title: Influence of an interaction between lithium salts and a functional polymorphism in SLC1A2 on the history of illness in bipolar disorder.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Clinical Neurosciences, Istituto Scientifico Ospedale San Raffaele, San Raffaele Turro, Milan, Italy. dallaspezia.sara@hsr.it
authors.forename: Sara
authors.initials: S
authors.lastname: Dallaspezia
authors.forename: Sara
authors.initials: S
authors.lastname: Poletti
authors.forename: Cristina
authors.initials: C
authors.lastname: Lorenzi
authors.forename: Adele
authors.initials: A
authors.lastname: Pirovano
authors.forename: Cristina
authors.initials: C
authors.lastname: Colombo
authors.forename: Francesco
authors.initials: F
authors.lastname: Benedetti
mesh_terms: D000328:Adult; D000483:Alleles; D001714:Bipolar Disorder / Q000188:drug therapy* / Q000235:genetics; D027342:Excitatory Amino Acid Transporter 2; D005260:Female; D059647:Gene-Environment Interaction; D050491:Glutamate Plasma Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D008094:Lithium / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012008:Recurrence; D044465:White People
chemical_list: D027342:Excitatory Amino Acid Transporter 2; D050491:Glutamate Plasma Membrane Transport Proteins; C493397:SLC1A2 protein, human; D008094:Lithium