People with schizophrenia face a higher seizure risk than the general population.
The connection between schizophrenia and seizures is complex, involving shared genetic factors, overlapping brain circuits, and medication effects, particularly with antipsychotics like clozapine.
This article explains the relationship between these conditions, examines the evidence, and outlines practical steps to reduce seizure risk while maintaining effective mental health treatment.
Understanding the Link Between Schizophrenia and Seizures
The relationship between schizophrenia and epilepsy has been documented for decades, but recent research clarifies the mechanisms behind this connection.
Large population studies show that individuals with schizophrenia develop epilepsy at rates significantly higher than the general population, approximately 6.99 per 1,000 person-years compared to 1.19 per 1,000 in controls, representing a nearly sixfold increase in risk.
This elevated risk works in both directions. People with epilepsy also show higher rates of psychotic disorders, with psychosis occurring in roughly 5 to 7 percent of those with epilepsy.
The bidirectional nature of this relationship suggests shared biological vulnerabilities rather than one condition directly causing the other.
Shared Genetic and Brain Factors
Modern genetic research reveals significant overlap in the biological pathways that contribute to both schizophrenia and epilepsy.
Studies using Mendelian randomization, a method that uses genetic variants to infer causal relationships, show that certain epilepsy subtypes, particularly focal epilepsies, increase the risk of psychiatric conditions including depression and obsessive-compulsive disorder.
Interestingly, juvenile absence epilepsy may actually reduce schizophrenia risk, highlighting that epilepsy is not a single entity when it comes to psychiatric outcomes.
Brain imaging studies point to the limbic system, particularly the hippocampus and surrounding temporal lobe structures, as a critical area of overlap.
These regions regulate emotion, memory, and sensory processing, and dysfunction in these circuits appears to predispose individuals to both seizures and psychotic symptoms.
How Antipsychotic Medications Affect Seizure Risk?
While shared biology plays a role, the most significant and modifiable contributor to seizure risk in people with schizophrenia is antipsychotic medication.
All antipsychotics can lower seizure threshold to some degree, but the risk varies dramatically by medication, dose, and how quickly the dose is increased.
Clozapine: The Highest Risk Medication
Clozapine remains the most effective treatment for treatment-resistant schizophrenia, but it carries the highest seizure risk among antipsychotics. The risk is directly related to dose and blood concentration levels.
At doses below 300 mg per day, seizure incidence is approximately 1 percent. This rises to 2.7 percent at doses between 300 and 600 mg daily, and reaches 4.4 percent at doses exceeding 600 mg per day.
The FDA includes a black box warning for seizures with clozapine. Research shows that EEG abnormalities and seizures are linked to plasma clozapine levels, making therapeutic drug monitoring an essential tool for managing risk.
Factors like smoking status affect how the body metabolizes clozapine, smokers typically have lower blood levels due to enzyme induction, so monitoring becomes even more important when patients change their smoking habits.
Other Antipsychotics and Relative Risk
Not all antipsychotics carry equal seizure risk. Chlorpromazine, an older first-generation antipsychotic, shows a steep dose-response relationship, with seizure rates around 0.5 percent at doses below 1,000 mg daily but jumping to 9 percent at higher doses.
Several second-generation antipsychotics show seizure rates similar to placebo in randomized trials:
- Risperidone demonstrates seizure incidence comparable to placebo in controlled studies
- Aripiprazole may have anticonvulsant properties in preclinical models and shows low clinical seizure risk
- Ziprasidone exhibits minimal seizure risk in clinical trials
- Olanzapine and quetiapine show slightly elevated risk compared to placebo but remain substantially safer than clozapine
The period of highest risk occurs during medication initiation and rapid dose escalation, regardless of which antipsychotic is used.
Types of Psychosis in Epilepsy
When psychosis occurs in people with epilepsy, the timing relative to seizures provides crucial diagnostic and treatment information. Clinicians classify psychosis of epilepsy into distinct subtypes based on this temporal relationship.
Postictal Psychosis
Postictal psychosis develops after seizures, typically following a lucid interval of 24 to 72 hours.
During this window, individuals remain oriented and alert but then develop delusions, hallucinations, and often severe insomnia. Episodes usually last one to six days and may resolve spontaneously.
In a large study of 684 people with temporal lobe epilepsy, postictal psychosis occurred in 7 percent of patients, with aggressive behavior present in nearly one-quarter of episodes.
Risk factors include early epilepsy onset, longer disease duration, seizure clustering, bilateral EEG abnormalities, and the presence of ictal fear during seizures.
Interictal Psychosis
Interictal psychosis occurs independently of seizure timing and often resembles schizophrenia in its presentation, with paranoid delusions and auditory hallucinations requiring long-term antipsychotic treatment.
However, people with interictal psychosis may show better premorbid functioning and less prominent negative symptoms compared to primary schizophrenia.
Ictal Psychosis
Ictal psychosis represents psychotic symptoms as a direct manifestation of ongoing seizure activity, typically complex partial status epilepticus originating from the temporal lobe.
Treatment focuses on stopping the seizure activity rather than addressing psychosis as a separate problem.
Risk Factors for Seizures in Schizophrenia
Several factors beyond medication choice influence seizure risk in people with schizophrenia. Understanding these helps clinicians and patients make informed treatment decisions.
Medication-related factors:
- Rapid dose escalation of antipsychotics
- High plasma drug concentrations
- Use of multiple medications that lower seizure threshold
- Drug interactions affecting metabolism
Clinical and historical factors:
- Personal history of seizures or epilepsy
- Family history of seizures
- History of head injury or traumatic brain injury
- Intellectual disability or neurodevelopmental disorders
- Metabolic disturbances like low sodium levels
- Sleep deprivation
- Concurrent substance use
Childhood febrile seizures deserve special mention. A nationwide Danish study found that recurrent febrile seizures in childhood increase long-term risks of both epilepsy and psychiatric disorders, with risk rising with the number of febrile seizure episodes.
This suggests that early-life brain network instability may set trajectories for both conditions.
Managing Seizure Risk While Treating Schizophrenia
Effective management requires balancing the need for adequate psychiatric treatment against seizure risk. Several evidence-based strategies can minimize risk without compromising mental health outcomes.
Medication Selection and Dosing
For patients with known seizure risk factors, choosing antipsychotics with lower proconvulsant potential makes sense.
Aripiprazole represents a favorable first-line option given its low seizure risk and possible anticonvulsant properties. Risperidone and ziprasidone also offer reasonable safety profiles.
When clozapine is necessary for treatment-resistant schizophrenia, slow titration is essential. Starting at low doses and increasing gradually allows the brain to adapt and reduces acute seizure risk.
Therapeutic drug monitoring helps ensure levels remain in the therapeutic range without climbing into high-risk territory.
Therapeutic Drug Monitoring for Clozapine
Blood level monitoring serves multiple purposes in clozapine treatment. It helps identify patients who metabolize the drug unusually quickly or slowly, guides dose adjustments when clinical response is inadequate, and flags dangerously high levels before seizures occur.
Current guidelines recommend considering seizure prophylaxis when clozapine plasma levels exceed 500 to 600 micrograms per liter, and certainly as levels approach 1,000 micrograms per liter.
However, prophylactic antiseizure medications are not routinely recommended for all patients starting clozapine, the decision should be individualized based on risk factors.
Choosing Antiseizure Medications Wisely
When people with schizophrenia also have epilepsy, selecting the right antiseizure medication matters for cognitive function.
Cognitive impairment is already a core feature of schizophrenia, so medications that further impair thinking should be avoided when possible.
Lamotrigine, levetiracetam, and lacosamide show less cognitive impairment than older options like phenytoin, phenobarbital, and topiramate. However, levetiracetam can cause irritability and aggression in some patients, occurring in approximately 2.6 percent of users.
Perampanel carries an even higher risk of behavioral problems at 4.4 percent. These behavioral effects require monitoring in people with schizophrenia, where mood and impulse control may already be concerns.
When to Consider Seizure Prophylaxis
Rather than routinely prescribing antiseizure medications to everyone taking clozapine, a selective, risk-based approach makes more sense. Consider prophylaxis in these situations:
- Patients with a personal history of seizures or epilepsy
- Rapid clozapine titration required by clinical circumstances
- Clozapine plasma levels consistently above 500 to 600 micrograms per liter
- After a clozapine-related seizure has occurred
- Multiple concurrent risk factors (head injury history, substance use, metabolic issues)
Valproate has traditionally been used for seizure prophylaxis in clozapine patients, but case reports suggest that combining valproate with clozapine may increase the risk of clozapine-related neutropenia, a dangerous drop in white blood cells.
When valproate is used, close monitoring of blood counts is essential. Lamotrigine or other alternatives may be preferable in some cases.
Preventing Postictal Psychosis in Epilepsy
For people with epilepsy who experience postictal psychosis, prevention strategies focus on reducing seizure clusters and addressing early warning signs.
Seizure clustering is a major trigger, so optimizing antiseizure medication regimens and having rescue medications available for breakthrough seizures can reduce episodes.
Insomnia often precedes the full development of postictal psychosis. Addressing sleep disruption early, with short-term sedatives or low-dose antipsychotics at the first signs of sleep disturbance after seizures, may prevent progression to full psychotic episodes.
Given that nearly one-quarter of postictal psychosis episodes involve aggressive behavior, safety planning is critical. Families and caregivers should understand the risk, recognize early signs, and know when to seek emergency help.
The Role of Brain Imaging and EEG
Brain imaging studies in people with both epilepsy and psychosis reveal important patterns.
Bilateral hippocampal abnormalities, white matter changes in the corpus callosum and cingulum, and diffuse network disruptions appear more common in those who develop psychosis compared to those with epilepsy alone.
EEG findings also provide prognostic information. In temporal lobe epilepsy, bilateral epileptiform activity on EEG increases the risk of postictal psychosis sixfold.
The presence of ictal fear during seizures nearly triples the risk. These markers can help identify high-risk individuals who may benefit from more aggressive seizure control and closer psychiatric monitoring.
Despite the biological plausibility that EEG could help stratify seizure risk when starting clozapine, there is no current consensus recommending routine EEG screening for all patients.
EEG is generally reserved for those with predisposing factors or concerning symptoms, with management focusing on practical risk reduction through careful dosing and blood level monitoring.
Special Considerations for Treatment-Resistant Schizophrenia
Clozapine remains the gold standard for treatment-resistant schizophrenia despite its seizure risk. The key is not to avoid clozapine in appropriate patients but to use it expertly with proper safeguards.
Best practices include starting at low doses (typically 12.5 to 25 mg daily), increasing slowly (no more than 25 to 50 mg every few days), obtaining baseline and periodic blood levels, and adjusting the regimen based on both clinical response and plasma concentrations.
Patients should be educated about seizure warning signs and the importance of reporting symptoms like unusual sensations, brief lapses in awareness, or unexplained injuries.
If a seizure occurs during clozapine treatment, the response should be measured rather than reflexive. Evaluate for reversible precipitants like rapid dose increases, high plasma levels, metabolic problems, or drug interactions.
Often, reducing the clozapine dose or slowing further increases, combined with addressing other risk factors, allows continued use of this uniquely effective medication.
Integrated Care for Complex Cases
Managing the intersection of schizophrenia and seizures requires coordination across specialties. Psychiatrists, neurologists, primary care providers, and pharmacists all play important roles.
Regular screening should occur in both directions. Epilepsy clinics should screen annually for psychotic symptoms, sleep disruption around seizures, and early signs of postictal psychosis.
Psychiatric clinics should screen for seizure history, unexplained loss of consciousness, and family history of epilepsy, with neurology referral when indicated.
For patients with both conditions, treatment plans should explicitly address medication interactions, cognitive effects, and behavioral side effects.
Therapeutic drug monitoring, when appropriate, should be part of routine care rather than reserved for crisis situations.
What the Research Tells Us?
Recent genetic studies using sophisticated methods like Mendelian randomization provide nuanced insights. The relationship between epilepsy and schizophrenia is not uniform across all epilepsy types.
Focal epilepsies show causal links to several psychiatric conditions, while juvenile absence epilepsy may actually protect against schizophrenia.
This heterogeneity means that “epilepsy” should not be treated as a single entity when assessing psychiatric risk. The specific epilepsy syndrome, seizure focus location, age of onset, and seizure control all influence psychiatric outcomes.
Population studies consistently show that temporal lobe epilepsy carries the highest psychosis risk, with rates reaching 10 to 15 percent in some series.
Left temporal lobe foci, hippocampal sclerosis, and poor seizure control further elevate risk. These clinical markers should trigger proactive psychiatric assessment and preventive strategies.
Moving Forward With Confidence
The connection between schizophrenia and seizures is real and clinically significant, but it should not paralyze treatment decisions.
Most of the excess seizure risk in schizophrenia is modifiable through careful medication selection, appropriate dosing, therapeutic monitoring, and attention to other risk factors.
Clozapine’s unique effectiveness in treatment-resistant schizophrenia justifies its use despite seizure concerns, provided clinicians implement proper safeguards.
Similarly, people with epilepsy who develop psychosis can be treated effectively with antipsychotics chosen for their lower seizure liability.
The key is moving from a reactive stance, waiting for problems to occur, to a proactive, risk-stratified approach that identifies vulnerable individuals early, implements preventive strategies, and monitors systematically for warning signs.
If you or someone you care about is navigating schizophrenia, epilepsy, or both conditions together, specialized support makes a difference.
At The Summit Wellness Group, our team understands the complexities of co-occurring mental health conditions and provides individualized care that addresses your unique needs. Contact our mental health team to learn how we can support your recovery journey.
