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CNS Disorders

  1. Richard A. Glennon1,
  2. Leslie Iversen2

Published Online: 15 SEP 2010

DOI: 10.1002/0471266949.bmc101.pub2

Burger's Medicinal Chemistry and Drug Discovery

Burger's Medicinal Chemistry and Drug Discovery

How to Cite

Glennon, R. A. and Iversen, L. 2010. Antidepressants. Burger's Medicinal Chemistry and Drug Discovery. 219–264.

Author Information

  1. 1

    Virginia Commonwealth University, Richmond, VA

  2. 2

    University of Oxford, Oxford, UK

Publication History

  1. Published Online: 15 SEP 2010


This chapter reviews the antidepressant drugs currently available in Europe and/or the United States from the perspectives of their clinical efficacy, pharmacokinetics, pharmacology, structure–activity relationships, metabolism, and mechanisms of action. The older nonselective monoamine oxidase inhibitors (e.g., phenelzine, tranylcypromine) have largely been replaced by agents that selectively inhibit monoamine oxidase A (e.g., moclobemide) or by inhibitors of norepinephrine/serotonin monoamine transporter reuptake mechanisms. The first generation of such drugs, the tricyclic antidepressants, suffered from a number of dangerous and unpleasant adverse side effects caused by their many other pharmacological actions on the heart and on cholinergic and other monoamine receptors in the brain. Most of the current generation of antidepressants are serotonin-selective reuptake inhibitors or mixed norepinephrine/serotonin reuptake inhibitors that possess a safer side-effect profile. These drugs have gained widespread use in the treatment of depression and a number of related psychiatric conditions, including phobias and the treatment of generalized anxiety disorder (GAD). Some agents that act as norepinephrine-selective reuptake inhibitors (e.g., reboxetine) are also clinically effective and there is considerable overlap between noradrenergic and serotonergic mechanisms in the CNS. Monoamine selectivity can also be altered by the formation of active metabolites in vivo. All antidepressants require several weeks of treatment before the maximum clinical benefit is seen. This may be attributable to drug-induced alterations in the expression of receptors in brain (e.g., downregulation of 5-HT1A receptors) and/or alterations in the expression of neurotrophic factors (e.g., brain-derived neurotrophic factor, vascular endothelial growth factor) associated with changes in neurogenesis in certain brain regions. New approaches to future antidepressant drug discovery include antagonists for glutamate NMDA receptors, substance P NK1 receptors, corticotrophin releasing factor receptors, or agonists/antagonists for galanin receptors.


  • norepinephrine;
  • serotonin;
  • dopamine;
  • monoamine oxidase inhibitors;
  • monoamine transporters;
  • serotonin 5-HT receptors;
  • serotonin-selective reuptake inhibitors;
  • adrenoceptors;
  • norepinephrine transporter;
  • tricyclic antidepressants;
  • antidepressant side effects;
  • fluoxetine (Prozac);
  • paroxetine;
  • imipramine;
  • amitriptyline