ASM Selection & Treatment Initiation
The decision to initiate antiseizure medication (ASM) therapy is among the most consequential in epilepsy management. It requires balancing the risk of seizure recurrence against the potential burden of long-term pharmacotherapy, including adverse effects, drug interactions, teratogenicity, and psychosocial consequences. Once the decision is made, ASM selection must be individualized based on seizure and epilepsy type, patient demographics, comorbidities, reproductive considerations, and cost. Landmark trials such as SANAD I and SANAD II have provided Class I evidence to guide first-line ASM choices. Despite the availability of more than 25 ASMs, approximately one-third of patients develop drug-resistant epilepsy—defined by the International League Against Epilepsy (ILAE) as failure of two adequately trialed ASMs—underscoring the importance of optimizing initial treatment selection.
Bottom Line
- When to start: ASM therapy is recommended after two unprovoked seizures (≥24 hours apart) or after a single seizure with high recurrence risk (epileptiform EEG, structural lesion, prior brain injury); the decision after a single unprovoked seizure without risk factors should incorporate patient preference
- ASM selection factors: Seizure/epilepsy type (focal vs. generalized), patient age and sex, comorbidities (mood, migraine, obesity), reproductive potential (teratogenicity risk), drug interactions, and cost all guide choice
- Focal epilepsy first-line: Lamotrigine is preferred based on SANAD I and SANAD II; levetiracetam, lacosamide, oxcarbazepine, and carbamazepine (extended-release) are reasonable alternatives
- Generalized epilepsy first-line: Valproate is most effective (SANAD II) and preferred in males; lamotrigine or levetiracetam preferred in females of childbearing potential
- Monotherapy goal: Start with a single ASM at the lowest effective dose; approximately 50% of patients achieve seizure freedom with the first ASM
- Drug-resistant epilepsy: Defined as failure to achieve sustained seizure freedom after adequate trials of two tolerated, appropriately chosen ASMs; affects ~30% of patients
When to Initiate ASM Therapy
After a First Unprovoked Seizure
The recurrence risk after a single unprovoked seizure is approximately 40–50% within 2 years. Immediate ASM treatment reduces early recurrence risk but does not alter long-term remission rates. The decision to treat should be shared with the patient and guided by risk factors for recurrence:
- Factors favoring treatment: Epileptiform abnormalities on EEG, structural brain lesion on MRI, prior neurologic insult (stroke, TBI, CNS infection), remote symptomatic etiology, nocturnal seizure, Todd paralysis
- Factors favoring observation: Normal EEG and MRI, provoked or situation-related seizure, patient preference against medication, low-risk occupation/lifestyle
- Psychosocial considerations: Driving restrictions (vary by state/country), employment implications, patient anxiety about recurrence vs. medication side effects
After Two or More Unprovoked Seizures
Two unprovoked seizures occurring more than 24 hours apart define epilepsy by ILAE criteria, and ASM treatment is generally recommended. The recurrence risk after a second unprovoked seizure exceeds 60–70%. The ILAE 2014 definition also allows a diagnosis of epilepsy after a single seizure if the estimated recurrence risk equals or exceeds that after two unprovoked seizures (≥60% over 10 years).
Clinical Pearl: The “Treat or Wait” Decision
- Early treatment reduces the probability of seizure recurrence in the first 2 years but does not improve long-term prognosis of epilepsy
- After a first seizure with a normal EEG and MRI, approximately 30% of patients will have a recurrence—meaning 70% would be treated unnecessarily
- Conversely, after a first seizure with an epileptiform EEG, recurrence risk approaches 60–70%, strongly supporting early treatment
- The AAN/AES practice guideline (2015) states that treatment after a first seizure is “possibly effective” in reducing recurrence risk and should be discussed with the patient
Factors in ASM Selection
Seizure and Epilepsy Type
The most critical factor in ASM selection is the seizure type and epilepsy syndrome. ASMs are classified as broad-spectrum (effective for both focal and generalized epilepsies) or narrow-spectrum (effective primarily for focal seizures). Narrow-spectrum sodium channel blockers—carbamazepine, oxcarbazepine, eslicarbazepine, phenytoin—and gabapentinoids may exacerbate generalized absence and myoclonic seizures and must be avoided in idiopathic generalized epilepsy (IGE).
| Spectrum | ASMs | Indications | Key Caveats |
|---|---|---|---|
| Broad-spectrum | Valproate, lamotrigine, levetiracetam, topiramate, zonisamide, brivaracetam, clobazam, felbamate, perampanel | Focal and generalized epilepsies; preferred when seizure classification is uncertain | Lamotrigine may exacerbate myoclonic seizures in some IGE patients; topiramate was not effective for absence seizures in one trial |
| Narrow-spectrum (focal only) | Carbamazepine, oxcarbazepine, eslicarbazepine, phenytoin, lacosamide, gabapentin, pregabalin, tiagabine, vigabatrin | Focal epilepsy with or without bilateral tonic-clonic seizures | May worsen absence, myoclonic, and atonic seizures; avoid in IGE or unclassified epilepsy |
| Narrow-spectrum (absence only) | Ethosuximide | Generalized absence seizures only | Not effective for any other seizure type; drug of choice for absence-only epilepsy |
Patient-Specific Factors
| Factor | Preferred ASMs | ASMs to Avoid | Rationale |
|---|---|---|---|
| Childbearing potential | Lamotrigine, levetiracetam | Valproate, topiramate, phenobarbital | Valproate has the highest teratogenicity rate (>8%); topiramate intermediate (oral clefts); lamotrigine and levetiracetam have low malformation rates (≤3%) |
| Elderly | Lamotrigine, levetiracetam, lacosamide, gabapentin | Phenytoin, carbamazepine, phenobarbital | Older ASMs have more drug interactions, cognitive effects, and bone density loss; gabapentin/lamotrigine preferred in geriatric trials |
| Depression/bipolar | Lamotrigine (mood stabilizer), valproate | Levetiracetam, topiramate, perampanel, phenobarbital | Levetiracetam can cause irritability/depression; lamotrigine is FDA-approved for bipolar I maintenance |
| Migraine comorbidity | Topiramate, valproate | — | Both FDA-approved for migraine prophylaxis; topiramate preferred if weight loss is desired |
| Obesity | Topiramate, zonisamide (weight loss) | Valproate, gabapentin, pregabalin (weight gain) | Topiramate/zonisamide cause appetite suppression; valproate/gabapentinoids promote weight gain |
| Renal impairment | Valproate, lamotrigine, phenytoin (hepatic metabolism) | Gabapentin, pregabalin, levetiracetam (require dose adjustment) | Renally eliminated ASMs need dose reduction; hepatically metabolized ASMs unaffected |
| Hepatic impairment | Levetiracetam, gabapentin, pregabalin, lacosamide | Valproate, phenytoin, carbamazepine | Renally eliminated ASMs preferred; valproate hepatotoxicity risk; phenytoin unpredictable levels |
| Adherence concerns | Perampanel, zonisamide (long half-life, once daily) | Carbamazepine, oxcarbazepine (rebound seizures with missed doses) | Long half-life ASMs are forgiving of missed doses; carbamazepine/oxcarbazepine withdrawal can trigger GTC seizures |
Landmark Clinical Trials
SANAD I (Lancet, 2007)
The Standard and New Antiepileptic Drugs (SANAD I) trial was a large, unblinded, randomized controlled trial conducted in the UK comparing first-line ASMs:
- Arm A (focal epilepsy): Carbamazepine vs. gabapentin vs. lamotrigine vs. oxcarbazepine vs. topiramate. Lamotrigine was significantly better than carbamazepine for time to treatment failure and noninferior for seizure freedom at 12 months; gabapentin was inferior to carbamazepine for seizure control
- Arm B (generalized/unclassified epilepsy): Valproate vs. lamotrigine vs. topiramate. Valproate was significantly better than topiramate for time to treatment failure and better than lamotrigine for 12-month seizure freedom; topiramate was the least well tolerated
- Key conclusion: Lamotrigine recommended as first-line for focal epilepsy; valproate recommended as first-line for generalized/unclassified epilepsy
SANAD II (Lancet, 2021)
SANAD II was an open-label, noninferiority, multicenter, phase 4 randomized controlled trial that compared newer ASMs:
- Arm A (focal epilepsy): Lamotrigine vs. levetiracetam vs. zonisamide. Lamotrigine was superior to both levetiracetam and zonisamide for time to 12-month remission; levetiracetam was noninferior to lamotrigine for time to treatment failure
- Arm B (generalized/unclassified epilepsy): Valproate vs. levetiracetam. Valproate was superior to levetiracetam for time to 12-month and 24-month remission; levetiracetam was noninferior for time to treatment failure
- Key conclusion: Lamotrigine remains the recommended first-line ASM for focal epilepsy; valproate remains the most effective for generalized epilepsy but should be avoided in females of childbearing potential
Practical Implications of SANAD Trials
- Lamotrigine is the best first-line monotherapy for focal epilepsy—but requires slow titration (6–8 weeks to therapeutic dose), which may be problematic when urgent seizure control is needed
- Levetiracetam is a reasonable alternative for focal epilepsy, especially when rapid titration is needed (therapeutic dose achieved in 1–2 weeks), but may be slightly less effective long-term
- Valproate remains the most effective ASM for IGE in males; however, it should not be used in women of childbearing potential due to its teratogenicity (major malformation rate >8%)
- For women with IGE, lamotrigine or levetiracetam are preferred, despite being less effective than valproate; levetiracetam has Class I evidence for myoclonic seizures
Monotherapy vs. Polytherapy
The Monotherapy Principle
Initial treatment should always begin with a single ASM (monotherapy). This approach minimizes adverse effects, simplifies adherence, avoids drug interactions, and facilitates identification of the responsible agent if side effects occur. Approximately 47–50% of patients with newly diagnosed epilepsy achieve seizure freedom with the first appropriately chosen ASM.
When to Add a Second ASM
If the first ASM fails, the approach depends on the reason for failure:
- Failure due to intolerability: Replace with an alternative monotherapy, preferably one without the same adverse effect profile; if the adverse effect was mechanism-related, consider a different mechanism of action
- Failure due to lack of efficacy (well tolerated): Either substitution monotherapy or adjunctive (add-on) therapy are equally effective options; add-on therapy is preferred if the first ASM was partially effective
- Failure due to both: Substitution monotherapy is preferred unless the tolerability issue was purely dose-related
Pseudoresistance: Common Causes of Apparent ASM Failure
- Nonadherence: The most common cause; may be intentional (side effects, cost) or unintentional (forgetfulness); a drug level can help identify this
- Nonepileptic events: Psychogenic nonepileptic seizures (PNES) account for 20–30% of patients referred to epilepsy monitoring units; do not respond to ASMs
- Incorrect seizure classification: Narrow-spectrum ASMs given for generalized epilepsy misclassified as focal—may worsen seizures
- Subtherapeutic dosing: Insufficient dose escalation; a serum concentration can reveal room for dose optimization
- Lifestyle factors: Sleep deprivation, alcohol use, and missed medications are common in IGE patients, particularly juvenile myoclonic epilepsy
Titration Principles and Therapeutic Drug Monitoring
General Titration Approach
Most ASMs should be started at a low dose and titrated gradually (“start low, go slow”) to minimize dose-related adverse effects. The rate of titration varies by ASM and clinical urgency:
| ASM | Starting Dose | Titration Rate | Target Dose | Therapeutic Range |
|---|---|---|---|---|
| Lamotrigine | 25 mg/d | 25 mg q2wk (monotherapy) | 200–300 mg/d | 2–20 μg/mL |
| Levetiracetam | 500 mg/d | 500 mg/wk | 1000 mg/d; labeled max 3000 mg/d (up to 4000 mg/d used off-label) | 12–46 μg/mL |
| Valproate (ER) | 500 mg/d | 250–500 mg/wk | 1000–2000 mg/d | 50–100 μg/mL |
| Carbamazepine | 200 mg/d | 200 mg q3d | 400–800 mg/d | 4–12 μg/mL |
| Lacosamide | 100 mg/d | 100 mg/wk | 200 mg/d; max 600 mg/d | — |
| Oxcarbazepine | 300–600 mg/d | 300 mg/wk | 600–1200 mg/d; max 2400 mg/d | 15–35 μg/mL (MHD) |
| Topiramate | 25 mg/d | 25 mg/wk | 100 mg/d; max 400 mg/d | — |
| Cenobamate | 12.5 mg/d | See titration protocol | 100–200 mg/d; max 400 mg/d | — |
| Phenytoin | 200–400 mg/d | 30–60 mg increments | 200–400 mg/d | 10–20 μg/mL (total); 1–2 μg/mL (free) |
| Zonisamide | 100 mg/d | 100 mg q1–2wk | 200 mg/d; max 600 mg/d | 10–40 μg/mL |
When to Monitor Drug Levels
Routine therapeutic drug monitoring (TDM) is not necessary for all ASMs. It is most valuable in the following situations:
- ASMs with nonlinear kinetics: Phenytoin (saturable metabolism makes small dose changes produce large concentration changes)
- Dose optimization: To determine whether a higher dose can be safely attempted when seizures persist despite the initial target dose
- Suspected toxicity: Symptoms consistent with supratherapeutic levels (ataxia, diplopia, tremor)
- Pregnancy: Lamotrigine clearance increases markedly during pregnancy due to pregnancy/estradiol-induced UGT1A4 glucuronidation (may rise >200% by the third trimester); monthly levels recommended
- Drug interactions: When enzyme inducers or inhibitors are added or removed
- Adherence assessment: Unexpectedly low levels may indicate nonadherence
- Establishing an individual reference range: Obtain 2–3 levels during the period of best seizure control to define the patient’s “individual therapeutic concentration”
Treatment Goals and Seizure Freedom
Defining Treatment Success
The goal of ASM therapy is complete seizure freedom with no or minimal side effects. However, “seizure freedom” is defined operationally and varies by context:
- Clinical trials: Typically defined as no seizures during a defined maintenance period (e.g., 6–12 months)
- Clinical practice: Generally requires at least 12 months of seizure freedom; many epileptologists use a “rule of 3” (seizure-free interval of at least three times the longest pretreatment interseizure interval)
- Driving eligibility: Varies by jurisdiction; most US states require 3–12 months of seizure freedom
Probability of Seizure Freedom
Prospective longitudinal data from the Glasgow cohort (Kwan and Brodie, NEJM 2000; updated through 2018) have established the following estimates:
- First ASM: ~47–50% achieve seizure freedom
- Second ASM (monotherapy or add-on): ~13% of the remaining patients achieve seizure freedom
- Third ASM and beyond: Each subsequent ASM achieves seizure freedom in only ~2–5% of patients
- Cumulative: Overall, approximately 64% of patients eventually achieve seizure freedom with ASMs; the remaining ~36% have drug-resistant epilepsy
Drug-Resistant Epilepsy
ILAE Definition (2010)
Drug-resistant epilepsy is defined as failure of adequate trials of two tolerated, appropriately chosen and used ASM schedules (whether as monotherapy or in combination) to achieve sustained seizure freedom. This definition requires:
- Adequate trial: Appropriate ASM for the seizure/epilepsy type, at an adequate dose, for a sufficient duration
- Tolerated: The ASM was not discontinued due to adverse effects before reaching an effective dose
- Sustained seizure freedom: No seizures for at least three times the longest pretreatment interseizure interval, or 12 months (whichever is longer)
After Two ASM Failures: Next Steps
- Reevaluate the diagnosis: Rule out nonepileptic events, confirm seizure classification, consider EEG/video-EEG monitoring
- Epilepsy surgery evaluation: All patients with drug-resistant focal epilepsy should be referred for presurgical evaluation; surgery can achieve seizure freedom in 60–80% of selected temporal lobe epilepsy patients
- Consider cenobamate: Exceptional seizure-free rates (21% in phase 3 trials) support its early use in drug-resistant focal epilepsy, especially for patients who are not ideal surgical candidates
- Optimize pharmacotherapy: Use drug levels to ensure adequate dosing; consider mechanistically complementary combinations (e.g., sodium channel blocker + SV2A ligand); avoid combining two sodium channel blockers
- Neuromodulation: Vagus nerve stimulation, responsive neurostimulation (RNS), and deep brain stimulation (DBS) are FDA-approved options for drug-resistant epilepsy
Synergistic ASM Combinations
When monotherapy fails, rational polytherapy should aim for supra-additive efficacy and infra-additive toxicity. Evidence-based principles include:
- Combine different mechanisms: A sodium channel blocker (lamotrigine, lacosamide) plus an SV2A ligand (levetiracetam, brivaracetam) is a well-supported combination; the Glasgow cohort showed this pairing had the best chance of achieving seizure freedom
- Avoid similar mechanisms: Two sodium channel blockers (e.g., lacosamide + carbamazepine) increase adverse effects through pharmacodynamic interactions without proportional gains in efficacy
- Synergistic combinations with human evidence: Lamotrigine + valproate (strongest evidence); lamotrigine + levetiracetam; cannabidiol + clobazam; lamotrigine + topiramate; cenobamate + clobazam
- Avoid >2 ASMs when possible: Three-drug combinations increase the risk of pharmacokinetic and pharmacodynamic interactions; replace ineffective agents rather than adding a third
ASMs That Should Not Be Combined
- Brivaracetam + levetiracetam: Both bind SV2A; brivaracetam was ineffective when added to levetiracetam in clinical trials due to receptor saturation
- Two sodium channel blockers (e.g., carbamazepine + lacosamide, carbamazepine + oxcarbazepine): Pharmacodynamic interaction produces dizziness, diplopia, and ataxia at therapeutic levels; lacosamide efficacy was inferior when combined with another sodium channel blocker
- Enzyme inducers + perampanel: Enzyme inducers reduce perampanel efficacy; higher doses required but increase behavioral side effects
References
- Abou-Khalil B. Update on antiseizure medications 2025. Continuum (Minneap Minn) 2025;31(1):123–165.
- Marson AG, Al-Kharusi AM, Alwaidh M, et al. The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial. Lancet 2007;369(9566):1000–1015.
- Marson AG, Al-Kharusi AM, Alwaidh M, et al. The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial. Lancet 2007;369(9566):1016–1026.
- Marson A, Burnside G, Appleton R, et al. The SANAD II study of valproate versus levetiracetam for newly diagnosed generalised and unclassifiable epilepsy. Lancet 2021;397(10282):1375–1386.
- Marson A, Burnside G, Appleton R, et al. The SANAD II study of levetiracetam, zonisamide, or lamotrigine for newly diagnosed focal epilepsy. Lancet 2021;397(10282):1363–1374.
- Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med 2000;342(5):314–319.
- Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 2010;51(6):1069–1077.
- Krumholz A, Wiebe S, Gronseth GS, et al. Evidence-based guideline: management of an unprovoked first seizure in adults. Neurology 2015;84(16):1705–1713.
- Mattson RH, Cramer JA, Collins JF, et al. Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and secondarily generalized tonic-clonic seizures. N Engl J Med 1985;313(3):145–151.
- Chen Z, Brodie MJ, Liew D, Kwan P. Treatment outcomes in patients with newly diagnosed epilepsy treated with established and new antiepileptic drugs: a 30-year longitudinal cohort study. JAMA Neurol 2018;75(3):279–286.
- Cohen JM, Alvestad S, Cesta CE, et al. Comparative safety of antiseizure medication monotherapy for major malformations. Ann Neurol 2023;93:551–562.