- Email: [email protected]
MOVEMENT DISORDERS ASSOCIATED WITH FLUVOXAMINE
LETTERS TO THE EDITOR
BUSPIRONE IN ODD
disorders in patients taking Ruoxetine, paroxetine, and sertraline; their pathogenesis has been attributed to serotonin-mediated inhibition of dopaminergic transmission (Lipinski et al., 1989). A serotonergic-dopaminergic interaction is also suggested by the fact that other movement disorders, such as tics or Tourette's disorder, arise or may worsen in patients treated with SSRIs (Delgado et al., 1990; Fennig et al., 1994) or with imipramine and clomipramine. A 14-year-old patient treated with Ruvoxamine is of interest because even though he had previously received no dopamine blockers and had no history of tic-like symptoms, both tics and associated dystonic extrapyramidal symptoms appeared. C.M. was the elder of 2 brothers. Four of his father's brothers had bipolar mood disorders, and his father suffered from panic attacks and OCD. The child had been delivered normally, after an uneventful pregnancy, and his psychomotor development was normal. At nursery school he had some difficulties in social interactions and showed low tolerance to frustration, but no noteworthy mental disorders were reported until the age of 12 years, when he began to have various behavioral problems. He would isolate himself from his schoolmates, refusing group relations, including sports. At home he tended to stay alone, seeing no friends, and showed no interest in the pastimes typical of boys of his age. C.M. began to suffer from insomnia and to behave in an oppositional manner toward his parents, especially his father. His main problems, however, were at school, where his concentration and output both dropped and his relations with schoolmates had become much worse; he often argued with them because they mocked him. From C.M.'s personal history and a psychiatric assessment, a dysthymic disorder was diagnosed, on the basis of DSM-IV, confirmed by a score of 27 on the Children's Depression Inventory. Cognitive assessment showed an IQ of 86 to 96 on the Verbal scale and 78 for Performance. Treatment was started with Ruvoxamine, 100 mg/day. After 4 weeks of therapy only slight improvement was seen in the patient's mood and sleeping pattern. The dosage was therefore raised to 150 mg/day, and after 9 weeks at this level there was a striking change in the tone of his mood, which became hyperthymic, and reactions to his companions improved. At the same time, however, he began to experience various involuntary movements. Some were eyelid and nasal tics, and others involved lateral stretching of the line of the lips and torsion of the neck, like a dystonic movement. The boy was therefore started on haloperidol, 1.5 mg/day, but it had no effect. The involuntary movements stopped only when Ruvoxamine was withdrawn. That the involuntary movements appeared when the Ruvoxamine dosage was increased and stopped when the drug was discontinued indicates a causal relation. The appearance-or worsening-of tics during Ruvoxamine traitment has already
10 the Editor: I noted with disappointment that in the index to volume 37 of the Journal (pp. 1347-1356), there were no references to articles on oppositional defiant disorder (ODD). ODD seems to be increasing in prevalence, at least as it appears in clinical practice. It probably now rates as the second most common disruptive behavioral disorder in childhood. However, despite the prevalence of this disorder and its recalcitrance to treatment, there seems to be a dearth of research into its nature. Treatment of this disorder has proved remarkably frustrating. Parent training, behavioral modification approaches, and a variety of medications have been used with modest but inconsistent results. On the basis of an open-label study by Gross (1995) in which he reported up to a 90% response rate to buspirone, I have been using this medication with encouraging results. While the response rate in my practice is probably more like 65% to 70%, buspirone has proved to be far more effective and reliable than stimulants, mood stabilizers, or selective serotonin reuptake inhibitors. I have been using doses of 60 ± 15 mg q.d. in divided doses. Response appears to be independent of age or weight. Other than a failure to respond, the 2 most significant problems I have encountered with high-dose treatment with buspirone have been the following: (1) a small percentage of children, roughly 10%, experience significant increases in appetite and weight, and (2) in some children there is an unfortunate tendency for the effectiveness to dissipate gradually after 3 to 4 months, apparently the result of enzymatic changes in the liver. While buspirone may not be the ideal medication for treatment of ODD, its pharmacological action may nonetheless provide important clues to the underlying nature of this disorder and lead us to more effective treatments in the future. I would strongly urge any young researcher looking for a fertile field for his/her career to pursue the investigation of this difficult and perplexing disorder. John E. Dunne, M.D. Southlake Professional Group Renton, WA Gross MD (1995), Buspirone in ADHD with ODD (letter). JAm Acad Child Adolesc Psychiatry 34: 1260
MOVEMENT DISORDERS ASSOCIATED WITH FLUVOXAMINE
10 the Editor: Selective serotonin reuptake inhibitors (SSRIs) have become routine tools for the treatment of mood disorders, obsessivecompulsive disorder (OCD), and Tourette's disorder in children and adolescents. Adverse reactions include extrapyramidal
942
J.
AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 38:8, AUGUST 1999
LETTERS TO THE EDITOR
been reported in 2 patients with OCD (Fennig et al., 1994; Delgado et al., 1990). In another case treated with fluvoxamine, extrapyramidal effects were reported (George and Trimble, 1993). The patient described here presents the clinical peculiarity of the simultaneous onset of tics and extrapyramidal symptoms, which have always been separate in the cases described so far. Both effects might be due to an imbalance in the dopaminergic neurotransmission system. Given the anatomical and physiological evidence of inhibitory serotoninergic projections to mid- and forebrain regions containing dopamine neurons, it is plausible that SSRl antidepressants influence extrapyramidal motor function through a pharmacodynamic interaction between central serotoninergic and dopaminergic functions (Baldessarini et al., 1992). In view of the increasing use of SSRIs as antidepressants in children and adolescents, clinicians prescribing these drugs to young patients need to be aware of the possibility of adverse motor reactions. Carlo Lenti, M.D. University of Milan, Italy Baldessarini RJ, Marsh ER, Kula NS (1992), Interactions of fluoxetine with metabolism of dopamine and serotonin in rat brain regions. Brain Res 579: 152-156 Delgado PL, Goodman WK, Price LH, Heninger GR, Charney DS (1990), Fluvoxamine/pimozide treatment of concurrent Tourette's and obsessivecompulsive disorder. Br J Psychiatry 157:762-765 Fennig S, Naisberg-Fennig S, Pato M, Weitzman A (1994), Emergence of symptoms of Tourette's syndrome during fluvoxamine treatment of obsessive-compulsive disorder. Br J Psychiatry 164:839-841 George MS, Trimble MR (1993), Dysthymic reaction associated with fluvoxamine. J Clin Psychophannaco!13:220-221 Lipinski JF Jr, Mallya G, Zimmerman P, Pope HG Jr (1989), Fluoxetineinduced akathisia: clinical and theoretical implications. J Clin Psychiatry 50:339-342
FLUOXETINE AND COMPULSIVE SEXUAL BEHAVIOR
10 the Editor: ]. is a 16-year-old male who meets DSM-IV criteria for posttraumatic stress disorder and paraphilia not otherwise specified. He had been raped repeatedly by a paternal uncle between the ages of 8 and 13 years. Subsequently, he was admitted to a residential program where he sexually molested a number of his peers. He was transferred to a residential program for sexual perpetrators, where he had been for 2 1/ 2 years. While there, he continued to make attempts to abuse other children and he complained of intrusive thoughts of wanting to fondle other peers in the program. He would also steal peers' undergarments and use them as objects for selfgratification and masturbation, and then shred these garments in order not to get caught. He was admitted to our inpatient unit for stabilization of symptoms and for assessment of his potential for danger to
]. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 38:8, AUGUST 1999
his peers. Medication trials during his stay at the residential program had included olanzapine 5 mg/day and sertraline up to 50 mg/day. Whereas the use of selective serotonin reuptake inhibitors (SSRls) is clearly established in the reduction of obsessivecompulsive disorder symptoms, we considered whether the use of a high dose of an SSRl would reduce the paraphilia through a decrease in testosterone levels. A gonadotropin-releasing hormone (GnRH) analog has been shown to be effective in reducing testosterone levels with a subsequent reduction in deviant sexual fantasies in men with long-standing paraphilias (Rosier and Witztum, 1998). Moreover, sexual dysfunction and, in particular, a decrease in libido due to SSRls has been extensively established in the literature (Rosen et al., 1999). At the time of admission the patient's drug-free baseline testosterone level was 613 ng!dL (adult reference range = 241-827 ng!dL; 13 to 15-year-old reference range = 15 to 500 ng/dL). The next day he was started on fluoxetine 10 mg/day; the dosage was increased to 30 mg!day over the course of 1 week. At 10 days his testosterone level was 494 mg/dL, a 19% reduction from admission. The fluoxetine dose was increased to 5b mg. On day 14 his testosterone level was 466 ng/dL, a further reduction of 6% and a total reduction of 24% since admission. During his inpatient stay, ]. evidenced no attempts to sexually assault or molest his peers. Upon discharge, after 17 days of inpatient treatment, he expressed a marked decrease in symptoms, stating, "I don't have any of those sex thoughts any more," and "I think that this medication is really working." The discharge dose was 60 mg of fluoxetine. He was discharged to residential care for ongoing therapy for trauma-reiated issues. The observation that testosterone levels decreased as fluoxetine doses were increased is interesting and may warrant further investigation. The therapeutic implications are considerable. Blaise Aguirre, M.D. Lowell Youth Treatment Center Lowell, MA Rosen R, Lane R, Menza M (1999), Effects of SSRI's on sexual function: a critical review. J C!in Psychophannaco!19:67-85 Rosier A, Witztum E (1998), Treatment of men with paraphilia with a long acting analogue of gonadotropin-releasing hormone. N Eng! J Med 338:416-422 The Letters column is a corner of the Journal that encourages opinion, controversy, and preliminary ideas. We especially invite reader comments on the articles we publish as well as issues or interests of concern to child and adolescent psychiatry. The Editor reserves the right to solicit responses and publish replies. All statements expressed in this column are those of the authors and do not reflect opinions of the Journal. Letters should not exceed 750 words, including a maximum of 5 references. They must be signed, typed double-spaced, and submitted in duplicate. All letters are subject to editing and shortening. They will be considered for publication but may not necessarily be published nor will their receipt be acknowledged. Please direct your letters to Mina K. Dulcan, M.D., Editor, Journal of the AACAP Editorial Office, Children's Memorial Hospital, 2300 Children's Plaza #156, Chicago, IL 60614-3394
943
BUSPIRONE IN ODD
disorders in patients taking Ruoxetine, paroxetine, and sertraline; their pathogenesis has been attributed to serotonin-mediated inhibition of dopaminergic transmission (Lipinski et al., 1989). A serotonergic-dopaminergic interaction is also suggested by the fact that other movement disorders, such as tics or Tourette's disorder, arise or may worsen in patients treated with SSRIs (Delgado et al., 1990; Fennig et al., 1994) or with imipramine and clomipramine. A 14-year-old patient treated with Ruvoxamine is of interest because even though he had previously received no dopamine blockers and had no history of tic-like symptoms, both tics and associated dystonic extrapyramidal symptoms appeared. C.M. was the elder of 2 brothers. Four of his father's brothers had bipolar mood disorders, and his father suffered from panic attacks and OCD. The child had been delivered normally, after an uneventful pregnancy, and his psychomotor development was normal. At nursery school he had some difficulties in social interactions and showed low tolerance to frustration, but no noteworthy mental disorders were reported until the age of 12 years, when he began to have various behavioral problems. He would isolate himself from his schoolmates, refusing group relations, including sports. At home he tended to stay alone, seeing no friends, and showed no interest in the pastimes typical of boys of his age. C.M. began to suffer from insomnia and to behave in an oppositional manner toward his parents, especially his father. His main problems, however, were at school, where his concentration and output both dropped and his relations with schoolmates had become much worse; he often argued with them because they mocked him. From C.M.'s personal history and a psychiatric assessment, a dysthymic disorder was diagnosed, on the basis of DSM-IV, confirmed by a score of 27 on the Children's Depression Inventory. Cognitive assessment showed an IQ of 86 to 96 on the Verbal scale and 78 for Performance. Treatment was started with Ruvoxamine, 100 mg/day. After 4 weeks of therapy only slight improvement was seen in the patient's mood and sleeping pattern. The dosage was therefore raised to 150 mg/day, and after 9 weeks at this level there was a striking change in the tone of his mood, which became hyperthymic, and reactions to his companions improved. At the same time, however, he began to experience various involuntary movements. Some were eyelid and nasal tics, and others involved lateral stretching of the line of the lips and torsion of the neck, like a dystonic movement. The boy was therefore started on haloperidol, 1.5 mg/day, but it had no effect. The involuntary movements stopped only when Ruvoxamine was withdrawn. That the involuntary movements appeared when the Ruvoxamine dosage was increased and stopped when the drug was discontinued indicates a causal relation. The appearance-or worsening-of tics during Ruvoxamine traitment has already
10 the Editor: I noted with disappointment that in the index to volume 37 of the Journal (pp. 1347-1356), there were no references to articles on oppositional defiant disorder (ODD). ODD seems to be increasing in prevalence, at least as it appears in clinical practice. It probably now rates as the second most common disruptive behavioral disorder in childhood. However, despite the prevalence of this disorder and its recalcitrance to treatment, there seems to be a dearth of research into its nature. Treatment of this disorder has proved remarkably frustrating. Parent training, behavioral modification approaches, and a variety of medications have been used with modest but inconsistent results. On the basis of an open-label study by Gross (1995) in which he reported up to a 90% response rate to buspirone, I have been using this medication with encouraging results. While the response rate in my practice is probably more like 65% to 70%, buspirone has proved to be far more effective and reliable than stimulants, mood stabilizers, or selective serotonin reuptake inhibitors. I have been using doses of 60 ± 15 mg q.d. in divided doses. Response appears to be independent of age or weight. Other than a failure to respond, the 2 most significant problems I have encountered with high-dose treatment with buspirone have been the following: (1) a small percentage of children, roughly 10%, experience significant increases in appetite and weight, and (2) in some children there is an unfortunate tendency for the effectiveness to dissipate gradually after 3 to 4 months, apparently the result of enzymatic changes in the liver. While buspirone may not be the ideal medication for treatment of ODD, its pharmacological action may nonetheless provide important clues to the underlying nature of this disorder and lead us to more effective treatments in the future. I would strongly urge any young researcher looking for a fertile field for his/her career to pursue the investigation of this difficult and perplexing disorder. John E. Dunne, M.D. Southlake Professional Group Renton, WA Gross MD (1995), Buspirone in ADHD with ODD (letter). JAm Acad Child Adolesc Psychiatry 34: 1260
MOVEMENT DISORDERS ASSOCIATED WITH FLUVOXAMINE
10 the Editor: Selective serotonin reuptake inhibitors (SSRIs) have become routine tools for the treatment of mood disorders, obsessivecompulsive disorder (OCD), and Tourette's disorder in children and adolescents. Adverse reactions include extrapyramidal
942
J.
AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 38:8, AUGUST 1999
LETTERS TO THE EDITOR
been reported in 2 patients with OCD (Fennig et al., 1994; Delgado et al., 1990). In another case treated with fluvoxamine, extrapyramidal effects were reported (George and Trimble, 1993). The patient described here presents the clinical peculiarity of the simultaneous onset of tics and extrapyramidal symptoms, which have always been separate in the cases described so far. Both effects might be due to an imbalance in the dopaminergic neurotransmission system. Given the anatomical and physiological evidence of inhibitory serotoninergic projections to mid- and forebrain regions containing dopamine neurons, it is plausible that SSRl antidepressants influence extrapyramidal motor function through a pharmacodynamic interaction between central serotoninergic and dopaminergic functions (Baldessarini et al., 1992). In view of the increasing use of SSRIs as antidepressants in children and adolescents, clinicians prescribing these drugs to young patients need to be aware of the possibility of adverse motor reactions. Carlo Lenti, M.D. University of Milan, Italy Baldessarini RJ, Marsh ER, Kula NS (1992), Interactions of fluoxetine with metabolism of dopamine and serotonin in rat brain regions. Brain Res 579: 152-156 Delgado PL, Goodman WK, Price LH, Heninger GR, Charney DS (1990), Fluvoxamine/pimozide treatment of concurrent Tourette's and obsessivecompulsive disorder. Br J Psychiatry 157:762-765 Fennig S, Naisberg-Fennig S, Pato M, Weitzman A (1994), Emergence of symptoms of Tourette's syndrome during fluvoxamine treatment of obsessive-compulsive disorder. Br J Psychiatry 164:839-841 George MS, Trimble MR (1993), Dysthymic reaction associated with fluvoxamine. J Clin Psychophannaco!13:220-221 Lipinski JF Jr, Mallya G, Zimmerman P, Pope HG Jr (1989), Fluoxetineinduced akathisia: clinical and theoretical implications. J Clin Psychiatry 50:339-342
FLUOXETINE AND COMPULSIVE SEXUAL BEHAVIOR
10 the Editor: ]. is a 16-year-old male who meets DSM-IV criteria for posttraumatic stress disorder and paraphilia not otherwise specified. He had been raped repeatedly by a paternal uncle between the ages of 8 and 13 years. Subsequently, he was admitted to a residential program where he sexually molested a number of his peers. He was transferred to a residential program for sexual perpetrators, where he had been for 2 1/ 2 years. While there, he continued to make attempts to abuse other children and he complained of intrusive thoughts of wanting to fondle other peers in the program. He would also steal peers' undergarments and use them as objects for selfgratification and masturbation, and then shred these garments in order not to get caught. He was admitted to our inpatient unit for stabilization of symptoms and for assessment of his potential for danger to
]. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 38:8, AUGUST 1999
his peers. Medication trials during his stay at the residential program had included olanzapine 5 mg/day and sertraline up to 50 mg/day. Whereas the use of selective serotonin reuptake inhibitors (SSRls) is clearly established in the reduction of obsessivecompulsive disorder symptoms, we considered whether the use of a high dose of an SSRl would reduce the paraphilia through a decrease in testosterone levels. A gonadotropin-releasing hormone (GnRH) analog has been shown to be effective in reducing testosterone levels with a subsequent reduction in deviant sexual fantasies in men with long-standing paraphilias (Rosier and Witztum, 1998). Moreover, sexual dysfunction and, in particular, a decrease in libido due to SSRls has been extensively established in the literature (Rosen et al., 1999). At the time of admission the patient's drug-free baseline testosterone level was 613 ng!dL (adult reference range = 241-827 ng!dL; 13 to 15-year-old reference range = 15 to 500 ng/dL). The next day he was started on fluoxetine 10 mg/day; the dosage was increased to 30 mg!day over the course of 1 week. At 10 days his testosterone level was 494 mg/dL, a 19% reduction from admission. The fluoxetine dose was increased to 5b mg. On day 14 his testosterone level was 466 ng/dL, a further reduction of 6% and a total reduction of 24% since admission. During his inpatient stay, ]. evidenced no attempts to sexually assault or molest his peers. Upon discharge, after 17 days of inpatient treatment, he expressed a marked decrease in symptoms, stating, "I don't have any of those sex thoughts any more," and "I think that this medication is really working." The discharge dose was 60 mg of fluoxetine. He was discharged to residential care for ongoing therapy for trauma-reiated issues. The observation that testosterone levels decreased as fluoxetine doses were increased is interesting and may warrant further investigation. The therapeutic implications are considerable. Blaise Aguirre, M.D. Lowell Youth Treatment Center Lowell, MA Rosen R, Lane R, Menza M (1999), Effects of SSRI's on sexual function: a critical review. J C!in Psychophannaco!19:67-85 Rosier A, Witztum E (1998), Treatment of men with paraphilia with a long acting analogue of gonadotropin-releasing hormone. N Eng! J Med 338:416-422 The Letters column is a corner of the Journal that encourages opinion, controversy, and preliminary ideas. We especially invite reader comments on the articles we publish as well as issues or interests of concern to child and adolescent psychiatry. The Editor reserves the right to solicit responses and publish replies. All statements expressed in this column are those of the authors and do not reflect opinions of the Journal. Letters should not exceed 750 words, including a maximum of 5 references. They must be signed, typed double-spaced, and submitted in duplicate. All letters are subject to editing and shortening. They will be considered for publication but may not necessarily be published nor will their receipt be acknowledged. Please direct your letters to Mina K. Dulcan, M.D., Editor, Journal of the AACAP Editorial Office, Children's Memorial Hospital, 2300 Children's Plaza #156, Chicago, IL 60614-3394
943