General Hospital Psychiatry xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
General Hospital Psychiatry journal homepage: http://www.ghpjournal.com
Case Report
Priapism associated with iloperidone: a case report Lisette A. Rodriguez-Cabezas, M.D. ⁎, Betty Y. Kong, Ph.D., Gaurava Agarwal, M.D. Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois
a r t i c l e
i n f o
Article history: Received 7 January 2014 Revised 12 March 2014 Accepted 18 March 2014 Available online xxxx Keywords: Priapism Iloperidone Antipsychotics Bipolar Psychosis
a b s t r a c t Priapism is a known side effect of antipsychotics. The causal mechanism seems to be mediated through α1adrenergic receptor blockade which many antipsychotics are known to possess. We present the first detailed case of iloperidone-induced priapism in a patient with bipolar disorder with psychotic features. His case highlights some of the important risk factors clinicians should consider when using iloperidone, as it may be the highest-risk antipsychotic for causing priapism given it is a very potent blocker of the alpha-adrenergic receptor. © 2014 Published by Elsevier Inc.
1. Introduction Priapism is a prolonged painful erection that persists beyond sexual stimulation [1]. While rare, priapism is a well-recognized medical emergency given its potential long-term sequelae, including erectile dysfunction, urinary retention and gangrene [2]. First-generation and second-generation antipsychotics have been associated with priapism [3]. Ischemic priapism, which accounts for 95% of all priapism cases and is the predominant type reported with antipsychotic medications, results from dysregulation of blood flow in the corpora cavernosa, leading to tissue hypoxia and acidosis [4]. The molecular mechanism thought to cause this dysregulation involves the blocking affinity of antipsychotic medications for the α1-adrenergic receptors in the corpora cavernosa, leading to arteriodilatation and inhibition of detumescence [5,6]. Indeed, one study demonstrated an increased odds ratio of priapism for antipsychotics with high α1 affinity compared with those with low/medium α1 affinity [6]. Additionally, a review of the literature identified 50 case reports of priapism linked to various antipsychotics, 38 of which were due to antipsychotics with high α1 blockade (clozapine, risperidone, ziprasidone, quetiapine) [5]. Iloperidone is a newer atypical antipsychotic medication and is the most potent drug at the α1 receptor of all antipsychotic medications tested. It is almost 10-fold higher in potency than the next most potent antipsychotic, ziprasidone [7]. Given this receptor binding profile, one might predict more side effects of iloperidone related to its high α1 binding affinity, including the risk of priapism. Indeed, ⁎ Corresponding author. Northwestern University Feinberg School of Medicine, Department of Psychiatry and Behavioral Sciences, 446 East Ontario Street, Suite 7-100, Chicago, IL 60611, United States. Tel.: +1 312 926 8100; fax: +1 312 694 0872. E-mail address: [email protected] (L.A. Rodriguez-Cabezas).
compared to other antipsychotic medications, iloperidone caused more orthostatic hypotension [8]. Other common adverse reactions reported include dry mouth, fatigue, nasal congestion, somnolence and weight gain [8]. Lastly, a rare but concerning side effect of iloperidone and many second-generation antipsychotics is prolongation of the QTc interval, a cardiac electrical abnormality that predisposes patients to ventricular arrhythmias and thus obligates routine electrocardiogram monitoring while on the medications [9]. While three cases of priapism were reported during premarketing evaluation of iloperidone, no detailed reports have thus far been published in the literature [8]. Here, we describe the first case of a patient with bipolar disorder with psychotic features who experienced an episode of priapism after starting iloperidone. 2. Case presentation A 42-year-old white male with bipolar I disorder with psychotic features and diabetes mellitus type 2 presented for management of his priapism. For his bipolar disorder, the patient had been taking 1500 mg of lithium and 80 mg paroxetine per day. The patient had been taking these two medications for a long time without notable issues. Two weeks prior to presentation, he began displaying symptoms of acute mania, including decreased need for sleep, agitation and irritability. His psychiatrist initiated iloperidone 6 mg daily and lowered paroxetine to 40 mg. The patient weighed 245 lb, with calculated body mass index of 37.2. The patient developed a sustained painful erection after two doses of iloperidone, approximately 24 h after initiation of the medication. He denied changes in any of his other medications or recent use of recreational drugs, including heroin, cocaine, alcohol or anabolic steroids. He also denied any recent sexual activity. Despite urological intervention with corporeal aspiration, irrigation with phenylephrine
http://dx.doi.org/10.1016/j.genhosppsych.2014.03.011 0163-8343/© 2014 Published by Elsevier Inc.
Please cite this article as: Rodriguez-Cabezas L.A., et al, Priapism associated with iloperidone: a case report, Gen Hosp Psychiatry (2014), http://dx.doi.org/10.1016/j.genhosppsych.2014.03.011
e2
L.A. Rodriguez-Cabezas et al. / General Hospital Psychiatry xxx (2014) xxx–xxx
and a Winter’s shunt, his priapism was refractory to these treatments. Iloperidone and paroxetine were discontinued at this time. He was observed for 3 days, and no surgical intervention was required as the phallus detumesced with milking. He was able to urinate on his own and achieve nocturnal erections approximately 6 days after the last dose of iloperidone. The patient continued to be paranoid, grandiose, hyperverbal, disorganized and irritable. Lurasidone was started due to its low alpha blockade potential. Although the patient was improving, he suddenly refused continuation of lurasidone but agreed to initiate aripiprazole, which he reported tolerating well in the past. Aripiprazole was uptitrated to 20 mg, and his mood stabilized with resolution of psychotic symptoms. He tolerated all medications well with complete resolution of his presenting symptoms and without return of priapism. 3. Discussion Priapism is a serious medical condition that can lead to permanent penile damage. There were several factors that may have led our patient to have increased risk of development of priapism with initiation of iloperidone. First, our patient was concurrently taking paroxetine. The metabolism of iloperidone is mediated by CYP2D6, and paroxetine is a known potent CYP2D6 inhibitor [10,11]. The coadministration of iloperidone with CYP2D6 inhibitors has been reported to cause a 2.3-fold increase in iloperidone plasma exposure [12]. Therefore, the patient should have been started on no more than half the normal starting dose of iloperidone to reduce the risk of adverse events [13]. Our patient was also diabetic, which may have further increased his risk for priapism [5]. One case reported repeated episodes of priapism in a patient on risperidone, trazadone, quetiapine and olanzapine who was found to have elevated blood glucose levels [14]. Previously, he had been on risperidone, trazadone and quetiapine with normal blood glucose levels and no documented episodes of priapism. This suggests that the risk of priapism may be aggravated by poor glucose control. Another risk factor for priapism in our patient may be the coadministration of lithium with iloperidone, as several cases have been reported in patients taking lithium and risperidone concurrently [15]. It was suggested that lithium may potentiate the
α-adrenegric blocking activity of risperidone. Lastly, according to the Naranjo algorithm, a questionnaire used to calculate the probability of a certain adverse event in relation to a specific drug, this patient scored 6 out of 13, suggesting that his priapism was a probable adverse drug reaction from the iloperidone. In conclusion, we report here the first case report of iloperidoneassociated priapism. Clinicians should be aware of possible risk factors that may increase the risk of the development of priapism when starting iloperidone as it may pose a higher risk of priapism at baseline given its mechanism of action. References [1] Montague DK, Jarow J, Broderick GA, Dmochowski RR, Heaton JP, Lue TF, et al. American Urological Association guideline on the management of priapism. J Urol 2003;170:1318–24. [2] El-Bahnasawy MS, Dawood A, Farouk A. Low-flow priapism: risk factors for erectile dysfunction. BJU Int 2002;89:285–90. [3] Salonia A, Eardley I, Giuliano F, Hatzichristou D, Moncada I, Vardi Y, et al. European Association of Urology guidelines on priapism. Eur Urol 2014;65:480–9. [4] Broderick GA, Kadioglu A, Bivalacqua TJ, Ghanem H, Nehra A, Shamloul R. Priapism: pathogenesis, epidemiology, and management. J Sex Med 2010;7:476–500. [5] Sood S, James W, Bailon MJ. Priapism associated with atypical antipsychotic medications: a review. Int Clin Psychopharmacol 2008;23:9–17. [6] Andersohn F, Schmedt N, Weinmann S, Willich SN, Garbe E. Priapism associated with antipsychotics: role of alpha1 adrenoceptor affinity. J Clin Psychopharmacol 2010;30:68–71. [7] Richelson E, Souder T. Binding of antipsychotic drugs to human brain receptors focus on newer generation compounds. Life Sci 2000;68:29–39. [8] Vanda Pharmaceuticals I. Fanapt (iloperidone) package insert. Rockville, MD; 2013. [9] Iloperidone (Fanapt) — another second-generation antipsychotic. Med Lett Drugs Ther 2010;52:13–4 [quiz 17]. [10] Ereshefsky L, Riesenman C, Lam YW. Antidepressant drug interactions and the cytochrome P450 system. The role of cytochrome P450 2D6. Clin Pharmacokinet 1995;29(Suppl. 1):10–8 [discussion 18-9]. [11] Citrome L. Iloperidone: chemistry, pharmacodynamics, pharmacokinetics and metabolism, clinical efficacy, safety and tolerability, regulatory affairs, and an opinion. Expert Opin Drug Metab Toxicol 2010;6:1551–64. [12] Clinical pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2013. [13] Weiden PJ. Iloperidone for the treatment of schizophrenia: an updated clinical review. Clin Schizophr Relat Psychoses 2012;6:34–44. [14] du Toit RM, Millson RC, Heaton JP, Adams MA. Priapism. Can J Psychiatry 2004;49:868–9. [15] Paklet L, Abe AM, Olajide D. Priapism associated with risperidone: a case report, literature review and review of the South London and Maudsley hospital patients' database. Ther Adv Psychopharmacol 2013;3:3–13.
Please cite this article as: Rodriguez-Cabezas L.A., et al, Priapism associated with iloperidone: a case report, Gen Hosp Psychiatry (2014), http://dx.doi.org/10.1016/j.genhosppsych.2014.03.011
Contents lists available at ScienceDirect
General Hospital Psychiatry journal homepage: http://www.ghpjournal.com
Case Report
Priapism associated with iloperidone: a case report Lisette A. Rodriguez-Cabezas, M.D. ⁎, Betty Y. Kong, Ph.D., Gaurava Agarwal, M.D. Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois
a r t i c l e
i n f o
Article history: Received 7 January 2014 Revised 12 March 2014 Accepted 18 March 2014 Available online xxxx Keywords: Priapism Iloperidone Antipsychotics Bipolar Psychosis
a b s t r a c t Priapism is a known side effect of antipsychotics. The causal mechanism seems to be mediated through α1adrenergic receptor blockade which many antipsychotics are known to possess. We present the first detailed case of iloperidone-induced priapism in a patient with bipolar disorder with psychotic features. His case highlights some of the important risk factors clinicians should consider when using iloperidone, as it may be the highest-risk antipsychotic for causing priapism given it is a very potent blocker of the alpha-adrenergic receptor. © 2014 Published by Elsevier Inc.
1. Introduction Priapism is a prolonged painful erection that persists beyond sexual stimulation [1]. While rare, priapism is a well-recognized medical emergency given its potential long-term sequelae, including erectile dysfunction, urinary retention and gangrene [2]. First-generation and second-generation antipsychotics have been associated with priapism [3]. Ischemic priapism, which accounts for 95% of all priapism cases and is the predominant type reported with antipsychotic medications, results from dysregulation of blood flow in the corpora cavernosa, leading to tissue hypoxia and acidosis [4]. The molecular mechanism thought to cause this dysregulation involves the blocking affinity of antipsychotic medications for the α1-adrenergic receptors in the corpora cavernosa, leading to arteriodilatation and inhibition of detumescence [5,6]. Indeed, one study demonstrated an increased odds ratio of priapism for antipsychotics with high α1 affinity compared with those with low/medium α1 affinity [6]. Additionally, a review of the literature identified 50 case reports of priapism linked to various antipsychotics, 38 of which were due to antipsychotics with high α1 blockade (clozapine, risperidone, ziprasidone, quetiapine) [5]. Iloperidone is a newer atypical antipsychotic medication and is the most potent drug at the α1 receptor of all antipsychotic medications tested. It is almost 10-fold higher in potency than the next most potent antipsychotic, ziprasidone [7]. Given this receptor binding profile, one might predict more side effects of iloperidone related to its high α1 binding affinity, including the risk of priapism. Indeed, ⁎ Corresponding author. Northwestern University Feinberg School of Medicine, Department of Psychiatry and Behavioral Sciences, 446 East Ontario Street, Suite 7-100, Chicago, IL 60611, United States. Tel.: +1 312 926 8100; fax: +1 312 694 0872. E-mail address: [email protected] (L.A. Rodriguez-Cabezas).
compared to other antipsychotic medications, iloperidone caused more orthostatic hypotension [8]. Other common adverse reactions reported include dry mouth, fatigue, nasal congestion, somnolence and weight gain [8]. Lastly, a rare but concerning side effect of iloperidone and many second-generation antipsychotics is prolongation of the QTc interval, a cardiac electrical abnormality that predisposes patients to ventricular arrhythmias and thus obligates routine electrocardiogram monitoring while on the medications [9]. While three cases of priapism were reported during premarketing evaluation of iloperidone, no detailed reports have thus far been published in the literature [8]. Here, we describe the first case of a patient with bipolar disorder with psychotic features who experienced an episode of priapism after starting iloperidone. 2. Case presentation A 42-year-old white male with bipolar I disorder with psychotic features and diabetes mellitus type 2 presented for management of his priapism. For his bipolar disorder, the patient had been taking 1500 mg of lithium and 80 mg paroxetine per day. The patient had been taking these two medications for a long time without notable issues. Two weeks prior to presentation, he began displaying symptoms of acute mania, including decreased need for sleep, agitation and irritability. His psychiatrist initiated iloperidone 6 mg daily and lowered paroxetine to 40 mg. The patient weighed 245 lb, with calculated body mass index of 37.2. The patient developed a sustained painful erection after two doses of iloperidone, approximately 24 h after initiation of the medication. He denied changes in any of his other medications or recent use of recreational drugs, including heroin, cocaine, alcohol or anabolic steroids. He also denied any recent sexual activity. Despite urological intervention with corporeal aspiration, irrigation with phenylephrine
http://dx.doi.org/10.1016/j.genhosppsych.2014.03.011 0163-8343/© 2014 Published by Elsevier Inc.
Please cite this article as: Rodriguez-Cabezas L.A., et al, Priapism associated with iloperidone: a case report, Gen Hosp Psychiatry (2014), http://dx.doi.org/10.1016/j.genhosppsych.2014.03.011
e2
L.A. Rodriguez-Cabezas et al. / General Hospital Psychiatry xxx (2014) xxx–xxx
and a Winter’s shunt, his priapism was refractory to these treatments. Iloperidone and paroxetine were discontinued at this time. He was observed for 3 days, and no surgical intervention was required as the phallus detumesced with milking. He was able to urinate on his own and achieve nocturnal erections approximately 6 days after the last dose of iloperidone. The patient continued to be paranoid, grandiose, hyperverbal, disorganized and irritable. Lurasidone was started due to its low alpha blockade potential. Although the patient was improving, he suddenly refused continuation of lurasidone but agreed to initiate aripiprazole, which he reported tolerating well in the past. Aripiprazole was uptitrated to 20 mg, and his mood stabilized with resolution of psychotic symptoms. He tolerated all medications well with complete resolution of his presenting symptoms and without return of priapism. 3. Discussion Priapism is a serious medical condition that can lead to permanent penile damage. There were several factors that may have led our patient to have increased risk of development of priapism with initiation of iloperidone. First, our patient was concurrently taking paroxetine. The metabolism of iloperidone is mediated by CYP2D6, and paroxetine is a known potent CYP2D6 inhibitor [10,11]. The coadministration of iloperidone with CYP2D6 inhibitors has been reported to cause a 2.3-fold increase in iloperidone plasma exposure [12]. Therefore, the patient should have been started on no more than half the normal starting dose of iloperidone to reduce the risk of adverse events [13]. Our patient was also diabetic, which may have further increased his risk for priapism [5]. One case reported repeated episodes of priapism in a patient on risperidone, trazadone, quetiapine and olanzapine who was found to have elevated blood glucose levels [14]. Previously, he had been on risperidone, trazadone and quetiapine with normal blood glucose levels and no documented episodes of priapism. This suggests that the risk of priapism may be aggravated by poor glucose control. Another risk factor for priapism in our patient may be the coadministration of lithium with iloperidone, as several cases have been reported in patients taking lithium and risperidone concurrently [15]. It was suggested that lithium may potentiate the
α-adrenegric blocking activity of risperidone. Lastly, according to the Naranjo algorithm, a questionnaire used to calculate the probability of a certain adverse event in relation to a specific drug, this patient scored 6 out of 13, suggesting that his priapism was a probable adverse drug reaction from the iloperidone. In conclusion, we report here the first case report of iloperidoneassociated priapism. Clinicians should be aware of possible risk factors that may increase the risk of the development of priapism when starting iloperidone as it may pose a higher risk of priapism at baseline given its mechanism of action. References [1] Montague DK, Jarow J, Broderick GA, Dmochowski RR, Heaton JP, Lue TF, et al. American Urological Association guideline on the management of priapism. J Urol 2003;170:1318–24. [2] El-Bahnasawy MS, Dawood A, Farouk A. Low-flow priapism: risk factors for erectile dysfunction. BJU Int 2002;89:285–90. [3] Salonia A, Eardley I, Giuliano F, Hatzichristou D, Moncada I, Vardi Y, et al. European Association of Urology guidelines on priapism. Eur Urol 2014;65:480–9. [4] Broderick GA, Kadioglu A, Bivalacqua TJ, Ghanem H, Nehra A, Shamloul R. Priapism: pathogenesis, epidemiology, and management. J Sex Med 2010;7:476–500. [5] Sood S, James W, Bailon MJ. Priapism associated with atypical antipsychotic medications: a review. Int Clin Psychopharmacol 2008;23:9–17. [6] Andersohn F, Schmedt N, Weinmann S, Willich SN, Garbe E. Priapism associated with antipsychotics: role of alpha1 adrenoceptor affinity. J Clin Psychopharmacol 2010;30:68–71. [7] Richelson E, Souder T. Binding of antipsychotic drugs to human brain receptors focus on newer generation compounds. Life Sci 2000;68:29–39. [8] Vanda Pharmaceuticals I. Fanapt (iloperidone) package insert. Rockville, MD; 2013. [9] Iloperidone (Fanapt) — another second-generation antipsychotic. Med Lett Drugs Ther 2010;52:13–4 [quiz 17]. [10] Ereshefsky L, Riesenman C, Lam YW. Antidepressant drug interactions and the cytochrome P450 system. The role of cytochrome P450 2D6. Clin Pharmacokinet 1995;29(Suppl. 1):10–8 [discussion 18-9]. [11] Citrome L. Iloperidone: chemistry, pharmacodynamics, pharmacokinetics and metabolism, clinical efficacy, safety and tolerability, regulatory affairs, and an opinion. Expert Opin Drug Metab Toxicol 2010;6:1551–64. [12] Clinical pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2013. [13] Weiden PJ. Iloperidone for the treatment of schizophrenia: an updated clinical review. Clin Schizophr Relat Psychoses 2012;6:34–44. [14] du Toit RM, Millson RC, Heaton JP, Adams MA. Priapism. Can J Psychiatry 2004;49:868–9. [15] Paklet L, Abe AM, Olajide D. Priapism associated with risperidone: a case report, literature review and review of the South London and Maudsley hospital patients' database. Ther Adv Psychopharmacol 2013;3:3–13.
Please cite this article as: Rodriguez-Cabezas L.A., et al, Priapism associated with iloperidone: a case report, Gen Hosp Psychiatry (2014), http://dx.doi.org/10.1016/j.genhosppsych.2014.03.011
