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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 4 to 28 of 28. Go back in thread:
Posted by Brainbeard on September 8, 2009, at 11:13:40
In reply to Increasing SSRI/SNRI above the 'regular' doses., posted by Jay_Bravest_Face on September 7, 2009, at 23:35:36
If you want to decrease or eliminate REM-sleep - that's what most typical antidepressants do, in regular doses. Bupropion aka Wellbutrin actually increases REM-sleep though, as do most stimulants, caffeine included.
The MAOIs are real REM-killers: they almost completely abolish REM-sleep!
The TCA's and the SSRIs suppress it by as much as 75-85% in the short term (days) and 40-50% in the long term (weeks/months).
I take this from an online article about REM-sleep and memory consolidation, link: http://www.bbsonline.org/Preprints/OldArchive/bbs.vertes.html, see under: '3. REM SLEEP AND ANTIDEPRESSANT DRUGS'. Excellent information, references included.
I wouldn't know if SSRIs would suppress REM-sleep more on higher doses.
There is one thing you should be aware of, though. DREAMING DOES NOT EXCLUSIVELY OCCUR DURING REM-SLEEP. In fact, it has been proposed that because (S)SRIs suppress normal REM-sleep dreaming, they force the brain to produce dreaming using other brain circuits - namely the frontal lobe. Frontal lobe dreams are characterized by their feverish, loopy character and can be very lengthy, sometimes epic. Although dreams are naturally bizarre, these non-REM dreams can be bizarre in a more artificial way. Presumably, these dreams are not so much being created by the emotional parts of the brain but by the intellectual part.
This may be partly hypothetical, but, surprisingly, it is a FACT that (S)SRI's, although they suppress REM-sleep, tend to INTENSIFY dreaming! See this abstract of a book called 'Serotonin and Sleep: Molecular, Functional and Clinical Aspects': http://www.springerlink.com/content/t0j6l83036527689/. These intense dreams are non-REM dreams.
So, when you're experiencing intense dreaming, this MAY not be related to REM-sleep at all, in which case antidepressant suppression of REM-sleep may only make things worse.
It all depends on wether your dreams are REM or non-REM.
Posted by bleauberry on September 8, 2009, at 12:50:39
In reply to Increasing SSRI/SNRI above the 'regular' doses., posted by Jay_Bravest_Face on September 7, 2009, at 23:35:36
I have feel that SSRI/SNRIs do more than the simple mechanisms implied by their names.
For example, at 50mg Zoloft has already reached nearly 98% occupancy of serotonin reuptake sites. So it would not make sense that any higher dose would do any additional good. But obviously, some people do better at 100mg or 200mg. So something else is going on there. We know Zoloft has weak affinity for dopamine reuptake as well, so perhaps that is at play. But from what I've read, that really doesn't even begin to have any appreciable effect until at least 200mg.
But who knows. Researchers talk about these meds they got it all figured out. They don't.
I read one account of a lady requiring minimum 40mg Lexapro to stay well, but she did best at 60mg. The serotonin reuptake sites were already completely saturated at a far lower dose, so what was the higher dose doing? Something else. Serotonin was already maxed out. But what? Dunno. Obviously something.
Maybe it is a completely different mechanism at play, such as manipulating gene instruction, and has nothing at all to with neurotransmitter sites.
I'm sure individual liver metabolism is a player. Some people build up blood levels quickly, while others tend to excrete quickly. I am not sure that particular mechanism plays that big of a role however.
Body weight is probably a consideration. 120mg Prozac is a heck of a lot for someone weighing 120 pounds, but doesn't look so astronomical if the person is 240 pounds.
I know nothing of the topic, but with most meds there is some sort of binding with proteins. Who knows, maybe some people just need more of a dose to overcome unusually aggressive protein binding.
Me, I'm just the opposite. Tiny eensy weensy doses feel like atomic bombs.
Posted by Brainbeard on September 8, 2009, at 13:56:43
In reply to Re: Increasing SSRI/SNRI above the 'regular' doses., posted by bleauberry on September 8, 2009, at 12:50:39
> For example, at 50mg Zoloft has already reached nearly 98% occupancy of serotonin reuptake sites.
I don't think that is correct. In Preskorn's online book about the SSRIs, you see the percentages of serotonin reuptake inhibition (SRI) for the usual therapeutic doses of most SSRIs. You can see the table here: http://www.preskorn.com/books/ssri_s3.html#tab3-7. 50mg of sertraline leads to 80% inhibition of the reuptake pump. That is still far removed from oversaturation.
When you look at figure 5.3 from the same book -
http://www.preskorn.com/books/ssri_s5.html#fig5-3 - you see that there is a huge difference in serotonin reuptake inhibition between a 25 and a 50mg dose of sertraline (about 55 vs. 80%). After that, the curve for SRI is slowly but steadily rising, reaching about 90% of serotonin uptake reduction at 200mg. So even after 200mg, a further decrease of serotonin reuptake would be theoretically possible.Here: http://www.springerlink.com/content/c37438727t74156l/ is an interesting study that measured serotonin receptor occupancy at high doses of venlafaxine, sertraline and citalopram. Unfortunately, the doses aren't menioned in this abstract. In accordance with Preskorn, the abstract mentions that the minimum therapeutic dose (50mg for sertraline) of any SSRI yields about 80% serotonin receptor (5HT) occupancy. The higher doses in this study yielded a 5HT occupancy of 85%, which was considered significant. The abstract concludes thus: 'It is likely that 15% unoccupied 5-HTT remains, which should be addressed in future drug development.'
So there you go: an incentive to experiment with ultra-high doses of SSRIs.Oversaturation of serotonin receptors comes at a price though: serotonergic side-effects will peak (diarrhea, emotional numbness, sexual dysfunction), while the risk of abnormal bleeding increases dramatically since SRI also inhibits blood platelets, responsible for clotting.
Posted by Jay_Bravest_Face on September 9, 2009, at 3:05:37
In reply to Re: Increasing SSRI/SNRI above the 'regular' doses., posted by Brainbeard on September 8, 2009, at 13:56:43
Well, I came across a journal article that said SSRI's may act on dopamine and norepinephrine at the higher doses. I am about 5'11" and 120mg of Prozac was increadible for me. My doc really wanted me to try Zoloft to help a bit with possible dopamine that high dose Zoloft can do. I found from my doc and from the web that you can safely go to 400mg of Zoloft. Zoloft and Prozac are really the only a.d.'s that have helped me over 15 or so years. I also use a benzo and Zyprexa. I actually have long since been rid of the so-called 'apathy' SSRI's can create, and these higer doses seem to be the answer. Like I said..and bleuberry did...I think the higher doses do more then just serotonin increase in the synapse.
Jay
Posted by Brainbeard on September 9, 2009, at 4:32:29
In reply to Re: Increasing SSRI/SNRI above the 'regular' : ALL, posted by Jay_Bravest_Face on September 9, 2009, at 3:05:37
> I think the higher doses do more then just serotonin increase in the synapse.
>Prozac is an atypical SSRI because it's a 5HT2C-antagonist (cf. Stephen Stahl), thereby increasing dopamine and noradrenaline concentrations in strategic regions of the brain. It does this at even a very low dose.
Posted by Phillipa on September 9, 2009, at 19:56:28
In reply to Re: Increasing SSRI/SNRI above the 'regular' : ALL, posted by Brainbeard on September 9, 2009, at 4:32:29
Brainbeard don't get it how can an SSRI be so different? You know when first out was given the only form available 20mg and day l wallpapered a foyer had paper for for three years, day two anxiety, day three pure out panic. And this was when anxiety was very well controlled on .25 of xanax a day and working? I just don't get it. Dumped the rest and pdoc seemed to think I'd had a miraculous response and wanted me to take it every three days I refused? Could you explain? Thanks Phillipa
Posted by Brainbeard on September 10, 2009, at 6:27:01
In reply to Re: Increasing SSRI/SNRI above the 'regular' : ALL » Brainbeard, posted by Phillipa on September 9, 2009, at 19:56:28
Shouldn't we leave the mystery untouched, instead of explaining the inexplicable?
But seriously, any activating drug could cause anxiety.
It wouldn't be a bad idea to take Prozac every three days, it has a huge half-life. You could take it every week and build steady state blood levels after a couple of months.
Posted by zzzz7 on September 10, 2009, at 16:05:40
In reply to Re: Increasing SSRI/SNRI above the 'regular' doses., posted by bleauberry on September 8, 2009, at 12:50:39
I used to take 120mg of Prozac. Now I can't take .1mg or I crash. I went from being able to take great amounts to being totally oversensitive to them. No one knows why.
Posted by sowhysosad on September 10, 2009, at 19:25:21
In reply to Re: Increasing SSRI/SNRI above the 'regular' doses, posted by zzzz7 on September 10, 2009, at 16:05:40
Did you at any stage suddenly quit an SSRI/SNRI without tapering, or suffer a severe adverse event (like akathisia) after starting one?
I only ask because I seem to have become sensitive to SSRI's and I believe one or the other may have triggered it.
> I used to take 120mg of Prozac. Now I can't take .1mg or I crash. I went from being able to take great amounts to being totally oversensitive to them. No one knows why.
Posted by Phillipa on September 10, 2009, at 20:19:39
In reply to Re: Increasing SSRI/SNRI above the 'regular' doses » zzzz7, posted by sowhysosad on September 10, 2009, at 19:25:21
Like why my body won't let go of the 50mg of luvox which is so low. When taken off it I didn't sleep for two weeks. The Er said go back on it did and slept. Strange? Especially since that pdoc had given me outrageously high benzo doses. Phillipa
Posted by zzzz7 on September 11, 2009, at 18:29:32
In reply to Re: Increasing SSRI/SNRI above the 'regular' doses » zzzz7, posted by sowhysosad on September 10, 2009, at 19:25:21
I always tapered the SSRIs. I don't think I had any usual symptoms; many/most have some akathisia when they start.
What are you able to take/what have you tried to do vis-a-vis your depression given your sensitivity to SSRIs now?
Posted by zzzz7 on September 11, 2009, at 18:30:10
In reply to Re: Increasing SSRI/SNRI above the 'regular' doses, posted by Phillipa on September 10, 2009, at 20:19:39
You need to taper Luvox for a long time usually. Maybe that was it.
Posted by Phillipa on September 11, 2009, at 20:43:31
In reply to Re: Increasing SSRI/SNRI above the 'regular' doses, posted by zzzz7 on September 11, 2009, at 18:30:10
What a stupid doc to cold turkey me off the 50mg been on for years. How did your learn this about luvox? Is it the only one? Love Phillipa
Posted by sowhysosad on September 11, 2009, at 20:46:22
In reply to Re: Increasing SSRI/SNRI above the 'regular' doses » sowhysosad, posted by zzzz7 on September 11, 2009, at 18:29:32
I'm on low-dose (10mg) generic Prozac at the moment which helps a little, but still suffer bouts of tachycardia accompanied by agitation/dysphoria.
I'm guessing it's caused by the fluoxetine's effect on norepinephrine (through 5-HT2C antagonism) rather than its serotonergic action. I'm hoping to switch to a cleaner SSRI instead.
But when the sensitivity was at its worst, low-dose Cipralex (Lexapro) and even small amounts of 5-HTP were causing anxiety and insomnia.
> What are you able to take/what have you tried to do vis-a-vis your depression given your sensitivity to SSRIs now?
Posted by Brainbeard on September 12, 2009, at 6:30:08
In reply to Re: Increasing SSRI/SNRI above the 'regular' doses » zzzz7, posted by sowhysosad on September 11, 2009, at 20:46:22
Luvox (fluvoxamine) is actually the least activating SSRI. Which is another way of saying it's the most sedating. Before there was Lexapro (escitalopram), Luvox may actually have been the cleanest and most typical SSRI. Although it does act on sigma-1 receptors (which is supposed to be good for depression and anxiety), which Lexapro does too.
My main problem with Luvox (apart from the fact that it can be very apathizing) is that, through its inhibition of 1a2 enzymes, it makes it practically impossible to drink coffee (it makes coffee stay in your blood about six times as long, which doesn't feel right for most people).
Posted by SLS on September 12, 2009, at 6:47:59
In reply to Re: Increasing SSRI/SNRI above the 'regular' doses » zzzz7, posted by sowhysosad on September 10, 2009, at 19:25:21
> Did you at any stage suddenly quit an SSRI/SNRI without tapering, or suffer a severe adverse event (like akathisia) after starting one?
>
> I only ask because I seem to have become sensitive to SSRI's and I believe one or the other may have triggered it.You are one heck of a smart guy. I believe you are right about the occurrence (allowance) of a severe discontinuation syndrome producing subsequent over-sensitivities to medications and an increase in the severity of withdrawal symptoms.
http://www.dr-bob.org/babble/wdrawl/20050214/msgs/460726.html
- Scott
Posted by SLS on September 12, 2009, at 6:52:59
In reply to Re: Increasing SSRI/SNRI above the 'regular' doses, posted by Brainbeard on September 12, 2009, at 6:30:08
> Although it does act on sigma-1 receptors (which is supposed to be good for depression and anxiety), which Lexapro does too.
How do sigma-1 receptors affect neural activity in the brain? How does Lexapro affect these receptors?
Thanks.
- Scott
Posted by sowhysosad on September 12, 2009, at 15:57:14
In reply to Re: Increasing SSRI/SNRI above the 'regular' doses, posted by Brainbeard on September 12, 2009, at 6:30:08
> Although it does act on sigma-1 receptors (which is supposed to be good for depression and anxiety), which Lexapro does too.
What is Lex's effect on sigma-1 receptors, BB? Agonist or antagonist?
Does anyone know whether Lex has any effect on glutamate function?
Posted by sowhysosad on September 12, 2009, at 16:06:51
In reply to Re: Increasing SSRI/SNRI above the 'regular' doses » sowhysosad, posted by SLS on September 12, 2009, at 6:47:59
> You are one heck of a smart guy. I believe you are right about the occurrence (allowance) of a severe discontinuation syndrome producing subsequent over-sensitivities to medications and an increase in the severity of withdrawal symptoms.
Thanks Scott, but I believe it was you that first put the idea in my head so I can't claim any credit!
I rode out the worst start-up effects on fluoxetine (albeit at only 10mg) and I believe my 5HT receptors may have desensitized again.
My theory was that hitting the receptors hard with elevated serotonin levels in the synapse would force them back into compliance!
However, I still have the aforementioned spells of tachycardia/agitation/dysmorphia which I believe might be mediated through fluoxetine's noradrenergic mechanism rather than its serotonergic one.
I might ask to switch to a cleaner SSRI like escitalopram to see if it improves.
Posted by zzzz7 on September 12, 2009, at 18:01:36
In reply to Re: Increasing SSRI/SNRI above the 'regular' doses » zzzz7, posted by Phillipa on September 11, 2009, at 20:43:31
All the SSRIs besides Prozac (and sometimes even that) will cause problems when stopped abruptly.
Posted by zzzz7 on September 12, 2009, at 18:03:17
In reply to Re: Increasing SSRI/SNRI above the 'regular' doses, posted by Brainbeard on September 12, 2009, at 6:30:08
I drank tons of coffee on it. : )
Posted by zzzz7 on September 12, 2009, at 18:06:18
In reply to Re: Increasing SSRI/SNRI above the 'regular' doses » SLS, posted by sowhysosad on September 12, 2009, at 16:06:51
It's consistent with its 5-HT-related mechanisms, as well. Hopefully you can find out with the other SSRIs.
Posted by sowhysosad on September 12, 2009, at 18:22:26
In reply to Re: Increasing SSRI/SNRI above the 'regular' doses » sowhysosad, posted by zzzz7 on September 12, 2009, at 18:06:18
> It's consistent with its 5-HT-related mechanisms, as well.
Good point, but fluoxetine's the only SSRI that's given me tachycardia (and even arrhythmia) for any length of time in the past.
It's also the only SSRI with any significant action on noradrenaline. I'm sure it's no coincidence.
Posted by Phillipa on September 12, 2009, at 20:21:45
In reply to Re: Increasing SSRI/SNRI above the 'regular' doses » Phillipa, posted by zzzz7 on September 12, 2009, at 18:01:36
ZZZ and I knew that from paxil and let that idiot just stop the low dose. But the paxil was only 10mg and sure had the zaps. Thanks for answering. Phillipa
Posted by Brainbeard on September 13, 2009, at 4:01:39
In reply to Re: Increasing SSRI/SNRI above the 'regular' doses » Brainbeard, posted by SLS on September 12, 2009, at 6:52:59
Sigma receptors were, when first discovered, thought to be a subtype of opioid receptors. Later it appeared they were in a class of their own. Not that much is known about sigma receptors, but the sigma-1 receptor appears to play a role in depression and anxiety. This is what emerges from animal tests and seems to correspond with the effects of AD's that affect sigma-1 receptors.
We know so little about sigma-1, that it isn't even clear wether either sigma-1 antagonism or -agonism (or both) provides relief from depression and/or anxiety. Fact is that Luvox (fluvoxamine) is a potent sigma-1 AGONIST. From what I know, at this point it isn't clear yet wether Lexapro (escitalopram) is a sigma-1 agonist or an antagonist. It is beyond me why noone instigates some research after this.
The reason that both Luvox and Lexapro can offer a more rapid therapeutic response than expected from the SRI-mechanism (i.e., somewhere in the first two weeks) is supposed to be their effects on sigma-1.
Even Zoloft (sertraline), by the way, is a weak sigma-1 agonist (its affinity for sigma-1 is stronger than its affinity for the dopamine receptor!)
SWSS, Prozac isn't the only SSRI with noradrenergic effects - Paxil (paroxetine) has significant effects on noradrenaline, as well as Zoloft on higher doses.
This is the end of the thread.
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