In a 28-year-old man taking levetiracetam (Keppra) for seizures who has had several months of blurred vision and depressive symptoms, how should I evaluate the visual disturbances and select an appropriate antidepressant?

Evaluation and Management of Blurred Vision and Depression in a Patient on Levetiracetam

Immediate Evaluation of Visual Disturbances

Levetiracetam-induced blurred vision is a recognized adverse effect occurring in approximately 2% of patients, but several months of persistent visual symptoms warrant urgent ophthalmologic evaluation to exclude serious pathology. 1

Critical Differential Diagnoses to Exclude

• Obtain baseline visual acuity testing (Snellen chart) and color discrimination testing (Ishihara tests) to establish objective documentation of visual impairment 2
• Perform fundoscopic examination to assess for papilledema, which could indicate increased intracranial pressure requiring urgent neuroimaging 2
• Order brain MRI with and without contrast to exclude structural lesions (tumor, vascular malformation, demyelinating disease) that could cause both seizures and visual symptoms 2
• Consider urgent ophthalmology referral if visual acuity is significantly impaired or if fundoscopic abnormalities are present 2

Levetiracetam-Related Visual Effects

• Diplopia occurs in 2% of levetiracetam-treated patients and is typically mild to moderate in intensity 1
• Blurred vision and amblyopia are reported adverse effects but usually emerge during the first 4 weeks of treatment 1
• Visual symptoms persisting for several months are atypical for simple medication side effects and demand thorough investigation 1

Antidepressant Selection in Patients Taking Levetiracetam

Selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) are the preferred first-line antidepressants for patients on levetiracetam, as levetiracetam has no significant cytochrome P450 interactions and will not interfere with antidepressant metabolism. 3

Optimal Antidepressant Choices

• Sertraline, escitalopram, or venlafaxine are preferred agents because they have minimal drug-drug interactions with levetiracetam and do not lower seizure threshold at therapeutic doses 3
• Avoid tricyclic antidepressants (TCAs) despite their use in other neurologic conditions, as they can lower seizure threshold and cause anticholinergic side effects including blurred vision 2
• Avoid bupropion as it significantly lowers seizure threshold and is contraindicated in patients with seizure disorders 3

Levetiracetam-Induced Mood Effects: A Critical Consideration

Before initiating antidepressant therapy, strongly consider whether levetiracetam itself is causing or exacerbating depressive symptoms, as this occurs in 4-13% of patients and may require medication adjustment rather than polypharmacy. 1, 4

Evidence for Levetiracetam-Induced Depression

• Depression is reported in 4% of adult levetiracetam-treated patients in controlled trials, occurring more frequently than in placebo groups 1
• Neuropsychiatric side effects including depression, anxiety, agitation, and hostility occur in 13.3% of adults, with 0.7% presenting with severe symptoms 5
• Levetiracetam-induced depression can emerge beyond the initial titration period and may be the most common reason for drug discontinuation 5
• Two case reports document probable levetiracetam-associated depression in elderly patients (Naranjo score 6), with symptoms resolving within 4-8 days of discontinuation 4
• Morning chronotype individuals are significantly more susceptible to levetiracetam-induced mood changes (86% of intolerant patients were morning chronotypes vs. 20% of tolerant patients) 6

Mechanism and Risk Factors

• The mechanism of levetiracetam-induced behavioral changes remains unknown but may involve its binding to synaptic vesicle protein 2A (SV2A) 5
• Patients with pre-existing psychiatric history are at higher risk for developing behavioral adverse effects 5
• Renal impairment increases risk as levetiracetam is predominantly renally excreted, and accumulation may worsen neuropsychiatric effects 4

Clinical Decision Algorithm

Step 1: Assess Temporal Relationship

• If depressive symptoms began or worsened within weeks to months of starting levetiracetam or dose escalation, strongly suspect medication-induced depression 4, 7
• If depression predated levetiracetam initiation, it is more likely an independent condition requiring treatment 5

Step 2: Evaluate Severity and Seizure Control

• If seizures are well-controlled on levetiracetam and depression is moderate to severe, consider switching to an alternative antiepileptic drug (lamotrigine or lacosamide) rather than adding an antidepressant 3
• If seizures are poorly controlled, maintain levetiracetam and add an SSRI/SNRI while monitoring closely 3

Step 3: Trial Approach

• Consider a 2-4 week trial off levetiracetam (with appropriate seizure precautions and alternative antiepileptic coverage) to assess whether depressive symptoms resolve 4
• If symptoms resolve, this confirms levetiracetam as the causative agent and alternative antiepileptic therapy should be continued 4
• If symptoms persist, initiate SSRI/SNRI therapy and consider reintroducing levetiracetam if seizure control was superior 8

Monitoring Requirements When Combining Antidepressants with Levetiracetam

• Monitor for excessive sedation, drowsiness, or respiratory depression when combining levetiracetam with any CNS-active medication 9
• Reassess depressive symptoms at 2-week intervals using standardized scales (Beck Depression Inventory-II or Montgomery-Asberg Depression Rating Scale) 8
• Question patients about seizure occurrences at each follow-up visit to ensure antidepressant therapy has not affected seizure control 3

Common Pitfalls to Avoid

• Do not attribute months of blurred vision solely to levetiracetam side effects without comprehensive ophthalmologic and neurologic evaluation, as serious pathology may be missed 2
• Do not automatically add an antidepressant without first considering levetiracetam as the cause of depression, as this leads to unnecessary polypharmacy and may not address the underlying problem 4, 5
• Do not use tricyclic antidepressants in patients with seizure disorders due to seizure threshold lowering and anticholinergic effects that can worsen visual symptoms 2, 3
• Do not prescribe bupropion to patients with epilepsy as it is contraindicated due to significant seizure risk 3