by Marah Aymen Allen, BS, medical student; Danya Ansari, MBBS; and Sadiq Naveed, MD, MPH

Ms. Allen is a medical student, University of New England College of Osteopathic Medicine in Portland, Maine. Dr. Ansari is with Islamabad Medical and Dental College in Islamabad, Pakistan. Dr. Naveed is Psychiatry Program Director, Eastern Connecticut Health Network in Manchester, Connecticut.

Funding: No funding was provided for this article.

Disclosures: The authors have no conflicts of interest relevant to the content of this article.

Innov Clin Neurosci. 2024;21(10–12):22–24

Abstract

Fluoxetine, a selective serotonin reuptake inhibitor (SSRI), is one of the most widely prescribed antidepressant drugs in the United States due to its safety and efficacy. SSRIs are the first-line treatment for major depressive disorder and are also indicated for anxiety disorders, eating disorders, bipolar disorder, post-traumatic stress disorder, and obsessive-compulsive disorder. Common side effects of SSRIs include insomnia, nausea, anxiety, headache, weight change, sexual dysfunction, and suicide risk. Seizures are a less common side effect of fluoxetine. This article presents the case of 19-year-old transgender male patient who developed seizures as a side effect of an intentional overdose of fluoxetine. Although marketed frequently as a safe medication, providers should be aware of the adverse effects of fluoxetine.

Keywords: Fluoxetine, seizures, overdose, neuropsychiatry

Fluoxetine is a selective serotonin receptor inhibitor (SSRI) commonly used as an acute and maintenance treatment for major depressive disorder (MDD) and generalized anxiety disorder. Fluoxetine is currently approved for treating several psychiatric conditions for the child, adolescent, and adult populations due to its efficacy and safe side effect profile. SSRIs are also indicated for eating disorders and maintenance treatment of obsessive-compulsive disorder.^1,2 

Fluoxetine exerts its effects by inhibiting presynaptic serotonin reuptake receptors in the synaptic cleft. This increases the duration and availability of serotonin molecules to synapse on postsynaptic receptors in the prefrontal cortex.³  Fluoxetine is a potent inhibitor of the hepatic cytochrome CYP2D6, which increases the risk of drug-drug interactions and adverse side effects. However, due to fluoxetine’s selectivity for serotonin receptors, side effects are generally mild and transient.⁴ Research has demonstrated an increased rate of fluoxetine-induced gastrointestinal side effects, including nausea, vomiting, diarrhea, weight loss, and anorexia, as the dosage of fluoxetine increases.⁵ The most frequent overdose symptoms experienced after sole ingestion of fluoxetine include tachycardia, lethargy, drowsiness, QTc prolongation, tremor, nausea, vomiting, and agitation.⁶ Some isolated case reports of fluoxetine overdose have demonstrated fluoxetine-induced seizures.⁷ Here, we describe the case of a 19-year-old patient who experienced a seizure in the emergency department after ingesting approximately 2,000mg of fluoxetine. There are very few cases of isolated fluoxetine-induced seizures, making this report significant. A close eye must be kept on the potentially serious adverse effects of fluoxetine overdose. 

Case Report

A 19-year-old Caucasian transgender male individual with a past medical history of MDD requiring two prior inpatient psychiatric hospitalizations at the ages of 13 and 15 years, autism spectrum disorder, and gender dysphoria, was brought to the emergency department after a suicide attempt. The patient ingested approximately 90 20mg tablets and 20 10mg tablets of fluoxetine (amounting to 2,000mg in total), following a disagreement with a family member. The patient texted his mother 10 minutes after ingesting the fluoxetine and was brought to the emergency department for an evaluation. 

While in the emergency department, the patient had a generalized tonic-clonic seizure lasting 90 seconds, witnessed by both the emergency department staff and the patient’s mother. The patient was given 1mg intravenous push of lorazepam to treat convulsive status epilepticus. The urine drug screen was negative for other toxic substances, and the patient had no personal history of seizures or family history of seizure disorders. Computerized tomography of the head was unremarkable for acute findings; moreover, the electroencephalogram showed no evidence of underlying seizure disorder. Consequently, the patient was admitted to the intensive care unit for monitoring, and no subsequent seizure activity was noted. The patient remained stable throughout the night without any notable occurrences.

Review of Literature

An electronic search of PubMed, using the search terms “fluoxetine” and “seizures,” was conducted, yielding nine case reports and one chart review study, including a detailed review of three relevant cases. Table 1 provides a summary of these cases. These cases reported fluoxetine overdoses in individuals ranging from 14 to 84 years of age at varying dosages (20–1,500mg). Prasher et al⁸ evaluated a 42-year-old woman with a medical history of Down syndrome and severe depression who developed tonic-clonic seizures after administration of fluoxetine at therapeutic levels. Other case studies examined the effect of co-ingesting fluoxetine with antipsychotics or anxiolytics, which also led to the development of tonic-clonic seizures.^9,10 Borys et al¹¹ analyzed 234 cases of fluoxetine overdoses, with three cases reporting fluoxetine-associated seizures.

Discussion

The etiology of this 19-year-old patient’s seizure remains uncertain. However, it is highly likely that the ingestion of a large dose of fluoxetine contributed to the single episode of a tonic-clonic seizure. Seizures reported after sole ingestion of fluoxetine have been noted in very few cases and typically occur at a high ingestion dose, with the minimum toxic dosage reported at 1,200mg.¹¹ In most cases of fluoxetine overdose, patients remain asymptomatic; however, if symptoms do manifest, they include tachycardia, dizziness, nausea, and vomiting.¹⁷ Patients with underlying genetic disorders, such as Down syndrome, or pre-existing brain diseases, such as post-stroke depression and traumatic brain injury, are noted to be more susceptible to developing seizures after administration of fluoxetine at therapeutic dosages.^8,14,15 Additional research is warranted to explain the correlation between fluoxetine-induced seizures and those who have underlying neurodevelopmental disorders. 

Conflicting opinions have been noted on the epileptic property of fluoxetine and its effect on the threshold for neuroleptic activity. Favale et al¹⁸ have shown the positive effect of adjunct fluoxetine therapy in those with refractory epileptic disorders, decreasing the incidences of seizures. However, Gigli et al¹⁹ have demonstrated that fluoxetine increases the rate of epileptic activity in patients, and there is no benefit in prescribing fluoxetine to patients with epilepsy. Research has indicated that fluoxetine has a dose-response effect on efficacy and adverse effects. Patients who took fluoxetine as an adjunct therapy for its anti-epileptic property were given 20mg in addition to the usual treatment. Those who developed adverse effects and seizure-like symptoms were given 40mg of fluoxetine. This indicates a dose-response effect of fluoxetine; as the dosages increase, patients become more susceptible to developing adverse effects, including tonic-clonic seizures.²⁰ 

Seizure activity is commonly reported as a side effect of co-ingestion of fluoxetine and other metabolites.⁷ Fluoxetine is a potent inhibitor of the hepatic CYP3A4 enzyme, and therefore co-ingesting other CYP3A4 metabolites, such as benzodiazepines and buspirone, leads to an increase in plasma concentrations of these medications. This makes patients more susceptible to developing seizure-like activity.⁹ A possible explanation of this patient’s seizure activity might be the altered activity of the CYP3A4 enzyme due to his underlying autism spectrum disorder; however, more research is indicated to further explore this correlation.

Conclusion 

Based on the review of case reports, fluoxetine-associated seizures are noted in patients with pre-existing neurological illnesses, neurodevelopmental disorders, and traumatic brain injury. Patients at therapeutic doses of fluoxetine can be susceptible to seizures in the presence of co-ingestion of other psychotropic agents. Clinicians need to be aware of this potential adverse event, and due diligence is needed in such patients.

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