonistes LHRH et dautres rduisent le dsir sexuel. Un algorithme pour lutilisation de ces mdicaments dans letraitement des paraphilies et de lhypersexualit non paraphilique est prsent. Les modes daction, les dosages, les cibles du trai ement et les mthodes usuelles t de prescription de ces agents sont recenss dans cet article. On y prsente aussi certaines orientations futures de la recherche en traitement pharmacologique.

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