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Association Between Priapism and Concurrent Use of Risperidone and Ginkgo biloba

      To the Editor: Priapism, defined as prolonged and persistent erection of the penis that is not due to sexual stimulation and that is not alleviated by sexual intercourse or masturbation, is a urological emergency that needs timely diagnosis and treatment. Rarely, priapism can be a serious adverse effect of antipsychotic medications; virtually all antipsychotic medications have been reported to cause priapism because of their α-adrenergic antagonism.
      • Bressler R
      Herb-drug interactions: interactions between Ginkgo biloba and prescription medications.
      Ginkgo biloba is used worldwide as a complementary medicine for its antioxidant and neuro-protective effects. However, its drug interaction with other medications, including antipsychotic agents, should be considered before it is prescribed for any purpose.
      Report of a Case. A 26-year-old man presented to the emergency department of our hospital with a persistent and painful erection of the penis that had lasted for 4 hours. He had a history of paranoid schizophrenia, for which he was treated with 3 mg/d of risperidone for 3 years. He reported no other chronic illness, recent trauma, or use of drugs. He denied any adverse effects due to antipsychotic therapies. Two weeks before admission, he began taking 160 mg/d of generic Ginkgo biloba for occasional tinnitus.
      On arrival at the emergency department, his blood pressure was 150/88 mm Hg; his pulse rate, 94 beats/min; and his temperature, 35.9°C. Findings on physical examination were normal except for a persistent erection of the penis. His hematocrit was 37%, and no dysmorphic red blood cells were noted on microscopic examination. Color flow Doppler sonography of the penis showed a decreased blood flow in the cavernosal arteries. His priapism was refractory to analgesics and ice packing. Blood gas analysis of the aspired cavernous venous blood revealed a pH value of 6.79, a Pco2 of 114.9 torr, and undetectable Po2, findings consistent with veno-occlusion (low-flow) priapism. Two hours after corporal irrigation with diluted epinephrine, priapism subsided. The patient was discharged uneventfully and was instructed to discontinue the use of risperidone and Ginkgo biloba. On direct questioning, he reported having no prolonged erection or priapism when he was being treated with risperidone. The 3 mg/d dose of risperidone was resumed without adverse effect. On follow-up at 6 months, he reported normal erections with no further episodes of priapism.
      Discussion. Priapism has multiple etiologies, including hematologic, neurological, iatrogenic, and pharmacological causes. Drug-induced priapism is usually of the ischemic (low-flow, veno-occlusion) type; arterial (high-flow) priapism is relatively rare and predominantly caused by trauma. An estimated 50% of those who experience drug-induced priapism are taking antipsychotic agents; α-adrenergic antagonism is thought to be the most important underlying mechanism.
      • Wang CS
      • Kao WT
      • Chen CD
      • Tung YP
      • Lung FW
      Priapism associated with typical and atypical antipsychotic medications.
      Risperidone, an atypical antipsychotic agent used primarily to treat psychosis and schizophrenia, has serotonergic, dopaminergic, and α-adrenergic antagonist properties. Its propensity to cause priapism can be linked to its high affinity for α1-adrenergic blockade, an affinity higher than that of other atypical antipsychotics such as clozapine and olanzapine.
      • Compton MT
      • Miller AH
      Priapism associated with conventional and atypical antipsychotic medications: a review.
      Ginkgo biloba is extracted from leaves of Ginkgo biloba (the maidenhair tree); its most active ingredients are flavonoids (ginkgo-flavone glycosides) and terpenoids (ginkgolides and bilobalide). Because of its vasoregulatory activity and free-radical scavenging properties, Ginkgo biloba has been used to treat early-stage Alzheimer disease, vascular dementia, peripheral claudication, and tinnitus of vascular origin. Its use is generally well tolerated, but adverse effects such as gastrointestinal upset, headache, and dizziness have been reported.
      • Diamond BJ
      • Shiflett SC
      • Feiwel N
      • et al.
      Ginkgo biloba extract: mechanisms and clinical indications.
      Extracts of Ginkgo biloba have many ingredients, the pharmacological and pharmacokinetic effects of which can be difficult to ascertain. Different active compounds may exert their pharmacological effects on different sites or organs. In humans, risperidone is mainly metabolized by cytochrome P450 isoform 2D6 (CYP2D6) and cytochrome P450 isoform 3A4 (CYP3A4),
      • Berecz R
      • Dorado P
      • De La Rubia A
      • Caceres MC
      • Degrell I
      • LLerena A
      The role of cytochrome P450 enzymes in the metabolism of risperidone and its clinical relevance for drug interactions.
      both of which enzymes are inhibited by Ginkgo biloba.
      • Yale SH
      • Glurich I
      Analysis of the inhibitory potential of Ginkgo biloba, Echinacea purpurea, and Serenoa repens on the metabolic activity of cytochrome P450 3A4, 2D6, and 2C9.
      Hence, concurrent use of Ginkgo biloba may increase the serum concentration of risperidone and increase the risk of adverse effects, such as priapism in our patient. The superimposed injectable long-acting preparation of risperidone, which has an additive effect in its oral form, has been postulated to be the cause of paradoxical priapism.
      • Kirshner A
      • Davis RR
      Priapism associated with the switch from oral to injectable risperidone.
      The development of prolonged erection or priapism in patients treated with antipsychotic agents has been linked to the following: (1) an increased dose of medication, (2) the restarting of medications after a period of nonadherence, (3) the switch to a different class of drug, or (4) the use of a combination regimen of antipsychotics.
      • Reeves RR
      • Mack JE
      Priapism associated with two atypical antipsychotic agents.
      Several studies have shown that Ginkgo biloba has vessel-dilating properties; it increases nitric oxide activity or acts directly on the endothelium, as for example by inhibiting cyclic adenosine monophosphate phosphodiesterase activity.
      • Paick JS
      • Lee JH
      An experimental study of the effect of ginkgo biloba extract on the human and rabbit corpus cavernosum tissue.
      • McKay D
      Nutrients and botanicals for erectile dysfunction: examining the evidence.
      Anecdotal evidence suggests that Ginkgo biloba can be used in the treatment of erectile dysfunction.
      • Dell'Agli MM
      • Galli GV
      • Bosisio E
      Inhibition of cGMP-phosphodiesterase-5 by biflavones of Ginkgo biloba.
      It has also been reported to reverse selective serotonin reuptake inhibitor-induced sexual dysfunction.
      • Ashton AK
      • Ahrens K
      • Gupta S
      • Masand PS
      Antidepressant-induced sexual dysfunction and Ginkgo biloba [letter].
      • Cohen AJ
      • Bartlik B
      Ginkgo biloba for antidepressant-induced sexual dysfunction.
      Nonetheless, no evidence has been reported that Ginkgo biloba alone can cause priapism. Although our patient did not use Ginkgo biloba to treat erectile dysfunction, he may have experienced an additive or synergistic effect between Ginkgo biloba and risperidone; however, further studies are needed to clarify this issue. We also could not ascertain why the risperidonepriapism reaction precipitated by Ginkgo biloba required 2 weeks. This drug reaction could be either dose dependent or idiosyncratic.
      In conclusion, herbal medicines may potentiate the adverse drug effects of preexisting treatment regimens. Clinicians should be aware of the potential adverse effects and drug-drug interactions of a complementary medicine, particularly in patients being treated with antipsychotic agents.

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