Dear Editor:

I read with interest the article by Allen et al¹ about a 19-year-old male transgender patient who developed seizures after intentionally taking 2,000mg of fluoxetine. His medical history was positive for major depressive disorder (MDD), requiring two prior inpatient psychiatric hospitalizations, autism spectrum disorder (ASD), and gender dysphoria. The patient made a full recovery after brief treatment in the intensive care unit (ICU). The study is impressive, but some points should be discussed.

The first point is that fluoxetine is known to trigger seizures. Several case reports and human studies have shown that fluoxetine has epileptogenic potential.² In particular, seizures can be triggered in patients who have been exposed to an overdose of fluoxetine.² It has also been shown in an animal model of epilepsy that epileptogenesis is accelerated and intensified by fluoxetine.³ From these studies, it was concluded that caution should be exercised when prescribing selective serotonin reuptake inhibitors (SSRIs) to people at risk of epilepsy.³

The second point is that fluoxetine may not only induce seizures but also have a beneficial effect on seizure activity. In a female patient with drug-resistant focal seizures, developmental delay and behavioral disturbance due to the c.2809A>G variant in KCNT1, fluoxetine was shown to have a strong gain-of-function effect in transiently transfected Chinese hamster ovary cells.⁴ The gain-of-function effect resulted in an increased maximum current density and a hyperpolarizing shift in the current activation threshold, as well as inhibition of currents expressed by both wildtype and mutant KCNT1 channels. Clinically, fluoxetine resulted in sustained electroclinical improvement with the disappearance of seizures and better background electroencephalogram (EEG) organization, along with improvement in behavior and mood.⁴ For this reason, the seizure in the index patient is not necessarily due to fluoxetine intoxication.

The third point is that the toxicity of fluoxetine may also depend on the presence or absence of certain cytochrome P450 polymorphisms.⁵ Genotyping of liver cytochromes could play a role in predicting serious side effects of fluoxetine to help clinicians educate patients and their families, provide more intensive monitoring, and initiate prophylactic treatment when needed. Therefore, it should be known whether the index patient had any of the CYP2D6 or CYP2C19 polymorphisms that play a role in the metabolization of fluoxetine.

The fourth point is the discrepancy between stating that the patient had a single tonic-clonic seizure lasting 90 seconds in the emergency department and stating that the patient received a course of lorazepam for the treatment of status epilepticus.¹ Did the patient suffer a single seizure, or did he actually develop status epilepticus? This discrepancy should be clarified.

The fifth point is that alternative triggers of seizures were not adequately excluded in the index patient. Although the individual and family history was negative for epilepsy, screening for illicit drugs was negative, and the EEG showed no epileptiform discharges, it would have been imperative to perform magnetic resonance imaging of the brain to assess whether there were any subtle morphologic abnormalities that could explain the new-onset seizure activity. Cerebral computed tomography is not sufficient to rule out discrete structural abnormalities. Has infectious and immunologic encephalitis been definitively ruled out by cerebrospinal fluid examination? Since the patient had a history of ASD and ASD can be associated with seizures, it would have been imperative to rule out a genetic cause for ASD. The family history does not necessarily have to be positive for a hereditary ASD.

In summary, before attributing the occurrence of new-onset seizures to fluoxetine intoxication, alternative causes must be thoroughly ruled out and toxic levels of the implicated drug should be detected.

With regards,

Josef Finsterer, MD, PhD

Dr. Finsterer is with the Neurology and Neurophysiology Center in Vienna, Austria.

Funding/financial disclosures. The author has no conflicts of interest relevant to the content of this letter. No funding was received for the preparation of this letter.

References

1. Allen MA, Ansari D, Naveed S. Fluoxetine-induced seizure: a case report and review of literature. Innov Clin Neurosci. 2024;21
   (10–12):22–24.
2. Kolbeck MK, Schult RF, Nacca N. Generalized seizures after acute fluoxetine overdose in four adolescents. Am J Emerg Med. 2024;75:
   197.e5–197.e7.
3. Dezsi G, Ozturk E, Wong D, et al. Fluoxetine accelerates epileptogenesis and magnifies disease severity in a rat model of acquired epilepsy. Epilepsia. 2024;65(9):2787–2797.
4. Mosca I, Freri E, Ambrosino P, et al. Case report: marked electroclinical improvement by fluoxetine treatment in a patient with KCNT1-related drug-resistant focal epilepsy. Front Cell Neurosci. 2024;18:1367838.
5. Campbell S, Otten H, Anand V. CYP450 genetic polymorphisms: generalized tonic-clonic seizure after Intentional fluoxetine and melatonin overdose. S D Med. 2023;76(7):
   305–308.