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Influence of an Interaction between Lithium Salts and a Functional Polymorphism in SLC1A2 on the History of Illness in Bipolar Disorder

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Abstract

Background

Bipolar disorder (BD) is a recurrent and disabling illness, characterized by periods of depression and mania. The history of the illness differs widely between patients, with episode frequency emerging as a strong predictor of poor illness outcome. Lithium salts are the first-choice long-term mood-stabilizing therapy, but not all patients respond equally to the treatment. Evidence suggests that alterations in glutamatergic systems may contribute to the pathophysiology of depression. Moreover, glutamate signaling is involved in brain development and synaptic plasticity, both of which are modified in individuals affected by BD, and has been implicated in the etiology of the disorder. The inactivation of glutamate is handled by a series of molecular glutamate transporters (excitatory amino acid transporters [EAATs]), among which EAAT2/SLC1A2 is responsible for up to 95% of extracellular glutamate clearance. A functional single-nucleotide polymorphism at −181 bp from the transcription start site of the SLC1A2 gene has been described. This T-to-G (DNA forward strand) polymorphism, commonly known as SLC1A2 −181A>C, affects transporter expression, with the variant G allele inducing a 30% reduction in promoter activity compared with the T allele.

Objective

The aims of the study were to investigate if factors affecting glutamate function, such as SLC1A2 −181A>C (rs4354668), could affect recurrence of illness in BD, and if they interact with lithium salt treatment.

Methods

We performed an observational study in our university hospital in Milan. We enrolled 110 subjects (76 females, 34 males) affected by BD type I. The exclusion criteria were other diagnoses on Axis I, mental retardation on Axis II, a history of epilepsy, and major medical and neurologic disorders. Fifty-four patients had been treated with lithium salts for more than 6 months. Patients were genotyped for SLC1A2 −181A>C by polymerase chain reaction–restriction fragment length polymorphism, and the influence of genotype on BD episode recurrence rates, and the interaction between the single nucleotide polymorphism and lithium treatment, were analyzed.

Results

The SLC1A2 −181A>C genotype significantly influenced the total recurrence of episodes, with T/T homozygotes showing a significantly lower frequency of episodes (F = 3.26; p = 0.042), and an interaction between lithium treatment and genotype (F = 3.77; p = 0.026) was found to influence the history of the illness.

Conclusion

According to our results, the glutamatergic system could be hypothesized to exert some influence on the history of illness in BD. The SLC1A2 functional polymorphism was shown to significantly influence the total episode recurrence rate, with wild-type T homozygotes presenting the lowest number of episodes, G homozygotes reporting the highest number, and heterozygotes showing an intermediate phenotype. We confirmed the efficacy of lithium treatment in reducing the recurrence of illness in BD, and we found an interaction between lithium treatment and the SLC1A2 −181A>C genotype, confirming previous studies reporting an interaction between lithium salts and the glutamatergic system.

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Funding Disclosures

None of the authors have financial disclosures that are pertinent to the content of this article. The authors’ research unit received research grants from the Italian Ministry of University and Scientific Research, the Italian Ministry of Health, and the European Union (FP7 grant no. 222963).

Author Contributions

Sara Dallaspezia and Francesco Benedetti designed the study. Francesco Benedetti obtained the funding for the study. Sara Dallaspezia, Sara Poletti, Cristina Colombo, and Francesco Benedetti were involved in the participants’ recruitment and selection. Cristina Lorenzi and Adele Pirovano performed the genotyping. Sara Dallaspezia and Sara Poletti wrote the first draft of the manuscript, with the other authors contributing to data interpretation and final manuscript preparation. All authors take final responsibility for the decision to submit the manuscript for publication. Sara Dallaspezia, Sara Poletti, and Francesco Benedetti had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

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  1. Department of Clinical Neurosciences, Istituto Scientifico Ospedale San Raffaele, San Raffaele Turro, Via Stamira d’Ancona 20, Milan, Italy

    Sara Dallaspezia, Sara Poletti, Cristina Lorenzi, Adele Pirovano, Cristina Colombo & Francesco Benedetti

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  1. Sara Dallaspezia
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  2. Sara Poletti
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  3. Cristina Lorenzi
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  4. Adele Pirovano
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  6. Francesco Benedetti
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Correspondence to Sara Dallaspezia.

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Dallaspezia, S., Poletti, S., Lorenzi, C. et al. Influence of an Interaction between Lithium Salts and a Functional Polymorphism in SLC1A2 on the History of Illness in Bipolar Disorder. Mol Diagn Ther 16, 303–309 (2012). https://doi.org/10.1007/s40291-012-0004-5

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