![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 105 to 129 of 139. Go back in thread:
Posted by zeugma on April 20, 2006, at 8:38:06
In reply to Re: Drugs versus Psychotherapy - Backlash? » zeugma, posted by linkadge on April 20, 2006, at 8:09:44
> Ok so suppose the NET transporter lowers itself to compensate for a deficiancy of norepinephrine. Then still, the pathelogical condition is not an abnormality in NET but rather an abnormality in norepinephrine availabilty.
>
> Ie, I cant see how taking these depressed patients who's brains respond to low norepinephrine by decreasing NET, and exposing them to a drug that decreases it further, is going to remedy the situation, or make their brains function more like the contol brains.
>
> Linakdgeif the downregulation of NET in response to abnormality in NE neurotransmission is a result of a homeostatic process, then amplifying the brain's own response with a NET inhibitor would be a strengthening of this response (possibly enough to compensate for the dysregulation).
The key is that 'normal' neurotransmission may be achieved by different routes. The brain is a highly 'degenerate' system; there are numerous ways to get the same functional result (definition of degeneracy i am using: "In physics two or more physical states are said to be degenerate if they are both at the same energy level." -Wikipedia). The use of a NET inhibitor might bring noradrenergic function in line with that of an individual who was unmedicated but euthymic despite the very different configurations of NET/NE systems in each.
-z
Posted by zeugma on April 20, 2006, at 9:02:56
In reply to Re: Drugs versus Psychotherapy - Backlash?, posted by linkadge on April 20, 2006, at 8:15:27
> In either case, I don't really see the problem as lying in a malfunctioning uptake system.>>
The evidence seems to be that the uptake systems are associated with drug response, if not with the disorder itself:
I suppose the key is the ability to attain a homeostatic state that has the same functionality as an euthymic individual's.
>
> I remember reading somewhere that a fair portion of tested depressed patients had an abnormality in the TPH-2 gene (tryptophan hydroxylase)(or something like that) which coded for a much lower level of serotonin synthesis. That might explain things better.>>
>There are likely abnormalities at all levels of neurotransmission. At some point psychiatrists will stop using trial and error and use genomic evidence to treat particular patients. I believe very strongly that the current pharmocopoeia is not used to maximum benefit because this information is not routinely used to guide treatment. It is certainly easier to study gene effects on treatment response, than to design new drugs.
-z
>
Posted by SLS on April 20, 2006, at 10:20:16
In reply to Re: Drugs versus Psychotherapy - Backlash? » linkadge, posted by zeugma on April 20, 2006, at 9:02:56
So, then, what's the deal?
Is the reduction in the numbers of NET reported in the previous study you cited the result of inadequate gene expression, or is it the result of a compensatory mechanism?
- Scott> > In either case, I don't really see the problem as lying in a malfunctioning uptake system.>>
>
> The evidence seems to be that the uptake systems are associated with drug response, if not with the disorder itself:
>
> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15939518&query_hl=211&itool=pubmed_docsum
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> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16005136&query_hl=212&itool=pubmed_docsum
>
> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15993855&query_hl=215&itool=pubmed_docsum
>
> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15337646&query_hl=230&itool=pubmed_docsum
>
>
> I suppose the key is the ability to attain a homeostatic state that has the same functionality as an euthymic individual's.
> >
> > I remember reading somewhere that a fair portion of tested depressed patients had an abnormality in the TPH-2 gene (tryptophan hydroxylase)(or something like that) which coded for a much lower level of serotonin synthesis. That might explain things better.>>
> >
>
> There are likely abnormalities at all levels of neurotransmission. At some point psychiatrists will stop using trial and error and use genomic evidence to treat particular patients. I believe very strongly that the current pharmocopoeia is not used to maximum benefit because this information is not routinely used to guide treatment. It is certainly easier to study gene effects on treatment response, than to design new drugs.
>
> -z
> >
>
>
Posted by zeugma on April 20, 2006, at 10:57:59
In reply to Re: Drugs versus Psychotherapy - Backlash? » zeugma, posted by SLS on April 20, 2006, at 10:20:16
So, then, what's the deal?
Is the reduction in the numbers of NET reported in the previous study you cited the result of inadequate gene expression, or is it the result of a compensatory mechanism?>>
Definitely not inadequate NET gene expression, but compensation for inadequate gene expression downstream:
Daily treatment of rats with DMI (10 mg/kg, i.p.) for 3 or 14 days significantly increased postmortem cerebral TH mRNA in the locus coeruleus (LC) area by 47-68%. Again, TH protein concentrations in LC decreased at 3 and 14 days, by 25-40%, with transient significant reduction in amygdala tissue after 3 days of treatment that were not sustained. These findings indicate that DMI exerts complex, typically opposite and perhaps compensatory, gradually evolving effects on the expression of TH protein (decreases) and its message (increases), possibly in response to increased synaptic availability of NE.
it is possible that the reduction of NET in the other studies is an attempt to upregulate inadequate gene expression (of tyrosine hydroxylase), and that the inhibitor facilitates this process. I think that antidepressants, when they work, probably build on the brain's own compensatory mechanisms.then again, I am just speculating. What do you think?
-z
Posted by linkadge on April 20, 2006, at 17:55:02
In reply to Re: Drugs versus Psychotherapy - Backlash? » linkadge, posted by zeugma on April 20, 2006, at 8:38:06
"The use of a NET inhibitor might bring noradrenergic function in line with that of an individual who was unmedicated but euthymic despite the very different configurations of NET/NE systems in each."
Maybe, or it may even further serve to mask/ intensify an additional, yet unidentified predisposing factor.
Some people even think that the TCA's work independantly of their effects on monoamines. For instance the TCA surmontil has no effect on monoamine reuptake, yet is an effective antidepressant in animal models. It also leads to identical adaptive changes in monoamine receptor sites as other TCA's.
Another argument is that we have drugs such as straterra, which are NRI's but display only weak, negligable effect in depression.
One would think that if the if NET inhibition was the key mechanism, then any drug which inhibited it would be an antidepressnat.
Linkadge
Posted by linkadge on April 20, 2006, at 18:06:26
In reply to Re: Drugs versus Psychotherapy - Backlash? » linkadge, posted by zeugma on April 20, 2006, at 9:02:56
These studies are great, but you can probably find just as many others which suggest that drug responce is not really associated with any abnormalities in the SERT genes.
For instance, in this study, which has been replicated in different populations, some researchers found that the double-short varient of the serotonin transporter was associated with a higher lifetime occurance of depression and anxiety disorders. But heres the thing, The SS varient of the serotonin transporter gene codes for a lower reuptake of serotonin.
http://www.futurepundit.com/archives/001611.html
Some people mistakenly site this as an argument for SSRI use, without noting that this gene actually codes for a lower reuptake of serotonin than those with one or two long varients. So it doesn't make sence to have these people taking SSRI's. Perhaps Tianeptine would bring them to a better homeostasis.
Linkadge
Posted by linkadge on April 20, 2006, at 18:11:21
In reply to Re: Drugs versus Psychotherapy - Backlash? » SLS, posted by zeugma on April 20, 2006, at 10:57:59
I was under the impression that a high level norepinephine firing in the locus coeruleus corresponded to high anxiety states, and that drugs like clonidine relieved anxiety by reducing firing.
Linkadge
Posted by zeugma on April 20, 2006, at 18:44:25
In reply to Re: Drugs versus Psychotherapy - Backlash?, posted by linkadge on April 20, 2006, at 18:06:26
>
>
> For instance, in this study, which has been replicated in different populations, some researchers found that the double-short varient of the serotonin transporter was associated with a higher lifetime occurance of depression and anxiety disorders. But heres the thing, The SS varient of the serotonin transporter gene codes for a lower reuptake of serotonin.
>
> http://www.futurepundit.com/archives/001611.html
>
> Some people mistakenly site this as an argument for SSRI use, without noting that this gene actually codes for a lower reuptake of serotonin than those with one or two long varients. So it doesn't make sence to have these people taking SSRI's. Perhaps Tianeptine would bring them to a better homeostasis.
>
I agree completely that the double-short variant of the serotonin transporter is associated with a poorer response to SSRI's. This study bears it out:Buspirone or more selective 5-HT1A agonists might be effective in this population, or the new antidepressant (stil in phase III) vilazodone, which is a combined SRI/5-HT1A agonist.
-z
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Posted by zeugma on April 20, 2006, at 18:49:59
In reply to Re: Drugs versus Psychotherapy - Backlash?, posted by linkadge on April 20, 2006, at 17:55:02
Another argument is that we have drugs such as straterra, which are NRI's but display only weak, negligable effect in depression.
One would think that if the if NET inhibition was the key mechanism, then any drug which inhibited it would be an antidepressnat.>>
I don't know the answer to this. In the case of Strattera, I have supposed that since Strattera's metabolite is a kappa opiod partial agonist, a depressogenic effect counteracts its NRI-based antidepressant effect.
Even reboxetine is not a pure NRI: it blocks nicotinic ACh receptors. Reboxetine seems to be an effective antidepressant from numerous studies, and yet it doesn't seem to work for anybody who posts here. Maybe everyone who has taken reboxetine and gotten a positive result is so deliriously happy that they have no need to post here.
-z
Posted by linkadge on April 20, 2006, at 18:52:48
In reply to Re: Drugs versus Psychotherapy - Backlash?, posted by zeugma on April 20, 2006, at 18:44:25
I mean, if you said that SS varient represented only a minority of depressed persons, then the theory would still look good on paper. But if the majority of depressed people actually posess the SS varient then it would be an arguement against the purported mechanism.
Its great to say that SSRI's work well for people with the L/S or L/L varients, but if they only represent the minority of depressed persons, then it might not look so good.
Linkadge
Posted by zeugma on April 20, 2006, at 19:27:58
In reply to Re: Drugs versus Psychotherapy - Backlash? » zeugma, posted by linkadge on April 20, 2006, at 18:52:48
> I mean, if you said that SS varient represented only a minority of depressed persons, then the theory would still look good on paper. But if the majority of depressed people actually posess the SS varient then it would be an arguement against the purported mechanism.
>
> Its great to say that SSRI's work well for people with the L/S or L/L varients, but if they only represent the minority of depressed persons, then it might not look so good.
>
> Linkadge
This is actually quite fascinating. The link you posted connected the s/s serotonin transporter with stress/anxiety and reactive depression. In generalized anxiety disorder it seems that it breaks down this way:Psychopharmacology (Berl). 2006 Mar 9; [Epub ahead of print]
Serotonin transporter gene promoter polymorphism predicts SSRI response in generalized social anxiety disorder.Stein MB, Seedat S, Gelernter J.
Departments of Psychiatry and Family & Preventive Medicine, University of California, 9500 Gilman Drive (0985), La Jolla, San Diego, CA, 92093-0985, USA, mstein@ucsd.edu.
OBJECTIVES: To determine whether variation in the serotonin transporter gene promoter (5HTTLPR) influences the efficacy of selective serotonin reuptake inhibitors (SSRIs) in generalized social anxiety disorder (GSAD). METHODS: Consecutive series of N=32 patients with DSM-IV GSAD for whom DNA and standardized outcome data from a 12-week SSRI trial were available. After ensuring that neither clinical response [clinical global impression of change scale (CGI-C)] nor 5HTTLPR genotype was confounded by ethnicity or sex, we determined whether the number of copies (0, 1, or 2) of hi-risk alleles using either the diallelic L-S system or the triallelic La-Lg-S system, predicted response and change in Liebowitz social anxiety scale (LSAS) and brief social phobia scale (BSPS) scores during SSRI treatment. RESULTS: Twenty-one patients (66%) were responders to SSRI (i.e., CGI-C much or very much improved). A trend was seen for a linear association between 5HTTLPR genotype and likelihood of response to SSRI: diallelic classification L/L 7/8 (88%), L/S 12/18 (67%), S/S 2/6 (33%), p=0.051; triallelic classification L'/L' 4/5 (80%), L'/S' 14/19 (74%), S'/S' 3/8 (38%), p=0.093. Reduction in LSAS (and BSPS) scores during SSRI treatment was significantly (p<0.02) associated with 5HTTLPR genotype using either the diallelic or triallelic classification. CONCLUSIONS: Variation in a functional polymorphism known to influence serotonin reuptake is associated with SSRI response in patients with GSAD. Independent replication in larger samples is required before the predictive utility of this information can be confirmed and generalized to clinical settings.
This is exactly what I would have thought from reading your link. But consider this:
Prog Neuropsychopharmacol Biol Psychiatry. 2006 Mar 30; [Epub ahead of print]
Serotonin transporter polymorphisms and clinical response to sertraline across ethnicities.Ng CH, Easteal S, Tan S, Schweitzer I, Ho BK, Aziz S.
Professorial Unit, The Melbourne Clinic, University of Melbourne, Australia.
The aim of this pilot study was to examine the relationship between clinical response, adverse effects, sertraline (SERT) plasma concentrations and the genetic polymorphism of the serotonin transporter gene-linked polymorphic region (5HTTLPR) in 2 ethnic patient groups. The study involved 45 patients in a clinical trial who received a fixed dose regimen of 50 mg SERT for one week, then a variable-dose regimen for a further 6 weeks for major depressive disorder. At weeks 1 and 6, the following assessments were completed: Hamilton Depression Rating Scale (HDRS), Clinical Global Impression (CGI), drug adverse reaction scale and measurement of plasma SERT levels. Genomic analysis for the long and short allele variants of the 5HTTLPR polymorphism was also carried out. Caucasian subjects had a higher rate of l/l genotype while Chinese subjects had higher frequencies of l/s and s/s genotypes. Comparison of the subjects with the 5HTTLPR s/s genotype and those with the l/l and l/s genotypes found no significant differences in the HDRS scores, CGI scores, response rates, adverse effects and SERT plasma concentrations at week 6.
Who knows? I'm inclined to say that the s/s genotype is more prone to anxiety, and that the serotonin transporter polymorphisms might have a closer bearing on anxiety states than depression. But it is obviously complex and also there are so many other variables (MAO, COMT, etc.). But I am pretty sure that the s/s polymorphism really is associated with a a poorer response to conventional antidepressants, despite the study above. It's also worth noting that the l/l and l/s genotypes were more common in the Causcasian patients in that study.
-z
Posted by zeugma on April 20, 2006, at 19:34:02
In reply to Re: Drugs versus Psychotherapy - Backlash? » linkadge, posted by zeugma on April 20, 2006, at 19:27:58
also, the Stein et al. study used a 12-week duration which is surely more adequate than a six-week study if you are trying to pick up possibly subtle effects/ screen for placebo effects. The Mulder/Joyce et al. studies are very trustworthy because they have done extensive work on drug response, and they have worked with Cloninger, who is one of the leading theorists of temperament (which is the dimension that your link was really concerned with).
-z
Posted by zeugma on April 20, 2006, at 20:08:27
In reply to Re: Drugs versus Psychotherapy - Backlash?, posted by zeugma on April 20, 2006, at 19:34:02
I found this article on how clonazepam upregulates the serotonin transporter:
Neuropharmacology. 1995 Oct;34(10):1327-33.
Serotonin turnover rate, [3H]paroxetine binding sites, and 5-HT1A receptors in the hippocampus of rats subchronically treated with clonazepam.Lima L, Trejo E, Urbina M.
Laboratorio de Neuroquimica, Instituto Venezolano de Investigaciones Cientificas, Caracas, Venezuela.
Selective central benzodiazepine agonists, such as clonazepam, are known to modify serotonin and 5-hydroxyindoleacetic content in the brain. In order to further study the effect of this benzodiazepine on serotonin turnover rate, rats received clonazepam, 10 mg/kg for 10 days, and the concentrations of serotonin and 5-hydroxyindoleacetic acid were determined in the hippocampus after inhibition of monoamineoxidase with pargyline. The results indicate a reduction in the turnover rate of the monoamine. In addition, the systemic administration of clonazepam produced a decrease in the Bmax of [3H]DPAT binding to 5-HT1A sites in the hippocampus. By contrast, this effect was not observed if clonazepam was delivered into the dorsal raphe nucleus by osmotic minipumps. The binding of [3H]paroxetine to 5-HT reuptake sites was increased by the treatment with clonazepam. The present observations indicate that clonazepam produces a reduction of serotonin turnover rate in the hippocampus of the rat concomitant with a down-regulation of 5-HT1A binding sites, probably by an effect at the forebrain projections. There is also an up-regulation of the serotonin transporter, which might contribute to a reduction in the synaptic availability of serotonin during clonazepam treatment.
This might make clonazepam an option similar to tianeptine in its effect on the 5-HT transporter. And it is consonant with the idea that the s/s genotype is prone to anxiety/stress.
-z
Posted by linkadge on April 20, 2006, at 20:52:10
In reply to Re: Drugs versus Psychotherapy - Backlash? » linkadge, posted by zeugma on April 20, 2006, at 19:27:58
Interesting. Another thing to consider is that all of the currently available SSRI's increase the synthesis of a very potent gabergic neurosteriod called allopregnanalone. I believe that it is an intrinsic effect of the molecule, and not an effect of an SSRI in general.
This could definately confound some of the responces. Ie a person could respond to this
mechanism but perhaps still have a s/s transporter gene.SSRI's often made my anxiety much much worse. They also had minimal effect on my depression.
They helped my depression a little when things weren't stresfull, but heavy stress + SSRI's always made me near psychotic.Heres what I never understood. They don't discover these drugs by doing all of these advanced biochemical studies in humans. They discover all of the antidepressants by throwing regular mice in a vat of water and seeing which ones keep the mice swimming longer. They don't base their presumptions on the ability of the drugs to fix any rat's bad biochemisty, so why all of a sudden are these drugs supposedly fixing humans at the biochemical level? Oh sure, some of these drugs can keep you "swimming" a little longer, but they're a far cry from feeling good.
Linkadge
Posted by linkadge on April 20, 2006, at 21:04:27
In reply to interesting- re clonazepam and 5-HT transporter, posted by zeugma on April 20, 2006, at 20:08:27
Hey, I like that one about clonazepam.
Several lines of evidence seem to point to exess serotonergic neurotransmission (in certain areas of the brain) in high anxiety states, I found periacin (a multiple serotonin antagonist) to be profoundly calming. It can be a little depressing, but very calming.
I think that oftentimes when stressfull events end you can become very depressed since your cortisol drops and your HPA axis needs time to heal. Taking an SSRI might bring prompt relif from depression simply by almost mimicking the stress and mimicking previous levels of cortisol.Linkadge
Posted by scatterbrained on April 21, 2006, at 4:09:16
In reply to Drugs versus Psychotherapy - Backlash?, posted by SLS on April 6, 2006, at 9:43:54
I don't know how I feel about psychotherapy being considered as effective as meds, I certainly haven't found that to be the case. I have found psychotherapy effective prior to my major depression causing awful problems with cognition and prior to anhedonia. I think one needs to have a certain level of emotional and intellectual responsiveness for therapy to work. This is impossible given the symptoms I am experiencing.Anhedonia causes a flat,indifference which nothing can penetrate . and because of deficits in my working memory I can't do the cognitive therapy "worst case scenario" type thing in my head, nor anything else, because I forget what I'm thinking about half way through. Biological treatments have been the only thing that have ,although transiently, helped clear up my head and take away my anhedonia. I do believe that for certain people, the right psychotherapy is a safer and more effective treatment.I would actually venture to say that most people with depression would probably benefit from psychotherapy. But when you have something that is as severe as what i have and what many other people on this site have, especially if it effects cognition, then it's in the neurological realm not the psychological. I think there are two different illnesses that are being unfairly lumped together.
Posted by SLS on April 21, 2006, at 7:55:22
In reply to Re: Drugs versus Psychotherapy - Backlash? » SLS, posted by zeugma on April 20, 2006, at 10:57:59
> I think that antidepressants, when they work, probably build on the brain's own compensatory mechanisms.
>
> then again, I am just speculating. What do you think?Right now, I can't think at all. I wish I could keep up with the conversation you guys are having, but my mind is just too vegetative. Wellbutrin has quit working for me, and I'm left feeling pretty dumb.
- Scott
Posted by naughtypuppy on April 21, 2006, at 12:42:52
In reply to Re: Drugs versus Psychotherapy - Backlash? » zeugma, posted by linkadge on April 20, 2006, at 20:52:10
> Interesting. Another thing to consider is that all of the currently available SSRI's increase the synthesis of a very potent gabergic neurosteriod called allopregnanalone. I believe that it is an intrinsic effect of the molecule, and not an effect of an SSRI in general.
>
> This could definately confound some of the responces. Ie a person could respond to this
> mechanism but perhaps still have a s/s transporter gene.
>
>
>
> SSRI's often made my anxiety much much worse. They also had minimal effect on my depression.
> They helped my depression a little when things weren't stresfull, but heavy stress + SSRI's always made me near psychotic.
>
> Heres what I never understood. They don't discover these drugs by doing all of these advanced biochemical studies in humans. They discover all of the antidepressants by throwing regular mice in a vat of water and seeing which ones keep the mice swimming longer. They don't base their presumptions on the ability of the drugs to fix any rat's bad biochemisty, so why all of a sudden are these drugs supposedly fixing humans at the biochemical level? Oh sure, some of these drugs can keep you "swimming" a little longer, but they're a far cry from feeling good.Good point. I never had much faith in studies that induced artificial stressors on normal mice. People with mood disorders are largely that way because they have a predisposition for it. Other people will react less to the same level of stress. How many times have we been told "Well, It doesn't bother me so why should it bother you so much?".
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> Linkadge
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Posted by linkadge on April 21, 2006, at 13:37:08
In reply to Re: Drugs versus Psychotherapy - Backlash? » linkadge, posted by naughtypuppy on April 21, 2006, at 12:42:52
I agree, although it is interesting to note that the forced swim test is highly predictive of medications that will work for depressive disorders. Perhaps people with depressive dispositions simply need less to become depressed.
Linkadge
Posted by SLS on April 21, 2006, at 14:20:15
In reply to interesting- re clonazepam and 5-HT transporter, posted by zeugma on April 20, 2006, at 20:08:27
I would be interested to know what are the acute direct effects of clonazepam on the 5-HT system. So many people find it depressogenic almost immediately. I found this to be true of me.
Also, increasing the number of 5-HT1a postsynaptic receptors in the hippocampus might actually produce memory impairments. I believe they are inhibitory rather than excitatory. They hyperpolarize the membrane.http://www.nirs.go.jp/report/nene/h14/04/65.html
What I find weird is that chronic exposure to various classes of antidepressants increases the disinhibitory response to 5-HT1a antagonists. I guess there must be some sort of accomodation downstream to balance out the increased number of receptors so as to make them less sensitive to activation by serotonin. If the excitatory postsynaptic receptors remain unchanged, the net effect should be an enhanced signal-to-noise ratio, despite the increased synaptic serotonin that results from SERT inhibition. This should result in the enhancement of serotonergic neurotranmission. Thus we have a possible explanation for the production of a serotonergic antidepressant response.
http://www.biopsychiatry.com/5ht1a.htm
At the moment this makes sense to me. In five minutes I guarantee I'll be confused again!
- Scott
> I found this article on how clonazepam upregulates the serotonin transporter:
>
> Neuropharmacology. 1995 Oct;34(10):1327-33.
>
>
> Serotonin turnover rate, [3H]paroxetine binding sites, and 5-HT1A receptors in the hippocampus of rats subchronically treated with clonazepam.
>
> Lima L, Trejo E, Urbina M.
>
> Laboratorio de Neuroquimica, Instituto Venezolano de Investigaciones Cientificas, Caracas, Venezuela.
>
> Selective central benzodiazepine agonists, such as clonazepam, are known to modify serotonin and 5-hydroxyindoleacetic content in the brain. In order to further study the effect of this benzodiazepine on serotonin turnover rate, rats received clonazepam, 10 mg/kg for 10 days, and the concentrations of serotonin and 5-hydroxyindoleacetic acid were determined in the hippocampus after inhibition of monoamineoxidase with pargyline. The results indicate a reduction in the turnover rate of the monoamine. In addition, the systemic administration of clonazepam produced a decrease in the Bmax of [3H]DPAT binding to 5-HT1A sites in the hippocampus. By contrast, this effect was not observed if clonazepam was delivered into the dorsal raphe nucleus by osmotic minipumps. The binding of [3H]paroxetine to 5-HT reuptake sites was increased by the treatment with clonazepam. The present observations indicate that clonazepam produces a reduction of serotonin turnover rate in the hippocampus of the rat concomitant with a down-regulation of 5-HT1A binding sites, probably by an effect at the forebrain projections. There is also an up-regulation of the serotonin transporter, which might contribute to a reduction in the synaptic availability of serotonin during clonazepam treatment.
>
> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8570030&query_hl=98&itool=pubmed_docsum
>
> This might make clonazepam an option similar to tianeptine in its effect on the 5-HT transporter. And it is consonant with the idea that the s/s genotype is prone to anxiety/stress.
>
> -z
Posted by linkadge on April 21, 2006, at 15:03:10
In reply to Re: interesting- re clonazepam and 5-HT transporte, posted by SLS on April 21, 2006, at 14:20:15
I could be wrong, but I think that abstract is confusing since its refering to both presynaptic autoreceptors, and post synaptic 5-ht1a receptors in the forebrain as simply 5-ht1a receptors.
I think that it means that activation of presynaptic autoreceptors inhibits the firing in the ca3 region, and that after ECT these autoreceptors are downregulated and hence fire more in responce to a 5-ht1a autoreceptor antagonist.
(Again, I could be way off!!!)
SSRI's depend on desensitizing autoreceptors to lead to increased sertonergic firing. But, in the case of ECT, manipulation of SERT is unneccessary to reduce autoreceptor activity.
Linkadge
Posted by linkadge on April 21, 2006, at 15:05:50
In reply to Re: interesting- re clonazepam and 5-HT transporte, posted by linkadge on April 21, 2006, at 15:03:10
RTMS produces reduced sensitivity of both 5-ht1a autoreceptors and 5-ht1b autoreceptors.
http://www.altered-states.net/barry/newsletter203/5htp.htm
Linkadge
Posted by SLS on April 21, 2006, at 16:05:46
In reply to Re: interesting- re clonazepam and 5-HT transporte, posted by linkadge on April 21, 2006, at 15:03:10
> I could be wrong, but I think that abstract is confusing since its refering to both presynaptic autoreceptors, and post synaptic 5-ht1a receptors in the forebrain as simply 5-ht1a receptors.
I am under the impression that 5-HT1a receptors in the hippocampus are primarily postsynaptic and inhibitory. Either way, it seems that these receptors are modulatory rather than excitatory.
I know this is simplistic, but it seems to me that pushing the system in one direction (SRI) or the other (tianeptine) results in the same thing. This would be a series of compensatory changes that produce a more functional balance of receptors and neurotransmitter.
- Scott
Posted by linkadge on April 21, 2006, at 17:37:50
In reply to Re: interesting- re clonazepam and 5-HT transporte, posted by SLS on April 21, 2006, at 16:05:46
Yeah, I suppose that agents like buspar and gepirone exert their anxiolitic effects via post synaptic 5-ht1a receptors.
I think that activation of post synaptic 5-ht1a receptors causes declaritive memory problems by inhibiting cholinergic function. 5-ht1a agonists are also called serenics. 5-ht1a receptor agonists are known to reduce REM sleep, and I think that is related to their supressing effects on cholinergic function.
OTOH, serotonergic agents are neurotrophic via post synaptic 5-ht1a receptors.
So I think that when you take a 5-ht1a agonist, it kinda calms you down, shuts you up, and gets you growing new brain cells instead of blabbing about the connections you've already made.
Linkadge
Posted by linkadge on April 21, 2006, at 17:39:45
In reply to Re: interesting- re clonazepam and 5-HT transporte, posted by SLS on April 21, 2006, at 16:05:46
Increased levels of the autoreceptors have been found in suicide. I think increased autoreceptors result in less serotonin release.
http://biopsychiatry.com/5ht1asui.htm
Linkadge
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Dr. Bob is Robert Hsiung, MD,
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Script revised: February 4, 2008
URL: http://www.dr-bob.org/cgi-bin/pb/mget.pl
Copyright 2006-17 Robert Hsiung.
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