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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 23 of 23. This is the beginning of the thread.
Posted by dondon on March 29, 2006, at 16:09:51
What are some 5ht2 antagonists besides mirtazapine, trazodone and nefazodone? And Is ginkgo biloba a 5ht2 antagonist?
Posted by linkadge on March 29, 2006, at 18:27:19
In reply to 5ht2 antagonists, posted by dondon on March 29, 2006, at 16:09:51
Yes, acutually ginkgo is a 5-ht2a antagonist. I think recalling reading that it decreases the binding of serotonin to 2a receptors by about 33%.
The tricylics, cypreheptadine, atypical antipsychotics, marajuanna, anandamide, also have some degree of 5-ht2 antagonism (mostly 5-ht2a antagonism). Oh, and the herb feverfew blocks 5-ht2a and 5-ht2b fairly potently.
Linkadge
Posted by linkadge on March 29, 2006, at 18:28:39
In reply to 5ht2 antagonists, posted by dondon on March 29, 2006, at 16:09:51
It is also interesting to note, that the 5-ht2a receptor seems to modulate stress induced BDNF downregulation. I remember reading a few studies that suggested that 5-ht2a antagonism was sufficiant to prevent stress induced BDNF decrease. This may be why the TCA's have a slightly wider utility.
Linkadge
Posted by zeugma on March 29, 2006, at 19:29:59
In reply to Re: 5ht2 antagonists » dondon, posted by linkadge on March 29, 2006, at 18:28:39
There is actually evidence that buspirone aids in the downregulation of the 5-HT2A/C receptors:
: Pharmacopsychiatry. 2006 Jan;39(1):1-8.
Combined treatment with citalopram and buspirone: effects on serotonin 5-HT2A and 5-HT2C receptors in the rat brain.Syvalahti E, Penttila J, Majasuo H, Palvimaki EP, Laakso A, Hietala J.
Department of Pharmacology and Clinical Pharmacology, University of Turku, 20520 Turku, Finland. erkka.syvalahti@utu.fi
INTRODUCTION: We wanted to elucidate whether the proposed advantages of citalopram-buspirone combination treatment are related to changes in 5-HT(2A/C) receptor-mediated neurotransmission. METHODS: The affinity of buspirone to 5-HT2A and 5-HT2C receptors was measured in vitro, and the influence of buspirone on 5-HT2C receptor-mediated phosphoinositide hydrolysis was estimated. Four groups of rats received citalopram (10 mg/kg), buspirone (6 mg/kg), citalopram-buspirone combination, or saline once a day s.c. for 14 days. Treatment effects on 5-HT2A and 5-HT2C receptors were investigated by receptor autoradiography with antagonist and agonist radioligands. RESULTS: Buspirone was found to be a weak 5-HT2C receptor antagonist, with a low affinity for 5-HT2A and 5-HT2C receptors. Repeated buspirone-citalopram combination treatment markedly decreased [3H]ketanserin and [125I]DOI binding to 5-HT2A receptors. Repeated administration of buspirone and buspirone-citalopram combination increased the affinity of [3H]mesulergine toward 5-HT2C receptors, and buspirone-citalopram combination also decreased [125I]DOI binding to 5-HT2C receptors. DISCUSSION: We suggest that downregulation of brain 5-HT2A receptors and possibly of 5-HT2C receptor agonist sites is involved in the beneficial clinical effects of buspirone-SSRI augmentation treatment. Furthermore, a conversion of brain 5-HT2C receptors from high- to low-affinity state may provide an additional mechanism for the anti-anxiety effects of buspirone.>>
Amitriptyline and nortriptyline are both powerful antagonists of these receptors. Possibly this is why i found addition of buspirone to nortriptyline beneficial.
-z
Posted by linkadge on March 29, 2006, at 19:45:57
In reply to Re: 5ht2 antagonists » linkadge, posted by zeugma on March 29, 2006, at 19:29:59
The downregulation of the 5-ht2 system seems to correlate to theraputic repsonce in many cases.
The question has been asked as to the exact mechanism of 5-ht2 downregulation. I personlly am under the impression that the greater the intrinsic 5-ht1a agonism, the greater the 5-ht2 downregulation.
I think that the 5-ht2 system mediates some responces to stress, and that downregulation reduces some of these responces.
Melatonin is another good agent to keep in mind. It has the ability to restore sensitivity to the 5-ht1a receptors.
http://biopsychiatry.com/melatemp.htm
Melatonin can actually sometimes cause depression. I think this is due to its anticonvulsant action. I had some depressive effects at first, but after a little while it actually seemed to be turning things around.
Linkadge
Posted by zeugma on March 29, 2006, at 20:06:04
In reply to Re: 5ht2 antagonists, posted by linkadge on March 29, 2006, at 19:45:57
Do you know if melatonin has effects on REM?
5-HT2 antagonists increase slow wave sleep without affecting REM.
NE reuptake inhibitors specifically block REM:http://www.sro.org/pdf/863.pdf
5HT reuptake inhibitors have very interesting effects on sleep. At first they diminish REM strongly, but mice lacking the serotonin transporter eventually experience increased REM, and I believe this is responsible in some cases for SSRI poop-out/apathy syndromes:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12598736&query_hl=13&itool=pubmed_docsumSSRI's can also cause REM behavior dosorder, which essentially is a process where the REM mechanism and the atonia-inducing mechanism become uncoupled, and people act out their dreams in ways which are not at all amusing. Before the advent of SSRI's, REM behavior disorder was mostly limited to older patients with Parkinson's disease, which is the medical disorder most linked to depression. I do not believe it is a coincidence that REM process derangements and depression are often found in Parkinson's disease. in fact, narcolepsy-like syndromes occur in Parkinson's too, and narcoleptic symptoms reflect a REM process disorder:
-z
Posted by linkadge on March 30, 2006, at 9:20:41
In reply to melatonin, REM, Parkinson's disease » linkadge, posted by zeugma on March 29, 2006, at 20:06:04
These are really good questions, and it probably should give me the impetous to read a little more on the topic.
I am not sure how melatonin administration affects sleep stages.
Sleep seems to be a very interesting topic to psychiatric disorders.
I remember reading that melatonin administration eliminated the antidepressant effect of fluoxetine in mice (but I don't know exactly how that fits into the picture).
Interupting REM sleep seems sufficiant to produce an antidepressant responce in many cases. I think that REM sleep maybe tries to ballence the cholinergic/adrenergic axis.
Linkadge
Posted by Cairo on March 30, 2006, at 19:41:10
In reply to Re: melatonin, REM, Parkinson's disease » zeugma, posted by linkadge on March 30, 2006, at 9:20:41
My daughter's neuropsych mentioned that her friend, who is in charge of the Cleveland Clinic's pediatric sleep clinic, told her that only 1 in 3 patients respond to melatonin, but when they respond, they respond well. For what it's worth...
Cairo
> These are really good questions, and it probably should give me the impetous to read a little more on the topic.
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> I am not sure how melatonin administration affects sleep stages.
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> Sleep seems to be a very interesting topic to psychiatric disorders.
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> I remember reading that melatonin administration eliminated the antidepressant effect of fluoxetine in mice (but I don't know exactly how that fits into the picture).
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> Interupting REM sleep seems sufficiant to produce an antidepressant responce in many cases. I think that REM sleep maybe tries to ballence the cholinergic/adrenergic axis.
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> Linkadge
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Posted by zeugma on March 30, 2006, at 21:13:30
In reply to Re: melatonin, REM, Parkinson's disease, posted by Cairo on March 30, 2006, at 19:41:10
It has been known for a long time that antidepressants tend to lower the seizure threshold, and to suppress REM sleep; and that antiepileptic compunds can control manic episodes, and suppress NREM sleep. So the simplistic deduction, akin to that of the monoamine theorists of the 1960's, is that depressives have too much REM and manics not enough. This is not very satisfying, because it explains nothing. What is the purpose of REM anyway?
i find this theory intriguing (I lack the knowledge to assess its plausibility, but it at least explains what REM is for, even if the explanation is spurious [I am having trouble writing now]:
Med Hypotheses. 2004;62(4):546-8.
Purpose of REM sleep: endogenous anti-epileptogenesis in man -- a hypothesis.Jaseja H.
Physiology department, G.R. Medical College, Gwalior, MP 474001, India. dr_jaseja@yahoo.com
Neuro-scientists, worldwide, are endeavoring to elucidate the purpose of sleep which still remains largely elusive. There is, however, consensus on many aspects of sleep functions; one such aspect is its relationship with seizures/epilepsy. There is unequivocal agreement on increased susceptibility to epilepsy during nonrapid eye movement (NREM, slow-wave) sleep. Large number of studies have shown increased frequency of seizures and interictal epileptiform discharges in epileptic patients during NREM sleep (esp., stages I and II) which is associated with EEG synchronization. Similarly, there is widespread acceptance of de-synchronized brain-activity states being associated with rarity/total absence of epileptic potentials, one such state being rapid eye movement (REM) sleep. Certain drugs and substances which inhibit NREM sleep have been found to possess anti-convulsant properties. Not surprisingly, drugs/chemicals which enhance/promote NREM sleep or suppress/inhibit REM sleep are associated with increased susceptibility to seizures and are contraindicated in epilepsy. The manner and pattern in which REM phase occurs in sleep are also naturally programmed to exert anti-epileptogenic influence. This hypothesis-article highlights and conceptualizes the primary function of REM-sleep as endogenous anti-epileptogenic system in the body akin to the endogenous analgesia and immune systems man is born with.
>>>>>>>>>>>>>>>>>
So, if this author is on the right track, perhaps manics have a breakdown of the anti-epileptigenic system, and depressives a pathologically powerful system (perhaps perversely parallel to an individual with hypoalgesia, who soon becomes riddled with wounds he cannot feel).
I am just thinking out loud, and I do not know enough to theorize. It really just seems suggestive to me, and I have never heard of the body possessing a system devoted to suppressing seizures. It seems everyone got tired of vague metaphors about mania being a 'slow seizure,' and it seems the REM hypothesis of depression made its exit with fluoxetine, and maybe the theory led nowhere in particular.
But everyone can readily accept, on a commonsense level, the existence of analgesic and immune systems (we are all too prone to pain and infection). Is it plausible that we are also seizure-prone enough to have such a delicate system for averting them?
-z
Posted by zeugma on March 30, 2006, at 23:02:11
In reply to Re: melatonin, REM, Parkinson's disease » zeugma, posted by linkadge on March 30, 2006, at 9:20:41
I think that REM sleep maybe tries to ballence the cholinergic/adrenergic axis..>
I know that the cholinergic system is strongly implicated in ADHD (it is well established that exposure to prenatal nicotine is a risk factor for ADHD, and studies on rats exposed to PN develop abnormalities that may be an animal model of ADHD).
I wonder if there have been any studies of ACh/NE in seizure disorders?
-z
Posted by River1924 on March 31, 2006, at 0:13:48
In reply to Re: 5ht2 antagonists, posted by linkadge on March 29, 2006, at 18:27:19
Is this the same receptor that is involved with lack of motivation with SSRI use (as mentioned in another post somewhere?) Would Ginko help with that? Antihistamine qualities in any drug ( like seroquel or cypreheptadine)make me so sleepy I can't function at all. (Even with provigil and dexedrine ER.) So I can't use those but I have to take an SSRI for suicidal ideation... and I think motivation is a big problem with me.
Thanks, River.
> Yes, acutually ginkgo is a 5-ht2a antagonist. I think recalling reading that it decreases the binding of serotonin to 2a receptors by about 33%.
>
> The tricylics, cypreheptadine, atypical antipsychotics, marajuanna, anandamide, also have some degree of 5-ht2 antagonism (mostly 5-ht2a antagonism). Oh, and the herb feverfew blocks 5-ht2a and 5-ht2b fairly potently.
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> Linkadge
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Posted by linkadge on April 1, 2006, at 11:30:46
In reply to Re: melatonin, REM, Parkinson's disease, posted by zeugma on March 30, 2006, at 21:13:30
That was very interesting. Sleep deprivation can cause seizures.
Linkadge
Posted by linkadge on April 1, 2006, at 11:39:50
In reply to Re: melatonin, REM, Parkinson's disease » linkadge, posted by zeugma on March 30, 2006, at 23:02:11
Theres really so much to it!
Somtimes if I am feeling particularly wired, and feeling that I won't sleep, I take supplemental choline right before bedtime.
It has been suprisingly helpfull. I usually wake up the next day somewhat depressed, but the anxiety usually drops significantly.
I think that sleep abnormalities may also exist in psychosis. The TCA's made me kindof psychotic.
If I do take it, It ususally shortens my sleep onset latency.
The funny thing that I try to explain to my doctor, is that I know, within 5 minautes of waking, if it is going to be a good day or a miserable one.
Linkadge
Posted by linkadge on April 1, 2006, at 11:41:43
In reply to Re: 5ht2 antagonists » linkadge, posted by River1924 on March 31, 2006, at 0:13:48
Yes, taking a 5-ht2a antagonist is one route to try and counteract SSRI induced apathy.
THe 5-ht2 receptors assert inhibitory control over certain dopaminergic pathways. Antagonists of the 5-ht2 system can enhance dopamine in several areas, limbic, frontal cortex etc.
Linkadge
Posted by linkadge on April 1, 2006, at 11:44:06
In reply to Re: melatonin, REM, Parkinson's disease » linkadge, posted by zeugma on March 30, 2006, at 23:02:11
Oh, and supplemental choline (at night) has helped my depersionalization too quite a bit.
Linkadge
Posted by zeugma on April 1, 2006, at 14:17:15
In reply to Re: melatonin, REM, Parkinson's disease » zeugma, posted by linkadge on April 1, 2006, at 11:44:06
i'm afraid to take choline because I think my cholinergic system is completely messed up.
The issue of sleep and seizures is so complicated. For example it appears that norepinephrine is anticonvulsant, because NET KO mice had a lower seizure susceptibility.. but it seems one way they induce seizures in mice is by administering pilocarpine, which is a cholinergic agonist, so maybe it's predictable that NE blocks seizures in these mice.
And a friend with epilepsy is almost as religious about going to sleep early as I am, because he becomes increasingly seizure-prone with loss of sleep.
I read that valproate fails to exert an antiseizure effect in micelacking dopamine beta hydroxylase (the enzyme that synthesizes NE from DA).
-z
Posted by linkadge on April 1, 2006, at 15:39:44
In reply to Re: melatonin, REM, Parkinson's disease » linkadge, posted by zeugma on April 1, 2006, at 14:17:15
Yeah that is true. Norepinephrine seems to control hippocampal timing, or oscilations or something like that.
But I think that in certain situations norepinephrine is anticonvulsant and in others it is proconvulsant. The thing is that most current NRI's have some proconvulsant activity.
All the TCA's and venlafaxine can be proconvusant in certain situations, but whether this is attributable to their effects on norepinehprine is unclear.
Lithium can be both proconvulsant and anticonvulsant. Lithium seems to increase the
ability of cholinergic agonists to induce seizures, yet it can still tame mania, so I don't know if mania and seizures are always directly comparable.But on the other hand, we use ECT to treat depression.
I think that if you induce a seizure below certain threshold it can increase the seizure threshold. I know that ECT can increase the seizure threshold, and so can rTMS.
Then there is a big overlap between epilepsy and depression.
Linkadge
Posted by jrbecker on April 1, 2006, at 22:15:41
In reply to Re: melatonin, REM, Parkinson's disease, posted by zeugma on March 30, 2006, at 21:13:30
>Eur Neuropsychopharmacol. 2006 Mar 6; [Epub ahead of print] Links
Melatonin affects the immobility time of rats in the forced swim test: The role of serotonin neurotransmission.Micale V, Arezzi A, Rampello L, Drago F.
Department of Experimental and Clinical Pharmacology, University of Catania, Catania, Italy.
The efficacy of melatonin or its derivatives in depressive patients has been recently considered for clinical application. However, the evidence for its effect on experimental models of depression is not consolidated. Here, the effects of melatonin on the model of forced swim test (FST) paradigm were studied in male rats of the Wistar strain after acute intraperitoneal (i.p.) administration of 0.1, 0.5 or 1 mg/kg of the hormone. Melatonin at doses of 0.5 and 1 mg/kg, but not of 0.1 mg/kg, decreased the immobility of rats in the FST paradigm suggesting a possible antidepressant-like activity. The dose of 0.5 mg/kg appeared to be as potent as clomipramine 50 mg/kg in reducing the immobility time of rats in the FST paradigm. The effect of melatonin on immobility time of rats in the FST paradigm was abolished by the simultaneous injection of the non-selective melatonin antagonist, luzindole (0.25 mg/kg, subcutaneously). Similarly, administration of small quantities of serotonin (5-HT, 5 ng/1 mul) or of the 5-HT(2A)/5-HT(2C) receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (2 ng/1 mul) injected into the amygdale totally suppressed the reduction of immobility time in the FST paradigm induced by melatonin 0.5 mg/kg. These results may suggest that effects of melatonin on the behavioral reaction of rats in the FST paradigm are due to an interaction of the hormone with central 5-HT neurotransmission.
PMID: 16527463 [PubMed - as supplied by publisher]
Posted by Sarah T. on April 2, 2006, at 4:51:58
In reply to Re: melatonin, REM, Parkinson's disease » zeugma, posted by linkadge on April 1, 2006, at 15:39:44
I have to go back and refresh my memory on this, but I do remember reading that there is a certain type of seizure that, on EEG, is indistinguishable from panic attacks. And one theory about the origin of panic attacks is that there is too much norepinephrine which causes hyperactivity of noradrenergic neurons in the locus ceruleus.
Posted by linkadge on April 2, 2006, at 9:52:06
In reply to Re: melatonin, REM, Parkinson's disease, posted by jrbecker on April 1, 2006, at 22:15:41
More potent than clomipramine, interesting.
Linkadge
Posted by linkadge on April 2, 2006, at 10:23:33
In reply to norepinephrine, seizures, etc. - Linkadge, zeugma » linkadge, posted by Sarah T. on April 2, 2006, at 4:51:58
I've heard similar theories.
Linkadge
Posted by zeugma on April 2, 2006, at 11:06:24
In reply to Re: melatonin, REM, Parkinson's disease, posted by jrbecker on April 1, 2006, at 22:15:41
The effect of melatonin on immobility time of rats in the FST paradigm was abolished by the simultaneous injection of the non-selective melatonin antagonist, luzindole (0.25 mg/kg, subcutaneously). Similarly, administration of small quantities of serotonin (5-HT, 5 ng/1 mul) or of the 5-HT(2A)/5-HT(2C) receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (2 ng/1 mul) injected into the amygdale totally suppressed the reduction of immobility time in the FST paradigm induced by melatonin 0.5 mg/kg.>>
It is intriguing to conjoin the above observation, which notes that melatonin's activity in a behavioral paradigm of depression can be reversed by a 5-HT2(A/C) agonist, with this study:
Brain Res. 2000 Mar 31;860(1-2):112-8.
Melatonin reversal of DOI-induced hypophagia in rats; possible mechanism by suppressing 5-HT(2A) receptor-mediated activation of HPA axis.Raghavendra V, Kulkarni SK.
Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India.
Serotonin type 2A (5-HT(2A)) receptor-mediated neurotransmitter is known to activate hypothalamic-pituitary-adrenal (HPA) axis, regulate sleep-awake cycle, induce anorexia and hyperthermia. Interaction between melatonin and 5-HT(2A) receptors in the regulation of the sleep-awake cycle and head-twitch response in rat have been reported. Previous studies have shown that melatonin has suppressant effect on HPA axis activation, decreases core body temperature and induces hyperphagia in animals. However, melatonin interaction with 5-HT(2A) receptors in mediation of these actions is not yet reported. We have studied the acute effect of melatonin and its antagonist, luzindole on centrally administered (+/-)-1-(2, 5-dimethoxy-4-iodophenyl) 2-amino propane (DOI; a 5-HT(2A/2C) agonist)-induced activation of HPA axis, hypophagia and hyperthermia in 24-h food-deprived rats. Like ritanserin [(1 mg/kg, i.p.) 5-HT(2A/2C) antagonist], peripherally administered melatonin (1.5 and 3 mg/kg, i.p.) did not affect the food intake, rectal temperature or basal adrenal ascorbic acid level. However, pretreatment of rats with it significantly reversed DOI (10 microgram, intraventricular)-induced anorexia and activation of HPA axis. But the hyperthermia induced by DOI was not sensitive to reversal by melatonin. Mel(1) receptor subtype antagonist luzindole (5 microgram, intraventricular) did not modulate the DOI effect but antagonized the melatonin (3 mg/kg, i.p.) reversal of 5-HT(2A) agonist response. The present data suggest that melatonin reversal of DOI-induced hypophagia could be due to suppression of 5-HT(2A) mediated activation of HPA axis.>>
The HPA axis is ubiquitious in studies of mood disorder related pathology. It seems there is an important correlation here, those who know more about the HPA axis in pathologies of mood and body, please comment.
-z
Posted by linkadge on April 2, 2006, at 18:49:56
In reply to Re: melatonin, the FST, and 5-HT2(A) » jrbecker, posted by zeugma on April 2, 2006, at 11:06:24
You posted an article a while back about the importance, in psychiatric disorders, of the functionality of 5-h1a vs. 5-ht2a.
5-ht2a antagonists like cyproheptadine have melatonergic properties. I think that blocking 5-ht2a at the right time in the night can increase melatonin production.
I also mentioned anandamide, the endogenious "bliss molecule", acts to potentiate 5-ht1a and antagonize 5-ht2a receptor responces.
There are anandamide uptake inhibitors in the pipelines.
Prozac, significantly decreases melatonin excretion, probably via indirect stimulation of 5-ht2a.See:
http://bjp.rcpsych.org/cgi/content/abstract/166/2/196
Also according to a few sites, melatonin reduced the antidepressant effect of fluoxetine, or desipramine. (do a google search on fluoxetine + melatonin). So taken together, melatonin and SSRI's must affect depression in different ways.
I think some studies have found that melatonin is of use in schizophrenic disorders, perhaps the combination of antioxidant and serotonergic receptor regulation may have a favorable impact on the course of illness.
Since melatonin is a powerful antioxidant, I would be concerned about taking medications that can reduce the levels of the hormone, ie SSRI's.
It is probably why we such a surge in the coadminstration of SSRI's and atypical antipsychotics. I think that if we had potent 5-ht2a antagonists, we might be able to more safely tackle such problems with SSRI's.
Linkadge
This is the end of the thread.
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