Posted by Astounder on November 3, 2007, at 12:44:09
In reply to Re: Dopamine agonists cause sedation. But why??, posted by linkadge on November 2, 2007, at 22:07:51
> Sorry, I should clarify. Objective hypothermia is not, but subjective hypothermia is. "Shivering", or chills, for instance is a symptom of serotonin syndrome.
5-HT2a antagonists might attenuate this symptom, since the 5-HT2a-dependent hyperthermia can be fever-like:
Note that another symptom of serotonin syndrome is diaphoresis, another fever-like symptom. But we can't know for sure, because AFAIK the only antiserotonergic drugs that have been used to reverse the syndrome are unselective.
> The first study you mentioned does not prove that this symptom is entirely mediated by 5-ht2a. For starters, cyproheptadine only partially prevented hypothermia.
That only reinforces my point: Cyproheptadine & chlorpromazine are not as selective for for the 5-HT2 series as risperidone or ritanserin, which more potently reversed the hyperthermia. Cyproheptadine & Thorazine have significant 5-HT1a affinity.
Furthmore, it may be that stimulation of the 5-HT1a receptor partially antagonizes the hyperthermia from 5-HT2a stimulation. The selective 5-HT1a full agonist 8-OH-DPAT induces hypothermia that is blocked by a 5-HT1a antagonist.
So it makes sense drugs that block 5-HT1a significantly like cyproheptadine & chlorpromazine are not as effective in reducing the hyperthermia.
>Also ritanserin is not a selective 5-ht2a antagonist.
Ritanserin is highly selective for 5-HT2a over 5-HT1a. Look at the binding data:
In vitro data in humans from the PDSP Ki database:
5-HT1a 2919 Ki (nM)
5-HT2a 0.01-59.1 Ki (nM)For risperidone:
5-HT1a 190-427 (nM)
5-HT2a 0.15-7 Ki (nM)And there is data that suggests risperidone is an agonist, and not an antagonist, at the 5-HT1a receptor.
> Yes, but a few case studies of sucessful combination doesn't make it safe for everbody. From one article I read, severly depressed patients apparently tollerated such combinations with less incedence of SS than when the two drugs happened to interact in drug crossovers. Perhaps a compromised serotonergic system is itself protective againsts serotonin syndrome.
They're not case studies; they were active drug controlled clinical studies with 60 and 30 patients. The patients were not selected on the grounds of being treatment resistant; in fact the pilot study included dysthymics.
I can't find any case studies of serotonin syndrome resulting from the sole combination of amitriptyline and a MAOI, whereas there's plenty for MAOIs and other drugs that significantly block serotonin reuptake. Clomipramine and imipramine are the only significantly serotonergic tricyclics other than amitriptyline. One major difference between clomipramine, imipramine, and amitriptyline is potency at the 5-HT2a receptor. According to this review, tricyclics do not produce the serotonin syndrome, other than clomipramine and imipramine:
I'm not advocating usage of the combination. Neither of the studies suggested increased efficacy over monotherapy, and Elavil and MAOIs can cause fatalities by themselves (arrhythmias and tyramine hypertension, respectively). It's just something I'd rather try before, say, reserpine pretreatment or opiates.
> Why? Cardiac fibrosis is apparently related to potent 5-ht2b agonism of any form. The two recently withdrawn parkinsons drugs, pergolide and cabergoline have no effect on plasma 5-ht, but are potent 5-ht2b agonists. SSRI's too are indirect 5-ht2b agonists. They cause hippocampal proliferation via increased agonism at 5-ht1a. They will affect SERT levels in cardiac tissue too and will functionally increase 5-ht2b agonism there. SSRI's work by increasing receptor 5-ht related events. They are not specific to any particular receptor nor are they specific to SERT levels in the brain.
I was writing a long rebuttal, but this study stopped me:
http://circ.ahajournals.org/cgi/content/full/113/1/2
From above, fenfluramine causes valve disease even though it decreases plasma 5-HT levels, so you're right in that plasma 5-HT levels are not necessary in stimulating 5-HT2b receptors, though they are present in the case of ingested serotonin or a carcinoid tumor.
The only drugs that are definitely known to cause cardiac fibrosis are direct 5-HT2b agonists, though SERT knockout mice display valvulopathy, so obviously SERT can be involved in the etiology.
> When the cases of cardiac valve issues start manifesting in another 10-20 years...
Good point. The are studies showing no correlation between SSRIs and valve disease are not going to be definitive because people haven't been taking them for an entire lifetime. We'll see what happens in the next few decades.
Yet another reason for me to not take SSRIs. They were placebos with side-effects when I was taking them, and the withdrawal was terrible.
poster:Astounder
thread:791344
URL: http://www.dr-bob.org/babble/20071027/msgs/793130.html