![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 25 of 28. This is the beginning of the thread.
Posted by raybakes on December 13, 2004, at 3:08:30
Just came across this study that found that SSRIs upregulate the dopamine transporter (DAT).
"The results demonstrated the inhibition of SERT by SSRI in human in vivo during the chronic treatment and, unexpectedly, an elevation of DAT. This apparent SSRI-induced modulation of the dopamine system may be associated with the side effects of these agents, including sexual dysfunction."
Ray
Posted by raybakes on December 13, 2004, at 3:08:31
In reply to SSRI/dopamine antagonism, posted by raybakes on December 11, 2004, at 9:13:12
What's worrying about the SSRI upregulation of DAT is that higher levels of DAT expression are implicated in parkinson's..
'Dopamine transporter: involvement in selective dopaminergic neurotoxicity and degeneration.'
Posted by linkadge on December 13, 2004, at 3:08:31
In reply to Re: SSRI/dopamine antagonism, posted by raybakes on December 11, 2004, at 12:02:28
Dopamine is kind of the life-force chemical.
I've been using SSRI's for about 5 years now (only 21) I have tremor, muscle stiffness, and diffuclty writing.
Linkadge
Posted by KaraS on December 13, 2004, at 3:08:31
In reply to Re: SSRI/dopamine antagonism, posted by linkadge on December 11, 2004, at 13:10:12
> Dopamine is kind of the life-force chemical.
>
> I've been using SSRI's for about 5 years now (only 21) I have tremor, muscle stiffness, and diffuclty writing.
>
>
> Linkadge
Linkadge,Do you have the tremors when you're not on an SSRI? I had the tremors when I took Prozac but they went away when I went off of it.
Kara
Posted by tealady on December 13, 2004, at 3:08:32
In reply to Re: SSRI/dopamine antagonism » linkadge, posted by KaraS on December 11, 2004, at 15:03:36
Me too with many SSRI's..fine off them after a while.
(see why I rip up scrips? :-)Jan
Now to find if this dopamine transporter hing has anything to do with inhibition and buildup of tyrosine hydroxylase or if that is something entirely separate and not related to SSRI's at all.
Posted by linkadge on December 13, 2004, at 3:08:32
In reply to Re: SSRI/dopamine antagonism » KaraS, posted by tealady on December 11, 2004, at 15:59:58
Actually, if I discontune the SSRI, the tremors and facial grimaces, shoulder rotations etc get worse !
It was made aware to me that if sometimes a psycotropic that causes dystonia can cause more when the drug is removed.
Linakdge
Posted by KaraS on December 13, 2004, at 3:08:33
In reply to Re: SSRI/dopamine antagonism » KaraS, posted by tealady on December 11, 2004, at 15:59:58
> Me too with many SSRI's..fine off them after a while.
> (see why I rip up scrips? :-)
>Yes, I do but the problem is what to replace them with?
> Jan
>
> Now to find if this dopamine transporter hing has anything to do with inhibition and buildup of tyrosine hydroxylase or if that is something entirely separate and not related to SSRI's at all.
I only know that introducing more serotonin alone somehow leads to a dampening of dopamine activity.K
Posted by KaraS on December 13, 2004, at 3:08:33
In reply to Re: SSRI/dopamine antagonism, posted by linkadge on December 11, 2004, at 16:31:31
> Actually, if I discontune the SSRI, the tremors and facial grimaces, shoulder rotations etc get worse !
>
> It was made aware to me that if sometimes a psycotropic that causes dystonia can cause more when the drug is removed.
For how long though? Could it be that the dystonia is worse right after you go off of the drug but that eventually (many months or even years down the road) it goes away?
>
>
> Linakdge
Posted by raybakes on December 13, 2004, at 3:10:03
In reply to Re: SSRI/dopamine antagonism, posted by linkadge on December 11, 2004, at 16:31:31
> Actually, if I discontune the SSRI, the tremors and facial grimaces, shoulder rotations etc get worse !
>
> It was made aware to me that if sometimes a psycotropic that causes dystonia can cause more when the drug is removed.
>
Looking at several articles and abstracts it seems possible that SSRIs block the action of SERT but the body compensates by upregulating DAT which has some serotonin activity but screws up dopamine.Coming off SSRIs reactivates SERT, which like DAT has activity for both serotonin and dopamine - so poor dopamine gets zapped again!
"Results from our DA uptake experiments indicate that SERT is an important modulator of both 5-HT and DA uptake and that ~40% of the DA uptake observed in striatum is due to promiscuous SERT activity."Do you think that could be an explaination or is something else happening?
Ray
Posted by linkadge on December 13, 2004, at 3:10:03
In reply to Re: SSRI/dopamine antagonism » linkadge, posted by raybakes on December 12, 2004, at 7:41:16
I never waited long enough to see if the movement issues subsided. I was having trouble writing legably in school and the doctor didn't have any answers so I just went back to the original dose.
I also have the jaw clenching issue, which doesn't help the orthidontic problem I have with my jaw joint. I'm complaining like I'm 65, better stop.
Many doctors would pump you so high on the AD's that you are smiling all day long. I am a strong believer that we should use the medications at the lowest possable effective dose. Just enough that you can implement all the other things that might help.
Docotors may say that if you're not in remission then it might return, but I'm more afraid that if I take my medication as prescribed (40mg of celexa, yeah right!!) not only will I be on it for the rest of my life, but that I might actually be *worsening* the course of my illness.
I've already seen enough change in my mental state from being exposed to SSRI's for 5 years,
to believe that they are that pancea that we once thought.
Linkadge
Posted by raybakes on December 13, 2004, at 7:43:22
In reply to Re: SSRI/dopamine antagonism, posted by linkadge on December 12, 2004, at 14:53:16
This looks interesting...
It's a bit long winded, but goes into how estrogen and soy affect serotonin metabolism - low social status in monkeys has an effect, and progesterone analogues negate estogen's positive effects, but not natural progesterone.
Ray
Posted by tealady on December 13, 2004, at 17:50:52
In reply to Re: SSRI/dopamine antagonism, posted by raybakes on December 13, 2004, at 7:43:22
Hi Ray, thanks interesting article.
I found this to be an easier to read version http://www.sph.uth.tmc.edu/course/occupational_envHealth/bamick/home/TPSH%20Seminar%20Series%20Materials/Shively%20January%202004/Shively-Pharmacogenomics2003.pdf
The article seems to be saying...
* in depression, 5-HT and SERT both low (pp5)
progestins block estrogen effects..so lower TPH (pp4 TPH reduced to Ovarietomized level when progestin added)..read "low dose contraceptive pill"..so less 5-HT synthesis..leads to lower 5-HT
if estrogen( any form) up
. Tryptophan hydroxylase (TPH) up
leads to serotonin (5-HT) synthesis up
. serotonin reuptake transporter(SERT) up
. neuronal firing up(probably..seemed to be assumed)and vice-versa
sustained Low grade stess..as in lower status in the group(perhaps sustained raised cortisol levels?) leads to lowered TPH
** Also 5-HT prevents SERT degradation. (protective effect of 5-HT blocked by SSRI)
Now we have a typically depressed female with lowish estrogen levels (maybe after being on the pill, or perimenopause, menopause etc) ...given an SSRI (reuptake inhibitor) or some progestins ..or both is they are lucky!
SSRI blocks reuptake leads to
SERT lowered **
serotonin(5-HT) in synapses up
so initially feel a bit of an antidepressant effect
but 5-HT was low to start with * ..so still not enough 5-HT for enough reliefIn addition the SSRI ups DAT(previous post)..so less dopamine in synapse..so feels like its not the answer even if it has a slight effect
As well the SSRI has lowered the SERT..
also the extra 5-HT(even though not a lot) has desensitied the receptors ....hmm this IS how it works!
Guess that fits http://www.dr-bob.org/babble/alter/20031003/msgs/265672.htmlI guess you can tell I was not impressed with SSRI's, despite admiting to some slight antidepressant relief..there was something wrong with how I felt
Jan
Posted by pablo1 on December 13, 2004, at 18:04:02
In reply to SSRI/dopamine antagonism- easier to read/print ver » raybakes, posted by tealady on December 13, 2004, at 17:50:52
So, I'm really not following this but would some of this 'body's response' business have to do with the month it supposedly takes to adjust to SSRI's? I've been on Zoloft about a month & am beginning to get extra sensitive to my other dopamine meds and Zoloft already has quite a bit of dopamine effect. As a consequence, I'm a bit wired & not sleeping well. I also quit drinking but initially that just made me sleep more.
Effexor messed up my sleep patterns making me sleepy in the day & waking repeatedly at night which seemed more of a norepenephrine thing and when I went off Effexor after 6 weeks I got this incredible dopamine rebound for a couple weeks. It was obvious that it had been sapping my dopamine away & I felt it come back stonger than I ever felt. Agh, this stuff is just too complicated!
I don't know what is supposed to change after a month on SSRI's but I feel them right away when starting as a sort of sedating effect. I think all that's supposed to change is the side effects go away & the calming continues but I don't know. If I'm not feeling any actual improvement after 50 zoloft 50mg, I'm giving this up too, especially with the sleep disturbances.
Posted by linkadge on December 13, 2004, at 19:08:02
In reply to Re: SSRI/dopamine antagonism- easier to read/print, posted by pablo1 on December 13, 2004, at 18:04:02
What has worked for you ?
Linkadge
Posted by raybakes on December 14, 2004, at 6:01:07
In reply to SSRI/dopamine antagonism- easier to read/print ver » raybakes, posted by tealady on December 13, 2004, at 17:50:52
Thanks Jan - found it really useful reading your interpretation!
Ray
Posted by Mistermindmasta on December 15, 2004, at 1:11:38
In reply to Re: SSRI/dopamine antagonism » linkadge, posted by raybakes on December 12, 2004, at 7:41:16
> > Actually, if I discontune the SSRI, the tremors and facial grimaces, shoulder rotations etc get worse !
> >
> > It was made aware to me that if sometimes a psycotropic that causes dystonia can cause more when the drug is removed.
> >
>
> Looking at several articles and abstracts it seems possible that SSRIs block the action of SERT but the body compensates by upregulating DAT which has some serotonin activity but screws up dopamine.
>
> Coming off SSRIs reactivates SERT, which like DAT has activity for both serotonin and dopamine - so poor dopamine gets zapped again!
>
>
> "Results from our DA uptake experiments indicate that SERT is an important modulator of both 5-HT and DA uptake and that ~40% of the DA uptake observed in striatum is due to promiscuous SERT activity."
>
> Do you think that could be an explaination or is something else happening?
>
> Ray
>
>That's pretty goofy that the serotonin receptor regulates the dopamine receptor in the striatal region, but quite interesting. I can think of one improbable possibility for this: in the PFC, there is no DAT. The NET acts as the reuptake mechanism for DA. Similarly, I hypothesize that when a certain percentage of SERT are blocked, the DAT actually begins to reuptake serotonin to make up for less SERT activity. That's probably a stretch since NE and DA are much more chemically similar than 5-HT and DA. But who knows...
Posted by raybakes on December 15, 2004, at 9:18:07
In reply to Re: SSRI/dopamine antagonism, posted by Mistermindmasta on December 15, 2004, at 1:11:38
Similarly, I hypothesize that when a certain percentage of SERT are blocked, the DAT actually begins to reuptake serotonin to make up for less SERT activity. That's probably a stretch since NE and DA are much more chemically similar than 5-HT and DA. But who knows...
Yes, this abstract from earlier in the thread agrees with what you say...
"The results demonstrated the inhibition of SERT by SSRI in human in vivo during the chronic treatment and, unexpectedly, an elevation of DAT. This apparent SSRI-induced modulation of the dopamine system may be associated with the side effects of these agents, including sexual dysfunction."
Ray
Posted by zeugma on December 15, 2004, at 13:33:30
In reply to Re: SSRI/dopamine antagonism, posted by Mistermindmasta on December 15, 2004, at 1:11:38
this part is true also:
That's pretty goofy that the serotonin receptor regulates the dopamine receptor in the striatal region, but quite interesting. I can think of one improbable possibility for this: in the PFC, there is no DAT. The NET acts as the reuptake mechanism for DA.
The NET clears most extracellular DA from the PFC. This is why Strattera is hypothesized to work for ADHD (it does, although with many qualifications) and why the TCA's have been secon-line meds for ADHD for decades despite their being for the most part sedating meds.
The NET actually has a higher affinity for DA than for NE.
Posted by rod on December 18, 2004, at 8:27:44
In reply to Re: SSRI/dopamine antagonism » Mistermindmasta, posted by zeugma on December 15, 2004, at 13:33:30
Hi,
Maybe this has been said before in this thread, because I havent read all posts, but I personally find this very interesting: Something called "Transmitter relocation"
---------------
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12065714The selective serotonin reuptake inhibitor citalopram induces the storage of serotonin in catecholaminergic terminals.
Suarez-Roca H, Cubeddu LX.
Pharmacology Section, Instituto de Investigaciones Clinicas, School of Medicine, University of Zulia, Maracaibo, Venezuela.
We investigated whether selective inhibition of serotonin (5-hydroxytryptamine; 5-HT) transporter with citalopram leads to accumulation of 5-HT in catecholaminergic neurons. In the rabbit olfactory tubercle, citalopram (1-10 microM) inhibited [(3)H]5-HT uptake; however, the maximal degree of inhibition achieved was 70%. Addition of nomifensine (1-10 microM) was required for complete inhibition of [(3)H]5-HT uptake. In slices labeled with 0.1 microM [(3)H]5-HT, cold 5-HT (0.03-1 microM) induced a large increase in the efflux (release) of stored [(3)H]5-HT, an effect blocked by coperfusion with 1 microM citalopram. Similar concentrations (0.03-1 microM) of norepinephrine (NE) or dopamine (DA) failed to release [(3)H]5-HT. When labeling with 0.1 microM [(3)H]5-HT was carried out in the presence of citalopram, 1) low concentrations of 5-HT failed to release [(3)H]5-HT; 2) DA and NE were more potent and effective in releasing [(3)H]5-HT than in control slices; 3) coperfusion of NE, DA, or 5-HT with citalopram enhanced the release of [(3)H]5-HT induced by the catecholamines but not by 5-HT; and 4) coperfusion of NE or DA with nomifensine antagonized NE- and DA-evoked [(3)H]5-HT release, with a greater effect on NE than on DA. These results suggest that in the rabbit olfactory tubercle, where there is coexistence of 5-HT, NE, and DA neurons, inhibition of the 5-HT transporter led to accumulation of 5-HT in catecholaminergic terminals. Thus, during treatment with selective serotonin uptake inhibitors (SSRIs), 5-HT may be stored in catecholaminergic neurons acting as a false neurotransmitter and/or affecting the disposition of DA and/or NE. Transmitter relocation may be involved in the antidepressant action of SSRIs.
PMID: 12065714 [PubMed - indexed for MEDLINE]
------------------
Does anybody know if 5-ht in dopaminerigc neurons cause similar neurotoxicity like (as far as I know) MDMA induced serotonin cell death via dopamine deamination in serotonergic nerves storage vesicles?
I am wondering if my years of SSRI treatment (which caused overall worsening) are responsible for my resistand depression now (which is linked to a hypodopaminrgic state in my opinion. Also my doc thinks there is something wrong with my dopamine receptors)???
bye
Roland
Posted by KaraS on December 18, 2004, at 17:52:36
In reply to Re: SSRI/dopamine antagonism, posted by rod on December 18, 2004, at 8:27:44
> Hi,
>
> Maybe this has been said before in this thread, because I havent read all posts, but I personally find this very interesting: Something called "Transmitter relocation"
>
> ---------------
> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12065714
>
> The selective serotonin reuptake inhibitor citalopram induces the storage of serotonin in catecholaminergic terminals.
>
> Suarez-Roca H, Cubeddu LX.
>
> Pharmacology Section, Instituto de Investigaciones Clinicas, School of Medicine, University of Zulia, Maracaibo, Venezuela.
>
> We investigated whether selective inhibition of serotonin (5-hydroxytryptamine; 5-HT) transporter with citalopram leads to accumulation of 5-HT in catecholaminergic neurons. In the rabbit olfactory tubercle, citalopram (1-10 microM) inhibited [(3)H]5-HT uptake; however, the maximal degree of inhibition achieved was 70%. Addition of nomifensine (1-10 microM) was required for complete inhibition of [(3)H]5-HT uptake. In slices labeled with 0.1 microM [(3)H]5-HT, cold 5-HT (0.03-1 microM) induced a large increase in the efflux (release) of stored [(3)H]5-HT, an effect blocked by coperfusion with 1 microM citalopram. Similar concentrations (0.03-1 microM) of norepinephrine (NE) or dopamine (DA) failed to release [(3)H]5-HT. When labeling with 0.1 microM [(3)H]5-HT was carried out in the presence of citalopram, 1) low concentrations of 5-HT failed to release [(3)H]5-HT; 2) DA and NE were more potent and effective in releasing [(3)H]5-HT than in control slices; 3) coperfusion of NE, DA, or 5-HT with citalopram enhanced the release of [(3)H]5-HT induced by the catecholamines but not by 5-HT; and 4) coperfusion of NE or DA with nomifensine antagonized NE- and DA-evoked [(3)H]5-HT release, with a greater effect on NE than on DA. These results suggest that in the rabbit olfactory tubercle, where there is coexistence of 5-HT, NE, and DA neurons, inhibition of the 5-HT transporter led to accumulation of 5-HT in catecholaminergic terminals. Thus, during treatment with selective serotonin uptake inhibitors (SSRIs), 5-HT may be stored in catecholaminergic neurons acting as a false neurotransmitter and/or affecting the disposition of DA and/or NE. Transmitter relocation may be involved in the antidepressant action of SSRIs.
>
> PMID: 12065714 [PubMed - indexed for MEDLINE]
>
> ------------------
>
> Does anybody know if 5-ht in dopaminerigc neurons cause similar neurotoxicity like (as far as I know) MDMA induced serotonin cell death via dopamine deamination in serotonergic nerves storage vesicles?
>
> I am wondering if my years of SSRI treatment (which caused overall worsening) are responsible for my resistand depression now (which is linked to a hypodopaminrgic state in my opinion. Also my doc thinks there is something wrong with my dopamine receptors)???
>
>
> bye
> Roland
Hi Roland,Interesting abstract. I've been wondering if several years usage of SSRIs has done the same thing to me. I have no drive or motivation though I've been off of the SSRIs for a few months now. (I had none while I was on them either.) When I try to add in dopaminergics like Ritalin, selegiline (and a couple of holistic ones), I get put to sleep. If I take it for a few days, I start to feel sick. Something is definitely wrong.
Dr. Jay Goldstein theorized that hypersensitive dopamine autoreceptors could be the problem - at least for some people. I don't know for certain that is my problem but I do think that the problem is related somehow to faulty dopamine production or utlization.
I don't like to think too much about whether it was caused by the SSRIs. It's too upsetting. I'm just trying to figure out what to do about it now. There aren't many things out there now that can downregulate the DA autoreceptors but I am going to try them next.
K
Posted by ed_uk on December 19, 2004, at 3:44:31
In reply to Re: SSRI/dopamine antagonism, posted by KaraS on December 18, 2004, at 17:52:36
Hi Kara,
Have you tried amisulpride (Solian) ?
Ed.
Posted by KaraS on December 19, 2004, at 4:17:07
In reply to Re: SSRI/dopamine antagonism » KaraS, posted by ed_uk on December 19, 2004, at 3:44:31
> Hi Kara,
>
> Have you tried amisulpride (Solian) ?
>
> Ed.
Not yet but it's on my list. I'm thinking of an MAOI next. Right now I have to take care of my newly (re)emerging anxiety problems.
Posted by KaraS on December 19, 2004, at 12:51:53
In reply to Re: SSRI/dopamine antagonism, posted by KaraS on December 19, 2004, at 4:17:07
> > Hi Kara,
> >
> > Have you tried amisulpride (Solian) ?
> >
> > Ed.
>
>
> Not yet but it's on my list. I'm thinking of an MAOI next. Right now I have to take care of my newly (re)emerging anxiety problems.
Also Ed,Are there any medications that you can't take Amisulpride with or is there anything else specifically that I should know about it? Since it would have to be obtained outside the U.S., there isn't as much info on it here.
Thanks,
-K
Posted by ed_uk on December 19, 2004, at 13:23:33
In reply to Re: SSRI/dopamine antagonism - Amisulpride - Ed, posted by KaraS on December 19, 2004, at 12:51:53
Hi Kara,
Here is the UK data sheet for amisulpride. I hope that it provides you with the information that you need.
1. NAME OF THE MEDICINAL PRODUCT
Solian 50Solian 100
Solian 200
Solian 400
Solian Solution, 100 mg/ml
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Active ingredient: Amisulpride (INN) 50 mg, 100 mg, 200 mg or 400 mg per tablet; Solian Solution: Amisulpride (INN) 100 mg/ml.For excipients, see 6.1
3. PHARMACEUTICAL FORM
Solian 50, 100, 200, 400: TabletSolian Solution: Oral Solution. A clear yellow liquid in appearance.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Solian is indicated for the treatment of acute and chronic schizophrenic disorders, in which positive symptoms (such as delusions, hallucinations, thought disorders) and/or negative symptoms (such as blunted affect, emotional and social withdrawal) are prominent, including patients characterised by predominant negative symptoms.
4.2 Posology and method of administration
For acute psychotic episodes, oral doses between 400 mg/d and 800 mg/d are recommended. In individual cases, the daily dose may be increased up to 1200 mg/d. Doses above 1200 mg/d have not been extensively evaluated for safety and therefore should not be used. No specific titration is required when initiating the treatment with Solian. Doses should be adjusted according to individual response.For patients with mixed positive and negative symptoms, doses should be adjusted to obtain optimal control of positive symptoms.
Maintenance treatment should be established individually with the minimally effective dose.
For patients characterised by predominant negative symptoms, oral doses between 50 mg/d and 300 mg/d are recommended. Doses should be adjusted individually.
Solian can be administered once daily at oral doses up to 300 mg, higher doses should be administered bid.
Elderly: Solian should be used with particular caution because of a possible risk of hypotension or sedation.
Children: Solian is contra-indicated in children under 15 years of age as its safety has not yet been established.
Renal insufficiency: Solian is eliminated by the renal route. In renal insufficiency, the dose should be reduced to half in patients with creatinine clearance (CRCL) between 30-60 ml/min and to a third in patients with CRCL between 10-30 ml/min. As there is no experience in patients with severe renal impairment (CRCL < 10 ml/min) particular care is recommended in these patients. (see 4.4 Special warnings and precautions for use)
Hepatic insufficiency: since the drug is weakly metabolised a dosage reduction should not be necessary.
Solian Solution: Method of administration: The graduations on the dosage pipette measure the milligrams of active ingredient. After introducing the measuring syringe into the bottle, draw the plunger of the measuring syringe up to the graduation mark corresponding to the number of milligrams to be administered. The oral solution should be drunk with a liquid, which does not contain alcohol.
4.3 Contraindications
Hypersensitivity to the active ingredient or to other ingredients of the drugConcomitant prolactin-dependent tumours e.g. pituitary gland prolactinomas and breast cancer
Phaeochromocytoma
Children under 15 years of age
Pregnancy or lactation
Women of childbearing potential unless using adequate contraception
Combination with the following medications which could induce torsades de pointes:
Class Ia antiarrhythmic agents such as quinidine, disopyramide, procainamide.
Class III antiarrhythmic agents such as amiodarone, sotalol.
Other medications such as bepridil, cisapride, sultopride, thioridazine, IV erythromycin, IV vincamine, halofantrine, pentamidine, sparfloxacin.
This list is not exhaustive.
Combination with levodopa
(see 4.5 Interactions with other medical products and other forms of interaction)
4.4 Special warnings and special precautions for use
As with other neuroleptics, Neuroleptic Malignant Syndrome, characterized by hyperthermia, muscle rigidity, autonomic instability, altered consciousness and elevated CPK, may occur. In the event of hyperthermia, particularly with high daily doses, all antipsychotic drugs including Solian should be discontinued.Solian is eliminated by the renal route. In cases of severe renal insufficiency, the dose should be decreased and intermittent treatment should be prescribed (see 4.2 Posology and method of administration).
Solian can lower the seizure threshold. Therefore patients with a history of epilepsy should be closely monitored during Solian therapy.
In elderly patients, Solian, like other neuroleptics, should be used with particular caution because of a possible risk of hypotension or sedation.
As with other antidopaminergic agents, caution should be also exercised when prescribing Solian to patients with Parkinson's disease since it may cause worsening of the disease. Solian should be used only if neuroleptic treatment cannot be avoided.
Acute withdrawal symptoms including nausea, vomiting and insomnia have very rarely been described after abrupt cessation of high doses of antipsychotic drugs. Recurrence of psychotic symptoms may also occur, and the emergence of involuntary movement disorders (such as akathisia, dystonia and dyskinesia) has been reported. Therefore, gradual withdrawal is advisable.
Prolongation of the QT interval.
Amisulpride induces a dose-dependent prolongation of the QT interval. This effect, known to potentiate the risk of serious ventricular arrhythmias such as torsades de pointes is enhanced by the pre-existence of bradycardia, hypokalaemia, congenital or acquired long QT interval.
Hypokalaemia should be corrected.
Before any administration, and if possible according to the patient's clinical status, it is recommended to monitor factors which could favour the occurrence of this rhythm disorder:
bradycardia less than 55 bpm,
hypokalaemia,
congenital prolongation of the QT interval.
on-going treatment with a medication likely to produce pronounced bradycardia (<55bpm), hypokalaemia, decreased intracardiac conduction, or prolongation of the QTc interval (see 4.5 Interaction with other medicinal products and other forms of interaction).
4.5 Interaction with other medicinal products and other forms of Interaction
COMBINATIONS WHICH ARE CONTRAINDICATEDMedications which could induce torsades de pointes
Class Ia antiarrhythmic agents such as quinidine, disopyramide, procainamide.
Class III antiarrhythmic agents such as amiodarone, sotalol.
Others medications such as bepridil, cisapride, sultopride, thioridazine, IV erythromycin, IV vincamine, halofantrine, pentamidine, sparfloxacin.
This list is not exhaustive.
Levodopa: reciprocal antagonism of effects between levodopa and neuroleptics.
COMBINATIONS WHICH ARE NOT RECOMMENDED
Solian may enhance the central effects of alcohol.
COMBINATIONS WHICH REQUIRE PRECAUTIONS FOR USE
Medications which enhance the risk of torsades de pointes:
Bradycardia-inducing medications such as beta-blockers, bradycardia-inducing calcium channel blockers such as diltiazem and verapamil, clonidine, guanfacine ; digitalis.
Medications which induce hypokalaemia: hypokalemic diuretics, stimulant laxatives, IV amphotericin B, glucocorticoids, tetracosactides.
Neuroleptics such as pimozide, haloperidol ; imipramine, antidepressants ; lithium.
COMBINATIONS TO BE TAKEN INTO ACCOUNT
CNS depressants including narcotics, anaesthetics, analgesics, sedative H1 antihistamines, barbiturates, benzodiazepines and other anxiolytic drugs, clonidine and derivatives
Antihypertensive drugs and other hypotensive medications
Dopamine agonists (eg: levodopa) since it may attenuate their action
4.6 Pregnancy and lactation
In animals, Solian did not show direct reproductive toxicity. A decrease in fertility linked to the pharmacological effects of the drug (prolactin mediated effect) was observed. No teratogenic effects of Solian were noted.The safety of Solian during human pregnancy has not been established. Therefore, use of the drug is contraindicated during pregnancy and in women of child bearing potential unless using adequate contraception.
It is not known whether Solian is excreted in breast milk, breast-feeding is therefore contra-indicated.
4.7 Effects on ability to drive and use machines
Even used as recommended, Solian may affect reaction time so that the ability to drive vehicles or operate machinery can be impaired.
4.8 Undesirable effects
The following adverse effects have been observed in controlled clinical trials. It should be noted that in some instances it can be difficult to differentiate adverse events from symptoms of the underlying disease.Common adverse effects (5-10 %): insomnia, anxiety, agitation
Less common adverse effects (0.1-5 %): somnolence, gastrointestinal disorders such as constipation, nausea, vomiting, dry mouth.
In common with other neuroleptics:
Solian causes an increase in plasma prolactin levels which is reversible after drug discontinuation. This may result in galactorrhoea, amenorrhoea, gynaecomastia, breast pain, orgasmic dysfunction and impotence.
Weight gain may occur under therapy with Solian.
Acute dystonia (spasm torticolis, oculogyric crisis, trismus) may appear. This is reversible without discontinuation of Solian upon treatment with an antiparkinsonian agent.
Extrapyramidal symptoms may occur: tremor, rigidity, hypokinesia, hypersalivation, akathisia. These symptoms are generally mild at optimal dosages and partially reversible without discontinuation of Solian upon administration of antiparkinsonian medication. The incidence of extrapyramidal symptoms which is dose related, remains very low in the treatment of patients with predominantly negative symptoms with doses of 50-300mg/day.
Tardive dyskinesia characterised by rhythmic, involuntary movements primarily of the tongue and/or face have been reported, usually after long term administration. Antiparkinsonian medication is ineffective or may induce aggravation of the symptoms.
Hypotension and bradycardia have been reported occasionally. Cases of QT prolongation and very rare cases of torsades de pointes have been reported.
Acute withdrawal reactions have very rarely been reported (see Section 4.4 Special warnings and special precautions for use).
Allergic reactions, elevations of hepatic enzymes, mainly transaminases and cases of seizures have been very rarely reported.
Very rare cases of Neuroleptic Malignant Syndrome have been reported (see Section 4.4 Special warnings and special precautions for use).
4.9 Overdose
Experience with Solian in overdosage is limited. Exaggeration of the known pharmacological effects of the drug have been reported. These include drowsiness and sedation, coma, hypotension and extrapyramidal symptoms.In cases of acute overdosage, the possibility of multiple drug intake should be considered.
Since Solian is weakly dialysed, hemodialysis should not be used to eliminate the drug.
There is no specific antidote to Solian. Appropriate supportive measures should therefore be instituted with close supervision of vital functions including continuous cardiac monitoring due to the risk of prolongation of the QT interval.
If severe extrapyramidal symptoms occur, anticholinergic agents should be administered.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Amisulpride binds selectively with a high affinity to human dopaminergic D2/D3 receptor subtypes whereas it is devoid of affinity for D1, D4 and D5 receptor subtypes.Unlike classical and atypical neuroleptics, amisulpride has no affinity for serotonin, -adrenergic, histamine H1 and cholinergic receptors. In addition, amisulpride does not bind to sigma sites.
In animal studies, at high doses, amisulpride blocks dopamine receptors located in the limbic structures in preference to those in the striatum.
At low doses it preferentially blocks pre-synaptic D2/D3 receptors, producing dopamine release responsible for its disinhibitory effects.
This pharmacological profile explains the clinical efficacy of Solian against both negative and positive symptoms of schizophrenia.
5.2 Pharmacokinetic properties
In man, amisulpride shows two absorption peaks: one which is attained rapidly, one hour post-dose and a second between 3 and 4 hours after administration. Corresponding plasma concentrations are 39 ± 3 and 54 ± 4 ng/ml after a 50 mg dose.The volume of distribution is 5.8 l/kg, plasma protein binding is low (16%) and no drug interactions are suspected.
Absolute bioavailability is 48%. Amisulpride is weakly metabolised: two inactive metabolites, accounting for approximately 4% of the dose, have been identified. There is no accumulation of amisulpride and its pharmacokinetics remain unchanged after the administration of repeated doses. The elimination half-life of amisulpride is approximately 12 hours after an oral dose.
Amisulpride is eliminated unchanged in the urine. Fifty percent of an intravenous dose is excreted via the urine, of which 90% is eliminated in the first 24 hours. Renal clearance is in the order of 20 l/h or 330 ml/min.
A carbohydrate rich meal (containing 68% fluids) significantly decreases the AUCs, Tmax and Cmax of amisulpride but no changes were seen after a high fat meal. However, the significance of these findings in routine clinical use is not known.
Hepatic insufficiency: since the drug is weakly metabolised a dosage reduction should not be necessary in patients with hepatic insufficiency.
Renal insufficiency: The elimination half-life is unchanged in patients with renal insufficiency while systemic clearance is reduced by a factor of 2.5 to 3. The AUC of amisulpride in mild renal failure increased two fold and almost tenfold in moderate renal failure (see chapter 4.2). Experience is however limited and there is no data with doses greater than 50 mg.
Amisulpride is very weakly dialysed.
Limited pharmacokinetic data in elderly subjects > 65 years) show that a 10-30 % rise occurs in Cmax, T1/2 and AUC after a single oral dose of 50 mg. No data are available after repeat dosing.
5.3 Preclinical safety data
An overall review of the completed safety studies indicates that Solian is devoid of any general, organ-specific, teratogenic, mutagenic or carcinogenic risk. Changes observed in rats and dogs at doses below the maximum tolerated dose are either pharmacological effects or are devoid of major toxicological significance under these conditions. Compared with the maximum recommended dosages in man, maximum tolerated doses are 2 and 7 times greater in the rat (200 mg/kg/d) and dog (120 mg/kg/d) respectively in terms of AUC. No carcinogenic risk, relevant to man, was identified in the rat at up to 1.5 to 4.5 times the expected human AUC.A mouse carcinogenicity study (120 mg/kg/d) and reproductive studies (160, 300 and 500 mg/kg/d respectively in rat, rabbit and mouse) were performed. The exposure of the animals to amisulpride during these latter studies was not evaluated.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Solian 50, 100 and 200: Potato starch, lactose monohydrate, methylcellulose, colloidal hydrated silica, magnesium stearate.Solian 400: Sodium starch glycollate, lactose monohydrate, microcrystalline cellulose, hypromellose, magnesium stearate, polyoxyl 40 stearate, titanium dioxide (E171).
Solian Solution: Saccharin sodium, sodium gluconate, glucono delta lactone, hydrochloric acid, methyl parahydroxybenzoate, propyl parahydroxybenzoate, potassium sorbate, caramel flavour (tonka beans extract, vanillin, benzaldehyde, acetyl methyl carbinol, gamma and delta decalactones, esters from acetic, butyric and 2 methyl butyric acid, esters from ethyl and cinnamyl alcohol, propylene glycol and ethyl alcohol), purified water
6.2 Incompatibilities
None known.
6.3 Shelf life
Solian 50, 100, 200, 400: 3 yearsSolian Solution;
Shelf life of the medicinal product as packaged for sale: 3 years
Shelf life after first opening the container: 2 months
Dispose of within two months of opening
6.4 Special precautions for storage
Solian 50 and 200: Store in a dry place below 25oC in its original container.Solian 100, 400 and Solution: No special precautions (for storage).
6.5 Nature and contents of container
Solian 50, 100, 200 and 400: PVC/aluminium foil blister packs containing 60 tabletsSolian Solution: 60 ml brown glass bottle (type III) and child resistant cap with a PVDC/PE seal, with a 5ml graduated oral syringe
6.6 Instructions for use and handling
No special precautions
7. MARKETING AUTHORISATION HOLDER
Sanofi-SynthelaboPO Box 597
Guildford
Surrey
8. MARKETING AUTHORISATION NUMBER(S)
Solian 50: PL 11723/0308Solian 100: PL 11723/0355
Solian 200: PL 11723/0309
Solian 400: PL 11723/0356
Solian Solution: PL 11723/0377
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Solian 50: 1 February 2001Solian 100: 5 September 2000
Solian 200: 29 January 2001
Solian 400: 5 September 2000
Solian Solution: 16 May 2001
10. DATE OF REVISION OF THE TEXT
Solian 50: March 2003Solian 100: March 2004
Solian 200: March 2004
Solian 400: March 2004
Solian Solution: October 2004
Legal category: POM
Posted by pablo1 on December 19, 2004, at 16:16:20
In reply to Re: SSRI/dopamine antagonism - Amisulpride » KaraS, posted by ed_uk on December 19, 2004, at 13:23:33
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