![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
[email protected]Shown: posts 1 to 25 of 41. This is the beginning of the thread.
Posted by Brainbeard on July 2, 2009, at 16:14:09
At the end of the rainbow? Perhaps.
It has only lately occurred to me that, in my desperate and frantic searching for a way to enhance dopaminergic functioning, I have overlooked or at least wasn't aware of a particular way of raising dopamine (DA) (and noradrenaline (NA)) levels and/or firing, namely 5HT2A/C-antagonism.
Stephen Stahl opened my eyes. I knew that a low dose of Prozac raises DA (and NA) levels in crucial parts of the brain, but I didn't know it did that because of 5HT2C-antagonism. I've experienced that low dose Risperdal, which I thought was supposed to help with anxiety, turned me into a social superman besides boosting my 'mental libido' (the part between the ears as opposed to what's going on below the belt) - without doing much for anxiety. I now understand that because of Risperdal's 5HT2A-antagonism, it indeed elevates dopamine levels, resulting in mentioned phenomena.
There is a nice presentation by Stahl on the web where he explains how 5HT2A and -C-antagonism result in increased dopamine release. I can't give a direct link because it seems to be a subscription page; nevertheless, when you follow the following link and click on the first search result, you do end up in the presentation: http://www.google.nl/search?hl=nl&safe=active&rlz=1B3GGGL_nlNL255NL258&q=Schizophrenia%3A+From+Circuits+to+Symptoms+Presented+by+Stephen+M.+Stahl&btnG=Zoeken&meta=
Quoting from the presentation: 'What receptor properties can enhance the ability of an atypical to improve mood and cognition? What does the 5HT2A antagonist property have to do with that? Normally, the serotonin neuron (...) talks to the dopamine and norepinephrine neurons and tells them to be quiet, to step on the brake. If you interfere with that, you don't inhibit anymore; and, if you don't inhibit anymore, you disinhibit, which is a fancy way of saying, "turning it on." So, to disinhibit means not another way to do it, but rather to turn things on. If you block the natural ability of serotonin to stop norepinephrine and dopamine release, you enable the dopamine and the norepinephrine to be released. So blocking this causes release.'
And: 'What other receptor binding properties might enhance this ability, besides those of 5HT2A? We get into some speculation, but useful speculation. The 5HT2C receptor is also connected to the dopamine and to the norepinephrine neurons, and it also reduces those through gamma-aminobutyric acid (GABA) interneurons; if you block them, it also increases dopamine and norepinephrine.'
For this reason, Stahl explains, low doses of both Prozac (fluoxetine) and ziprasidone (Geodon) can be activating, because they block 5HT2C and/or 5HT2A without much (or any) serotonergic (Prozac) or antidopaminergic (Geodon) action going on.
Furthermore, 5HT1A-agonism seems to be essential to complete the trick: 'Any other properties? The 5HT1A agonist properties could be useful. Presynaptic actions could help antidepressant effects, and postsynaptic actions could help cognitive effects. Dr. Meltzer has done seminal work showing that you don't get these increases -- of the good, smart neurotransmitters of dopamine and norepinephrine, particularly dopamine -- unless you work through a 5HT1A receptor.'
Stahl gives extensive descriptions of these phenomena in his Essential Psychopharmacology, fragments of which can be read on the web, for instance here: http://books.google.nl/books?id=cWbYxSfKN3cC&pg=PA351&dq=Stephen+Stahl+5HT2A-antagonism+dopamine+5HT1A+serotonin
In Depression And Bipolar Disorder, he explains the link between 5HT1A-agonism and 5HT2A/C mediated DA release: http://books.google.nl/books?id=zqvVZOea2JAC&pg=PA120&dq=Stahl++stimulation+of+serotonin+1A+receptors+acutely+reduces+the+serotonergic+inhibition+of+DA
(read the text UNDER the small text belonging to the picture).Here's a research abstract that shows that 5HT2A-antagonism revives SSRI-decreased noradrenergic firing: http://www.journals.elsevierhealth.com/periodicals/bps/article/PIIS0006322306006597/abstract
So, all the moaning and whining about SSRI-induced apathy could once and for all be abolished if SSRIs would standardly get served with 5HT2A/C blockade plus 5HT1A-agonism.
And this is where things get dirty. There ARE pure 5HT2A and/or -C antagonists, but they don't have enough marketing potential since as stand-alone's they're not very impressive. So they are only known under desperately unimaginative names like SR46349-B. The 5HT2A/C-blockers that HAVE been marketed are for the bigger part pretty dirty drugs, which is to day, they have affinity for a range of receptors and do a dozen of things simultaneously, often in a dose-related manner.
The atypical antipsychotics (AAP's) are almost all characterized by 5HT2A-blockade. See this table for a comparison of antipsychotic beinding data: http://www.nature.com/npp/journal/v28/n3/fig_tab/1300027t1.html
Risperdal, mentioned earlier, is a potent 5HT2A-blocker, but because it crosses the blood-brain-barrier, even at low doses it raises prolactin levels wildly. Let me assure you, hyperprolactinemia is not something to take lightly. It can cause tumors or make your bones brittle. In my case, it leads to gynecomastia, which isn't fun when you're not a travestite with Pamela Anderson as your role model.
Zyprexa is an excellent 5HT2A and -C-blocker, but it's a much too strong antihistaminergic - what use is extra DA and NA when you're sleeping all day - and strongly diabetogenic on top of that.
Geodon (ziprasidone) is an interesting candidate since it's a strong 5HT2A-blocker, a relatively strong 5HT2C-blocker, a weaker 5HT1A-agonist, AND its antagonistic touch of D2 is soft enough not to raise prolactin levels much or cause extrapyramidal symptoms even at therapeutic doses. Geodon is also a moderately strong serotonin and noadrenaline reuptake blocker. Stahl refers to it as sort of a mini-Effexor. Its withdrawal syndrome, though, doesn't seem to be very mini if you may believe the anecdotal evidence. Anyway, Geodon (ziprasidone) is an interesting candidate for augmenting SSRI-therapy in a low dose - perhaps less than 20mg would already be enough? At such a dose, the whole cascade of the drug's other actions would hardly yet be put into motion.
An even more interesting candidate, in my opinion, would be sertindole, which is a potent 5HT2A/C-blocker that touches D2 only lightly in comparison. In contrast to Geodon, that has a very short half-life, sertindole has a long half-life and it's blocking effects on 5HT2A are reported to be long-lasting. Sertindole was temporarily withdrawn from the market after reports of sudden death and the like because of its tendency to prolong QT-interval; later studies revealed, however, that this tendency wasn't any greater than that of most other AAP's; Risperdal, for instance, is a worse offender when it comes to QT-interval-prolonging. Anyhow, the QT-interval-prolonging is dose related, and I think that even a 4mg dose (therapeutic dosage for schizofrenia is >20mg) would be enough for the goal I have in mind. Sertindole, sadly, is considered a second-line treatment and hasn't even been investigated, it seems, as an augmentation strategy for SSRI-treatment. So who will ever prescribe it for me?!
Then you have the good ol' TCA's, of course, most of which throw in a bit of 5HT2A or -C antagonism among all the other stuff they're doing. You can see and compare their 5HT2A-antagonistic properties in this table: http://www3.interscience.wiley.com/cgi-bin/fulltext/121665024/main.html,ftx_abs#t3
When you remember the (A)AP-table, you will realize that the 5HT2A or -C antagonism of the TCA's is rather weak and will probably only come into full play at therapeutic rather than low doses. That's a pity, because at such doses the side-effects of TCA's are so severe that only the truly heroic stand their ground. Which leaves the rest tantalized. Amitriptyline, for instance, has perhaps the best ratio of SRI versus NRI versus 5HT2A (and -C)-blockade. But it's a stronger antihistaminergic than Zyprexa (see there), and it's a very strong anticholinergic, and a very dirty drug overall, so though certainly undeserved, it IS imaginable that some doctor's have called the drug 'rat poison'.
To draw towards the end. My personal suggestion (towards myself, that is) for a fine antidepressant cocktail with both anxiolytic and stimulating and motivating qualities would be: sertraline (Zoloft) + sertindole or ziprasidone (Geodon) or, if those aren't available, Risperdal + Buspar (buspirone), the 5HT1A-agonist.
On paper, it looks good. What do you think?
Posted by SLS on July 2, 2009, at 21:43:40
In reply to The Final Pathway To The Dopaminergic Pot Of Gold?, posted by Brainbeard on July 2, 2009, at 16:14:09
Wonderful post.
Thanks.
- Scott
Posted by Sigismund on July 3, 2009, at 1:42:01
In reply to The Final Pathway To The Dopaminergic Pot Of Gold?, posted by Brainbeard on July 2, 2009, at 16:14:09
I never managed to persist with Stahl.
Off the top of my head I wonder about very low dose Dexedrine and Ritalin with agomelatine at night.
I worry a bit about 5ht2A blockade. For some reason I feel better about 5ht2C. Probably some prejudice in favour of hallucinogens.
Posted by Brainbeard on July 3, 2009, at 5:14:12
In reply to Re: The Final Pathway To The Dopaminergic Pot Of Gold?, posted by Sigismund on July 3, 2009, at 1:42:01
> I worry a bit about 5ht2A blockade. For some reason I feel better about 5ht2C. Probably some prejudice in favour of hallucinogens.
Then low dose Prozac would be the drug for you: strong 5HT2C-antagonism and 5HT2A-AGONISM if psychofarmanaut Claude Rifat is right (http://www.lycaeum.org/drugs/SSRI/balance.html)! Rifat goes as far as saying that Prozac actually is a mild hallucinogen.
Posted by Brainbeard on July 3, 2009, at 5:17:55
In reply to Re: The Final Pathway To The Dopaminergic Pot Of Gold? » Brainbeard, posted by SLS on July 2, 2009, at 21:43:40
> Wonderful post.
>
> Thanks.
>
>
> - ScottMost welcome!
It's the result of an almost dysphorically hypomanical obsession, really. But it does tie some knots together, doesn't it?
Personally I can stare at tables showing receptor affinities forever, musing about the consequences of such data..
Posted by SLS on July 3, 2009, at 9:38:15
In reply to Re: The Final Pathway To The Dopaminergic Pot Of Gold?, posted by Brainbeard on July 3, 2009, at 5:17:55
> > Wonderful post.
> >
> > Thanks.
> >
> >
> > - Scott
>
> Most welcome!
>
> It's the result of an almost dysphorically hypomanical obsession, really. But it does tie some knots together, doesn't it?
>
> Personally I can stare at tables showing receptor affinities forever, musing about the consequences of such data..I wish I still had that kind of focus and mental energy.
Be well.
- Scott
Posted by Sigismund on July 3, 2009, at 15:02:01
In reply to Re: The Final Pathway To The Dopaminergic Pot Of Gold?, posted by Brainbeard on July 3, 2009, at 5:14:12
>Then low dose Prozac would be the drug for you:
Maybe
>strong 5HT2C-antagonism and 5HT2A-AGONISM if psychofarmanaut Claude Rifat is right (http://www.lycaeum.org/drugs/SSRI/balance.html)!
That was an interesting article. I keep meaning to read the references in your original post, but I don't understand the first thing about receptor binding affinity....the higher the number the stronger it is?
>Rifat goes as far as saying that Prozac actually is a mild hallucinogen.
Hmmmm, OK. But it might give me more insomnia. Like Rifat (I might assume) anything remotely pleasant has been legislated out of existence.
Posted by Brainbeard on July 4, 2009, at 4:04:31
In reply to Re: The Final Pathway To The Dopaminergic Pot Of Gold? » Brainbeard, posted by Sigismund on July 3, 2009, at 15:02:01
> >Then low dose Prozac would be the drug for you:
>
> Maybe
>
I was only talking theoretically, really.>I don't understand the first thing about receptor binding affinity....the higher the number the stronger it is?
Exactly the opposite. The lower the number, the higher the affinity.
> Hmmmm, OK. But it might give me more insomnia. Like Rifat (I might assume) anything remotely pleasant has been legislated out of existence.
Not completely. For instance, it never ceases to amaze me how easily stimulants are prescribed in America. Adderall, a combination of amphetamine salts - it would be unthinkable in Europe!
And despite the hypocrisy of dividing drugs in 'therapeutic' and 'recreative' drugs, some drugs of the latter class are actually quite bad for your brain. Like XTC, which was originally brought on the market as a diet pill..
Posted by psychobot5000 on July 5, 2009, at 15:56:54
In reply to The Final Pathway To The Dopaminergic Pot Of Gold?, posted by Brainbeard on July 2, 2009, at 16:14:09
Mr. Brainbeard,
I thought I would add my little story to your thread. I've been diagnosed with hypodopaminergic depression, and have struggled with the symptoms all my life. For what it's worth, low-dose Geodon (10mg b.i.d.) has indeed been very effective at helping my dopamine-deficient symptoms (difficulty concentrating, anhedonia, low-motivation, etc) without any negative effects on anxiety or anything else. Its positive effects on this symptom-cluster are quite pronounced. So I think it might indeed by a beneficial part of the SSRI cocktail you propose.
Best,
Psychbot
Posted by SLS on July 5, 2009, at 16:51:55
In reply to Re: The Final Pathway To The Dopaminergic Pot Of Gold? » Brainbeard, posted by psychobot5000 on July 5, 2009, at 15:56:54
> Mr. Brainbeard,
>
> I thought I would add my little story to your thread. I've been diagnosed with hypodopaminergic depression, and have struggled with the symptoms all my life. For what it's worth, low-dose Geodon (10mg b.i.d.) has indeed been very effective at helping my dopamine-deficient symptoms (difficulty concentrating, anhedonia, low-motivation, etc) without any negative effects on anxiety or anything else. Its positive effects on this symptom-cluster are quite pronounced. So I think it might indeed by a beneficial part of the SSRI cocktail you propose.
I just wrote to you on the Medication board that 20mg of Geodon would produce anxiety and dysphoria. I'm glad that is not happening to you.
- Scott
Posted by ABMIND on July 5, 2009, at 20:34:24
In reply to Re: The Final Pathway To The Dopaminergic Pot Of Gold? » psychobot5000, posted by SLS on July 5, 2009, at 16:51:55
Hi all,
I've been looking for info re: Geodon -maybe someone out there can help.Here's a little background:
I've been on a variety of antidepressants over the last 10 yrs. --60mgs of Cymbalta for the last 3 years. 6 mths ago I switched psychiatrists b/c my therapist suggested I might have ADHD (inattentive type) along with my major depression & anxiety (social & GAD).So, I found an 'expert' in adult ADHD (I'm 40) I went on Strattera for 1 month, then on adderall for a month with no change in symptoms. Then he started me on Vyvanse 40 mg then went up to 80mg. On the higher dose I felt calmer, a little less emotionally reactive & agitated but my head was stilled filled with tons of thoughts about the 1000 things I needed to get done.
So, the doctor increased the Cymbalta to 90mg. I felt pretty good in regards to my anxiety & depression & my "to do" lists had stopped running through my head. My therapist noticed a big difference, but I was still having trouble with things like organization, prioritizing & actually getting started on tasks.
At my next appointment the doctor took me off the Vyvanse and changed me to Concerta started at 18mg. then up to 72 mg. I took it for 3 weeks and my anxiety & depression became much worse.
When I went back to the doc this past Thurs. he took me off Concerta & put me on Geodon. Told me to take 20mg for 3 days, then 40 for 3 days, then up to 60mg. (keeping the Cymbalta at 90mg)
OK, finally my question(s)...
Is Geodon a typical drug for depression & anxiety? Web sites I've found have listed it as an antipsychotic for schizophrenia or bipolar, with bad withdrawal effects. I few years back I had a horrible time getting off Effexor and I am afraid to 'try out' Geodon and then have problems weening off it, if it doesn't work.
I wanted to get back on the Vyvanse, but he said that it didn't help with the ADHD, so is Geodon going to help me with the ADHD?
Does anyone take 90mg of Cymbalta & 60 mg of Geodon? Will I expect to see improvement in my executive function skills? Or will the doc put me on another stimulant? My doctor did not explain any of this to me when he gave me the Geodon samples.
Is 60 mg too high? Someone wrote that it will start acting like an antipsychotic!!?? What does that mean??!! Is this the doctor's way of giving me a new diagnosis??I would really appreciate any advice. Thanks
Posted by psychobot5000 on July 6, 2009, at 1:02:38
In reply to Re: The Final Pathway To The Dopaminergic Pot Of G, posted by ABMIND on July 5, 2009, at 20:34:24
> Hi all,
> I've been looking for info re: Geodon -maybe someone out there can help.
>
> Here's a little background:
> I've been on a variety of antidepressants over the last 10 yrs. --60mgs of Cymbalta for the last 3 years. 6 mths ago I switched psychiatrists b/c my therapist suggested I might have ADHD (inattentive type) along with my major depression & anxiety (social & GAD).
>
> So, I found an 'expert' in adult ADHD (I'm 40) I went on Strattera for 1 month, then on adderall for a month with no change in symptoms. Then he started me on Vyvanse 40 mg then went up to 80mg. On the higher dose I felt calmer, a little less emotionally reactive & agitated but my head was stilled filled with tons of thoughts about the 1000 things I needed to get done.
>
> So, the doctor increased the Cymbalta to 90mg. I felt pretty good in regards to my anxiety & depression & my "to do" lists had stopped running through my head. My therapist noticed a big difference, but I was still having trouble with things like organization, prioritizing & actually getting started on tasks.
>
> At my next appointment the doctor took me off the Vyvanse and changed me to Concerta started at 18mg. then up to 72 mg. I took it for 3 weeks and my anxiety & depression became much worse.
>
> When I went back to the doc this past Thurs. he took me off Concerta & put me on Geodon. Told me to take 20mg for 3 days, then 40 for 3 days, then up to 60mg. (keeping the Cymbalta at 90mg)
>
> OK, finally my question(s)...
>
> Is Geodon a typical drug for depression & anxiety? Web sites I've found have listed it as an antipsychotic for schizophrenia or bipolar, with bad withdrawal effects. I few years back I had a horrible time getting off Effexor and I am afraid to 'try out' Geodon and then have problems weening off it, if it doesn't work.
>
> I wanted to get back on the Vyvanse, but he said that it didn't help with the ADHD, so is Geodon going to help me with the ADHD?
> Does anyone take 90mg of Cymbalta & 60 mg of Geodon? Will I expect to see improvement in my executive function skills? Or will the doc put me on another stimulant? My doctor did not explain any of this to me when he gave me the Geodon samples.
> Is 60 mg too high? Someone wrote that it will start acting like an antipsychotic!!?? What does that mean??!! Is this the doctor's way of giving me a new diagnosis??
>
> I would really appreciate any advice. ThanksDear sir,
First, not to take over this thread, but, briefly, no Geodon is not really a 'typical' drug for depression and anxiety. However, it is a -legitimate- drug for those things, even if its use for them is 'off-label.' So I don't think you need to worry about that too much. I'm taking it myself, for symptoms very similar to yours.
From what I've read, I do think 60mg twice per day (is it once or twice a day that you'd be taking the 20/40/60mg dose) is too high a dose for depression or innattentive ADD symptoms. However, I very much doubt your doctor's use of Geodon at an 'antipsychotic dose' (i.e. a relatively high one) is a way to give you a new diagnosis. I just think he may be misled on what's the best dose for your problem. What happens at the higher doses is, you get high enough levels of the drug in your system to start blocking certain dopamine receptors (D2) to a significant degree, which is very useful for people who have schizophrenia or other diseases, but probably counter-productive for people with depression or people who have difficulty concentrating and organizing. At the lower doses, theoretically at least, you can get the positive effects on mood and on 'cognitive function' from the drug's action on another target, the serotonin receptor 2a ( 5HT-2a), while only getting a tiny amount of the unwanted action on D2.
For what it's worth, I also have difficulty concentrating, organizing, and thinking, and my low dose (10mg, twice per day) of Geodon has been helpful with that--mostly in the few hours after each dose. So maybe it'll be helpful with your cognitive symptoms also.
Best of luck,
PsychbotP.S. Ultimately, you probably want to take a relatively low dose of this drug, if you can get away with it, just for general health-reasons. Geodon is part of a class of drugs that are not to be used lightly. So don't panic or anything, but that's another reason for being a little wary about the higher doses, especially if the lower might work better.
Posted by Brainbeard on July 6, 2009, at 2:51:18
In reply to Re: The Final Pathway To The Dopaminergic Pot Of G » ABMIND, posted by psychobot5000 on July 6, 2009, at 1:02:38
Psychbot, it's good to hear about your experience with low dose Geodon.
Abmind, I personally feel that Cymbalta and Geodon in higher dosages is not an ideal combination in your case. Psychbot has already explained that the antidopaminergic properties of Geodon are probably less than therapeutic for you. Besides that, Geodon is also a serotonin and noradrenaline reuptake inhibitor (SNRI) - like Cymbalta. I wonder if your doc is aware of this. High(er) dose Geodon will boost your synaptic serotonin and noradrenaline levels to new heights - the question is how that will affect you, and also how the two drugs will interact. But perhaps even more important, as you've already mentioned yourself, is that Geodon, being sort of a 'mini-Effexor', does seem to have a rather harsh withdrawal syndrome. So you may want to think about wether you're willing to take that risk.
All in all, I think it would be a sound, careful, and even promising approach to try low dose Geodon first (10-40mg a day).
Posted by ABMIND on July 6, 2009, at 7:46:07
In reply to Re: The Final Pathway To The Dopaminergic Pot Of G, posted by Brainbeard on July 6, 2009, at 2:51:18
Thanks for the input, brainbeard & psychbot. Still not sure what to do...
Posted by metafunj on September 12, 2009, at 2:03:05
In reply to Re: The Final Pathway To The Dopaminergic Pot Of G, posted by ABMIND on July 6, 2009, at 7:46:07
I have suffered with anhedonia as well as concentration memory problems ever since stopping prozac about 6 years ago. I was stubborn and thought my brain would heal if I left it alone, but it has only gotten worse with time.
I was told by a neurologist friend that SSRIs can leave someone with excess serotonin because they no longer have as many 5HT transporters after years of SSRI use.
If this is the case, then I continue to have elevated serotonin but no longer have the 5 HT2C antagonism I had while on prozac. Now the the elevated serotonin could be agonizing the 5 HT2C
receptor decreasing dopamine and norepinephrine release.I'm thinking of trying it again at a low dose for 5 HT2C blockade. Other possible candiates are Remeron for 2A/2C blockade or the anti histamine Cyproheptadine, which also has 2A/2C blockade and is used for the treatment of serotonin syndrome.
I was also considering trying Buspar to lower my overall serotonin levels through its 5HT1A agonism. I believe Ginkgo biloba also decreases serotonin release.
Maybe a combination of the low dose prozac and buspar could lead to that pot of gold.
If its a problem of serotonin acting against dopamine I'd rather fix that problem than just take stimulants, or something like provigil.
I hope everyone here is finding something that works.
Posted by Brainbeard on September 12, 2009, at 6:45:14
In reply to Re: The Final Pathway To The Dopaminergic Pot Of G, posted by metafunj on September 12, 2009, at 2:03:05
Buspirone only temporarily decreases serotonin levels; they return back to normal within a couple of hours. So that probably couldn't provide a steady solution if your analysis is right.
Remeron appears to be very sedating to most, not to mention its weight gain. I feel that sedation is likely to ruin the benefits of 5HT2A/C-antagonism.
Cyproheptadine is an interesting drug, but also very antihistaminergic=sedative. Seems like a bit of a horse med, as we say in Holland.
Your best bet may be the Prozac + buspirone. Personally, I do feel that stimulating drugs might help your symptoms. They can at least provide motivation and initiative, and perhaps make you happier as well.
Unfortunately, stimulating meds usually have an anxiogenic effect on me. I sometimes feel biochemically stuck between lust for life + anxiety or lack of anxiety + apathy. I know I'm not the only one.
It's too bad that pure 5HT2A/C-antagonists haven't found their way onto the market. It seems that they didn't do too well as antidepressants in the trials.
Posted by SLS on September 12, 2009, at 7:06:13
In reply to Re: The Final Pathway To The Dopaminergic Pot Of G, posted by Brainbeard on September 12, 2009, at 6:45:14
> Buspirone only temporarily decreases serotonin levels; they return back to normal within a couple of hours. So that probably couldn't provide a steady solution if your analysis is right.
>
> Remeron appears to be very sedating to most, not to mention its weight gain. I feel that sedation is likely to ruin the benefits of 5HT2A/C-antagonism.
>
> Cyproheptadine is an interesting drug, but also very antihistaminergic=sedative. Seems like a bit of a horse med, as we say in Holland.
>
> Your best bet may be the Prozac + buspirone. Personally, I do feel that stimulating drugs might help your symptoms. They can at least provide motivation and initiative, and perhaps make you happier as well.
>
> Unfortunately, stimulating meds usually have an anxiogenic effect on me. I sometimes feel biochemically stuck between lust for life + anxiety or lack of anxiety + apathy. I know I'm not the only one.
>
> It's too bad that pure 5HT2A/C-antagonists haven't found their way onto the market. It seems that they didn't do too well as antidepressants in the trials.It is unfortunate that the manner in which drugs are developed and brought to market currently provides no incentive to produce drugs that are active only as adjuncts to other drugs. A case in point would be gepirone, a 5-HT1a partial agonist. By itself, it did not seem to be robust as an antidepressant, but it would probably make a good augmentor for one. Another deficit is that compounds that have had their patents expire are not developed further to be marketed. An example of this would be ritanserin. It is a potent and selective antagonist of 5-HT2 receptors. Personally, I would like to have seen clorgyline brought to market as well. It is a MAOI that is specific for MAO-A.
- Scott
Posted by metafunj on September 12, 2009, at 10:22:10
In reply to Re: The Final Pathway To The Dopaminergic Pot Of G, posted by SLS on September 12, 2009, at 7:06:13
I agree with you guys. It would be nice if your doctor could just choose the pharmacological mechanisms you need and create custom made medications. Maybe someday far in the future that will be possible, when targeting certain receptors becomes easier and health begins to outweigh profit.
I have heard that drugs with antihistamine properties can be sedating but I have a friend that takes Remeron at night and he's fine. I have read that the higher the dose of Remeron the more it stimulates noradrenic receptors and activates you.Maybe, you're right about the stimulant Brainbeard. I basically have no anxiety so I think I could handle the dopamine boost and it would probably help with the ADHD like symptoms I've had since quitting prozac.
I had read some of your posts on the anhedonia topic and had wondered why you didn't try a stimulant instead of going the serotonin route, but if it gives you anxiety that makes sense.
I'm taking Wellbutrin SR 150 twice a day now and so far it seems like it mainly works on noradrenaline, making me kinda edgy and easily startled but not really doing anything for the emotional blunting and cognitive problems yet.
I just wonder if 5mg prozac would give enough 5HT2C stimulation with little reuptake inhibition.
Posted by Brainbeard on September 13, 2009, at 3:49:15
In reply to Re: The Final Pathway To The Dopaminergic Pot Of G, posted by metafunj on September 12, 2009, at 10:22:10
> I just wonder if 5mg prozac would give enough 5HT2C stimulation with little reuptake inhibition.
Prozac appears to be such a strong 5HT2C-antagonist that doses between 2.5 and 5mg certainly have a significant effect. For me, 5mg had a stronger antidepressant effect. I suspect that at such a dose, mild SRI will come into play.
Posted by metafunj on September 13, 2009, at 9:09:27
In reply to Re: The Final Pathway To The Dopaminergic Pot Of G, posted by Brainbeard on September 13, 2009, at 3:49:15
Thanks, maybe I'll try taking 5mg every other day to get 2.5. I could combine it with the wellbutrin I'm taking now. It would be like turning the heat on a pot from below and then put the lid on the pot, making it heat up faster.
Does prozac do anything at the 5 HT2A receptor? Have you found that drugs with 5 HT2A antagonism exert a strong dopaminergic effect?
Posted by Brainbeard on September 13, 2009, at 10:03:34
In reply to Re: The Final Pathway To The Dopaminergic Pot Of G, posted by metafunj on September 13, 2009, at 9:09:27
> Does prozac do anything at the 5 HT2A receptor?
Yes, as an SSRI, Prozac blindly activates 5HT2A-receptors. That is to say, any SSRI tends to blindly stimulate ALL serotonin receptors including all subtypes. 5HT1A-activation may be one of the leading mechanisms behind the (S)SRI's success as antidepressants. 5HT2A-activation is not good, and is probably one of the main reasons for the SSRI's initial (and perhaps partly prolonged) side-effects of increased anxiety and agitation. I'm not sure what happens after sustained activation - down-regulation of 5HT2A-receptors? If so, long-term agonizing of 5HT2A-receptors may have the same outcome as 5HT2A-antagonism, namely (indirect) inhibition of
5HT2A-receptors putting a brake on dopamine and noradrenaline.>Have you found that drugs with 5 HT2A antagonism exert a strong dopaminergic effect?
>
Well, I have mixed experiences. Low dose Risperdal (0.5mg), a potent 5HT2A-antagonist, seemed to have some pronounced pro-dopaminergic effects on me.Low dose Geodon (ziprasidone, 5-60mg) was a bit of a disappointment since besides whatever good it was doing me, it also made me feel emotionally flat, which was the opposite of what I had hoped for.
I tried to take amitriptyline doses high enough to reach significant 5HT2A-antagonism, but the antihistaminergic sedation was too much for me to swallow.
Just 25mg of nortriptyline (amitriptyline's metabolite) did help my sleep a lot, combined with Luvox (fluvoxamine) and clomipramine, but I'm not sure if that was due to its mild 5HT2A-antagonism. It might well be. Could also be the NRI though.
Posted by metafunj on September 14, 2009, at 11:35:59
In reply to Re: The Final Pathway To The Dopaminergic Pot Of G, posted by Brainbeard on September 13, 2009, at 10:03:34
It's interesting that NRI would make you tired. I find it makes me kinda jumpy. I take wellbutrin and last night couldn't sleep, I may have to adjust the time I take the 2nd dose.
I have a friend who tried a lot of drugs and the only thing that worked was mirtazapine. Probably because of the 5HT antagonism along with 5ht1a agonism due to its serotonin boosting effects. He doesn't have any weight gain yet and says it doesn't make him tired, so I may try it in the future.
Posted by rgb on September 19, 2009, at 11:34:58
In reply to Re: The Final Pathway To The Dopaminergic Pot Of Gold?, posted by Sigismund on July 3, 2009, at 1:42:01
> Off the top of my head I wonder about very low dose Dexedrine and Ritalin with agomelatine at night.
Interesting idea (sadly, I don't have access to either...).
>
> I worry a bit about 5ht2A blockade. For some reason I feel better about 5ht2C. Probably some prejudice in favour of hallucinogens.Seconded. I was under the impression that 2A *increases* dopamine release and 2C decreases it, but I don't know where I got that impression :)
To confuse things further, apparently different agonists can activate the 2A receptor in different ways, explaining why only some of them cause psychedelic effects:
Posted by metafunj on September 19, 2009, at 21:06:50
In reply to Re: The Final Pathway To The Dopaminergic Pot Of G, posted by Brainbeard on September 12, 2009, at 6:45:14
Hey Brainbeard I had some questions.
Do you think taking Buspar + Prozac would cause movement disorders in the future due to buspar's D2 antagonism or do you think the increase in DA release from 5 HT2C antagonism would prevent this by increasing dopamine? I'm not sure if this increase is in the same place in the brain that would effect movement.
I've read about some people having dark moods on buspar. Do you have any idea why this could be? Do you think it could be from D2 antagonism or too much of a decrease in serotonin transmittion to other receptors?
If SSRIs cause indirect agonism of the 5HT1A receptor how come they don't cause the release of dopamine? It is said because SSRIs agonize the
5HT2A/C receptors they inhibit dopamine release, but Buspar taken with an SSRI can increase dopamine in spite of the indirect 5HT2A/C agonism. So if buspar acts just like serotonin, why wouldn't the indirect agonism of an SSRI increase dopamine release and decrease serotonin release similar to Buspar?The reason I ask about all this meds have caused such a problem in the past that I am fearful of the effects they could have long term. I'm starting to think a stimulant like provigil might be better, but i think it sure would be harder to get a script for.
Posted by Brainbeard on September 20, 2009, at 4:54:59
In reply to Re: The Final Pathway To The Dopaminergic Pot Of G » Brainbeard, posted by metafunj on September 19, 2009, at 21:06:50
I think movement disorders or other extrapyramidal side-effects (EPS) are unlikely to be caused by Buspar. To date, I haven't heard of any case of Buspar caused EPS. The partial D2-antagonism is probably too weak for that. Especially when you take it at recommended doses, I don't think there will be a problem. In some trials, people have been taking doses of up to 1200mg of Buspar (as an antipsychotic), apparently without trouble.
5HT2C or -A-antagonism in itself can probably not (completely) prevent EPS; it seems that the reason that the atypical antipsychotics are less likely to induce EPS must rather be seen in their weaker adherence to D2-receptors.
> I've read about some people having dark moods on buspar. Do you have any idea why this could be? Do you think it could be from D2 antagonism or too much of a decrease in serotonin transmittion to other receptors?I think this is probably a temporary effect of the decrease in serotonergic tone that Buspar causes. It seems that some people experience a transient depressive phase while starting Buspar therapy.
> If SSRIs cause indirect agonism of the 5HT1A receptor how come they don't cause the release of dopamine?Good question. They very well might indirectly cause a release of dopamine, that might on the other hand be countered by their indirect agonism at 5HT2A/C-receptors.
> It is said because SSRIs agonize the
5HT2A/C receptors they inhibit dopamine release, but Buspar taken with an SSRI can increase dopamine in spite of the indirect 5HT2A/C agonism. So if buspar acts just like serotonin, why wouldn't the indirect agonism of an SSRI increase dopamine release and decrease serotonin release similar to Buspar?Indirect or direct agonism probably makes a big difference. Direct agonism of 5HT2B-receptors, for instance, is likely to cause heart valve damage. The ergoid dopamine-agonists are 5HT2B-agonists and carry this cardiac risk. The indirect 5HT2B-agonism of SSRI's, on the other hand, doesn't seem to cause this cardiovalvulopathy. Also, direct agonism of 5HT2A-receptors is likely to induce hallucinations. Still, the indirect agonism of 5HT2A-receptors by SSRI's is very unlikely to cause hallucinations. So apparently, there is a big difference.
Buspar is really a very mild medication that is practically free of serious side-effects. It can make you a little bit dizzy at medium-high doses (for me: doses above 10mg at a time). Personally, I don't even find this dizziness unpleasant.
If I were you, Buspar would be one of the last meds I would worry about. If it can help you, I would surely take it. It may take some time to reach full therapeutic effect, although in combination with Prozac the dopaminergic boost is immediate.
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