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Treatment in Psychiatry   |    
Lamotrigine Dosing for Pregnant Patients With Bipolar Disorder
Crystal T. Clark, M.D., M.Sc.; Autumn M. Klein, M.D., Ph.D.; James M. Perel, Ph.D.; Joseph Helsel, B.S.; Katherine L. Wisner, M.D., M.S.
Am J Psychiatry 2013;170:1240-1247. doi:10.1176/appi.ajp.2013.13010006
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Presented in part at the international biennial congress of the Marcé Society for Perinatal Mental Health, Paris, October 3–5, 2012; and at the 52nd annual meeting of the New Clinical Drug Evaluation Unit, Phoenix, May 29–June 1, 2012.

The authors report no financial relationships with commercial interests.

Dr. Klein died in April 2013.

Supported by NIMH grant R01 MH 075921 to Dr. Wisner.

From the Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago; the Departments of Neurology, Obstetrics and Gynecology, Psychiatry, and Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh.

Address correspondence to Dr. Clark (crystal.clark@northwestern.edu).

Copyright © 2013 by the American Psychiatric Association

Received January 02, 2013; Revised March 13, 2013; Accepted March 25, 2013.

Abstract

Objective  Little information is available on the need for dosage changes for lamotrigine in pregnant women with bipolar disorder. The authors present new data on serial serum levels of lamotrigine in pregnant patients on lamotrigine monotherapy. They also review the epilepsy literature on use of lamotrigine during pregnancy.

Method  Lamotrigine serum samples were obtained from eight mother-infant pairs at different time points during pregnancy and the postpartum period.

Results  All of the women were taking lamotrigine throughout pregnancy. Serum-level-to-dose ratios were lower during pregnancy than the postpartum period. Lamotrigine was taken once daily in doses ranging from 100 mg to 300 mg. Three patients had an increase of 50 mg to their daily dose across pregnancy. The change in serum lamotrigine levels in the postpartum period ranged from a 30% decrease to a 640% increase compared with the first level obtained during pregnancy. Level-to-dose ratios obtained within 4 weeks after delivery reflected a mean level 402% greater than the baseline level during gestation. Compared with the third trimester, lamotrigine serum concentration increased an average of 154% within 5 weeks after delivery. The most dramatic increase in lamotrigine serum level early after delivery occurred at 1.5 weeks. The mean infant cord level was 66% of the maternal serum level at delivery. The mean breast-fed infant serum level was 32.5% of the maternal serum levels.

Conclusions  The pattern of lamotrigine changes during pregnancy in these women with bipolar disorder was consistent with that described in the epilepsy literature.

Abstract Teaser
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FIGURE 1. Ratio of Lamotrigine Serum Level to Daily Dose During Pregnancy and the Postpartum Perioda

a Ratio was calculated using the following formula: lamotrigine level (µg/mL) × 100/prescribed daily lamotrigine dose (mg).

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TABLE 1.Demographic and Clinical Characteristics of Eight Mothers Taking Lamotrigine During Pregnancy and Their Infantsa
Table Footer Note

a MDI=Mental Development Index; PDI=Psychomotor Development Index; GED=General Educational Development certificate; n/a=not available (patient 3 did not provide consent for her infant’s participation).

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References

Grof  P;  Robbins  W;  Alda  M;  Berghoefer  A;  Vojtechovsky  M;  Nilsson  A;  Robertson  C:  Protective effect of pregnancy in women with lithium-responsive bipolar disorder.  J Affect Disord 2000; 61:31–39
[CrossRef] | [PubMed]
 
Viguera  AC;  Whitfield  T;  Baldessarini  RJ;  Newport  DJ;  Stowe  Z;  Reminick  A;  Zurick  A;  Cohen  LS:  Risk of recurrence in women with bipolar disorder during pregnancy: prospective study of mood stabilizer discontinuation.  Am J Psychiatry 2007; 164:1817–1824
[CrossRef] | [PubMed]
 
Viguera  AC;  Nonacs  R;  Cohen  LS;  Tondo  L;  Murray  A;  Baldessarini  RJ:  Risk of recurrence of bipolar disorder in pregnant and nonpregnant women after discontinuing lithium maintenance.  Am J Psychiatry 2000; 157:179–184
[CrossRef] | [PubMed]
 
Payne  JL;  Roy  PS;  Murphy-Eberenz  K;  Weismann  MM;  Swartz  KL;  McInnis  MG;  Nwulia  E;  Mondimore  FM;  MacKinnon  DF;  Miller  EB;  Nurnberger  JI;  Levinson  DF;  DePaulo  JR  Jr;  Potash  JB:  Reproductive cycle-associated mood symptoms in women with major depression and bipolar disorder.  J Affect Disord 2007; 99:221–229
[CrossRef] | [PubMed]
 
Tomson  T;  Battino  D;  Bonizzoni  E;  Craig  J;  Lindhout  D;  Sabers  A;  Perucca  E;  Vajda  F; EURAP study group:  Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry.  Lancet Neurol 2011; 10:609–617
[CrossRef] | [PubMed]
 
Meador  K;  Reynolds  MW;  Crean  S;  Fahrbach  K;  Probst  C:  Pregnancy outcomes in women with epilepsy: a systematic review and meta-analysis of published pregnancy registries and cohorts.  Epilepsy Res 2008; 81:1–13
[CrossRef] | [PubMed]
 
Morrell  MJ;  Hayes  FJ;  Sluss  PM;  Adams  JM;  Bhatt  M;  Ozkara  C;  Warnock  CR;  Isojärvi  J:  Hyperandrogenism, ovulatory dysfunction, and polycystic ovary syndrome with valproate versus lamotrigine.  Ann Neurol 2008; 64:200–211
[CrossRef] | [PubMed]
 
Joffe  H;  Cohen  LS;  Suppes  T;  McLaughlin  WL;  Lavori  P;  Adams  JM;  Hwang  CH;  Hall  JE;  Sachs  GS:  Valproate is associated with new-onset oligoamenorrhea with hyperandrogenism in women with bipolar disorder.  Biol Psychiatry 2006; 59:1078–1086
[CrossRef] | [PubMed]
 
Tomson  T;  Ohman  I;  Vitols  S:  Lamotrigine in pregnancy and lactation: a case report.  Epilepsia 1997; 38:1039–1041
[CrossRef] | [PubMed]
 
Ohman  I;  Vitols  S;  Tomson  T:  Lamotrigine in pregnancy: pharmacokinetics during delivery, in the neonate, and during lactation.  Epilepsia 2000; 41:709–713
[CrossRef] | [PubMed]
 
Tran  TA;  Leppik  IE;  Blesi  K;  Sathanandan  ST;  Remmel  R:  Lamotrigine clearance during pregnancy.  Neurology 2002; 59:251–255
[CrossRef] | [PubMed]
 
de Haan  GJ;  Edelbroek  P;  Segers  J;  Engelsman  M;  Lindhout  D;  Dévilé-Notschaele  M;  Augustijn  P:  Gestation-induced changes in lamotrigine pharmacokinetics: a monotherapy study.  Neurology 2004; 63:571–573
[CrossRef] | [PubMed]
 
Pennell  PB;  Newport  DJ;  Stowe  ZN;  Helmers  SL;  Montgomery  JQ;  Henry  TR:  The impact of pregnancy and childbirth on the metabolism of lamotrigine.  Neurology 2004; 62:292–295
[CrossRef] | [PubMed]
 
Petrenaite  V;  Sabers  A;  Hansen-Schwartz  J:  Individual changes in lamotrigine plasma concentrations during pregnancy.  Epilepsy Res 2005; 65:185–188
[CrossRef] | [PubMed]
 
Cohen  AF;  Land  GS;  Breimer  DD;  Yuen  WC;  Winton  C;  Peck  AW:  Lamotrigine, a new anticonvulsant: pharmacokinetics in normal humans.  Clin Pharmacol Ther 1987; 42:535–541
[CrossRef] | [PubMed]
 
Green  MD;  Bishop  WP;  Tephly  TR:  Expressed human UGT1.4 protein catalyzes the formation of quaternary ammonium-linked glucuronides.  Drug Metab Dispos 1995; 23:299–302
[PubMed]
 
Fotopoulou  C;  Kretz  R;  Bauer  S;  Schefold  JC;  Schmitz  B;  Dudenhausen  JW;  Henrich  W:  Prospectively assessed changes in lamotrigine-concentration in women with epilepsy during pregnancy, lactation, and the neonatal period.  Epilepsy Res 2009; 85:60–64
[CrossRef] | [PubMed]
 
Chen  H;  Yang  K;  Choi  S;  Fischer  JH;  Jeong  H:  Up-regulation of UDP-glucuronosyltransferase (UGT) 1A4 by 17β-estradiol: a potential mechanism of increased lamotrigine elimination in pregnancy.  Drug Metab Dispos 2009; 37:1841–1847
[CrossRef] | [PubMed]
 
Reimers  A;  Helde  G;  Brodtkorb  E:  Ethinyl estradiol, not progestogens, reduces lamotrigine serum concentrations.  Epilepsia 2005; 46:1414–1417
[CrossRef] | [PubMed]
 
Ohman  I;  Beck  O;  Vitols  S;  Tomson  T:  Plasma concentrations of lamotrigine and its 2-N-glucuronide metabolite during pregnancy in women with epilepsy.  Epilepsia 2008; 49:1075–1080
[CrossRef] | [PubMed]
 
Franco  V;  Mazzucchelli  I;  Gatti  G;  Specchio  LM;  La Neve  A;  Papantonio  A;  Ozkaynakçi  AE;  Perucca  E:  Changes in lamotrigine pharmacokinetics during pregnancy and the puerperium.  Ther Drug Monit 2008; 30:544–547
[PubMed]
 
Pennell  PB;  Gidal  BE;  Sabers  A;  Gordon  J;  Perucca  E:  Pharmacology of antiepileptic drugs during pregnancy and lactation.  Epilepsy Behav 2007; 11:263–269
[CrossRef] | [PubMed]
 
Liston  HL;  Markowitz  JS;  DeVane  CL:  Drug glucuronidation in clinical psychopharmacology.  J Clin Psychopharmacol 2001; 21:500–515
[CrossRef] | [PubMed]
 
Sabers  A;  Tomson  T:  Managing antiepileptic drugs during pregnancy and lactation.  Curr Opin Neurol 2009; 22:157–161
[CrossRef] | [PubMed]
 
Kacirova  I;  Grundmann  M;  Brozmanova  H:  Serum levels of lamotrigine during delivery in mothers and their infants.  Epilepsy Res 2010; 91:161–165
[CrossRef] | [PubMed]
 
Newport  DJ;  Pennell  PB;  Calamaras  MR;  Ritchie  JC;  Newman  M;  Knight  B;  Viguera  AC;  Liporace  J;  Stowe  ZN:  Lamotrigine in breast milk and nursing infants: determination of exposure.  Pediatrics 2008; 122:e223–e231
[CrossRef] | [PubMed]
 
Myllynen  PK;  Pienimäki  PK;  Vähäkangas  KH:  Transplacental passage of lamotrigine in a human placental perfusion system in vitro and in maternal and cord blood in vivo.  Eur J Clin Pharmacol 2003; 58:677–682
[PubMed]
 
Rambeck  B;  Kurlemann  G;  Stodieck  SR;  May  TW;  Jürgens  U:  Concentrations of lamotrigine in a mother on lamotrigine treatment and her newborn child.  Eur J Clin Pharmacol 1997; 51:481–484
[CrossRef] | [PubMed]
 
Collier  AC;  Ganley  NA;  Tingle  MD;  Blumenstein  M;  Marvin  KW;  Paxton  JW;  Mitchell  MD;  Keelan  JA:  UDP-glucuronosyltransferase activity, expression and cellular localization in human placenta at term.  Biochem Pharmacol 2002; 63:409–419
[CrossRef] | [PubMed]
 
Gentile  S:  Prophylactic treatment of bipolar disorder in pregnancy and breastfeeding: focus on emerging mood stabilizers.  Bipolar Disord 2006; 8:207–220
[CrossRef] | [PubMed]
 
Nordmo  E;  Aronsen  L;  Wasland  K;  Småbrekke  L;  Vorren  S:  Severe apnea in an infant exposed to lamotrigine in breast milk.  Ann Pharmacother 2009; 43:1893–1897
[CrossRef] | [PubMed]
 
Liporace  J;  Kao  A;  D’Abreu  A:  Concerns regarding lamotrigine and breast-feeding.  Epilepsy Behav 2004; 5:102–105
[CrossRef] | [PubMed]
 
Page-Sharp  M;  Kristensen  JH;  Hackett  LP;  Beran  RG;  Rampono  J;  Hale  TW;  Kohan  R;  Ilett  KF:  Transfer of lamotrigine into breast milk.  Ann Pharmacother 2006; 40:1470–1471
[CrossRef] | [PubMed]
 
Wakil  L;  Epperson  CN;  Gonzalez  J;  O’Reardon  JP;  Kim  DR:  Neonatal outcomes with the use of lamotrigine for bipolar disorder in pregnancy and breastfeeding: a case series and review of the literature.  Psychopharmacol Bull 2009; 42:91–98
[PubMed]
 
First  MB;  Spitzer  RL;  Gibbon  M;  Williams  JBW:  Structured Clinical Interview for DSM-IV Axis I Disorders, Patient Edition .  New York,  New York State Psychiatric Institute, Biometrics Research, 1996
 
Williams  J;  Terman  M:  Structured Interview Guide for the Hamilton Depression Rating Scale With Atypical Depression Supplement (SIGH-ADS) .  New York,  New York State Psychiatric Institute, 2003
 
Spitzer  RL;  Endicott  J:  Schedule for Affective Disorders and Schizophrenia–Change Version , 3rd ed.  New York,  New York State Psychiatric Institute, Biometrics Research, 1978
 
Bayley  N:  Scales of Infant Development .  New York,  Psychological Corp, 1969
 
Young  RC;  Biggs  JT;  Ziegler  VE;  Meyer  DA:  A rating scale for mania: reliability, validity and sensitivity.  Br J Psychiatry 1978; 133:429–435
[CrossRef] | [PubMed]
 
Montgomery  SA;  Asberg  M:  A new depression scale designed to be sensitive to change.  Br J Psychiatry 1979; 134:382–389
[CrossRef] | [PubMed]
 
Altman  EG;  Hedeker  D;  Peterson  JL;  Davis  JM:  The Altman Self-Rating Mania Scale.  Biol Psychiatry 1997; 42:948–955
[CrossRef] | [PubMed]
 
Rush  AJ;  Giles  DE;  Schlesser  MA;  Fulton  CL;  Weissenburger  J;  Burns  C:  The Inventory for Depressive Symptomatology (IDS): preliminary findings.  Psychiatry Res 1986; 18:65–87
[CrossRef] | [PubMed]
 
Rush  AJ;  Carmody  T;  Reimitz  PE:  The Inventory of Depressive Symptomatology (IDS): Clinician (IDS-C) and Self-Report (IDS-SR) ratings of depressive symptoms.  Int J Methods Psychiatr Res 2006; 9:45–59
[CrossRef]
 
Sabers  A:  Algorithm for lamotrigine dose adjustment before, during, and after pregnancy.  Acta Neurol Scand 2012; 126:e1–e4
[CrossRef] | [PubMed]
 
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