Keppra vs Depakote for Epilepsy: Key Differences

Keppra (levetiracetam) and Depakote (valproate) are two of the most widely prescribed epilepsy medications, and they are not interchangeable. Keppra tends to be picked first for many adults because it has fewer drug interactions and is safer in pregnancy. Depakote is often stronger for certain generalized seizure types, but it carries a serious risk of birth defects and has more cognitive side effects.

Research-informed explainer, last updated April 11, 2026. This article draws on peer-reviewed work from four neurologists listed in the Convene directory, including specialists who led the international evidence review of epilepsy drugs and the research on their cognitive and pregnancy risks.

What are these drugs used for?

Both Keppra and Depakote are antiseizure medications (sometimes called AEDs, for antiepileptic drugs). You take them every day to prevent seizures, not to stop one that is already happening. They work in different ways and they fit different situations.

Keppra is the brand name for levetiracetam. It is prescribed for focal seizures (seizures that start in one part of the brain) and for some generalized seizures (seizures that involve both sides of the brain from the start).

Depakote is the brand name for valproate (also sold as valproic acid or divalproex sodium). It has been used since the 1970s and remains one of the most effective drugs for generalized seizures, including tonic-clonic seizures (the kind with whole-body convulsions), absence seizures (brief staring spells), and myoclonic seizures (sudden jerks). It is also used for migraine prevention and bipolar disorder, which is why you may know someone taking it for a reason that is not epilepsy.

The 2018 review of epilepsy in Nature Reviews Disease Primers lays out where each drug fits in current practice and how doctors think about matching a drug to the patient [9].

At a glance

How doctors choose between them based on seizure type

The first question a neurologist usually asks is what kind of seizure you are having. The 2017 international classification of seizure types, which most epilepsy doctors now use, divides seizures by where they start in the brain (focal or generalized) and by what happens during the seizure [4][5]. That classification matters because drugs do not all work on every seizure type.

For focal seizures, Keppra is a common first choice. The ILAE (International League Against Epilepsy) evidence review of antiepileptic drugs as initial monotherapy rated levetiracetam as effective for focal seizures in adults, alongside a short list of other options [1]. Depakote can work for focal seizures too, but it is not usually the first drug tried.

For generalized seizures, the picture is different. Depakote has long been one of the most effective drugs, especially for the combination of tonic-clonic, absence, and myoclonic seizures seen in generalized epilepsies like juvenile myoclonic epilepsy. Keppra can work for generalized tonic-clonic seizures, but for some patients with generalized epilepsies Depakote still controls seizures when other drugs cannot.

Your doctor will also factor in the specific epilepsy syndrome you have (not just the seizure type), which is what the 2017 ILAE classification of the epilepsies is for [3]. Syndromes like juvenile myoclonic epilepsy, childhood absence epilepsy, and temporal lobe epilepsy each have their own preferred drug lists.

The side-effect trade-offs

This is where the two drugs pull apart the most, and it is the reason the choice often depends on who you are, not just what your seizures look like.

Keppra side effects tend to be mood-related. Some people feel irritable, anxious, or depressed on it. A smaller group gets angry outbursts (sometimes called "Keppra rage" in patient communities). Drowsiness and headache are also common in the first few weeks and usually fade.

Depakote side effects are more varied. Weight gain is common. So are tremor, hair thinning, and nausea. Rarer but more serious problems include liver damage and pancreatitis, which is why your doctor will check bloodwork periodically.

On thinking and memory, Depakote tends to cause more noticeable problems than Keppra for some people. A review of cognitive side effects across antiepileptic drugs, published in Epilepsy & Behavior, found that older drugs including valproate can slow processing speed and affect attention at higher doses, while newer drugs generally have milder cognitive effects [6]. If you are in school, driving a lot, or doing work that requires sustained focus, this is worth asking about.

Pregnancy and birth defects

This is the most important single difference between the two drugs, and it is why many neurologists think carefully before starting Depakote in women and girls who could become pregnant.

A systematic review of pregnancy registries and cohort studies, published in Epilepsy Research, found that valproate carries a significantly higher risk of major birth defects than other commonly used antiseizure drugs [7]. The risk goes up with higher doses.

The concern does not stop at birth. A long-term study published in Neurology followed children who had been exposed to antiseizure drugs in the womb and tested their IQ at age six. Children exposed to valproate, especially at doses above 800 mg per day, had meaningfully lower IQ scores than children exposed to other drugs like lamotrigine and carbamazepine [8]. This finding has shaped prescribing guidelines worldwide.

Because of this, many epilepsy specialists now avoid starting valproate in women of childbearing age when another drug can do the job. Keppra is often preferred in this situation, even though it has its own mood-related side effects to watch for. If you are already on Depakote and thinking about pregnancy, do not stop the drug on your own. Talk to your neurologist well before you try to conceive so you can plan a switch safely.

Drug interactions

Keppra has very few drug interactions. It is not processed by the liver in the same way most medications are, which means it does not compete with other drugs for the same enzymes.

Depakote is the opposite. It interacts with many drugs, including other antiseizure medications, some antibiotics, and blood thinners. It can also raise the level of some drugs in your blood to a risky range. If you take multiple medications for other conditions, this is worth bringing up directly with your doctor and pharmacist.

What if the first drug doesn't work?

About one in three people with epilepsy does not get full seizure control from the first drug they try. The formal definition of drug-resistant epilepsy, established by an ILAE task force, is failure of two tolerated and appropriately chosen antiseizure drugs to achieve sustained seizure freedom [2]. If you have tried two drugs at adequate doses and you are still having seizures, that is your cue to ask about next steps, which can include adding a second drug, switching to a different one, or being evaluated at a specialized epilepsy center for options like surgery, neurostimulation, or dietary therapy.

Getting to that evaluation sooner rather than later matters. The longer uncontrolled seizures go on, the harder they can be to treat, and the more they disrupt your life.

Questions to ask your doctor

• What type of seizure and what epilepsy syndrome do I actually have? How does that change which drug is a good fit?
• Why are you recommending this specific drug for me instead of the other option?
• If I could become pregnant, how does that change the recommendation?
• What side effects should I watch for in the first few weeks, and which ones should make me call you right away?
• How will we know if the drug is working, and how long should we give it before switching?
• If this drug does not control my seizures, what would we try next, and at what point should I see an epilepsy specialist?

The bottom line

Keppra and Depakote are both effective antiseizure drugs, and neither one is better for everyone. Keppra is often the safer first pick for adults with focal seizures and for women who might become pregnant. Depakote is one of the most effective options for generalized seizures but comes with real risks in pregnancy and more side effects for some people.

The right choice depends on your seizure type, your age, your other medications, and whether pregnancy is a factor. If you are not sure why you are on the drug you are on, or if your seizures are not well controlled, ask your neurologist to walk you through the reasoning and whether a different drug might fit your life better.