Trazodone-Induced Priapism and Increased Recurrence Risk With Antipsychotics

Priapism is a urologic emergency consisting of a painful penile erection lasting longer than 4 hours beyond orgasm or an erection unrelated to sexual stimulation (1, 2). The most common type of priapism is ischemic priapism, also known as low-flow veno-occlusive priapism, which accounts for more than 95% of all cases (1). Venous occlusion causes decreased cavernous arterial inflow, which leads to tissue hypoxia and, if untreated, irreparable damage to penile tissue (1, 2). Other forms include arterial (high-flow nonischemic) and stuttering (recurrent or intermittent) priapism (1). Priapism has been associated with substance use (including cocaine use), hematologic disorders (such as sickle cell anemia), and malignancy (1, 2). Oftentimes, the etiology of priapism is idiopathic, although when a source can be identified, it is most commonly associated with medications (most frequently psychotropic agents) (1, 2).

Trazodone, an antidepressant and insomnia aid, is perhaps the most widely discussed agent associated with priapism, with incidence rates between 1 out of 1,000 and 1 out of 10,000 (1). First-generation and second-generation antipsychotics have been associated with priapism, although less frequently than trazodone (2). The mechanism has yet to be fully identified, but the most widely accepted hypothesis is that antipsychotic-induced priapism is related to alpha-adrenergic receptor blockade in the corpus cavernosum (1, 2). Most antipsychotics are more potent at blocking alpha-1 than alpha-2 adrenergic receptors, although many antipsychotics act at both receptors (1). Blockade of the alpha-1 adrenergic receptors inhibits the sympathetic nervous system and prevents smooth muscle contraction and detumescence, and alpha-2 blockade exacerbates priapism by stimulating the release of nitric oxide-like substance, which is a potent muscle relaxant (1).

Here, we describe a case in which a patient, with a history of trazodone-induced priapism and a history of safe trials with clozapine, developed clozapine-induced priapism in the absence of trazodone.

Case Presentation

The patient was a 26-year-old man with a psychiatric history of schizoaffective disorder and cannabis use disorder and no other medical history. His outpatient services included an active assisted outpatient treatment order, which is a court order mandating psychiatric treatment, and an assertive community treatment team, which is a mobile psychiatric team that visits patients twice weekly in the community. He had multiple previous psychiatric hospitalizations, including lengthy state hospitalizations, and a history of trazodone-induced priapism, as described below. Informed consent was obtained from the patient after discharge via telephone and with the assistance of his outpatient providers.

During a previous hospitalization, the patient was effectively treated with clozapine, chlorpromazine, valproic acid, and trazodone as needed; he had no history of priapism at that time. Several months later, he presented to an emergency department complaining of a painful erection (lasting 1 day) and noted that he had taken a trazodone prior to this development. The priapism was managed with corporal aspiration, and he was discharged with instructions to discontinue trazodone. According to his outpatient treatment team, he had no further episodes of priapism after discontinuation of trazodone, and he continued taking his other medications. He was rehospitalized several months later and treated again with trazodone, in addition to valproic acid, lorazepam, chlorpromazine, and paliperidone palmitate (a long-acting injectable compound); clozapine had been discontinued. He again developed priapism, which self-resolved with discontinuation of trazodone (no urologic intervention was required).

Approximately 4 months later, the patient was admitted to our inpatient psychiatric unit for psychotic decompensation due to medication nonadherence. At the time of admission, his prescribed medications were paliperidone palmitate, olanzapine, and valproic acid. The inpatient team collaborated closely with his assertive community treatment team on deciding treatment plans, and the treatment team reported that he had done well on clozapine, although the exact dose was unclear. Given the patient’s history of a good response to clozapine, clozapine being listed as a primary treatment on his assisted outpatient treatment order (with a dose range of 50–900 mg), and his history of only a partial response to dual-antipsychotic therapies during periods of adherence, clozapine treatment was reinitiated. In addition, valproic acid was continued, and clonazepam was added for impulsivity and agitation. Over 9 days, the dose of clozapine was gradually increased to 250 mg at bedtime to target symptoms of psychosis, which had a partial effect.

On day 11 of this admission, the patient reported a persistently painful erection consistent with priapism. Urology was consulted, and corporal aspiration and drainage was conducted. Given concern for clozapine-induced priapism, the dose of clozapine was decreased to 200 mg; however, given persistent psychotic symptoms, cariprazine administration was cautiously initiated on day 15. Cariprazine was selected because there have been no reported cases of cariprazine-induced priapism, and it has a relatively weak affinity for alpha-1 adrenergic receptors. The patient improved on this regimen, particularly with respect to delusional thought content and impulsive and agitated behaviors. He was evaluated for medical causes of priapism, including sickle cell anemia, with no significant findings. The patient was observed for 7 days with no subsequent episodes of priapism before discharge.

Discussion

Antipsychotics are responsible for approximately 50% of cases of medication-induced priapism (1). Antipsychotics associated with priapism historically include first-generation antipsychotics within the phenothiazine class (such as chlorpromazine, perphenazine, and fluphenazine) that generally have high affinities for alpha-adrenergic receptors (3–15) (Table 1). Originally, second-generation antipsychotics were considered less likely than first-generation antipsychotics to cause priapism; however, the majority of second-generation antipsychotics have been linked to priapism to some degree (1). The first second-generation antipsychotic reported to cause priapism was clozapine, and more than 10 case reports of clozapine-induced priapism have been published to date (1) (Table 1).

The most significant risk factor for developing priapism is a history of prolonged erections (2). Up to 50% of patients with priapism were found to have a history of delayed detumescence (1). In this report, we described a patient with a history of suspected trazodone-induced priapism, although ultimately, a definite cause could not be established. The patient was stable, without priapism, on multiple dual-antipsychotic regimens, including clozapine and chlorpromazine, and he subsequently experienced clozapine-induced priapism in the absence of trazodone. Several medical conditions have been implicated as risk factors for the development of priapism, including hematologic dyscrasias, infections, neurogenic disorders, neoplasms, and diabetes (1–3); however, laboratory workup results for these medical comorbidities were negative for our patient. Although patients may develop priapism at any time during the administration of antipsychotic medications, it frequently occurs after initiating medication administration or with subsequent changes in the dose (1). Polypharmacy may increase the likelihood of priapism through synergistic effects of the medications, particularly when patients are concurrently prescribed lithium and antipsychotics (lithium may increase antagonism of alpha-adrenergic receptors by antipsychotics) (1). However, our patient was not prescribed lithium nor any other agent likely to contribute to his priapism. On the basis of extensive evaluation, his priapism was thought to be medication induced, with clozapine as the most likely causative agent.

Including this event, our patient had a total of three known episodes of priapism, two of which required urologic intervention. When priapism is suspected, urgent evaluation and treatment are indicated, because priapism lasting more than 36 hours can lead to irreversible tissue damage and impaired sexual function (1). Even when promptly treated, up to 50% of patients may have permanent sexual dysfunction, and early intervention is the best prognostic factor in treatment (2). Physical examination findings expected with ischemic priapism include rigid and tender corpora and a soft glans penis (1). Serological testing should include a complete blood count with differential and coagulation profiles, and corporal blood gas analysis is indicated (1). Management of priapism involves emergent urological intervention to prevent tissue damage, which was the intervention used with our patient. Cold compresses and oral hydration can be offered while awaiting urologic consultation (2). Urologic intervention involves decompression of the corpora cavernosa through penile aspiration until fresh red (oxygenated) blood is obtained. If this is unsuccessful or only partially successful, the next step is often intracavernosal injection of sympathomimetic agents, such as phenylephrine (1). If priapism persists, penile shunt surgery may be indicated, which should be performed within 72 hours (1). Fortunately, our patient responded well to corporal aspiration and did not require additional intervention.

Although the association between clozapine and priapism has been noted previously, this case report describes an instance in which a patient developed clozapine-induced priapism despite a history of medication tolerance without adverse events. Although the upper limits of the safe-dose range of clozapine for this patient were unknown, according to his providers, it was significantly higher during previous exposure than the limit observed during this episode. This suggests that previous episodes of trazodone-induced priapism may have lowered the threshold for subsequent incidents, causing a previously safe medication to become dangerous and lead to recurrence. Although the number of studies are limited, some researchers have reported that almost a quarter of patients who experience priapism may have a recurrence (11). There are no well-studied or officially recommended strategies to prevent recurring episodes of priapism, although given the proposed mechanism of action, some have suggested using alpha-adrenergic agonists (such as pseudoephedrine) to prevent future episodes (1, 2).

Our patient was subsequently able to tolerate an antipsychotic regimen including a lower dose of clozapine augmented by cariprazine, which previous case reports have suggested to be a particularly effective combination for treatment-resistant psychotic disorders (12). His psychotic symptoms improved significantly with this regimen, and importantly, he had no further episodes of priapism. We hypothesize that this was due to clozapine’s receptor-binding profile. Clozapine binds with very high affinity, even at low doses, to the alpha-1A and alpha-1B receptors (which may be the first receptors occupied); however, at higher doses, clozapine also binds to alpha-2C and alpha-2B receptors, which may exacerbate priapism by stimulating the release of nitric oxide–like substance (1, 13). Presently, there are no dose ranges of clozapine that are known to be safe or unsafe with regard to priapism, and the relevant dose range is likely to be variable among individuals.

Overall, prescribers should be aware that although priapism is uncommon, it can occur as a side effect of most psychotropic agents. Patients, particularly those with a history of priapism, should be carefully monitored for its occurrence, even when prescribed agents that were previously tolerated and are less commonly associated with priapism. If a history of priapism is noted (or if the patient has an identified risk factor), it may be prudent to select antipsychotic agents with lower alpha-adrenergic activity (4). Patients should be educated about this rare, but potentially dangerous, side effect and encouraged to discuss any concerns with their providers.

Key Points/Clinical Pearls