General Hospital Psychiatry 37 (2015) 192.e1–192.e2
Contents lists available at ScienceDirect
General Hospital Psychiatry journal homepage: http://www.ghpjournal.com
Case Report
Effects of testosterone therapy on bipolar disorder with Klinefelter syndrome☆,☆☆ Kazuhiro Kawahara, M.D. a, Tadashi Jono, M.D., Ph.D. b,⁎, Yoshitomo Nishi, M.D. a, Hirokage Ushijima, M.D., Ph.D. c, Manabu Ikeda, M.D., Ph.D. b a b c
Department of Neuropsychiatry, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan Department of Neuropsychiatry, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan Department of Child and Adolescent Psychiatry, Kohnodai Hospital, National Center of Global Health and Medicine, Chiba, Japan
a r t i c l e
i n f o
Article history: Received 22 September 2014 Revised 5 December 2014 Accepted 9 December 2014 Keywords: Bipolar disorder Klinefelter syndrome Testosterone therapy Extra-X chromosome
a b s t r a c t Klinefelter syndrome (KS) is widely associated with cognitive impairment and language problems. KS patients may also exhibit psychiatric symptoms. We present the case of an 18-year-old man with KS who experienced rapidly repeating relapses of manic episodes. He was unresponsive to the usual pharmacotherapies for bipolar disorders such as mood stabilizers and second-generation antipsychotics. Mood was eventually improved with testosterone therapy in addition to pharmacotherapy, with no relapse of manic episodes for 3 years after discharge. Testosterone therapy may prevent relapsing manic episodes of bipolar disorder in patients with KS. © 2015 Elsevier Inc. All rights reserved.
1. Introduction The prevalence of Klinefelter syndrome (KS) ranges from 1.09 to 1.72 per 1000 male births, based on neonatal survey data from the 1970s [1]. KS is widely associated with cognitive impairment and language problems. In general, sex chromosome aneuploidies are considered risk factors for psychosis [2]. Everman and Stoudemire [3] reviewed 31 published cases of bipolar disorder patients with chromosomal abnormalities, although they concluded that the relationship between X-linkage and bipolar disorder remained controversial. However, bipolar disorder with KS has been described in several case reports [3]. We present the case of an 18-year-old man with KS that testosterone therapy was effective to prevent relapsing manic episodes. 2. Case report An 18-year-old man with KS was admitted for acute mania. He had been diagnosed with KS (47 XXY) at 2 years old. At 12 years old, he showed a verbal intelligence quotient (IQ) of 72, performance IQ of 65 and full-scale IQ of 65 according to the Wechsler Intelligence Scale for Children-III. According to his family, he had been introverted, quiet,
☆ Funding source: None. ☆☆ Conflicts of interest: None. ⁎ Corresponding author. Department of Neuropsychiatry, Faculty of Life Sciences, Kumamoto University, Honjo 1-1-1, Chuo-ku, Kumamoto 860-8556, Japan. Tel.: +81 96 373 5184; fax: +81 96 373 5186. E-mail address: [email protected] (T. Jono). http://dx.doi.org/10.1016/j.genhosppsych.2014.12.003 0163-8343/© 2015 Elsevier Inc. All rights reserved.
nonassertive and sometimes socially withdrawn in his school years. He had received several testosterone injections in 1 year at 14 years old, but he and his family refused to continue with testosterone injections. He experienced his first hypomanic episode and minor depressive episode in junior high school. During his high school years, he experienced short-term mood swings. One manic episode occurred while he was engaged in on-the-job training during his third year of high school, at which time he left school suddenly one day and went to a nearby theater, where he started guiding buses to the theater parking lots in a loud voice and with exaggerated gestures. The next day, he was admitted to our hospital. At the time of admission, his mental status was characterized by talkativeness, elevated mood, grandiosity and agitation. He exhibited labile affect and disorganized thoughts with flight of ideas. On physical examination, he was 185 cm tall and weighed 71.2 kg. He had a small penis with nodular testes. Results of other physical examination were within normal limits. Computed tomography of the brain without contrast showed no abnormalities, although electroencephalography demonstrated bitemporal 8–9 Hz alpha waves on both sides. Laboratory results were within normal limits. Endocrine studies revealed normal levels of triiodothyronine (T3), thyroxine (T4) and thyroid-stimulating hormone. Other hormone levels were as follows: testosterone, 185.6 ng/dl (normal adult male level, 270–1100 ng/dl); luteinizing hormone, 28.5 mIU/ml (normal, 1.3-12 mIU/ml); follicle-stimulating hormone, 38.5 mIU/ml (normal, 1.2–10 mIU/ml); estradiol, 13.8 pg/ml (normal, 0–35 pg/ml); and prolactin, 49.6 ng/dl (normal, 2–12 ng/dl). We prescribed lithium (800 mg/day) and quetiapine (600 mg/day) for manic symptoms. On hospital day 5, combination therapy was continued
192.e2
K. Kawahara et al. / General Hospital Psychiatry 37 (2015) 192.e1–192.e2
with olanzapine (20 mg/day) instead of quetiapine. On hospital day 10, manic symptoms began to subside. We had to decrease olanzapine to 5 mg/day due to oversedation. On hospital day 30, manic symptoms relapsed. He suddenly began singing and talking loudly. We used antipsychotics such as risperidone, aripiprazole and haloperidol, and manic symptoms subsided within 10 days. Similar manic episodes subsequently repeated 3 times at roughly 1-month intervals. When his mood was subsequently stable after the fifth manic episode, he was prescribed combination therapy with sodium valproate (1000 mg/day), lithium (1000 mg/day), aripiprazole (30 mg/day) and quetiapine (400 mg/day). After stabilization of mood, injection of testosterone was performed once a month to treat low testosterone levels. Mood remained stable and the patient was discharged with a prescription for sodium valproate (800 mg/day), lithium (1000 mg/day), aripiprazole (30 mg/day) and quetiapine (400 mg/day). Since discharge, the patient has remained free from relapses of manic episodes for 3 years.
3. Discussion This patient with KS had to be hospitalized for a long time due to recurrent manic episodes. He also developed mild depressive episodes. We therefore diagnosed bipolar disorder with KS. Psychiatric symptoms in KS patients are heterogeneous and atypical, complicating the diagnosis of this pathology [4]. The prevalence of bipolar disorder with KS was rare [3]. Bruining et al. [5] found the presence of learning disorders (65%), attention-deficit hyperactivity disorder (63%), depressive disorders (24%), psychotic disorders (8%) and schizophrenia (2%) in 51 boys with KS. Moreover, only 10% of subjects with KS are diagnosed prenatally, with another 25% diagnosed during childhood or adulthood, leaving 65% undiagnosed [6,7]. The prevalence rate of bipolar disorder with KS might thus be higher than estimated in previous reports. In the present case, the patient experienced relapses of mania with rapid onset and recurrence at roughly 1-month intervals, despite combination therapy with mood stabilizers (lithium, sodium valproate) and second-generation antipsychotics (aripiprazole, quetiapine, risperidone and olanzapine). The patient has not experienced relapses in manic episodes since injection of testosterone once a month was restarted. Dosages of psychotropic drugs were subsequently able to decrease. His prolactin level was high. Prolactin is known to contribute in lowering testosterone level. The antipsychotics such as haloperidol and risperidone to his mania and agitation might influence the increase of his prolactin level. We think that testosterone was less affected by his high prolactin level because his testosterone level had been shown to be at low level before his admission for several years. He showed
lower IQ than it is usually predicted in KS. The extra-X chromosome can lead to intellectual disability [8] and might play a role as a vulnerability factor of psychiatric disorder. In this case, low testosterone level and intellectual disability might be two of the reasons of repeated relapses of manic episodes. Although the evidence for effects of testosterone therapy on KS remains unclear, some studies have demonstrated positive effects [9]. Testosterone therapy improves functions in several aspects of neuromotor, speech and language, intellectual and reading [10]. Testosterone therapy has positive effects, including sleep, mood and irritability [11]. Rinieris et al. [12] reported two cases in which depressive patients with KS who were given testosterone therapy developed no recurrences of depression. Testosterone therapy in KS might be effective not only for cognitive and physical symptoms, but also for preventing psychiatric symptoms such as bipolar disorders. There is some possibility that the coexistence of bioplar disorder and KS is being overlooked. Endocrine examination and chromosome analysis will provide an important and informative routine in treatment strategies for bipolar disorder with mild intellectual disability. Testosterone therapy may be effective in preventing relapsing manic episodes in KS. References [1] Morris JK, Alberman E, Scott C, Jacobs P. Is the prevalence of Klinefelter syndrome increasing? Eur J Hum Genet 2008;16:163–70. [2] Verri A, Cremante A, Clerici F, Destefani V, Radicioni A. Klinefelter's syndrome and psychoneurologic function. Mol Hum Reprod 2010;16:425–33. [3] Everman DB, Stoudemire A. Bipolar disorder associated with Klinefelter's syndrome and other chromosomal abnormalities. Psychosomatics 1994;35:35–40. [4] Slim I, Kissi YE, Ayachi M, Maaroufi-Beizig A, Mlika S, Ach K, et al. Diagnosis and treatment difficulties of psychiatric symptoms in Klinefelter syndrome: a case report. BMJ Case Rep 2009. http://dx.doi.org/10.1136/bcr.08.2008.0741 [Epub 2009 Mar 26]. [5] Bruining H, Swaab H, Kas M, van Engeland H. Psychiatric characteristics in a selfselected sample of boys with Klinefelter syndrome. Pediatrics 2009;123:865–70. [6] Bojesen A, Juul S, Gravholt CH. Prenatal and postnatal prevalence of Klinefelter syndrome: a national registry study. J Clin Endocrinol Metab 2003;88:622–6. [7] Abramsky L, Chapple J. 47, XXY (Klinefelter syndrome) and 47, XYY: estimated rates of and indication for postnatal diagnosis with implications for prenatal counselling. Prenat Diagn 1997;17:363–8. [8] Boada R, Janusz J, Hutaff-Lee C, Tartaglia N. The cognitive phenotype in Klinefelter syndrome: a review of the literature including genetic and hormonal factors. Dev Disabil Res Rev 2009;15:284–94. [9] Høst C, Skakkebæk A, Groth KA, Bojesen A. The role of hypogonadism in Klinefelter syndrome. Asian J Androl 2014;16:185–91. [10] Samango-Sprouse CA, Sadeghin T, Mitchell FL, Dixon T, Stapleton E, Kingery M, et al. Positive effects of short course androgen therapy on the neurodevelopmental outcome in boys with 47, XXY syndrome at 36 and 72 months of age. Am J Med Genet A 2013;161:501–8. [11] Nielsen J, Pelsen B, Sorensen K. Follow-up of 30 Klinefelter males treated with testosterone. Clin Genet 1988;33:262–9. [12] Rinieris PM, Malliaras DE, Batrinos ML, Stefanis CN. Testosterone treatment of depression in two patients with Klinefelter's syndrome. Am J Psychiatry 1979;136:986–8.
Contents lists available at ScienceDirect
General Hospital Psychiatry journal homepage: http://www.ghpjournal.com
Case Report
Effects of testosterone therapy on bipolar disorder with Klinefelter syndrome☆,☆☆ Kazuhiro Kawahara, M.D. a, Tadashi Jono, M.D., Ph.D. b,⁎, Yoshitomo Nishi, M.D. a, Hirokage Ushijima, M.D., Ph.D. c, Manabu Ikeda, M.D., Ph.D. b a b c
Department of Neuropsychiatry, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan Department of Neuropsychiatry, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan Department of Child and Adolescent Psychiatry, Kohnodai Hospital, National Center of Global Health and Medicine, Chiba, Japan
a r t i c l e
i n f o
Article history: Received 22 September 2014 Revised 5 December 2014 Accepted 9 December 2014 Keywords: Bipolar disorder Klinefelter syndrome Testosterone therapy Extra-X chromosome
a b s t r a c t Klinefelter syndrome (KS) is widely associated with cognitive impairment and language problems. KS patients may also exhibit psychiatric symptoms. We present the case of an 18-year-old man with KS who experienced rapidly repeating relapses of manic episodes. He was unresponsive to the usual pharmacotherapies for bipolar disorders such as mood stabilizers and second-generation antipsychotics. Mood was eventually improved with testosterone therapy in addition to pharmacotherapy, with no relapse of manic episodes for 3 years after discharge. Testosterone therapy may prevent relapsing manic episodes of bipolar disorder in patients with KS. © 2015 Elsevier Inc. All rights reserved.
1. Introduction The prevalence of Klinefelter syndrome (KS) ranges from 1.09 to 1.72 per 1000 male births, based on neonatal survey data from the 1970s [1]. KS is widely associated with cognitive impairment and language problems. In general, sex chromosome aneuploidies are considered risk factors for psychosis [2]. Everman and Stoudemire [3] reviewed 31 published cases of bipolar disorder patients with chromosomal abnormalities, although they concluded that the relationship between X-linkage and bipolar disorder remained controversial. However, bipolar disorder with KS has been described in several case reports [3]. We present the case of an 18-year-old man with KS that testosterone therapy was effective to prevent relapsing manic episodes. 2. Case report An 18-year-old man with KS was admitted for acute mania. He had been diagnosed with KS (47 XXY) at 2 years old. At 12 years old, he showed a verbal intelligence quotient (IQ) of 72, performance IQ of 65 and full-scale IQ of 65 according to the Wechsler Intelligence Scale for Children-III. According to his family, he had been introverted, quiet,
☆ Funding source: None. ☆☆ Conflicts of interest: None. ⁎ Corresponding author. Department of Neuropsychiatry, Faculty of Life Sciences, Kumamoto University, Honjo 1-1-1, Chuo-ku, Kumamoto 860-8556, Japan. Tel.: +81 96 373 5184; fax: +81 96 373 5186. E-mail address: [email protected] (T. Jono). http://dx.doi.org/10.1016/j.genhosppsych.2014.12.003 0163-8343/© 2015 Elsevier Inc. All rights reserved.
nonassertive and sometimes socially withdrawn in his school years. He had received several testosterone injections in 1 year at 14 years old, but he and his family refused to continue with testosterone injections. He experienced his first hypomanic episode and minor depressive episode in junior high school. During his high school years, he experienced short-term mood swings. One manic episode occurred while he was engaged in on-the-job training during his third year of high school, at which time he left school suddenly one day and went to a nearby theater, where he started guiding buses to the theater parking lots in a loud voice and with exaggerated gestures. The next day, he was admitted to our hospital. At the time of admission, his mental status was characterized by talkativeness, elevated mood, grandiosity and agitation. He exhibited labile affect and disorganized thoughts with flight of ideas. On physical examination, he was 185 cm tall and weighed 71.2 kg. He had a small penis with nodular testes. Results of other physical examination were within normal limits. Computed tomography of the brain without contrast showed no abnormalities, although electroencephalography demonstrated bitemporal 8–9 Hz alpha waves on both sides. Laboratory results were within normal limits. Endocrine studies revealed normal levels of triiodothyronine (T3), thyroxine (T4) and thyroid-stimulating hormone. Other hormone levels were as follows: testosterone, 185.6 ng/dl (normal adult male level, 270–1100 ng/dl); luteinizing hormone, 28.5 mIU/ml (normal, 1.3-12 mIU/ml); follicle-stimulating hormone, 38.5 mIU/ml (normal, 1.2–10 mIU/ml); estradiol, 13.8 pg/ml (normal, 0–35 pg/ml); and prolactin, 49.6 ng/dl (normal, 2–12 ng/dl). We prescribed lithium (800 mg/day) and quetiapine (600 mg/day) for manic symptoms. On hospital day 5, combination therapy was continued
192.e2
K. Kawahara et al. / General Hospital Psychiatry 37 (2015) 192.e1–192.e2
with olanzapine (20 mg/day) instead of quetiapine. On hospital day 10, manic symptoms began to subside. We had to decrease olanzapine to 5 mg/day due to oversedation. On hospital day 30, manic symptoms relapsed. He suddenly began singing and talking loudly. We used antipsychotics such as risperidone, aripiprazole and haloperidol, and manic symptoms subsided within 10 days. Similar manic episodes subsequently repeated 3 times at roughly 1-month intervals. When his mood was subsequently stable after the fifth manic episode, he was prescribed combination therapy with sodium valproate (1000 mg/day), lithium (1000 mg/day), aripiprazole (30 mg/day) and quetiapine (400 mg/day). After stabilization of mood, injection of testosterone was performed once a month to treat low testosterone levels. Mood remained stable and the patient was discharged with a prescription for sodium valproate (800 mg/day), lithium (1000 mg/day), aripiprazole (30 mg/day) and quetiapine (400 mg/day). Since discharge, the patient has remained free from relapses of manic episodes for 3 years.
3. Discussion This patient with KS had to be hospitalized for a long time due to recurrent manic episodes. He also developed mild depressive episodes. We therefore diagnosed bipolar disorder with KS. Psychiatric symptoms in KS patients are heterogeneous and atypical, complicating the diagnosis of this pathology [4]. The prevalence of bipolar disorder with KS was rare [3]. Bruining et al. [5] found the presence of learning disorders (65%), attention-deficit hyperactivity disorder (63%), depressive disorders (24%), psychotic disorders (8%) and schizophrenia (2%) in 51 boys with KS. Moreover, only 10% of subjects with KS are diagnosed prenatally, with another 25% diagnosed during childhood or adulthood, leaving 65% undiagnosed [6,7]. The prevalence rate of bipolar disorder with KS might thus be higher than estimated in previous reports. In the present case, the patient experienced relapses of mania with rapid onset and recurrence at roughly 1-month intervals, despite combination therapy with mood stabilizers (lithium, sodium valproate) and second-generation antipsychotics (aripiprazole, quetiapine, risperidone and olanzapine). The patient has not experienced relapses in manic episodes since injection of testosterone once a month was restarted. Dosages of psychotropic drugs were subsequently able to decrease. His prolactin level was high. Prolactin is known to contribute in lowering testosterone level. The antipsychotics such as haloperidol and risperidone to his mania and agitation might influence the increase of his prolactin level. We think that testosterone was less affected by his high prolactin level because his testosterone level had been shown to be at low level before his admission for several years. He showed
lower IQ than it is usually predicted in KS. The extra-X chromosome can lead to intellectual disability [8] and might play a role as a vulnerability factor of psychiatric disorder. In this case, low testosterone level and intellectual disability might be two of the reasons of repeated relapses of manic episodes. Although the evidence for effects of testosterone therapy on KS remains unclear, some studies have demonstrated positive effects [9]. Testosterone therapy improves functions in several aspects of neuromotor, speech and language, intellectual and reading [10]. Testosterone therapy has positive effects, including sleep, mood and irritability [11]. Rinieris et al. [12] reported two cases in which depressive patients with KS who were given testosterone therapy developed no recurrences of depression. Testosterone therapy in KS might be effective not only for cognitive and physical symptoms, but also for preventing psychiatric symptoms such as bipolar disorders. There is some possibility that the coexistence of bioplar disorder and KS is being overlooked. Endocrine examination and chromosome analysis will provide an important and informative routine in treatment strategies for bipolar disorder with mild intellectual disability. Testosterone therapy may be effective in preventing relapsing manic episodes in KS. References [1] Morris JK, Alberman E, Scott C, Jacobs P. Is the prevalence of Klinefelter syndrome increasing? Eur J Hum Genet 2008;16:163–70. [2] Verri A, Cremante A, Clerici F, Destefani V, Radicioni A. Klinefelter's syndrome and psychoneurologic function. Mol Hum Reprod 2010;16:425–33. [3] Everman DB, Stoudemire A. Bipolar disorder associated with Klinefelter's syndrome and other chromosomal abnormalities. Psychosomatics 1994;35:35–40. [4] Slim I, Kissi YE, Ayachi M, Maaroufi-Beizig A, Mlika S, Ach K, et al. Diagnosis and treatment difficulties of psychiatric symptoms in Klinefelter syndrome: a case report. BMJ Case Rep 2009. http://dx.doi.org/10.1136/bcr.08.2008.0741 [Epub 2009 Mar 26]. [5] Bruining H, Swaab H, Kas M, van Engeland H. Psychiatric characteristics in a selfselected sample of boys with Klinefelter syndrome. Pediatrics 2009;123:865–70. [6] Bojesen A, Juul S, Gravholt CH. Prenatal and postnatal prevalence of Klinefelter syndrome: a national registry study. J Clin Endocrinol Metab 2003;88:622–6. [7] Abramsky L, Chapple J. 47, XXY (Klinefelter syndrome) and 47, XYY: estimated rates of and indication for postnatal diagnosis with implications for prenatal counselling. Prenat Diagn 1997;17:363–8. [8] Boada R, Janusz J, Hutaff-Lee C, Tartaglia N. The cognitive phenotype in Klinefelter syndrome: a review of the literature including genetic and hormonal factors. Dev Disabil Res Rev 2009;15:284–94. [9] Høst C, Skakkebæk A, Groth KA, Bojesen A. The role of hypogonadism in Klinefelter syndrome. Asian J Androl 2014;16:185–91. [10] Samango-Sprouse CA, Sadeghin T, Mitchell FL, Dixon T, Stapleton E, Kingery M, et al. Positive effects of short course androgen therapy on the neurodevelopmental outcome in boys with 47, XXY syndrome at 36 and 72 months of age. Am J Med Genet A 2013;161:501–8. [11] Nielsen J, Pelsen B, Sorensen K. Follow-up of 30 Klinefelter males treated with testosterone. Clin Genet 1988;33:262–9. [12] Rinieris PM, Malliaras DE, Batrinos ML, Stefanis CN. Testosterone treatment of depression in two patients with Klinefelter's syndrome. Am J Psychiatry 1979;136:986–8.
