"Broad spectrum" antidepressants: is more better for the treatment of depression?
The majority of antidepressants in current use selectively inhibit the reuptake of serotonin and/or norepinephrine. "Broad spectrum" antidepressants are compounds that inhibit the reuptake of norepinephrine, serotonin and dopamine, the three biogenic amines most closely linked to depression. The pharmacological profile of one such compound has recently been described (European Journal of Pharmacology, 461 (2003) 99). DOV 21,947, an azabicyclo[3.1.0]hexane, potently inhibits norepinephrine, serotonin and dopamine reuptake by the corresponding human transporter proteins. DOV 21,947 is orally active in the forced swim and tail suspension tests, preclinical procedures that are highly predictive of antidepressant action in patients. A closely related compound, DOV 216,303 is safe and well-tolerated in Phase I studies. The plasma concentrations of DOV 216,303 following both single and multiple doses appear sufficient to inhibit norepinephrine, serotonin, and dopamine reuptake. Based on the pivotal role proposed for dopamine in depression, it has been hypothesized that a broad spectrum antidepressant will produce a more rapid onset and/or higher efficacy than agents inhibiting the reuptake of serotonin and/or norepinephrine.
Skolnick
Phil
P
DOV Pharmaceutical, Inc., 433 Hackensack Avenue, Hackensack, NJ 07601, USA. pskolnick@dovpharm.com
Popik
Piotr
P
Janowsky
Aaron
A
Beer
Bernard
B
Lippa
Arnold S
AS
D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use*; D001372:Aza Compounds / Q000627:therapeutic use*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000627:therapeutic use*; D003863:Depression / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007103:Immobilization; D008297:Male; D051379:Mice; D014179:Neurotransmitter Uptake Inhibitors / Q000627:therapeutic use*; D013550:Swimming; D016896:Treatment Outcome
C474071:1-(3,4-dichlorophenyl)-3-azabicyclo-(3.1.0)hexane hydrochloride; D000928:Antidepressive Agents; D001372:Aza Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D014179:Neurotransmitter Uptake Inhibitors