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?