Abstract
Objective
We aimed to assess the prevalence, clinical characteristics, and risk factors for psychosis in a cohort of people with epilepsy in West China.
Methods
We used retrospective information from databases of three tertiary epilepsy centers, which included follow‐up records from 2006 onward. Those with complete baseline data and at least one follow‐up record were included. A psychiatrist confirmed the diagnosis of psychosis. Psychiatric features were evaluated using the Brief Psychiatric Rating Scale, Scale for the Assessment of Positive Symptoms, and Scale for the Assessment of Negative Symptoms. Demographic data and clinical characteristics were used to develop risk models for interictal psychosis (IIP), ictal psychosis (IP), and postictal psychosis (PIP).
Results
Eight hundred eighty‐two people were identified. Of them, 112 (13%) were diagnosed with psychosis of epilepsy (POE), including 62 with IIP (7%), 29 with IP (3%), and 21 with PIP (2%). Twenty‐seven of the 882 (3%) were diagnosed with epilepsy following the onset of psychosis. Individuals with pre‐epilepsy psychosis, compared to those with POE, exhibited a lower proportion of refractory epilepsy, less frequent seizures, reduced seizure severity, and higher frequency and severity of hallucinations and delusions. In people with POE, bizarre behavior, avolition, and anhedonia were the three most common psychotic symptoms. Modeling identified several risk factors; earlier age at seizure onset, family history of schizophrenia, current frequent seizures, temporal lobe epilepsy (TLE), hippocampal sclerosis, perampanel use, and taking at least two antiseizure medications were associated with an increased risk of IIP. Severe head trauma, current frequent seizures, and TLE were risk factors for PIP, whereas current frequent seizures alone were a risk factor for IP.
Significance
Psychosis is often comorbid with epilepsy. Our study suggests that the prevalence of POE may be two times higher than previously reported. Prompt recognition and early management of psychosis are warranted.
Keywords: comorbidity, ictal psychosis, interictal psychosis, postictal psychosis, psychosis of epilepsy
Key points.
Psychosis is often comorbid with epilepsy; the prevalence of POE may be two times higher than previously reported.
Bizarre behavior, avolition, and anhedonia were the three most common psychotic symptoms in people with POE.
Polytherapy and perampanel use may be associated with IIP.
1. INTRODUCTION
Psychosis affects up to 7% of people with epilepsy. 1 This condition carries the risk of impulsive behavior resulting from hallucinations and delusions, often leading to violent actions. Aggressive behavior poses a significant threat to public safety. 2 Suicide risk among people with epilepsy and psychosis is 12.5 times higher than in the general population. Psychosis may occur either before (pre‐epilepsy psychosis) or after epilepsy onset, often referred to as psychosis of epilepsy (POE). Based on the temporal relationship between psychotic symptoms and seizures, POE is categorized into ictal psychosis (IP), postictal psychosis (PIP), and interictal psychosis (IIP). 3 Identifying prevalence, characteristics, and risk factors associated with psychosis in people with epilepsy is essential for improving risk stratification, enabling early preventive interventions, and enhancing our understanding of underlying mechanisms.
Previous studies have identified risk factors for POE, including a family history of schizophrenia, febrile seizures, status epilepticus, drug‐resistant epilepsy (DRE), frequent seizures, temporal lobe epilepsy (TLE), and hippocampal sclerosis (HS). 1 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 However, only TLE has consistently emerged as a risk factor, whereas the role of other factors has been inconsistent. 12 Conversely, psychosis can occur in people with epilepsy as an adverse effect of antiseizure medications (ASMs), such as ethosuximide, vigabatrin, topiramate, phenobarbital, levetiracetam, and perampanel. 13 The specific contribution of these drugs to POE development has not been systematically investigated. In a West China cohort, we assess the clinical characteristics of people with comorbid epilepsy and psychosis to identify risk factors for the different POE subtypes.
2. MATERIALS AND METHODS
2.1. Participants
Individuals were recruited from longitudinal follow‐up cohorts of three epilepsy centers: West China Hospital, Chengdu ShangJin Nanfu Hospital, and West China Tianfu Hospital. The cohort consisted of people diagnosed with epilepsy according to the International League Against Epilepsy (ILAE) criteria and who were routinely followed up. Individuals were included if they attended between January 1, 2006 and May 1, 2024 and agreed to participate, and had complete baseline data and at least one follow‐up visit. The baseline was defined as the 12 months preceding the first prescription of an ASM. People were excluded if there were incomplete baseline data or a lack of follow‐up data.
The ethics committee of West China Hospital and Chengdu ShangJin Nanfu Hospital approved the study (2023–732). All participants or their guardians provided informed written consent.
2.2. Standard protocol
Participants were managed by J.L. or D.Z., neurologists specializing in epilepsy. At the initial consultation, detailed epilepsy features were documented and evaluated following ILAE guidelines. Annual routine follow‐ups were conducted, during which clinical characteristics and investigation findings were updated.
When individuals presented with suspected psychotic symptoms, a systematic approach was used to exclude secondary causes such as substance use, medication side effects, metabolic disturbances, brain tumors, infections, and neurodegenerative diseases. Following this, individuals were referred to an experienced psychiatrist (Z.D.), who used the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders to confirm the diagnosis. J.L. and D.Z. then classified the psychotic episodes—based on the temporal relationship between psychosis and seizure activity—as IP, PIP, or IIP.
2.3. Collected variables
Demographic and epilepsy‐related variables were recorded, including age, sex, epilepsy or schizophrenia family history, age at seizure onset, birth trauma, status epilepticus, electroencephalographic (EEG) and magnetic resonance imaging (MRI) findings, epilepsy type, TLE, HS, ASMs, Chalfont‐National Hospital Seizure Severity Scale (NHS3) scores, seizure frequency, and drug‐refractory epilepsy. 14
TLE was diagnosed based on symptoms and epileptiform discharges predominantly in the temporal region on routine or video‐EEG. MRI diagnosed HS based on (1) reduced hippocampal volume and (2) increased T2 signal intensity in the hippocampus. Frequent seizures were defined as a seizure frequency greater than once per month. Due to the unavailability of ethosuximide and vigabatrin in China, only topiramate, phenobarbital, levetiracetam, and perampanel were considered as drugs with potential negative psychotropic properties. Baseline variables were collected during the baseline period, and follow‐up variables were updated using advanced tests. The most recent follow‐up data were included in the analysis.
Z.D. collected psychiatric variables using the Social Disability Screening Schedule (SDSS), Brief Psychiatric Rating Scale (BPRS), Scale for the Assessment of Positive Symptoms (SAPS), and Scale for the Assessment of Negative Symptoms (SANS).
2.4. Assessment scales
NHS3 is a clinician‐rated seven‐factor scale generating scores from 1 to 27, where higher scores indicate higher seizure severity (Table 1). 15
TABLE 1.
Assessment scales.
| Scale name | Dimension | Items |
|---|---|---|
| NHS3 | NA |
|
| SDSS | NA | Occupational role, marital role, parental role, social withdrawal, social activities, participation in household activities, family functioning, self‐care, interest and attention to environment, responsibility or plan |
| BPRS | Anxiety/depression | Somatic concern, anxiety, feelings of guilt, depressive mood |
| Lack of vitality | Emotional withdrawal, motor retardation, blunted affect, disorientation | |
| Thought disorders | Conceptual disorganization, grandiosity, hallucinatory behavior, unusual thought content | |
| Activation | Tension, mannerisms and posturing, excitement | |
| Hostility | Hostility, suspiciousness, uncooperativeness | |
| SAPS | Hallucinations | Auditory hallucinations, voices commenting, voices conversing, somatic or tactile hallucinations, olfactory hallucinations, visual hallucinations, global rating |
| Delusions | Persecutory delusions, delusions of jealousy, delusions of guilt or sin, grandiose delusions, religious delusions, somatic delusions, delusions of reference, delusions of being controlled, delusions of mind reading, thought broadcasting, thought insertion, thought withdrawal, global rating | |
| Bizarre behavior | Clothing and appearance, social and sexual behavior, aggressive and agitated behavior, repetitive or stereotyped behaviors, global rating | |
| Positive thought disorders | Derailment, tangentiality, incoherence, illogicality, circumstantiality, pressure of speech, distractible speech, clanging, global rating | |
| SANS | Affective flattening | Unchanging facial expression, decreased spontaneous movements, paucity of expressive gestures, poor eye contact, affective nonresponsiveness, inappropriate affect, lack of vocal inflections, global rating |
| Alogia | Poverty of speech, poverty of content of speech, blocking, increased latency of response, global rating | |
| Avolition | Grooming and hygiene, impersistence at work or school, physical anergia, global rating | |
| Anhedonia | Recreational interests and activities, sexual activity, ability to feel intimacy and closeness, relationships with friends or peers, global rating | |
| Inattention | Social inattentiveness, inattentiveness during mental status examination, global rating |
Abbreviations: BPRS, Brief Psychiatric Rating Scale; NA, not applicable; NHS3, Chalfont‐National Hospital Seizure Severity Scale; SANS, Scale for the Assessment of Negative Symptoms; SAPS, Scale for the Assessment of Positive Symptoms; SDSS, Social Disability Screening Schedule.
SDSS is a clinician‐rated 10‐item scale assessing social ability, each item scored from 0 (no impairment) to 2 (severe impairment). A total score of ≥2 indicates social functional impairment (Table 1). 16
BPRS is a clinician‐rated 18‐item scale divided into five factors (anxiety/depression, lack of vitality, thought disorders, activation, hostility), with scores ranging from 0 to 7. Higher scores indicate greater symptom severity (Table 1). 17
SAPS is a clinician‐rated 34‐item scale across four subscales (hallucinations, delusions, bizarre behavior, positive thought disorders), scored from 0 to 5. Higher scores represent greater severity of positive symptoms (Table 1). 18
SANS is a clinician‐rated 24‐item scale across five subscales (affective flattening, alogia, avolition, anhedonia, inattention), scored from 0 to 5. Higher scores reflect greater severity of negative symptoms (Table 1). 18
2.5. Outcome assessment
The prevalence and clinical characteristics of pre‐epilepsy psychosis and POE were the primary outcomes. Risk factors associated with different types of POE (IIP, IP, and PIP) were the secondary outcomes.
2.6. Statistical analysis
The Kolmogorov–Smirnov test indicated that all continuous variables were nonnormally distributed. The Kruskal–Wallis test was used for continuous variables, whereas chi‐squared or Fisher exact tests were applied to categorical variables. We used radar charts to visualize the frequency and severity of diverse psychiatric symptoms concurrently, assessed using BPRS, SAPS, and SANS, among four groups (IIP, IP, PIP, and pre‐epilepsy psychosis). Univariate analyses were conducted to identify potential IP, PIP, and IIP risk factors. Collinearity screening was performed for variables significant in univariate analyses, and those exhibiting collinearity were excluded.
Cox regression was employed to identify the final risk factors for IIP and PIP. We used Kaplan–Meier curve to show the proportion of individuals remaining free from IIP and PIP throughout their condition. In contrast, logistic regression was used for IP, given its lack of temporal dependence on follow‐up data. Least absolute shrinkage and selection operator (LASSO) models were employed to validate the accuracy of the risk models. Statistical analyses were performed using R (v3.6.2), and DataGraph 4.6 software was used to generate data images.
3. RESULTS
The cohort included 1196 individuals diagnosed with epilepsy who agreed to participate. Of them, 182 had incomplete baseline data, and 132 had no follow‐up data and were excluded. Eventually, 882 people were included in this study (Figure 1).
FIGURE 1.
Participant flowchart.
3.1. Prevalence
Of the 882 people, 27 (3%) experienced psychiatric symptoms before the onset of epileptic seizures and were diagnosed with pre‐epilepsy psychosis. At the end of the follow‐up, 112 (13%) were diagnosed with POE, including 62 (7%) with IIP, 29 (3%) with IP, and 21 (2%) with PIP (Figure 1).
3.2. Clinical characteristics of pre‐epilepsy psychosis
Compared to people with POE, those with pre‐epilepsy psychosis had a higher proportion of females and a greater age at epilepsy onset. They had lower rates of baseline and current frequent seizures, lower seizure severity, fewer epilepsy‐related MRI abnormalities, and a lower prevalence of HS. They also had a lower proportion of DRE and were less likely to be taking more than one ASM (Table 2). The frequency and severity of hallucinations and delusions were significantly higher in those with pre‐epilepsy psychosis than in POE. Other psychotic symptoms did not differ significantly between groups (Figure 2, Table S1). Their first epileptic seizure often occurred 3 years (95% confidence interval [CI] = 2–5 years) after the onset of psychotic symptoms. Their social dysfunction was evident, with a median SDSS score of 6 (95% CI = 2–13 points; Table 2).
TABLE 2.
Epilepsy features of people with epilepsy with and without comorbid psychosis.
| Feature | Group | |||||
|---|---|---|---|---|---|---|
| Epilepsy without comorbid psychosis | Pre‐epilepsy psychosis | POE | IIP | IP | PIP | |
| n | 743 | 27 | 112 | 62 | 29 | 21 |
| Age, years [median (Q1‐Q3)] | 26 (20–35) | 28 (19–43) | 24 (16–35) a | 24 (17–32) a | 18 (11–28) a | 37 (23–43) |
| Sex, female [n(%)] | 360 (48%) | 23 (85%) a, , b | 51 (46%) | 28 (45%) | 16 (55%) | 7 (33%) |
| Age at seizure onset, years [median (Q1‐Q3)] | 17 (11–25) | 24 (15–38) a, , b | 12 (6–25) a | 10 (5–22) a | 13 (7–20) | 24 (11–33) |
| Epilepsy‐related history [n (%)] | ||||||
| Asphyxia at birth | 25 (3%) | 3 (11%) a | 6 (5%) | 1 (2%) | 3 (10%) | 2 (10%) |
| Febrile convulsion | 102 (14%) | 1 (4%) | 19 (17%) | 7 (11%) | 7 (24%) | 5 (24%) |
| Severe traumatic brain injury | 56 (8%) | 4 (15%) | 16 (14%) a | 7 (11%) | 3 (10%) | 6 (29%) a |
| Encephalitis | 62 (8%) | 1 (4%) | 7 (6%) | 5 (8%) | 1 (3%) | 1 (5%) |
| Craniotomy | 47 (6%) | 1 (4%) | 6 (5%) | 4 (6%) | 2 (7%) | 0 (0%) |
| Family history of epilepsy [n (%)] | 56 (8%) | 2 (7%) | 15 (13%) a | 6 (10%) | 5 (17%) | 4 (19%) |
| Family history of schizophrenia [n (%)] | 25 (3%) | 1 (4%) | 8 (7%) | 8 (13%) a | 0 (0%) | 0 (0%) |
| Baseline frequent seizures [>1/month] [n (%)] | 287 (39%) | 8 (30%) b | 59 (53%) a | 33 (53%) a | 15 (52%) | 11 (52%) |
| Current frequent seizures [>1/month] [n (%)] | 188 (25%) | 9 (33%) b | 73 (65%) a | 41 (66%) a | 16 (55%) a | 16 (76%) a |
| NHS3 [median (Q1‐Q3)] | 8 (1–12) | 7 (6–8) b | 8 (6–11) | 9 (7–11) a | 8 (4–12) | 6 (4–8) |
| Status epilepticus [n (%)] | 211 (28%) | 6 (22%) | 29 (26%) | 16 (26%) | 5 (17%) | 8 (38%) |
| Epilepsy‐related abnormalities on MRI[n (%)] | 300 (40%) | 9 (33%) b | 61 (54%) a | 38 (61%) a | 14 (48%) | 9 (43%) |
| HS [n (%)] | 114 (15%) | 3 (11%) b | 37 (33%) a | 24 (39%) a | 8 (28%) | 5 (24%) |
| Epilepsy type, focal [n (%)] | 589 (79%) | 21 (78%) | 101 (90%) a | 56 (90%) a | 26 (90%) | 19 (90%) |
| TLE [n (%)] | 277 (37%) | 15 (56%) | 72 (64%) a | 43 (69%) a | 16 (55%) | 13 (62%) a |
| Drug‐resistant epilepsy [n (%)] | 299 (40%) | 8 (30%) b | 68 (61%) a | 44 (71%) a | 11 (38%) | 13 (62%) a |
| ≥2 ASMs [n (%)] | 362 (49%) | 13 (48%) b | 81 (72%) a | 51 (82%) a | 15 (52%) | 15 (71%) a |
| Drugs with potential negative psychotropic properties [n (%)] | ||||||
| Perampanel | 33 (4%) | 0 (0%) | 12 (10%) a | 8 (13%) a | 2 (7%) | 2 (10%) |
| Levetiracetam | 424 (57%) | 12 (44%) | 58 (52%) | 32 (52%) | 17 (59%) | 9 (43%) |
| Topiramate | 10 (1%) | 0 (0%) | 1 (1%) | 0 (0%) | 1 (4%) | 0 (0%) |
| Phenobarbital | 7 (1%) | 0 (0%) | 1 (1%) | 1 (2%) | 0 (0%) | 0 (0%) |
| Interval between the onset of epilepsy and that of psychosis, years [median (Q1‐Q3)] | NA | 3 (2–5) b | 9 (4–14) | 11 (6–14) | 0 (0–2) | 6 (1–18) |
| SDSS total score [median (Q1‐Q3)] | NA | 6 (2–13) | 6 (2–11) | 8 (3–14) | 2 (0–4) | 6 (2–8) |
| Antipsychotic drugs [n (%)] | NA | 16 (59%) | 42 (38%) | 37 (60%) | 0 (0%) | 5 (24%) |
| Olanzapine | NA | 5 (19%) | 15 (13%) | 13 (21%) | 0 (0%) | 2 (10%) |
| Aripiprazole | NA | 6 (22%) | 5 (4%) | 5 (8%) | 0 (0%) | 0 (0%) |
| Quetiapine | NA | 4 (15%) | 7 (11%) | 7 (11%) | 0 (0%) | 0 (0%) |
| Risperidone | NA | 6 (22%) | 15 (13%) | 12 (19%) | 0 (0%) | 3 (14%) |
Abbreviations: ASM, antiseizure medication; HS, hippocampal sclerosis; IIP, interictal psychosis; IP, ictal psychosis; MRI, magnetic resonance imaging; NA, not applicable; NHS3, Chalfont‐National Hospital Seizure Severity Scale; PIP, postictal psychosis; POE, psychosis of epilepsy; SDSS, Social Disability Screening Schedule; TLE, temporal lobe epilepsy.
Compared to the epilepsy without comorbid psychosis group, p < .05.
Compared to the POE group, p < .05.
FIGURE 2.
Psychiatric features of psychosis in epilepsy. (A) Radar map showing the frequency of psychotic symptoms in people with interictal psychosis (IIP), ictal psychosis (IP), postictal psychosis (PIP), and pre‐epilepsy psychosis. Each axis indicates a different psychotic symptom assessed using the Brief Psychiatric Rating Scale (BPRS), Scale for the Assessment of Positive Symptoms (SAPS), and Scale for the Assessment of Negative Symptoms (SANS), with the frequency of the symptom ranging from 0% to 100%. (B) Radar map displaying the severity of psychotic symptoms in people with IIP, IP, PIP, and pre‐epilepsy psychosis. Each axis represents a different psychotic symptom assessed using the BPRS, SAPS, and SANS, with the severity of the symptom ranging from 0 to 100.
3.3. Clinical characteristics of POE and its subgroups
Compared to people with epilepsy without psychosis, those with POE had an earlier median age at epilepsy onset. They were also more likely to have a history of severe traumatic brain injury and a family epilepsy history. Additionally, they had more frequent baseline seizures, current seizures, and epilepsy‐related MRI lesions. HS was more prevalent among those with POE, as was focal epilepsy, TLE, DRE, and the likelihood of using more than one ASM. Comparison of epilepsy features between subgroups of POE and the people with epilepsy without psychosis are also shown in Table 2.
3.3.1. BPRS results
Approximately 90% of people with POE had symptoms related to anxiety and depression, lack of vitality, thought disturbances, activation, and hostility. There were no significant differences in the frequency of these symptoms among the IIP, IP, and PIP subgroups (Figure 2A, Table S1). However, symptom severity differed, with those with IIP showing significantly greater severity in lack of vitality, thought disturbances, and overall psychotic symptom severity compared to IP. No significant differences in severity were observed between those with IIP or PIP (Figure 2B, Table S1).
3.3.2. SAPS results
The most common positive symptoms were bizarre behavior (79%), hallucinations (58%), and delusions (54%). People with IIP had a significantly higher frequency of bizarre behavior, positive thought disorders, and delusions compared to IP. However, there were no significant differences in symptom frequency between those with IIP or PIP (Figure 2A, Table S1). People with IIP presented significantly greater severity in bizarre behavior, positive thought disorders, delusions, and overall positive symptom severity compared to those with IP. People with IIP also had slightly higher severity of bizarre behavior than those with PIP (Figure 2B, Table S1).
3.3.3. SANS results
The most frequently observed negative symptoms included avolition (71%), anhedonia (63%), and affective flattening (58%). Compared to IP, those with IIP showed a significantly higher frequency of negative symptoms except inattention: affective flattening, alogia, avolition, anhedonia (Figure 2A, Table S1). Severitywise, people with IIP had significantly greater severity of all negative symptoms compared to people with IP. However, no significant differences were noted between IIP and PIP (Figure 2B, Table S1).
The median interval between the first epileptic seizure and the onset of psychotic symptoms was 9 years for POE, 11 years for IIP, 6 years for PIP, and 0 years for IP. Most people with POE had social functional deficits. In terms of severity, people with IIP had the most significant impairment, followed by PIP, with IP showing the least impairment. Sixty percent of those with IIP were prescribed antipsychotic medication, compared to 24% of those with PIP and none with IP (Table 2).
3.4. Risk factors associated with IIP, IP, and PIP
Of the ASMs under consideration, only levetiracetam and perampanel were included in the analysis, as phenobarbital or topiramate was used by only a few people (Table 2). Univariate analysis showed that some factors significantly increased the risk of developing IIP: earlier age of seizure onset (hazard ratio [HR] = .96, 95% CI = .94–.98, p = .0010), greater epilepsy severity (HR = 1.06, 95% CI = 1.02–1.11, p = .0053), family schizophrenia history (HR = 2.86, 95% CI = 1.36–6.02, p = .0058), frequent baseline seizures (HR = 1.67, 95% CI = 1.02–2.76, p = .0429), frequent current seizures (HR = 5.13, 95% CI = 3.02–8.70, p < .0001), epilepsy‐related abnormalities on MRI (HR = 2.17, 95% CI = 1.30–3.63, p = .0029), HS (HR = 2.71, 95% CI = 1.62–4.52, p = .0001), TLE (HR = 3.57, 95% CI = 2.08–6.14, p < .0001), DRE (HR = 3.23, 95% CI = 1.86–5.60, p < .0001), use of more than one ASM (HR = 3.80, 95% CI = 1.98–7.29, p < .0001), and perampanel use (HR = 2.64, 95% CI = 1.26–5.56, p = .0105; Table S2). The final Cox proportional hazards model identified the following as independent risk factors for IIP: earlier age at seizure onset (HR = .97, 95% CI = .95–.99, p = .0235), family history of schizophrenia (HR = 2.61, 95% CI = 1.21–5.60, p = .0141), frequent current seizures (HR = 3.40, 95% CI = 1.92–6.02, p = .0000), HS (HR = 1.41, 95% CI = .68–2.93, p = .1659), TLE (HR = 2.35, 95% CI = 1.34–4.14, p = .0031), use of more than one ASM (HR = 2.02, 95% CI = 1.02–3.99, p = .0430), and perampanel (HR = 1.84, 95% CI = .85–3.99, p = .1220; Table 3). The Kaplan–Meier curve suggests a progressive reduction in the probability of remaining free from IIP as the duration increases. The likelihood decreases to approximately 90% by the 10‐year mark and further declines to approximately 70% by the 40‐year mark (Figure 3A). All risk factors were retained in the LASSO regression model (Figure 3B).
TABLE 3.
Risk factors associated with IIP, IP, and PIP.
| Risk factor | HR (95% CI) | p |
|---|---|---|
| IIP [Cox model] | ||
| Age at seizure onset | .97 (.95–.99) | .0235 |
| Family history of schizophrenia | 2.61 (1.21–5.60) | .0141 |
| Current frequent seizures | 3.40 (1.92–6.02) | .0000 |
| HS | 1.41 (.68–2.93) | .1659 |
| TLE | 2.35 (1.34–4.14) | .0031 |
| ≥ 2 ASMs | 2.02 (1.02–3.99) | .0430 |
| Perampanel | 1.84 (.85–3.99) | .1220 |
| IP [logistic model] | ||
| Current frequent seizures | 2.83 (1.34–5.98) | .0062 |
| PIP [Cox model] | ||
| Frequent current seizures | 9.76 (3.51–27.14) | <.0001 |
| TLE | 2.00 (1.36–5.22) | .0430 |
| Severe traumatic brain injury | 3.78 (1.41–10.18) | .0084 |
Note: Bold values indicate statistical significance, p < .05.
Abbreviations: ASM, antiseizure medication; CI, confidence interval; HR, hazard ratio; HS, hippocampal sclerosis; IIP, interictal psychosis; IP, ictal psychosis; PIP, postictal psychosis; TLE, temporal lobe epilepsy.
FIGURE 3.
Models for interictal psychosis (IIP), postictal psychosis (PIP), and ictal psychosis (IP). (A) Kaplan–Meier curve for IIP, showing a progressive reduction in the probability of remaining free from IIP as epilepsy duration lengthens. (B) Least absolute shrinkage and selection operator (LASSO) model for IIP. The vertical black dashed lines (log[λ] = −3.68) represent the optimal model resulting in six nonzero features: family history of schizophrenia, age of seizure onset, current frequent seizures, temporal lobe epilepsy (TLE), hippocampal sclerosis (HS), and using at least two antiseizure medications. (C) Kaplan–Meier curve for PIP. The probability of remaining free from PIP gradually diminishes as the duration extends, with a particularly sharp decline observed after surpassing 25 years of progression. (D) LASSO model for PIP. The vertical black dashed lines (log[λ] = −4.97) represent the optimal model resulting in six nonzero features: family history of epilepsy, birth asphyxia, history of severe traumatic brain injury, Chalfont‐National Hospital Seizure Severity Scale score, current frequent seizures, and TLE. (E) Forest plot of logistic regression result of IP. (F) LASSO model for IP. The vertical black dashed lines (log[λ] = −6.02) represent the optimal model resulting in nine nonzero features: family history of epilepsy, history of febrile convulsions, history of encephalitis, history of seizure status, HS, TLE, focal epilepsy, current frequent seizures, and DRE. CI, confidence interval; OR, odds ratio.
For PIP, univariate analysis identified the following as risk factors: a history of severe head trauma (HR = 3.82, 95% CI = 1.48–9.89, p = .0058), frequent current seizures (HR = 9.78, 95% CI = 3.53–27.07, p < .0001), TLE (HR = 3.02, 95% CI = 1.24–7.38, p = .0150), and DRE (HR = 2.58, 95% CI = 1.06–6.27, p = .0370; Table S2). No factors were excluded during collinearity screening. The Cox proportional hazards model confirmed the following as independent risk factors for PIP: a history of severe head trauma (HR = 3.78, 95% CI = 1.41–10.18, p = .0084), frequent current seizures (HR = 9.76, 95% CI = 3.51–27.14, p < .0001), and TLE (HR = 2.00, 95% CI = 1.36–5.22, p = .0430; Table 3). The Kaplan–Meier curve indicated that the probability of remaining free from PIP gradually diminishes as epilepsy duration extends, with a sharp decline observed after exceeding 25 years of progression (Figure 3C). These risk factors were also retained in the LASSO regression model (Figure 3D).
For IP, the univariate analysis indicated that younger age (HR = .93, 95% CI = .89–.97, p = .0012) and frequent current seizures (HR = 2.87, 95% CI = 1.38–5.97, p = .0048) were significant risk factors (Table S2). The logistic regression model confirmed frequent current seizures (HR = 2.83, 95% CI = 1.34–5.98, p = .0062) as a significant risk factor (Table 3, Figure 3E). This risk factor was also retained in the LASSO regression model (Figure 3F).
4. DISCUSSION
The diagnostic framework of ILAE includes the comorbidity of psychosis with epilepsy. Still, due to inconsistent medical conditions, there remains a diagnostic gap in different in regions. This is one of the first large‐sample studies examining the prevalence, characteristics, and risk factors for psychosis in Chinese individuals with epilepsy.
Our study shows that the prevalence of POE was approximately 13%, which exceeded estimates derived from meta‐analyses of cross‐sectional and case–control studies. 1 , 12 , 19 The increased prevalence of POE in our cohort may be due to several factors. Multidisciplinary collaboration and psychiatrist involvement improve symptom detection and raise awareness of POE among health care providers. Ethnic, social, and cultural factors also play a role. Chinese people with epilepsy often report high perceived discrimination, internalized stigma, and insufficient social and psychological support, 20 potentially contributing to the higher POE prevalence. Our findings also underscore significant social functioning deficits in individuals with epilepsy who have comorbid psychosis, with the majority being unable to work, sustain social relationships, or participate in community activities. The intense aggressive behavior exhibited by these individuals could threaten public safety. These findings significantly impact public health policies and clinical care. Enhanced screening targeting high‐risk groups is critical for early intervention.
Previous risk factor studies of POE have often failed to distinguish the different POE subtypes despite evidence suggesting significant clinical differences between IP, PIP, and IIP. 12 This lack of differentiation may compromise the precision and utility of findings. We employed two methods to model IIP, PIP, and IP risk factors, yielding consistent results and enhancing findings. Risk factor analysis indicates that IIP and PIP are associated with TLE and current frequent seizures. Both have intervals of 10 years or more between seizure onset and the emergence of psychotic symptoms, suggesting they may represent similar clinical entities. In contrast, IP appears to be relatively independent. These findings align with some prior studies 10 , 21 but not all. 22
Compared to earlier studies, we confirmed that family schizophrenia history, 7 , 8 early age onset, 9 frequent seizures, 1 , 10 TLE, 9 , 11 and HS 4 , 5 , 6 are associated with IIP. We did not identify correlations between IIP and histories of febrile seizures or status epilepticus. Our results contribute to a deeper understanding of the mechanisms of IIP. With the accumulation of seizures, the transient inhibition of brain function caused by epileptic discharge gradually develops into long‐term chronic injury of brain structure, resulting in alternation and spread of the epileptogenic network. HS may be a key link in the development of IIP. Existing evidence supports the association between IIP and HS, which is the most frequent pathological finding in people with IIP. 23 In‐depth analyses show significant reductions in calcium‐binding protein‐positive cells and mossy fiber sprouting across hippocampal regions in people with IIP compared to those with epilepsy without psychosis. 24 , 25 Calcium‐binding protein‐positive cells typically represent γ‐aminobutyric acidergic (GABAergic) neurons. A reduction in GABAergic neurons within the hippocampus may lead to hyperactivity. Some suggest that increased hippocampal excitation can overactivate the dopamine system of the striatum–ventral tegmental area. This heightened the role of central dopamine neurotransmission, potentially triggering psychotic symptoms. 26 , 27 Thus, hippocampal GABAergic dysfunction may play a role in IIP, which warrants further work.
Our model suggests that using more than one ASM is an independent risk factor of IIP. Evidence suggests that serotonin, GABA, and glutamate (via the α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor) may play key roles in the pharmacological mechanism of the association of ASMs and psychosis. 28 The latter two were targets of various ASMs. One view is that structural injury occurring in the long‐term course of people with TLE may lead to the growth of immature GABAergic and glutamatergic neurons that have opposite effects to mature GABAergic and glutamatergic neurons. ASMs that reinforce GABA would increase neuronal excitement instead of decreasing it, and ASMs that usually inhibit glutamatergic signal transmission might have a facilitating effect. 29 These neurotransmitters' structural change and perturbations increase susceptibility to IIP in people with TLE on polytherapy. In our study, perampanel, but not levetiracetam, increases the risk for IIP. This may be because levetiracetam‐induced adverse events often emerge shortly after starting, 30 and so were quickly recognized as a drug‐induced effect and excluded. Conversely, perampanel‐induced psychosis may occur after several months of use, and adverse events are thus included. 31 , 32
We found that in people with pre‐epilepsy psychosis, the onset of epilepsy is usually approximately 3 years after the development of psychosis, which is consistent with previous reports. 33 Epilepsy features are similar to those seen in people with epilepsy without psychosis. Compared to people with POE, those with pre‐epilepsy psychosis were less likely to develop DRE. However, psychotic symptoms were significantly more severe in pre‐epilepsy psychosis compared to POE. This highlights the importance of balancing antiseizure and antipsychotic treatment strategies for pre‐epilepsy psychosis. Valproate remains an option due to its broad‐spectrum antiseizure properties and antimanic effects. Lamotrigine may be an alternative when valproate is contraindicated or unsuitable. 34 Drugs with potentially harmful psychotropic properties, such as topiramate, phenobarbital, levetiracetam, and perampanel, should be avoided as initial choices. 13
Our study has limitations. First, given its retrospective nature, we cannot definitively establish causal relationships between risk factors and POE. Future prospective cohort studies are necessary to address this limitation. Second, our design may have introduced unassessed confounders and information biases. To mitigate this, we included common previously reported risk factors for POE. We excluded people with incomplete baseline data. Lastly, our cohort's relatively small sample with PIP and IP may reduce the precision of associated findings. However, this cohort represents one of the larger samples reported to date. We plan to expand the cohort and continue the follow‐up in the long term to provide further insights.
5. CONCLUSIONS
Psychosis is a severe condition demanding greater attention when it presents in people with epilepsy. The prevalence of POE is higher than expected, and prompt recognition and early management of psychosis are warranted.
FUNDING INFORMATION
S.S. is supported by the China Postdoctoral Science Foundation (2024 M762241). H.S. is supported by the Health Commission of Sichuan Province Medical Science and Technology Program (24WSXT028). J.W.S. is based at the NIHR University College London Hospitals Biomedical Research Centre, which the UK Department of Health sponsors. D.Z. is supported by the Joint Funds of the National Natural Science Foundation of China (U21A20393), project for disciplines of excellence from West China Hospital (ZYGD23032) and Science & Technology Department (2021YFC2401204, 2022YFC2503805). J.L. is supported by the National Natural Science Foundation of China (82071459).
CONFLICT OF INTEREST STATEMENT
None of the authors has conflicts of interest concerning this work to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
Supporting information
TABLES S1–S2.
ACKNOWLEDGMENTS
We sincerely thank Caleb Onyenaturuchi Egbuta for language review.
Shen S, Sun H, Dong Z, Yi T, Sander JW, Zhou D, et al. Prevalence, clinical characteristics, and risk factors for psychosis in people with epilepsy: A multicenter retrospective cohort study. Epilepsia. 2025;66:2904–2915. 10.1111/epi.18409
Sisi Shen, Hanlin Sun, and Zaiquan Dong contributed equally.
DATA AVAILABILITY STATEMENT
The data used to support this study's findings are available to bona fide researchers from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
TABLES S1–S2.
Data Availability Statement
The data used to support this study's findings are available to bona fide researchers from the corresponding author upon reasonable request.