Breakthrough Seizures after Starting Vilazodone for Depression James McKean,1,2,3,* Hannah Watts,1,2 and Robert Mokszycki1,4 1

Advocate Christ Medical Center, Oak Lawn, Illinois; 2Department of Emergency Medicine, Advocate Christ Medical Center, Oak Lawn, Illinois; 3Department of Emergency Medicine, Advocate BroMenn Medical Center, Normal, Illinois; 4Department of Pharmacy, Advocate Christ Medical Center, Oak Lawn, Illinois

Vilazodone is a new selective serotonin reuptake inhibitor (SSRI) and serotonin 5-HT1a partial agonist that is approved by the United States Food and Drug Administration to treat major depression. SSRIinduced seizures are rare and are more likely to be associated with larger doses and severe symptoms such as those present in serotonin syndrome. Several case reports have implicated SSRIs, buspirone, or the combination of these agents as the cause of seizures, but these reports were confounded with either coingestions or doses that exceeded FDA recommendations. We describe a 22-year-old woman with a history of seizure disorder who had been seizure free for the previous 8 years and experienced two breakthrough seizures shortly after starting vilazodone. Her dose of vilazodone had recently been titrated to 40 mg/day when she experienced the first seizure. She was instructed to taper vilazodone over the next several days, then discontinue the drug, and then follow up with her neurologist. Based on the patient’s history, physical examination, and recent dose increase, it was plausible that vilazodone was the cause of the seizures. Use of the Naranjo adverse drug reaction probability scale indicated a possible relationship (score of 4) between her development of seizures and vilazodone therapy. The pharmacodynamics of this particular class of SSRI has both proconvulsive and anticonvulsive mechanisms. This is of particular concern in patients with a history of seizure disorder who are starting antidepressive therapy. In persons with epilepsy who are taking vilazodone and experience breakthrough seizures, practitioners should consider this drug as a potential cause of these seizures. Thus, until future research and experience with vilazodone can provide a definitive answer, clinicians should be cautious when prescribing this medication to treat depression in patients with a history of seizure disorder. KEY WORDS vilazodone, seizures, depression, adverse drug reaction. (Pharmacotherapy 2015;35(3):e6–e8) doi: 10.1002/phar.1549

Vilazodone is a new selective serotonin reuptake inhibitor (SSRI) and serotonin 5-HT1a partial agonist approved by the United States Food and Drug Administration in 2011 to treat major depression.1, 2 SSRI-induced seizures are rare and are more likely to be associated with larger doses and severe symptoms such as those pres*Address for correspondence: James McKean, Department of Emergency Medicine, Advocate Christ Medical Center, 4440 W. 95th Street Oak Lawn, IL 60453; e-mail: [email protected] Ó 2015 Pharmacotherapy Publications, Inc.

ent in serotonin syndrome.3 Several case reports have implicated SSRIs, buspirone, or the combination of these agents as the cause of seizures, but these reports were confounded with either coingestions or doses above FDA recommendations.4 However, a single case report describes citalopram-induced seizures after only 4 days of therapy with a standard dosage.5 Evidence also exists that suggests that citalopram may have a therapeutic effect in as little as 1 week.6 Vilazodone is also known to achieve a therapeutic effect in as little as 1 week compared with placebo.7 Unfortunately, it is still unclear at this

VILAZODONE-INDUCED SEIZURES McKean et al time if this adverse effect was idiosyncratic, dose related, due to the onset of action, or due to an unknown patient-specific factor.6, 7 In this report, we describe a case of a witnessed breakthrough seizure in a patient being treated for depression with vilazodone. Case Report A 22-year-old woman with a history of seizure disorder presented to the emergency department after experiencing seizures that were witnessed by her family. Her last seizure had occurred 8 years earlier. She had one 5-minute seizure before her arrival in the emergency department and one 3 days earlier. Leg cramping preceded both seizures, which then turned into generalized tonic-clonic movements, similar to her previous seizures. Both seizures were short-lived and extinguished spontaneously. She did not injure herself during these seizures, nor did she have episodes of incontinence or tongue biting. After a short period of drowsiness, she returned to her baseline status relatively quickly after both seizures. She denied fevers and neck pain or stiffness. She denied vision changes, sensory changes, focal weakness, speech changes, or headache. In addition, she experienced no chest pain, nausea, vomiting, diarrhea, rash, or back or abdominal pain. The patient had no other medical history other than her seizure disorder. She had originally taken phenytoin for seizure control, but the drug had been discontinued for more than 5 years as recommended by her neurologist. She denied recent travel and sick contact exposure and denied any use of alcohol, cigarettes, or illicit drugs. She did not take any herbal products or alternative medicine. Of note, the patient had recently started treatment for feelings of depression. Her primary care physician was in the process of titrating up her dose of vilazodone for treatment of her depression. She had taken 10 mg/day for 1 week, then 20 mg/day the next week; she was in her third week of treatment, taking 40 mg/day, when she experienced her seizure. This was the only medication she was taking or had taken in the recent past. On physical examination, the patient was a healthy-appearing young woman, looking her stated age, in no apparent distress, and who was alert and oriented to person, place, and time. Her vital signs were a temperature of 37°C, pulse 70 beats/min, respiratory rate 18 breaths/ min, blood pressure 105/72 mm Hg, and pulse

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oximetry 100% on room air. Her bedside finger stick glucose level was 83 mg/dl. Head examination showed no signs of trauma. Neck examination showed a supple, nontender neck with full range of motion. Skin examination showed no abnormality or rash. Her cardiovascular, respiratory, and abdominal examinations were within normal limits. Her neurologic examination showed normal cranial nerves, full strength in all four extremities, normal sensory examination, no pronator drift, and normal finger-to-nose testing. She was not currently feeling depressed and had no thoughts of hurting herself or others. The remainder of the physical examination was unremarkable. The patient’s laboratory results were unremarkable: sodium 140 mEq/L, potassium 3.4 mEq/L, chloride 106 mEq/L, bicarbonate 26 mEq/L, blood urea nitrogen 16 mg/dl, creatinine 0.81 mg/ dl, glucose 79 mg/dl, aspartate aminotransferase 23 U/L, alanine aminotransferase 29 U/L, alkaline phosphatase 81 U/L, calcium 8.9 mg/dl, and albumin 3.7 g/dl. After researching vilazodone and discussing this case with our emergency department pharmacist, it was deemed that this new medication had the potential for lowering our patient’s seizure threshold and being the causative agent for her breakthrough seizures. Vilazodone was tapered over the next few days and then discontinued. We recommended follow-up with both her primary care physician for prescribing a different depression treatment and her neurologist for a repeat neurologic examination. We recommended that she not drive or operate heavy machinery until cleared by her neurologist. Discussion In our emergency department, a young person with epilepsy was treated for breakthrough seizures during titration of her newly started vilazodone. She had not had a seizure in more than 8 years, and based on her thorough history, physical, and laboratory studies, vilazodone was the most likely cause of her recurrence. To our knowledge, only one documented case report of seizures induced by vilazodone has been published.8 A 23-month-old, 11-kg female patient with no significant medical history acutely ingested up to 60 mg of vilazodone and developed tonic-clonic seizures within 120 minutes of the ingestion. She was given lorazepam 1 mg intravenously followed by an additional 2 mg intravenously for continued seizure activ-

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ity. She developed tachycardia (pulse 170 beats/ min) and hyperthermia (100.5°F) and was intubated and transferred to the intensive care unit. The patient continued to have persistent seizure activity and was treated with phenobarbital. She recovered over the next 24 hours and was subsequently discharged from the intensive care unit without further complications. After a thorough work-up, it was determined that vilazodone was the cause of the patient’s seizures. A recent animal study suggests that selective SSRIs are biphasic and have both anticonvulsive and proconvulsive properties, depending on the doses administered.9 Multiple mechanisms are thought to contribute to this biphasic response through serotonin 5-HT3 receptor activation, including an inhibition of excitatory neurons, an increase in c-aminobutyric acid release, and an increase in nitric oxide synthase (NOS) activity. The first two mechanisms are considered anticonvulsive, whereas the last is considered proconvulsive.10 Several anticonvulsive medications, including phenytoin and carbamazepine, increase serotonin release, which is thought to contribute to their antiepileptic effects.11 5-HT1a receptor agonists have also demonstrated anticonvulsive effects in animal and human models,12 and a lack of 5-HT1a receptor expression has been identified in patients with temporal lobe epilepsy and depression.13, 14 A recent animal model suggests that vilazodone is a partial 5-HT1a agonist that can produce a net inhibitory effect on the 5-HT1a receptors in the raphe nuclei.15 It is possible that either of these mechanisms was responsible for the seizure occurring in our patient. Even though the patient was taking only therapeutic doses of the medication, it is possible that the increase in dose caused her to enter the proconvulsive phase of the biphasic mechanism. Due to the patient’s history of depression, it is also possible that the antagonistic effect of an already limited 5-HT1a receptor pool triggered the seizure. Further data will be needed to accurately assess the mechanism behind vilazodone-induced seizures. In our patient, use of the Naranjo adverse drug reaction probability scale16 indicated a possible relationship (score of 4) between her development of seizures and vilazodone therapy. Conclusion Vilazodone is a relatively new SSRI that is FDA approved for the treatment of depression and has the potential to lower the seizure threshold in cer-

tain at-risk patients. The pharmacodynamics of this particular class of SSRI has both proconvulsive and anticonvulsive mechanisms. This is of particular concern in patients with a history of seizure disorder who are starting antidepressive therapy. In persons with epilepsy who are taking vilazodone and experience breakthrough seizures, practitioners should consider this drug as a potential cause of these seizures. Thus, clinicians should be cautious when prescribing this medication to treat depression in patients with a history of seizure disorder. References 1. FDA approves Viibryd to treat major depressive disorder. FDA. gov. 21 Jan 2011. Accessed February 15, 2014. Available from http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ ucm240642.htm. 2. Forest Pharmaceuticals. Viibryd (vilazodone) package insert. St. Louis, MO; 2012. 3. Nelson L, Erdman A, Booze L, et al. Selective serotonin reuptake inhibitor poisoning: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol 2007;45: 315–32. 4. Suchard J. Fluoxetine overdose-induced seizure. Western J Emerg Med 2008;9:154–6. 5. Iskandar J, Schmidley J, Sharma T. Citalopram-induced seizures in a health adult taking an FDA-approved dosage: a case report. Prim Care Companion CNS Disord 2011;13:pii: PCC.10l01113. 6. Hsu J, Su T, Huang C, Chen S, Chou Y. Faster onset of antidepressant effects of citalopram compared with sertraline in drug-na€ıve first-episode major depressive disorder in a Chinese population: a 6-week double-blind, randomized comparative study. J Clin Psycopharmacol 2001;31:577–81. 7. Jain R, Chen D, Edwards J, Mathews M. Early and sustained improvement with vilazodone in adult patients with major depressive disorder: post hoc analyses of two phase III trials. Curr Med Res Opin 2014;30:263–70. 8. Carstairs S, Griffith E. Recurrent seizure activity in a child after acute vilazodone ingestion. Ann Emerg Med 2012;60: 819. 9. Payandemehr B, Bahremand A, Rahimian R, et al. 5-HT3 receptor mediates the dose-dependent effects of citalopram on pentylenetetrazole-induced clonic seizure in mice: involvement of nitric oxide. Epilepsy Res 2012;101:217–27. 10. Gholipour T, Ghasemi M, Riazi K, Ghaffarpour M, Dehpour A. Seizure susceptibility alteration through 5-HT3 receptor: modulation by nitric oxide. Seizure 2010;19:17–22. 11. Richerson G, Buchanan F. The serotonin axis: shared mechanisms in seizures, depression and SUDEP. Epilepsia 2011;52 (suppl 1):28–38. 12. Fulvio S. Antioxidant effect of buspirone in epilepsy – is the case closed? Rev Psiq Clin 2012;39:209. 13. Martinez A, Finegersh A, Cannon D, et al. The 5-HT1a receptor and 5-HT transporter in temporal lobe epilepsy. Neurology 2013;80:1465–71. 14. Hasler G, Bonwetsch R, Giovacchini G, et al. 5-HT1A receptor binding in temporal lobe epilepsy patients with and without major depression. Biol Psychiatry 2007;62:1258–64. 15. Amsterdam C, Seyfried C. Mechanism of action of the bimodal antidepressant vilazodone: evidence for serotonin1a-receptor-mediated auto-augmentation of extracellular serotonin output. Psychopharmacology 2014;231(12):2547–58. 16. Naranjo CA, Busto U, Sellers EM, et al. A method of estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239–45.

Breakthrough seizures after starting vilazodone for depression.

Vilazodone is a new selective serotonin reuptake inhibitor (SSRI) and serotonin 5-HT1a partial agonist that is approved by the United States Food and ...
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