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Originally Posted by Novick Marianco,
What are the dopaminergic effects you notice in your patients recieving high dose effexor?
Obviously like you've expressed, effexor, like most antidepressants is going to have consequences on the dopaminergic system (changes in levels and receptor density). However, it's been my personal experience that wellbutrin "crosses over" much more with something like ritalin or amphetamine compared to high dose effexor (>225mg). I've noticed this in terms of motivation, concentration and sense of well being.
While I understand that clinical human respsonse is much more important than effects in rats, an interesting observation about effexor is that it's documented to increase D3 receptor density in the exact same area of the brain (islands of cajella) that we notice increased D3 expression in our HYPOdopaminergic rats. The D3 receptor is an auto-receptor that acts as a "brake" on dopamine release. When effexor is given along with a D3 agonist, rats have trouble discriminating it from cocaine. One interpretation (though far from the only one) is that the administration of the D3 agonist effectively downregulates effexor's effect on D3 receptors, preventing their sensitization, allowing for increased dopaminergic activity. Marianco, do you have any experience with priampaxole used to augment antidepressants? |
At high doses of Effexor, I would expect dopamine effects to take place - including improved attention, organization on tasks, reduced depressive symptoms, reduced blood pressure (negating the expected higher blood pressure from increasing norepinephrine).
Unfortunately, almost none of my patients have been able tolerate Effexor at high doses for long. The one that did tolerate it (with no side effects) had inadequate reponse - continuing to be depressed despite treatment at about 575 mg a day. Akathisia - from excessive serotonine activity - is the primary limiting factor. But for the patients I treat, Effexor has not been very tolerable. I keep it in mind, however, since some do respond to Effexor, particularly at doses up to 225 mg a day.
Each clinician may have a different experience than I, since everyone's patient population is different and may have different responses to medications. As the saying goes, "your mileage may vary".
Note that dopamine activity regulates norepinephrine output in the brain through a tract from the dopamine nuclei to the locus ceruleus, possibly contributing to some of dopamine's somewhat paradoxical effects: increased calmness, sedation, and lowered blood pressure.
Pramipexole (Mirapex) is an interesting medication which has its use in psychiatry to treat depression (besides its neurological use to treat Parkinson's Disease and Restless Legs Syndrome; and its use in Fibromyalgia). As far as I know, it is a dopamine agonist on D2, D3 receptors, Alpha-2 Norepineprhine receptors (similar to clonidine); it increases Nurr 1 gene expression (needed for survival of dopaminergic neurons); and is a potent anti-oxidant. Other effects include reducing norepinephrine output (as described above), reduced thyroid stimulating hormone (and thus reduce thyroid hormone levels), and increased growth hormone level. As can be seen, the Mirapex story is not that simple.
As a dopamine agonist, it can potentially improve mood. As far as I know, it is primarily useful as adjunctive treatment - alone, not strong enough for long-term treatment of depression. Reducing norepinephrine activity and thyroid hormone levels, if significant enough in an individual, can also increase depressive symptoms.
I have experience with it. Unfortunately, in the patient population I treat, no one has been able to tolerate Mirapex. The most common reasons patients stop using it is anxiety, dizziness/faintness, fatigue, oversedation and reduced alertness.
Some clinicians have more luck with it than I. It depends on the population of patients a physician has (most of my patients, in general, are under constant, unrelenting, extreme stress and have very severe, treatment, resistant illnesses - they are not the usual middle class worried well). Thus, I keep it in mind as an option because it is a relatively clean dopamine agonist, and may work in some patients where other medications don't.
Other effects to keep in mind: sudden unexpected, uncontrollable attacks of sleep can occur (this increases the risk of patients getting into car accidents and of dying by accident - thus one has to be very careful in informing patients about the risks). A patient can also develop hallucinations and paranoid delusions (limiting its use in patients with psychosis), pupil dilatation (not good when the patient is stopped by the police), increased heart rate.