Zonisamide add‐on for drug‐resistant partial epilepsy

Katie Carmichael; Jennifer Pulman; Shaheen Emmanuel Lakhan; Prachi Parikh; Anthony G Marson

doi:10.1002/14651858.CD001416.pub3

Tratamiento complementario con zonisamida para la epilepsia parcial resistente a fármacos

Collapse all Expand all

References

References to studies included in this review

Jump to:

excluded studies
awaiting assessment
additional references
other published versions

Brodie MJ, Duncan R, Vespignani H, Solyom A, Bitensky V. Zonisamide is a effective adjunctive therapy for patients with refractory partial epilepsy: results from a randomised, double‐blind, placebo‐controlled study. Epilepsia 2004;45(Suppl 3):155.

Google Scholar

Brodie MJ, Duncan R, Vespignani H, Solyom A, Bitenskyy V, Lucas C. Dose‐dependent safety and efficacy of zonisamide: a randomized, double‐blind, placebo‐controlled study in patients with refractory partial seizures. Epilepsia 2005;46(1):31‐41.

Brodie MJ, Vespignani H. Efficacy of zonisamide against refractory partial seizures in an evaluable patient population. Epilepsia 2005;46(Suppl 6):117‐8.

Brodie MJ, Vespignani H, Solyom A, Bitensky V. Dose‐dependent safety and efficacy of zonisamide in refractory, localization‐related epilepsy: a randomized, double‐blind, placebo‐controlled trial. Epilepsia 2004;45(Suppl 7):131.

Faught E, Ayala R, Montouris G, Leppik IE. Randomized controlled trial of zonisamide for the treatment of refractory partial‐onset seizures. Neurology 2001;57(10):1774‐9.

Lu Y, Xiao Z, Yu W, Xiao F, Xiao Z, Hu Y, et al. Efficacy and safety of adjunctive zonisamide in adult patients with refractory partial‐onset epilepsy. Clinical Drug Investigation 2011;31(4):221‐9.

Sackellares JC, Ramsay RE, Wilder BJ, Browne III TR, Shellenberger MK. Randomized, controlled clinical trial of zonisamide as adjunctive treatment for refractory partial seizures. Epilepsia 2004;45(6):610‐7.

Wilder BJ, Ramsay RE, Guterman A. A double blind multicenter placebo controlled study of the efficacy of zonisamide in the treatment of complex partial seizures in medically refractory patients. Internal report of the Dainippon Pharmaceutical Company1986.

Google Scholar

Schmidt D, Jacob R, Loiseau P, Deisenhammer E, Klinger D, Despland A, et al. Zonisamide for add‐on treatment of refractory partial epilepsy: a European double blind trial. Epilepsy Research 1993;15(1):67‐73.

References to studies excluded from this review

Jump to:

included studies
awaiting assessment
additional references
other published versions

Shimizu A, Yamamoto J, Yamada Y, Tanaka M, Kawasaki T. The antiepileptic effect of zonisamide on patients with refractory seizures and its side effects. Japanese Journal of Psychiatry and Neurology 1988;42(3):583.

References to studies awaiting assessment

Jump to:

included studies
excluded studies
additional references
other published versions

Anderson TJ, Donaldson IM, McConnell H, Pollock M, Dobbs BR. Zonisamide: comparison with sodium valproate as additional treatment in refractory seizures. New Zealand Medical Journal 1988;101(854):611.

Google Scholar

Additional references

Jump to:

included studies
excluded studies
awaiting assessment
other published versions

Baulac M, Leppik IE. Efficacy and safety of adjunctive zonisamide therapy for refractory partial seizures. Epilepsy Research 2007;75:75‐83.

British National Formulary. www.bnf.org(accessed May 2013).

Cockerell OC, Johnson AL, Sander JW, Hart YM, Shorvon SD. Remission of epilepsy: results from the National General Practice Study of Epilepsy. Lancet 1995;346:140‐4.

Hauser WA, Annegers JF, Kurland LT. Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota 1935 ‐ 1984. Epilepsia 1993;34:453‐68.

Higgins JPT, Altman DG, Sterne JAC (editors). Chapter 8: Assessing risk of bias in included studies. Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane‐handbook.org.

Lefebvre C, Manheimer E, Glanville J. Chapter 6: Searching for studies. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.2 [updated September 2009]. The Cochrane Collaboration, 2009. Available from www.cochrane‐handbook.org.

Leppik IE. Zonisamide: chemistry, mechanism of action, and pharmacokinetics. Seizure 2004;S13:S5‐S9.

Marson AG, Williamson PR, Hutton JL, Clough HE, Chadwick DW. Carbamazepine versus valproate monotherapy for epilepsy. Cochrane Database of Systematic Reviews 2000, Issue 3. [DOI: 10.1002/14651858.CD001030]

Marson A, Al‐Kharusi A, Alwaidh M, Appleton R, Baker GA, Chadwick DW, et al. The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial. The Lancet 2007;369(9566):1000‐15.

McCullagh P, Nelder JA. Generalized Linear Models. Second Edition. London: Chapman and Hall, 1989.

Mori A, Noda Y, Packer L. The anticonvulsant zonisamide scavenges free radicals. Epilepsy Research 1998;30:153‐8.

Sander JW, Shorvon SD. Epidemiology of the epilepsies. Journal of Neurology, Neurosurgery, and Psychiatry 1996;61(5):433‐43.

Ueda Y, Doi T, Tokumaru J, Willmore LJ. Effect of zonisamide on molecular regulation of glutamate and GABA transporter proteins during epileptogenesis in rats with hippocampal seizures. Molecular Brain Research 2003;116(1‐2):1‐6.

References to other published versions of this review

Jump to:

included studies
excluded studies
awaiting assessment
additional references

Chadwick DW, Marson AG. Zonisamide add‐on for drug‐resistant partial epilepsy. Cochrane Database of Systematic Reviews 2005, Issue 4. [DOI: 10.1002/14651858.CD001416.pub2]

Marson AG, Kadir ZA, Chadwick DW. The new antiepileptic drugs: a systematic review of their efficacy and tolerability. BMJ 1996;313:1169‐74.

Marson AG, Kadir ZA, Hutton JL, Chadwick DW. The new antiepileptic drugs: a systematic review of their efficacy and tolerability. Epilepsia 1997;38(8):859‐80.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Jump to:

excluded studies
awaiting classification

Brodie 2005

Methods	Randomised, double‐blind, placebo‐controlled, parallel‐group study Allocation concealment using telephone randomisation Random permuted blocks of 6 per participating centre Blinded using identical tablets and packaging 12 week pre‐randomisation baseline period, 24‐week treatment period including 6‐week dose titration
Participants	Multicentre study, 49 centres in Europe and 5 in South Africa 351 participants. At least 12 seizures during 12‐week baseline period, with no period of more than 3 weeks seizure‐free Taking 1 to 3 AEDs Aged 12 to 77 51% male
Interventions	Placebo, 100 mg, 300 mg or 500 mg placebo, randomised in 2:1:1:2 ratio
Outcomes	Reduction in seizure frequency, proportion with a 50% or greater reduction in seizure frequency Adverse events
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Patients were randomised sequentially in blocks of six"
Allocation concealment (selection bias)	Unclear risk	Insufficient details were provided
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"Treatments were blinded using a double dummy technique throughout the study"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient details about blinding of outcome assessors was provided
Incomplete outcome data (attrition bias) All outcomes	Low risk	A modified ITT analysis was conducted as "all patients who received at least one dose of study drug were included in the safety analysis". 4 participants not included in the analysis were spread fairly evenly among groups (1 participant lost from 2 groups, 2 participants lost from 1 group)
Selective reporting (reporting bias)	Low risk	This study was deemed to be at a low risk of selective reporting
Other bias	Low risk	Allocation to groups led to different durations of stable‐dose phase

Faught 2001

Methods	Randomised, double‐blind, placebo‐controlled, parallel‐group study. 2 treatment arms: 1 placebo and 1 zonisamide Randomisation concealment by allocated sequentially numbered, sealed packages. Random list generated by random permuted blocks. Blinding by identical packing and tablets All participants received placebo during 28‐day prospective baseline. Treatment period was 12 weeks. Participants receiving zonisamide were divided into 2 groups, 1 (group B1) of which received 100 mg/day during weeks 1 to 5, the second (group B2) of which received 100 mg/day during week 1 followed by 200 mg/day during weeks 2 to 5. Both groups received an escalating dose of zonisamide for weeks 5 to 7 followed by 400 mg/day during weeks 8 to 12
Participants	Multicentre (20) US study Total randomised: 203 participants between April 1994 and March 1996 with at least 4 partial seizures/month taking 1 or 2 AEDs, 85 to placebo, 60 to group B1, 58 to group B2 Ages 13 to 68 years, 104 male, 99 female Median monthly seizure frequency for the randomised groups during baseline ranged between 11.2 and 13 seizures/month
Interventions	Zonisamide 400 mg/day or placebo (weeks 8 to 12) Zonisamide 100 mg/day or 200 mg/day or placebo (weeks 1 to 5) All treatments and packaging were identical
Outcomes	Primary: median percentage reduction from baseline of all partial seizures Secondary: proportion of participants showing a 50% reduction in all partial seizures from baseline Adverse events
Notes	Of the randomised participants 8 failed to complete week 5 in the placebo group, 15 in the zonisamide group By the end of week 12, 13 participants had withdrawn from the placebo group, 23 from zonisamide
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Randomization codes were generated centrally, with separate randomization sequences for each site."
Allocation concealment (selection bias)	Low risk	"Each investigator had a sealed copy of the code to be opened in an emergency. Otherwise, assignments were not revealed until all patients at all sites had completed the study."
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Insufficient detail was provided about blinding of personnel
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient detail was provided about blinding of outcome assessors
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	The analysis for "the primary populations was a modified ITT" as it included participants who had received at least one dose of study medication
Selective reporting (reporting bias)	Low risk	No evidence of selective reporting
Other bias	Low risk	No evidence of any other source of bias

Lu 2011

Methods	Randomised, double‐blind, placebo‐controlled, parallel trial. 12‐week baseline phase, 4‐week titration phase, 12‐week stable treatment phase. Placebo or zonisamide treatment interventions
Participants	Single centre in China. 104 participants randomised, 53 received zonisamide (29 M:24 F) and 51 received placebo (32 M: 19 F). Mean age of zonisamide group = 36.83 years +/‐ 10.77 and mean age in placebo group = 29.81 years +/‐ 8.24. All participants had simple partial seizures, complex partial seizures or secondary generalised seizures
Interventions	Placebo or zonisamide (titrated to 300 mg/day or 400 mg/day)
Outcomes	The following outcomes were measured: 1. Responder rate (50% or greater reduction in seizures frequency during treatment phase compared to baseline) 2. Seizure freedom 3. Adverse effects
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No information given other than "zonisamide and placebo were assigned to our centre in a ratio of 1:1" (page 223)
Allocation concealment (selection bias)	Low risk	"Random allocation of patients to their treatment group was concealed via the use of numbered containers" Comment: it is not explicitly stated whether the containers were opaque or not
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"Investigators were blind to treatment each patient received until the end of the study" and "Zonisamide and placebo tablets had the same size, colour and shape. The tablets were randomly numbered by the study sponsors"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	It is unclear whether the investigators who were blinded were also the outcome assessors or not
Incomplete outcome data (attrition bias) All outcomes	Low risk	One patient was lost from each group, therefore missing data were balanced between groups
Selective reporting (reporting bias)	Low risk	No evidence of selective reporting
Other bias	Low risk	Both providers of zonisamide were manufacturers of the drug

Sackellares 2004

Methods	Randomised, double‐blind, placebo‐controlled, parallel‐group study 2 treatment arms, 1 placebo, 1 zonisamide. The initial target dose of zonisamide was 7 mg/kg/day, but when it became apparent that this was associated with a significant incidence of adverse effects, it was titrated over the first 4 weeks to 400 mg/day. Thereafter a non‐blinded observer recommended dose adjustments to obtain plasma levels of 20 to 30 µg/ml. Median dosage in this group was 400 mg/day (range 200 to 600 mg/day) Randomisation concealment by allocated sequentially numbered, sealed packages. Random list generated by random permuted blocks. Blinding by identical packing and tablets Baseline was variable, between 8 and 12 weeks, being extended if frequency was below 4 partial seizures/month Treatment period was 12 weeks
Participants	Conducted at 4 US centres between August 1983 and July 1986 Total randomised: 152 participants, all with 4 or more partial seizures/month while taking 1 or 2 AEDs. 78 were randomised to zonisamide, 74 to placebo Age 17 to 67 years, 101 male 51 female Median monthly seizure frequency pre‐baseline: 7.5 zonisamide, 11.1 placebo
Interventions	Zonisamide median dosage 400 mg/day (100 mg capsules) Placebo Treatments and packaging were identical
Outcomes	Primary: median percentage reduction in seizure frequency of all partial seizures from baseline Secondary: proportion of participants with a 50% reduction in all partial seizures from baseline
Notes	Because of the variable baseline periods, baseline seizure frequency was recalculated for the 8 weeks immediately before entry into the treatment period 14 people failed to complete the 12‐week treatment period in the zonisamide group, 7 in the placebo group
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Randomisation codes were generated by the study sponsor". "Each patient who qualified to receive double‐blind treatment was assigned a randomisation number and given zonisamide or placebo"
Allocation concealment (selection bias)	Low risk	"Random allocation of patients to their treatment groups was concealed via the use of numbered containers"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	This study was deemed to be at low risk of performance bias
Blinding of outcome assessment (detection bias) All outcomes	Low risk	This study was deemed to be at low risk of detection bias
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Insufficient or unclear details were provided with regard to attrition bias
Selective reporting (reporting bias)	Low risk	No evidence of selective reporting
Other bias	Low risk	Baseline period was extended if the frequency of seizures did not meet a prespecified threshold

Schmidt 1993

Methods	Randomised, double‐blind, placebo‐controlled, parallel group study 2 treatment arms, 1 placebo, 1 zonisamide. The initial target dose of zonisamide was 7 mg/kg/day, but when it became apparent that this was associated with a significant incidence of adverse effects, it was titrated over the first 4 weeks to 400 mg/day. Thereafter a non‐blinded observer recommended dose adjustments to obtain plasma levels of 20 to 30 µg/ml. Median dosage in this group was 400 mg/day Randomisation concealment by allocated sequentially numbered, sealed packages. Random list generated by random permuted blocks. Blinding by identical packing and tablets Baseline was variable, between 8 and 12 weeks, being extended if frequency was below 4 partial seizures/month Treatment period was 12 weeks
Participants	Participants from 10 European centres recruited between June 1984 and October 1986 Total randomised: 144 participants, all with 4 or more partial seizures/month while taking 1 or 2 AEDs. 73 were randomised to zonisamide, 71 to placebo Age 17 to 60 years, 85 male 59 female Median monthly seizure frequency pre‐baseline: 11.3 zonisamide, 11.0 placebo
Interventions	Zonisamide median dosage 400 mg/day (100 mg capsules) Placebo Treatments and packaging were identical
Outcomes	Primary: median percentage reduction in seizure frequency of all partial seizures from baseline Secondary: proportion of participants with a 50% reduction in all partial seizures from baseline
Notes	Because of the variable baseline periods, baseline seizure frequency was recalculated for the 8 weeks immediately before entry into the treatment period 7 people failed to complete the 12‐week treatment period in the zonisamide group, 2 in the placebo group
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Patients were randomised sequentially in blocks of four"
Allocation concealment (selection bias)	Unclear risk	Insufficient details provided
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Insufficient details were provided about blinding of personnel
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Blinding of outcome assessors was not detailed
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	A modified ITT analysis was conducted including patients who had received "at least 7 days of treatment"
Selective reporting (reporting bias)	Low risk	This study was deemed to be at low risk of selective reporting
Other bias	Low risk	Baseline period was extended if the frequency of seizures did not meet a prespecified threshold

AED: antiepileptic drug
F: female
ITT: intention‐to‐treat
M: male

Characteristics of excluded studies [ordered by study ID]

Jump to:

included studies
awaiting classification

Study	Reason for exclusion
Shimizu 1988	No control group was used

Characteristics of studies awaiting assessment [ordered by study ID]

Jump to:

included studies
excluded studies

Anderson 1988

Methods	No details
Participants	No details
Interventions	Zonisamide add‐on versus sodium valproate add‐on
Outcomes	No details
Notes	No details

Data and analyses

Open in table viewer

Comparison 1. Zonisamide versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 50% responder rate ‐ whole treatment period Show forest plot	5		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.1 Comparison 1 Zonisamide versus placebo, Outcome 1 50% responder rate ‐ whole treatment period.
1.1 Any dose	5	949	Risk Ratio (M‐H, Fixed, 95% CI)	1.92 [1.52, 2.42]
1.2 300 to 500 mg zonisamide	5	891	Risk Ratio (M‐H, Fixed, 95% CI)	2.00 [1.58, 2.54]
2 50% responder rate ‐ best‐case Show forest plot	5	949	Risk Ratio (M‐H, Fixed, 95% CI)	2.23 [1.78, 2.79]
Open in figure viewer Analysis 1.2 Comparison 1 Zonisamide versus placebo, Outcome 2 50% responder rate ‐ best‐case.
3 50% responder rate ‐ worst‐case Show forest plot	5	949	Risk Ratio (M‐H, Fixed, 95% CI)	1.42 [1.16, 1.75]
Open in figure viewer Analysis 1.3 Comparison 1 Zonisamide versus placebo, Outcome 3 50% responder rate ‐ worst‐case.
4 50% responder rate ‐ dose effect Brodie 2005 Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 1.4 Comparison 1 Zonisamide versus placebo, Outcome 4 50% responder rate ‐ dose effect Brodie 2005.
4.1 100 mg per day	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.2 300 mg per day	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.3 500 mg per day	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5 50% responder rate ‐ dose effect Faught 2001 Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 1.5 Comparison 1 Zonisamide versus placebo, Outcome 5 50% responder rate ‐ dose effect Faught 2001.
5.1 100 mg per day	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.2 200 mg per day	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.3 400 mg per day	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6 Withdrawal rates Show forest plot	5		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.6 Comparison 1 Zonisamide versus placebo, Outcome 6 Withdrawal rates.
6.1 Any dose	5	949	Risk Ratio (M‐H, Fixed, 95% CI)	1.47 [1.07, 2.01]
6.2 300 to 500 mg zonisamide	5	892	Risk Ratio (M‐H, Fixed, 95% CI)	1.64 [1.20, 2.25]
7 Adverse effects Show forest plot	5		Risk Ratio (M‐H, Fixed, 99% CI)	Subtotals only
Open in figure viewer Analysis 1.7 Comparison 1 Zonisamide versus placebo, Outcome 7 Adverse effects.
7.1 Ataxia	3	494	Risk Ratio (M‐H, Fixed, 99% CI)	3.77 [1.28, 11.11]
7.2 Dizziness	5	949	Risk Ratio (M‐H, Fixed, 99% CI)	1.46 [0.88, 2.44]
7.3 Nausea	4	598	Risk Ratio (M‐H, Fixed, 99% CI)	1.21 [0.61, 2.40]
7.4 Fatigue	4	598	Risk Ratio (M‐H, Fixed, 99% CI)	1.41 [0.76, 2.62]
7.5 Somnolence	5	949	Risk Ratio (M‐H, Fixed, 99% CI)	1.83 [1.08, 3.11]
7.6 Agitation/irritability	4	598	Risk Ratio (M‐H, Fixed, 99% CI)	2.35 [1.05, 5.27]
7.7 Anorexia	3	494	Risk Ratio (M‐H, Fixed, 99% CI)	2.71 [1.29, 5.69]

Figure 1

Study flow diagram.

Navigate to figure in ReviewOpen in new tab

Figure 2

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

Navigate to figure in ReviewOpen in new tab

Analysis 1.1

Comparison 1 Zonisamide versus placebo, Outcome 1 50% responder rate ‐ whole treatment period.

Navigate to figure in ReviewOpen in new tab

Analysis 1.2

Comparison 1 Zonisamide versus placebo, Outcome 2 50% responder rate ‐ best‐case.

Navigate to figure in ReviewOpen in new tab

Analysis 1.3

Comparison 1 Zonisamide versus placebo, Outcome 3 50% responder rate ‐ worst‐case.

Navigate to figure in ReviewOpen in new tab

Analysis 1.4

Comparison 1 Zonisamide versus placebo, Outcome 4 50% responder rate ‐ dose effect Brodie 2005.

Navigate to figure in ReviewOpen in new tab

Analysis 1.5

Comparison 1 Zonisamide versus placebo, Outcome 5 50% responder rate ‐ dose effect Faught 2001.

Navigate to figure in ReviewOpen in new tab

Analysis 1.6

Comparison 1 Zonisamide versus placebo, Outcome 6 Withdrawal rates.

Navigate to figure in ReviewOpen in new tab

Analysis 1.7

Comparison 1 Zonisamide versus placebo, Outcome 7 Adverse effects.

Navigate to figure in ReviewOpen in new tab

Summary of findings for the main comparison. Zonisamide versus placebo for drug‐resistant partial epilepsy

Zonisamide versus placebo for drug‐resistant partial epilepsy
Patient or population: patients with drug‐resistant partial epilepsy Settings: hospital out‐patient setting Intervention: zonisamide versus placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Zonisamide versus placebo
50% responder rate ‐ whole treatment period ‐ any dose	Study population		RR 1.92 (1.52 to 2.42)	949 (5 studies)	⊕⊕⊕⊕ high	3 out of 5 studies found a non‐significant effect of zonisamide on responder rate but the combined overall effect was statistically significant
	191 per 1000	367 per 1000 (290 to 462)
	Moderate
	175 per 1000	336 per 1000 (266 to 424)
Withdrawal rates ‐ any dose	Study population		RR 1.47 (1.07 to 2.01)	949 (5 studies)	⊕⊕⊕⊕ high	No study produced a statistically significant effect of zonisamide on withdrawal rates independently but a statistically significant effect was found overall
	113 per 1000	166 per 1000 (121 to 227)
	Moderate
	95 per 1000	140 per 1000 (102 to 191)
Adverse effects ‐ ataxia	Study population		3.77 (1.28 to 11.11)	494 (3 studies)	⊕⊕⊕⊕ high	No study found a statistically significant effect of zonisamide on ataxia independently, but there was a significant effect when study data were combined
	26 per 1000	100 per 1000 (34 to 294)
	Moderate
	24 per 1000	90 per 1000 (31 to 267)
Adverse effects ‐ dizziness	Study population		1.46 (0.88 to 2.44)	949 (5 studies)	⊕⊕⊕⊕ high	No study found a statistically significant effect of zonisamide on dizziness independently
	88 per 1000	128 per 1000 (77 to 215)
	Moderate
	118 per 1000	172 per 1000 (104 to 288)
Adverse effects ‐ nausea	Study population		1.21 (0.61 to 2.4)	598 (4 studies)	⊕⊕⊕⊕ high	No study found a statistically significant effect of zonisamide on nausea independently
	76 per 1000	91 per 1000 (46 to 181)
	Moderate
	69 per 1000	83 per 1000 (42 to 166)
Adverse effects ‐ fatigue	Study population		1.41 (0.76 to 2.62)	598 (4 studies)	⊕⊕⊕⊕ high	No study found a statistically significant effect of zonisamide on fatigue independently
	86 per 1000	122 per 1000 (66 to 226)
	Moderate
	79 per 1000	111 per 1000 (60 to 207)
Adverse effects ‐ somnolence	Study population		1.83 (1.08 to 3.11)	949 (5 studies)	⊕⊕⊕⊕ high	4 out of 5 studies found no statistically significant difference in the occurrence of somnolence between the zonisamide group and the control group
	75 per 1000	138 per 1000 (81 to 234)
	Moderate
	118 per 1000	216 per 1000 (127 to 367)
Adverse effects ‐ agitation/irritability	Study population		2.35 (1.05 to 5.27)	598 (4 studies)	⊕⊕⊕⊕ high	1 out of 4 studies found a significant effect of zonisamide on agitation/irritability and there was a statistically significant effect overall
	43 per 1000	101 per 1000 (45 to 227)
	Moderate
	44 per 1000	103 per 1000 (46 to 232)
Adverse effects ‐ anorexia	Study population		2.71 (1.29 to 5.69)	494 (3 studies)	⊕⊕⊕⊕ high	None of 3 studies found significant effects of zonisamide on anorexia, but overall there was a significant effect when data were combined
	62 per 1000	167 per 1000 (80 to 351)
	Moderate
	81 per 1000	220 per 1000 (104 to 461)
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. 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.

Summary of findings for the main comparison. Zonisamide versus placebo for drug‐resistant partial epilepsy

Navigate to table in Review

Comparison 1. Zonisamide versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 50% responder rate ‐ whole treatment period Show forest plot	5		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 Any dose	5	949	Risk Ratio (M‐H, Fixed, 95% CI)	1.92 [1.52, 2.42]
1.2 300 to 500 mg zonisamide	5	891	Risk Ratio (M‐H, Fixed, 95% CI)	2.00 [1.58, 2.54]
2 50% responder rate ‐ best‐case Show forest plot	5	949	Risk Ratio (M‐H, Fixed, 95% CI)	2.23 [1.78, 2.79]

3 50% responder rate ‐ worst‐case Show forest plot	5	949	Risk Ratio (M‐H, Fixed, 95% CI)	1.42 [1.16, 1.75]

4 50% responder rate ‐ dose effect Brodie 2005 Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

4.1 100 mg per day	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.2 300 mg per day	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.3 500 mg per day	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5 50% responder rate ‐ dose effect Faught 2001 Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

5.1 100 mg per day	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.2 200 mg per day	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.3 400 mg per day	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6 Withdrawal rates Show forest plot	5		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

6.1 Any dose	5	949	Risk Ratio (M‐H, Fixed, 95% CI)	1.47 [1.07, 2.01]
6.2 300 to 500 mg zonisamide	5	892	Risk Ratio (M‐H, Fixed, 95% CI)	1.64 [1.20, 2.25]
7 Adverse effects Show forest plot	5		Risk Ratio (M‐H, Fixed, 99% CI)	Subtotals only

7.1 Ataxia	3	494	Risk Ratio (M‐H, Fixed, 99% CI)	3.77 [1.28, 11.11]
7.2 Dizziness	5	949	Risk Ratio (M‐H, Fixed, 99% CI)	1.46 [0.88, 2.44]
7.3 Nausea	4	598	Risk Ratio (M‐H, Fixed, 99% CI)	1.21 [0.61, 2.40]
7.4 Fatigue	4	598	Risk Ratio (M‐H, Fixed, 99% CI)	1.41 [0.76, 2.62]
7.5 Somnolence	5	949	Risk Ratio (M‐H, Fixed, 99% CI)	1.83 [1.08, 3.11]
7.6 Agitation/irritability	4	598	Risk Ratio (M‐H, Fixed, 99% CI)	2.35 [1.05, 5.27]
7.7 Anorexia	3	494	Risk Ratio (M‐H, Fixed, 99% CI)	2.71 [1.29, 5.69]

Comparison 1. Zonisamide versus placebo

Navigate to table in Review

	Cochrane Review language Select your preferred language for Cochrane Reviews and other content. Sections without translation will be in English.

	Website language Select your preferred language for the Cochrane Library website.

Cochrane Review language

Website language

References

References to studies included in this review

Brodie 2005 {published data only}

Faught 2001 {published and unpublished data}

Lu 2011 {published data only}

Sackellares 2004 {published data only}

Schmidt 1993 {published and unpublished data}

References to studies excluded from this review

Shimizu 1988 {published data only}

References to studies awaiting assessment

Anderson 1988 {published data only}

Additional references

Baulac 2007

British National Formulary

Cockerell 1995

Hauser 1993

Higgins 2011

Lefebvre 2009

Leppik 2004

Marson 2000

Marson 2007

McCullagh 1989

Mori 1998

Sander 1996

Ueda 2003

References to other published versions of this review

Chadwick 2005

Marson 1996

Marson 1997

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Characteristics of excluded studies [ordered by study ID]

Characteristics of studies awaiting assessment [ordered by study ID]

Data and analyses

Copy or download citation

Cochrane Review language

Website language

Previously accessed institutions

Institutional users

Previously accessed institutions

Other access options