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

 

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