Has anyone tried a dopamine agonist?

[jim_morrison]

Btw heres the presumptive mechanisms thought to mediate the antidepressant effect of various TCA's;

Amitriptyline - 5-HT reuptake inhibition ++ / NE reuptake inhibition ++ /
5-HT2 antagonism ++

Imipramine - 5-HT reuptake inhibition ++ / NE reuptake inhibition ++ /
5-HT2 antagonism +

Clomipramine - 5-HT reuptake inhibition +++ / NE reuptake inhibition + /
5-HT2 antagonism ++

Nortriptyline - 5-HT reuptake inhibition + / NE reuptake inhibition +++/
5-HT2 antagonism ++

Desipramine - NE reuptake inhibition +++

[miko]

For me - Amitryptyline is the best. It have stongest anticholinergic effect. Other 3 cyclics don't work on me.

[Medline]

Originally Posted by jim_morrison

Btw heres the presumptive mechanisms thought to mediate the antidepressant effect of various TCA's;

Amitriptyline - 5-HT reuptake inhibition ++ / NE reuptake inhibition ++ /
5-HT2 antagonism ++

Imipramine - 5-HT reuptake inhibition ++ / NE reuptake inhibition ++ /
5-HT2 antagonism +

Clomipramine - 5-HT reuptake inhibition +++ / NE reuptake inhibition + /
5-HT2 antagonism ++

Nortriptyline - 5-HT reuptake inhibition + / NE reuptake inhibition +++/
5-HT2 antagonism ++

Desipramine - NE reuptake inhibition +++

Amitriptyline can be combined with MAOIs like tranylcypromine:

http://www.ncbi.nlm.nih.gov/pubmed/8453432
http://www.ncbi.nlm.nih.gov/pubmed/1573032
http://www.ncbi.nlm.nih.gov/pubmed/2071885
http://www.ncbi.nlm.nih.gov/pubmed/6342565
http://www.ncbi.nlm.nih.gov/pubmed/7435677

but Imipramine is strictly contraindicated because of risk of serotonin syndrome:

http://www.ncbi.nlm.nih.gov/pubmed/12927331
http://www.ncbi.nlm.nih.gov/pubmed/14063404

The German manufacturer of tranylcypromine states that "primary noradrenergic TCAs like Amitriptyline, Doxepin, Trimipramine and Nortriptyline can be combined with tranylcypromine - but Imipramine and Clomipramine can not - because of risk of potential fatal serotonin syndrome". You sure Amitriptyline and Imipramine cause the same degree of 5HT reuptake inhibition? And if they do, I am confused by this.

[jim_morrison]

Originally Posted by Medline

Amitriptyline can be combined with MAOIs like tranylcypromine:

http://www.ncbi.nlm.nih.gov/pubmed/8453432
http://www.ncbi.nlm.nih.gov/pubmed/1573032
http://www.ncbi.nlm.nih.gov/pubmed/2071885
http://www.ncbi.nlm.nih.gov/pubmed/6342565
http://www.ncbi.nlm.nih.gov/pubmed/7435677

but Imipramine is strictly contraindicated because of risk of serotonin syndrome:

http://www.ncbi.nlm.nih.gov/pubmed/12927331
http://www.ncbi.nlm.nih.gov/pubmed/14063404

The German manufacturer of tranylcypromine states that "primary noradrenergic TCAs like Amitriptyline, Doxepin, Trimipramine and Nortriptyline can be combined with tranylcypromine - but Imipramine and Clomipramine can not - because of risk of potential fatal serotonin syndrome". You sure Amitriptyline and Imipramine cause the same degree of 5HT reuptake inhibition? And if they do, I am confused by this.

Oops my bad, I guess what I was referring to was the similair NE:5HT ratio balance of Imipramine, and Amitriptyline, 1:2.5 and 1:1.6 respectively, atleast according to Preskorn (Figure 3.3), but I see your point, imipramine is generally regarded as a more potent SERT reuptake inhibitor.

http://www.preskorn.com/books/ssri_s3.html

[rocknroll714]

Don't forget the following as well:

• 5-HT6 receptor antagonism
• 5-HT7 receptor antagonism
• NMDA channel blockade (PCP site)
• Sigma-1 receptor agonism

Some of the TCAs (e.g., amitriptyline) I gotta say are really badass. Get rid of their histamine, muscarinic acetylcholine, and alpha-adrenergic receptor antagonism, as well as their ion channel blocking actions, balance the remaining pharmacology (receptor affinities), and they'd be friggin' awesome. Something like this:

• Serotonin/norepinephrine reuptake inhibition
• 5-HT2A, 5-HT2C, 5-HT6, 5-HT7 receptor antagonism
• a2-adrenergic receptor antagonism
• Sigma-1 receptor agonism
• Weak NMDA receptor antagonism

Hell, maybe even take a hint from amineptine (which is a TCA in fact) and get some dopamine pumping via dopamine reuptake inhibition as well. And wala, you have by far the best antidepressant ever made.

P.S., see here:

http://en.wikipedia.org/wiki/Tricycl...t#Pharmacology

Notice the binding table.

Enjoy.

[jim_morrison]

What does sigma-1 receptor agonism do anyway? I've heard that being touted as one of zolofts defining features too.

I agree though, they'd be pretty badass if they were 'clean', heck even take out the muscarinic acetylcholine receptor blockade (If theres one type of psychopharm med on the planet which I would not touch its an anticholinergic!), the ion channel blocking, and the alpha-adrenergic receptor antagonism, but leave in the histamine blockade and I would have settled for them.

Edit; one thing though, from one perspective, cymbalta induces serotonin/norepinephrine reuptake inhibition quite similair to that of the TCA's, yet in that big head-to-head meta analysis of 12 new generation drugs, cymbalta scored quite poorly, any thoughts on why this might be?

[euphoria]

Originally Posted by miko

Dopamine agonists it's good too. Many things makes me happy, and I feel pleasure from music, sport and other things. Like in the past...

How severe was your anhedonia before trying the dopamine agonists? Currently I get so little pleasure from anything that it's not even worth trying, so I'm going to ask for one to augment sertraline. There isn't much better than serotonin/dopamine synergy for anhedonia . Also, does it work for all "hedonic pursuits" or just some? Thanks.

[crayzyMed]

Originally Posted by euphoria

How severe was your anhedonia before trying the dopamine agonists? Currently I get so little pleasure from anything that it's not even worth trying, so I'm going to ask for one to augment sertraline. There isn't much better than serotonin/dopamine synergy for anhedonia . Also, does it work for all "hedonic pursuits" or just some? Thanks.

Be carefull to slowly titrate your dose tough, dopamine agonists will make you feel alot worse the first 2 weeks.

[miko]

My anhedonia came gradually. Music, sport - anything from the past, haven't meaning for me :f becouse I haven't pleasue from this things.. I don't tolerate any SSRI. Sertraline is SSRI I try 6 months --> big akathisia, sweating, fast heat rate -> benzo :f I hate this drugs! I haven't feel worse in all my life. When I'm taking 5-HT2 antagonists with SSRI akathisia is not so strong, so I think I need dopamine. I try dopamine agonists and it's the best med for me. For this moment I can take - wellbutrin, coaxil, dopamine agonists, selegiline - this things works for me.

I haven't any withdrawal feelings from dopamine agonists. And I "jump" from 0,25 to 0,5 mg ropinirole without any feelings.

Try it for week or two? I think this med it's Underestimated.

Sorry for english.

[crayzyMed]

Originally Posted by miko

My anhedonia came gradually. Music, sport - anything from the past, haven't meaning for me :f becouse I haven't pleasue from this things.. I don't tolerate any SSRI. Sertraline is SSRI I try 6 months --> big akathisia, sweating, fast heat rate -> benzo :f I hate this drugs! I haven't feel worse in all my life. When I'm taking 5-HT2 antagonists with SSRI akathisia is not so strong, so I think I need dopamine. I try dopamine agonists and it's the best med for me. For this moment I can take - wellbutrin, coaxil, dopamine agonists, selegiline - this things works for me.

I haven't any withdrawal feelings from dopamine agonists. And I "jump" from 0,25 to 0,5 mg ropinirole without any feelings.

Try it for week or two? I think this med it's Underestimated.

Sorry for english.

Thank you for your experience

Very interesting combo, should supercharge dopamine!

[rocknroll714]

Originally Posted by jim_morrison

What does sigma-1 receptor agonism do anyway? I've heard that being touted as one of zolofts defining features too.

I agree though, they'd be pretty badass if they were 'clean', heck even take out the muscarinic acetylcholine receptor blockade (If theres one type of psychopharm med on the planet which I would not touch its an anticholinergic!), the ion channel blocking, and the alpha-adrenergic receptor antagonism, but leave in the histamine blockade and I would have settled for them.

Edit; one thing though, from one perspective, cymbalta induces serotonin/norepinephrine reuptake inhibition quite similair to that of the TCA's, yet in that big head-to-head meta analysis of 12 new generation drugs, cymbalta scored quite poorly, any thoughts on why this might be?

The sigma receptors are very mysterious. Agonists of the receptors have been touted as antidepressant, anxiolytic, and even hallucinogenic, while antagonists are antipsychotic and possibly analgesic (they potentiate opioid-induced antinociception). Amphetamine, methamphetamine, MDMA, morphine, heroin, cocaine, ketamine, PCP, DXM, and DMT, among many others, are all sigma receptor agonists, as well as are many of the SSRIs and TCAs. Opipramol is a selective sigma agonist used in Germany as an anxiolytic. Noscapine is also a selective sigma agonist which is available over-the-counter in some countries as an antitussive. It induces dissociative-like hallucinogenic effects in high doses. See these excerpts from Wikipedia (there's a good deal of information on Bluelight as well):

Abuse

Noscapine has a history of over-the-counter drug abuse in several countries, being readily available from local pharmacies as a prescription drug. The effects, beginning around 45 to 120 mins after consumption, are similar to dextromethorphan and alcohol intoxication. Unlike dextromethorphan, noscapine is not an NMDA receptor antagonist.

Possible side-effects [of noscapine]

• Loss of coordination
• Hallucinations (auditory and visual)
• Dilated pupils
• Loss of stereoscopic vision

Regarding duloxetine (I'm Kobie, Tony is IllusionalFate):

[01:26] Kobie: weird how duloxetine is a selective SNRI with a balanced action and it's like the second worst SRI
[01:26] Kobie: only after fluvoxamine
[01:27] Kobie: then you've got venlafaxine which is a horribly unbalanced SNRI and it's at the top of the list
[01:27] Kobie: according to that 12 antidepressant meta-analysis at least
[01:27] Kobie: i wonder how reliable that review really is
[01:27] Tony: yeah weird

Another mystery..

[rocknroll714]

Some binding data on duloxetine from this study:





I don't understand it either.

[crayzyMed]

Opipramol looks interesting:

Hi Ed,Philipa and everyone :

Sorry for my slowness!!

Yes I took Insidon (Opipramol) when I lived for a while in the Sudan.

It was a very effective for anxiety from the first dose and I really liked it a lot.

I was also taking at the time Prozac and some benzos,but I stopped benzos and Opipramol enhanced my overall peace of mind.

Unfortunatly I stopped it because I left the country and could not find it in any other country I lived in.

It gives a sort of mellow,warm protective feeling without the apathy of the SSRIs,the dependance of the benzos,and the nightmarish Akathisia of the antipsychotics.

It is a pity that it is near extintion on this planet!

By the way its effect is very different from Luvox.

Opipramol may not suit everybody,but it is really a unique drug.

Ed and every body o you know where Opipramol exist now?

Best regarde,
Dark Horse .

I am an American living in Germany. I have had GAD, depression, and panic attacks my whole life. I have been on a variety of SSRI's and TCA's. Most recently I was on imipramine and diazapam for my anxiety etc. I could tolerate it but the imipramine still bothered me. My German doctor suggested that I try opipramol. I did a seamless switch from the imipramine. The opipramol started working and I eventually got off diazapam also. So far so good. My question is, does anyone know if opipramol is available in the U.S.? I will probably go back in 2 yrs and am concerned about not being able to find this drug that really works for me. Any help would be greatly appreciated.

[jim_morrison]

Originally Posted by rocknroll714

Some binding data on duloxetine from this study:





I don't understand it either.

Yeah, it's a mystery, perhaps venlafaxine really is incorporating the opioid system afterall

"Venlafaxine has an analgesic effect that is independent of its antidepressant activity. The results of clinical studies suggest that the opioidergic system has a role in the analgesic effect of venlafaxine. Antinociceptive effect of venlafaxine is influenced by opioid receptor subtypes (mu-, kappa1- kappa3- and delta-opioid receptor subtypes) combined with the alpha2-adrenergic receptor. This opioid profile may be one of the explanations to venlafaxine efficacy in severe depression, unlike the SSRIs and other antidepressants which lack opioid activity."

http://www.emedexpert.com/facts/venlafaxine-facts.shtml

...Not sure how much I buy into that though, considering that further down the page it contradictorily states; "Venlafaxine is not a controlled substance. It has virtually no affinity for opiate, benzodiazepine, phencyclidine (PCP), or N-methyl-D-aspartic acid (NMDA) receptors."

[jim_morrison]

Although see here http://www.cnsforum.com/imagebank/it...c/default.aspx
and http://www.preskorn.com/columns/9911.html here,
and you'll notice that venlafaxines binding profile is much higher for 5HT and NE than claimed by other sources, Perhaps it's metabolite O-desmethylvenlafaxine (ODV) (Which stahl claims is responsible for about 50-70% of the benefit in normal metabolisers) is pulling most of the weight for it. *shrugs*

[miko]

Two years ago I have opipramol for 1 year (with doxepine), and it's good for anxiety, but it's not antidepressant (haven't increase mood) - a little sedating... good med.

[euphoria]

Originally Posted by miko

Two years ago I have opipramol for 1 year (with doxepine), and it's good for anxiety, but it's not antidepressant (haven't increase mood) - a little sedating... good med.

When I chose sertraline as my anxiolytic/antidepressant, part of the reason was its sigma receptor affinity, a property it shares with opipramol (sertraline probably at a substantially milder level though). Also for the weak DRI ability, but really just because sertraline is ranked as one of the best SSRIs for anxiety & depression.

[jim_morrison]

Originally Posted by euphoria

When I chose sertraline as my anxiolytic/antidepressant, part of the reason was its sigma receptor affinity, a property it shares with opipramol (sertraline probably at a substantially milder level though). Also for the weak DRI ability, but really just because sertraline is ranked as one of the best SSRIs for anxiety & depression.

I wonder how much the DRI affinity actually adds to sertraline, I guess a good measure would be if it causes less sexual dysfunction than the other SSRI's?

The other good thing about zoloft, aswell as lexapro, is that neither have Cytochrome P450 enzyme inhibiting properties (in contrast with most other SSRI's, hence less potential for drug interactions), and also the fact that both have optimal half lifes of approx 25 - 30 hrs, hence not too short nor too long. I believe that both of these factors may contribute to the fact that both drugs often score high with patient acceptability.