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Neuroprotective Agents in Mood Disorders: Pathophysiological and Therapeutic Implications

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

Abstract

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.

Keywords

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

Abbreviations

ACC

Anterior cingulate cortex

ALS

Amyotrophic lateral sclerosis

APP

Amyloid peptide precursor protein

Bcl-2

B-cell lymphoma 2

BDNF

Brain Derived Neurotrophic Factor

BPD

Bipolar disorder

Cho

Choline-containing compounds

CNS

central nervous system

Cr

phosphocreatine and creatine

CREB

Cyclic adenine monophospate response element-binding protein

DLPFC

Dorsolateral prefrontal cortex

ECT

Electroconvulsive therapy

ERK

Extracellular Signal-Regulated Kinase

GABA

Gamma-aminobutyric acid

GDNF

Glial cell line-derived neurotrophic factor

GM

Gray matter

GSK-3

Glycogen synthase kinase-3

1H MRS

Proton magnetic resonance spectroscopy

HPA

hypothalamic-pituitary-adrenal

MAPK

Mitogen-activated protein kinases

MDD

Major depressive disorder

mI

myo-inositol

MPTP

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

NAA

N-acetyl aspartate

NGF

Nerve Growth Factor

NMDA

N-methyl-D-aspartate

OFC

Orbitofrontal cortex

PFC

Prefrontal cortex

PI-3-K

Phosphatidylinositol-3-kinase

PKA

Protein kinase A

PKC

Protein kinase C

SGPFC

Subgenual prefrontal cortex

SNP

Single nucleotide polymorphism

SSRIs

Selective serotonin reuptake inhibitors

VEGF

Vascular Endothelial Growth Factor

Notes

Acknowledgements

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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