Neurotrophic signaling cascades are major long-term targets for lithium: clinical implications Peixiong Yuan a , Todd D. Gould a , Neil A. Gray a , Rosilla F. Bachmann a , Robert J. Schloesser a , Martin J.K. Lan a , Jing Du a , Gregory J. Moore b , Husseini K. Manji a, * a Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, NIMH, NIH, 49 Convent Drive, Building 49, Room B1EE16, Bethesda, MD 20892-4405, USA b Department of Psychiatry, Wayne State University School of Medicine, Detroit, MI, USA Abstract Although mood disorders have traditionally been regarded as good prognosis diseases, a growing body of data suggests that the long-term outcome for many patients is often much less favorable than previously thought. Recent morphometric studies have been investigating potential structural brain changes in mood disorders, and there is now evidence from a variety of sources demonstrating significant reductions in regional CNS volume, as well as regional reductions in the numbers and/or sizes of glia and neurons. In this perspective paper, we discuss the preclinical and clinical evidence that lithium has neuroprotective and neurotrophic effects, and furthermore, show that these effects may have great relevance for the optimal treatment of severe mood disorders. Lithium has been noted to have neuroprotective effects in cell culture, and in animal models of neurodegeneration such as stroke, Huntington’s disease and Alzheimer’s disease. This may be due to the findings that lithium regulates the expression and/or activity of numerous molecules and enzymes involved in neuroplasticity, neuroprotection and mitochondrial function including bcl-2, GSK-3 and the ERK/MAP kinase pathway. Emerging clinical evidence additionally suggests that lithium may have similar effects in patients; these findings include an increase in N-acetyl aspartate (NAA) and gray matter in patients following long-term lithium treatment. Together, the data has implications not only for the optimal treatment of severe mood disorders, but potentially also for the treatment of other, more classical, neurodegenerative disorders. q 2004 Association for Research in Nervous and Mental Disease. Published by Elsevier B.V. All rights reserved. Keywords: Manic depressive illness; Lithium; Neuroprotection; Alzheimer’s disease; Stroke; Huntington’s disease; Brain; Psychopharmacology; Mood stabilizer 1. Introduction Bipolar disorder is among the most disabling of all medical disorders. It frequently appears in early life, runs a chronic course, and adversely affects the prognosis of other medical illnesses. This is not altogether surprising given the extensive bidirectional ‘mind-body’ interactions mediated via the autonomic nervous system, immune system and a host of neuroendocrine factors. In the context of the high morbidity and mortality associated with severe mood disorders, it is unfortunate that their neurobiological determinants have not been precisely defined. Of all brain systems, the monoaminergic neurotransmitter systems have received the greatest attention in neurobiologic studies of mood disorders, which were implicated by the following observations: (i) effective antidepressant drugs exert their primary biochemical effects by regulating intrasynaptic concentrations of serotonin and norepinephrine; (ii) anti- hypertensives which deplete these monoamines sometimes precipitate depressive episodes in susceptible individuals. Furthermore, the monoaminergic systems are exten- sively distributed throughout the network of limbic, striatal, and prefrontal cortical neuronal circuits thought to support the behavioral and visceral manifestations of mood disorders. Clinical studies over the past 40 years have attempted to uncover the biological factors mediating the pathophysiology of depressive disorders utilizing a variety 1566-2772/$ - see front matter q 2004 Association for Research in Nervous and Mental Disease. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.cnr.2004.09.006 Clinical Neuroscience Research 4 (2004) 137–153 www.elsevier.com/locate/clires * Corresponding author. Tel.: C1 301 496 9802; fax: C1 301 480 0123. E-mail address: manjih@intra.nimh.nih.gov (H.K. Manji).