Differential physiological effects of a low dose and high doses of venlafaxine in major depression.
Venlafaxine is an antidepressant drug with demonstrated serotonin (5-HT) and norepinephrine (NE) reuptake blockade properties in electrophysiological and microdialysis experiments in laboratory animals. In healthy volunteers, its 5-HT reuptake-inhibiting potential has also been clearly documented, but not its NE reuptake blockade action. This double-blind study compared the effects of a low dose (75 mg) and of a forced titration of high (up to 375 mg in 1 wk) daily doses of venlafaxine. Forty-four patients with major depression according to DSM-IV criteria were assessed bi-weekly for the first 2 wk and weekly for the next 2 wk. Inhibition of 5-HT reuptake was estimated using the depletion of whole-blood 5-HT, while that of NE was assessed using the attenuation of the systolic blood-pressure elevations produced by intravenous injections of tyramine. Forty-two patients completed the study. Both the low and the high doses of venlafaxine decreased the levels of 5-HT to the same extent: the reduction was of about 55% after 1 wk and of 75% after 4 wk. The 75 mg/d dose of venlafaxine did not alter the tyramine pressor response, whereas, in patients receiving the higher regimens of venlafaxine, there was a significant attenuation of the pressor effect of tyramine. There was no significant difference between the two treatment arms regarding the modifications of the depression scores. The present data showed that, at its minimal effective dose in depression (75 mg/d), venlafaxine acted as a selective 5-HT reuptake inhibitor, whereas when administered at higher doses (225 and 375 mg/d), it acted as a dual 5-HT and NE reuptake inhibitor.
Debonnel
Guy
G
Department of Psychiatry, McGill University, Montréal, QC, and Royal Ottawa Hospital, ON, Canada.
Saint-André
Elise
E
Hébert
Chantal
C
de Montigny
Claude
C
Lavoie
Normand
N
Blier
Pierre
P
D018759:Adrenergic Uptake Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D000328:Adult; D018687:Antidepressive Agents, Second-Generation / Q000008:administration & dosage* / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D003511:Cyclohexanols / Q000008:administration & dosage* / Q000494:pharmacology; D003865:Major Depressive Disorder / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009638:Norepinephrine / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000187:drug effects* / Q000378:metabolism; D011569:Psychiatric Status Rating Scales; D012701:Serotonin / Q000097:blood; D050486:Serotonin Plasma Membrane Transport Proteins / Q000187:drug effects* / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D012720:Severity of Illness Index; D013997:Time Factors; D016896:Treatment Outcome; D014439:Tyramine / Q000494:pharmacology; D000069470:Venlafaxine Hydrochloride
D018759:Adrenergic Uptake Inhibitors; D018687:Antidepressive Agents, Second-Generation; D003511:Cyclohexanols; D009638:Norepinephrine; D050484:Norepinephrine Plasma Membrane Transport Proteins; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D014439:Tyramine; D000069470:Venlafaxine Hydrochloride; C493230:SLC6A4 protein, human