Suicidality at the time of a focal epilepsy diagnosis was associated with a higher risk for future treatment resistance to antiseizure medications (ASMs), independent of concurrent mood or anxiety disorders, a recent cohort study showed.

Nearly 40% of adults with newly diagnosed focal epilepsy had some form of psychiatric disturbance at diagnosis, and 22% expressed current or past suicidality, investigators found. Patients who reported suicidal thoughts at the time of diagnosis were more than twice as likely to develop treatment resistance, whereas co-occurring depression or anxiety alone did not influence seizure control.

“Suicidality at the time of focal epilepsy diagnosis was associated with future drug resistance and may be a marker of more severe neuropathology,” lead investigator Sarah N. Barnard, MD, MPH, Department of Neuroscience, School of Translational Medicine, Monash University, and Alfred Health, both in Melbourne, Australia and her colleagues, wrote.

Early identification of suicidality in patients newly diagnosed with epilepsy “may help stratify risk and guide more proactive treatment strategies to improve long-term outcomes,” they added.

The study was published online on March 9 in JAMA Neurology.

Psychiatric Comorbidities in Focal Epilepsy

Prior studies suggest a bidirectional relationship between psychiatric disorders and epilepsy. Mood disorders, anxiety, and suicidality may precede seizure onset, which could potentially reflect shared biological mechanisms such as neurotransmitter imbalances, hyperactive stress responses, and chronic neuroinflammation, the investigators noted.

Patients with psychiatric comorbidities also have lower rates of seizure remission with both ASMs and surgery.

However, the role of psychiatric comorbidities at the time of epilepsy diagnosis, particularly mood or anxiety disorders or suicidality, in predicting treatment resistance to ASMs has not been well established.

The new study included a post hoc analysis of the Human Epilepsy Project, an international, multicenter, prospective cohort study of adults aged 18-60 years with newly diagnosed focal epilepsy across 34 centers in the US, Europe, and Australia.

Researchers enrolled 347 participants (60.2% women; 80.1% White individuals) within 4 months of starting ASM therapy. The media age at seizure onset was 33 years.

Baseline psychiatric comorbidities were assessed using the Mini International Neuropsychiatric Interview for mood and anxiety disorders and the Columbia-Suicide Severity Rating Scale for current and past suicidality.

Psychiatric symptoms were present in 38% of participants at epilepsy diagnosis: 16% had mood or anxiety disorders without suicidality and 22% expressed suicidality with or without concurrent psychiatric diagnoses. Among those with suicidality, 73% also had mood or anxiety disorders.

Seizure frequency was collected prospectively through an electronic diary and review of medical records. Treatment resistance was defined using the International League Against Epilepsy criteria as failure to respond to at least two ASMs despite therapeutic dosing.

Between 22% and 32% of participants received ASM polytherapy, with the highest use seen among those who reported suicidality and the lowest among participants without psychiatric symptoms. However, most participants across all groups received monotherapy.

Levetiracetam was the most commonly prescribed first-line ASM (48%), followed by lamotrigine (14%) and carbamazepine (6.6%). Concurrent psychotropic medication use at enrollment was low (4%), which suggested that ASM prescribing was unlikely to have been limited by psychiatric comorbidity.

However, the investigators did not assess whether untreated vs treated psychiatric conditions influenced the risk for future treatment-resistant epilepsy. Given the few participants who were receiving psychotropic therapy at baseline, researchers were unable to compare outcomes between treated and untreated groups.

Effect of Psychiatric Symptoms

After a median 3-year follow up, 55% of participants were treatment sensitive, 24% were treatment resistant, and 21% were classified as indeterminate.

In multivariable analysis that controlled for mood and anxiety disorders, suicidality at diagnosis was associated with a more than two fold increased risk for treatment resistance (adjusted relative risk [aRR], 2.02; 95% CI, 1.32-3.09; P = .001).

Suicidality alone increased the probability of treatment resistance to 47.1% compared with 16.3% among participants with no psychiatric symptoms or suicidality at baseline. Mood or anxiety disorders alone were not independently associated with treatment resistance after adjustment. Participants with both suicidality and a mood disorder were 39.6% more likely to develop treatment resistance (aRR, 2.43; 95% CI, 1.26-4.68; P = .008).

In addition to the inability to assess whether the risk for ASM resistance was influenced by treated vs untreated psychiatric illness, other limitations included a study population with mostly healthy adults, a lack of long-term follow-up with psychiatric symptoms, inability to objectively measure ASM nonadherence, and a lack of assessment of social factors.

A Neurobiological Vulnerability?

Biological factors may explain why suicidality at epilepsy diagnosis could predict later treatment resistance, investigators noted.

These may include disruptions in key neurotransmitters, including serotonin, GABA, and glutamate, hyperactivity of the hypothalamic-pituitary-adrenal axis with elevated cortisol, and chronic neuroinflammation marked by cytokines, they added. These pathways could help explain the increased risk for seizures that do not respond to standard ASMs.

Similar mechanisms may link suicidality with other neurologic conditions, including migraine and headache disorders.

The investigators acknowledged that their findings point to a neurobiological vulnerability in patients with suicidality that may drive treatment resistance in focal epilepsy.

“Psychiatric screening at time of diagnosis may facilitate early identification of patients at risk for treatment refractory epilepsy syndromes,” they wrote.

Barnard reported receiving grants from the National Health and Medical Research Council (NHMRC) during the conduct of the study. She also reported receiving salary support from the Epilepsy Study Consortium for management of the Human Epilepsy Project. Her postdoctoral research, to which this study is related, is supported by the NHMRC of Australia.