Re: Why are SSRI’s too stimulating !!!!!!
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Originally Posted by
SideFX
I have thought that Pregabalin would stop me falling asleep - gaining weight - water in ears and head sensation....But could make other SideFX much worse.
Pregabalin has a similar effect on the brain as BZDs, just by a different route, John. BZDs slow neuron 'firing' by helping to increase the influx of negatively charged chlorine ions which makes it harder for the cell to raise its typical resting voltage from -70 mv to the depolarisation (firing) voltage of -55 mV, pregabalin inhibits the influx of positively charged calcium ions instead. Sedation is a common side-effect.
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What role does increasing Norepinephrine play in anxiety and panic disorder - Surely this would increase anxiety??
It might if noradrenaline/norepinephrine (NA) reuptake inhibitors increased NA levels - and they do for a few weeks at the beginning, but just as with serotonergic ADs and serotonin levels, with chronic dosing they actually reduce NA synthesis and expression. OTOH, anxiety and/or depression increase NA and serotonin (also dopamine) levels significantly. These disorders are not caused by too little of this, or that neurotransmitter, just the opposite. See: Zangen A, 1999 and my Serotonin - The 'chemical imbalance' myth.
Re: Why are SSRI’s too stimulating !!!!!!
Quote:
Originally Posted by
panic_down_under
Pregabalin has a similar effect on the brain as BZDs, just by a different route, John. BZDs slow neuron 'firing' by helping to increase the influx of negatively charged chlorine ions which makes it harder for the cell to raise its typical resting voltage from -70 mv to the depolarisation (firing) voltage of -55 mV, pregabalin inhibits the influx of positively charged calcium ions instead. Sedation is a common side-effect.
It might if noradrenaline/norepinephrine (NA) reuptake inhibitors increased NA levels - and they do for a few weeks at the beginning, but just as with serotonergic ADs and serotonin levels, with chronic dosing they actually reduce NA synthesis and expression. OTOH, anxiety and/or depression increase NA and serotonin (also dopamine) levels significantly. These disorders are not caused by too little of this, or that neurotransmitter, just the opposite. See:
Zangen A, 1999 and my
Serotonin - The 'chemical imbalance' myth.
That was a very interesting link PDU...So all meds raise one or more level of neurotransmitters and then downstream this encourages neurogenesis, which in turn creates healthy normal levels of neurones....Thus recovery will be reached irrespective of the med, as long as it’s well tolerated ???? That makes sense to the delayed response Ta John
Re: Why are SSRI’s too stimulating !!!!!!
Quote:
Originally Posted by
SideFX
So all meds raise one or more level of neurotransmitters
Yes, usually beginning within about an hour of the first dose, however, after a week or two bio-feedback mechanisms come into play and reduce synthesis and expression which causes the affected neurotransmitter levels to drop dramatically in some regions of the brain associated with anxiety/depression.
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and then downstream this encourages neurogenesis, which in turn creates healthy normal levels of neurones....
Not sure if the drop in neurotransmitter levels is the important factor, but it is certainly seems to be part of the process.
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Thus recovery will be reached irrespective of the med, as long as it’s well tolerated ????
No AD is intrinsically better than the others, however, one or two will often prove more effective than the others for an individual. Some also respond better to noradrenaline/norepinephrine reuptake inhibitors (NRI) such as nortriptyline, desipramine and lofepramine than they do serotonin reuptake inhibitors. Unfortunately, these days many GPs and even some psychiatrists are barely aware they exist. :sad: Old time psychiatrists also favour supplementing a SSRI with a NRI over prescribing SNRIs. Not only can they essentially create a bespoke SNRI, but it avoids some of the SNRIs problems such as their short half-lives which can make both starting and stopping them difficult.
Re: Why are SSRI’s too stimulating !!!!!!
Quote:
Originally Posted by
panic_down_under
Yes, usually beginning within about an hour of the first dose, however, after a week or two bio-feedback mechanisms come into play and reduce synthesis and expression which causes the affected neurotransmitter levels to drop dramatically in some regions of the brain associated with anxiety/depression.
Not sure if the drop in neurotransmitter levels is the important factor, but it is certainly seems to be part of the process.
No AD is intrinsically better than the others, however, one or two will often prove more effective than the others for an individual. Some also respond better to noradrenaline/norepinephrine reuptake inhibitors (NRI) such as nortriptyline, desipramine and lofepramine than they do serotonin reuptake inhibitors. Unfortunately, these days many GPs and even some psychiatrists are barely aware they exist. :sad: Old time psychiatrists also favour supplementing a SSRI with a NRI over prescribing SNRIs. Not only can they essentially create a bespoke SNRI, but it avoids some of the SNRIs problems such as their short half-lives which can make both starting and stopping them difficult.
Okay PDU think I understand the way recovery is reached, or at least the mechanism involved in AD’s
So how come Peroxatine was a silver bullet and turned me around in circa 6 weeks - Yet the Mirtazipine & Venlafaxine combo took about a year ??? If the same mechanism is being triggered, why so long for the latter...The latter got me so stable I came of Diazipam easily and reduced Venlafaxine from 375 to 150 walk in the park.
I just can’t see any med doing what Peroxatine did ie kick in fully at 6 weeeks and it would be nice to know why the mechanism of TCA action is so different to SSRI’s which some people cannot tolerate...Am I also right in thinking that Peroxatine has an effect on NET as well as SERT and with a NET ki of circa 50 ???? Cause that balance was perfect for me, but I kept stopping and starting and it bit my arse big big time on the 3rd attempt to restart !!!!! Ta John
Re: Why are SSRI’s too stimulating !!!!!!
Quote:
Originally Posted by
SideFX
So how come Peroxatine was a silver bullet and turned me around in circa 6 weeks - Yet the Mirtazipine & Venlafaxine combo took about a year ???
Maybe the improvement was due to remission, not the venlafaxine, John. Anxiety disorders and depression wax and wane over time. If an AD at maximum dose isn't working within 12 weeks or so, maybe an extra couple of weeks if it isn't the first time on ADs, or is fluoxetine, then it is unlikely to at 6/9/12 months.
Why did you keep taking mirtazapine and venlafaxine for so long if it wasn't working?
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I just can’t see any med doing what Peroxatine did ie kick in fully at 6 weeeks
ADs usually kick-in at 4-12 weeks the first time with the top of the bell curve at 6 weeks.
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and it would be nice to know why the mechanism of TCA action is so different to SSRI’s which some people cannot tolerate...
The dual action of most of them, plus the combination of receptors they hit.
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Am I also right in thinking that Peroxatine has an effect on NET as well as SERT and with a NET ki of circa 50 ????
It is a more potent NET inhibitor than the other SSRIs but much less so that many of the TCAs.
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Cause that balance was perfect for me, but I kept stopping and starting and it bit my arse big big time on the 3rd attempt to restart !!!!!
You might have done just as well on another SSRI.
Re: Why are SSRI’s too stimulating !!!!!!
Hi PDU I know it’s been a long time and I would like to seek your advise again…In the end I remained on all 4 meds and over the past few years, got back to about 60/70% ability to cope with life.
However I have very slowly been tapering off the Pregabalin and got from 600mg to 150mg. Then I got slammed with huge withdrawals, or at least I am putting it down to the cumulative drop.
Anyway it’s been 5 weeks and although I feel a bit better, I’m still in distress and trying to continue working. Thing is I have the shakes, hot flashes, burning skin sensations back. Panic and anxiety, mixed with some depression. I fear the end is coming and I’m afraid and don’t know what to do. Could you kindly revisit this thread and give some valuable input, as I was never in remission after 6 long years. But able to get by, without everything being a white knuckle ride.
I am still on Vortioxitine, Mirtazapine, Diazepam and now up dosed to 300mg Pregabalin
My GP doesn’t know what to do and has advised that it could take some time to stabilise back to where I was 5 weeks ago. Not healed, but able to cope with life.
Can we have a discussion around meds please as I know you are a fountain of knowledge. Thanking you in advance John
Re: Why are SSRI’s too stimulating !!!!!!
Quote:
Originally Posted by
panic_down_under
Maybe the improvement was due to remission, not the venlafaxine, John. Anxiety disorders and depression wax and wane over time. If an AD at maximum dose isn't working within 12 weeks or so, maybe an extra couple of weeks if it isn't the first time on ADs, or is fluoxetine, then it is unlikely to at 6/9/12 months.
Why did you keep taking mirtazapine and venlafaxine for so long if it wasn't working?
ADs usually kick-in at 4-12 weeks the first time with the top of the bell curve at 6 weeks.
The dual action of most of them, plus the combination of receptors they hit.
It is a more potent NET inhibitor than the other SSRIs but much less so that many of the TCAs.
You might have done just as well on another SSRI.
Hi PDU I know it’s been a long time and I would like to seek your advise again…In the end I remained on all 4 meds and over the past few years, got back to about 60/70% ability to cope with life.
However I have very slowly been tapering off the Pregabalin and got from 600mg to 150mg. Then I got slammed with huge withdrawals, or at least I am putting it down to the cumulative drop.
Anyway it’s been 5 weeks and although I feel a bit better, I’m still in distress and trying to continue working. Thing is I have the shakes, hot flashes, burning skin sensations back. Panic and anxiety, mixed with some depression. I fear the end is coming and I’m afraid and don’t know what to do. Could you kindly revisit this thread and give some valuable input, as I was never in remission after 6 long years. But able to get by, without everything being a white knuckle ride.
I am still on Vortioxitine, Mirtazapine, Diazepam and now up dosed to 300mg Pregabalin
My GP doesn’t know what to do and has advised that it could take some time to stabilise back to where I was 5 weeks ago. Not healed, but able to cope with life.
Can we have a discussion around meds please as I know you are a fountain of knowledge. Thanking you in advance John
Re: Why are SSRI’s too stimulating !!!!!!
Quote:
Originally Posted by
SideFX
However I have very slowly been tapering off the Pregabalin and got from 600mg to 150mg. Then I got slammed with huge withdrawals, or at least I am putting it down to the cumulative drop.
...Thing is I have the shakes, hot flashes, burning skin sensations back. Panic and anxiety, mixed with some depression.
How long after the last dose decrease did you begin having these symptoms, John?
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I am still on Vortioxitine, Mirtazapine, Diazepam and now up dosed to 300mg Pregabalin
My GP doesn't know what to do
Did he start you on all these meds, or a psychiatrist?
Imo, there are two significant issues with your med regime. Firstly there's now good evidence1 that benzodiazepines both worsen anxiety in the longer run and reduce the effectiveness of serotonergic ADs. The second is that the diazepam and pregabalin are basically doling the same job, slow the 'firing' rate of neurons, albeit from different directions. Diazepam does it by increasing the inflow of negatively charged chlorine ions which makes it harder for a cell to raise its electrical voltage to the depolarization level. Pregabalin slows firing by decreasing the influx of positively charged calcium ions. I don't see the point of taking two meds to do the same thing. It would have been more efficient to just raise the dose of one of them.
Which brings us to the other two. Despite what is says on the packaging, mirtazapine isn't a true AD, but a sedative so its main role in your case may be to help you sleep and it may reduce anxiety to some extent through sedation.
Vortioxetine combines the actions of a SSRI with that of buspirone (Buspar). It was noticed that buspirone can enhance the effectiveness of SSRIs and other serotonergic ADs and also ease some of their side-effects. So some bright spark decided to make an AD that had the attributes of both in a single pill. While the idea might be good on paper, vortioxetine hasn't exactly set the AD market on fire. I suspect the reason is the AD has a fixed ratio of the combined attributes whereas when adding buspirone to a SSRI there is are a wide range of possible ratios for fine tuning.
Which raises the question of is it worth continuing with vortioxetine, or would another AD be better? I don't know. It comes down to whether vortioxetine is not effective, or is it being inhibited by the diazepam?
I think taking the diazepam is more problematic than the pregabalin, but you really need to be talking with a psychiatrist about this, imo.
[1]
Boldrini M, Butt TH, Santiago AN, et al. (2014)
Benzodiazepines and the potential trophic effect of antidepressants on dentate gyrus cells in mood disorders.
Int J Neuropsychopharmacol. Dec;17(12):1923-33 (Abstract | Full text)
Sun Y, Evans J, Russell B, et al (2013)
A benzodiazepine impairs the neurogenic and behavioural effects of fluoxetine in a rodent model of chronic stress.
Neuropharmacology. Sep;72:20-8 (Abstract)
Song J, Zhong C, Bonaguidi MA, et al (2012)
Neuronal circuitry mechanism regulating adult quiescent neural stem-cell fate decision.
Nature. Sep 6;489(7414):150-4 (Article | Study full text)
Wu X, Castren E. (2009)
Co-treatment with diazepam prevents the effects of fluoxetine on the proliferation and survival of hippocampal dentate granule cells.
Biol Psychiatry. Jul 1;66(1):5-8 (Abstract)
See also: the 'Ugly' part of Benzodiazepines: The Good, The Bad, and the Ugly.
Re: Why are SSRI’s too stimulating !!!!!!
[QUOTE=panic_down_under;2073634]How long after the last dose decrease did you begin having these symptoms, John?
Did he start you on all these meds, or a psychiatrist?
A psychiatrist did in whilst in hospital
Imo, there are two significant issues with your med regime. Firstly there's now good evidence1 that benzodiazepines both worsen anxiety in the longer run and reduce the effectiveness of serotonergic ADs. The second is that the diazepam and pregabalin are basically doling the same job, slow the 'firing' rate of neurons, albeit from different directions. Diazepam does it by increasing the inflow of negatively charged chlorine ions which makes it harder for a cell to raise its electrical voltage to the depolarization level. Pregabalin slows firing by decreasing the influx of positively charged calcium ions. I don't see the point of taking two meds to do the same thing. It would have been more efficient to just raise the dose of one of them.
Pregabalin did far more and continued without tolerance, the benzo did nothing after a few weeks, as is usual for benzos.
Which brings us to the other two. Despite what is says on the packaging, mirtazapine isn't a true AD, but a sedative so its main role in your case may be to help you sleep and it may reduce anxiety to some extent through sedation.
I agree mirtazipine is a very weak AD, but a strong antihistamine, however in combo with venlafaxine years ago, was my saviour
Vortioxetine combines the actions of a SSRI with that of buspirone (Buspar). It was noticed that buspirone can enhance the effectiveness of SSRIs and other serotonergic ADs and also ease some of their side-effects. So some bright spark decided to make an AD that had the attributes of both in a single pill. While the idea might be good on paper, vortioxetine hasn't exactly set the AD market on fire. I suspect the reason is the AD has a fixed ratio of the combined attributes whereas when adding buspirone to a SSRI there is are a wide range of possible ratios for fine tuning.
Not up to speed with this AD, just know I struggled to tolerate it and may still do, don’t know anymore
Which raises the question of is it worth continuing with vortioxetine, or would another AD be better? I don't know. It comes down to whether vortioxetine is not effective, or is it being inhibited by the diazepam?
Diazepam had no effect on my previous recover in 2012 and I discontinued it easily
I think taking the diazepam is more problematic than the pregabalin, but you really need to be talking with a psychiatrist about this, imo.
Okay thanks for your input anyway Ta John