A longitudinal study of the effects of lithium treatment on prefrontal and subgenual prefrontal gray matter volume in treatment-responsive bipolar disorder patients.
OBJECTIVE
Recent molecular, preclinical, and preliminary clinical studies suggest that the therapeutic effects of mood stabilizers may be mediated by modulating expression of potent neurotrophic and neuroprotective factors having the potential to reverse impairments of cellular resilience, reductions in brain volume, and cell death or atrophy. Our main goal was to investigate the potential clinical significance of these findings in relation to bipolar disorder.


METHODS
The longitudinal effect of lithium on brain gray matter volume was investigated in well-characterized (DSM-IV criteria) bipolar depressed subjects (N = 28) at baseline (medication-free) and after lithium administration (4 weeks). Total brain gray matter, prefrontal gray matter, and left subgenual prefrontal gray matter volumes were determined using validated semiautomated segmentation and region of interest methodology. The study was conducted from November 1997 until April 2004 at Wayne State University School of Medicine, Detroit, Mich.


RESULTS
Significant increases in total brain gray matter volume in bipolar subjects were observed after 4 weeks of lithium administration (p = .0043). Moreover, regional analyses in the bipolar subjects revealed significant differences between responders (>50% decrease in Hamilton Depression Rating Scale total score) and nonresponders; only responders showed a significant increase in gray matter volume in the prefrontal cortex (p = .003) and an increase at trend level in the left subgenual prefrontal cortex volume (p = .0786).


CONCLUSIONS
The increase in gray matter volume in these areas, which various neuroimaging and postmortem neuropathology studies have implicated in the neuropathophysiology of bipolar disorder, suggests that the observed effects may be linked to clinical response. The findings also support the notion that future treatments that more directly target molecules in critical central nervous system pathways that regulate cellular plasticity hold promise as novel, improved, long-term treatments for mood disorders as well as some neurodegenerative conditions, such as Alzheimer's disease.


BACKGROUND
clinicaltrials.gov Identifier: NCT00870311.
Moore
Gregory J
GJ
Behavioral Neuroimaging Research Division, Departments of Psychiatry and Radiology, Penn State University College of Medicine, Hershey, PA 17033, USA. gmoore@psu.edu
Cortese
Bernadette M
BM
Glitz
Debra A
DA
Zajac-Benitez
Caroline
C
Quiroz
Jorge A
JA
Uhde
Thomas W
TW
Drevets
Wayne C
WC
Manji
Husseini K
HK
D000328:Adult; D018692:Antimanic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D001714:Bipolar Disorder / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology*; D039721:Diagnostic and Statistical Manual of Mental Disorders; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D016651:Lithium Carbonate / Q000494:pharmacology* / Q000627:therapeutic use*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D017397:Prefrontal Cortex / Q000033:anatomy & histology / Q000187:drug effects / Q000503:physiopathology; D012720:Severity of Illness Index; D011795:Surveys and Questionnaires; D055815:Young Adult
D018692:Antimanic Agents; D016651:Lithium Carbonate