Anticonvulsant

Anticonvulsants (also known as antiepileptic drugs, antiseizure drugs, or anti-seizure medications (ASM)) are a diverse group of pharmacological agents used in the treatment of epileptic seizures.<ref name="Al-Otaibi pp. 321–344">Template:Cite journal</ref> Anticonvulsants are also used in the treatment of bipolar disorder<ref name="Joshi Bow Agius 2019 pp. 595–603">Template:Cite journal</ref><ref>Template:Cite journal</ref> and borderline personality disorder,<ref>American Psychiatric Association, and American Psychiatric Association. Work Group on Borderline Personality Disorder. Practice guideline for the treatment of patients with borderline personality disorder. American Psychiatric Pub, 2001.</ref> since many seem to act as mood stabilizers, and for the treatment of neuropathic pain.<ref>Template:Cite journal</ref> Anticonvulsants suppress the uncontrolled and excessive firing of neurons during seizures and in doing so can also prevent the spread of the seizure within the brain.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Conventional antiepileptic drugs have diverse mechanisms of action but many block sodium channels or enhance γ-aminobutyric acid (GABA) function. Several antiepileptic drugs have multiple or uncertain mechanisms of action.<ref>Template:Cite web</ref> Next to voltage-gated sodium channels and components of the GABA system, their targets include GABA_A receptors, the GABA transporter type 1, and GABA transaminase.<ref name="rogawski">Template:Cite journal</ref> Additional targets include voltage-gated calcium channels, SV2A, and α2δ.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> By blocking sodium or calcium channels, antiepileptic drugs reduce the release of the excitatory neurotransimtter glutamate, whose release is considered to be elevated in epilepsy, but also that of GABA.<ref name="Kammerer2011">Template:Cite journal</ref> This is probably a side effect or even the actual mechanism of action for some antiepileptic drugs, since GABA can itself, directly or indirectly, act pro-convulsively.<ref name="Kammerer2011" /> Another potential target of antiepileptic drugs is the peroxisome proliferator-activated receptor alpha.<ref name="pmid23724059">Template:Cite journal</ref><ref name="pmid23206503">Template:Cite journal</ref><ref name=Porta2009>Template:Cite journal</ref><ref name="pmid11716839">Template:Cite journal</ref><ref name="pmid4085542">Template:Cite journal</ref><ref name="pmid2288480">Template:Cite journal</ref><ref name="pmid16934763">Template:Cite journal</ref>

Some anticonvulsants have shown antiepileptogenic effects in animal models of epilepsy.<ref>Template:Cite journal</ref> That is, they either prevent the development of epilepsy or can halt or reverse the progression of epilepsy. However, no drug has been shown in human trials to prevent epileptogenesis (the development of epilepsy in an individual at risk, such as after a head injury).<ref name="pmid17998971">Template:Cite journal</ref>

Many anticonvulsants are known teratogens and increase the risk of birth defects in the unborn child if taken while pregnant.<ref>Template:Cite journal</ref>

Terminology

Anticonvulsants are more accurately called antiepileptic drugs (AEDs) because not every epileptic seizure involves convulsion, and vice versa, not every convulsion is caused by an epileptic seizure.<ref>Template:Cite web</ref> They are also often referred to as antiseizure drugs because they provide symptomatic treatment only and have not been demonstrated to alter the course of epilepsy.<ref>Template:Cite book</ref>

Approval

The usual method of achieving approval for a drug is to show it is effective when compared against placebo, or that it is more effective than an existing drug. In monotherapy (where only one drug is taken) it is considered unethical by most to conduct a trial with placebo on a new drug of uncertain efficacy. This is because untreated epilepsy leaves the patient at significant risk of death. Therefore, almost all new epilepsy drugs are initially approved only as adjunctive (add-on) therapies. Patients whose epilepsy is uncontrolled by their medication (i.e., it is refractory to treatment) are selected to see if supplementing the medication with the new drug leads to an improvement in seizure control. Any reduction in the frequency of seizures is compared against a placebo.<ref name="pmid17998971"/> The lack of superiority over existing treatment, combined with lacking placebo-controlled trials, means that few modern drugs have earned FDA approval as initial monotherapy. In contrast, Europe only requires equivalence to existing treatments and has approved many more. Despite their lack of FDA approval, the American Academy of Neurology and the American Epilepsy Society still recommend a number of these new drugs as initial monotherapy.<ref name="pmid17998971"/>

Drugs

In the following list, the dates in parentheses are the earliest approved use of the drug.

Aldehydes

• Paraldehyde (1882). One of the earliest anticonvulsants. It is still used to treat status epilepticus, particularly where there are no resuscitation facilities.<ref>Browne TR. Paraldehyde, chlormethiazole, and lidocaine for treatment of status epilepticus. In: Delgado-Escueta AV, Wasterlain CG, Treiman DM, Porter RJ, eds. Status Epilepticus. Mechanisms of Brain Damage and Treatment (Advances in Neurology, Vol 34). New York, Raven Press 1983: 509–517</ref><ref>Template:Cite journal</ref>

Aromatic allylic alcohols

• Stiripentol (2007). Indicated for the treatment of Dravet syndrome.<ref name="pmid23018548">Template:Cite journal</ref><ref name="EMA">Template:Cite web</ref><ref name="Diacomit EPAR" /><ref name="Diacomit FDA label">Template:Cite web</ref>

Barbiturates

Template:Main Barbiturates are drugs that act as central nervous system (CNS) depressants, and by virtue of this they produce a wide spectrum of effects, from mild sedation to anesthesia. The following are classified as anticonvulsants:<ref>Suddock JT, Kent KJ, Cain MD. Barbiturate Toxicity. 2023 Apr 12. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan–. PMID 29763050.( 26 / August / 2023 )</ref>

• Phenobarbital (1912). See also the related drug primidone.
• Methylphenobarbital (1935). Known as mephobarbital in the US. No longer marketed in the UK.
• Barbexaclone (1982). Only available in some European countries.

Benzodiazepines

Template:Main The benzodiazepines are a class of drugs with hypnotic, anxiolytic, anticonvulsive, amnestic and muscle relaxant properties. Benzodiazepines act as a central nervous system depressant. The relative strength of each of these properties in any given benzodiazepine varies greatly and influences the indications for which it is prescribed. Long-term use can be problematic due to the development of tolerance to the anticonvulsant effects and dependency.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Of many drugs in this class, only a few are used to treat epilepsy:

• Clobazam (1979). Notably, used on a short-term basis around menstruation in women with catamenial epilepsy.
• Clonazepam (1974).
• Clorazepate (1972).

The following benzodiazepines are used to treat status epilepticus:

• Diazepam (1963). Can be given rectally by trained care-givers.
• Midazolam (N/A). Increasingly being used as an alternative to diazepam. This water-soluble drug is squirted into the side of the mouth but not swallowed. It is rapidly absorbed by the buccal mucosa.
• Lorazepam (1972). Given by injection in hospital.

Nitrazepam, temazepam, and especially nimetazepam are powerful anticonvulsant agents, however their use is rare due to an increased incidence of side effects and strong sedative and motor-impairing properties.

Bromides

• Potassium bromide (1857). The earliest effective treatment for epilepsy. There would not be a better drug until phenobarbital in 1912. It is still used as an anticonvulsant for dogs and cats but is no longer used in humans.

Carbamates

• Felbamate (1993). This effective anticonvulsant has had its usage severely restricted due to rare but life-threatening side effects.<ref name="Sankar">Template:Cite book</ref><ref name="pmid10331676">Template:Cite journal</ref><ref name="MedlinePlus Felbamate">Template:Cite web</ref>
• Cenobamate (2019).

Carboxamides

File:Carbamazepine 3D.png

Carbamazepine

Template:Main The following are carboxamides:

• Carbamazepine (1963). A popular anticonvulsant that is available in generic formulations.
• Oxcarbazepine (1990). A derivative of carbamazepine that has similar efficacy and is better tolerated and is also available generically.
• Eslicarbazepine acetate (2009).
• Photoswitchable analogues of carbamazepine (2024) are research compounds developed to control its pharmacological activity locally and on demand using light, with the purpose to reduce adverse systemic effects.<ref>Template:Cite journal</ref> One of these compounds (carbadiazocine, based on a bridged azobenzene) has been shown to produce analgesia with noninvasive illumination in a rat model of neuropathic pain.

Fatty acids

Template:Main The following are fatty-acids:

• The valproates — valproic acid, sodium valproate, and divalproex sodium (1967).
• Vigabatrin (1989).
• Progabide (1987).
• Tiagabine (1996).

Vigabatrin and progabide are also analogs of GABA.

Fructose derivatives

• Topiramate (1995).

Gabapentinoids

Gabapentinoids are used in epilepsy, neuropathic pain, fibromyalgia, restless leg syndrome, opioid withdrawal and generalized anxiety disorder (GAD). Gabapentinoids block voltage-gated calcium channels, mainly the N-Type, and P/Q-type calcium channels. The following are gabapentinoids:

• Pregabalin (2004)
• Mirogabalin (2019) (Japan only)
• Gabapentin (1993)
• Gabapentin enacarbil (Horizant) (2011)
• Gabapentin extended release (Gralise) (1996)

Gabapentinoids are analogs of GABA, but they do not act on GABA receptors. They have analgesic, anticonvulsant, and anxiolytic effects.

Hydantoins

Template:Main The following are hydantoins:

• Ethotoin (1957).
• Phenytoin (1938).
• Mephenytoin.
• Fosphenytoin (1996).

Oxazolidinediones

Template:Main The following are oxazolidinediones:

• Paramethadione.
• Trimethadione (1946).
• Ethadione.

Propionates

• Beclamide.

Pyrimidinediones

• Primidone (1952).

Pyrrolidines

• Brivaracetam (2016).
• Etiracetam.
• Levetiracetam (1999).
• Seletracetam.

Succinimides

Template:Main The following are succinimides:

• Ethosuximide (1955).
• Phensuximide.
• Mesuximide.

Sulfonamides

• Acetazolamide (1953).
• Sultiame.
• Methazolamide.
• Zonisamide (2000).

Triazines

• Lamotrigine (1990).

Ureas

• Pheneturide.
• Phenacemide.

Valproylamides

• Valpromide.
• Valnoctamide.

Other

• Perampanel.
• Stiripentol.<ref name="Diacomit EPAR">Template:Cite web</ref>
• Pyridoxine (1939).

Non-pharmaceutical anticonvulsants

The ketogenic diet and vagus nerve stimulation are alternative treatments for epilepsy without the involvement of pharmaceuticals. The ketogenic diet consists of a high-fat, low-carbohydrate diet, and has shown good results in patients whose epilepsy has not responded to medications and who cannot receive surgery. The vagus nerve stimulator is a device that can be implanted into patients with epilepsy, especially that which originates from a specific part of the brain. However, both of these treatment options can cause severe adverse effects. Additionally, while seizure frequency typically decreases, they often do not stop entirely.<ref>Template:Cite journal</ref><ref>Template:Cite web</ref>

Treatment guidelines

According to guidelines by the American Academy of Neurology and American Epilepsy Society,<ref name=aan&aes>AAN Guideline Summary for Clinicians – Efficacy and Tolerability of the New Antiepileptic Drugs, I: Treatment of New Onset Epilepsy Template:Webarchive Retrieved on 29 June 2010</ref> mainly based on a major article review in 2004,<ref>Template:Cite journal</ref> patients with newly diagnosed epilepsy who require treatment can be initiated on standard anticonvulsants such as carbamazepine, phenytoin, valproic acid/valproate semisodium, phenobarbital, or on the newer anticonvulsants gabapentin, lamotrigine, oxcarbazepine or topiramate. The choice of anticonvulsants depends on individual patient characteristics.<ref name=aan&aes/> Both newer and older drugs are generally equally effective in new onset epilepsy.<ref name=aan&aes/> The newer drugs tend to have fewer side effects.<ref name=aan&aes/> For newly diagnosed partial or mixed seizures, there is evidence for using gabapentin, lamotrigine, oxcarbazepine or topiramate as monotherapy.<ref name=aan&aes/> Lamotrigine can be included in the options for children with newly diagnosed absence seizures.<ref name=aan&aes/>

History

The first anticonvulsant was bromide, suggested in 1857 by the British gynecologist Charles Locock who used it to treat women with "hysterical epilepsy" (probably catamenial epilepsy). Bromides are effective against epilepsy, and also cause impotence, which is not related to its anti-epileptic effects. Bromide also suffered from the way it affected behaviour, introducing the idea of the "epileptic personality" which was actually a result of medication. Phenobarbital was first used in 1912 for both its sedative and antiepileptic properties. By the 1930s, the development of animal models in epilepsy research led to the development of phenytoin by Tracy Putnam and H. Houston Merritt, which had the distinct advantage of treating epileptic seizures with less sedation.<ref name="g470">Template:Cite book</ref> By the 1970s, a National Institutes of Health initiative, the Anticonvulsant Screening Program, headed by J. Kiffin Penry, served as a mechanism for drawing the interest and abilities of pharmaceutical companies in the development of new anticonvulsant medications.

Marketing approval history

The following table lists anticonvulsant drugs together with the date their marketing was approved in the US, UK and France. Data for the UK and France are incomplete. The European Medicines Agency approves drugs throughout the European Union. Some of the drugs are no longer marketed.

Drug	Brand	US	UK	France
acetazolamide	Diamox	1953-07-2727 July 1953<ref name="NDA 008943">Template:Cite web</ref>	1988<ref name="EpilepsyAction">Epilepsy Action: Druglist. Template:Webarchive Retrieved on 1 November 2007.</ref>
brivaracetam	Briviact	2016-02-1818 February 2016<ref name="NDA 205836">Template:Cite web</ref><ref>Template:Cite web</ref>
carbamazepine	Tegretol	1974-07-1515 July 1974<ref name="NDA 016608">Template:Cite web (Initial approval on 11 March 1968 was for trigeminal neuralgia.)</ref><ref name="Tegretol1978WJM">Template:Cite journal</ref>	1965<ref name="EpilepsyAction"/>	1963<ref name="Loiseau_et_al_1999">Template:Cite journal</ref>
cenobamate	Xcopri	2019-11-2121 November 2019
clobazam	Onfi/Frisium	2011-10-2121 October 2011<ref name="NDA 202067">Template:Cite web</ref><ref>Template:Cite web</ref>	1979<ref name="EpilepsyAction"/>
clonazepam	Klonopin/Rivotril	1975-06-044 June 1975<ref name="NDA 017533">Template:Cite web</ref>	1974<ref name="EpilepsyAction"/>
diazepam	Valium	1963-11-1515 November 1963<ref name="NDA 013263">Template:Cite web</ref>
divalproex sodium	Depakote	1983-03-1010 March 1983<ref name="NDA 018723">Template:Cite web</ref>
eslicarbazepine	Aptiom	2013-08-1111 August 2013<ref name="NDA 022416">Template:Cite web</ref><ref>Template:Cite web</ref>
ethosuximide	Zarontin	1960-11-022 November 1960<ref name="NDA 012380">Template:Cite web</ref>	1955<ref name="EpilepsyAction"/>	1962<ref name="Loiseau_et_al_1999"/>
ethotoin	Peganone	1957-04-2222 April 1957<ref name="NDA 010841">Template:Cite web</ref>
everolimus	Afinitor/Votubia	2009-03-3030 January 2009<ref name="NDA 022334">Template:Cite web</ref>
felbamate	Felbatol	1993-07-2929 July 1993<ref name="NDA 020189">Template:Cite web</ref>
fosphenytoin	Cerebyx	1996-08-055 August 1996<ref name="NDA 020450">Template:Cite web</ref>
gabapentin	Neurontin	1993-12-3030 December 1993<ref name="NDA 020235">Template:Cite web</ref>	1993-05May 1993<ref name="EpilepsyAction"/><ref name="Loiseau_et_al_1999"/>	1994-10October 1994<ref name="Loiseau_et_al_1999"/>
lacosamide	Vimpat	2008-10-2828 October 2008<ref name="NDA 022253">Template:Cite web</ref>
lamotrigine	Lamictal	1994-12-2727 December 1994<ref name="NDA 020241">Template:Cite web</ref>	1991-10October 1991<ref name="EpilepsyAction"/><ref name="Loiseau_et_al_1999"/>	1995-05May 1995<ref name="Loiseau_et_al_1999"/>
levetiracetam	Keppra	1999-11-3030 November 1999<ref name="NDA 021035">Template:Cite web</ref>	2000-09-2929 September 2000<ref name="EpilepsyAction"/><ref name="keppra">EPAR: Keppra. Template:Webarchive Retrieved on 1 November 2007.</ref>	2000-09-2929 September 2000<ref name="keppra"/>
mephenytoin	Mesantoin	1946-10-2323 October 1946<ref name="NDA 006008">Template:Cite web</ref>
metharbital	Gemonil	1952<ref name="NDA 008322">Template:Cite web</ref><ref name="renamed_from_0632060468_on_20081125071809">Template:Cite book</ref>
methsuximide	Celontin	1957-02-088 February 1957<ref name="NDA 010596">Template:Cite web</ref>
methazolamide	Neptazane	1959-01-2626 January 1959<ref name="NDA 011721">Template:Cite web</ref>
oxcarbazepine	Trileptal	2000-01-1414 January 2000<ref name="NDA 021014">Template:Cite web</ref>	2000<ref name="EpilepsyAction"/>
phenobarbital	Luminal	Unknown	1912<ref name="EpilepsyAction"/>	1920<ref name="Loiseau_et_al_1999"/>
phenytoin	Dilantin/Epanutin	1938<ref name="Loiseau_et_al_1999"/><ref name="NDA 008762">Template:Cite web (Marketed in 1938, approved 1953)</ref>	1938<ref name="EpilepsyAction"/>	1941<ref name="Loiseau_et_al_1999"/>
piracetam	Nootropil	never approved
phensuximide	Milontin	1953<ref name="NDA 008855">Template:Cite web</ref><ref name="isbn0824785495">Template:Cite book (first usage)</ref>
pregabalin	Lyrica	2004-12-3030 December 2004<ref name="NDA 021446">Template:Cite web</ref>	2004-07-066 July 2004<ref name="EpilepsyAction"/><ref name="lyrica">EPAR: Lyrica Template:Webarchive Retrieved on 1 November 2007.</ref>	2004-07-066 July 2004<ref name="lyrica"/>
primidone	Mysoline	1954-03-088 March 1954<ref name="NDA 009170">Template:Cite web</ref>	1952<ref name="EpilepsyAction"/>	1953<ref name="Loiseau_et_al_1999"/>
rufinamide	Banzel/Inovelon	2008-11-1414 November 2008<ref name="NDA 021911">Template:Cite web</ref><ref>Template:Cite web</ref>
sodium valproate	Epilim	Unknown	1977-12December 1977<ref name="Loiseau_et_al_1999"/>	1967-06June 1967<ref name="Loiseau_et_al_1999"/>
stiripentol	Diacomit	2018-08-2020 August 2018<ref name="NDA 206709">Template:Cite web</ref><ref>Template:Cite web</ref>	2007-01January 2007<ref name="Diacomit EPAR" />	2007-01January 2007<ref name="Diacomit EPAR" />
tiagabine	Gabitril	1997-09-3030 September 1997<ref name="NDA 020646">Template:Cite web</ref><ref name="DrugPatentWatch NDA020646">Template:Cite web</ref>	1998<ref name="EpilepsyAction"/>	1997-11November 1997<ref name="Loiseau_et_al_1999"/>
topiramate	Topamax	1996-12-2424 December 1996<ref name="NDA 020505">Template:Cite web</ref>	1995<ref name="EpilepsyAction"/>
trimethadione	Tridione	1946-01-2525 January 1946<ref name="NDA 005856">Template:Cite web</ref>
valproic acid	Depakene/Convulex	1978-02-2828 February 1978<ref name="NDA 018081">Template:Cite web</ref>	1993<ref name="EpilepsyAction"/>
vigabatrin	Sabril	2009-08-2121 August 2009<ref name="NDA 020427">Template:Cite web</ref>	1989<ref name="EpilepsyAction"/>
zonisamide	Zonegran	2000-03-2727 March 2000<ref name="NDA 020789">Template:Cite web</ref>	2005-03-1010 March 2005<ref name="EpilepsyAction"/><ref name="zonegran">EPAR: Zonegran. Template:Webarchive Retrieved on 1 November 2007</ref>	2005-03-1010 March 2005<ref name="zonegran"/>

Pregnancy

Many of the commonly used anticonvulsant/anti-seizure medications (ASMs), such as valproate, phenytoin, carbamazepine, phenobarbitol, gabapentin have been reported to cause an increased risk of birth defects including major congenital malformations such as neural tube defects.<ref name=":0">Template:Cite journal</ref> The risk of birth defects associated with taking these medications while pregnant may be dependent on the dose of the drug and on the timing of gestation (how well developed the baby is).<ref name=":0" /> While trying to conceive a child and during pregnancy, medical advice should be followed to optimize the management of the person's epilepsy in order to keep the person and the unborn baby safe from epileptic seizures and also ensure that the risk of birth defects due to in utero exposure of anticonvulsants is as low as possible.<ref name="Harden" /> Anticonvulsant medications should be carefully monitored during use in pregnancy.<ref name="Harden">Template:Cite journal</ref><ref>Template:Cite journal</ref> For example, since the first trimester is the most susceptible period for fetal development, planning a routine antiepileptic drug dose that is safer for the first trimester could be beneficial to prevent pregnancy complications.

Valproic acid, and its derivatives such as sodium valproate and divalproex sodium, causes cognitive deficit in the child, with an increased dose causing decreased intelligence quotient and use is associated with adverse neurodevelopmental outcomes (cognitive and behavioral)  in children.<ref name="BromleyWeston2014">Template:Cite journal</ref><ref>Template:Cite journal</ref> On the other hand, evidence is conflicting for carbamazepine regarding any increased risk of congenital physical anomalies or neurodevelopmental disorders by intrauterine exposure.<ref name="BromleyWeston2014" /> Similarly, children exposed lamotrigine or phenytoin in the womb do not seem to differ in their skills compared to those who were exposed to carbamazepine.<ref name="BromleyWeston2014" />

There is inadequate evidence to determine if newborns of women with epilepsy taking anticonvulsants have a substantially increased risk of hemorrhagic disease of the newborn.<ref name=Harden/>

There is little evidence to suggest that anticonvulsant/ASM exposure through breastmilk has clinical effects on newborns. The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study showed that most blood concentrations in breastfed infants of mothers taking carbamazepine, oxcarbazepine, valproate, levetiracetam, and topiramate were quite low, especially in relationship to the mother's level and what the fetal level would have been during pregnancy. (Note: valproic acid is NOT a recommended ASM for people with epilepsy who are considering having children.) <ref>Template:Cite journal</ref>

Infant exposure to newer ASMs (cenobamate, perampanel, brivaracetam, eslicarbazepine, rufinamide, levetiracetam, topiramate, gabapentin, oxcarbazepine, lamotrigine, and vigabatrin) via breastmilk was not associated with negative neurodevelopment (such as lower IQ and autism spectrum disorder) at 36 months.<ref>Template:Cite web</ref>

Several studies that followed children exposed to ASMs during pregnancy showed that a number of widely used ones (including lamotrigine and levetiracetam) carried a low risk of adverse neurodevelopmental outcomes (cognitive and behavioral) in children when compared to children born to mothers without epilepsy and children born to mothers taking other anti-seizure medications. Data from several pregnancy registries showed that children exposed to levetiracetam or lamotrigine during pregnancy had the lowest risk of developing major congenital malformations compared to those exposed to other ASMs. The risk of major congenital malformations for children exposed to these ASMs were within the range for children who were not exposed to any ASMs during pregnancy.<ref>Template:Cite journal</ref>

People with epilepsy can have healthy pregnancies and healthy babies. However, proper planning and care is essential to minimize the risk of congenital malformations or adverse neurocognitive outcomes for the fetus while maintaining seizure control for the pregnant person with epilepsy. If possible, when planning pregnancy, people with epilepsy should switch to ASMs with the lowest teratogenic risk for major congenital malformations as well as the least risk of adverse neurodevelopmental outcomes (e.g., lower IQ or autism spectrum disorder). They should also work with their healthcare providers to identify the lowest effective ASM dosage that will maintain their seizure control while regularly checking medication levels throughout pregnancy.<ref>Template:Cite journal</ref>

Data from studies conducted on women taking antiepileptic drugs for non-epileptic reasons, including depression and bipolar disorder, show that if high doses of the drugs are taken during the first trimester of pregnancy then there is the potential of an increased risk of congenital malformations.<ref>Template:Cite journal</ref>

Research

The mechanism of how anticonvulsants cause birth defects is not entirely clear. During pregnancy, the metabolism of many anticonvulsants is affected. There may be an increase in the clearance and resultant decrease in the blood concentration of lamotrigine, phenytoin, and to a lesser extent carbamazepine, and possibly decreases the level of levetiracetam and the active oxcarbazepine metabolite, the monohydroxy derivative.<ref name="Harden" /> In animal models, several anticonvulsant drugs have been demonstrated to induce neuronal apoptosis in the developing brain.<ref name="Bittigau">Template:Cite journal</ref><ref name="Manthey">Template:Cite journal</ref><ref name="Katz">Template:Cite journal</ref><ref name="Kim">Template:Cite journal</ref><ref name="Forcelli">Template:Cite journal</ref>

Further reading

• Anti epileptic activity of novel substituted fluorothiazole derivatives by Devid Chutia, RGUHS

External links

• Drug Reference for FDA Approved Epilepsy Drugs