Lack of Interaction between Sertraline and Lamotrigine in Psychiatric Patients: A Retrospective Study

• Abstract
• Introduction
• Methods and Patients
• Patients
• Drug analyses
• Statistical analyses
• Ethics
• Results
• Discussion
• References

Abstract

Introduction:

This study evaluates the pharmacokinetic interaction between sertraline and lamotrigine in psychiatric patients.

Methods:

We identified patients with at least 1 measurement of trough lamotrigine plasma concentration (at steady-state) during lamotrigine therapy and compared dose and plasma concentrations between patients who received lamotrigine with sertraline and patients who received lamotrigine without sertraline.

Results:

The dose corrected concentration of lamotrigine in patients receiving lamotrigine in combination with sertraline was 60.4 μmol/L×1 000/mg/day (SD: 31.1) (N=7) compared to 51.1 μmol/L×1 000/mg/day (SD: 27.6) (N=44) in patients using lamotrigine without sertraline (p=0.42).

Discussion:

The slightly slower metabolism of lamotrigine in patients receiving lamotrigine with sertraline compared with those receiving lamotrigine alone is not believed to be of clinical significance. However, due to the limited power, we may have overlooked a difference that could be clinically relevant.

Introduction

Lamotrigine is an antiepileptic drug that is also used in the treatment of bipolar disorders [1] [2]. Unlike most other antiepileptic drugs, the major route of elimination (76%) of lamotrigine is by direct conjugation with glucuronic acid (glucuronidation) [3]. This conjugation reaction is catalyzed by the uridine 5′-diphosphate (UDP)-glucuronosyltransferases (UGTs) of which the isoforms UGT2B7 and UGT1A4 are the major ones in humans [3] [4]. Sertraline is a selective reuptake inhibitor used in the treatment of major depression and other psychiatric disorders [5]. For sertraline, the major route of elimination in humans is N-demethylation via cytochrome P450 [6], and glucuronidation takes place to only a minor extent, involving the UGT isoforms UGT2B7, UGT1A3, UGT1A6 and UGT2B4 [6]. Although the UGT isoform UGT2B7 is involved in the metabolism of both lamotrigine and sertraline, the manufacturer of Lamictal^® [GlaxoSmithKline] reports that in vitro studies do not indicate that the formation of the primary metabolite of lamotrigine, the 2-N-glucuronide, is affected by sertraline [7] However, 1 clinical report describes 2 patients with epilepsy who experienced signs of lamtorigine toxicity after sertraline was added [8]. The authors speculate that the symptoms may be due to an effect of sertraline on the metabolism of lamotrigine via competitive inhibition of glucoronidation [8]. We therefore evaluated this potential interaction in a population of psychiatric patients treated with lamotrigine, some of them receiving concomitant treatment with sertraline.

Methods and Patients

Patients

We identified all patients treated at the Aarhus University Psychiatric Hospital, Risskov, Denmark, who had at least one trough plasma concentration of lamotrigine measured (at steady-state) at the Department of Clinical Biochemistry, Aarhus University Hospital. The corresponding daily doses of lamotrigine were obtained from the medical records where we also retrieved information on concomitant use of sertraline. We excluded patients with concomitant use of carbamazepine, phenytoin, phenobarbital, primidone and valproate because of the known pharmacokinetic interactions with lamotrigine [9]

Drug analyses

All lamotrigine samples were analyzed at the Department of Clinical Biochemistry, Aarhus University Hospital. Lamotrigine concentrations were determined in plasma using reverse-phase high-pressure liquid chromatography. In brief, drugs were extracted on an RP-8, 40-μm cartridge and separated on an RP-18 endcapped (5 μm) 250-4 Lichrospher 100 column. Samples were analyzed as total concentrations. The detection limit was 1 µmol/L and the CV was 5%.

For patients not receiving sertraline, the first measurement of trough plasma lamotrigine (at steady-state) was selected for analysis. For patients receiving sertraline concomitantly we used the first measurement of trough plasma lamotrigine (at steady-state) after sertraline had been introduced.

Statistical analyses

We compared the plasma concentration, daily dose and dose-corrected plasma concentration of lamotrigine between patients who were treated and not treated concomitantly with sertraline using a 2-sample t-test assuming equal variances (2-tailed) (STATA version 9.0, StataCorp LP, College Station, Texas, USA).

Ethics

The study did not involve patient contact and therefore did not need approval from the scientific ethical committee. The Danish Data Protection Agency approved the study.

Results

Among the 51 psychiatric patients who fulfilled the selection criteria we identified 24 males and 27 females. There were 44 patients (20 males and 24 females) who received lamotrigine without concomitant sertraline and 7 patients (4 males and 3 females) who received a combination of lamotrigine and sertraline. The mean age was 42.0 years (SD 12.9) among the 44 patients who received lamotrigine alone and 37.4 years (SD 13.1) among the 7 patients who received a combination of lamotrigine and sertraline (p=0.39). The mean concentration of lamotrigine in patients using lamotrigine without sertraline was 16.6 μmol/L (SD: 14.2) compared to a mean concentration of lamotrigine of 18.7 μmol/L (SD: 11.1) in psychiatric patients concomitantly treated with sertraline (p=0.71). The mean dose of lamotrigine in psychiatric patients using lamotrigine without sertraline was 339 mg/day (SD: 195) compared to a mean dose of lamotrigine of 314 mg/day (SD: 118) in psychiatric patients treated concomitantly with sertraline (p=0.75). The mean dose-corrected concentration of lamotrigine was 51.1 μmol/L×1 000/mg/day (SD: 27.6) in patients not receiving concomitant treatment with sertraline and 60.4 μmol/L×1 000/mg/day (SD: 31.1) in patients receiving the combination (p=0.42). [Fig. 1] shows a plot of the lamotrigine concentration vs. dose for all 51 patients.

Discussion

By systematically studying a population of psychiatric patients treated under routine conditions with lamotrigine, we were unable to confirm a previous case report suggesting that sertraline significantly inhibits the metabolism of lamotrigine resulting in increased lamotrigine concentrations and potential toxicity [8]. Lamotrigine has a large interaction potential, i. e., concomitant treatment with valproate leads to a doubling of the lamotrigine plasma concentration, and concomitant treatment with oral contraceptives leads to halving of the lamotrigine plasma concentration. However, the mean dose-corrected concentration of lamotrigine was only slightly lower (< 20%) in patients not using sertraline concomitantly compared to patients treated with the combination of the 2 drugs. This difference – even if valid despite the p-value of 0.42  –  is not believed to be of clinical significance, at least not in the treatment of bipolar disorder. Unfortunately, the power of the study was reduced due to the fact that we identified only 7 patients receiving the drug combination, and a clinically relevant difference may therefore have been overlooked. However, even with only 5 patients in each group, we would have been able to detect a doubling of the mean dose-corrected concentration with more than 80% chance (and with an alfa of 0.05). Our findings corroboate findings from a retrospective study showing that sertraline had very minor and statistically non-significant effect on the apparent metabolism of lamotrigine [10] and data from preclinical in vitro studies suggesting that the interaction is minor and not likely to be of clinical relevance [7].

Conflict of Interest

The authors declare no conflicts of interest.

Acknowledgements

None

• References

• 1 Calabrese JR, Bowden CL, Sachs G et al. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I disorder. J Clin Psychiatry 2003; 64: 1013-1024
  CrossrefPubMedSearch in Google Scholar
• 2 Licht RW, Nielsen JN, Gram LF et al. Lamotrigine versus lithium as maintenance treatment in bipolar I disorder: an open, randomized effectiveness study mimicking clinical practice. The 6 trial of the Danish University Antidepressant Group (DUAG-6). Bipolar Disord 2010; 12: 483-493
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• 3 Dickins M, Chen C. Lamotrigine. Chemistry, Biotransformation and Pharmacokinetics. In: Levy RH, Mattson RH, Meldrum BS, Perucca E. editors. Antiepileptic Drugs. Fifth Edition ed. Philidelphia: Lippincott, Williams & Wilkins; 2002: 370-379
  Search in Google Scholar
• 4 Rowland A, Elliot DJ, Williams JA et al. In vitro characterization of lamotrigine N2-glucuronidation and the lamotrigine-valproic acid interaction. Drug Metab Dispos 2006; 34: 1055-1062
  PubMedSearch in Google Scholar
• 5 Cipriani A, Brambilla P, Furukawa T et al. Fluoxetine versus other types of pharmacotherapy for depression. Cochrane Database Syst Rev October 2005; 19 (04) CD004185
  PubMedSearch in Google Scholar
• 6 Obach RS, Cox LM, Tremaine LM. Sertraline is metabolized by multiple cytochrome P450 enzymes, monoamine oxidases, and glucuronyl transferases in human: an in vitro study. Drug Metab Dispos 2005; 33: 262-270
  PubMedSearch in Google Scholar
• 7 GlaxoSmithKline. Lamictal prescribing information. 2007. http://us.gsk.com/products/assets/us_lamictal.pdf
  PubMed
• 8 Kaufman KR, Gerner R. Lamotrigine toxicity secondary to sertraline. Seizure 1998; 7: 163-165
  PubMedSearch in Google Scholar
• 9 Gidal BE, Sheth R, Parnell J et al. Evaluation of VPA dose and concentration effects on lamotrigine pharmacokinetics: implications for conversion to lamotrigine monotherapy. Epilepsy Res 2003; 57: 85-93
  CrossrefPubMedSearch in Google Scholar
• 10 Reimers A, Skogvoll E, Sund JK et al. Drug interactions between lamotrigine and psychoactive drugs: evidence from a therapeutic drug monitoring service. J Clin Psychopharmacol 2005; 25: 342-348
  CrossrefPubMedSearch in Google Scholar

Correspondence

• References

• 1 Calabrese JR, Bowden CL, Sachs G et al. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I disorder. J Clin Psychiatry 2003; 64: 1013-1024
  CrossrefPubMedSearch in Google Scholar
• 2 Licht RW, Nielsen JN, Gram LF et al. Lamotrigine versus lithium as maintenance treatment in bipolar I disorder: an open, randomized effectiveness study mimicking clinical practice. The 6 trial of the Danish University Antidepressant Group (DUAG-6). Bipolar Disord 2010; 12: 483-493
  CrossrefPubMedSearch in Google Scholar
• 3 Dickins M, Chen C. Lamotrigine. Chemistry, Biotransformation and Pharmacokinetics. In: Levy RH, Mattson RH, Meldrum BS, Perucca E. editors. Antiepileptic Drugs. Fifth Edition ed. Philidelphia: Lippincott, Williams & Wilkins; 2002: 370-379
  Search in Google Scholar
• 4 Rowland A, Elliot DJ, Williams JA et al. In vitro characterization of lamotrigine N2-glucuronidation and the lamotrigine-valproic acid interaction. Drug Metab Dispos 2006; 34: 1055-1062
  PubMedSearch in Google Scholar
• 5 Cipriani A, Brambilla P, Furukawa T et al. Fluoxetine versus other types of pharmacotherapy for depression. Cochrane Database Syst Rev October 2005; 19 (04) CD004185
  PubMedSearch in Google Scholar
• 6 Obach RS, Cox LM, Tremaine LM. Sertraline is metabolized by multiple cytochrome P450 enzymes, monoamine oxidases, and glucuronyl transferases in human: an in vitro study. Drug Metab Dispos 2005; 33: 262-270
  PubMedSearch in Google Scholar
• 7 GlaxoSmithKline. Lamictal prescribing information. 2007. http://us.gsk.com/products/assets/us_lamictal.pdf
  PubMed
• 8 Kaufman KR, Gerner R. Lamotrigine toxicity secondary to sertraline. Seizure 1998; 7: 163-165
  PubMedSearch in Google Scholar
• 9 Gidal BE, Sheth R, Parnell J et al. Evaluation of VPA dose and concentration effects on lamotrigine pharmacokinetics: implications for conversion to lamotrigine monotherapy. Epilepsy Res 2003; 57: 85-93
  CrossrefPubMedSearch in Google Scholar
• 10 Reimers A, Skogvoll E, Sund JK et al. Drug interactions between lamotrigine and psychoactive drugs: evidence from a therapeutic drug monitoring service. J Clin Psychopharmacol 2005; 25: 342-348
  CrossrefPubMedSearch in Google Scholar