Enhanced norepinephrine output during long-term desipramine treatment: a possible role for the extraneuronal monoamine transporter (SLC22A3).
To study the delay (2-6 weeks) between initial administration of norepinephrine reuptake inhibitor antidepressants and onset of clinical antidepressant action, we examined the effects of desipramine treatment on urinary and plasma catecholamines and their metabolites during the initial 6 weeks of treatment in depressed patients. Catecholamines and metabolites in 24-h urine collections and 8:00 a.m. plasma samples were measured at baseline and after 1, 4, and 6 weeks of desipramine treatment. Desipramine treatment produced significant increases in urinary norepinephrine (NE) and normetanephrine (NMN) and plasma NE at Weeks 4 and 6, but not at Week 1. The ratio of urinary NE/NMN was increased at Weeks 4 and 6, suggesting a reduction in the metabolism of NE to NMN at extraneuronal sites by Weeks 4 and 6. The increases in urinary NE and NMN and plasma NE at Weeks 4 and 6 of desipramine treatment were associated with a reduction in the conversion of NE to NMN. This would be compatible with a blockade of the extraneuronal monoamine transporter (organic cation transporter 3; SLC22A3) by NMN. Inhibition of the extraneuronal monoamine transporter may be an important component in the clinical pharmacology of the norepinephrine reuptake inhibitor antidepressant drugs, such as desipramine.
Mooney
John J
JJ
Department of Psychiatry, Harvard Medical School, Boston, MA, USA. jmooney@bidmc.harvard.edu
Samson
Jacqueline A
JA
Hennen
John
J
Pappalardo
Kathleen
K
McHale
Nancy
N
Alpert
Jonathan
J
Koutsos
Martha
M
Schildkraut
Joseph J
JJ
D018759:Adrenergic Uptake Inhibitors / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use*; D000328:Adult; D002395:Catecholamines / Q000097:blood / Q000378:metabolism / Q000652:urine; D003866:Depressive Disorder / Q000097:blood / Q000188:drug therapy* / Q000652:urine; D003891:Desipramine / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008995:Monoamine Oxidase / Q000378:metabolism; D009638:Norepinephrine / Q000096:biosynthesis* / Q000097:blood / Q000652:urine; D009647:Normetanephrine / Q000096:biosynthesis / Q000097:blood / Q000652:urine; D027701:Organic Cation Transport Proteins / Q000187:drug effects* / Q000378:metabolism*; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects / Q000378:metabolism; D000099254:Organic Cation Transporter 3
D018759:Adrenergic Uptake Inhibitors; D002395:Catecholamines; D003891:Desipramine; D008995:Monoamine Oxidase; D009638:Norepinephrine; D009647:Normetanephrine; D027701:Organic Cation Transport Proteins; D018341:Receptors, Adrenergic, alpha-2; D000099254:Organic Cation Transporter 3