, Volume 232, Issue 7, pp 1325–1336 | Cite as

Lithium and GSK-3β promoter gene variants influence cortical gray matter volumes in bipolar disorder

  • Francesco Benedetti
  • Sara Poletti
  • Daniele Radaelli
  • Clara Locatelli
  • Adele Pirovano
  • Cristina Lorenzi
  • Benedetta Vai
  • Irene Bollettini
  • Andrea Falini
  • Enrico Smeraldi
  • Cristina Colombo
Original Investigation



Lithium is the mainstay for the treatment of bipolar disorder (BD) and inhibits glycogen synthase kinase-3β (GSK-3β). The less active GSK-3β promoter gene variants have been associated with less detrimental clinical features of BD. GSK-3β gene variants and lithium can influence brain gray and white matter structure in psychiatric conditions, so we studied their combined effect in BD.


The aim of this study is to investigate the effects of ongoing long-term lithium treatment and GSK-3β promoter rs334558 polymorphism on regional gray matter (GM) volumes of patients with BD.

Materials and methods

GM volumes were estimated with 3.0 Tesla MRI in 150 patients affected by a major depressive episode in course of BD. Duration of lifetime lithium treatment was retrospectively assessed. Analyses were performed by searching for significant effects of lithium and rs334558 in the whole brain.


The less active GSK-3β rs334558*G gene promoter variant and the long-term administration of lithium were synergistically associated with increased GM volumes in the right frontal lobe, in a large cluster encompassing the boundaries of subgenual and orbitofrontal cortex (including Brodmann areas 25, 11, and 47). Effects of lithium on GM revealed in rs334558*G carriers only, consistent with previously reported clinical effects in these genotype groups, and were proportional to the duration of treatment.


Lithium and rs334558 influenced GM volumes in areas critical for the generation and control of affect, which have been widely implicated in the process of BD pathophysiology. In the light of the protective effects of lithium on white matter integrity, our results suggest that the clinical effects of lithium associate with a neurotrophic effect on the whole brain, probably mediated by GSK-3β inhibition.


Lithium GSK-3β Neuroplasticity Bipolar disorder Gray matter 


Authors and contributors

All individuals included as authors of papers contributed substantially to the scientific process leading up to the writing of the paper. FB designed the study. ES, CC, FB, and AF obtained the funding. CL and CC were involved in participants’ recruitment and selection and collected the clinical data. SP, DR, IB, and BV carried out the brain imaging scanning with the neuroradiological supervision of AF and post-processed the images. SP carried out the imaging-genetic analysis with contributions from FB. CL and AP performed the genotyping. FB wrote the first draft of the manuscript. FB and SP 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. All authors take final responsibility for the decision to submit for publication. The authors are entirely responsible for the scientific content of the paper.


The CERMAC received research grants from the Italian Ministry of University and Scientific Research, from the Italian Ministry of Health, from the European Union (FP7 grant 222963), from Trenta ore per la Vita Association, and from Janssen-Cilag.

Conflict of interest

None of the authors have conflicts of interest.


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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Francesco Benedetti
    • 1
    • 3
  • Sara Poletti
    • 1
    • 3
  • Daniele Radaelli
    • 1
    • 3
  • Clara Locatelli
    • 1
    • 3
  • Adele Pirovano
    • 1
  • Cristina Lorenzi
    • 1
  • Benedetta Vai
    • 1
    • 3
    • 4
  • Irene Bollettini
    • 1
    • 3
    • 5
  • Andrea Falini
    • 2
    • 3
  • Enrico Smeraldi
    • 1
    • 3
  • Cristina Colombo
    • 1
  1. 1.Department of Clinical NeurosciencesScientific Institute and University Vita-Salute San RaffaeleMilanItaly
  2. 2.Department of NeuroradiologyScientific Institute and University Vita-Salute San RaffaeleMilanItaly
  3. 3.C.E.R.M.A.C. (Centro di Eccellenza Risonanza Magnetica ad Alto Campo)University Vita-Salute San RaffaeleMilanItaly
  4. 4.PhD Program in Evolutionary PsychopathologyLibera Università Maria Ss. AssuntaRomeItaly
  5. 5.PhD Program in Philosophy and Sciences of Mind, Neuroscience sectionUniversity Vita-Salute San RaffaeleMilanItaly

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