Dr. Adler is professor and Mr. Shaw is a research assistant in the Department of Psychiatry, both at New York University (NYU) School of Medicine in New York City. Dr. Sitt is a psychologist at the Hallowell Center in New York City. Ms. Maya is Clinical Trials Coordinator at the William and Sylvia Silberstein Institute for Aging and Dementia at NYU School of Medicine. Ms. Morrill is a graduate research assistant at the Center for Couples and Family Research and a doctoral student in clinical psychology at Clark University in Worcester, Massachussetts.

Disclosure: Dr. Adler is consultant to Eli Lilly, McNeil/Johnson & Johnson, the National Institute on Drug Abuse (NIDA), Organon, Psychogenics, sanofi-aventis, and Shire; is on the speaker’s bureaus of McNeil/Johnson & Johnson and Shire; and receives research support from Bristol-Myers Squibb, Eli Lilly, McNeil/Johnson & Johnson, the NIDA, and Shire. Mr. Shaw, Dr. Sitt, Ms. Maya, and Ms. Morrill report no affiliation with or financial interest in any organization that may pose a conflict of interest.

Acknowledgments: This study was commissioned by the New York University School of Medicine in cooperation with Eli Lilly and was funded in part by a research grant from Eli Lilly.

Please direct all correspondence to: Lenard A. Adler, MD, Department of Psychiatry, NYU School of Medicine, 530 First Ave #7D, New York, NY 10016; Tel: 212-263-3580; Fax: 212-263-3581; E-mail: lenard.adler@nyumc.org.


 

Focus Points

• This article explores new findings about issues with diagnosing and treating attention-deficit/hyperactivity disorder (ADHD) in adults by primary care physicians (PCPs).
• Despite a high rate of prevalence and significant impairments, most adults with ADHD have not been diagnosed and remain untreated.
• PCPs had less training and had lower comfort levels treating adults with ADHD than with depression and anxiety disorders.
• PCPs were more likely to refer adult patients with ADHD to specialists for diagnosis and/or treatment than they were for adult patients with major depressive disorder or generalized anxiety disorder.
• PCPs would be more likely to diagnose adult ADHD if quick, easy-to-use screening tools were developed and validated.

 

Abstract

Introduction: The objective of this article is to compare primary care physicians’ (PCPs’) experiences with diagnosing and treating adult attention-deficit/hyperactivity disorder (ADHD) versus other mental health disorders.


Methods: Four hundred PCPs who have patients with ADHD, bipolar disorder, depression, generalized anxiety disorder (GAD), or obsessive-compulsive disorder completed a public release survey assessing their experiences and attitudes on diagnosing and treating these disorders.


Results: Forty-eight percent of PCPs felt uncomfortable diagnosing adult ADHD and 44% reported that there were no clear diagnostic criteria. Seventy-five percent rated the quality and accuracy of existing adult ADHD diagnostic tools as either poor or fair. Seventy-two percent reported that ADHD is easier to diagnose in children than adults. Sixty-five percent reported deferring to specialists to diagnose adult ADHD, compared to 2% for depression and 3% for GAD. Eighty-five percent reported that they would be more comfortable diagnosing and treating adult ADHD if thorough, straightforward screening tools were validated and if there were effective medications that were neither stimulants nor controlled substances.


Discussion: While this survey indicated that adult ADHD is generally accepted by PCPs, the results also indicate that PCPs are significantly less likely to diagnose and treat ADHD in adults without deferring to a specialist, when compared to GAD and depression.  The recent development of new screening tools for adult ADHD as well as non-stimulant and novel stimulant medications may reduce PCPs’ reliance on specialist referrals.


Conclusion: This study highlights a potential need for PCPs for increased education and training in adult ADHD.  As the study was conducted 6 years ago, follow-up investigations into the current PCP awareness of adult ADHD are indicated.

Introduction

Attention-deficit/hyperactivity disorder (ADHD) is a chronic and commonly occurring neuropsychiatric disorder that is usually first diagnosed in childhood and is associated with an inability to sustain attention and/or an inability to regulate motor behavior.1 Research has shown ADHD to negatively impact attention,2,3 behavioral inhibition,2,3 memory,2,3 and functional outcomes2,4-8 in many settings of daily life including home,2,9 school,2,5 work,2,5 driving,5,10 and interpersonal relationships.5,10

The prevalence of ADHD in children is approximately 6% to 8% world wide11 and it is estimated that 66% continue to meet full criteria or partial criteria with significant impairment as adults, indicating that as many as 8 million adults in the United States have the disorder.4,12-15 The National Comorbidity Survey Replication (NCS-R), a nationally representative survey conducted in the US between 2001–2003 of ~10,000 English-speaking household residents ≥18 years of age, demonstrated that the prevalence of ADHD in adults in the US is ~4.4%.16

While recognition of adult ADHD has grown recently in the medical community and general population, the disorder remains under-recognized and under-treated when compared to other commonly occurring mental health disorders such as mood, anxiety, or substance use disorders.17 Results from a 2005 survey found that ~1.5 million adults in the US were diagnosed with and receiving treatment for ADHD, indicating that only 1 in 4 adults with the disorder have been diagnosed and are receiving adequate medical attention.18 The NCS-R found that >40% of respondents who met the criteria for ADHD reported that they had not been previously diagnosed with the disorder despite seeing a healthcare professional in the previous year.16,19 In fact, only 10% of the sample with ADHD had received treatment for the disorder within the year prior to the interview.16 Furthermore, only 25% of respondents with ADHD who had received treatment within the previous year for a mental health or substance use disorder reported also receiving treatment for ADHD.16

The principal goal of this study was to examine the experiences and attitudes of primary care physicians (PCPs) regarding the diagnosis and treatment of ADHD in adults through a public release survey. For some portions of the survey, PCPs were asked to also rate their experiences and attitudes regarding other disorders such as major depressive disorder (MDD), generalized anxiety disorder (GAD), bipolar disorder, and obsessive-compulsive disorder (OCD).

Methods

The survey was approved by the New York University School of Medicine Institutional Board of Research Associates. Participants in the survey included 400 PCPs recruited randomly from the master directory of the American Medical Association. Physicians were selected using the following criteria. First, they were currently practicing as part of a family, general, or internal medicine practice Second, they had been practicing for at least 2 years. Last, they were currently treating at least 30 adult patients per week with any combination of the target disorders, which were ADHD, bipolar disorder, MDD, GAD, or OCD. These disorders were chosen because they are commonly occurring, impairing disorders characterized by low rates of diagnosis and adequate treatment among patients in treatment.20-22

Potential participants were mailed an invitation to participate in an online survey. Each invitation explained the purpose of the research in general terms and contained a unique password and URL to access the survey. Passwords were provided for security purposes and to prevent duplicate responding. The survey was made available online from May 14—May 28, 2003 by Harris Interactive. Physicians completing the survey received a $40 honorarium. Fewer than 40% of physicians who received the invitation completed the survey. Demographic information of the physicians can be found in Table 1.

 

 

The survey asked the physicians to rate the following items on a five-point scale from lowest (ie, poor) to highest (ie, extremely knowledgeable/thorough): their knowledge of the target disorders; the quality of their education and/or training received regarding the target disorders; their perceptions regarding specific aspects relating to the diagnosis and treatment of adult ADHD (ie, adult ADHD is more difficult to diagnose than childhood ADHD); their perception regarding the quality of diagnostic tools available for the target disorders; and their perception regarding the importance of specific qualities/parameters necessary for an effective screening tool for adult ADHD. Lastly, physicians were asked to rate the frequency that they refer patients to a specialist for the treatment of each of the target disorders and the reasons why they collaborate with or defer to a specialist when diagnosing adult ADHD.

All reported significance refers to 95% confidence, using unweighted data. Descriptive results are reported for all analyses. For the purposes of explanation, a data reduction was performed when presenting results for items rated on a five-point scale and results are hereafter presented only for the two highest-rated items.

Results

Knowledge Differential

Respondents reported that they saw significantly more patients in an average week with depression and GAD than any of the other three target disorders (Table 2). This correlated with the finding that respondents consider themselves significantly more knowledgeable about both MDD and GAD than they are about bipolar disorder, OCD, or ADHD (Figure 1). Only 34% of respondents answered that they were either very or extremely knowledgeable about adult ADHD (Figure 1). Furthermore, only 13% of respondents reported that they had received very or extremely thorough clinical training in adult ADHD which was significantly less than all of the other target disorders except for OCD (Figure 2). Seventy-seven percent of physicians reported that they believe that adult ADHD is not well understood by the medical community (Figure 3).

 

 

 

 

Knowledge and Understanding of Adult ADHD in Primary Care

Somewhat contrary to the reported lack of knowledge and understanding of adult ADHD, only 26% of respondents concurred that ADHD is a condition that the vast majority of children outgrow (Figure 3). However, 72% reported that it is more difficult to diagnose ADHD in adulthood than in childhood (Figure 3). Nearly half of respondents reported that they were not confident in their ability to diagnose ADHD in adults (48%) and believe that there are no clear criteria for diagnosing adults with the disorder (44%; Figure 3). Seventy-three percent of respondents reported that the underlying symptoms of ADHD are similar in children and adults but the manifestations of these symptoms differ throughout the life course (Figure 3).

Dependence on Referrals

Only 35% of respondents reported that they would diagnose adult ADHD without referring patients to a specialist, whereas the vast majority reported that they would diagnose major depression (98%) and GAD (97%) themselves (Figure 4). Respondents reported that they were most likely to refer adult patients seeking a diagnosis of ADHD to either a psychiatrist (86%) or psychologist (55%; Figure 5). Fifty-two percent of respondents attributed inexperience or lack of confidence as the primary reason for collaborating with or deferring to specialists when diagnosing adult ADHD, and 22% reported that they believed adult ADHD to have no clear diagnostic criteria (Figure 6). Furthermore, only 5% of respondents reported that they make the final decision regarding medication when treating adult ADHD with 42% reporting that they collaborate with specialists and 53% reporting that they refer their adult ADHD patients to specialists.

 

 

 

 

Need for an Adult ADHD Screening Tool

Ratings of the quality of adult ADHD screening tools were significantly worse compared to screening tools for the other target disorders. Seventy-five percent of respondents reported that they thought the quality and accuracy of diagnostic tools for adult ADHD was either poor or fair (Figure 7). Eighty-five percent of respondents indicated that they would take a more active role in diagnosing and treating adult ADHD if an easy-to-use, relatively quick to administer screening tool was developed and validated by physicians or institutions they respect (Figure 8). However, only ~50% of respondents indicated that screening tools for adult ADHD should be based on the current Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition23 criteria for diagnosing ADHD in children (Figure 8).

 

 

Need for Alternative Treatments

A significant number of respondents (13%) reported that they refer adult ADHD patients to specialists for treatment because many of the pharmacologic treatments, such as methylphenidate and amphetamines, are psychostimulants and controlled substances (Figure 6). Seventy-five percent of respondents indicated that they would take a more active role in diagnosing and treating adult ADHD if effective, non-stimulant medications that were not controlled substances were available (Figure 3).

Discussion

While the results of this survey indicate that adult ADHD is generally accepted by PCPs, it also highlighted a need within the primary care community for more education and training in diagnosing and treating adults with the disorder. Although the majority of respondents reported that they thought the underlying symptoms of ADHD are the same for children and adults, they indicated that they thought adults manifest these symptoms differently than children and that the disorder is more difficult to diagnose in adulthood than in childhood. This difficulty may be partially attributed to the DSM-IV criteria for ADHD, which often reflect behavior in school or playground settings, being the same for both children and adults.6,24-27

Although the willingness of PCPs to diagnose and treat adult ADHD without deferring to a specialist was strikingly low when compared with MDD and GAD, the majority of respondents reported that they would be more active in diagnosing and treating adult ADHD if they had an easy-to-use, validated screening tool. It should be noted that since this survey was conducted, the Adult ADHD Self-Report (ASRS) v1.1 Screener has been developed and validated. The ASRS v.1. Screener uses adult-specific, context-based language to identify adults at risk for ADHD.28,29 The ASRS v1.1 Screener is self-administered and contains the six symptoms of ADHD psychometrically determined to be most predictive of the disorder.19,29 The ASRS v1.1 Screener has shown good sensitivity and specificity and has a positive predictive value between 57% and 93%.29,30 The ASRS is also available in an 18-item format (ASRS v1.1 Symptom Checklist), which contains the 18 items corresponding to the adult presentation of ADHD symptoms in the DSM-IV. The ASRS v1.1 Screener and Symptom Checklist are copyrighted by the World Health Organization and are available at no cost on the Internet.31,32

The majority of respondents also reported that they would be more active in treating adult ADHD if non-stimulant medications that were not controlled substances were available. Around the same time that this survey was conducted, the first non-stimulant medication, atomoxetine, was approved and released for the treatment of adult ADHD. Additionally, the first pro-drug stimulant, lisdexamfetamine dimesylate, with a reduced overdose toxicity and drug tampering, was recently approved for the treatment of pediatric and adult ADHD.33-37 Together with the availability of novel extended-release formulations of traditional psychostimulants and the advent of non-stimulant and safer stimulant medications as viable treatment options, the reluctance to treat adult ADHD amongst the primary care community may be reduced.

There were several limitations to the current investigation. First, <40% of the selected PCPs completed the survey, which may indicate a selection bias. Second, the survey was conducted in 2003 and there has likely been an increase in the awareness and familiarity of adult ADHD amongst PCPs as well as the general population. Third, advances made in the understanding of adult ADHD in the scientific community as well as the development of new diagnostic/symptom assessment scales and medications may have had a positive impact on the willingness of PCPs to diagnose and treat the disorder in adults.

Conclusion

Although the prevalence of adult ADHD is comparable to that of MDD and GAD, this survey highlighted a potential need amongst PCPs for more education and training in adult ADHD. However, follow-up investigations into the current PCP awareness of adult ADHD are needed as new, easy-to-use screening tools for adult ADHD and non-stimulant and novel stimulant medications have been developed in the 6 years since the survey was conducted. PP

References

1. Barkley RA. Genetics of childhood disorders: XVII. ADHD, part 1: the executive functions and ADHD. J Am Acad Child Adolesc Psychiatry. 2000;39(8):1064-1068.
2. Spencer T, Biederman J, Wilens T, Faraone SV. Is attention-deficit hyperactivity disorder in adults a valid disorder? Harv Rev Psychiatry. 1994;1(6):326-335.
3. Hervey AS, Epstein JN, Curry JF. Neuropsychology of adults with attention-deficit/hyperactivity disorder: a meta-analytic review. Neuropsychology. 2004;18(3):485-503.
4. Biederman J, Monuteaux MC, Mick E, et al. Young adult outcome of attention deficit hyperactivity disorder: a controlled 10 year follow-up study. Psychol Med. 2006;36(2):167-179.
5. Barkley RA. Major life activity and life outcomes associated with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2002;63(suppl 12):10-15.
6. Barkley RA. Development course, adult outcome, and clinic-referred ADHD adults. In: Barkley RA. Attention Deficit Hyperactivity Disorder: A Handbook for Diagnosis and Treatment. 2nd ed. New York, NY: Guilford Press; 1998:186-224.
7. Biederman J, Petty C, Fried R, Fontanella J, Doyle AE, Seidman LJ. Impact of psychometrically defined deficits of executive functioning in adults with attention deficit hyperactivity disorder. Am J Psychiatry. 2006;163(10):1730-8.
8. Biederman J, Faraone, SV, Spencer TJ, Mick E, Monuteaux MC, Aleardi M. Functional impairments in adults with self-reports of diagnosed ADHD: a controlled study of 1001 adults in the community. J Clin Psychiatry. 2006;67(4):524-40.
9. Eakin L, Minde K, Hechtman L, et al. The marital and family functioning of adults with ADHD and their spouses. J Atten Disord. 2004;8:1-10.
10. Barkley RA, Murphy KR, Dupaul GI, Bush T. Driving in young adults with attention deficit hyperactivity disorder: knowledge, performance, adverse outcomes, and the role of executive functioning. J Int Neuropsychol Soc. 2002;8(5):655-672.
11. Faraone SV, Sergeant J, Gillberg C, Biederman J. The worldwide prevalence of ADHD: is it an American condition? World Psychiatry. 2003;2(2):104-113.
12. Biederman J, Faraone SV, Keenen K, Knee D, Tsuang MT. Family-genetic and psychosocial risk factors in DSM-III attention deficit disorder. J Am Acad Child Adolesc Psychiatry. 1990;29(4):526-533.
13. Mannuzza S, Klein RG, Bessler A, Malloy P, LaPadula M. Adult outcome of hyperactive boys: educational achievement, occupational rank, and psychiatric status. Arch Gen Psychiatry. 1993;50(7):565-576.
14. Weiss G, Hechtman L. Hyperactive Children Grow Up: ADHD in Children, Adolescents, and Adults. 2nd ed. New York, NY: Guilford Press; 1993.
15. Elliot H. Attention deficit hyperactivity disorder in adults: a guide for the primary care physician. South Med J. 2002;95(7):736-742.
16. Kessler RC, Adler L, Barkley R, et al. The prevalence and correlates of adult ADHD in the united states: results from the national comorbidity survey replication. Am J Psychiatry. 2006;163(4):716-723.
17. Wang PS, Lane M, Olfson M, Pincus HA, Wells KB, Kessler RC. Twelve-month use of mental health services in the united states: results from the national comorbidity survey replication. Arch Gen Psychiatry. 2005;62(6):629-640.
18. Castle L, Aubert RE, Verbrugge RR, Khalid M, Epstein RS. Trends in medication treatment for ADHD. J Atten Disord. 2007;10(4):335-342.
19. Kessler RC, Adler LA, Barkley R, et al. Patterns and predictors of attention-deficit/hyperactivity disorder persistence into adulthood: results from the national comorbidity survey replication. Biol Psychiatry. 2005;57(11):1442-1451.
20. Wittchen HU, Carter RM, Pfister H, Montgomery SA, Kessler RC. Disabilities and quality of life in pure and comorbid generalized anxiety disorder and major depression in a national survey. Int Clin Psychopharmacol. 2000;15(6):319-328.
21. Wittchen HU, Kessler RC, Beesdo K, Krause P, Hofler M, Hoyer J. Generalized anxiety and depression in primary care: prevalence, recognition, and management. J Clin Psychiatry. 2002;63(suppl 8):24-34.
22. Üstün TB, Sartorius N. Mental Illness in General Health Care: An International Study. Chichester, UK: John Wiley & Sons; 1995.
23. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
24. Sallee F, Smirnov A. Atomoxetine: novel therapy for attention-deficit/hyperactivity disorder and potential therapeutic implications. Primary Psychiatry. 2003;10(4):41-48.
25. Murphy K, Barkley RA. Attention deficit hyperactivity disorder in adults: comorbidities and adaptive impairments. Compr Psychiatry. 1996;37(6): 393-401.
26. Sachdev P. Attention deficit hyperactivity disorder in adults. Psychol Med. 1999;29(3):507-514.
27. Stein MA, Fischer M, Szumowski E. Evaluation of adults for ADHD. J Am Acad Child Adolesc Psychiatry. 1999;38(8):940-941.
28. Adler LA, Spencer T, Faraone SV, et al. Validity of pilot adult ADHD self-report scale (ASRS) to rate adult ADHD symptoms. Ann Clin Psychiatry. 2006;18(3):145-148.
29. Kessler RC, Adler L, Ames M, et al. The World Health Organization Adult ADHD Self-Report Scale (ASRS): a short screening scale for use in the general population. Psychol Med. 2005;35(2):245-56.
30. Kessler RC, Adler LA, Gruber MJ, Sarawate CA, Spencer T, Van Brunt DL. Validity of the world health organization adult ADHD self-report scale (ASRS) screener in a representative sample of health plan members. Int J Methods Psychiatr Res. 2007;16(2):52-65.
31. Adult ADHD Self-Report Scale (ASRS-v1.1) Symptom Checklist Instructions. Available at: www.med.nyu.edu/psych/assets/adhdscreen18.pdf. Accessed March 31, 2009.
32. Adult Self-Report Scale-V1.1 (ASRS-V1.1) Screener. Available at: www.med.nyu.edu/psych/assets/adhdscreener.pdf. Accessed March 31, 2009.
33. Biederman J, Krishnan S, Zhang Y, McGough JJ, Findling RL. Efficacy and tolerability of lisdexamfetamine dimesylate (NRP-104) in children with attention-deficit/hyperactivity disorder: a phase III, multicenter, randomized, double-blind, forced-dose, parallel-group study. Clin Ther. 2007;29(3):450-63.
34. Biederman J, Boellner SW, Childress A, Lopez FA, Krishnan S, Zhang Y. Lisdexamfetamine dimesylate and mixed amphetamine salts extended-release in children with ADHD: a double-blind, placebo-controlled, crossover analog classroom study. Biol Psychiatry. 2007;62(9):970-6.
35. Krishnan S, Montcrief S. Toxicity profile of lisdexamfetamine dimesylate in three independent rat toxicology studies. Basic Clin Pharmacol Toxicol. 2007;101(4):231-40.
36. Krishnan SM, Stark JG. Multiple daily-dose pharmacokinetics of lisdexamfetamine dimesylate in healthy adult volunteers. Curr Med Res Opin. 2008;24(1):33-40.
37. Faraone SV, Upadhyaya HP. The effect of stimulant treatment for ADHD on later substance abuse and the potential for medication misuse, abuse, and diversion. J Clin Psychiatry. 2007;68(11):e28.

 

Drs. Choua and Lee are residents in the Department of Psychiatry at Elmhurst Hospital Center at the Mount Sinai School of Medicine in New York City. Dr. Castro is a fellow at Child Study Center at Yale University in New Haven, Connecticut. Drs. Zapata-Vega and Maurer are assistant professors of psychiatry at the Mount Sinai School of Medicine.

Disclosures: The authors report no affiliation with or financial interest in any orgnization that may pose a conflict of interest.
Acknowledgments: The authors would like to thank Drs. M. Rondon, A. Altamirano, and C. Longshore for their contributions.

Please direct all correspondence to: Raquel Choua, MD, Resident, Dept of Psychiatry, Elmhurst Hospital Center, Mount Sinai School of Medicine, 79-01 Broadway H-3-111, Elmhurst, NY 11373; Tel: 718-334-3995; Fax: 718-334-5721; E-mail: Raquel.Choua@mssm.edu.


 

Focus Points

• Priapism has multiple etiologies, including sickle cell anemia, leukemia, and perineal trauma.
• Priapism, a urologic emergency, is a rare but potentially disabling adverse event caused by alcohol, illicit drugs, and some psychiatric medications.
• Cases of priapism, before the advent of sildenafil, were associated with typical antipsychotics in approximately 15% to 20% of medication-induced priapism cases.
• The most likely mechanism of medication-induced priapism is through a-adrenergic blockade.
• Co-administration of two or more psychotropic medications may increase the risk of developing priapism in a patient  through inhibition of enzymatic pathways that may lead to drug-drug interactions with increased a-adrenergic blockade.
• Clinicians should assess psychotropic-induced sexual side effects and educate patients about the potentially serious consequences of untreated priapism.


Abstract

Priapism is a prolonged and unwanted erection of the penis, unrelated to sexual stimulation; some psychotropic medications may be among its multiple causes. The following is a report of a 23-year-old male who developed prolonged erections followed by multiple episodes of priapism on a combination of sertraline with three atypical antipsychotics—risperidone, olanzapine, and quetiapine—administered consecutively, as well as lesser episodes on quetiapine monotherapy. No episodes were developed in the patient on combinations of sertraline and aripiprazole or ziprasidone given for a shorter amount of time. Other causes of priapism were ruled out. A literature search was conducted on Pubmed/Medline to locate cases of priapism associated with the specific psychotropic medications given to the patient. Several cases of priapism associated to atypical antipsychotics were found—risperidone (17), olanzapine (12), quetiapine (5), aripiprazole (2), and ziprasidone (3), both in monotherapy and in combination with other psychotropics. Three cases were found involving sertraline, one of them in combination with risperidone. Antipsychotic-induced priapism seems to be linked to a1-adrenergic blockage. Sertraline antagonizes the a1-adrenergic receptors and has an inhibitory effect on some of the cytochromes that also metabolize antipsychotics. According to the literature consulted, history of prolonged erections, concurrent medications, and medical conditions (eg, sickle cell disease) may be linked to the development of priapism. In men with a history of priapism or at risk for priapism, selection of psychotropics with low a-adrenergic antagonism and attention to the potential interactions of drugs is advisable. Clinicians should ask about sexual side effects (eg, prolonged erections), educate patients about the potentially serious consequences of untreated priapism, and promptly refer for urological evaluation when needed.

 

Introduction

Priapism is a prolonged and unwanted erection of the penis, often unrelated to sexual stimulation.1 Priapism is classified in two types, including high-flow or “non-ischemic” priapism in which well-oxygenated blood accumulates in the penis and low-flow, or “ischemic” priapism in which venous blood persists in the corpora cavernosa.2 The latter category is the one associated with antipsychotics and is considered a urologic emergency with potentially serious long-term complications such as impotence that can develop in 40% to 50% of the patients, regardless of treatment.3

A review of the literature on priapism by Thompson and  colleagues,3 before the advent of sildenafil, indicated that medications were associated with 15% to 41% of cases; typical antipsychotics were the most commonly implicated, accounting for 15% to 26% of medication-induced cases, followed by antihypertensive medications involved in 11% to 14% of the total cases of priapism. The most likely mechanism of psychotropic-induced priapism is an increase in parasympathetic tone, in relation to sympathetic tone, through a-blockade obstructing the venous drainage from the corpora cavernosa of the penis.2,3

 

Case Report

A young man developed priapism on several antipsychotics, both during monotherapy and in combination with sertraline. The patient, a 23-year-old Hispanic male, was referred to psychiatry from a primary care clinic, with an approximately 1-year history and previous treatment of depressive symptoms and bizarre delusions. A primary care physician had treated him initially with mirtazapine 15 mg/day, buspirone 10 mg BID, and olanzapine 10 mg/day. Later, he was placed on sertraline 100 mg/day, quetiapine 100 mg/day, and hydroxyzine 50 mg at bedtime, but as per his own report compliance was partial.

The patient was started on sertraline 150 mg/day and risperidone 1 mg at bedtime. During the first month of treatment he developed three episodes of prolonged erections and one documented episode of priapism which resolved spontaneously while in the medical emergency room (ER).

The patient had never experienced erectile abnormalities prior to starting psychotropic medications. He was found to have hypertriglyceridemia, but had no history of perineal trauma, medical illnesses (such as sickle cell disease, diabetes, malignancies, or infections), use of alcohol, or medications for the treatment of erectile dysfunction. His screening for drugs of abuse was negative. Therefore, urologic service diagnosed this episode as “risperidone-induced priapism.”

To prevent further episodes of priapism, his treatment was changed to aripiprazole 10 mg/day while sertraline was continued at 150 mg/day. On this combination, he reported symptoms suggestive of akathisia; therefore, aripiprazole was discontinued and olanzapine 10 mg at bedtime was started while sertraline was increased to 200 mg/day to target his mood symptoms. He reported three additional episodes of priapism during the 2 weeks he was on this new regimen.

Olanzapine was discontinued and he was started on ziprasidone 40 mg/day. Soon after, the patient required inpatient stabilization for worsening of psychotic symptoms. While hospitalized, ziprasidone was optimized up to 100 mg BID, while clonazepam 1 mg TID and hydroxyzine 50 mg used as needed were added for symptomatic relief of anxiety and insomnia. He did not report any episodes of priapism while on ziprasidone but this medication was replaced with quetiapine, since the patient continued to exhibit psychotic features. After six weeks of hospitalization, he was discharged on sertraline 200 mg/day and quetiapine 600 mg at bedtime.  During the following month, the patient experienced two more events of priapism; nevertheless, he did not seek medical attention due to spontaneous resolution.

The presence of bizarre delusions and significant negative symptoms of psychosis led to the consideration of schizophrenia undifferentiated type as the most likely diagnosis. In view of his repeated episodes of priapism, sertraline was tapered down gradually (50 mg every month) during a 4-month period until discontinuation, while quetiapine was increased up to 700 mg/day. During this time, he suffered three more episodes of priapism. During the first months after discontinuing sertraline and decreasing quetiapine back to 600 mg, he visited the medical ER after a 6-hour period of painful erection that resolved spontaneously. He was seen one more time by the urologic service and given pseudoephedrine to take as needed for 1 month. Shortly after, he reported one additional episode of prolonged erection.

Interestingly, he presented with one additional episode of priapism approximately 1 year after total discontinuation of sertraline, while being maintained on quetiapine 600 mg. For the following 9 months, until the patient stopped coming for treatment, he remained without further sexual side effects. Throughout the course of treatment, the patient had limited contact with the urologic service in spite of repeated warnings regarding the potential long-term consequences of untreated priapism. The Figure shows the number of prolonged erections and priapism episodes reported by the patient during psychiatric outpatient and medical ER visits, as well as the number of days on each therapeutic regimen.

 

 

Discussion

It is more likely that the patient’s episodes of both prolonged erections and priapism were related to medication since other major potential causes were ruled out.

In terms of his general health, the only abnormal finding was hypertriglyceridemia. There is one case reported in the urologic literature of a patient whose priapism was most likely due to this metabolic disturbance.4 Nonetheless, the aforementioned patient suffered from diabetes as well and his levels of triglycerides were 12 times the upper limit of normal values. In this patient, the highest levels registered were three times the normal values and he developed priapism after having normal lipid panels as well. In addition, the onset of priapism was clearly temporally related to the initiation or increase in doses of psychotropic medications.

As per the Pubmed/Medline search (from 1994 to the third week of February 2007) conducted by the authors of this article, there are 17 reported cases of priapism associated with risperidone,5-21 12 with olanzapine18,22-32 (one of which corresponds to a case of clitoral priapism32), five with quetiapine,19,33-36 three with ziprasidone,10,37,38 and two with aripiprazole39,40 (both in monotherapy and in combination with other psychotropic medications). Literature also reports priapism associated with the selective serotonin reuptake inhibitor (SSRI) sertraline alone41 and in combination with lithium42 and risperidone.20 It should be noted that the number of cases published in the literature is most likely a reflection of publication bias and the length of time the medications have been available; it is in no way a reflection on the prevalence of priapism associated with each particular medication.

As reported by Thompson and colleagues,3 data suggest that as many as 50% of the patients presenting with priapism after taking antipsychotics have a prior history of painless prolonged erections, lasting <1 hour, as it was the case in the described patient as well as in other examples included in the search conducted by the authors of this article.5,9,20

In general, it is believed that priapism constitutes an idiosyncratic reaction, where doses of medication may play little role and can occur at any time during treatment with antipsychotics.3,43 Nonetheless, there have been cases that go against this general notion. For example, there is a recent case report of a patient who developed priapism while receiving risperidone by mouth and intramuscularly but did not experience any adverse events when the medication was used either by mouth or through injection. The authors concluded that the additive effects of the doses led to priapism.13

Even though the patient in this case report was switched to different atypical antipsychotics, with less α1-adrenergic blockade affinity than risperidone, he continued to experience priapism. The recurrence of priapism despite changes in medications is a described issue in the literature3 and is related, most likely, to the α1-adrenergic blockade properties of most antipsychotics. According to Richelson,44 ziprasidone and risperidone are the drugs with most affinity for the receptor, among the atypical antipsychotics. Other antipsychotics, such as clozapine, quetiapine, loxapine, and olanzapine, have a lower affinity for the a1 receptors, which may translate into fewer sexual side effects.

The patient in the case presented in this article developed most of the episodes of priapism while on a combination of sertraline and atypical antipsychotics. Sertraline has an antagonistic property at α1-adrenergic receptors, at least 10-fold more than other SSRIs.45,46 Moreover, sertraline is metabolized by the cytochrome P450 (CYP) enzyme systems, specifically at 2C9, 3A4, 2C19, 2D6 and 2B6,47 and exhibits an inhibitory activity on several CYP enzymes.45 The inhibitory effect on the enzymes may have increased the levels of antipsychotics that were metabolized through the same pathway, thus, overloading the clearance system. The higher levels of antipsychotics in his system, as a result of the pharmacokinetic interaction, may have elevated the risk for the development of priapism. An example of this interaction could have been the case with quetiapine that is metabolized through CYP 3A4.48 Sertraline acts as an inhibitor in this enzymatic pathway. Risperidone is metabolized as well at the CYP 2D6,49 another enzymatic pathway that is inhibited by sertraline. In the case of olanzapine, it is metabolized mainly by CYP 1A4 and 2D6,50 and sertraline, as mentioned before, inhibits CYP 2D6.

It is also a known fact that there are individuals that produce functionally abnormal or poorly active forms of CYP 2D6.51 In these individuals, the metabolism of medications can be altered by the mentioned deficiencies. As our patient was not tested with genotyping or phenotyping procedures, and blood levels of antipsychotics were not tested, it is difficult to state that he could be included among the “poor metabolizers.” Nonetheless, the idea that the enzymatic pathways were poorly functional could explain, at least in part, the fast “overload” of these systems, especially when an inhibitor of the cytochromes was a component of his treatment.

The lack of episodes of priapism while the patient was on a combination of ziprasidone (known to have a high affinity for a-adrenergic receptors)44,52 and sertraline remains unclear to the authors of this article. One of the possibilities explored was that hydroxyzine or clonazepam, through the anticholinergic and γ-aminobutyric acid (GABA) agonist activity, respectively, exerted a protective effect; thus, the patient was prevented from having an episode of priapism. A search looking for data pointing toward the possibility of using these medications in the setting of priapism was performed on Medline. The authors of this article found a report of a patient who developed prolonged penile erection while on hydroxyzine.53 In the case of clonazepam, this benzodiazepine has been associated with erectile dysfunction.54 According to the urologic literature reviewed, GABA agonists such as baclofen have been used in the treatment of priapism, but clonazepam appears to be an adjunctive agent used only with the purpose of decreasing the distress of the person suffering from this adverse event.55  

 

Conclusion

When approaching patients with history of priapism associated with psychiatric medication, clinicians should be aware of the possibility of recurrence of this adverse event despite changes in antipsychotics. It is the psychiatrist’s responsibility to make a prompt referral to urology service if the patient develops priapism, since it constitutes a medical emergency.

When using a combination of medications, it is important to select psychotropics with low α-adrenergic antagonism in a patient at risk and to consider the potential interactions of the drugs. Moreover, clinicians should be able to ask about sexual side effects and history of prolonged erections in order to educate their patients about the potentially serious consequences of leaving episodes of priapism untreated. Due to the variable association between dose and priapism, it is advisable to monitor the patient on a regular basis, especially when modifications of treatment are performed. PP

 

References

1. Pautler SE, Brock GB. Priapism: from priapus to the present time. Urol Clin North Am. 2001;28(2):391-403.
2. Compton MT, Miller AH. Priapism associated with conventional and atypical antipsychotic medications: a review. J Clin Psychiatry. 2001;62(5):362-366.
3. Thompson JW, Ware MR, Blashfield RK. Psychotropic medication and priapism: A comprehensive review. J Clin Psychiatry. 1990;51(10)430-433.
4. Gerstenbluth RE, Kick PS, Srodes AD, Seftel AD. Priapism secondary to hypertriglyceridemia. J Urol. 2003;169(3):1088.
5. Tekell JL, Smith EA, Silva JA. Prolonged erection associated with risperidone treatment. Am J Psychiatry. 1995;152(7):1097.
6. Ankem MK, Ferlise VJ, Han KR, Gazi MA, Koppisch AR, Weiss RE. Risperidone-induced priapism. Scand J Urol Nephrol. 2002;36(1):91-92.
7. Nicolson R, McCurley R. Risperidone-associated priapism. J Clin Psychopharmacol. 1997;17(2):133-134.
8. Owley T, Leventhal B, Cook EH Jr. Risperidone-induced prolonged erections following the addition of Lithium. J Child Adolesc Psychopharmacol. 2001;11(4):441-442.
9. Relan P, Gupta N, Mattoo SK. A case of risperidone-induced priapism. J Clin Psychiatry. 2003;64(4):482-483.
10. Reeves RR, Mack JE. Priapism associated with two atypical antipsychotic agents. Pharmacotherapy. 2002;22(8):1070-1073.
11. Freudenreich O. Exacerbation of idiopathic priapism with risperidone-citalopram combination. J Clin Psychiatry. 2002;63(3):249-250.
12. Emes CE, Millson RC. Risperidone-induced priapism. Can J Psychiatry. 1994;39(5):315-316.
13. Kirshner A, Davis RR. Priapism associated with the switch from oral to injectable risperidone. J Clin Psychopharmacol. 2006;26(6):626-628.
14. Madhusoodanan S, Brenner R. Risperidone-associated priapism in an elderly man. Am J Geriatr Psychiatry. 2002;10(3):355.
15. Yang P, Tsai JH. Occurrence of priapism with risperidone-paroxetine combination in an autistic child. J Child Adolesc Psychopharmacol. 2004;14(3):342-343.
16. Slauson SD, LoVecchio F. Risperidone-induced priapism with rechallenge. J Emerg Med. 2004;27(1):88-89.
17. Bourgeois JA, Mundh H. Priapism associated with risperidone: a case report. J Clin Psychiatry. 2003;64(2):218-219.
18. Seger A, Lamberti JS. Priapism associated with polypharmacy. J Clin Psychiatry. 2001;62(2):128.
19. du Toit RM, Millson RC, Heaton JP, Adams MA. Priapism. Can J Psychiatry. 2004;49(12):868-869.
20. Haberfellner EM. Priapism with sertraline-risperidone combination. Pharmacopsychiatry. 2007;40(1):44-45.
21. Makesar D,Thome J.Risperidone-induced priapism. World J Biol Psychiatry. 2007;8(1):45-47.
22. Deirmenjian JM, Erhart SM, Wirshing DA, Spellberg BJ, Wirshing WC. Olanzapine-induced reversible priapism: a case report. J Clin Psychopharmacol. 1998;18(4):351-353.
23. Weisman RL. Quetiapine in the successful treatment of schizophrenia with comorbid alcohol and drug dependence: a case report. Int J Psychiatry in Medicine. 2003;33(1):85-89.
24. Jagadheesan K, Thakur A, Akhtar S. Irreversible priapism during olanzapine and Lithium therapy. Aust N Z J Psychiatry. 2004;38(5):381.
25. Songer DA, Barclay JC. Olanzapine-induced priapism. Am J Psychiatry, 2001;158(12):2087-2088.
26. Childers JB, Schwartz AC, Compton MT. Olanzapine-associated priapism. Psychosomatics. 2003;44(4):351-352.
27. Matthews SC, Dimsdale JE. Priapism after a suicide attempt by ingestion of olanzapine and gabapentin. Psychosomatics. 2001;42(3):280-281.
28. Kuperman JR, Asher I, Modai I. Olanzapine-associated priapism. J Clin Psychopharmacol. 2001;21(2):247.
29. Compton MT, Saldivia A, Berry SA. Recurrent priapism during treatment with clozapine and olanzapine. Am J Psychiatry. 2000;157(4):659.
30. Gordon M, de Groot CM. Olanzapine-associated priapism. J Clin Psychopharmacol. 1999;19(2):192.
31. Heckers S, Anick D, Boverman JF, Stern TA. Priapism following olanzapine administration in a patient with multiple sclerosis. Psychosomatics. 1998;39(3):288-290.
32. Bucur M, Mahmood T. Olanzapine-induced clitoral priapism. J Clin Psychopharmacol. 2004;24(5):572-573.
33. Pais VM, Ayvazian PJ. Priapism from quetiapine overdose: first report and proposal of mechanism. Urology. 2001;58(3):462.
34. Harrison G, Dilley JW, Loeb L, Nelson K. Priapism and quetiapine: a case report. Psychopharmacol Bull. 2006;39(1):117-119.
35. Davol P, Rukstalis D. Priapism associated with routine use of quetiapine: case report and review of the literature. Urology. 2005;66(4):880.
36. Andrés Prado MJ, Vidal Formoso M. Priapism associated with quetiapine in an elderly patient [Spanish]. Actas Esp Psyquiatr. 2006;34(3):209-210.
37. Reeves RR, Kimble R. Prolonged erections associated with ziprasidone treatment: a case report. J Clin Psychiatry. 2003;64(1):97-98.
38. Kaufman KR, Stern L, Mohebati A, Olsavsky A, Hwang J. Ziprasidone-induced priapism requiring surgical treatment. Eur Psychiatry. 2006;21(1):48-50.
39. Mago R, Anolik R, Johnson RA, Kunkel EJ. Recurrent priapism associated with use of aripiprazole. J Clin Psychiatry. 2006;67(9):1471-1472.
40. Negin B, Murphy TK. Priapism associated with oxcarbazepine, aripiprazole, and lithium. J Am Acad Child Adolesc Psychiatry. 2005;44(12):1223-1224.
41. Rand EH. Priapism in a patient taking sertraline. J Clin Psychiatry. 1998;59(10):538.
42. Mendelson WB, Franko T. Priapism with sertraline and lithium. J Clin Psychopharmacol. 1994;14(6):434-435.
43. Weiner DM, Lowe FC. Psychotropic drug-induced priapism. Incidence, mechanism and management. CNS Drugs. 1998;9(5):371-379.
44. Richelson E. Receptor pharmacology of neuroleptics: relation to clinical effects. J Clin Psychiatry. 1999;60(10):5-14.
45. Shim JJ, Yonkers KA. Sertraline. In: Schatzberg AF, and Nemeroff CB, eds. Textbook of Psychopharmacology. 3rd ed. Washington, DC: American Psychiatric Association Press; 2004:247-257.
46. Hiemke C, Hartter S. Pharmacokinetics of selective serotonin reuptake inhibitors, Pharmacol Ther. 2000;85(1):11-28.
47. Obach S, Cox L, Tremaine L. Sertraline is metabolized by multiple cytochrome P450 enzymes, monoaminoxidases and glucuronyltransferases in human: an in vitro study. Drug Metab Dispos. 2005;33:262-270.
48. Lieberman JA: Quetiapine. In: Schatzberg AF, and Nemeroff CB, eds. Textbook of Psychopharmacology. 3rd ed. Washington, DC: American Psychiatric Association Press; 2004:473-486.
49. Goff D. Risperidone. In: Schatzberg AF, and Nemeroff CB, eds. Textbook of Psychopharmacology. 3rd ed. Washington, DC: American Psychiatric Association Press; 2004:495-505.
50. Schulz SC, Olson S, Kotlyar M. Olanzapine. In: Schatzberg AF, and Nemeroff CB, eds. Textbook of Psychopharmacology. 3rd ed. Washington, DC: American Psychiatric Association Press; 2004:457-472.
51. Baker G.B, Fang J, Sinha S, Coutts T. Metabolic drug interactions with selective serotonin reuptake inhibitor antidepressants. Neurosci Biobehav Rev. 1998;22(2):325-333.
52. Daniel D, Copeland L, Tammiga C. Ziprasidone. In: Schatzberg AF, and Nemeroff CB, eds. Textbook of Psychopharmacology. 3rd ed. Washington, DC: American Psychiatric Association Press; 2004:507-518.
53. Thavundayil JX, Hambalek R, Kin NM, Krishnan B, Lal S. Prolonged penile erections induced by hydroxyzine: possible mechanism of action. Neuropsychobiology. 1994;30(1):4-6.
54. Fossey MD, Hamner MB. Clonazepam-related sexual dysfunction in male veterans with PTSD. Anxiety. 1994-1995;1(5):233-236.
55. Rourke KF, Fischler AH, Jordan GH. Treatment of recurrent idiopathic priapism with oral Baclofen. J Urol. 2002;168(6):255.

Return

 

Drs. Choua and Lee are residents in the Department of Psychiatry at Elmhurst Hospital Center at the Mount Sinai School of Medicine in New York City. Dr. Castro is a fellow at Child Study Center at Yale University in New Haven, Connecticut. Drs. Zapata-Vega and Maurer are assistant professors of psychiatry at the Mount Sinai School of Medicine.

Disclosures: The authors report no affiliation with or financial interest in any orgnization that may pose a conflict of interest.
Acknowledgments: The authors would like to thank Drs. M. Rondon, A. Altamirano, and C. Longshore for their contributions.

Please direct all correspondence to: Raquel Choua, MD, Resident, Dept of Psychiatry, Elmhurst Hospital Center, Mount Sinai School of Medicine, 79-01 Broadway H-3-111, Elmhurst, NY 11373; Tel: 718-334-3995; Fax: 718-334-5721; E-mail: Raquel.Choua@mssm.edu.


 

Focus Points

• Priapism has multiple etiologies, including sickle cell anemia, leukemia, and perineal trauma.
• Priapism, a urologic emergency, is a rare but potentially disabling adverse event caused by alcohol, illicit drugs, and some psychiatric medications.
• Cases of priapism, before the advent of sildenafil, were associated with typical antipsychotics in approximately 15% to 20% of medication-induced priapism cases.
• The most likely mechanism of medication-induced priapism is through a-adrenergic blockade.
• Co-administration of two or more psychotropic medications may increase the risk of developing priapism in a patient  through inhibition of enzymatic pathways that may lead to drug-drug interactions with increased a-adrenergic blockade.
• Clinicians should assess psychotropic-induced sexual side effects and educate patients about the potentially serious consequences of untreated priapism.


Abstract

Priapism is a prolonged and unwanted erection of the penis, unrelated to sexual stimulation; some psychotropic medications may be among its multiple causes. The following is a report of a 23-year-old male who developed prolonged erections followed by multiple episodes of priapism on a combination of sertraline with three atypical antipsychotics—risperidone, olanzapine, and quetiapine—administered consecutively, as well as lesser episodes on quetiapine monotherapy. No episodes were developed in the patient on combinations of sertraline and aripiprazole or ziprasidone given for a shorter amount of time. Other causes of priapism were ruled out. A literature search was conducted on Pubmed/Medline to locate cases of priapism associated with the specific psychotropic medications given to the patient. Several cases of priapism associated to atypical antipsychotics were found—risperidone (17), olanzapine (12), quetiapine (5), aripiprazole (2), and ziprasidone (3), both in monotherapy and in combination with other psychotropics. Three cases were found involving sertraline, one of them in combination with risperidone. Antipsychotic-induced priapism seems to be linked to a1-adrenergic blockage. Sertraline antagonizes the a1-adrenergic receptors and has an inhibitory effect on some of the cytochromes that also metabolize antipsychotics. According to the literature consulted, history of prolonged erections, concurrent medications, and medical conditions (eg, sickle cell disease) may be linked to the development of priapism. In men with a history of priapism or at risk for priapism, selection of psychotropics with low a-adrenergic antagonism and attention to the potential interactions of drugs is advisable. Clinicians should ask about sexual side effects (eg, prolonged erections), educate patients about the potentially serious consequences of untreated priapism, and promptly refer for urological evaluation when needed.

 

Introduction

Priapism is a prolonged and unwanted erection of the penis, often unrelated to sexual stimulation.1 Priapism is classified in two types, including high-flow or “non-ischemic” priapism in which well-oxygenated blood accumulates in the penis and low-flow, or “ischemic” priapism in which venous blood persists in the corpora cavernosa.2 The latter category is the one associated with antipsychotics and is considered a urologic emergency with potentially serious long-term complications such as impotence that can develop in 40% to 50% of the patients, regardless of treatment.3

A review of the literature on priapism by Thompson and  colleagues,3 before the advent of sildenafil, indicated that medications were associated with 15% to 41% of cases; typical antipsychotics were the most commonly implicated, accounting for 15% to 26% of medication-induced cases, followed by antihypertensive medications involved in 11% to 14% of the total cases of priapism. The most likely mechanism of psychotropic-induced priapism is an increase in parasympathetic tone, in relation to sympathetic tone, through a-blockade obstructing the venous drainage from the corpora cavernosa of the penis.2,3

 

Case Report

A young man developed priapism on several antipsychotics, both during monotherapy and in combination with sertraline. The patient, a 23-year-old Hispanic male, was referred to psychiatry from a primary care clinic, with an approximately 1-year history and previous treatment of depressive symptoms and bizarre delusions. A primary care physician had treated him initially with mirtazapine 15 mg/day, buspirone 10 mg BID, and olanzapine 10 mg/day. Later, he was placed on sertraline 100 mg/day, quetiapine 100 mg/day, and hydroxyzine 50 mg at bedtime, but as per his own report compliance was partial.

The patient was started on sertraline 150 mg/day and risperidone 1 mg at bedtime. During the first month of treatment he developed three episodes of prolonged erections and one documented episode of priapism which resolved spontaneously while in the medical emergency room (ER).

The patient had never experienced erectile abnormalities prior to starting psychotropic medications. He was found to have hypertriglyceridemia, but had no history of perineal trauma, medical illnesses (such as sickle cell disease, diabetes, malignancies, or infections), use of alcohol, or medications for the treatment of erectile dysfunction. His screening for drugs of abuse was negative. Therefore, urologic service diagnosed this episode as “risperidone-induced priapism.”

To prevent further episodes of priapism, his treatment was changed to aripiprazole 10 mg/day while sertraline was continued at 150 mg/day. On this combination, he reported symptoms suggestive of akathisia; therefore, aripiprazole was discontinued and olanzapine 10 mg at bedtime was started while sertraline was increased to 200 mg/day to target his mood symptoms. He reported three additional episodes of priapism during the 2 weeks he was on this new regimen.

Olanzapine was discontinued and he was started on ziprasidone 40 mg/day. Soon after, the patient required inpatient stabilization for worsening of psychotic symptoms. While hospitalized, ziprasidone was optimized up to 100 mg BID, while clonazepam 1 mg TID and hydroxyzine 50 mg used as needed were added for symptomatic relief of anxiety and insomnia. He did not report any episodes of priapism while on ziprasidone but this medication was replaced with quetiapine, since the patient continued to exhibit psychotic features. After six weeks of hospitalization, he was discharged on sertraline 200 mg/day and quetiapine 600 mg at bedtime.  During the following month, the patient experienced two more events of priapism; nevertheless, he did not seek medical attention due to spontaneous resolution.

The presence of bizarre delusions and significant negative symptoms of psychosis led to the consideration of schizophrenia undifferentiated type as the most likely diagnosis. In view of his repeated episodes of priapism, sertraline was tapered down gradually (50 mg every month) during a 4-month period until discontinuation, while quetiapine was increased up to 700 mg/day. During this time, he suffered three more episodes of priapism. During the first months after discontinuing sertraline and decreasing quetiapine back to 600 mg, he visited the medical ER after a 6-hour period of painful erection that resolved spontaneously. He was seen one more time by the urologic service and given pseudoephedrine to take as needed for 1 month. Shortly after, he reported one additional episode of prolonged erection.

Interestingly, he presented with one additional episode of priapism approximately 1 year after total discontinuation of sertraline, while being maintained on quetiapine 600 mg. For the following 9 months, until the patient stopped coming for treatment, he remained without further sexual side effects. Throughout the course of treatment, the patient had limited contact with the urologic service in spite of repeated warnings regarding the potential long-term consequences of untreated priapism. The Figure shows the number of prolonged erections and priapism episodes reported by the patient during psychiatric outpatient and medical ER visits, as well as the number of days on each therapeutic regimen.

 

 

Discussion

It is more likely that the patient’s episodes of both prolonged erections and priapism were related to medication since other major potential causes were ruled out.

In terms of his general health, the only abnormal finding was hypertriglyceridemia. There is one case reported in the urologic literature of a patient whose priapism was most likely due to this metabolic disturbance.4 Nonetheless, the aforementioned patient suffered from diabetes as well and his levels of triglycerides were 12 times the upper limit of normal values. In this patient, the highest levels registered were three times the normal values and he developed priapism after having normal lipid panels as well. In addition, the onset of priapism was clearly temporally related to the initiation or increase in doses of psychotropic medications.

As per the Pubmed/Medline search (from 1994 to the third week of February 2007) conducted by the authors of this article, there are 17 reported cases of priapism associated with risperidone,5-21 12 with olanzapine18,22-32 (one of which corresponds to a case of clitoral priapism32), five with quetiapine,19,33-36 three with ziprasidone,10,37,38 and two with aripiprazole39,40 (both in monotherapy and in combination with other psychotropic medications). Literature also reports priapism associated with the selective serotonin reuptake inhibitor (SSRI) sertraline alone41 and in combination with lithium42 and risperidone.20 It should be noted that the number of cases published in the literature is most likely a reflection of publication bias and the length of time the medications have been available; it is in no way a reflection on the prevalence of priapism associated with each particular medication.

As reported by Thompson and colleagues,3 data suggest that as many as 50% of the patients presenting with priapism after taking antipsychotics have a prior history of painless prolonged erections, lasting <1 hour, as it was the case in the described patient as well as in other examples included in the search conducted by the authors of this article.5,9,20

In general, it is believed that priapism constitutes an idiosyncratic reaction, where doses of medication may play little role and can occur at any time during treatment with antipsychotics.3,43 Nonetheless, there have been cases that go against this general notion. For example, there is a recent case report of a patient who developed priapism while receiving risperidone by mouth and intramuscularly but did not experience any adverse events when the medication was used either by mouth or through injection. The authors concluded that the additive effects of the doses led to priapism.13

Even though the patient in this case report was switched to different atypical antipsychotics, with less α1-adrenergic blockade affinity than risperidone, he continued to experience priapism. The recurrence of priapism despite changes in medications is a described issue in the literature3 and is related, most likely, to the α1-adrenergic blockade properties of most antipsychotics. According to Richelson,44 ziprasidone and risperidone are the drugs with most affinity for the receptor, among the atypical antipsychotics. Other antipsychotics, such as clozapine, quetiapine, loxapine, and olanzapine, have a lower affinity for the a1 receptors, which may translate into fewer sexual side effects.

The patient in the case presented in this article developed most of the episodes of priapism while on a combination of sertraline and atypical antipsychotics. Sertraline has an antagonistic property at α1-adrenergic receptors, at least 10-fold more than other SSRIs.45,46 Moreover, sertraline is metabolized by the cytochrome P450 (CYP) enzyme systems, specifically at 2C9, 3A4, 2C19, 2D6 and 2B6,47 and exhibits an inhibitory activity on several CYP enzymes.45 The inhibitory effect on the enzymes may have increased the levels of antipsychotics that were metabolized through the same pathway, thus, overloading the clearance system. The higher levels of antipsychotics in his system, as a result of the pharmacokinetic interaction, may have elevated the risk for the development of priapism. An example of this interaction could have been the case with quetiapine that is metabolized through CYP 3A4.48 Sertraline acts as an inhibitor in this enzymatic pathway. Risperidone is metabolized as well at the CYP 2D6,49 another enzymatic pathway that is inhibited by sertraline. In the case of olanzapine, it is metabolized mainly by CYP 1A4 and 2D6,50 and sertraline, as mentioned before, inhibits CYP 2D6.

It is also a known fact that there are individuals that produce functionally abnormal or poorly active forms of CYP 2D6.51 In these individuals, the metabolism of medications can be altered by the mentioned deficiencies. As our patient was not tested with genotyping or phenotyping procedures, and blood levels of antipsychotics were not tested, it is difficult to state that he could be included among the “poor metabolizers.” Nonetheless, the idea that the enzymatic pathways were poorly functional could explain, at least in part, the fast “overload” of these systems, especially when an inhibitor of the cytochromes was a component of his treatment.

The lack of episodes of priapism while the patient was on a combination of ziprasidone (known to have a high affinity for a-adrenergic receptors)44,52 and sertraline remains unclear to the authors of this article. One of the possibilities explored was that hydroxyzine or clonazepam, through the anticholinergic and γ-aminobutyric acid (GABA) agonist activity, respectively, exerted a protective effect; thus, the patient was prevented from having an episode of priapism. A search looking for data pointing toward the possibility of using these medications in the setting of priapism was performed on Medline. The authors of this article found a report of a patient who developed prolonged penile erection while on hydroxyzine.53 In the case of clonazepam, this benzodiazepine has been associated with erectile dysfunction.54 According to the urologic literature reviewed, GABA agonists such as baclofen have been used in the treatment of priapism, but clonazepam appears to be an adjunctive agent used only with the purpose of decreasing the distress of the person suffering from this adverse event.55  

 

Conclusion

When approaching patients with history of priapism associated with psychiatric medication, clinicians should be aware of the possibility of recurrence of this adverse event despite changes in antipsychotics. It is the psychiatrist’s responsibility to make a prompt referral to urology service if the patient develops priapism, since it constitutes a medical emergency.

When using a combination of medications, it is important to select psychotropics with low α-adrenergic antagonism in a patient at risk and to consider the potential interactions of the drugs. Moreover, clinicians should be able to ask about sexual side effects and history of prolonged erections in order to educate their patients about the potentially serious consequences of leaving episodes of priapism untreated. Due to the variable association between dose and priapism, it is advisable to monitor the patient on a regular basis, especially when modifications of treatment are performed. PP

 

References

1. Pautler SE, Brock GB. Priapism: from priapus to the present time. Urol Clin North Am. 2001;28(2):391-403.
2. Compton MT, Miller AH. Priapism associated with conventional and atypical antipsychotic medications: a review. J Clin Psychiatry. 2001;62(5):362-366.
3. Thompson JW, Ware MR, Blashfield RK. Psychotropic medication and priapism: A comprehensive review. J Clin Psychiatry. 1990;51(10)430-433.
4. Gerstenbluth RE, Kick PS, Srodes AD, Seftel AD. Priapism secondary to hypertriglyceridemia. J Urol. 2003;169(3):1088.
5. Tekell JL, Smith EA, Silva JA. Prolonged erection associated with risperidone treatment. Am J Psychiatry. 1995;152(7):1097.
6. Ankem MK, Ferlise VJ, Han KR, Gazi MA, Koppisch AR, Weiss RE. Risperidone-induced priapism. Scand J Urol Nephrol. 2002;36(1):91-92.
7. Nicolson R, McCurley R. Risperidone-associated priapism. J Clin Psychopharmacol. 1997;17(2):133-134.
8. Owley T, Leventhal B, Cook EH Jr. Risperidone-induced prolonged erections following the addition of Lithium. J Child Adolesc Psychopharmacol. 2001;11(4):441-442.
9. Relan P, Gupta N, Mattoo SK. A case of risperidone-induced priapism. J Clin Psychiatry. 2003;64(4):482-483.
10. Reeves RR, Mack JE. Priapism associated with two atypical antipsychotic agents. Pharmacotherapy. 2002;22(8):1070-1073.
11. Freudenreich O. Exacerbation of idiopathic priapism with risperidone-citalopram combination. J Clin Psychiatry. 2002;63(3):249-250.
12. Emes CE, Millson RC. Risperidone-induced priapism. Can J Psychiatry. 1994;39(5):315-316.
13. Kirshner A, Davis RR. Priapism associated with the switch from oral to injectable risperidone. J Clin Psychopharmacol. 2006;26(6):626-628.
14. Madhusoodanan S, Brenner R. Risperidone-associated priapism in an elderly man. Am J Geriatr Psychiatry. 2002;10(3):355.
15. Yang P, Tsai JH. Occurrence of priapism with risperidone-paroxetine combination in an autistic child. J Child Adolesc Psychopharmacol. 2004;14(3):342-343.
16. Slauson SD, LoVecchio F. Risperidone-induced priapism with rechallenge. J Emerg Med. 2004;27(1):88-89.
17. Bourgeois JA, Mundh H. Priapism associated with risperidone: a case report. J Clin Psychiatry. 2003;64(2):218-219.
18. Seger A, Lamberti JS. Priapism associated with polypharmacy. J Clin Psychiatry. 2001;62(2):128.
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