In recent years, there has been considerable excitement about the possibility that
the “molecular medicine revolution” would lead to identification of numerous putative
targets designed to slow the atrophic/degenerative process in various neuropsychiatric
disorders. Indeed, tremendous progress has been made in the identification of cellular
processes and pathways involved in numerous degenerative diseases; however, to date,
proliferation of candidate drugs has not resulted in viable novel clinical treatments
for these devastating disorders (
1
). Ironically, the article by Bearden et al. (pages 7–16, in this issue) of the journal suggests that an old medication present
in our therapeutic armamentarium for half a century exerts neurotrophic effects not
only in animal models but also in humans. Bearden et al. used high-resolution magnetic resonance imaging and cortical pattern matching methods
to map gray matter differences in 28 bipolar patients, 20 lithium-treated, and 28
healthy control subjects. Their results showed gray matter density was significantly
greater in bipolar patients compared with healthy subjects in diffuse cortical regions,
notably bilateral cingulated and paralimbic cortices, areas utilized in attention,
motivation, and emotion. Additionally, their data revealed greater gray matter density
in the right anterior cingulate in lithium-treated patients relative to the bipolar
subjects not taking lithium. Their lithium-treated sample included subjects who were
on lithium for varying time durations at different individual doses. The lack of difference
in gray mater density between the untreated patients and healthy control subjects,
as well as growing evidence that lithium exerts major effects on a number of cellular
proteins and pathways (vide infra) known to regulate cell atrophy/death, lend support
to the view that gray matter enlargement is mediated through the trophic actions of
lithium in the brain.To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Biological PsychiatryAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- From chemical to drug: Neurodegeneration drug screening and the ethics of clinical trials.Nat Neurosci. 2002; 5: 1027-1029
- A molecular mechanism for the effect of lithium on development.Proc Natl Acad Sci U S A. 1996; 93: 8455-8459
- The multifaceted roles of glycogen synthase kinase 3β in cellular signaling.Prog Neurobiol. 2001; 65: 391-426
- Lithium and valproic acid: Parallels and contrasts in diverse signaling contexts.Pharmacol Ther. 2002; 96: 45-66
- Mood stabilizers target cellular plasticity and resilience cascades: Implications for the development of novel therapeutics.Mol Neurobiol. 2005; 32: 173-202
- Lithium reduces tau phosphorylation by inhibition of glycogen synthase kinase-3.J Biol Chem. 1997; 272 (25326–25322)
- GSK-3α regulates production of Alzheimer’s disease amyloid-β peptides.Nature. 2003; 423: 435-439
- The mood-stabilizing agents lithium and valproate robustly increase the levels of the neuroprotective protein bcl-2 in the CNS.J Neurochem. 1999; 72: 879-882
- Long term lithium treatment suppresses p53 and Bax expression but increases Bcl-2 expression: A prominent role in neuroprotection against excitotoxicity.J Biol Chem. 1999; 274: 6039-6042
- Chronic lithium treatment increases the expression of brain-derived neurotrophic factor in the rat brain.Psychopharmacology (Berl). 2001; 158: 100-106
- Lithium induces brain-derived neurotrophic factor and activates TrkB in rodent cortical neurons: An essential step for neuroprotection against glutamate excitotoxicity.Neuropharmacology. 2002; 43: 1173-1179
- The role of the extracellular signal-regulated kinase signaling pathway in mood modulation.J Neurosci. 2003; 23: 7311-7316
- Support of retinal ganglion cell survival and axon regeneration by lithium through a Bcl-2-dependent mechanism.Invest Ophthalmol Vis Sci. 2003; 44: 347-354
- Enhancement of hippocampal neurogenesis by lithium.J Neurochem. 2000; 75: 1729-1734
- Clinical and preclinical evidence for the neurotrophic effects of mood stabilizers: Implications for the pathophysiology and treatment of manic-depressive illness.Biol Psychiatry. 2000; 48: 740-754
- Potential use of lithium in neurodegenerative disorders.in: Bauer M. Grof P. Muller-Oerlinghausen B. Lithium in Neuropsychiatry The Comprehensive Guide. Informa UK Ltd, Abingdon, Oxon, United Kingdom2006: 381-398
- Regulation and function of glycogen synthase kinase-3 isoforms in neuronal survival.J Biol Chem. 2007; 282: 3904-3917
- Post-insult treatment with lithium reduces brain damage and facilitates neurological recovery in a rat ischemia/reperfusion model.Proc Natl Acad Sci U S A. 2003; 100: 6210-6215
- Chronic treatment with a low dose of lithium protects the brain against ischemic injury by reducing apoptotic death.Stroke. 2003; 34: 1287-1292
- Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo.Proc Natl Acad Sci U S A. 2005; 102: 6990-6995
- Neuroprotective effects of regulators of the glycogen synthase kinase-3β signaling pathway in a transgenic model of Alzheimer’s disease are associated with reduced amyloid precursor protein phosphorylation.J Neurosci. 2007; 27: 1981-1991
- Neuroimaging and neuropathological studies of depression: Implications for the cognitive-emotional features of mood disorders.Curr Opin Neurobiol. 2001; 11: 240-249
- Lithium increases N-acetyl-aspartate in the human brain: In vivo evidence in support of bcl-2’s neurotrophic effects?.Biol Psychiatry. 2000; 48: 1-8
- Lithium-induced increase in human brain grey matter.Lancet. 2000; 356: 1241-1242
- Cortical magnetic resonance imaging findings in familial pediatric bipolar disorder.Biol Psychiatry. 2005; 58: 197-203
- Manic-Depressive Illness: Bipolar and Recurrent Unipolar Disorders. 2nd ed. Oxford University Press, New York2007
- Lithium protection against glutamate excitotoxicity in rat cerebral cortical neurons: Involvement of NMDA receptor inhibition possibly by decreasing NR2B tyrosine phosphorylation.J Neurochem. 2002; 80: 589-597
- Does long-term medication with lithium, clozapine or antidepressants prevent or attenuate dementia in bipolar and depressed patients?.Int J Psychiatry Clin Pract. 2007; 11: 2-8
- Lithium and risk for Alzheimer’s disease in elderly patients with bipolar Disorder.Br J Psychiatry. 2007; 190: 359-360
Article info
Publication history
Accepted:
April 9,
2007
Received:
April 9,
2007
Identification
Copyright
© 2007 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
