Paraphilias: A double-blind crossover comparison of clomipramine versus desipramine

Archives o f Sexual Behavior, Vol. 21, No. 6, 1992

Paraphilias: A Double-Blind Crossover Comparison of Clomipramine Versus Desipramine Markus J. P. Kruesi, M.D., 1,4 Stuart Fine, M.B., 2 Lois Valladares, M.S., 3 Robert A. Phillips, Jr., Ph.D., 3 and Judith L. Rapoport, M.D. 1

A relationship has been suggested between cfinical presentation ofparaphilias and obsessive-compulsive disorder (OCD) with respect to the unwanted repetitive nature and insight into the irrationality of the paraphiliac behavior. This has led to speculation that paraphiliac disorders might belong to an "obsessive compulsive spectrum." To address this issue, and because of the striking selective benefit o f serotonin reuptake blocking antidepressants (such as clomipramine) in the treatment of OCD, 15 paraphiliacs entered a doubleblind crossover comparison of clomipramine vs. desipramine preceded by a 2-week single-blind placebo period. Four subjects responded to placebo and were dropped fi'om the study. Three others failed to complete the study. Although the study is limited by the small number of patients and the heterogeneity of the paraphilias, the observed benefit from both tricyclics (over the initial placebo) encourages further study. For the 8 subjects completing the protocol, there was no preferential response to the more specific serotonin reuptake inhibitor suggesting a difference in underlying pathophysiology between paraphilia and OCD. KEY WORDS: paraphilia; obsessive-compulsive disorder; clomipramine; desipramine; affective disorder.

1Child Psychiatry Branch, National Institute of Mental Health, Building 10, Room 6N240, 9000 Rockville Pike, Bethesda, Maryland 20892. 2Division of Child Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada. 3Fogel Foundation and Human Sexuality Institute, Washington, DC. 4To whom correspondence should be addressed. 587

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INTRODUCTION Paraphilias, recurrent intense sexual urges and fantasies in response to objects or situations that are not part of normative arousal patterns, are described as "compulsions" both by therapists as well as some legal sources (e.g., the New Jersey State Sex Offender Statute; Knoop, 1984). A variety of sources have suggested a relationship between obsessive-compulsive disorder (OCD) and paraphilias. The 18th century French psychiatrist, Magnan, considered compulsive sexual deviations diagnostically similar to OCD (Magnan, 1886, 1887). More recently, Jenike (1989) speculated that a variety of unwanted repetitive behaviors including compulsive sexual behavior may be part of a spectrum of obsessive-compulsive disorders. Some weak support for this idea already existed. Paraphilias have been reported as comorbid with OCD in a study in which 3 of 25 males with severe OCD were also pedophiles and another one was a transvestite (Monteiro et aL, 1987). In an NIMH family study of childhood and adolescent OCD, 3 of 43 fathers reported cross-dressing behavior (M. C. Lenane, personal communication). In open trials, fluoxetine, a serotonin uptake inhibitor efficacious for OCD, and other antidepressant agents affecting serotonergic function, have been reported to decrease symptoms in sex offenders (Kafka, 1991). Obsessive-compulsive disorder responds with striking selectivity to serotonin reuptake inhibitors, but not to other antidepressants and a "serotonin hypothesis" of OCD has been raised on this basis (for reviews see Leonard and Rapoport, 1989; Insel, 1990). Because of this unique pharmacological sensitivity, a clomipramine (CMI)-desipramine (DMI) doubleblind comparison was undertaken for a group of male paraphiliacs to see if a parallel selective response also held for this group. Desipramine, a tricyclic with relative noradrenergic potency and only weak serotonergic effects, was used to control for the possible sexual side effects of antidepressant compounds (Monteiro et al., 1987), to ensure adequate blinding, and to test for serotonergic selectivity.

METHODS

Subjects Patients meeting DSM-III-R criteria for paraphilia were referred by therapists and/or area patient-support groups, because their paraphiliac symptoms were also felt to have a "compulsive" nature. All patients had

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one or more of the DSM-III-R paraphilia and/or compulsive masturbation. Exclusion criteria were OCD (any "compulsions" other than paraphilia or compulsive masturbation), psychosis, need for other medications, and/or other medical or neurological illnesses. Procedure

Informed consent for this NIMH IRB-approved treatment study was obtained, and patients were interviewed with the Schedule for Affective Disorders and Schizophrenia, Lifetime Version (SADS-L; Endicott and Spitzer, 1978), which was scored by a rater blind to patient status. Information about paraphilic behavior was obtained by a semistructured questionnaire (details available on request). Depression and anxiety were rated at baseline and at the end of each treatment phase with the NIMH Global Assessment Scale (Murphy et al., 1982). Obsessional features were rated with the Leyton Obsessional Inventory (Cooper, 1970) at the same intervals. Patients first entered a 2-week single-blind placebo phase. Those subjects whose paraphiliac behavior improved by 50% or more on placebo were dropped from the study. Remaining patients continued the double-blind crossover treatment phases of desipramine and clomipramine for 5 weeks each. Clomipramine, desipramine, and placebo, in identical capsules, were started at 25 to 50 mg/day and increased until symptoms decreased, side effects became limiting, or the 250 mg/day limit was reached. At baseline, after placebo, and at Week 5 of each active drug phase, the paraphiliac behavior was rated by semistructured interview. Sexual side effects of the active medication phases were assessed from clinician notes and the Sexual Self-Efficacy Scale-Erectile Functioning (Fichten et al., 1988). Two tailed paired t tests were used to evaluate the differences in overall paraphiliac severity, obsessional symptoms, anxiety, and depression between week 5 of clomipramine treatment and Week 5 of desipramine treatment.

RESULTS Fifteen male subjects age 29-52 (x = 31 + 9) years entered the study. The particular paraphilias that were primary symptoms were exhibitionism (4), transvestism (3), obscene phone calls (4), fetishism (2), and compulsive masturbation (2). Ten of 15 (2/3) met criteria for more than one paraphilia. Total number of individuals meeting criteria for given paraphilias were frotteurism (3), voyerism (2), zoophilia (1), klismaphilia (1), exhibitionism (4), transvestism (4), pedophilia (2), telephone scatologica (7), sexual sadism

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(1), and compulsive masturbation (4). All had had previous treatment: psychotherapy (15), medroxyprogresterone acetate (3), and other pharmacologic treatment (4). By SADS-L (Endicott and Spitzer, 1978), 9 of 15 (60%) met RDC criteria for an affective disorder unipolar depression (5) and minor depression (4); 8 of 15 (53%) had substance abuse: alcoholism (8), drug abuse (2); 6 of 15 (40%) had anxiety disorders: panic (2), generalized anxiety disorder (6); antisocial personality disorder (4); 3 (20%) had no psychiatric diagnosis other than their paraphilia. Four were placebo responders (mean response 79% decrease on the paraphiliac severity scale) and were dropped from further study. Three additional subjects failed to complete both active drug phases: one left the country during the second active drug phase, one repeatedly missed appointments, and the third had a panic attack following the first dose of active medication and refused to continue the study. The 8 subjects completing the study received a mean maximal daily dose of 162.5 mg (range 75-250 rag) of clomipramine. For desipramine the mean maximal dose was 212.5 mg (range 100-250 mg). Of these 8 subjects, 4 were clinically depressed. Behavioral ratings are shown in Table I. Both drugs decreased the severity of paraphiliac symptoms relative to baseline and placebo (post-hoc paired t tests: CMI vs. placebo, t(7) = 4.19, p _< 0.005, DMI vs. placebo t(7) = 5.05, p _< 0.002); however clomipramine and desipramine were not statistically different from each other as seen in Table I. At least transient disturbance in sexual functioning was common with both active compounds, although there was a tendency for more problems on CMI vs. DMI. Specific side effects noted during the 5-week trial with each drug were delayed ejaculation (5 of 8 on clomipramine, 1 of 8 on desipramine); erectile dysfunction (5 of 8 on clomipramine, 3 of 8 on desipramine); pain on ejaculation (1 of 8 on clomipramine and 1 of 8 with desipramine). There was no apparent relation between sexual side effects and improvement on antidepressant. For example, sexual function often returned or improved while on active drug without worsening of paraphiliac behavior. Six to 9 months later, three of the eight remain on tricyclics. Two of these patients had exacerbation of paraphiliac behavior when the drug was discontinued or decreased and so resumed.

DISCUSSION The results do not support the concept of paraphilias as part of an obsessive-compulsive spectrum, as no clear superiority of CMI over DMI

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was seen, Leyton scores were not changed by clomipramine versus placebo, and placebo response was frequent. This is in contrast to OCD and other "spectrum disorders" for which striking superiority of clomipramine over other antidepressants and placebo is seen (Leonard et aL, 1989; Insel, 1990; Swedo et al., 1989; Gordon et al., 1992). Furthermore, placebo response is rare in adults with OCD (Mavissakalian et al., 1990), whereas the 4 of 15 (17%) placebo response rate seen in our subjects is similar to the 25% rate reported in anxiety disorder patients (Coryell and Noyes, 1988; Mavissakalian, 1987, 1988). Additional differences between OCD patients and paraphiliacs were seen in sexual side effects of the drugs. The 5 of 8 patients who had delayed or absent ejaculation on CMI is less than the results of Monteiro et al. (1987) where 16 of 17 OCD men on CMI experienced delayed or absent orgasm on CMI. The benefit of clomipramine and desipramine over placebo for the treatment of paraphilias is intriguing. To the best of our knowledge, this is the first double-blind placebo-controlled antidepressant medication trial in this patient group. However, even this controlled study is limited by the heterogeneity of primary diagnosis and significant comorbidity cautioning that enthusiasm for the results be tempered but not dismissed entirely. Although it would have been ideal to have "pure" paraphilias for comparison of drug effects, the heterogeneity of our sample is more clinically typical. Abel et al. (1988) found that 89.6% of 561 paraphilics had more than one paraphilia diagnosis. Similarly, psychiatric comorbidity is frequently seen in clinical samples of paraphiliacs. For example, Langevin et aL (1988) reported that over half of their clinical sample of sexual sadists also qualify for a diagnosis of alcoholism and 40% have antisocial personality disorder. Given the superiority of both clomipramine and desipramine over placebo, the high lifetime prevalence of anxiety and affective disorders in our sample, as well as the decreases in anxiety and depression ratings that accompanied therapeutic benefit, it appears that antidepressant medications may play a role in the treatment of paraphilias. Further research seems warranted and the results of this trial suggest that controlled comparisons of antidepressants with placebo will be more revealing than comparisons between active compounds.

ACKNOWLEDGMENTS E. Hibbs, Ph.D., performed blind ratings of the SADS on these patients. S. E. Swedo, M.D., offered valuable consultation during rewrites of this manuscript.

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