Posted by Michael Bell on April 12, 2004, at 20:20:33
In reply to Re: Dopamine agonists » Michael Bell, posted by Geoffrey Ruch on April 12, 2004, at 1:39:26
> I have not read any of the responses to your message, but I have a few questions eating at me and I was hoping you might be able to help me understand.
> First of all, I read on the internet, on a site written by a doctor specializing in Social Phobia and Avoidant Personality Disorder, that Parnate is superior to Nardil in treating these disorders. So I'm confused by your assertion that Nardil is superior. Can you tell me where you got this information from. I just started on Parnate a few weeks ago and I'm curious as to why I'm hearing conflicting information.
> Next, and most puzzling to me is in regards to Norepinephrine. I am aware that it acts both as a neurotransmitter (in the brain) as well as a hormone from the adrenal cortex. Now, many hypotheses about the cause of depression relate to the belief that Norepinephrine levels are low in the brains of depressives, and thus increasing levels of this neurotransmitter could help in the treatment of depression. Obviously there are numerous drugs out, including Tricyclics, MAO inhibitors, and newer drugs like Effexor, etc. that do just that. Additionally, naturopathic doctors recommend such supplements like the amino acid precursors L-Tyrosine and Phenylalanine (in part) because they can increase Norepinephrine levels in the brain (as well as Dopamine levels). And I've even read that L-Tyrosine has anti-stress qualities (ie. helping people cope with stress). For instance, in a book called "Prescription for Nutritional Healing," Tyrosine is at the top of the list of recommended supplements to deal with stress.
> Now with all this said, Norepinephrine as a hormone is involved in the "fight or flight" stress response, and it seems, therefore, that it would increase stress and not HELP with dealing with it; and it would seem that this would impact negatively on depression (ie. increased stress can cause depression). So I'm incredibly confused! I mean, what's the deal? Is Norepinephrine, as a neurotransmitter, a completely different substance from the hormone? Or are some people with depression lacking in this hormone in addition to the neurotransmitter?
> If you-- or anybody else-- could help me understand this (or direct me to where I could find help in understanding it) I would be GREATLY appreciative!!! I mean, if a depressed person under constant inner stress could benefit from increased levels of the NE neurotransmitter but be negatively impacted because of higher NE hormone levels, then what is one to do in such a case??? I'm sure the situation is very complex and it's not as simple as I have laid it out to be. Still, though, there has to be some kind of way to understand it. It's a shame I never asked my psychiatrist to explain it. Now I see a county doctor (in L.A.) who I see for about 20 minutes a session every month and a half, and I really haven't had the time to ask for an explanation.
> Anyway, thank you all for allowing me into this discussion!!! I hope it is not too "off-topic." But I think it is relevant nevertheless.
The difficult thing about understanding the neurotransmitter systems is that they all seem to modulate each other on some level. Therefore tinkering with one specific transmitter will often have indirect effects on others, or messenger hormones. Making it more complicated is the fact that each transmitter has a variety of pre- and post-synaptic receptors that respectively regulate and are stimulated by the matching neurotransmitter. Furthermore, these receptors will often down or up-regulate in response to increases or decreases in transmission.
Now I'll try to address your question, if I haven't put you to sleep yet.
Norepinephrine is very much implicated in some types of depression, as supported by countless studies on bipolar disorder, selective norepinephrine reuptake inhibitors and unipolar depression. However, there are different types, degrees and causes of depression. Therefore drugs that primarily affect the norepinephrine system may help some who are diagnosed with depression and not others.
Regarding SOCIAL PHOBIA - My conclusion that Nardil is more effective than Parnate for the vast majority of people comes from talking with my P-Doc, a whole lot of internet research, and the makeup of the drug itself.
People with primary social phobia seem to suffer from two major things:
1) Fear of social situations (the GABA part)
2) Reward deficiency in social situations (the DOPAMINE part)
I have no doubt that GABA disfunction is one of the main (if not the main) problems in social phobia. The most effect drugs for social phobia - klonopin, nardil, alcohol and ghb - all have huge effects on the GABA or benzo system. It is the main inhibitory transmitter/hormone in our brains and has been linked to anxiety issues by overwhelming evidence. NARDIL, unlike parnate, is an gaba transanimase inhibitor, meaning it inhibits the enzyme that breaks down GABA (like Sabril, I think). It has been hypothesized that it is this action that makes Nardil so effective for social phobia, on top of its antidepressant effect. But if you find Parnate is working well for you, then definitely stick with it. If you suffer from depression as well, Parnate should definitely alleviate that to some degree. Keep in mind it tends to be an activating drug.
Regarding #2: The thing that is so strange about social phobia is that there seems to be a disfunction of two transmitter systems that are polar (well, not quite) opposites: DOPAMINE and GABA. Reward deficiency syndrome as it relates to social anhedonia has been linked to hypofunction of the dopamine system in the mesolimbic portion of the brain. Release of dopamine and binding to postsynaptic receptors is the final pathway in the reward cascade.
Therefore you will often see people with social phobia complaining that, although drugs like Klonopin work wonders for the anxiety part of social phobia, they do not aid with the reward part. In other words, they are not prosocial meds, and do not increase your approach behavior. At the other end of the spectrum, Amisulpride has proven quite effective for dysthimia and anhedonia by binding to dopamine pre-synaptic receptors and increasing transmission.
So the question remains: IF GABA AND DOPAMINE TRANSMISSION/LEVELS ARE INVERSELY RELATED, HOW THE HELL DO PEOPLE WITH SOCIAL PHOBIA INCREASE ONE WITHOUT DECREASING THE OTHER?
Some people have tackled this dilemma by taking Klonopin to kill the anxiety along with adderall/dexedrine to jumpstart the dopamine system. When it works, this combo is very prosocial in nature, though I wouldn't recommend it to anyone who doesn't suffer from adhd.
My feeling all along has been that there is some other transmitter or hormone system that regulates anxiety and reward at the same time, and that it is actually disfunction of this system that is the root cause of social phobia.
My research (which could be way off) has led me to believe that problems with the cholecystokinin (CCK) system is a good candidate for being that mystery system, as it serves as a sort of nexus between gaba and dopamine, and has proven links to anxiety and reward problems. CCK-B antagonists have proven anxiogenic effects, and increase dopamine in certain parts of the brain. Interestingly, high levels of cholecystokinin are linked with anticipatory anxiety, social defeat. CCK also serves as an anti-opiate and lowers the body's natural level of opiods. The opiod system serves as a reward pathway as well.
Hmmm... I think I may import one of these cck antagonists from overseas when I get the chance.
More on this later...