HRTstudent

http://www.definitivemind.com/forums...read.php?t=173



Dopamine agonists are useful to a certain extent.

They are useful, for example, in conditions with suboptimal dopamine signaling, such as restless legs syndrome or Parkinsonism.

Dopamine is the primary signal for libido. Thus, when other signals are optimized, yet dopamine signaling is still low, then Dopamine may be added to try and improve functioning.

The problem is that dopamine signaling occurs on two different ways. Dopamine is produced continuously producing a baseline "tone". Dopamine is also produced in impulses - such as when producing a sense of well-being or reward. Dopamine signals are also subject to more receptor downregulation than other signals - meaning tolerance easily develops.

Libido requires both signaling patterns. But Dopamine agonists primarily supports the continuous baseline dopamine signal. This can improve libido to a certain extent but usually not fully. In most men, I find the effects of dopamine agonists to be fairly mild. Many have no effect at all. Some men get great reactions, but this is not common. It is better than nothing, however.

A dopamine reuptake inhibitor would provide a better solution - increasing both the continuous and pulsatile dopamine signals. However, these have generally not been approved by the FDA since they tend to be easily abused - obviously.

Animeptine was one such medication. To me, it would have been the perfect antidepressant - raising dopamine, serotonin and norepinephrine simultaneously - essentially it is a long-acting version of cocaine but not as potent. It was a tricyclic antidepressant. Unfortunately, when people started abusing it, the FDA in the US suspended it's application for release in 1999. It clearly improved people's sense of well-being rapidly. Too bad for all of us. At the very least, it should have been released as a controlled substance just as amphetamine, methamphetamine, and cocaine are available for clinical use.

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Bupropion (Wellbutrin) does not increase dopamine signaling. It raises norepinephrine signaling in norepinephrine neurons.

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Dopamine agonists can be divided into two classes - ergot-derived dopamine agonists (such as Cabergoline), and non-ergot-derived dopamine agonists (such as Requip).

This distinction is important. The ergot-derived dopamine agonists can cause cellular fibrosis - particularly of the heart valves, causing valve damage, and potentially heart failure. This is sad since Cabergoline, of the dopamine agonists, has been the most successful of the dopamine agonists for sexual function (in my experience), while minimizing side effects, while having significant convenience in use (since a dose can last 4 days).

Excessive doses of dopamine agonists can also cause dyskinetic movements - abnormal muscle movements - twitches, and other abnormal movements.

Constipation is the most frequently encountered side effect. Drop-attacks of sleep and falls from low blood pressure can also occur. Nausea is the one frequent side effect that is difficult to stop and would make a dopamine agonist intolerable. Sometimes psychotic symptoms can occur, particularly in those who have an ongoing psychotic disorder.

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In summary, dopamine agonists are useful. But they aren't miracle solutions since they don't fully restore dopamine signaling. I would say, in my experience, they sometimes help, and most of the time, they don't. Thus, the response will vary a lot. The shorter acting dopamine agonists are not as useful or even very convenient. And side effects may be significant.




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Thank you for the article link.

Stephen Stahl MD is very famous in psychiatry as an expert in psychopharmacology. He is a faculty member in the department of psychiatry at the UC San Diego, School of Medicine - my medical school.

I have his books.

When someone makes an assertion, particularly an academic assertion, as Stephen Stahl is making in this article, it is important to check the references.

Stahl asserts in this article that Bupropion is the only antidepressant that works as a dual norepinephrine reuptake inhibitor and dopamine reuptake inhibitor.

In this article, he refers to three articles which show that Bupropion (Wellbutrin) blocks the dopamine reuptake transporter, thus may lead to an increase in dopamine signaling.

The articles show that Bupropion does block the dopamine reuptake transporter. But it does so weakly. For example, one of the articles states that Bupropion blocks the dopamien reuptake transporter by about 20%. The article openly questions if this is clinically significant.

I openly question also if this is clinically significant. Interestingly, Stahl does not ask this very question.

And unfortunately, Stahl does not give the rest of the story: Bupropion not only weakly blocks the dopamine reuptake transporter, but Bupropion also increases the number of dopamine reuptake transporters. Further, it also increase the number of dopamine vesicular transporters - which stores dopamine in neuron vesicles. These additional effects of Bupropion may result in either reversing whatever increase Bupropion initially may cause to dopamine signaling or may result in a overall reduction in dopamine signaling. Further, Bupropion's increase in norepinephrine signaling may result in a reduction in dopamine production - leaving less to increase by blockade of the dopamine reuptake transporter.

When Wellbutrin (Bupropion) is initially given, blockade of dopamine transport may increase dopamine initially. This may improve conditions of low dopamine such as sexual dysfunction. Unfortunately, this effect is negated by the changes I describe above.

Notably, one gauge of how effective Bupropion is in increasing dopamine is whether or not it is effective in treating Parkinson's Disease, an illness causing death of dopamine cells and thus the lack of dopamine. Dopamine agonists are standard treatment for Parkinson's Disease. Selegiline, an antidepressant MAOI inhibitor is effective in Parkinson's disease. Bupropion, the touted antidepressant which is marketed as a norepinephrine and dopamine reuptake inhibitor, is not effective in treating Parkinson's Disease. It would not be even considered.

In my experience and with the mechanisms and issues described above, when Bupropion (Wellbutrin) is used long-term, it primarily increases norepinephrine. I see no improvement in dopamine signaling.

In the short-term, it may raise dopamine. But this is a temporary effect since Bupropion, itself, causes opposing changes to dopamine signaling, which may result in negating the increase in dopamine signaling, or worse, reduce overall dopamine signaling.

Of note is that Bupropion can cause loss of libido in a subset of patients.

When I have observed improvement in sexual function, it is transient. The number of patients where I noted an improvement in sexual function is less than 10 in the past 20 years.

One possible way to prolong the increase in dopamine from Bupropion is to use very small doses. I observe that doses around 37.5 mg a day generally are where sexual function is enhanced. As I titrate the dose up for the treatment of depression or attentional problems, this effect disappears. At low doses, one has a greater chance of escaping the negating effects on dopamine signaling. Low dose Bupropion, however, is largely ineffective for any other use - depression, smoking cessation, attention deficit, etc.

I use to use Bupropion a lot, thinking it would be the perfect antidepressant. Unfortunately, since most patients I see have excessive norepinephrine signaling, I now seldom use this medication, particularly when dopamine signaling is not clinically relevantly increased.

I still try occasionally to use low dose Bupropion to help improve libido. It is still worth a try, though it seldom pans out. What keeps it in my mind is that the two rare patients where it worked spectacularly, worked spectacularly. Often when something works well for a few patients, the hope is to hit the jackpot again with another. But like lotteries, only a few win.