1. ¹Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
2. ²Department of Psychiatry, Veterans Affairs Connecticut Healthcare System, West Haven, CT, USA
3. ³Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, CT, USA
4. ⁴Department of Genetics and Neurobiology, Yale University School of Medicine, New Haven, CT, USA

Correspondence: Dr MP Shah, Department of Psychiatry, Yale University School of Medicine, 300 George Street, Suite 901, New Haven, CT 06511, USA. Tel: 203 785 6180; Fax: 203 737 2513; E-mail: maulik.p.shah@gmail.com

Received 20 June 2008; Revised 23 September 2008; Accepted 11 October 2008; Published online 26 November 2008.

Abstract

Bipolar disorder (BD) is associated with abnormalities of the ventral anterior cingulate cortex (vACC) and its connection sites, including the amygdala, which are key components of a corticolimbic neural system that subserves emotional regulation. Decreased functional connectivity from the vACC to the amygdala in healthy individuals is associated with the short 's' allele—as opposed to the long 'l' allele—of a well-known serotonin transporter promoter polymorphism (5-HTTLPR, locus SLC6A4), as are features of BD. This study tests the hypothesis that the s allele influences dysfunction in the vACC–amygdala neural system in BD. A total of 30 euthymic individuals with BD (20 s carriers, 10 ll) and 48 healthy comparison (HC) participants (34 s, 14 ll) participated in an event-related functional magnetic resonance imaging scan while processing fearful, happy, or neutral faces. During fear and happy face processing, vACC activation was significantly lower in the BD compared to the HC group, and in s carriers compared to ll individuals within both the HC and BD groups, such that BD s carriers exhibited the greatest magnitude of vACC dysfunction. No significant differences were detected in amygdala activation. The findings suggest that the 5-HTTLPR s allele may contribute to a trait-related, genetically derived, neurobiological subgroup within BD characterized by prominent vACC dysfunction. Future treatment may be optimized for this BD subgroup by targeting the serotonergic system and the vACC.