Incidence of SSRI treatment and psychiatric specialist care in new-onset adult epilepsy: are newer antiseizure medications associated with more treatment of anxiety/depression?

This study found that while adults with new-onset epilepsy have a consistently higher risk of starting SSRI treatment compared to the general population, the shift toward newer antiseizure medications did not increase this likelihood, revealing a persistent and potentially widening treatment gap for depression, particularly among young adults.

The Gist

Imagine your brain is a bustling city. Sometimes, the traffic lights malfunction, causing sudden, chaotic gridlocks. In medical terms, we call these "seizures," and the condition is epilepsy.

For decades, the doctors' main job was to fix the traffic lights using heavy-duty, older tools called antiseizure medications (ASMs). However, these old tools had a nasty side effect: they tangled with other tools in the toolbox, making it very difficult to fix other problems in the city, like depression or anxiety.

In recent years, doctors switched to newer, sleeker tools (newer ASMs) that don't tangle with other medications. The big question this study asked was: "Now that the tools don't tangle anymore, are we finally fixing the depression and anxiety in epilepsy patients better than before?"

Here is the story of what the researchers found, told in simple terms.

The Big Experiment

The researchers acted like giant detectives in Sweden. They looked at the medical records of nearly 30,000 adults who were newly diagnosed with epilepsy between 2006 and 2020. They compared them to over 68,000 healthy people of the same age and gender (the "control group").

They watched to see who started taking SSRIs (the most common "mood-stabilizing" pills for depression) and who needed to see a psychiatric specialist (a mental health expert). They did this in three time blocks to see if things improved as the "newer tools" became more popular.

The Surprising Twist

The researchers expected that because the new medications were easier to use with antidepressants, the treatment for depression would skyrocket. They thought, "Now that the road is clear, everyone will get the help they need!"

But the road didn't clear up as much as they hoped.

Here is what they actually found:

1. The Gap Remains: People with epilepsy are still about twice as likely to get depression or anxiety compared to people without epilepsy. This has been true for the last 20 years.
2. No Magic Fix: Even though doctors switched to the newer, "non-tangling" medications, the rate of people getting treated for depression did not go up significantly. It stayed roughly the same.
3. The "Young Adult" Paradox: This is the most interesting part. In the general population, young adults (under 30) started getting treated for depression much more often over the years. Society got better at noticing sadness in young people. However, for young people with epilepsy, this improvement didn't happen. They were left behind. The treatment rate for them stayed flat while everyone else got better care.

The "Shadow" of Other Illnesses

The study also looked at what else was happening in these patients' lives. They found that if a person with epilepsy also had other "city problems"—like a stroke, a brain tumor, or diabetes—they were much more likely to get treated for depression.

However, there was a sad exception: People with intellectual disabilities were less likely to get treated. It's as if their depression was invisible, perhaps because it's harder to communicate their feelings, or doctors assumed their sadness was just part of their disability.

The Takeaway: A Missed Opportunity

Think of the shift to newer medications as upgrading from a rusty key to a smart key. You'd expect the door to open much easier now. But the study shows that while the key is better, we haven't actually tried to open the door any more often.

The researchers conclude that:

• Depression in epilepsy is still under-treated. Just because the medications don't clash anymore doesn't mean doctors are automatically checking for sadness.
• Young adults are being overlooked. While society is getting better at helping young people with mental health, it seems to have forgotten the young people with epilepsy.
• We need a new strategy. We can't just rely on better drugs; we need to actively screen for depression in epilepsy patients, just like we check their blood pressure or seizure frequency.

In short: We fixed the traffic lights (the seizures), but we forgot to check the mood of the drivers. The study is a wake-up call to make sure that when we treat the epilepsy, we don't leave the depression behind.

Technical Summary

1. Problem Statement and Background

• Clinical Context: Persons with epilepsy (PWE) face a significantly elevated risk of comorbid depression and anxiety, with lifetime prevalence estimates around 30%. This bidirectional relationship impacts quality of life and seizure control.
• Pharmacological Shift: Historically, older antiseizure medications (ASMs) like carbamazepine had complex drug-drug interactions (DDIs) that complicated the co-prescription of antidepressants (specifically Selective Serotonin Reuptake Inhibitors, SSRIs). In recent decades, clinical practice has shifted toward newer ASMs (e.g., levetiracetam) which lack these DDIs but are sometimes associated with psychiatric side effects.
• Knowledge Gap: It is unknown whether the shift to newer ASMs, combined with increased societal recognition of mental health, has led to an increase in the pharmacological treatment of depression/anxiety in PWE relative to the general population.
• Hypothesis: The authors hypothesized that the likelihood of SSRI initiation in adult-onset epilepsy would increase over time (2006–2020) as prescription habits shifted toward newer ASMs, potentially narrowing the treatment gap between PWE and the general population.

2. Methodology

• Study Design: A nationwide, population-based cohort study utilizing Swedish national health registers.
• Data Sources:
  • National Patient Register (NPR): For diagnostic codes (ICD-10) for inpatient, outpatient, and emergency care.
  • National Prescribed Drug Register (NPR): For all prescription drug dispensations (ATC codes).
  • Cause of Death Register: For mortality data.
• Study Population:
  • Cases: 28,569 individuals with incident epilepsy diagnosed between 2006 and 2020. Inclusion required an ICD-10 code G40 (epilepsy) and at least one subsequent ASM prescription (ATC N03A).
  • Controls: 68,509 age- and sex-matched individuals from the general population without epilepsy.
  • Exclusion Criteria: Prior SSRI use before epilepsy diagnosis (in the main analysis), prior seizure diagnoses, or ASM use before age 18.
• Time Periods: The study was stratified into three calendar periods based on the index date (epilepsy diagnosis): 2006–2010, 2011–2015, and 2016–2020.
• Outcomes:
  1. Primary: Time to new-onset SSRI treatment (ATC N06A) following the index date.
  2. Secondary: Time to first specialist psychiatric care (ICD-10 F32–F39).
• Statistical Analysis:
  • Cox Regression: Used to estimate adjusted Hazard Ratios (aHR) for SSRI initiation and psychiatric care, comparing PWE to controls within each time period.
  • Adjustments: Models were adjusted for age, sex, and a wide range of comorbidities (stroke, TBI, dementia, brain tumor, infection, diabetes, cardiovascular disease, intellectual disability, cancer).
  • Subgroup Analysis: Stratified by age (<30, 30–64, ≥65) and sex.
  • Sensitivity Analysis: A secondary analysis included patients with prior SSRI use to test robustness.

3. Key Contributions

• Longitudinal Trend Analysis: This is one of the first studies to examine whether the transition from older to newer ASMs over a 15-year period has altered the treatment patterns of comorbid depression in epilepsy.
• Differentiation of Treatment Gaps: The study distinguishes between absolute treatment rates and relative risks (HRs), revealing that while absolute rates of SSRI use increased in the general population, the relative risk for PWE did not necessarily improve, suggesting a widening gap in specific demographics.
• Comorbidity Profiling: The study identifies specific neurological and systemic comorbidities (e.g., stroke, TBI, dementia) that act as strong predictors for SSRI treatment in PWE, while highlighting a significant treatment deficit in those with intellectual disabilities.

4. Key Results

• ASM Trends: The study confirmed a shift in first-line ASM prescriptions: Carbamazepine (older) was dominant in 2006–2010, while Levetiracetam (newer) became dominant by 2016–2020.
• SSRI Initiation (Main Analysis):
  • PWE consistently had a higher risk of starting SSRIs compared to controls across all periods.
  • 2006–2010: aHR 1.92 (95% CI: 1.79–2.06).
  • 2011–2015: aHR 1.84 (95% CI: 1.72–1.97).
  • 2016–2020: aHR 1.81 (95% CI: 1.69–1.94).
  • Conclusion: There was no evidence of an increased likelihood of SSRI treatment in PWE relative to controls over time, despite the shift to newer ASMs.
• Age-Stratified Findings (Critical Insight):
  • Young Adults (<30 years): This group showed the highest relative risk initially (aHR 2.33 in 2006–2010). However, by 2016–2020, the aHR dropped to 1.63.
  • Reason for Drop: The absolute rate of SSRI use in controls (general population) increased significantly (from 8.1% to 11.1%), while the rate in young PWE remained static (18.2%). This indicates that the increased recognition of depression in young people has not extended to young people with epilepsy, creating a widening treatment gap.
  • Older Adults (≥65 years): Showed the highest absolute burden of SSRI use but a lower relative risk compared to younger groups.
• Specialist Psychiatric Care:
  • PWE had a significantly higher risk of requiring specialist psychiatric care (aHRs ranging from ~2.7 to 3.5).
  • Unlike SSRI initiation, the risk for specialist care did not decrease over time; in fact, the HR for the 2016–2020 period was the highest, suggesting persistent severe psychiatric morbidity.
• Comorbidities: Stroke, TBI, dementia, brain tumors, and cancer were consistently associated with increased SSRI risk. Conversely, Intellectual Disability (ID) was associated with a decreased likelihood of SSRI treatment (HR < 1), suggesting under-diagnosis or under-treatment in this vulnerable subgroup.
• Sensitivity Analysis: Results remained consistent when including patients with prior SSRI use, confirming the robustness of the findings.

5. Significance and Implications

• Clinical Practice: The shift to newer ASMs (like levetiracetam) has not resulted in better management of comorbid depression in epilepsy. The "treatment gap" remains significant, particularly for young adults.
• Public Health: The static rate of SSRI treatment in young PWE, contrasted with rising rates in the general population, suggests that epilepsy is a barrier to accessing mental health care. This may be due to diagnostic overshadowing (attributing symptoms to epilepsy) or lack of screening.
• Vulnerable Populations: The finding that individuals with intellectual disabilities are less likely to receive treatment highlights a critical area for intervention, likely due to communication barriers and diagnostic overshadowing.
• Future Directions: The authors advocate for routine screening for depression in new-onset epilepsy, regardless of the ASM prescribed, and the development of specialized assessment tools for patients with intellectual disabilities.

Limitations noted in the text: The study relies on register data, which may miss undiagnosed depression or non-pharmacological treatments. The exclusion of patients with prior SSRI use in the main analysis was a conservative approach to ensure "new-onset" depression, though sensitivity analyses addressed this.

Conclusion: Despite the pharmacological advantages of newer ASMs regarding drug interactions, the treatment of depression in epilepsy has not improved relative to the general population over the last 15 years. There is an urgent need to address the widening treatment gap, particularly in young adults and those with intellectual disabilities.