Lamotrigine add‐on for drug‐resistant partial epilepsy

Sridharan Ramaratnam; Mariangela Panebianco; Anthony G Marson

doi:10.1002/14651858.CD001909.pub2

Lamotrigina complementaria para la epilepsia parcial resistente a los fármacos

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References

References to studies included in this review

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excluded studies
additional references
other published versions

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References to other published versions of this review

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included studies
excluded studies
additional references

Ramaratnam S, Marson AG, Baker GA. Lamotrigine add‐on for drug‐resistant partial epilepsy. Cochrane Database of Systematic Reviews 2001, Issue 3. [DOI: 10.1002/14651858.CD001909]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

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excluded studies

Baulac 2010

Methods	Double‐blind, placebo‐controlled, randomised, parallel‐group study. Three arms: 1 placebo, 1 lamotrigine, and 1 pregabalin. Baseline period = 6 weeks; double‐blind treatment period = 17 weeks, which included initial 5 weeks dosage titration for lamotrigine and 6 weeks maintenance at 300 mg/day and additional treatment period of 6 weeks with dose escalation to 400 mg/day for those with continuing seizures. Double‐blind treatment period was followed by an open‐label study or a 2‐week taper phase.
Participants	97 centres in Europe, Canada, and Australia. Adults over the age of 18 years and body weight ≥40 kg, with a diagnosis of partial seizures (as defined by the International League Against Epilepsy Classification of Seizures). 546 persons screened, 434 randomised. M:F ratio 39.3:60.7 for placebo and 54.6:45.4 for lamotrigine. Mean age 39.1 in placebo group and 39.4 in Lamotrigine group. Minimum seizure frequency of 4 partial seizures during the 6‐week baseline period and no 28‐day period free of partial seizure, despite treatment with at least three AEDs from at least two different AED classes, each at or above the lowest recommended dose or the lowest adequate plasma concentration given for a minimum of 3 months; were allowed to take one to three AEDs concurrently, one of which had to be an enzyme inducer. Exclusion Criteria: previous treatment with pregabalin; previous treatment with lamotrigine within 6 months before entering baseline; history of rash with lamotrigine; previous treatment with valproic acid products within 2 months of baseline; and previous treatment with gabapentin, felbamate, or vigabatrin < 6 weeks prior to screening. history of status epilepticus in the last 1 year, significant psychiatric disorder, or use of concomitant medication that could interfere with response to study medications or affect seizure frequency. pregnant or planning to conceive, lactation.
Interventions	Group I (n = 141): received placebo. Group II (n = 141): received lamotrigine 300 mg/day after dose titration over 5 weeks, and if seizures occurred during 6‐week maintenance, further dose escalation to 400 mg/day from week 12 to 17. Group III (n = 152): received pregabalin.
Outcomes	(1) Seizure frequency. (2) Adverse events, including changes in physical and neurologic examinations, 12‐lead electrocardiograms (ECGs), and clinical laboratory tests (hematology, blood chemistry, pregnancy, and urinalysis).
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of randomisation not specified.
Allocation concealment (selection bias)	Unclear risk	The details were not mentioned in the publication.
Blinding (performance bias and detection bias) All outcomes	Unclear risk	No details provided regarding blinding of participants, study personnel, and outcome assessors. Regarding the medications, blinding was maintained by administering the same numbers of capsules per day per group.
Incomplete outcome data (attrition bias)	Low risk	35 withdrew from placebo group and 40 from lamotrigine group. The reasons for exclusion were reported.
Selective reporting (reporting bias)	Low risk	Protocol unavailable to check a priori outcomes, but appears all expected and pre‐specified outcomes are reported.
Other bias	Unclear risk	Responder rates were mentioned as percentages and actual numbers were not given. Author has been contacted regarding actual number of responders in each group. This study was sponsored by Pfizer Inc.

Binnie 1989

Methods	Randomized, double‐blind, cross‐over study. Two treatment arms: 1 placebo, and 1 lamotrigine. Baseline period = 8 weeks.Treatment I and II = 12 weeks each. Washout = 6 weeks, including taper period.
Participants	Single centre study from Netherlands. 34 adults aged between 16 to 51 years (mean 37.1 +/‐ 10.26). 16 were randomised to lamotrigine and 18 to placebo during the first treatment phase. All had drug‐resistant partial seizures. The age of onset of epilepsy ranged from 1 to 40 (mean 14.3 +/‐ 10.7), the duration of epilepsy was 6 to 49.5 (mean 22.8 +/‐ 11) years. Maximum number of other AEDs = 4.
Interventions	Add‐on lamotrigine, or placebo. Median daily dose of lamotrigine was 200 mg. Participants on valproate received lower doses.
Outcomes	(1) 50% responder rates. (2) Withdrawal from study for any reason. (3) Adverse effects.
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated random permuted blocks.
Allocation concealment (selection bias)	Low risk	Participants were allocated sequentially‐numbered sealed packages containing either lamotrigine or placebo.
Blinding (performance bias and detection bias) All outcomes	Low risk	Participants and parents were blinded. An unblinded investigator with knowledge of the medication and plasma concentrations instructed the blinded investigators about dispensing the trial medications. Identical tablets and packaging used.
Incomplete outcome data (attrition bias)	Low risk	No participants were excluded from analysis. No participant withdrew from the study during the first treatment phase.
Selective reporting (reporting bias)	Low risk	All outcomes stated in methods section of paper were reported in the results. There was no protocol available to check to priori outcomes.
Other bias	Unclear risk	This study was sponsored by GlaxoSmithKline, the manufactures of LTG.

Boas 1996

Methods	Randomized, double‐blind, cross‐over study. Two treatment arms: 1 placebo, 1 lamotrigine. Five phases: baseline period = 12 weeks; treatment I = 12 weeks; washout I = 4 weeks; treatment II = 12 weeks; washout II = 4 weeks.
Participants	4 centre study from Denmark. 56 adults with refractory drug‐resistant partial seizures, aged from 16 to 65 years. 30 were allocated to lamotrigine and 26 to placebo during the first treatment phase. There were 27 men and 29 women. Maximum number of other AEDs = 3.
Interventions	Lamotrigine or placebo was added to the patients' existing AEDs. The dose of lamotrigine varied from 75 to 400 mg. Participants on valproate received lower doses.
Outcomes	(1) 50% responder rates. (2) Withdrawal from study for any reason. (3) Adverse effects.
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated random permuted blocks.
Allocation concealment (selection bias)	Low risk	Partcipants were allocated sequentially‐numbered, sealed packages containing either lamotrigine or placebo.
Blinding (performance bias and detection bias) All outcomes	Unclear risk	No details provided regarding blinding of participants, study personnel, and outcome assessors. All treatments (tablets) and packaging were identical. Prepacked coded medication was dispensed by pharmacy.
Incomplete outcome data (attrition bias)	Low risk	No participants were excluded from analysis. 10 participants withdrew from the study; 8 randomised to lamotrigine and 2 to placebo. The reasons for exclusion were reported.
Selective reporting (reporting bias)	Low risk	All outcomes stated in methods section of paper were reported in the results. There was no protocol available to check a priori outcomes.
Other bias	Unclear risk	This study was sponsored by GlaxoSmithKline, the manufactures of LTG.

Duchowny 1999

Methods	Randomized, double blind, parallel group, multi‐centre study. Two treatment arms: 1 placebo, 1 lamotrigine. Pre‐randomization baseline period = 8 weeks. Treatment phase = 18 weeks (including 6‐week titration). Taper and follow‐up = 1 to 6 weeks, including 1‐week taper.
Participants	40 centres from USA and France: 199 children with refractory drug‐resistant partial seizures, aged from 2 to 16 years (27% were less than 6 years old, 60% aged between 6 to 12 years and 11% were over 12 years age). 98 were allocated to lamotrigine and 101 to placebo. There were 103 boys and 96 girls. Maximum number of other AEDs = 2.
Interventions	Add‐on lamotrigine or placebo. Median dose ranged from 2.7 to 12.9 mg/kg/day depending upon concurrent use of other AEDs. Participants on valproate received lower doses.
Outcomes	(1) 50% responder rates. (2) Withdrawal from study for any reason. (3) Adverse effects.
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated random permuted blocks.
Allocation concealment (selection bias)	Low risk	Patients were randomised with a blocked randomisation scheme to treatment with add‐on lamotrigine or matched placebo in bottles labelled with pre‐generated participant numbers.
Blinding (performance bias and detection bias) All outcomes	Low risk	Treatment assignments were unknown to all study‐site personnel, patients and sponsors. Lamotrigine and matching placebo were provided as berry‐flavoured, chewable, dispersible caplets or tablets in strengths of 5, 25, and 100 mg.
Incomplete outcome data (attrition bias)	Low risk	No participants were excluded from analysis. 2 enrolled participants withdrew before randomisation. 14 participants allocated to lamotrigine and 18 participants allocated to placebo withdrew during treatment phase. The reasons for exclusion were reported.
Selective reporting (reporting bias)	Low risk	All outcomes stated in methods section of paper were reported in the results. There was no protocol available to check a priori outcomes.
Other bias	Unclear risk	This study was sponsored by GlaxoSmithKline, the manufactures of LTG.

Jawad 1989

Methods	Randomised, double‐blind, cross‐over study. Two treatment arms: 1 placebo, 1 lamotrigine. Five phases: baseline period = 8 weeks; Treatment I = 12 weeks; Washout I = 6 weeks; treatment II = 12 weeks; Washout II = 6 weeks.
Participants	Single centre study from UK. 24 adults with refractory drug‐resistant partial seizures, aged between 16 to 60 years. 12 were allocated to lamotrigine and 12 to placebo in the first treatment phase. Maximum number of other AEDs = 2.
Interventions	Add‐on lamotrigine or placebo. The median daily dose of lamotrigine was 250 mg. Participants on valproate received lower doses. Unblinded investigator wrote prescriptions based on plasma concentration.
Outcomes	(1) 50% responder rates. (2) Withdrawal from study for any reason. (3) Adverse effects.
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated random permuted blocks.
Allocation concealment (selection bias)	Low risk	Partcipants were allocated by sequentially numbered, sealed packages containing either lamotrigine or placebo.
Blinding (performance bias and detection bias) All outcomes	Unclear risk	No details provided regarding blinding of participants, study personnel, and outcome assessors. Identical tablets and packaging used.
Incomplete outcome data (attrition bias)	Low risk	No participants were excluded from analysis. One participant who was allocated to lamotrigine withdrew from the study (the reason for exclusion was reported) and none withdrew from the placebo group.
Selective reporting (reporting bias)	Low risk	All outcomes stated in methods section of paper were reported in the results. There was no protocol available to check a priori outcomes.
Other bias	Unclear risk	This study was sponsored by GlaxoSmithKline, the manufactures of LTG.

Loiseau 1990

Methods	Randomised, double‐blind, cross‐over study. Two treatment arms: 1 placebo, 1 lamotrigine. Five phases: Pre‐randomisation baseline = 4 weeks. Treatment I = 8 weeks. Washout I = 4 weeks. Treatment II = 8 weeks. Washout II = 4 weeks.
Participants	Single centre study from France. 25 adults, aged between 20 to 54 (mean 34.2 +/‐ 12.41) years. All had drug‐resistant partial epilepsy. 11 were randomised to lamotrigine and 14 to placebo in the first treatment phase. The duration of epilepsy ranged from 3 to 45 years (mean 17.4 +/‐ 10.81). Maximum number of other AEDs = 2.
Interventions	Add‐on lamotrigine or placebo. The median daily lamotrigine dose was 300 mg. Participants on valproate received lower doses.
Outcomes	(1) 50% responder rates. (2) Withdrawal from study for any reason. (3) Adverse effects.
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated random permuted blocks.
Allocation concealment (selection bias)	Low risk	Participants were allocated by sequentially numbered, sealed packages containing either lamotrigine or placebo.
Blinding (performance bias and detection bias) All outcomes	Low risk	Neurologists, participants and parents were blinded. Investigators were blinded. All treatments (tablets) and packaging were identical. Pre‐packed coded medication dispensed by pharmacy.
Incomplete outcome data (attrition bias)	Low risk	No participants were excluded from analysis. 2 participants withdrew from the study; 1 receiving lamotrigine and 1 receiving placebo. The reasons for exclusion were reported.
Selective reporting (reporting bias)	Low risk	All outcomes stated in methods section of paper were reported in the results. There was no protocol available to check a priori outcomes.
Other bias	Unclear risk	This study was sponsored by GlaxoSmithKline, the manufactures of LTG.

Matsuo 1993

Methods	Randomised, double‐blind, parallel group, multi‐centre study. Three treatment arms: 1 placebo, 1 lamotrigine 300 mg and 1 lamotrigine 500 mg. Pre‐randomisation baseline = 12 weeks. Treatment phase = 24 weeks. Taper and follow‐up = 3 weeks.
Participants	Multicentre US study with 216 participants (67 males and 149 females) with a mean age of 33 (range 18 to 63) years. All had drug‐resistant partial epilepsy. 73 were randomised to receive placebo, while 71 received lamotrigine 300 mg per day and 72 received lamotrigine 500 mg per day. The mean duration of epilepsy was 21.9 years and the mean age at onset 11 years. Maximum number of other AEDs = 3. People receiving valproate were excluded.
Interventions	Add‐on lamotrigine 300 mg or lamotrigine 500 mg or placebo.
Outcomes	(1) 50% responder rates. (2) Withdrawal from study for any reason. (3) Adverse effects.
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated random permuted blocks.
Allocation concealment (selection bias)	Low risk	Randomisation concealment: allocated sequentially numbered, sealed packages containing either lamotrigine or placebo.
Blinding (performance bias and detection bias) All outcomes	Unclear risk	No details provided regarding blinding of participants, study personnel, and outcome assessors. Identical tablets and packaging used.
Incomplete outcome data (attrition bias)	Low risk	No participants were excluded from analysis. 25 participants withdrew from the study; 7 receiving lamotrigine 300 mg, 12 receiving lamotrigine 500 mg and 6 receiving placebo. The reasons for exclusion were reported.
Selective reporting (reporting bias)	Low risk	Protocol unavailable to check a priori outcomes, but appears all expected and pre‐specified outcomes were reported.
Other bias	Unclear risk	This study was sponsored by GlaxoSmithKline, the manufactures of LTG.

Messenheimer 1994

Methods	Randomised, double‐blind, cross‐over study. Two treatment arms: 1 placebo, 1 lamotrigine. Total study duration was 43 weeks. Pre‐randomisation baseline = 8 weeks. Treatment A = 14 weeks (including 2 weeks blinded tapering). Follow‐up period = 3 weeks. Treatment B = 14 weeks (including 2 weeks blinded tapering). Washout = 4 weeks.
Participants	Multi‐centre US study with 98 participants (46 men and 52 women) with drug‐resistant partial epilepsy. 46 were randomised to receive lamotrigine and 52 to placebo in the first treatment phase. Age range 18 to 64 years with a mean of 35. Age at onset of epilepsy was 12 years; mean duration 23.1 years. Up to 3 other AEDs were permitted. Concomitant use of valproate was not allowed.
Interventions	Add‐on lamotrigine or placebo. Median lamotrigine dose 400 mg/day.
Outcomes	(1) 50% responder rates. (2) Withdrawal from study for any reason. (3) Adverse effects.
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated random permuted blocks.
Allocation concealment (selection bias)	Low risk	Participants were allocated by sequentially numbered, sealed packages containing either lamotrigine or placebo.
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Investigators were blinded. No more information provided regarding blinding of neurologists, participants, and parents. All treatments (tablets) and packaging were identical. Pre‐packed coded medication dispensed by pharmacy.
Incomplete outcome data (attrition bias)	Low risk	No participants were excluded from analysis. 6 participants withdrew from the study; 2 receiving lamotrigine and 4 receiving placebo. The reasons for exclusion were reported.
Selective reporting (reporting bias)	Low risk	All outcomes stated in methods section of paper were reported in the results. There was no protocol available to check a priori outcomes.
Other bias	Unclear risk	This study was sponsored by GlaxoSmithKline, the manufactures of LTG.

Naritoku 2007

Methods	Double‐blind, randomised, parallel‐group, placebo‐controlled multi‐centre global study. Screening phase of up to 2 weeks during which eligibility was determined; an 8‐week baseline phase serving to exclude from randomisation patients who did not meet the minimum seizure frequency criterion; a 7‐week, double‐blind escalation phase during which lamotrigine XR (Extended Release) was introduced and titrated to its target dose; and a 12‐week, double‐blind maintenance phase during which dosage of study medication and concomitant AED were maintained.
Participants	International multi‐centre study from North and South America, Europe, and Asia. Uncontrolled partial seizures (at least 8 partial seizures in 8 weeks with at least one partial seizure during each 4‐week period of the baseline phase). Male and female patients 12 years of age or older with partial seizures with or without generalisation who were treated with a stable regimen of one or two AEDs for at least 4 weeks before starting the baseline phase. Total number enrolled = 243; (121 to treatment arm; 123 to placebo arm); 93% were aged between 16 and 65 years; mean age in lamotrigine group = 35.8 (12.7) and in placebo group = 37.5 (14.4) years. Males constituted 47% of participants in lamotrigine group and 53% of participants in placebo group. Exclusion criteria included: presence of primary generalized seizures, status epilepticus during or within 24 weeks before the start of the baseline phase, chronic treatment with three or more AEDs, current or previous use of lamotrigine, current use of felbamate or adherence to a ketogenic diet, and pregnancy or planned pregnancy during the study or within 3 weeks after the last dose of study medication.
Interventions	Treatment group received lamotrigine XR (Extended Release); other group received identical placebo. Dosage of lamotrigine XR was escalated gradually up to 200 mg/day in those receiving valproate, 300 mg/day in those receiving valproate and an enzyme inducing AED, and up to 500 mg/day in those receiving enzyme inducing AEDs without valproate.
Outcomes	(1) Seizure frequency. (2) Adverse events (3) Withdrawals from study. US subjects had following additional assessments: Profile of Mood States (POMS), Center for Epidemiologic Studies‐Depression Scale (CES‐D), research version of the Neurological Disorders Depression Inventory‐Epilepsy (NDDI‐E), Quality of Life in Epilepsy‐31‐P (QOLIE‐31‐P), Liverpool Adverse Experience Profile (AEP), Seizure Severity Questionnaire (SSQ), and Epworth Sleepiness Scale (ESS).
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of randomisation not specified.
Allocation concealment (selection bias)	Unclear risk	Details not reported in the publication.
Blinding (performance bias and detection bias) All outcomes	Unclear risk	No information provided.
Incomplete outcome data (attrition bias)	Low risk	24 subjects withdrew from treatment group and 16 from placebo group. The reasons for exclusion were reported.
Selective reporting (reporting bias)	Low risk	There was no protocol available to check a priori outcomes,but appears all expected and pre‐specified outcomes were reported.
Other bias	Unclear risk	This study was sponsored by GlaxoSmithKline, the manufactures of LTG.

Piña‐Garza 2008

Methods	Randomised, double‐blind, multi‐centre placebo‐controlled trial. Responder‐enriched design in which all patients received adjunctive lamotrigine during an open‐label phase (wherein dose was escalated to achieve optimal response); those who had a 40% or greater reduction in the frequency of partial seizures during the last 4 weeks of the optimisation period were randomly assigned to double‐blind treatment for up to 8 weeks with continued lamotrigine or placebo.
Participants	Total number enrolled = 38. Male or female infants aged 1 month to 24 months with at least 4 partial seizures (with or without generalisation) per month, uncontrolled by 1 AED and who showed 40% or greater reduction in seizure frequency during an initial open label phase. There were 19 subjects in each arm; median age was 13.5 months in lamotrigine arm and 14.2 months in placebo arm; median age of onset of epilepsy was 3 months and median duration of epilepsy was 9.1 months in lamotrigine arm and 8.5 months in placebo arm. Exclusion Criteria: subjects with progressive myoclonic epilepsy; progressive neurologic disease, seizures unrelated to epilepsy or resulting from drug withdrawal; use of felbamate, adrenocorticotropic hormone, previous use of lamotrigine, two AEDs as maintenance treatment, presence of hepatic dysfunction, having a functioning vagus nerve stimulator; or being on a ketogenic diet.
Interventions	Intervention group was continued on lamotrigine. Control group subjects had their lamotrigine dose tapered and changed to placebo. The maximum maintenance dose was 5.1 mg/kg/day for those on non–enzyme‐inducing AEDs or valproate and 15.6 mg/kg/day for those on enzyme‐inducing AEDs.
Outcomes	(1) Percentage of patients who had treatment failures during the double‐blind phase. (2) Cumulative percentage of patients who met escape criteria as a function of days on double‐blind study medication. Subjects were withdrawn from study if they met one of the following criteria: 50% increase in monthly partial seizure frequency compared with seizure frequency during the last 4 weeks of the open‐label optimisation period; a doubling of the highest consecutive 2‐day partial seizure count observed during the open‐label optimisation period; onset of a new and more severe seizure type; clinically significant worsening of non‐partial seizures that were also observed during the historical baseline phase or the open‐label optimisation period; the need to use any therapeutic intervention in addition to study medication to control seizures; or status epilepticus.
Notes	The protocol was amended midway through the study to randomly assign all patients with at least 40% reduction in seizure frequency, instead of planned inclusion of subjects with 40% to 80% reduction in seizure frequency. 43 subjects who had more than 80% reduction in seizure frequency before the protocol amendment were not included in the double‐blind study.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of randomisation not specified.
Allocation concealment (selection bias)	Unclear risk	Details not reported in the publication.
Blinding (performance bias and detection bias) All outcomes	Unclear risk	No information provided.
Incomplete outcome data (attrition bias)	Low risk	11 patients (8 in the lamotrigine group and 3 in placebo group) completed the double‐blind phase, 25 (9 in the lamotrigine group and 16 in placebo group) met escape criteria, and 2 (both in the lamotrigine group) prematurely withdrew because of protocol violations. The reasons for exclusion were reported.
Selective reporting (reporting bias)	Low risk	All expected and pre‐specified outcomes were reported. Protocol was not available.
Other bias	Unclear risk	This study was sponsored by GlaxoSmithKline, the manufactures of LTG.

Schachter 1995

Methods	Randomised, double‐blind, parallel‐group study. Two treatment arms: 1 placebo, 1 lamotrigine. Patients were randomised to lamotrigine or placebo in a ratio of 3:1. Pre‐randomisation baseline = 4 weeks. Treatment phase = 24 weeks. Taper and follow‐up = 3 weeks.
Participants	A 34 centre US study with 446 participants with refractory drug‐resistant partial seizures: 334 were randomised to lamotrigine and 112 to placebo. There were 236 men and 210 women. The mean age was 35 years (range 18 to 64). The mean duration of epilepsy was 21 years, median age at onset: 12 years in the lamotrigine group and 11.5 in the placebo group. Maximum number of other AEDs = 3. Concomitant valproate therapy was not permitted.
Interventions	Add‐on lamotrigine or placebo. Lamotrigine dose up to 500 mg/day.
Outcomes	(1) Withdrawals from treatment. (2) Adverse effects.
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated random permuted blocks.
Allocation concealment (selection bias)	Low risk	Participants were allocated by sequentially numbered, sealed packages containing either lamotrigine or placebo.
Blinding (performance bias and detection bias) All outcomes	Low risk	Neurologists, participants and parents were blinded. Investigators were blinded. Identical tablets and packaging used.
Incomplete outcome data (attrition bias)	Low risk	No participants were excluded from analysis. 73 participants withdrew from the study; 53 receiving lamotrigine and 20 receiving placebo. The reasons for exclusion were reported.
Selective reporting (reporting bias)	Low risk	All outcomes stated in methods section of paper were reported in the results. There was no protocol available to check a priori outcomes.
Other bias	Unclear risk	This study was sponsored by GlaxoSmithKline, the manufactures of LTG.

Schapel 1993

Methods	Randomised, double‐blind, cross‐over study. Two treatment arms: 1 placebo, 1 lamotrigine. Pre‐randomization baseline = 12 weeks. Treatment I and II = 12 weeks each. Washout I and II = 4 weeks each, including 1 week taper.
Participants	Multicentre Australian study. 41 participants (21 males and 20 females) with drug‐resistant partial seizures 20 were randomised to receive placebo and 21 to lamotrigine. The age ranged from 17 to 63 (median 28) years. The mean age at onset was 10.4 +/‐9.6 years. Maximum number of other AEDs permitted = 3. People receiving valproate monotherapy were excluded.
Interventions	Add‐on lamotrigine or placebo. Median daily dose of lamotrigine was 300 mg. Participants receiving valproate received lower doses.
Outcomes	(1) 50% responder rates. (2) Withdrawal from study for any reason. (3) Adverse effects.
Notes	Banks 1991 is linked to this study and investigated cognitive functions (concentration and attention; general cerebral efficiency; mnestic function).
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated random permuted blocks.
Allocation concealment (selection bias)	Low risk	Participants were allocated by sequentially numbered, sealed packages containing either lamotrigine or placebo.
Blinding (performance bias and detection bias) All outcomes	Unclear risk	No details provided regarding blinding of participants, study personnel, and outcome assessors. All treatments and packaging were identical. Pre‐packed coded medication dispensed by pharmacy.
Incomplete outcome data (attrition bias)	Low risk	No participants were excluded from analysis. None withdrew from the study.
Selective reporting (reporting bias)	Low risk	Protocol unavailable, but appears all expected and pre‐specified outcomes were reported.
Other bias	Unclear risk	This study was sponsored by GlaxoSmithKline, the manufactures of LTG.

Schmidt 1993

Methods	Randomised, double‐blind, cross‐over study. Two treatment arms: 1 placebo, 1 lamotrigine. Pre‐randomisation baseline not known. Treatment I and II = 12 weeks each, including 2‐week tapering period. Washout = 2 weeks .
Participants	Single centre German study. 23 adults (11 men and 12 women) with drug‐resistant partial seizures. 11 were randomised to receive lamotrigine and 12 to placebo in the initial treatment phase. Age of participants ranged from 16 to 62 years. Maximum number of other AEDs permitted was 2.
Interventions	Add‐on lamotrigine or placebo. Dosage varied from 50 mg to 450 mg (median dose was 300 mg).
Outcomes	(1) 50% responder rates. (2) Withdrawal from study for any reason. (3) Adverse effects.
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated random permuted blocks.
Allocation concealment (selection bias)	Low risk	Participants were allocated by sequentially numbered, sealed packages containing either lamotrigine or placebo.
Blinding (performance bias and detection bias) All outcomes	Unclear risk	No details provided regarding blinding of participants and parents. Unblinded investigator wrote prescriptions based on plasma concentration. Identical tablets and packaging were used.
Incomplete outcome data (attrition bias)	Low risk	No participants were excluded from analysis. 1 participant receiving lamotrigine and 9 receiving placebo withdrew from the study. The reasons for exclusion were reported.
Selective reporting (reporting bias)	Low risk	Protocol unavailable, but appears all expected and pre‐specified outcomes were reported.
Other bias	Unclear risk	This study was sponsored by GlaxoSmithKline, the manufactures of LTG.

Smith 1993

Methods	Randomised, double‐blind, cross‐over study. Two treatment arms: 1 placebo, 1 lamotrigine. Pre‐randomisation baseline = 4 weeks. Treatment I and II = 18 weeks each. Washout = 6 weeks.
Participants	Single centre UK study. 81 participants with drug‐resistant partial epilepsy (33 men and 48 women). 41 were randomised to lamotrigine and 40 to placebo in the initial treatment phase. The age range was 15 to 67 years (mean 33.7); duration of epilepsy ranged from 4 to 45 years (mean 21). The mean age at onset was 11.8 years (<1 to 52 years). Maximum number of other AEDS permitted was 2.
Interventions	Add‐on lamotrigine or placebo. Lamotrigine dose up to 400 mg/day. Median daily dose was 300 mg. Participants on valproate received lower doses.
Outcomes	(1) 50% responder rates. (2) Withdrawal from study for any reason. (3) Adverse effects. (4) Health‐related quality of life (HRQL).
Notes	HRQL model was completed by 40 to 54 of 81 participants.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer generated random permuted blocks.
Allocation concealment (selection bias)	Low risk	Partecipants were allocated sequentially numbered, sealed packages containing either lamotrigine or placebo.
Blinding (performance bias and detection bias) All outcomes	High risk	Patients (46/73) and investigators (52/73) were able to identify lamotrigine treatment. Identical tablets and packaging were used. Prepacked coded medication dispensed by pharmacy.
Incomplete outcome data (attrition bias)	Unclear risk	No participants were excluded from analysis. 9 people withdrew from the study; 6 receiving lamotrigine and 3 receiving placebo. The reasons for exclusion were reported. Patients who discontinued prematurely did not complete the HRQOL measure at the time of discontinuation, the exclusion of treatment failures may introduce a bias in favour of lamotrigine.
Selective reporting (reporting bias)	Low risk	Protocol unavailable, but appears all expected and pre‐specified outcomes were reported.
Other bias	Unclear risk	This study was sponsored by GlaxoSmithKline, the manufactures of LTG.

AED: antiepileptic drug

LTG: lamotrigine

Characteristics of excluded studies [ordered by study ID]

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included studies

Study	Reason for exclusion
Biton 2010	Ineligible population: subjects included had primary generalized epilepsy and not partial seizures
Biton 2013	Inelegible population: subjects included in the study had uncontrolled partial epilepsy and generalised tonic‐clonic seizures.
Brzakovic 2012	Inelegible population: subjects included in the study had uncontrolled partial epilepsy and generalised tonic‐clonic seizures.
Carignani 2004	Published as conference abstract: details of the methods and results are not available.
Carignani 2006	Published as conference abstract: details of the methods and results are not available.
Cramer 2013	Not randomised controlled trial.
French 2012	No randomised controlled trial.
Girolineto 2012	Comparative study among therapeutic equivalents of lamotrigine. Not placebo controlled.
Hammer 2008	Published as conference abstract: details of the methods and results are not available.
Hartung 2012	Inelegible population: subjects included in the study had epilepsy, migraine, pain, psychiatric disorders.
Helmstaedter 2013	Subjects included in the study had all epileptic types. Lacosamide as add‐on for epilepsy and in comparison with lamotrigine and topiramate.
Kang 2012	Inelegible population: subjects included in the study had all epileptic types.
Montouris 2007	Published as conference abstract: details of the methods and results are not available.
Ohtahara 2007	Comparative study of lamotrigine and zonisamide. Not placebo controlled
Sander 1990	Study of institutionalised people with severe epilepsy. Subjects included in the study had all epileptic types.
Semah 2014	No LTG add‐on.
Stolarek 1994	Details of the results are not available.
Tomson 2012	Published as conference abstract: details of the methods and results are not available.
Tomson 2013	Not randomised controlled trial.
Veendrick 2000	Published as conference abstract: details of the methods and results are not available.
Yamamoto 2012	Not randomised controlled trial.

AED: antiepileptic drug

Data and analyses

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Comparison 1. Efficacy of add‐on lamotrigine versus placebo ‐ 50% responders

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Intention‐to‐treat analysis Show forest plot	12		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.1 Comparison 1 Efficacy of add‐on lamotrigine versus placebo ‐ 50% responders, Outcome 1 Intention‐to‐treat analysis.
1.1 Cross‐over	8	382	Risk Ratio (M‐H, Fixed, 95% CI)	2.58 [1.44, 4.61]
1.2 Parallel group lamotrigine ‐ 300 mg	1	144	Risk Ratio (M‐H, Fixed, 95% CI)	1.23 [0.57, 2.67]
1.3 Parallel group lamotrigine ‐ 500 mg	1	145	Risk Ratio (M‐H, Fixed, 95% CI)	2.13 [1.08, 4.20]
1.4 Parallel group (children)	1	199	Risk Ratio (M‐H, Fixed, 95% CI)	2.64 [1.59, 4.38]
1.5 Parallel Group ‐Adults‐Lamotrigine ER	1	243	Risk Ratio (M‐H, Fixed, 95% CI)	1.70 [1.16, 2.50]
1.6 Parallel Group 300 to 600mg	1	282	Risk Ratio (M‐H, Fixed, 95% CI)	1.13 [0.74, 1.75]
1.7 Any dose lamotrigine, adults or children	12	1322	Risk Ratio (M‐H, Fixed, 95% CI)	1.80 [1.45, 2.23]
2 Worst case scenario Show forest plot	12	1322	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.82, 1.15]
Open in figure viewer Analysis 1.2 Comparison 1 Efficacy of add‐on lamotrigine versus placebo ‐ 50% responders, Outcome 2 Worst case scenario.
3 Best case scenario Show forest plot	12	1322	Risk Ratio (M‐H, Fixed, 95% CI)	2.88 [2.36, 3.50]
Open in figure viewer Analysis 1.3 Comparison 1 Efficacy of add‐on lamotrigine versus placebo ‐ 50% responders, Outcome 3 Best case scenario.

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Comparison 2. Treatment withdrawal (global outcome)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Withdrawal from treatment Show forest plot	14	1805	Risk Ratio (M‐H, Fixed, 95% CI)	1.11 [0.90, 1.36]
Open in figure viewer Analysis 2.1 Comparison 2 Treatment withdrawal (global outcome), Outcome 1 Withdrawal from treatment.
1.1 Parallel studies ‐ adults	4	1186	Risk Ratio (M‐H, Fixed, 95% CI)	1.16 [0.90, 1.50]
1.2 Parallel studies in children	1	199	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.42, 1.52]
1.3 Cross‐over studies	8	382	Risk Ratio (M‐H, Fixed, 95% CI)	1.82 [0.89, 3.72]
1.4 Parallel Studies in Infants	1	38	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.45, 1.06]

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Comparison 3. Adverse effects

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Ataxia Show forest plot	12	1524	Risk Ratio (M‐H, Fixed, 99% CI)	3.34 [2.01, 5.55]
Open in figure viewer Analysis 3.1 Comparison 3 Adverse effects, Outcome 1 Ataxia.
1.1 Parallel studies ‐ adults	3	943	Risk Ratio (M‐H, Fixed, 99% CI)	3.40 [1.67, 6.90]
1.2 Parallel studies ‐ children	1	199	Risk Ratio (M‐H, Fixed, 99% CI)	5.15 [0.72, 36.64]
1.3 Cross‐over studies	8	382	Risk Ratio (M‐H, Fixed, 99% CI)	2.98 [1.38, 6.41]
2 Dizziness Show forest plot	13	1767	Risk Ratio (M‐H, Fixed, 99% CI)	2.00 [1.51, 2.64]
Open in figure viewer Analysis 3.2 Comparison 3 Adverse effects, Outcome 2 Dizziness.
2.1 Parallel studies ‐ adults	4	1186	Risk Ratio (M‐H, Fixed, 99% CI)	2.09 [1.49, 2.94]
2.2 Parallel studies ‐ children	1	199	Risk Ratio (M‐H, Fixed, 99% CI)	4.33 [1.27, 14.79]
2.3 Cross‐over studies	8	382	Risk Ratio (M‐H, Fixed, 99% CI)	1.41 [0.83, 2.38]
3 Fatigue Show forest plot	12	1551	Risk Ratio (M‐H, Fixed, 99% CI)	0.82 [0.55, 1.22]
Open in figure viewer Analysis 3.3 Comparison 3 Adverse effects, Outcome 3 Fatigue.
3.1 Parallel studies ‐ adults	3	970	Risk Ratio (M‐H, Fixed, 99% CI)	0.81 [0.46, 1.42]
3.2 Parallel studies ‐ children	1	199	Risk Ratio (M‐H, Fixed, 99% CI)	1.89 [0.54, 6.63]
3.3 Cross‐over studies	8	382	Risk Ratio (M‐H, Fixed, 99% CI)	0.65 [0.34, 1.23]
4 Nausea Show forest plot	12	1486	Risk Ratio (M‐H, Fixed, 99% CI)	1.81 [1.22, 2.68]
Open in figure viewer Analysis 3.4 Comparison 3 Adverse effects, Outcome 4 Nausea.
4.1 Parallel Studies ‐ adults	3	905	Risk Ratio (M‐H, Fixed, 99% CI)	1.68 [1.02, 2.78]
4.2 Parallel studies ‐ children	1	199	Risk Ratio (M‐H, Fixed, 99% CI)	5.67 [0.81, 39.69]
4.3 Cross‐over studies	8	382	Risk Ratio (M‐H, Fixed, 99% CI)	1.67 [0.85, 3.29]
5 Somnolence Show forest plot	13	1767	Risk Ratio (M‐H, Fixed, 99% CI)	1.39 [0.96, 2.00]
Open in figure viewer Analysis 3.5 Comparison 3 Adverse effects, Outcome 5 Somnolence.
5.1 Parallel studies ‐ adults	4	1186	Risk Ratio (M‐H, Fixed, 99% CI)	1.58 [0.93, 2.67]
5.2 Parallel studies ‐ children	1	199	Risk Ratio (M‐H, Fixed, 99% CI)	1.37 [0.67, 2.81]
5.3 Cross‐over studies	8	382	Risk Ratio (M‐H, Fixed, 99% CI)	1.06 [0.51, 2.17]
6 Diplopia Show forest plot	3	943	Risk Ratio (M‐H, Fixed, 99% CI)	3.79 [2.15, 6.68]
Open in figure viewer Analysis 3.6 Comparison 3 Adverse effects, Outcome 6 Diplopia.
7 Headache Show forest plot	5	1385	Risk Ratio (M‐H, Fixed, 99% CI)	1.13 [0.87, 1.45]
Open in figure viewer Analysis 3.7 Comparison 3 Adverse effects, Outcome 7 Headache.

Figure 1

Study flow diagram for update.

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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Analysis 1.1

Comparison 1 Efficacy of add‐on lamotrigine versus placebo ‐ 50% responders, Outcome 1 Intention‐to‐treat analysis.

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Analysis 1.2

Comparison 1 Efficacy of add‐on lamotrigine versus placebo ‐ 50% responders, Outcome 2 Worst case scenario.

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Analysis 1.3

Comparison 1 Efficacy of add‐on lamotrigine versus placebo ‐ 50% responders, Outcome 3 Best case scenario.

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Analysis 2.1

Comparison 2 Treatment withdrawal (global outcome), Outcome 1 Withdrawal from treatment.

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Analysis 3.1

Comparison 3 Adverse effects, Outcome 1 Ataxia.

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Analysis 3.2

Comparison 3 Adverse effects, Outcome 2 Dizziness.

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Analysis 3.3

Comparison 3 Adverse effects, Outcome 3 Fatigue.

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Analysis 3.4

Comparison 3 Adverse effects, Outcome 4 Nausea.

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Analysis 3.5

Comparison 3 Adverse effects, Outcome 5 Somnolence.

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Analysis 3.6

Comparison 3 Adverse effects, Outcome 6 Diplopia.

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Analysis 3.7

Comparison 3 Adverse effects, Outcome 7 Headache.

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Lamotrigine versus placebo for drug‐resistant partial epilepsy
Patient or population: participants with drug‐resistant partial epilepsy Settings: outpatient setting Intervention: Lamotrigine versus placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Lamotrigine
50% or greater reduction in seizure frequency ‐ ITT analysis	157 per 1000	283 per 1000 (223 to 350)	RR 1.80 (95% CI 1.45 to 2.23)	1322 (12 studies)	⊕⊕⊕⊕ high¹	RR >1 indicates outcome is more likely in Lamotrigine group
Treatment withdrawal	159 per 1000	176 per 1000 (143 to 216)	RR 1.11 (95% CI 0.90 to 1.36)	1805 (14 studies)	⊕⊕⊕⊕ high²	RR >1 indicates outcome is more likely in Lamotrigine group
Ataxia	45 per 1000	150 per 1000 (90 to 250)	RR 3.34 (99% CI 2.01 to 5.55)	1524 (12 studies)	⊕⊕⊕⊝ moderate³	RR >1 indicates outcome is more likely in Lamotrigine group
Dizziness	128 per 1000	256 per 1000 (193 to 338)	RR 2.00 (99% CI 1.51 to 2.64)	1767 (13 studies)	⊕⊕⊕⊕ high¹	RR >1 indicates outcome is more likely in Lamotrigine group
Fatigue	113 per 1000	93 per 1000 (62 to 138)	RR 0.82 (99% CI 0.55 to 1.22)	1551 (12 studies)	⊕⊕⊕⊕ high¹	RR >1 indicates outcome is more likely in Lamotrigine group
Nausea	83 per 1000	150 per 1000 (101 to 222)	RR 1.81 (99% CI 1.22 to 2.68)	1486 (12 studies)	⊕⊕⊕⊕ high¹	RR >1 indicates outcome is more likely in Lamotrigine group
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes⁴. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk Ratio.
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ One or two studies do not contribute to the analysis, but no other bias. ² All studies contributed to the analysis. ³ Wide confidence intervals. ⁴Assumed risk is calculated as the event rate in the control group per 1000 people (number of events divided by the number of participants receiving control treatment).

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Table 1. Cognitive outcomes

Outcome	Study	Number tested	Lamotrigine mean	Placebo mean
Stroop time	Smith 1993	41	93.98	98.39
Stroop error	Smith 1993	44	2.18	2.41
Stroop colour word (Total score)	Banks 1991	10	32.4+/‐10.9	35.6+/‐9.42
Number cancellation: AC	Smith 1993	44	51.36	49.7
Number cancellation: AE	Smith 1993	43	3.6	3.04
Number cancellation: BC	Smith 1993	42	48.21	48.54
Number cancellation: C	Smith 1993	42	38.19	39.29
Critical flicker fusion	Smith 1993	40	30.44	30.37
Choice reaction time	Smith 1993	40	0.675	0.669
Digit symbol (Scaled score)	Banks 1991	10	5 +/‐2.45	6.6 +/‐ 2.71
Rey complex figure recall percentile	Banks 1991	10	22+/‐17.51	30.5+/‐27.33
Trail making part B percentile	Banks 1991	10	26+/‐30.35	30.5+/‐32.09

Table 1. Cognitive outcomes

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Table 2. Health related quality of life outcomes (Smith 1993)

Outcome	Number tested	Lamotrigine ‐ Mean	Placebo ‐ Mean	Clinical relevance
PSYCHOLOGICAL:
Depression	54	4.24	4.26	No significant difference
Happiness	51	3.8	1.96	Higher scores in LTG group; P = 0.003
Mood	50	24.36	26.8	No significant difference
Self‐esteem	50	30.06	29.16	No significant difference
Mastery	50	20.02	18.78	Higher scores in LTG group; P = 0.003
Anxiety	54	6.87	6.83	No significant difference
PHYSICAL (Nottingham Health Profile):
Energy	53	0.68	0.68	No significant difference
Pain	53	0.6	0.69	No significant difference
Emotional reaction	53	1.96	1.96	No significant difference
Sleep	53	0.89	0.76	No significant difference
Social isolation	53	0.92	0.94	No significant difference
Physical mobility	53	0.96	0.91	No significant difference
SEIZURE SEVERITY SCALE:
Percept	53	25.19	25.47	No significant difference
Ictal	53	19.47	20.53	Less severe seizures in LTG group; P = 0.017
Caregivers	53	20.35	21.80	Less severe seizures in LTG group; P = 0.035

Table 2. Health related quality of life outcomes (Smith 1993)

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Comparison 1. Efficacy of add‐on lamotrigine versus placebo ‐ 50% responders

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Intention‐to‐treat analysis Show forest plot	12		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 Cross‐over	8	382	Risk Ratio (M‐H, Fixed, 95% CI)	2.58 [1.44, 4.61]
1.2 Parallel group lamotrigine ‐ 300 mg	1	144	Risk Ratio (M‐H, Fixed, 95% CI)	1.23 [0.57, 2.67]
1.3 Parallel group lamotrigine ‐ 500 mg	1	145	Risk Ratio (M‐H, Fixed, 95% CI)	2.13 [1.08, 4.20]
1.4 Parallel group (children)	1	199	Risk Ratio (M‐H, Fixed, 95% CI)	2.64 [1.59, 4.38]
1.5 Parallel Group ‐Adults‐Lamotrigine ER	1	243	Risk Ratio (M‐H, Fixed, 95% CI)	1.70 [1.16, 2.50]
1.6 Parallel Group 300 to 600mg	1	282	Risk Ratio (M‐H, Fixed, 95% CI)	1.13 [0.74, 1.75]
1.7 Any dose lamotrigine, adults or children	12	1322	Risk Ratio (M‐H, Fixed, 95% CI)	1.80 [1.45, 2.23]
2 Worst case scenario Show forest plot	12	1322	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.82, 1.15]

3 Best case scenario Show forest plot	12	1322	Risk Ratio (M‐H, Fixed, 95% CI)	2.88 [2.36, 3.50]

Comparison 1. Efficacy of add‐on lamotrigine versus placebo ‐ 50% responders

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Comparison 2. Treatment withdrawal (global outcome)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Withdrawal from treatment Show forest plot	14	1805	Risk Ratio (M‐H, Fixed, 95% CI)	1.11 [0.90, 1.36]

1.1 Parallel studies ‐ adults	4	1186	Risk Ratio (M‐H, Fixed, 95% CI)	1.16 [0.90, 1.50]
1.2 Parallel studies in children	1	199	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.42, 1.52]
1.3 Cross‐over studies	8	382	Risk Ratio (M‐H, Fixed, 95% CI)	1.82 [0.89, 3.72]
1.4 Parallel Studies in Infants	1	38	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.45, 1.06]

Comparison 2. Treatment withdrawal (global outcome)

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Comparison 3. Adverse effects

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Ataxia Show forest plot	12	1524	Risk Ratio (M‐H, Fixed, 99% CI)	3.34 [2.01, 5.55]

1.1 Parallel studies ‐ adults	3	943	Risk Ratio (M‐H, Fixed, 99% CI)	3.40 [1.67, 6.90]
1.2 Parallel studies ‐ children	1	199	Risk Ratio (M‐H, Fixed, 99% CI)	5.15 [0.72, 36.64]
1.3 Cross‐over studies	8	382	Risk Ratio (M‐H, Fixed, 99% CI)	2.98 [1.38, 6.41]
2 Dizziness Show forest plot	13	1767	Risk Ratio (M‐H, Fixed, 99% CI)	2.00 [1.51, 2.64]

2.1 Parallel studies ‐ adults	4	1186	Risk Ratio (M‐H, Fixed, 99% CI)	2.09 [1.49, 2.94]
2.2 Parallel studies ‐ children	1	199	Risk Ratio (M‐H, Fixed, 99% CI)	4.33 [1.27, 14.79]
2.3 Cross‐over studies	8	382	Risk Ratio (M‐H, Fixed, 99% CI)	1.41 [0.83, 2.38]
3 Fatigue Show forest plot	12	1551	Risk Ratio (M‐H, Fixed, 99% CI)	0.82 [0.55, 1.22]

3.1 Parallel studies ‐ adults	3	970	Risk Ratio (M‐H, Fixed, 99% CI)	0.81 [0.46, 1.42]
3.2 Parallel studies ‐ children	1	199	Risk Ratio (M‐H, Fixed, 99% CI)	1.89 [0.54, 6.63]
3.3 Cross‐over studies	8	382	Risk Ratio (M‐H, Fixed, 99% CI)	0.65 [0.34, 1.23]
4 Nausea Show forest plot	12	1486	Risk Ratio (M‐H, Fixed, 99% CI)	1.81 [1.22, 2.68]

4.1 Parallel Studies ‐ adults	3	905	Risk Ratio (M‐H, Fixed, 99% CI)	1.68 [1.02, 2.78]
4.2 Parallel studies ‐ children	1	199	Risk Ratio (M‐H, Fixed, 99% CI)	5.67 [0.81, 39.69]
4.3 Cross‐over studies	8	382	Risk Ratio (M‐H, Fixed, 99% CI)	1.67 [0.85, 3.29]
5 Somnolence Show forest plot	13	1767	Risk Ratio (M‐H, Fixed, 99% CI)	1.39 [0.96, 2.00]

5.1 Parallel studies ‐ adults	4	1186	Risk Ratio (M‐H, Fixed, 99% CI)	1.58 [0.93, 2.67]
5.2 Parallel studies ‐ children	1	199	Risk Ratio (M‐H, Fixed, 99% CI)	1.37 [0.67, 2.81]
5.3 Cross‐over studies	8	382	Risk Ratio (M‐H, Fixed, 99% CI)	1.06 [0.51, 2.17]
6 Diplopia Show forest plot	3	943	Risk Ratio (M‐H, Fixed, 99% CI)	3.79 [2.15, 6.68]

7 Headache Show forest plot	5	1385	Risk Ratio (M‐H, Fixed, 99% CI)	1.13 [0.87, 1.45]

Comparison 3. Adverse effects

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References

References to studies included in this review

Baulac 2010 {published data only}

Binnie 1989 {published data only}

Boas 1996 {published and unpublished data}

Duchowny 1999 {published data only}

Jawad 1989 {published data only}

Loiseau 1990 {published data only}

Matsuo 1993 {published data only}

Messenheimer 1994 {published data only}

Naritoku 2007 {published data only}

Piña‐Garza 2008 {published data only}

Schachter 1995 {published and unpublished data}

Schapel 1993 {published and unpublished data}

Schmidt 1993 {published and unpublished data}

Smith 1993 {published and unpublished data}

References to studies excluded from this review

Biton 2010 {published data only}

Biton 2013 {published data only}

Brzakovic 2012 {published data only}

Carignani 2004 {published data only}

Carignani 2006 {published data only}

Cramer 2013 {published data only}

French 2012 {published data only}

Girolineto 2012 {published data only}

Hammer 2008 {published data only}

Hartung 2012 {published data only}

Helmstaedter 2013 {published data only}

Kang 2012 {published data only}

Montouris 2007 {published data only}

Ohtahara 2007 {published data only}

Sander 1990 {published data only}

Semah 2014 {published data only}

Stolarek 1994 {published data only}

Tomson 2012 {published data only}

Tomson 2013 {published data only}

Veendrick 2000 {published data only}

Yamamoto 2012 {published data only}

Additional references

Banks 1991

Barker‐Haliski 2014

Cockerell 1995

Commission 1989

Fisher 2005

GRADEpro 2014 [Computer program]

Hauser 1993

Higgins 2011

Kirkham 2010

Leach 1995

Lefebvre 2011

Loscher 2002

Lyer 2014

Moore 2012

Mula 2013

Panebianco 2015

RevMan 2014 [Computer program]

Vajda 2013

West 2015

References to other published versions of this review

Ramaratnam 2001

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Characteristics of excluded studies [ordered by study ID]

Data and analyses

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