What is the best treatment approach for a patient with comorbid sleep issues, depression, and frontal lobe epilepsy?

From the Guidelines

The best treatment approach for a patient with comorbid sleep issues, depression, and frontal lobe epilepsy is to start with cognitive behavioral therapy for insomnia (CBT-I) alongside an antiepileptic medication with mood-stabilizing properties, such as lamotrigine or valproate, and consider adding an SSRI for depression while monitoring for seizure threshold lowering. This approach is based on the strong recommendation for CBT-I in adults with chronic insomnia disorder, as stated in the American Academy of Sleep Medicine clinical practice guideline 1. The guideline emphasizes the effectiveness of CBT-I in improving sleep quality, sleep latency, and wake after sleep onset, with benefits that are durable over the long term without the need for additional interventions.

When selecting an antiepileptic medication, it is essential to consider the potential impact on mood and sleep. Lamotrigine and valproate are suitable options due to their mood-stabilizing properties, with lamotrigine starting at 25mg daily and gradually titrating to 100-200mg twice daily, and valproate starting at 250mg twice daily and titrating to therapeutic levels of 50-100 μg/mL. For depression, an SSRI like sertraline (50-200mg daily) or escitalopram (10-20mg daily) can be added, but should be introduced gradually while monitoring for any seizure threshold lowering.

Some key points to consider when implementing this treatment approach include:

• CBT-I is a multicomponent intervention that typically includes sleep restriction therapy, stimulus control, and cognitive therapy, with variations in the cognitive component and the inclusion of relaxation strategies or sleep hygiene across studies 1.
• The treatment should be delivered by a trained CBT-I provider, with in-person one-on-one delivery being the most widely evaluated and considered the best available treatment.
• Patients may face barriers to accessing CBT-I, including higher out-of-pocket costs and locating a skilled provider in their geographic region, and clinicians should discuss different CBT-I delivery modalities with their patients to align the delivery modality based on availability, affordability, treatment format, duration, and the patient’s preferences and values.
• Regular follow-up appointments every 4-6 weeks are essential to monitor seizure control, mood symptoms, sleep quality, and medication side effects, with adjustments to the treatment plan made based on the patient's response, aiming to optimize seizure control while minimizing impact on mood and sleep.

From the FDA Drug Label

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications Anyone considering prescribing levetiracetam or any other AED must balance the risk of suicidal thoughts or behaviors with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm A total of 13.3% of levetiracetam patients experienced other behavioral symptoms (reported as aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, irritability, etc.) compared to 6. 2% of placebo patients.

The connection between the onset of sleep issues, depression, and frontal lobe epilepsy is complex. Sleep issues and depression are common comorbidities in patients with epilepsy, including those with frontal lobe epilepsy.

• Levetiracetam use is associated with somnolence and fatigue, which can exacerbate sleep issues.
• Depression is a known risk factor for suicidal thoughts and behavior, which can be increased in patients with epilepsy, including those taking levetiracetam 2. The best treatment approach for a patient with comorbid sleep issues, depression, and frontal lobe epilepsy should involve careful consideration of the potential risks and benefits of AEDs like levetiracetam, as well as close monitoring for signs and symptoms of depression and suicidal thoughts or behavior.

From the Research

Connection between Sleep Issues, Depression, and Frontal Lobe Epilepsy

• There is evidence to suggest a connection between sleep issues, depression, and epilepsy, including frontal lobe epilepsy 3.
• Sleep-related seizures are common in frontal lobe epilepsy, and sleep/wake disorders are more common in adults with epilepsy than in the general population 3.
• Depression is a common comorbidity of epilepsy, and executive control may be particularly impaired in patients with temporal lobe epilepsy and comorbid depression 4.
• Weakened theta oscillation and functional connectivity in the frontal lobe may be a mechanism of executive control dysfunction in temporal lobe epilepsy with comorbid depression 4.

Treatment Approach for Comorbid Sleep Issues, Depression, and Frontal Lobe Epilepsy

• A multi-disciplinary approach, focusing on implementing behavioral interventions, improving sleep hygiene, managing psychological stressors, hypnotic treatment, and pharmacological therapy, may be effective in treating insomnia and comorbid depression and epilepsy 5.
• Cognitive behavioral therapy for insomnia and triple chronotherapy may be promising treatments for depression and sleep disturbances 6.
• Melatonin supplementation may be a well-tolerated and effective treatment for sleep disorders, including insomnia and circadian rhythm sleep-wake disorders 7.
• Treatment of sleep apnea may reduce seizures in adults with epilepsy 3.

Considerations for Treatment

• Zolpidem, a non-benzodiazepine hypnotic, may be effective in treating insomnia, but has a wide variety of adverse effects, including an increased risk of falls, hip fractures, and complex behaviors such as sleepwalking and hallucinations 5.
• The dose of zolpidem should be adjusted for elderly patients, and decisions to prescribe it should be made on a case-by-case basis, considering both the physical and psychiatric risks posed to the patient 5.
• Recognizing the bidirectional relationships between sleep and epilepsy is important for patient and caregiver education and counseling, and optimizing epilepsy outcomes 3.