0
Get Alert
Please Wait... Processing your request... Please Wait.
You must sign in to sign-up for alerts.

Please confirm that your email address is correct, so you can successfully receive this alert.

1
Images In Neuroscience   |    
Depression, III: Treatments
Husseini Manji, Ph.D.
Am J Psychiatry 2003;160:24-24. doi:10.1176/appi.ajp.160.1.24

Antidepressant treatments are currently targeted to synaptic elements that regulate concentrations of serotonin and norepinephrine at the postsynaptic monoamine receptors. Drug development for mood disorders has relied heavily on this focus in the past; so heavily, in fact, that there is little mechanistic diversity among current antidepressant drugs. Recently, however, investigations into the mechanisms of antidepressant actions have focused on downstream intracellular elements that are modulated by chronic, but not acute, antidepressant administration, particularly the F1 mediating cellular resilience and neuroplasticity. Two of these intracellular signaling pathways (involving the neuroprotective protein bcl-2 and brain-derived neurotrophic factor [BDNF]), altered by both antidepressants and mood stabilizers, are known to be neuroprotective and to mediate neurotrophic events. One pathway first involves signaling by growth factors (especially BDNF) through the intracellular enzymes ERK and RSK followed by CREB activation, leading ultimately to an increase in the transcription of bcl-2 (see Figure). A second pathway involves the activation of the G protein-related enzymes adenylate cyclase and protein kinase A, followed by CREB activation, leading subsequently to an increase in the expression of BDNF, one of the cellular growth factors. We already know that antidepressant treatment increases CREB phosphorylation (i.e., CREB activation) in the brain of rats. Antidepressants and ECT each increase the expression of BDNF. Chronic antidepressant treatment results in neurogenesis (i.e., new neuronal birth) in the hippocampus of rats (and presumably of humans). Lithium and valproate each increase the expression of bcl-2 at least in part through activation of the ERK-MAP intracellular cascade. Lithium is frankly neuroprotective in several animal models of neurodegeneration and actually increases gray matter volumes (possibly through reversal of illness-related atrophy) in patients with bipolar disorder. In addition, enhancement of neurotrophic pathways is apparent by both antidepressant and mood-stabilizing treatments. Thus, a potential novel target for treatment development in mood disorders will be medications with neurotrophic properties, some examples of which are under development currently, including phosphodiesterase (PDE4) inhibitors and AMPA receptor modulators (which increase BDNF expression).

Address reprint requests to Dr. Tamminga, Maryland Psychiatric Research Center, University of Maryland, P.O. Box 21247, Baltimore, MD 21228; ctamming@mprc.umaryland.edu (e-mail). Image courtesy of Dr. Manji.

 
+

References

+
+

CME Activity

There is currently no quiz available for this resource. Please click here to go to the CME page to find another.
Submit a Comments
Please read the other comments before you post yours. Contributors must reveal any conflict of interest.
Comments are moderated and will appear on the site at the discertion of APA editorial staff.

* = Required Field
(if multiple authors, separate names by comma)
Example: John Doe



Related Content
Articles
Books
The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition > Chapter 15.  >
The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition > Chapter 15.  >
The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition > Chapter 20.  >
The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition > Chapter 20.  >
The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition > Chapter 20.  >
Topic Collections
Psychiatric News
APA Guidelines
PubMed Articles