A critical review of the recent literature and selected therapy guidelines since 2006 on the use of lamotrigine in bipolar disorder

Figures & data

Table 1 Included guidelines and a summary of their recommendation for LTG use in depression and mania in acute or maintenance therapy are shown

Therapy guideline	Acute treatment: depression	Acute treatment: mania	Maintenance treatment	Main studies included
NICE guideline^Citation10	Not recommended for initiated single use in BDI	Not recommended	Add-on therapy	Bowden et al^Citation29 Calabrese et al^Citation21,Citation37 Ichim et al^Citation36 Nierenberg et al^Citation35
WFSBP guideline^Citation11^–^Citation15	Level: "B" (2002) Category of Evidence: "B" Recommendation Grade: "3" (2010)	Category of Evidence: "E," negative evidence	Level: "A"	Bowden et al^Citation29,Citation38 Brown et al^Citation25,Citation26 Calabrese et al^Citation21,Citation23,Citation30,Citation64 Fatemi et al^Citation45 Frye et al^Citation24 Goodwin et al^Citation31 Geddes et al^Citation22 Goldsmith et al^Citation5	Hurley^Citation46 Ichim et al^Citation36 Kusumakar and Yatham^Citation47 Nierenberg et al^Citation35 Nolen et al^Citation28 Schaffer et al^Citation27 van der Loos et al^Citation32 Waiden et al^Citation48^–^Citation50
CANMAT and ISBD guideline^Citation9	First-line agent	Not recommended	First line agent, especially for depressive episodes	Calabrese et al^Citation21,Citation23 Frye et al^Citation24 Geddes et al^Citation22 Maina et al51Nolen et al^Citation28 Sharma et al^Citation52 Suppes et al^Citation53
BAP guideline^Citation8	Recommendation Grade "A", Category of Evidence: 1	No information given	Category of evidence: 1, especially for depressive episodes	Bowden et al^Citation38 Calabrese et al^Citation21 Frye et al^Citation24 Geddes et al^Citation22 Goodwin et al^Citation31
S3 guideline^Citation17	Recommendation Grade: "0"	No recommendation possible, insufficient data	Recommendation grade: "B" for depressive episodes No information given for manic episodes	Bowden et al^Citation29,Citation38,Citation54 Brown et al^Citation25,Citation26 Calabrese et al^Citation21,Citation30,Citation37 Dossett et al^Citation55 Frye et al^Citation24 Ghaemi et al^Citation56 Goodwin et al^Citation56 Geddes et al^Citation22 Goldsmith et al^Citation5 Ketteret al^Citation41	Licht et al^Citation43 Mokhber et al^Citation57 Nierenberg et al^Citation35 Nierenberg^Citation58 Nolen et al^Citation28 Rubio et al^Citation59 Schaffer et al^Citation27 Schieber et al^Citation60 Spaulding et al^Citation61 van der Loos et al^Citation32
Ministry of Health clinical practice guidelines: bipolar disorder^Citation16	Add-on treatment in patients already on lithium, Recommendation Grade "A"	Not recommended	When antidepressant effect occurred in acute state, Recommendation grade: "A"	Calabrese et al^Citation23,Citation37,Citation62 Goldsmith et al5Smith et al^Citation44 van der Loos et al^Citation32

Note: Studies cited by guidelines were given.

Abbreviations: LTG, lamotrigine; NICE, National Institute for Health and Clinical Excellence; WFSBP, World Federation of Societies of Biological Psychiatry; CANMAT, Canadian Network for Mood and Anxiety Treatments; ISBD, International Society from Bipolar Disorder; BAP, British Association for Psychopharmacology.

Table 2 Overview of included studies on the use of LTG in BD

Authors	Design	Sample	Duration	Treatment	Results
Bowden et al^Citation38 Jadad:l	Open, multicenter study	75 patients, 41 rapid cycling	48 weeks	LTG: 25 mg/day week 1, increased to 200 mg/day, max 500 mg/day Add-on or monotherapy	MRS, HAM-D, and GAS (all patients): P < 0.05 LOCF: rapid cycling patients improved less in GAS and MRS; no difference in HAM-D change
Bowden et al^Citation25 Jadad:4	Double-blind RCT	175 patients Bipolar 1 Maintenance treatment	72 weeks	LTG (100–400 mg/d)Lithium (serum levels of 0.8-1.1 mEq/L) Monotherapy	LTG versus PLC: P = 0.02Lithium versus PLC: P = 0.03
Brown et al^Citation25 Jadad:4	Double-blind RCT	410 patients Bipolar 1 depression	7 weeks	LTG escalation regimen up to 200 mg/day according to Lamictal package insert^Citation7 GSK, 2005 OFC: 6/25, 12/25, 6/50, or 12/50 mg/day	CGI-S: OFC versus LTG: P = 0.002 overall MMRM, MADRS: OFC versus LTG: P = 0.002, overall MMRM YMRS: OFC versus LTG: P = 0.001, overall MMRM
Brown et al^Citation26 Jadad:4	Double-blind RCT	410 patients Bipolar 1 depression	25 weeks	LTG escalation regimen up to 200 mg/day according to Lamictal package insert^Citation7 GSK, 2005 OFC: 6/25, 12/25, 6/50, or 12/50 mg/day	CGI-S: OFC versus LTG: P = 0.008 overall MMRM, overall effect size = 0.22,MADRS: OFC versus LTG: P = 0.005, overall MMRM, overall effect size = 0.23YMRS: OFC versus LTG: P < 0.001, overall MMRM, overall effect size = 0.27
Calabrese et al^Citation30 Jadad:4	Double-blind RCT	463 patientsBipolar 1 maintenancetreatment	72 weeks	LTG (50, 200, 400 mg/day) lithium (serum levels of 0.8-1.1 mEq/L) Monotherapy	LTG (200/400 mg/day) versus PLC: P = 0.029 lithium versus PLC: P = 0.029
Calabrese et al^Citation2 Jadad: 3	Double-blind RCT	195 patients Bipolar 1 depression	7 weeks	LTG (50 and 200 mg/day) Monotherapy	LTG (50 mg/day): HAM-D-17, P = 0.24LTG (200 mg/day): HAM-D-17, P = 0.08
Calabrese et al^Citation37 Jadad: 3	Open-label, multicenter	324 patients, 182 randomly assigned to maintenance phase Rapid cycling	26 weeks	LTG (25 mg/day week 1–2; 50 mg/day, weeks 3–4; 100 mg/day week 5; max. 300 mg/day) Adjunctive treatment and monotherapy	Additional pharmacotherapy: LTG 50%, PLC 56%, P = 0.177
Chang et al^Citation34 Jadad: 1	Open-label, multicenter	109 patients Bipolar 2 depression	52 weeks	LTG (maximum dose 145.5 ± 1 13.2 mg/day) Adjunctive treatment	CGI-BP-S depression score (baseline to 52 weeks endpoint): t= 13.6, df = 108, P < 0.001
Frye et al^Citation24 Jadad: 5	Double blind crossover RCT	3 1 patients Bipolar 1/2, unipolar treatment- refractory depression/mania	18 weeks	LTG (maximum dose, 500 mg/day)GBP (maximum dose, 4800 mg/day)Monotherapy	CGI-BP response rate: LTG: 52%, GBP: 26%, PLC:23%
Goodwin et al^Citation31 Jadad:4	Pooled analysis of two double blind RCT	638 patients Bipolar 1 disorder	78 weeks	LTG (50–400 mg/day fixed dose or 100–400 mg/day flexible dose)Lithium (serum levels of 0.8–1.1 mEq/L) Monotherapy	LTG versus PLC: P < 0.001Lithium versus PLC: P < 0.001LTG versus lithium: P = 0.629
Ichim et al^Citation36 Jadad: 2	Double-blind RCT	30 patients Bipolar 1, mania	4 weeks	LTG (25 mg/day first week, 50 mg/day second week, 100 mg/day for last 2 weeks)Lithium (800 mg/day)Monotherapy	MRS score: LTG improvement 34.4 to 14.3,P = 0.0002Lithium: improvement 31.6 to 13.2, P = 0.0005,no differenceSame in BPRS, CGI-S and GAF scales
Licht et al^Citation43 Jadad: 3	Open randomized trial	155 patients Bipolar I maintenance treatment	Up to 5.8 years	LTG (100–400 mg/day)Lithium (serum levels of 0.5–1.0 mmol/L)Mono-therapy 6 months after randomization	Crude HRR (95% Cl, LTG relative to lithium): 0.92(0.60-1.40)Mania: crude HRR (95% Cl): 1.91 (0.73–5.04)Depression: crude HRR (95% CI): 0.69 (0.41–1.22)
van der Loos et al^Citation32 Jadad: 5	Double-blind RCT	124 patients Bipolar 1/2 depression	8 weeks	LTG (25 mg/day weeks 1 and 2; 50 mg/day weeks 3 and 4; 100 mg/day weeks 5 and 6; 200 mg/day weeks 7 and 8) Adjunctive treatment to lithium (serum levels of 0.6–1.0 mmol/L)	LTG versus PLC: P = 0.024
van der Loos et al^Citation33 Jadad: 5	Double-blind RCT	124 patients Bipolar 1/2 depression	68 weeks	LTG (200 mg/day)Paroxetine in nonresponders (20 mg/day)Adjunctive treatment to lithium (serum levels of 0.6–1.0 mmol/L)	LTG versus PLC: time to relapse, median time 10.0 months versus 3.5 months; no formal statistic test done
Nierenberg^Citation33 Jadad: 2	Open-label, multicenter study	66 patients Bipolar 1/2 depression	16 weeks	LTG (50 mg/day for first 2 weeks; 50 mg for weeks 3 and 4; target dose of between 150 and250 mg/day)Inositol (2.5 g to 5 g with a target dose of between 10 g and 25 g)Risperidone (0.5 mg and 1.0 mg with titration up to 6 mg)Adjunctive treatment	All between-group comparisons were not significant (P > 0.10)
Nolen et al^Citation28 Jadad: 3	Open randomized trial	19 patients Bipolar depression	10 weeks	LTG (25 mg/day for the first week; 50 mg/day in week 2; 100 mg/day in week 3; 200 mg/day in week 4; 300 mg/day in week 5; and finally 400 mg/day in weeks 6–10)Tranylcypromine (20 mg/day, increased each week with 20 mg/day to a maximum of 100 mg/day in weeks 5–10)	LTG versus tranylcypromine: no significant difference
Schaffer et al^Citation27 Jadad: 3	Double-blind RCT	20 patientsBipolar 1/2 depression	12 weeks (Table 1) single studies	LTG (25 mg/day for 2 weeks; 50 mg/day for another 2 weeks; after week 5, a maximum of 200 mg/day) Citalopram (10 mg/day for 2 weeks, 20 mg/day for the next 2 weeks, up to a maximum of 50 mg/day) Adjunctive treatment	LTG versus Citalopram : P = 0.78 No significant difference

Note: Jadad: a score for evaluation of RCT, developed by Jadad et al.⁶³

Abbreviations: LTG, lamotrigine; BD, bipolar disorder; MRS, manic rating scale; HAM-D, Hamilton Rating Scale for Depression; GAS, Global Assessment Scale; LOCF, last observation carried forward; RCT, randomized controlled trial; PLC, placebo; GSK, GlaxoSmithKline; OFC, olanzapine/fluoxetine combination; CGI-S, Clinical Global Impressions-Severity of Illness Scale; MMRM, mixed model repeated measure; MADRS, Montgomery–Åsberg Depression Rating Scale; YMRS, Young Mania Rating Scale; CGI-BP-S, Clinical Global Impression-Bipolar Version-Severity Scale; CGI-BP, Clinical Global Impression Scale modified for Bipolar Disorder; GBP, gabapentine; BPRS, Brief Psychiatric Rating Scale; GAF, Global Assessment of Functioning; HRR, hazard rate ratio; CI, confidence interval.

Table 3 Meta-analyses and review articles used in this publication and listing of included trials

Authors	Design	Studies included
Amann et al^Citation18	Meta-analysis	SCAA2008 SCAA2009 SCA100223 SCA30924 SCA40910 SCAA2010 SCAB2005 Calabrese et al^Citation21,Citation30,Citation37 Bowden et al^Citation29 Brown et al^Citation25 van der Loos et al^Citation32
Calabrese et al^Citation23	Report of five RCT	SCA100223 SCA30924 SCA40910 SCAA2010 SCAB2001
Cipriani et al^Citation19	Meta-analysis	SCAA2008 SCAA2009 Ichim et al^Citation36
Geddes et al^Citation22	Meta-analysis and Meta-regression of five RCT	SCA100223 SCA30924 SCA40910 SCAA2010 SCAB2001 Raw data sets conducted by GSK
Goldsmith et al^Citation5	Review	Calabrese et al^Citation21,Citation30,Citation37,Citation64 Bowden et al^Citation29 Frye et al^Citation24 Obrocea et al^Citation65
Yildiz et al^Citation20	Meta-analysis of RCT	Gw609 (GSK) Gw610 (GSK) Ichim et al^Citation36 Goldsmith et al^Citation5

Notes: SCAA2008, SCAA2009, SCA100223, SCA30924, SCA40910, SCAA2010, SCAB2005, SCAB2001, GW609, and GW610 are raw data sets conducted by GSK.

Abbreviations: RCT, randomized controlled trials; GSK, GlaxoSmithKline.

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