Suicidality at Focal Epilepsy Diagnosis Predicts Treatment Resistance

Adults expressing suicidality when diagnosed with focal epilepsy face a nearly threefold higher risk of failing antiseizure medications.

For Doctors in a Hurry

Researchers investigated whether psychiatric disturbances present at the time of focal epilepsy diagnosis predict future resistance to antiseizure medications.
This prospective, multicenter cohort study followed 347 adults with newly diagnosed focal epilepsy for up to six years.
Suicidality at diagnosis increased treatment resistance probability from 16.3% to 47.1% (relative risk, 2.89; 95% confidence interval, 1.65 to 5.05; P<.001).
The authors concluded that early suicidality is strongly associated with future drug resistance and may indicate severe underlying neuropathology.
Routine psychiatric screening at epilepsy diagnosis may facilitate the early identification of patients at high risk for refractory syndromes.

The Challenge of Predicting Drug-Resistant Epilepsy

Managing focal epilepsy relies heavily on antiseizure medications, yet approximately 30% of patients ultimately develop drug-resistant epilepsy despite optimal pharmacological therapy [1, 2]. Identifying which patients will fail standard medical management remains a persistent clinical challenge, often requiring years of trial and error before alternative interventions like resective surgery or neuromodulation (a technique that alters nerve activity through targeted electrical stimulation) are considered [3]. Recent evidence suggests that psychiatric comorbidities, which frequently co-occur with seizure disorders, may serve as early clinical markers for a more severe disease trajectory and subsequent medication refractoriness [4, 5]. A recent prospective study demonstrates how specific psychiatric symptoms present at the time of initial diagnosis might predict future treatment resistance, potentially helping clinicians stratify patient risk earlier in the disease course [6].

Tracking Early Psychiatric Symptoms in Focal Epilepsy

Psychiatric disturbances are common in epilepsy and are associated with an increased risk of premature mortality, lower quality of life, and poor response to antiseizure medications. This clinical overlap likely stems from shared underlying neurobiology, such as common neurotransmitter imbalances or structural brain network disruptions. To better understand this relationship, researchers evaluated the role of psychiatric disturbances present at the time of epilepsy diagnosis in predicting the risk of future treatment resistance in focal epilepsy.

The investigators utilized data from the Human Epilepsy Project, a prospective, observational, international, and multicenter cohort study with follow-up for up to 6 years. The study focused on adults between the ages of 18 and 60 years who were without significant other comorbidities. All participants had newly diagnosed focal epilepsy and were enrolled within 4 months of initiating antiseizure medication treatment. Patient recruitment occurred between 2012 and 2020, with data analysis performed from January to September 2025.

To accurately capture baseline mental health, the researchers employed standardized clinical tools at the time of enrollment. The presence of a psychiatric diagnosis, specifically mood or anxiety disorders, was measured by the Mini International Neuropsychiatric Interview, a structured diagnostic questionnaire used to identify major psychiatric conditions. Concurrently, baseline suicidality was measured by the Columbia-Suicide Severity Rating Scale. By systematically documenting these symptoms early in the disease course, the researchers aimed to determine if specific psychiatric profiles could serve as prognostic indicators for medication failure.

Defining Treatment Resistance and Baseline Psychiatric Rates

To categorize patient trajectories, the researchers established strict clinical definitions for medication response. Patients were classified as treatment resistant if they experienced the failure of their first two adequate antiseizure medication trials, defined by ongoing seizures at or above therapeutic doses. Conversely, patients were considered treatment sensitive if they achieved a minimum period of seizure freedom on their first two adequate medication trials. This seizure-free period was defined as either 12 months or a three-fold greatest pretreatment seizure-free interval, whichever was longer. An indeterminate treatment response was defined as meeting the criteria for neither category.

Out of 376 enrolled adults, 347 completed the psychiatric assessments at enrollment. Within this final cohort, the median age at seizure onset was 33 years (interquartile range, 23 to 44 years), and 209 individuals (60.2%) were female. When evaluating clinical trajectories, the study found that 191 patients (55%) were treatment sensitive. A smaller subset of 83 patients (24%) were treatment resistant, while the remaining 73 individuals (21%) had an indeterminate treatment response.

Baseline psychological evaluations revealed a high prevalence of mental health comorbidities. The overall rate of psychiatric disturbance, which included any mood disorder, anxiety disorder, or suicidality at the time of epilepsy diagnosis, was 38% (133 patients). Breaking down this group further, 57 individuals (16%) had mood or anxiety disorders without suicidality. Notably, 75 individuals (22%) expressed suicidality, which occurred either with or without a concurrent psychiatric disorder.

Suicidality as a Predictor of Medication Failure

When evaluating the impact of baseline mental health on future medication efficacy, the researchers found no significant overall associations between mood or anxiety disorders and treatment resistance. However, specific symptoms carried substantial prognostic weight. Suicidality at epilepsy diagnosis was associated with a greater than two-fold risk of developing treatment resistance (relative risk [RR], 2.02; 95% CI, 1.32 to 3.09; P = .001). The data showed that suicidality alone significantly increased the probability of treatment resistance from 16.3% (95% CI, 11.3% to 21.3%) in those with no psychiatric disturbance to 47.1% (RR, 2.89; 95% CI, 1.65 to 5.05; P < .001). For practicing physicians, this indicates that suicidal ideation or behavior serves as a strong, independent clinical marker for failing standard antiseizure medications, warranting closer follow-up.

The investigators also analyzed the predictive value of specific psychiatric diagnoses in isolation and in combination with suicidality. An anxiety disorder alone increased the probability of treatment resistance to 32.9% (RR, 2.02; 95% CI, 1.10 to 3.71; P = .02), although this was not statistically significant after correcting for multiple comparisons. Similarly, there was no significant change in the probability of treatment resistance when a mood disorder alone was present. The clinical trajectory worsened, however, when mood disorders were compounded by suicidal thoughts. The presence of a mood disorder with suicidality increased the probability of treatment resistance to 39.6% (RR, 2.43; 95% CI, 1.26 to 4.68; P = .008). These findings suggest that routine psychiatric screening at the time of diagnosis, with a specific focus on suicidality, may facilitate the early identification of patients at high risk for refractory epilepsy syndromes.

Clinical Implications for Early Screening

The results of this cohort study reveal that suicidality at the time of focal epilepsy diagnosis is strongly associated with future drug resistance and may be a marker of more severe neuropathology. For practicing physicians, this indicates that suicidal ideation in newly diagnosed patients extends beyond a concurrent mental health crisis. Instead, it serves as a critical prognostic indicator for the underlying seizure disorder itself. The presence of these psychiatric symptoms early in the disease course suggests a shared neurobiological mechanism, where the same structural or functional brain abnormalities driving the suicidality also contribute to the failure of antiseizure medications.

Given these prognostic implications, the authors emphasize that psychiatric screening at the time of diagnosis may facilitate early identification of patients at risk for treatment-refractory epilepsy syndromes. Integrating standardized assessment tools into routine initial neurological evaluations allows clinicians to stratify patient risk before multiple medication trials fail. By identifying this high-risk cohort immediately, neurologists and primary care physicians can adjust their clinical management strategies, potentially accelerating the timeline for considering surgical evaluation, neuromodulation, or more intensive monitoring protocols.

Study Info

Suicidality at Epilepsy Diagnosis and Future Treatment Resistance in Adults With Focal Epilepsy

Sarah Barnard, Jacqueline A. French, Zeli Chen, Manisha Holmes, et al.

Journal JAMA Neurology

Published March 09, 2026