Psychopharmacology

, Volume 197, Issue 4, pp 683–685

The effect of lamotrigine on platelet serotonin concentration in patients with bipolar depression

  • Marina Sagud
  • Nela Pivac
  • Maja Mustapic
  • Gordana Nedic
  • Alma Mihaljevic Peles
  • Milivoj Kramaric
  • Miro Jakovljevic
  • Dorotea Muck-Seler
Letter to the Editors

DOI: 10.1007/s00213-008-1074-2

Cite this article as:
Sagud, M., Pivac, N., Mustapic, M. et al. Psychopharmacology (2008) 197: 683. doi:10.1007/s00213-008-1074-2

Lamotrigine (3,5-diamino-6-(2,3-dichlorphenyl)-1,2,4-triazine) is an antiepileptic drug effective in the treatment of bipolar disorder in a depressive phase (Calabrese et al. 1999; Goldsmith et al. 2003) and in the prevention of relapse of bipolar depression (Calabrese et al, 2003). Preclinical studies suggested that the antidepressant effects of lamotrigine might be related to alterations of serotonin (5-hydroxytryptamine, 5-HT) neurotransmission (Consoni et al. 2006; Ahmad et al. 2005). Blood platelets might be used as a peripheral model for some processes (5-HT uptake, 5-HT2 receptors binding, and monoamine oxidase activity) in the central 5-HT synaptosomes (Camacho and Dimsdale 2000). Because there are no data evaluating the effects of lamotrigine on platelet markers in patients, the aim of the study was to determine the effects of 6-week lamotrigine treatment on platelet 5-HT concentration in patients with bipolar I disorder currently depressed (bipolar depression) and to compare the effect of lamotrigine with the effect of 6-week paroxetine treatment on platelet 5-HT concentration in patients with major depressive disorder (MDD).

Both patients with bipolar depression and MDD were diagnosed by a structured clinical interview (First et al. 1995) according to the Diagnostic and Statistical Manual of Mental Disorders IV (American Psychiatric Association 1994). In a nonrandomized prospective, open-label, comparative, 6-week study, 28 female patients 48.8 (SD 11.5) years old with bipolar depression were treated with lamotrigine (25–100 mg/day), and 51 female patients with MDD 49.5 (SD 7.9) years old received paroxetine (20 mg/day). Lamotrigine was added to the current treatment in 14 patients: lithium (six patients, 600–900 mg/day; lithium plasma concentration 0.55–0.80 mmol/l), quetiapine (two patients, 300–400 mg/day), risperidone (three patients, 2 mg/day), and olanzapine (three patients, 5–10 mg/day). All patients were allowed to take diazepam (up to 15 mg/day). Participants have signed informed consent, and the study was approved by the local Ethics Committee. They had scores greater than or equal to 18 on the 17-item Hamilton Depression Rating Scale (HAMD; Hamilton 1960). Patients with bipolar depression additionally required scores less than 7 on Young Mania Rating Scale (Young et al. 1978). The exclusion criteria were (1) substance abuse disorder within the previous 6 months, (2) diagnosis of schizophrenia, schizoaffective disorder, dementia, and post-traumatic stress disorder; (3) the presence of psychotic features, (4) treatment with any medication known to influence platelet 5-HT concentration in the previous 2–4 weeks, (5) duration of current depressive episode for more than 2 years, to exclude chronic depression, and (6) patients with bipolar disorder with a history of previous nonresponse to lamotrigine or lamotrigine-induced rash. Depressive symptoms (evaluated using HAMD) and platelet 5-HT concentration (nmol/mg proteins), measured using the spectrofluorimetric method (Muck-Seler et al. 2002), were determined at baseline (a day before lamotrigine or paroxetine administration) and after 6 weeks of treatment. No symptoms of mania have emerged during lamotrigine treatment. For the drop-outs, two patients in lamotrigine group were lost: one patient was lost during follow-up, and the other patient was excluded because of the rash, which was not visible on the examination, but the patient claimed she had a rash a day before; three patients in the paroxetine group were excluded because they complained of worsening of their depressive symptoms. No serious adverse events occurred during the study. Statistical evaluation of the results, expressed as means ± standard deviations, was performed using the repeated-measures analysis of variance (RMANOVA) followed by Tukey’s test and multifactorial analysis of variance (MANOVA) with significance accepted when P < 0.05.

Patients with bipolar depression or MDD had significantly (P < 0.001, RMANOVA) lower platelet 5-HT concentration after 6 weeks of lamotrigine or paroxetine treatment than at baseline (Table 1). MANOVA (df = 3,141) revealed the significant main effects (F = 46.01, P < 0.001), significant effect of time (baseline vs. 6 weeks) of treatment (F = 116.11, P < 0.001), significant effects of drugs (lamotrigine vs. paroxetine; F = 16.15, P < 0.001), and significant interaction between time and drugs (F = 5.48, P = 0.021) on platelet 5-HT concentration. To further assess the inhibitory effect of lamotrigine on platelet 5-HT concentration in patients with bipolar depression and to evaluate the possible effects of lamotrigine added to the current treatment with antipsychotic drugs or lithium on platelet 5-HT concentration, patients with bipolar depression were subdivided into those treated with lamotrigine (only) and lamotrigine with antipsychotics or lamotrigine without lithium and lamotrigine with lithium. The results showed (Table 1) the significant (RMANOVA) decrease in platelet 5-HT values in both patients with bipolar depression taking lamotrigine only and in those taking lamotrigine with antipsychotic drugs or lithium. At baseline, patients with bipolar depression (24.54 ± 2.67) and MDD (26.52 ± 2.45) had similar total HAMD scores. The significant (RMANOVA) decreases in total HAMD scores were observed after treatment with lamotrigine (9.77 ± 7.54) in bipolar (F[1, 25] = 165.517, P < 0.001) or paroxetine (11.98 ± 8.62) in MDD (F[1, 47] = 165.879, P < 0.001) patients.
Table 1

Platelet 5-HT concentration (mean ± SD) in female patients with bipolar depression (BD), before and after 6 weeks of lamotrigine treatment, in female patients with major depression (MDD), before or after 6 weeks of paroxetine treatment, and in patients with BD subdivided into groups with or without lithium or antipsychotic treatment

Treatment

N

Platelet 5-HT concentration (nmol/mg proteins)

Statistical analysis, RMANOVA

F value

df

P value

Patients with BD

Before lamotrigine

26

1.44 ± 0.45

   

After lamotrigine

26

0.93 ± 0.34****

21.74

1,25

0.001

Patients with MDD

Before paroxetine

48

1.30 ± 0.49

   

After paroxetine

48

0.46 ± 0.34****

141.35

1,47

0.001

Patients with BD

Lamotrigine only

     

 Before treatment

12

1.59 ± 0.47

   

 After treatment

12

1.03 ± 0.46*

9.34

1,11

0.011

Lamotrigine + antipsychotics

     

 Before treatment

14

1.31 ± 0.40

   

 After treatment

14

0.84 ± 0.16***

12.16

1,13

0.004

Lamotrigine without lithium

     

 Before treatment

20

1.47 ± 0.41

   

 After treatment

20

0.95 ± 0.37****

22.33

1,19

0.001

Lamotrigine with lithium

     

 Before treatment

6

1.49 ± 0.40

   

 After treatment

6

0.72 ± 0.07**

18.59

1,5

0.008

N is the number of subjects

*P = 0.011, **P = 0.008, ***P = 0.004, ****P < 0.001 vs. corresponding values before treatment (Tukey’s test)

To the best of our knowledge, this is the first report showing significantly lower platelet 5-HT concentration in bipolar depressed patients treated for 6 weeks with lamotrigine in relatively low doses (up to 100 mg/day). Lower platelet 5-HT concentration might be associated with suicidal behavior, previous treatment with selective serotonin reuptake inhibitors (SSRI), or female gender (see Muck-Seler et al. 1996, 2005). Because we included only female, nonsuicidal patients matched for age, who were not previously treated with SSRI, platelet 5-HT concentration was not significantly affected by these variables. This inhibitory effect of lamotrigine on platelet 5-HT concentration persisted when lamotrigine was added to the current antipsychotic or lithium treatment. Our results agree with in vitro data showing that lamotrigine inhibited 5-HT uptake in rat brain synaptosomes (Southam et al. 1998) and with the data from experimental animals, where lamotrigine reversed the chloroamphetamine-induced 5-HT syndrome in rats (Southam et al. 1998) and reduced the immobility in an animal model of depression, suggesting that the antidepressant effect of lamotrigine is mediated also by 5-HT mechanisms (Consoni et al. 2006). The antidepressant effect of lamotrigine in patients with bipolar depression was similar to the effect of paroxetine on platelet 5-HT concentration and on the HAMD scores in patients with MDD (Muck-Seler et al. 2002, 2005), probably because of its inhibitory effect on 5-HT uptake in human platelets in vitro (Southam et al. 1998). The antidepressant effect of lamotrigine (present study) is in line with data showing that lamotrigine, as an augmentation therapy in depression, accelerated the onset of action of paroxetine (Normann et al. 2002) and fluoxetine (Barbosa et al. 2003). In conclusion, lamotrigine, similarly to paroxetine in patients with MDD, decreased platelet 5-HT concentration in patients with bipolar depression. Our results suggest that lamotrigine possesses an in vivo 5-HT uptake inhibiting property, and this effect might have contributed to its antidepressant activity.

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Marina Sagud
    • 1
  • Nela Pivac
    • 2
  • Maja Mustapic
    • 2
  • Gordana Nedic
    • 2
  • Alma Mihaljevic Peles
    • 1
  • Milivoj Kramaric
    • 1
  • Miro Jakovljevic
    • 1
  • Dorotea Muck-Seler
    • 2
  1. 1.Department of PsychiatryClinical Hospital Centre ZagrebZagrebCroatia
  2. 2.Division of Molecular MedicineRudjer Boskovic InstituteZagrebCroatia

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