The Link Between Epilepsy, Antiepileptics, and Psychosis
People with epilepsy have a heightened risk of developing psychotic disorders compared to the general population [1.2.3]. While the relationship is complex, research indicates that the very medications used to control seizures—antiepileptic drugs (AEDs)—can sometimes be the trigger. Antiepileptic drug-induced psychotic disorder (AIPD) is a significant iatrogenic (medically-induced) adverse reaction [1.2.5]. Studies suggest that the prevalence of psychosis induced by these medications can range from 1% to as high as 8% [1.3.2]. One study analyzing over 2,600 epilepsy patients found that while 3.7% were diagnosed with a psychotic disorder, a notable 14.3% of those cases were triggered by their AEDs [1.2.1]. The onset of psychosis often occurs within the first month after starting a new AED [1.3.4].
Symptoms of AED-Induced Psychosis
The clinical presentation of AED-induced psychosis can be varied and distressing. Common symptoms include:
- Hallucinations: Auditory and visual hallucinations are frequently reported [1.2.4]. Patients might see things that aren't there or hear voices.
- Delusions: Persecutory delusions, where the individual believes they are being threatened or that others are conspiring against them, are prevalent. Other types include referential, religious, or grandiose delusions [1.2.4, 1.5.1].
- Disorganized Behavior and Thinking: This can manifest as aggression, agitation, unusual social behavior, and disorganized thoughts [1.2.4, 1.4.1].
- Mood Disturbances: Irritability, agitation, and emotional lability are common behavioral side effects that can accompany or precede psychosis [1.4.3, 1.6.3].
Which Antiepileptics are Most Commonly Implicated?
While many AEDs have been associated with psychiatric side effects, several are more frequently reported in scientific literature as potential triggers for psychosis.
Levetiracetam (Keppra)
Levetiracetam is widely used but is known for its potential to cause psychobehavioral abnormalities [1.4.1]. While the overall rate of psychosis is low, estimated between 1% and 1.4%, severe psychiatric symptoms can occur [1.4.3]. A 2024 study reported that 7.8% of 1,412 patients taking levetiracetam experienced severe psychiatric symptoms, including hallucinations and delusions [1.4.1]. These symptoms often necessitate dose reduction, discontinuation of the drug, or the addition of an antipsychotic [1.4.1, 1.4.3].
Topiramate (Topamax)
Topiramate is another AED where psychosis, although rare, is a documented side effect [1.5.1]. The incidence has been estimated at around 1.5% [1.5.3]. Psychotic symptoms can include paranoid delusions and hallucinations [1.5.4]. In many reported cases, these symptoms appear shortly after starting the medication and resolve quickly upon its discontinuation [1.5.1, 1.5.2].
Zonisamide (Zonegran)
Zonisamide is identified as a possible risk factor for developing psychosis [1.2.7]. Studies in Japan, where the drug has been used for a longer time, reported psychosis incidence ranging from 1.9% to as high as 18% in one study [1.2.7]. Clinical trials have noted that schizophrenic/schizophreniform behavior occurred in 2% of patients taking zonisamide compared to none on placebo [1.6.6]. Less common side effects listed for zonisamide include delusions and hallucinations [1.6.1].
Other Implicated AEDs
Other antiepileptics have also been linked to psychosis, though sometimes less frequently. These include:
- Phenytoin: Toxicity with this drug can manifest as acute psychosis, which resolves after withdrawal [1.2.5].
- Ethosuximide: Psychosis has been reported as a side effect since its early use, with symptoms including hallucinations and labile moods [1.7.1]. Paranoid psychosis is listed as a rare side effect [1.7.3].
- Vigabatrin, Felbamate, and Tiagabine: These newer AEDs have also had cases of psychosis reported during add-on therapy [1.2.3].
Comparison of AEDs and Psychosis Risk
| Medication | Reported Incidence of Psychosis | Common Psychotic Symptoms | Key Considerations |
|---|---|---|---|
| Levetiracetam | ~1-1.4%, with one study reporting 7.8% with severe symptoms [1.4.3, 1.4.1] | Hallucinations, delusions, aggression, agitation [1.4.1] | Symptoms may be controlled by dose reduction or discontinuation [1.4.3]. Risk may be higher in older patients [1.4.3]. |
| Topiramate | ~1.5% [1.5.3] | Paranoid delusions, visual and auditory hallucinations [1.5.2, 1.5.4] | Symptoms often resolve quickly after stopping the drug [1.5.5]. Risk may be higher in patients with a past psychiatric history [1.5.3]. |
| Zonisamide | 1.9% to 18% in some studies [1.2.7] | Delusions, hallucinations, agitation, irritability [1.6.1, 1.6.3] | Has shown a high odds ratio for psychosis development in some analyses [1.2.7]. |
| Phenytoin | Primarily associated with toxicity levels (>35 mg/l) [1.2.7, 1.2.5] | Schizophrenia-like psychosis, aggressive behavior [1.2.7, 1.2.5] | Psychosis is a sign of drug toxicity and resolves upon withdrawal [1.2.5]. |
| Ethosuximide | Rare, with a reported rate of 2% in one study of children [1.7.1] | Paranoid psychosis, hallucinations, mood lability [1.7.3, 1.7.1] | May also induce mania with psychotic features [1.7.1]. |
Identifying and Managing Risk
Not everyone who takes these medications will experience psychosis. Certain factors increase a patient's vulnerability.
Risk Factors
- Patient-Specific (Trait-Dependent): Female gender, a family history of psychosis, lower intellectual function, and an early onset of epilepsy are associated with a higher risk [1.8.5, 1.8.3, 1.8.4].
- Epilepsy-Related (State-Dependent): A previous personal history of psychosis, temporal lobe epilepsy, higher seizure frequency, longer duration of epilepsy, and being on multiple AEDs (polytherapy) also significantly increase the risk [1.8.5, 1.8.4, 1.2.1].
Management Strategies
If a patient develops psychotic symptoms after starting an AED, the first step is a thorough evaluation to confirm the drug is the likely cause [1.2.5]. The definitive diagnosis is often made retrospectively [1.2.5]. Management typically involves:
- Discontinuation or Dose Reduction: The most effective strategy is often to withdraw the suspected medication or reduce the dose [1.4.3, 1.5.1]. In many cases, psychotic symptoms resolve rapidly after stopping the drug [1.4.4, 1.5.5].
- Switching AEDs: Changing to an alternative antiepileptic with a lower risk of psychiatric side effects is a common approach [1.4.2].
- Adding Antipsychotics: In some situations, an antipsychotic medication like risperidone or quetiapine, which are considered relatively safe for seizure patients, may be added to control symptoms, especially if the causative AED cannot be stopped [1.4.1, 1.8.1].
Conclusion
The link between antiepileptic drugs and psychosis is an important, though relatively uncommon, adverse effect that requires vigilance from both clinicians and patients. While several AEDs, notably levetiracetam, topiramate, and zonisamide, are more frequently implicated, nearly any AED can potentially trigger psychosis in vulnerable individuals [1.2.3]. Recognizing the symptoms—such as hallucinations, delusions, and disorganized behavior—and understanding the risk factors, including female sex, prior psychiatric history, and temporal lobe epilepsy, is crucial for early detection [1.2.4, 1.8.3, 1.8.5]. Prompt management, typically involving the discontinuation of the offending drug, can lead to a complete resolution of symptoms, highlighting the importance of careful medication monitoring in epilepsy treatment. An authoritative outbound link on this topic can be found at the National Institutes of Health (NIH).
