Search for biological correlates of depression and mechanisms of action of antidepressant treatment modalities. Do neuropeptides play a role?
Dysregulation of the monoaminergic systems is likely a sufficient but not a necessary cause of depression. A wealth of data indicates that neuropeptides, e.g., NPY, CRH, somatostatin, tachykinins and CGRP play a role in affective disorders and alcohol use/abuse. This paper focuses on NPY in etiology and pathophysiology of depression. Decreased peptide and mRNA NPY were found in hippocampus of both the genetic, e.g., the FSL strain, and environmental rat models of depression, e.g., chronic mild stress and early life maternal separation paradigms. Rat models of alcoholism also show altered NPY. Furthermore, NPY is also reduced in CSF of depressed patients. Antidepressive treatments tested so far (lithium, topiramate, SSRIs, ECT and ECS, wheel running) increase NPY selectively in rat hippocampus and in human CSF. Moreover, NPY given icv to rat has antidepressive effects which are antagonized by NPY-Y1 blockers. The data support our hypothesis that the NPY system dysregulation constitutes one of the biological underpinnings of depression and that one common mechanism of action of antidepressive treatment modalities may be effects on NPY and its receptors. In a novel paradigm, early life maternal separation was superimposed on "depressed" FSL and control rats and behavioral and brain neurochemistry changes observed in adulthood. The consequences were more deleterious in genetically vulnerable FSL. Early antidepressive treatment modulated the adult sequelae. Consequently, if these data are confirmed, the ethical and medical question that will be asked is whether it is permissible and advisable to consider prophylactically treating persons at risk.
Mathé
Aleksander A
AA
Karolinska Institutet, Department of Clinical Neuroscience, Karolinska University Hospital Huddinge, Psychiatry M56, E-141 86 Stockholm, Sweden. aleksander.mathe@ki.se
Husum
Henriette
H
El Khoury
Aram
A
Jiménez-Vasquez
Patricia
P
Gruber
Susanne H M
SH
Wörtwein
Gitta
G
Nikisch
Georg
G
Baumann
Pierre
P
Agren
Hans
H
Andersson
Weronica
W
Södergren
Asa
A
Angelucci
Francesco
F
D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use*; D003866:Depressive Disorder / Q000134:cerebrospinal fluid / Q000188:drug therapy* / Q000628:therapy; D004195:Disease Models, Animal; D004565:Electroconvulsive Therapy; D005632:Fructose / Q000031:analogs & derivatives / Q000627:therapeutic use; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D018020:Lithium Compounds / Q000627:therapeutic use; D008426:Maternal Deprivation; D009478:Neuropeptide Y / Q000134:cerebrospinal fluid / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011919:Rats, Inbred Strains; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use; D012931:Social Environment; D000077236:Topiramate
D000928:Antidepressive Agents; D005632:Fructose; D018020:Lithium Compounds; D009478:Neuropeptide Y; D012333:RNA, Messenger; D017367:Selective Serotonin Reuptake Inhibitors; D000077236:Topiramate