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Congenital Adrenal Hyperplasia Associated with Mania and Serious Violence
CORRESPONDENCE Congenital Adrenal Hyperplasia Associated with Mania and Serious Violence To the Editor: e report the case of AB, a 21-year-old woman with congenital adrenal hyperplasia (CAH), who committed a homicide during an episode of mania associated with nonadherence to treatment for CAH. The court accepted that she had diminished responsibility for her actions because of the psychological effects of elevated testosterone levels. AB had the commonest form of CAH, a deficiency of the 21-hydroxylase enzyme, resulting in deficient cortisol and aldosterone production and an increase in adrenal androgen production under excessive adrenocorticotropic hormone drive (1). She presented in the classical manner at birth as a genetic female with hyponatremia and ambiguous genitalia requiring early surgical correction. Her weight increased significantly after puberty, and by the age of 15 she weighed 108 kg and her body mass index was 37. She blamed her weight gain on her treatment, and in late adolescence she developed secondary amenorrhea because of inconsistent adherence to steroid replacement therapy causing elevated 17-hydroxyprogesterone (17-OHP). From the age of 18, her plasma levels of 17-OHP, renin activity and testosterone were persistently elevated, suggesting nonadherence to medications. For a 12-month period from around the age of 19, she achieved normal levels of 17-OHP, plasma renin activity and testosterone, with suppressed adrenocorticotropic hormone, which in retrospect, were probably due to the resumption of all medications in the weeks before blood tests. AB identified herself as a homosexual female from adolescence. Her psychological development was otherwise unremarkable, with high academic achievement and no history of disturbed conduct or any form of substance abuse. There was no family history of psychiatric disorder and no history of any form of brain injury. In the year before the homicide, AB became depressed, but she did not receive any specific psychological or medical treatment. Around this time, she ceased glucocorticoid and mineralocorticoid replacement therapy in order to lose weight and increase muscle strength. She began to exercise obsessively and lost 40 kg in weight over a period of 6 months. A month before the homicide, her endocrinologist observed labile affect, grandiosity, uninhibited discussion of sexual matters and pressured speech, consistent with the emergence of hypomania. At that appointment AB acknowledged not having taken prednisone and fludrocortisone regularly for 6 months. Total testosterone levels had increased to 8 nmol/L (normal range ⬍ 3 nmol/L) and 17-OHP was ⬎ 500 nmol/L (normal range ⬍ 5 nmol/L; patient on oral contraceptive pill). The offense involved the premeditated stabbing of her sister following a trivial dispute. On reception to prison, AB was diagnosed with mania on the basis of her abnormally elevated mood, grandiose thinking, increased activity and pressured speech. She was treated with antipsychotic medication, initially olanzapine up to 10 mg daily, later changed to quetiapine 200 mg daily, as well as prednisone and fludrocortisone. After responding to treatment, she reported the experience of abnormally aggressive and callous thinking in the period leading up to the offense. Antipsychotic medication was withdrawn and there was no return of symptoms of either mania or depression in the year after the offense.
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Discussion. There are several possible explanations for AB’s behavior. The first is that the homicide was unrelated to either CAH or mania. This seems unlikely, because her relation0006-3223/$36.00
ship with her sister had been good, the crime was essentially without motive, and there was no history of earlier violent conduct. The second possibility is that the homicide was related to the manic phase of bipolar disorder and not to CAH. Irritability and lowered frustration tolerance are often features of manic states and an association has been reported between bipolar disorder and violent crime (2). However, the increased risk was found to be entirely due to comorbid substance abuse, was not associated with a particular phase of the illness, and the manic phase of bipolar disorder is uncommon in studies of homicide by the mentally ill (3,4). A third possibility is that rising testosterone levels were causally related to both the abnormal aggression and the elevated mood. AB’s testosterone level was 8 nmol/L a month before the offense, about four times the normal level for females. The rapid rises in AB’s testosterone level after ceasing medication are likely to have been similar in biological effect to the acute elevations in males who abuse anabolic steroids. Unless treated in utero, females with CAH are exposed to high prenatal androgen levels. This hormonal imprinting of the brain is considered responsible for tomboyish behavior in childhood, male pattern learning difficulties, and anovulation in some but not all affected females (1). Congenital adrenal hyperplasia is known to be associated with homosexual orientation in females (5) and with increased aggression and activity in prepubescent girls and adults (6,7), and females with CAH have been shown to have a masculine pattern of activation of the amygdala, a part of the brain associated with aggression (8). Psychological disturbances similar to those observed in exogenous androgen abuse have also been reported in a case of untreated CAH in a male (9). There are reports of homicidal aggression in previously normal users of anabolic steroids (10). There are also reports of a high incidence of mood disorder and manic states among athletes using anabolic steroids, with as many as a quarter of users developing symptoms of hypomania, and the risk appears to be associated with the dose of steroids (11). Furthermore, female to male transsexuals may exhibit increasing levels of anger and aggression as testosterone is increased during gender reassignation (12), but there are no reported cases of mania in this situation. We were only able to locate one study that specifically reported the psychiatric complications of CAH. Liang et al. (13) found 4 of a series of 11 CAH patients met the criteria for the diagnosis of a psychiatric disorder but did not report any cases of hypomania or mania. It may be that the sudden increase in AB’s testosterone level contributed to both abnormally elevated mood and the pattern of thinking that led to severe aggression, because her abnormal state of mind resolved after treatment of CAH. Olav Nielssen St. Vincent’s Hospital Clinical Research Unit for Anxiety and Depression level 4, O’Brien Building, Victoria Street Darlinghurst, NSW, 2000 Australia E-mail: [email protected] D. Jane Holmes-Walker Department Endocrinology Westmead Hospital Sydney, Australia Matthew Large School of Psychiatry University of New South Wales Sydney, Australia BIOL PSYCHIATRY 2011;69:e21– e22 © 2011 Society of Biological Psychiatry
e22 BIOL PSYCHIATRY 2011;69:e21– e22
Correspondence Kate Steinbeck
The Children’s Hospital at Westmead and University of Sydney Sydney, Australia This article was not funded. Dr. Nielssen interviewed Ms. AB to prepare a report for court, obtained AB’s permission to prepare the report, performed a literature search, and wrote the first draft of the paper. Dr. Holmes-Walker was Ms. AB’s treating endocrinologist and provided additional historical details and added to the discussion. Dr. Large conducted a further literature search and revised the paper. Professor Steinbeck drew on her expertise in this area to contribute to the discussion. We thank Ms. AB, who gave the first author permission to prepare this report. All authors report no biomedical financial interests or potential conflicts of interest. 1. Merke DP, Bornstein SR (2005): Congenital adrenal hyperplasia. Lancet 365:2125–2136. 2. Fazel S, Lichtenstein P, Grann M, Goodwin G, Langstrom N (2010): Bipolar disorder and violent crime. New evidence from population based longitudinal studies and systematic review. Arch Gen Psychiatry 67:931– 938. 3. Nielssen O, Westmore B, Large M, Hayes R (2007): Homicide in psychotic illness in New South Wales 1993-2002. Med J Aust 186:301–304. 4. Large M, Smith G, Nielssen O (2009): The relationship between the rate of homicide by those with schizophrenia and the overall homicide rate: A systematic review and meta-analysis. Schizophr Res 112:123–129.
www.sobp.org/journal
5. Meyer-Bahlburg HF, Dolezal C, Baker SW, New MI (2008): Sexual orientation in women with classical or non-classical congenital adrenal hyperplasia as a function of degree of prenatal androgen excess. Arch Sex Behav 37:85–99. 6. Pasterski V, Hindmarsh P, Geffner M, Brook C, Brain C, Hines M (2007): Increased aggression and activity level in 3- to 11-year-old girls with congenital adrenal hyperplasia (CAH). Horm Behav 52:368 –374. 7. Berenbaum SA, Resnick SM (1997): Early androgen effects on aggression in children and adults with congenital adrenal hyperplasia. Psychoneuroendocrinology 22:505–515. 8. Ernst M, Maheu FS, Schroth E, Hardin J, Golan LG, Cameron J, et al. (2007): Amygdala function in adolescents with congenital adrenal hyperplasia: A model for the study of early steroid abnormalities. Neuropsychologia 45:2104 –2113. 9. Keely EJ, Matwijiw I, Thliveris JA, Faiman C (1993): Congenital adrenal hyperplasia with testicular tumours, aggression and gonadal failure. Urology 41:346 –349. 10. Pope HG, Katz DL (1990): Homicide and near-homicide by anabolic steroid users. J Clin Psychiatry 51:28 –31. 11. Pope HG, Katz DL (1994): Psychiatric and medical effects of anabolicandrogenic steroid use. A controlled study of 160 athletes. Arch Gen Psychiatry 51:375–382. 12. Van Goozen SH, Cohen-Kettenis PT, Gooren LJ, Frijda NH, Van de Poll NE (1995): Gender differences in behaviour: Activating effects of cross-sex hormones. Psychoneuroendocrinology 20:343–363. 13. Liang HY, Chang HL, Chen CY, Chang PY, Lo FS, Lee LW (2008): Psychiatric manifestations in young females with congenital adrenal hyperplasia in Taiwan. Chang Gung Med J 31:66 –73.
doi:10.1016/j.biopsych.2010.09.058
W
Discussion. There are several possible explanations for AB’s behavior. The first is that the homicide was unrelated to either CAH or mania. This seems unlikely, because her relation0006-3223/$36.00
ship with her sister had been good, the crime was essentially without motive, and there was no history of earlier violent conduct. The second possibility is that the homicide was related to the manic phase of bipolar disorder and not to CAH. Irritability and lowered frustration tolerance are often features of manic states and an association has been reported between bipolar disorder and violent crime (2). However, the increased risk was found to be entirely due to comorbid substance abuse, was not associated with a particular phase of the illness, and the manic phase of bipolar disorder is uncommon in studies of homicide by the mentally ill (3,4). A third possibility is that rising testosterone levels were causally related to both the abnormal aggression and the elevated mood. AB’s testosterone level was 8 nmol/L a month before the offense, about four times the normal level for females. The rapid rises in AB’s testosterone level after ceasing medication are likely to have been similar in biological effect to the acute elevations in males who abuse anabolic steroids. Unless treated in utero, females with CAH are exposed to high prenatal androgen levels. This hormonal imprinting of the brain is considered responsible for tomboyish behavior in childhood, male pattern learning difficulties, and anovulation in some but not all affected females (1). Congenital adrenal hyperplasia is known to be associated with homosexual orientation in females (5) and with increased aggression and activity in prepubescent girls and adults (6,7), and females with CAH have been shown to have a masculine pattern of activation of the amygdala, a part of the brain associated with aggression (8). Psychological disturbances similar to those observed in exogenous androgen abuse have also been reported in a case of untreated CAH in a male (9). There are reports of homicidal aggression in previously normal users of anabolic steroids (10). There are also reports of a high incidence of mood disorder and manic states among athletes using anabolic steroids, with as many as a quarter of users developing symptoms of hypomania, and the risk appears to be associated with the dose of steroids (11). Furthermore, female to male transsexuals may exhibit increasing levels of anger and aggression as testosterone is increased during gender reassignation (12), but there are no reported cases of mania in this situation. We were only able to locate one study that specifically reported the psychiatric complications of CAH. Liang et al. (13) found 4 of a series of 11 CAH patients met the criteria for the diagnosis of a psychiatric disorder but did not report any cases of hypomania or mania. It may be that the sudden increase in AB’s testosterone level contributed to both abnormally elevated mood and the pattern of thinking that led to severe aggression, because her abnormal state of mind resolved after treatment of CAH. Olav Nielssen St. Vincent’s Hospital Clinical Research Unit for Anxiety and Depression level 4, O’Brien Building, Victoria Street Darlinghurst, NSW, 2000 Australia E-mail: [email protected] D. Jane Holmes-Walker Department Endocrinology Westmead Hospital Sydney, Australia Matthew Large School of Psychiatry University of New South Wales Sydney, Australia BIOL PSYCHIATRY 2011;69:e21– e22 © 2011 Society of Biological Psychiatry
e22 BIOL PSYCHIATRY 2011;69:e21– e22
Correspondence Kate Steinbeck
The Children’s Hospital at Westmead and University of Sydney Sydney, Australia This article was not funded. Dr. Nielssen interviewed Ms. AB to prepare a report for court, obtained AB’s permission to prepare the report, performed a literature search, and wrote the first draft of the paper. Dr. Holmes-Walker was Ms. AB’s treating endocrinologist and provided additional historical details and added to the discussion. Dr. Large conducted a further literature search and revised the paper. Professor Steinbeck drew on her expertise in this area to contribute to the discussion. We thank Ms. AB, who gave the first author permission to prepare this report. All authors report no biomedical financial interests or potential conflicts of interest. 1. Merke DP, Bornstein SR (2005): Congenital adrenal hyperplasia. Lancet 365:2125–2136. 2. Fazel S, Lichtenstein P, Grann M, Goodwin G, Langstrom N (2010): Bipolar disorder and violent crime. New evidence from population based longitudinal studies and systematic review. Arch Gen Psychiatry 67:931– 938. 3. Nielssen O, Westmore B, Large M, Hayes R (2007): Homicide in psychotic illness in New South Wales 1993-2002. Med J Aust 186:301–304. 4. Large M, Smith G, Nielssen O (2009): The relationship between the rate of homicide by those with schizophrenia and the overall homicide rate: A systematic review and meta-analysis. Schizophr Res 112:123–129.
www.sobp.org/journal
5. Meyer-Bahlburg HF, Dolezal C, Baker SW, New MI (2008): Sexual orientation in women with classical or non-classical congenital adrenal hyperplasia as a function of degree of prenatal androgen excess. Arch Sex Behav 37:85–99. 6. Pasterski V, Hindmarsh P, Geffner M, Brook C, Brain C, Hines M (2007): Increased aggression and activity level in 3- to 11-year-old girls with congenital adrenal hyperplasia (CAH). Horm Behav 52:368 –374. 7. Berenbaum SA, Resnick SM (1997): Early androgen effects on aggression in children and adults with congenital adrenal hyperplasia. Psychoneuroendocrinology 22:505–515. 8. Ernst M, Maheu FS, Schroth E, Hardin J, Golan LG, Cameron J, et al. (2007): Amygdala function in adolescents with congenital adrenal hyperplasia: A model for the study of early steroid abnormalities. Neuropsychologia 45:2104 –2113. 9. Keely EJ, Matwijiw I, Thliveris JA, Faiman C (1993): Congenital adrenal hyperplasia with testicular tumours, aggression and gonadal failure. Urology 41:346 –349. 10. Pope HG, Katz DL (1990): Homicide and near-homicide by anabolic steroid users. J Clin Psychiatry 51:28 –31. 11. Pope HG, Katz DL (1994): Psychiatric and medical effects of anabolicandrogenic steroid use. A controlled study of 160 athletes. Arch Gen Psychiatry 51:375–382. 12. Van Goozen SH, Cohen-Kettenis PT, Gooren LJ, Frijda NH, Van de Poll NE (1995): Gender differences in behaviour: Activating effects of cross-sex hormones. Psychoneuroendocrinology 20:343–363. 13. Liang HY, Chang HL, Chen CY, Chang PY, Lo FS, Lee LW (2008): Psychiatric manifestations in young females with congenital adrenal hyperplasia in Taiwan. Chang Gung Med J 31:66 –73.
doi:10.1016/j.biopsych.2010.09.058