Neuroprotective Agents in Mood Disorders: Pathophysiological and Therapeutic Implications

  • Giacomo SalvadoreEmail author
  • Rodrigo Machado-Vieira
  • Husseini K. Manji


Drug development for mood disorders such as major depressive disorder (MDD) and bipolar disorder (BPD) has undergone an important paradigm shift in the last decade due to our expanding knowledge of the pathophysiology and treatment of these illnesses. While previous research focused exclusively on abnormalities of the monoaminergic neurotransmitter systems, more recent preclinical and clinical studies have emphasized the role of impaired neuroplasticity and cellular resilience in mood disorders.

Also informing our thinking for drug development are the neurotrophic/neuroprotective properties associated with several agents currently used as treatments for mood disorders—including antidepressants, mood stabilizers, atypical antipsychotics, and a number of experimental agents currently under investigation. Many of these agents share some potent neurotrophic and neuroprotective properties, exert significant effects on signaling pathways that regulate cellular plasticity, and are believed to act directly on some of the core pathophysiological mechanisms underlying these devastating illnesses.

In this chapter, we discuss how drugs that modulate signaling pathways involved in regulating cell survival and cell death target some of the core pathophysiological mechanisms of BPD and MDD, with a particular emphasis on brain imaging and neuropathological abnormalities in mood disorders. Cellular and molecular mechanisms of action of agents with neurotrophic and neuroplastic properties are also discussed, with a special focus on the mood stabilizers lithium and valproate.


Major depression (MDD) Bipolar disorder (BPD) Imaging Postmortem studies Bcl-2 GSK-3 



Anterior cingulate cortex


Amyotrophic lateral sclerosis


Amyloid peptide precursor protein


B-cell lymphoma 2


Brain Derived Neurotrophic Factor


Bipolar disorder


Choline-containing compounds


central nervous system


phosphocreatine and creatine


Cyclic adenine monophospate response element-binding protein


Dorsolateral prefrontal cortex


Electroconvulsive therapy


Extracellular Signal-Regulated Kinase


Gamma-aminobutyric acid


Glial cell line-derived neurotrophic factor


Gray matter


Glycogen synthase kinase-3


Proton magnetic resonance spectroscopy




Mitogen-activated protein kinases


Major depressive disorder






N-acetyl aspartate


Nerve Growth Factor




Orbitofrontal cortex


Prefrontal cortex




Protein kinase A


Protein kinase C


Subgenual prefrontal cortex


Single nucleotide polymorphism


Selective serotonin reuptake inhibitors


Vascular Endothelial Growth Factor



The authors gratefully acknowledge the support of the Intramural Research Program of the National Institute of Mental Health. Ioline Henter provided outstanding editorial assistance.


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Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  • Giacomo Salvadore
    • 1
    Email author
  • Rodrigo Machado-Vieira
    • 1
    • 2
  • Husseini K. Manji
    • 1
  1. 1.Mood and Anxiety Disorders ProgramNational Institute of Mental HealthBethesdaUSA
  2. 2.Institute and Department of PsychiatryUniversity of Sao PauloMDUSA

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