The drug Degarelix shows potential in the treatment of pedophilic disorder

0
160

A drug that lowers levels of the male hormone testosterone in the body reduces the risk of men with pedophilic disorder sexually abusing children, a study from Karolinska Institutet published today in the journal JAMA Psychiatry shows.

About one in ten girls and one in twenty boys are sexually abused, primarily at the hands of men with pedophilic disorder.

Despite law enforcement, technical and political initiatives, the rate of child sexual abuse continues to rise, above all that committed online. There is therefore a pressing need for effective and scientifically proven treatments for people at risk of committing sexual offence.

Researchers at Karolinska Institutet and Gothenburg University in Sweden have now evaluated the effect of a drug called degarelix, which is approved for the treatment of prostate cancer.

The drug acts by switching off the production of testosterone, reducing within a matter of hours the levels of the hormone in the body, and is administered by injection every three months.

The double-blinded study included 52 men with pedophilic disorder in Sweden, who were randomly assigned to a degarelix or a placebo group.

Treatment with degarelix was shown to dampen two critical risk factors for committing abuse: high sexual desire and sexual attraction to children. The effects were noticeable within two weeks.

“It’s important to be able to offer a relatively fast-acting treatment, and the patients’ own experiences of the drug were overall positive,” says study leader Christoffer Rahm, chief psychiatrist at Psykiatri Södra Stockholm and researcher at the Department of Clinical Neuroscience, Karolinska Institutet.

Above all, the men described positive effects on their sexuality. Many reported that they felt an inner calm, that thoughts of sex were no longer dominant and that they lost their sexual interest in children. A majority wanted to continue on the drug after the study was over.

“This study is an important step towards an evidence-based treatment for pedophilic disorder,” says Dr Rahm. “We’re now planning a new study to assay the longer term effects of the drug and to compare them with psychotherapy.”

All participation was voluntary and the men were recruited via Preventell, a national helpline initiated by ANOVA, an andrology, sexual medicine and transmedicine clinic at Karolinska University Hospital in Sweden.

The helpline was set up to prevent sexual abuse and violence by fast-tracking people with dangerous or undesired sexuality into specialised treatment.

While some of the participants in the degarelix group developed hot flashes and reactions at the injection site, conclusions about any mental side-effects were hard to draw since many of the participants were already in a depressive state even before the study started. See the scientific article for a full list of effects and adverse reactions.

Funding: The study was financed by the Swedish Society of Medicine, the Söderström-Königska Foundation, the Fredrik and Ingrid Thuring Foundation, the Centre for Psychiatric Research at Karolinska Institutet (Department of Clinical Neuroscience), the Gothenburg Society of Medicine, Skaraborg Hospital research unit, Region Stockholm (ALF funding), and the Swedish Society for Medical Research. Knowledge partner ECPAT Sweden.


Child sexual abuse affects 1 in 5 girls and 1 in 10 boys worldwide.1 It is accompanied by adverse psychosocial outcome across the life span.1,2 Preventive measures have been advocated,3 but to date evidence for interventions has been limited.4,5

The estimated proportion of child sexual offenders who are prosecuted is 1%.1,4 Of those who were prosecuted, up to 95% were first-time offenders6 and half of them had pedophilic disorder,7 defined as recurrent sexual attraction to prepubescent children associated with distress or negative consequences.

Studies have found that not all men with pedophilic disorder commit a sexual offense, but those who do generally report struggling with their sexual urges for 10 years before committing a sexual crime.6,8

Consequently, an opportunity for prevention exists in treating high-risk individuals without prior convictions. Effective treatment could prevent child sexual abuse and reduce psychosocial stress for the individual with pedophilic disorder.

Currently recommended interventions include psychotherapy and antidepressants as well as testosterone-suppressing medications for high-risk individuals.9 Opinions about treatment are vehement. In many countries, an informed consent procedure is required for chemical castration.

However, chemical castration is used as a compulsory legal sentence for child sexual offenders in some jurisdictions in the US, Asia, and Europe but is prohibited in other countries owing to ethical concerns of coercion and uncertain efficacy.10,11

Because they lower testosterone through receptor desensitization, gonadotropin-releasing hormone agonists are considered effective in reducing paraphilic symptoms.12 However, the use of these agonists is limited to supervised correctional settings because of the lack of randomized clinical trials; their metabolic adverse effects; and the initial flare-up of testosterone, which may be associated with increased aggression and libido that require concurrent antiandrogen medication.9

Experience from the Swedish helpline PrevenTell suggests a need for both rapid-acting short-term treatment (eg, in critical phases of the disorder to quickly control sexual impulses or reduce a high degree of struggling) and long-term treatment.

Degarelix acetate is a gonadotropin-releasing hormone antagonist that was approved by the US Food and Drug Administration in 2008 for treating advanced prostate cancer.

Degarelix decreases testosterone to castration levels within 3 days without testosterone flare13; therefore, the drug could serve as a rapid-onset treatment for individuals seeking help in outpatient settings.9,14,15

For individuals without a prior conviction, no validated measures of risk exist. Therefore, the PRIOTAB (Pedophilia at Risk–Investigations of Treatment and Biomarkers) project, of which this present trial is a part, included the construction of a composite score based on previous observational studies of dynamic (ie, potentially changeable over time) risk factors for sexual offense recidivism.

One such risk factor is deviant sexual interest (eg, pedophilic disorder).16 Other factors are sexual preoccupation, impaired self-regulation, and low empathy.16 Because these 4 factors are all possibly mitigated by testosterone suppression, we believed that degarelix could have a risk-reducing effect.17-20

Bearing in mind the challenges associated with conducting a trial in a hard-to-reach population along with the issues of tolerability of previous therapies, we performed ancillary interviews of self-reported experiences of treatment. We regarded using sexually arousing material and measuring participants’ penile responses as too intrusive.

We hypothesized that men with pedophilic disorder who were randomized to receive degarelix compared with placebo would have a substantial reduction in risk of committing child sexual abuse after 2 weeks. Furthermore, we hypothesized that degarelix would be sufficiently tolerated by the participants and thus would be a safe and effective rapid-onset treatment option.

Discussion
In this phase 2 randomized clinical trial, a single dose (240 mg) of degarelix acetate statistically significantly reduced the dynamic risk factor scores for sexual offense with minimal adverse events among help-seeking men with pedophilic disorder, both in the short (2-week) and in the medium (10-week) terms.

The drug was also effective among high-risk participants (Table 3). The rapid onset of degarelix appears to have a crucial advantage compared with earlier medications for paraphilic disorders, which had a 1 to 3 months’ lag in exerting their effects on sexuality.9

The self-reports provided an empirical basis for the patient side of shared decision-making and may facilitate patient-centered care for pedophilic disorder.36 In weighing the benefits and harms of the drug, we found that the participants self-reported a more positive than negative attitude toward treatment, specifically regarding the effects on sexuality.

Thus, participants expressed relief of symptoms for which they sought help, in addition to experiencing the treatment aim of risk reduction. This finding may also be reflected in the reduced risk scores for pedophilic disorder and sexual preoccupation (Table 3).

Only 1 participant was lost to follow-up, and 58% of those randomized to receive degarelix wished to continue treatment (Table 4), which indicates to us a potential role for long-term treatment along with psychosocial support in most participants.

Ultimately, the treatment decision belongs to the physician, who should take into consideration the risk for abuse, patient preferences, and drug benefits and harms. In view of the participant wishes and effects expressed in the self-reports, we believe degarelix should be considered for help-seeking individuals with pedophilic disorder.

The maintained motivation among participants for such potent therapy and the low EQ-VAS ratings reflect the severity and associated distress of the condition. However, a modest effect on quality of life associated with treating the core symptoms of pedophilic disorder indicates the need to better understand the reasons for the struggles experienced by those with this condition.

Future research needs to address the effects and predictable long-term adverse effects of hormone deficiency as well as the sometimes excessive effects on sexuality, as reported by the participants (Table 4; eFigures 3 and 4 in Supplement 2).

Incremental add-back therapy of hormones could be considered in this regard.37 Given that 2 participants reported severe adverse events of suicidal ideation, vigilance for the risk of exacerbating suicidality in predisposed individuals is warranted.

Although depressive symptoms sometimes are manifestations of hypogonadism, a 12-month open-label trial of degarelix in patients with prostate cancer (n = 409) reported depression as an adverse event in only 1 individual.38

The high baseline prevalence of depression in the present trial (35%) may indicate an enriched sample of individuals susceptible to depressive deterioration from gonadotropin-releasing hormone antagonist treatment.

However, most participants may not be susceptible. In post hoc comparisons of the treatment groups over the study period (eTable 5 in Supplement 2), no differences in change of Montgomery-Åsberg Depression Rating Scale self-rating (MADRS-S) version scores were observed in depression severity, incidence of dysthymia, depression, or suicide risk.

Although uncertainty from insufficient power and post hoc analysis remained, most estimates within the CI of the difference in MADRS-S scores at 10 weeks between groups indicated a decrease (10 weeks: −4 [95% CI, −12 to 4]) among participants who were randomized to receive degarelix. When including the MADRS-S scores of all participants, we found that the difference at 10 weeks increased (data not shown).

In addition, future studies need to identify the risk factors that benefit from other kinds of intervention, such as psychotherapy. The impaired self-regulation and low empathy domains in the present trial highlighted the residual risk not amenable to degarelix treatment.

Abnormal results in these measures in a clinical setting are usually associated with attention-deficit/hyperactivity disorder or autistic features. We think that if these conditions are adequately addressed, the potential exists to both improve health and reduce the risk for committing child sexual offense.

Conclusions

Treatment with degarelix appeared to decrease the scores of risk factors for child sexual abuse after 2 weeks of administration for help-seeking men with pedophilic disorder.


Source:
Karolinska Institute

References
1. Collin-Vézina D , Daigneault I , Hébert M . Lessons learned from child sexual abuse research: prevalence, outcomes, and preventive strategies. Child Adolesc Psychiatry Ment Health. 2013;7(1):22. doi:10.1186/1753-2000-7-22
2. Stoltenborgh M , van Ijzendoorn MH , Euser EM , Bakermans-Kranenburg MJ . A global perspective on child sexual abuse: meta-analysis of prevalence around the world. Child Maltreat. 2011;16(2):79-101. doi:10.1177/1077559511403920
3. Walsh K , Zwi K , Woolfenden S , Shlonsky A . School-based education programmes for the prevention of child sexual abuse. Cochrane Database Syst Rev. 2015;(4):CD004380. doi:10.1002/14651858.CD004380.pub3
4. Khan O , Ferriter M , Huband N , Powney MJ , Dennis JA , Duggan C . Pharmacological interventions for those who have sexually offended or are at risk of offending. Cochrane Database of Systematic Reviews. Intervention version published February 18, 2015. Accessed September 9, 2019.
5. Långström N , Enebrink P , Laurén E-M , Lindblom J , Werkö S , Hanson RK . Preventing sexual abusers of children from reoffending: systematic review of medical and psychological interventions. BMJ. 2013;347:f4630. doi:10.1136/bmj.f4630
6. Knack N , Winder B , Murphy L , Fedoroff JP . Primary and secondary prevention of child sexual abuse. Int Rev Psychiatry. 2019;31(2):181-194. doi:10.1080/09540261.2018.1541872
7. Seto MC . Pedophilia and Sexual Offending Against Children: Theory, Assessment, and Intervention. 2nd ed. American Psychological Association; 2018.
8. Beier KM , Ahlers CJ , Goecker D , et al. Can pedophiles be reached for primary prevention of child sexual abuse? First results of the Berlin Prevention Project Dunkelfeld (PPD). J Forensic Psychiatry Psychol. 2009;20(6):851-867. doi:10.1080/14789940903174188
9. Thibaut F , De La Barra F , Gordon H , Cosyns P , Bradford JM ; WFSBP Task Force on Sexual Disorders. The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of paraphilias. World J Biol Psychiatry. 2010;11(4):604-655. doi:10.3109/15622971003671628
10. Lee JY , Cho KS . Chemical castration for sexual offenders: physicians’ views. J Korean Med Sci. 2013;28(2):171-172. doi:10.3346/jkms.2013.28.2.171
11. Turner D , Petermann J , Harrison K , Krueger R , Briken P . Pharmacological treatment of patients with paraphilic disorders and risk of sexual offending: an international perspective. World J Biol Psychiatry. 2019;20(8):616-625. doi:10.1080/15622975.2017.1395069
12. Turner D , Briken P . Treatment of paraphilic disorders in sexual offenders or men with a risk of sexual offending with luteinizing hormone-releasing hormone agonists: an updated systematic review. J Sex Med. 2018;15(1):77-93. doi:10.1016/j.jsxm.2017.11.013
13. van Poppel H , Nilsson S . Testosterone surge: rationale for gonadotropin-releasing hormone blockers? Urology. 2008;71(6):1001-1006. doi:10.1016/j.urology.2007.12.070
14. Rösler A , Witztum E . Treatment of men with paraphilia with a long-acting analogue of gonadotropin-releasing hormone. N Engl J Med. 1998;338(7):416-422. doi:10.1056/NEJM199802123380702
15. Sorrentino R . Degarelix: an antagonist to GnRH–theoretical and treatment considerations in paraphilia. J Sex Med. 2012;9(1):327-329. doi:10.1111/j.1743-6109.2011.02540.x
16. Hanson RK , Morton-Bourgon KE . The characteristics of persistent sexual offenders: a meta-analysis of recidivism studies. J Consult Clin Psychol. 2005;73(6):1154-1163. doi:10.1037/0022-006X.73.6.1154
17. Jordan K , Fromberger P , Stolpmann G , Müller JL . The role of testosterone in sexuality and paraphilia–a neurobiological approach. Part I: testosterone and sexuality. J Sex Med. 2011;8(11):2993-3007. doi:10.1111/j.1743-6109.2011.02394.x
18. van Honk J , Schutter DJ , Bos PA , Kruijt A-W , Lentjes EG , Baron-Cohen S . Testosterone administration impairs cognitive empathy in women depending on second-to-fourth digit ratio. Proc Natl Acad Sci U S A. 2011;108(8):3448-3452. doi:10.1073/pnas.1011891108
19. Aluja A , García LF , Martí-Guiu M , et al. Interactions among impulsiveness, testosterone, sex hormone binding globulin and androgen receptor gene CAG repeat length. Physiol Behav. 2015;147:91-96. doi:10.1016/j.physbeh.2015.04.022
20. Jordan K , Fromberger P , Stolpmann G , Müller JL . The role of testosterone in sexuality and paraphilia–a neurobiological approach. Part II: testosterone and paraphilia. J Sex Med. 2011;8(11):3008-3029. doi:10.1111/j.1743-6109.2011.02393.x
21. Spector IP , Carey MP , Steinberg L . The sexual desire inventory: development, factor structure, and evidence of reliability. J Sex Marital Ther. 1996;22(3):175-190. doi:10.1080/00926239608414655
22. Reid RC , Garos S , Carpenter BN . Reliability, validity, and psychometric development of the Hypersexual Behavior Inventory in an outpatient sample of men. Sex Addict Compulsivity. 2011;18(1):30-51. doi:10.1080/10720162.2011.555709
23. Conners CK . Conners’ Continuous Performance Test II (CPT II V.5). Multi-Health Systems, Inc; 2000.
24. Eriksson JM , Andersen LM , Bejerot S . RAADS-14 Screen: validity of a screening tool for autism spectrum disorder in an adult psychiatric population. Mol Autism. 2013;4(1):49. doi:10.1186/2040-2392-4-49
25. Baron-Cohen S , Wheelwright S , Hill J , Raste Y , Plumb I . The “Reading the Mind in the Eyes” Test revised version: a study with normal adults, and adults with Asperger syndrome or high-functioning autism. J Child Psychol Psychiatry. 2001;42(2):241-251. doi:10.1111/1469-7610.00715Pub
26. Sheehan D , Lecrubier YMINI . Mini Internationell Neuropsykiatrisk Intervju 6.0.0. Swedish version. February 2009. Accessed December 13, 2018. http://www.viss.nu/Global/Blanketter/MINI_vers_6.pdf
27. EuroQol Group. EuroQol–a new facility for the measurement of health-related quality of life. Health Policy Amst Neth. 1990;16(3):199-208. doi:10.1016/0168-8510(90)90421-9
28. Burström K , Sun S , Gerdtham U-G , et al. Swedish experience-based value sets for EQ-5D health states. Qual Life Res. 2014;23(2):431-442. doi:10.1007/s11136-013-0496-4PubMed
29. Wood KL . The Medical Dictionary for Drug Regulatory Affairs (MEDDRA) project. Pharmacoepidemiol Drug Saf. 1994;3(1):7-13. doi:10.1002/pds.2630030105
30. Sandelowski M . Whatever happened to qualitative description? Res Nurs Health. 2000;23(4):334-340. doi:10.1002/1098-240X(200008)23:4<334::AID-NUR9>3.0.CO;2-G
31. Pocock SJ . Group sequential methods in the design and analysis of clinical trials. Biometrika. 1977;64(2):191-199. doi:10.1093/biomet/64.2.191Google ScholarCrossref
32. Svanborg P , Asberg M . A comparison between the Beck Depression Inventory (BDI) and the self-rating version of the Montgomery Asberg Depression Rating Scale (MADRS). J Affect Disord. 2001;64(2-3):203-216. doi:10.1016/S0165-0327(00)00242-1
33. Bergman H , Källmén H . Alcohol use among Swedes and a psychometric evaluation of the alcohol use disorders identification test. Alcohol. 2002;37(3):245-251. doi:10.1093/alcalc/37.3.245
34. Nesvåg R , Lange EH , Faerden A , et al. The use of screening instruments for detecting alcohol and other drug use disorders in first-episode psychosis. Psychiatry Res. 2010;177(1-2):228-234. doi:10.1016/j.psychres.2010.01.007
35. Kessler RC , Adler L , Ames M , et al. The World Health Organization Adult ADHD Self-Report Scale (ASRS): a short screening scale for use in the general population. Psychol Med. 2005;35(2):245-256. doi:10.1017/S0033291704002892
36. Barry MJ , Edgman-Levitan S . Shared decision making–pinnacle of patient-centered care. N Engl J Med. 2012;366(9):780-781. doi:10.1056/NEJMp1109283
37. Carr BR , Stewart EA , Archer DF , et al. Elagolix alone or with add-back therapy in women with heavy menstrual bleeding and uterine leiomyomas: a randomized controlled Trial. Obstet Gynecol. 2018;132(5):1252-1264. doi:10.1097/AOG.0000000000002933
38. Klotz L , Boccon-Gibod L , Shore ND , et al. The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer. BJU Int. 2008;102(11):1531-1538. doi:10.1111/j.1464-410X.2008.08183.x

LEAVE A REPLY

Please enter your comment!
Please enter your name here

Questo sito usa Akismet per ridurre lo spam. Scopri come i tuoi dati vengono elaborati.