Thanks Marianco for your reply. I agree that your insights are invaluable. I can definitely appreciate the confounding issues of individual variance, receptor localization, and neurotransmitter-neurotransmitter interactions when trying to tease out antidepressant mechanism. I also agree that after all these years, wellbutrin in particular is a bit mysterious.
I also applaud your willingness to accept the effects of psychotropics that most deem "non significant", such as the receptor and
CYP interactions that you've pointed out for various drugs.
And I suppose that's why I'm going to attempt to convince you further of the dopaminergic effects of wellbutrin. While therapeutic use of wellbutrin does not inhibit the DAT to the >50% level that is seen with something like methylphenidate or cocaine, the literature clearly does indicate that it blocks the DAT in humans (not just rats). The value in the following studies usually shows values around 20% inhibition in the striatum for bupropion treatment. One of the most interesting looked at just bupropion's main metabolite (called radafaxine in the study), and also took into account its pharmacokinetics. While this value might be "low" and very different from the action of other DAT blockers (long lasting), it does seem to be a consistent effect of wellbutrin treatment, something that isn't documented in humans with any other antidepressant (to my knowledge), including zoloft and effexor (although the people at wyeth seem to be pretty protective of letting any information out that would indict effexor as being habit forming).
Also, regarding your statement that a drug that raises dopamine substantially should have efficacy in restless leg, dystonia, and parkinson's. From what I know of these disorders and from the literature, drugs that increase dopamine via DAT blockade can provide "adjunct" therapy at best, and sometimes make things worse. Other dopaminergic mechanisms such as direct dopamine agonism with l-dopa or other receptor agonist are usually preferred. Thus, wellbutrin's inefficacy in treating these symtpoms does not seem to rule out its dopaminergic activity.
Here are the studies that I'm referring to:
Volkow ND, Wang GJ, Fowler JS, Learned-Coughlin S, Yang J, Logan J, Schlyer D, Gatley JS, Wong C, Zhu W, Pappas N, Schueller M, Jayne M, Carter P, Warner D, Ding YS, Shea C, Xu Y. The slow and long-lasting blockade of dopamine transporters in human brain induced by the new antidepressant drug radafaxine predict poor reinforcing effects. Biol Psychiatry. 2005 Mar 15;57(6):640-6.
Argyelan M, Szabo Z, Kanyo B, Tanacs A, Kovacs Z, Janka Z, Pavics L. Dopamine transporter availability in medication free and in bupropion treated depression: a 99mTc-TRODAT-1 SPECT study. J Affect Disord. 2005 Dec;89(1-3):115-23.
Szabo Z, Argyelan M, Kanyo B, Pavics L, Janka Z. [Change of dopamine transporter activity (DAT) during the action of bupropion (in depression)] Neuropsychopharmacol Hung. 2004 Jun;6(2):79-81.
Meyer JH, Goulding VS, Wilson AA, Hussey D, Christensen BK, Houle S. Bupropion occupancy of the dopamine transporter is low during clinical treatment. Psychopharmacology (Berl). 2002 Aug;163(1):102-5.
Learned-Coughlin SM, Bergstrom M, Savitcheva I, Ascher J, Schmith VD, Langstrom B. In vivo activity of bupropion at the human dopamine transporter as measured by positron emission tomography. Biol Psychiatry. 2003 Oct 15;54(8):800-5.