![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 3 to 27 of 27. Go back in thread:
Posted by vanvog on March 12, 2013, at 9:05:26
In reply to Re: Effexor + Mirtazapine MORE effective than PARNATE! » vanvog, posted by SLS on March 12, 2013, at 8:36:26
To be fair, the second group was on 210.3 of Effexor, so they practically maxed out, the max suggested dose of Effexor XR being 225mg, but then again, you see lots of people on doses >300 mg/day.
Posted by Phillipa on March 12, 2013, at 10:04:06
In reply to Effexor + Mirtazapine MORE effective than PARNATE!, posted by vanvog on March 12, 2013, at 8:05:25
I guess different people different meds work for them is a factor also. Phillipa
Posted by linkadge on March 12, 2013, at 16:43:26
In reply to Effexor + Mirtazapine MORE effective than PARNATE!, posted by vanvog on March 12, 2013, at 8:05:25
I responded to effexor + remeron (california rocket fuel). I'm currently taking this. I didn't have much sucess with parnate besides tachycardia, insomnia and paranoia.
Linkadge
Posted by brklyn233342 on March 12, 2013, at 17:42:43
In reply to Re: Effexor + Mirtazapine MORE effective than PARNATE!, posted by linkadge on March 12, 2013, at 16:43:26
Thanks for the article,at least its something new,i heard of the california nick name but doesent it also include a mild stimulant in the combo?
Im agree my parnate would not work unless i was on high dose,im on 100 mg daily two doses,any can share if they are on a higher dose,can i go higher?
Posted by vanvog on March 12, 2013, at 18:12:53
In reply to Re: Effexor + Mirtazapine MORE effective than PARNATE!, posted by brklyn233342 on March 12, 2013, at 17:42:43
You see some people go above 120 mg/day of Parnate but not many go above 150 mg/day. Most pdocs don't go >80 mg/day on outpatinets.
Posted by linkadge on March 13, 2013, at 9:33:58
In reply to Re: Effexor + Mirtazapine MORE effective than PARNATE!, posted by vanvog on March 12, 2013, at 18:12:53
From what I understand, californa rocket fuel just refers to effexor and remeron.
Remeron has a noradrenergic releasing effect which could potentiate the NRI properties of effexor.
Linkadge
Posted by vanvog on March 13, 2013, at 12:00:18
In reply to Re: Effexor + Mirtazapine MORE effective than PARNATE!, posted by linkadge on March 13, 2013, at 9:33:58
Remeron acts as a pump of serotonin and norepinephrine (one's neurons are pumping out more of those neurotransmitters at a faster rate).
Effexor, like any reuptake inhibitor, makes one's neurons soak longer in serotonin and, at dosages around 225mg (give or take for each person) norepinephrine.
Posted by linkadge on March 13, 2013, at 13:41:41
In reply to Re: Effexor + Mirtazapine MORE effective than PARNATE!, posted by vanvog on March 13, 2013, at 12:00:18
I think remeron acts more on norepinephrine release than serotonin release.
Its effects on norepinephrine are due to blocking the presynaptic noradrenergic alpha-2 receptors. This promotes norepinephrine release.
I think the serotonin action comes mainly from receptor blockade (5-ht2a/c,5-ht3) which increases the availability at 5-ht1a receptors.
Blocking serotonin 5-ht2a/c receptors also increases catecholamine release in certain brain regions, which might augment the NRI effects of effexor.
Also, remeron can improve sleep, and melatonin release, which might improve receptor sensitivites.
Linkadge
Posted by tensor on March 13, 2013, at 14:07:58
In reply to Re: Effexor + Mirtazapine MORE effective than PARNATE!, posted by linkadge on March 13, 2013, at 13:41:41
> I think remeron acts more on norepinephrine release than serotonin release.
>
> Its effects on norepinephrine are due to blocking the presynaptic noradrenergic alpha-2 receptors. This promotes norepinephrine release.
>
> I think the serotonin action comes mainly from receptor blockade (5-ht2a/c,5-ht3) which increases the availability at 5-ht1a receptors.
>
> Blocking serotonin 5-ht2a/c receptors also increases catecholamine release in certain brain regions, which might augment the NRI effects of effexor.
>
> Also, remeron can improve sleep, and melatonin release, which might improve receptor sensitivites.
>
> Linkadge
>IMHO, mirtazapine is still the "smartest" psych med. The other newer (not so new anymore) meds are just polished versions of TCAs.
/tensor
Posted by vanvog on March 13, 2013, at 15:01:04
In reply to Re: Effexor + Mirtazapine MORE effective than PARNATE!, posted by vanvog on March 13, 2013, at 12:00:18
Stahl (PG) on how MIRTAZAPINE works:
Boost neurotransmitters serotonin and
norepinephrine/noradrenaline
Blocks alpha 2 adrenergic presynaptic
receptor, thereby increasing norepinephrine
neurotransmission
Blocks alpha 2 adrenergic presynaptic
receptor on serotonin neurons
(heteroreceptors), thereby increasing
serotonin neurotransmission
This is a novel mechanism independent of
norepinephrine and serotonin reuptake
blockade
Blocks 5HT2A, 5HT2C, and 5HT3 serotonin
receptors
Blocks H1 histamine receptors
Posted by linkadge on March 13, 2013, at 17:19:34
In reply to Re: Effexor + Mirtazapine MORE effective than PARNATE!, posted by vanvog on March 13, 2013, at 15:01:04
I remember reading somewhere that mirtazapine's affinity for presynaptic heteroreceptors (i.e. serotonin feedback inhibition) was less than that for the adrenergic autoreceptors. I will look. Mind you, sustained administration would produce a different changes on the serotonin system than acute administration.
Linkadge
Posted by Robert_Burton_1621 on February 13, 2015, at 6:50:52
In reply to Re: Effexor + Mirtazapine MORE effective than PARNATE! » vanvog, posted by SLS on March 12, 2013, at 8:36:26
> > I found this study of Parnate vs. a combo of Effexor and Mirtazapine which seems to indicate that the combo is twice as effective for MOST treatment resistant patients.> >
> This particular arm of the STAR*D study is meaningless."The mean daily dose at exit for tranylcypromine was 36.9"
The low dosage of Parnate used was woefully inadequate to treat depression. Most people don't respond to Parnate until a dosage of 40 - 80 mg/day is reached.>
- Scott
Scott, this is so well-said, well-spotted, and well-deserving of repeated emphasis.
Your observation is instructive because it prompts all of us who are "treatment-refactory" to pay very close attention to the protocols which are appplied in studies purporting to demonstrate the relative superiority of x strategy over y strategy.
Last year I was also, foolishly, excited by the discovery of this paper on ven + mirtaz v. tranyl. The excitement was aroused because I simply could not convince, at that time, any psychiatrist to prescribe parnate. (For one psychiatrist, I printed out and indexed a number recent research papers on the drug published since 2000, by eminent and rigorous psychopharmacologists, which supported its efficacy and corrected misconceptions as to its intrinsic "dangers", but to no avail). Rather, the efforts I went to in order to demonstrate the sincerity of my motivation, my desperation, to overcome my depressive illness were interpreted as evidence of a discreditable belief that there exists a "magic bullet" in the form of a mythical drug which will "cure" this illness once and for all. The particular psychiatrist who delivered this assessment (not the same one to whom I had given all the papers mentioned above), quite a senior and apparently reputable one, remarked that I had done more solid research into possible treatments than any patient he had seen before. It was clear that his remark was not intended as a compliment.
So my next strategy was to press the merits of the combination studied in this paper. And he was perfectly happy to prescribe the ven + mirtaz combo, though without any understanding of the mechanisms by which it was claimed to have such an effective, and extraordinarily positive, action in treatment-resistant cases. This same psychiatrist refused to consider an MAOI, on reasons which recent research, which should have been known to him if he were scientifically conscientious, has proven to be entirely erroneous.
The lesson I learnt from this experience is that, for psychiatrists, while all forms of ignorance may be equal, some are more equal than others.
The effect of this combination was (on me) negligble. The (posited) increase in noradrenergic neuro-transmission may have contributed to an acute, and very unpleasant, episode of troublesome anger I went through. Not wholly unsurprisingly given his deficient learning, the psychiatrist who prescribed this very combination refused to offer any constructive advice about this side-effect ("I don't treat side-effects"); I was simply advised to address my concerns to my GP.
The idea that this combo's appeal as an efficacious psychotropic with superb anti-depressant properties should be publicised popularly by the moniker "Californian rocket fuel" may well be some evidence for its source as a marketing ploy. I would, however, not wish to dismiss the positive experiences of people who have benefited from it.
Any "anti-depressant" benefit from Mirtazapine may in any case arise predominantly as a result of its extremely potent H1 antagonism. The supposition that it is "dual-action" has been pretty much exploded. But I don't possess sufficient learning to draw any conclusion.
Scott, you mention the Star*D trials. I agree that no competent psychopharmacologist could possibly assent to the proposition that their outcome has any clinical bearing on the relative efficacy of parnate. The only point I'd make in response is that the majority of psychiatrists, in my experience, are incompetent or barely competent psychopharmacologists; and the supposed definitiveness of the Star*D outcomes is routinely invoked in a knee-jerk and uncritical way whenever MAOIs are raised.
I was informed unequivocally by the same psychiatrist whose "advice" I was subject to for eight months last year that, given the trials of medication to which I had been non-responsive or only partially responsive in the past, there was (if I recall correctly) only a 6 - 10% chance (i.e., a pretty negligible chance) that I'd be responsive to anything else. This ex cathedra declaration was made in full awarenesss of, and must therefore have been taken to have incorporated due consideration of, my desire to trial an MAOI. But the idea that Star*D (or any trial using a similar a protocol as regards MAOIs) has anything at all to say about tranylcypromine is unsupportable; indeed, risible.
Posted by ed_uk2010 on February 13, 2015, at 10:24:49
In reply to Re: Effexor + Mirtazapine MORE effective than PARNATE! » SLS, posted by Robert_Burton_1621 on February 13, 2015, at 6:50:52
>It was clear that his remark was not intended as a compliment.
He felt threatened?
>"Californian rocket fuel"
I don't like this moniker. It makes it sound like a potent psychostimulant, which it isn't.
>I would, however, not wish to dismiss the positive experiences of people who have benefited from it.
I have know several people who have benefited from mirtazapine, either alone, or with an SSRI, or with venlafaxine. Personally, I dislike it. Low doses = cotton wool stuffed head. High doses = restless, agitated feeling + cotton wool.
>the majority of psychiatrists, in my experience, are incompetent or barely competent psychopharmacologists
:)
>there was (if I recall correctly) only a 6 - 10% chance (i.e., a pretty negligible chance) that I'd be responsive to anything else.
That must have been a very therapeutic consultation.
Posted by Robert_Burton_1621 on February 13, 2015, at 10:39:01
In reply to Re: Effexor + Mirtazapine MORE effective than PARNATE!, posted by linkadge on March 13, 2013, at 9:33:58
> From what I understand, californa rocket fuel just refers to effexor and remeron.
>
> Remeron has a noradrenergic releasing effect which could potentiate the NRI properties of effexor.
>
> LinkadgeAren't the NRI properties of Effexor pretty weak, even at very high doses?
Desipramine 0.83 most potent
Amitriptyline 35
Fluoxetine 240
Venlafaxine 1060 weakestSee the table of data by PK Gillman relating to "dual action", at his psychotropical.com site:
http://www.psychotropical.com/index.php/anti-depressants/general-intro-4
And if Mirtazapine has no effect on the tyramine pressor response, which suggests a sub-optimal property of "releasing" (?) noradrenaline, how is it that two agents with seemingly weak noradrenergic potency would together optimise inhibition of its reuptake to a degree greater than, for instance, nortriptyline or amitriptyline?
I am a neophyte at al this (as is no doubt obvious!), though would like to learn more!
Posted by Robert_Burton_1621 on February 13, 2015, at 10:57:20
In reply to Re: Effexor + Mirtazapine MORE effective than PARNATE! » Robert_Burton_1621, posted by ed_uk2010 on February 13, 2015, at 10:24:49
> He felt threatened?>Possibly, or was just lazy. Relying on a fixed idea that a patient doing his own research into medication = medication fixation, is a much more efficient (if totally disingenous and evasive) tactic of dealing with a concern than looking closely at the research on its own terms and arriving at a well-informed assessment. Of course, the research I managed to collate may have been irrelevant, or mistaken, or clinically unhelpful, or all three of these things, but since, from an intelligent but non-specialised perspective it struck me as being very relevant and worthy of consideration, it was disappointing that it was so breezily dismissed, if it was taken notice of at all.
> >"Californian rocket fuel" I don't like this moniker. It makes it sound like a potent psychostimulant, which it isn't.>
Exactly. The reason why I was so excited about it is that its pop label seemed to promise a psycho-motor boost, a revival of energy and drive, in the midst of my pretty bad and persistent psycho-motor retardation.
> >I would, however, not wish to dismiss the positive experiences of people who have benefited from it.
>
> I have know several people who have benefited from mirtazapine, either alone, or with an SSRI, or with venlafaxine. Personally, I dislike it. Low doses = cotton wool stuffed head. High doses = restless, agitated feeling + cotton wool.
>That was precisely my feeling: soggy cabbage brain, I called it, even after having a very stable and very good night's sleep.
> >the majority of psychiatrists, in my experience, are incompetent or barely competent psychopharmacologists
>
> :)
>
> >there was (if I recall correctly) only a 6 - 10% chance (i.e., a pretty negligible chance) that I'd be responsive to anything else.
>
> That must have been a very therapeutic consultation.
>Lol. My heart feel through the floor! That was his verdict after seven consecutive sessions. It would be the last I would attend.
Posted by ed_uk2010 on February 13, 2015, at 14:46:27
In reply to Re: Effexor + Mirtazapine MORE effective than PARNATE! » linkadge, posted by Robert_Burton_1621 on February 13, 2015, at 10:39:01
>Aren't the NRI properties of Effexor pretty weak, even at very high doses?
Yes, weak - but not absent. The fact that venlafaxine acts as a weak NRI at high dosages, but lacks the alpha-1 adrenergic receptor blocking property of tricyclic ADs, is probably why it sometimes induces hypertension. (Alpha-1 receptor blockade in blood vessels produces vaso-dilation and a decrease in BP).
>Desipramine 0.83 most potent
>Amitriptyline 35
>Fluoxetine 240
>Venlafaxine 1060 weakestThese affinity figures are interesting but have to be seen in context in order to be useful. Desipramine appears to have high affinity for the NE transporter. In this case, we might assume it was a potent NRI. Indeed it is, as it happens. But we don't know that from this data. Why?
a) The data doesn't tell us what desipramine does when it binds to the NE transporter. Does it just bind? Does it block it? Does it reverse it?
b) How much desipramine even reaches the transporters in question when a dose is given to a patient?
c) What does desipramine do at other sites? If, for example, it was 100 times more potent at the dopamine D2 receptor as an antagonist (IT ISN'T!), it would probably be an antipsychotic active at low doses! But it isn't.... that's just an example. If this really was the case, severe side effects from excessive D2 blockage would occur if one attempted to take it at a dose producing NRI activity. In reality, desipramine's relative selectivity for the NE transporter over other sites, its good absorption and bioavailability and its high affinity for the site as a 'blocker' allows it to act as a powerful NRI clinically.Things get more complex when looking at fluoxetine and venlafaxine. We seen that venlafaxine has lower affinity for the NE transporter than fluoxetine, but on its own this is not meaningful. Clinically, venlafaxine produces weak NRI activity at high doses whereas fluoxetine does not appear to have any significant NRI activity. How? Well.....
Receptor affinities become meaningful when considering three main points....1. What is the drug concentration at the receptor/uptake site in question when the drug is given at the therapeutic dose? I imagine that fluoxetine achieves much lower levels than venlafaxine because it appears to lack any NE activity clinically, despite its higher binding affinity.
[As an aside... What influences the drug concentration at the receptor/uptake site?
a) The drug dosage and regimen.
b) The % of the dose which is absorbed.
c) The bioavailability (proportion of dose reaching the blood stream) - this depends on absorption and 'first pass' metabolism in the intestinal wall (lesser) and liver (major). Some drugs are well absorbed but then almost completely inactivated before they even reach the bloodstream, their bioavailability is therefore low.
d) Does the drug have active metabolites (conversion products)? If so, what do they do and what concentration do they achieve at the receptor sites? Venlafaxine is an example of a drug with an active metabolite. The distribution and clearance of active metabolites often occurs quite differently to the parent drug. Fluoxetine is a good example, its major metabolite is so slowly excreted it gives the drug a surprisingly long duration of action.
e) How is the drug distributed in the body? For example, how does the concentration in the brain compare with the conentration measured in the blood. Some drugs barely penetrate into the brain at all, others penetrate readily and achieve high levels. This is very relevant for psych meds.
f) Where and how rapidly is the drug excreted from the body? Lithium is a good example. It is excreted by the kidney and achieves toxic/high levels if the dose is not reduced in those with kidney impairment.]2. What is the affinity of the drug for other receptors/uptake sites/enzymes? How do they compare?
Take a theoretical drug with moderate affinity for the NE transporter and exceptionally high affinity for the histamine H1 receptor - both as an antagonist. Assuming good bioavailability and penetration into the central nervous system.... If this drug was given at a tiny dose, it would essentially act as a sedative antihistamine. A high dose, on the other hand, would saturate H1 receptors and act at the NE transporters too.
Looking at venlafaxine data, we see that although its affinity for 5-HT (serotonin) reuptake sites is far higher than its affinity for NE transporters, its affinity for 5-HT transporters also seems rather low in comparison with the SSRIs. Clinically, the serotonergic properties of Effexor are potent. A high concentration must be achieved in the synapses compared with SSRIs.3. What does the drug in question actually do at the receptor once it's there?
a) Bind - but do little or nothing.
b) Influence the binding and action of neurotransmitters. This is how benzos work. They facilitate the binding and hence action of the neurotransmitter GABA at certain of its receptors (GABA-A). This is called a PAM effect - positive allosteric modulator. Negative allosteric modulators of benzo receptors have been synthesised. Perhaps unsurprisingly, they induce severe anxiety states and seizures.
c) Block the effect of the neurotransmitter at the receptor (antagonist). A drug may do this by preventing the neurotransmitter from even binding. Alternatively, the neurotransmitter may still bind but its action is inhibited.
d) Stimulate the receptor fully in the same way as the neurotransmitter (agonist, full agonist).
e) Stimulate the receptor, but in a way which produces less effect than the neurotransmitter (partial agonist).
f) Produce an effect which is the opposite of that produced by the neurotransmitter (inverse agonist).
g) Block the activity of an enzyme of reuptake site.So... you can see there are many factors which affect the clinical effects of the drug as well as the receptor affinity data, and that most of these factors influence the clinical effects by affecting the concentration of the drug or metabolite achieved at the receptor site when given at therapeutic doses. What the drug actually does at the receptor is also immensely relevant.
> I am a neophyte at al this (as is no doubt obvious!)
You probably know more than your last psych. He doesn't sound especially well-informed.
Hope the the immense babble I've just written is of some use.
Posted by ed_uk2010 on February 13, 2015, at 14:50:15
In reply to Re: Effexor + Mirtazapine MORE effective than PARNATE! » ed_uk2010, posted by Robert_Burton_1621 on February 13, 2015, at 10:57:20
>Possibly, or was just lazy.
Maybe, like of time is also an issue. But more likely, lack of appreciation of the value of your research may have been the problem. He assumed it was 'rubbish from the internet'.
>I called it, even after having a very stable and very good night's sleep.
Good for sleep. Terrible for waking up. True of many meds which aid sleep, sadly.
>It would be the last I would attend.
At least you found someone else! :)
Posted by SLS on February 14, 2015, at 7:10:34
In reply to Re: Effexor + Mirtazapine MORE effective than PARNATE! » SLS, posted by Robert_Burton_1621 on February 13, 2015, at 6:50:52
Thanks for the mention. Your story is very frustrating for me to read. It is all too common, and I'm sorry you have had to endure ignorance and arrogance. This can be a lethal combination. That any psychiatrist should tell you that you have little or no chance of responding to any treatment is like giving someone who is already depressed a reason to commit suicide. Of course, there is no way anyone in the world could predict such a thing. There is simply too little known about the brain and the drugs that act on it.
You must be big-time resilient, and I admire you greatly. I am tempted to tell you to not give up, but it seems to me that you never will. Ok - what the hell. "Don't give up!"
Take care, and good luck.
- Scott
----------------------------------------------
> > > I found this study of Parnate vs. a combo of Effexor and Mirtazapine which seems to indicate that the combo is twice as effective for MOST treatment resistant patients.> >
>
>
> > This particular arm of the STAR*D study is meaningless.
>
> "The mean daily dose at exit for tranylcypromine was 36.9"
>
> The low dosage of Parnate used was woefully inadequate to treat depression. Most people don't respond to Parnate until a dosage of 40 - 80 mg/day is reached.>
>
> - Scott
>
> Scott, this is so well-said, well-spotted, and well-deserving of repeated emphasis.
>
> Your observation is instructive because it prompts all of us who are "treatment-refactory" to pay very close attention to the protocols which are appplied in studies purporting to demonstrate the relative superiority of x strategy over y strategy.
>
> Last year I was also, foolishly, excited by the discovery of this paper on ven + mirtaz v. tranyl. The excitement was aroused because I simply could not convince, at that time, any psychiatrist to prescribe parnate. (For one psychiatrist, I printed out and indexed a number recent research papers on the drug published since 2000, by eminent and rigorous psychopharmacologists, which supported its efficacy and corrected misconceptions as to its intrinsic "dangers", but to no avail). Rather, the efforts I went to in order to demonstrate the sincerity of my motivation, my desperation, to overcome my depressive illness were interpreted as evidence of a discreditable belief that there exists a "magic bullet" in the form of a mythical drug which will "cure" this illness once and for all. The particular psychiatrist who delivered this assessment (not the same one to whom I had given all the papers mentioned above), quite a senior and apparently reputable one, remarked that I had done more solid research into possible treatments than any patient he had seen before. It was clear that his remark was not intended as a compliment.
>
> So my next strategy was to press the merits of the combination studied in this paper. And he was perfectly happy to prescribe the ven + mirtaz combo, though without any understanding of the mechanisms by which it was claimed to have such an effective, and extraordinarily positive, action in treatment-resistant cases. This same psychiatrist refused to consider an MAOI, on reasons which recent research, which should have been known to him if he were scientifically conscientious, has proven to be entirely erroneous.
>
> The lesson I learnt from this experience is that, for psychiatrists, while all forms of ignorance may be equal, some are more equal than others.
>
> The effect of this combination was (on me) negligble. The (posited) increase in noradrenergic neuro-transmission may have contributed to an acute, and very unpleasant, episode of troublesome anger I went through. Not wholly unsurprisingly given his deficient learning, the psychiatrist who prescribed this very combination refused to offer any constructive advice about this side-effect ("I don't treat side-effects"); I was simply advised to address my concerns to my GP.
>
> The idea that this combo's appeal as an efficacious psychotropic with superb anti-depressant properties should be publicised popularly by the moniker "Californian rocket fuel" may well be some evidence for its source as a marketing ploy. I would, however, not wish to dismiss the positive experiences of people who have benefited from it.
>
> Any "anti-depressant" benefit from Mirtazapine may in any case arise predominantly as a result of its extremely potent H1 antagonism. The supposition that it is "dual-action" has been pretty much exploded. But I don't possess sufficient learning to draw any conclusion.
>
> Scott, you mention the Star*D trials. I agree that no competent psychopharmacologist could possibly assent to the proposition that their outcome has any clinical bearing on the relative efficacy of parnate. The only point I'd make in response is that the majority of psychiatrists, in my experience, are incompetent or barely competent psychopharmacologists; and the supposed definitiveness of the Star*D outcomes is routinely invoked in a knee-jerk and uncritical way whenever MAOIs are raised.
>
> I was informed unequivocally by the same psychiatrist whose "advice" I was subject to for eight months last year that, given the trials of medication to which I had been non-responsive or only partially responsive in the past, there was (if I recall correctly) only a 6 - 10% chance (i.e., a pretty negligible chance) that I'd be responsive to anything else. This ex cathedra declaration was made in full awarenesss of, and must therefore have been taken to have incorporated due consideration of, my desire to trial an MAOI. But the idea that Star*D (or any trial using a similar a protocol as regards MAOIs) has anything at all to say about tranylcypromine is unsupportable; indeed, risible.
>
>
>
Posted by burial on February 14, 2015, at 8:54:45
In reply to Re: Effexor + Mirtazapine MORE effective than PARNATE! » Robert_Burton_1621, posted by SLS on February 14, 2015, at 7:10:34
I am on a cocktail of 300mg venlafaxine and 60mg mirtazapine and i can say it is great. I was on paroxetine plus mirtazapine before, and venlafaxine seemed way stronger than paroxetine although they both bind to NET.
http://www.ncbi.nlm.nih.gov/pubmed/18418363
According to this study, venlafaxine occupies 60% of NET and it may be that the metabolite, desvenlafaxine gives even more NET. I once read a study that desipramine occupied 80% of NET so it isn't that huge of a difference
Posted by Robert_Burton_1621 on February 14, 2015, at 9:24:19
In reply to Re: Effexor + Mirtazapine MORE effective than PARNATE! » Robert_Burton_1621, posted by SLS on February 14, 2015, at 7:10:34
> Thanks for the mention. Your story is very frustrating for me to read. It is all too common, and I'm sorry you have had to endure ignorance and arrogance. This can be a lethal combination. That any psychiatrist should tell you that you have little or no chance of responding to any treatment is like giving someone who is already depressed a reason to commit suicide. Of course, there is no way anyone in the world could predict such a thing. There is simply too little known about the brain and the drugs that act on it.
>You're right. The attitude initially only intensified and multiplied the instances of the daily suicidal ideation I was already affected by. Until I thought: there is something fishy about his reasoning. In this instance, his "ignorance and arrogance", as you acccurately describe it, prompted me to some further research which revealed that my options were not as limited as he mistakenly, brazenly, led me to believe.
I should make clear that he did not advise that *nothing* could ever benefit me; only that the chances of benefiting from alternative *medication* were small. His reasoning was: ok, you haven't responded to the medication I prescribed, and this must be because your condition is not fundamentally drug-treatable. Therefore, I'm going to send you to psychotherapy.
So, in spite of the fact that I had been suffering for close to two decades all of the signs (especially catatonia/psycho-motor retardation) of a condition which psychotherapy has been shown unlikley to improve and which are pathognomonic for a biological illness, he advised by implication that that was essentially my only hope.
But I've found someone else now, and that's a good thing!
> You must be big-time resilient, and I admire you greatly. I am tempted to tell you to not give up, but it seems to me that you never will. Ok - what the hell. "Don't give up!"
>Your attribution of resilience to me is profoundly reassuring, and I am grateful for it. I think I needed to hear that, in fact, since I have been battling internally the belief that I am viewed by others as pathetically lacking that quality. It is almost inevitable that chronic sufferers of severe depressive conditions will internalise the prejudice that their failure to improve precisely is a reflection of their *lack* of resilience, their fundamental woosiness. I know I have. There are few people who have not suffered severe depression who understand or who can imagine inwardly, and not merely patronisingly, the resilience that is necessary simply to get though the day.
I've noticed there seems to be a kind of uncouth, thuggish, "no-nonsense", "common-sensical", "back-to-basics" reaction in the world to the recent well-meaning campaigns to raise "awareness" of "depression". To some degree the reaction is reasonable, since the definition of what clinically constitutes "depression" has been broadened so much that everyone who suffers a personal set-back is now plausibly diagnosable as a clinical case. But the reaction doesn't limit itself to targeting the *abuse* of definitional parameters: it *assumes* their truth because doing so provides more devastating rhetorical ammunition against any person claiming to be diagnosed with "depression". It's essentially an expression of scepticism about the legitimacy of the clinical category itself; and it's usually most crudely summed up by the moralistic belief that people with depression just need to develop more "resilience".
The Pro-Dean of the Law School I attended made a point recently of publically announcing that the pedagogy of the School was to produce "tough" students. That's the kind of student they want. And the Dean of the same School stated that students who are too "precious" just need to learn the life-lesson that "stuff happens" and get over it. And she went into print belittling the students who had registered with disability services, claiming that they were just indolent because "they couldn't drag themselves out of bed" and were inventing psychiatric diagnoses ex post facto as excuses for this indolence.
She may have been right in some cases. The injustice is that everyone is painted with the same broad brush, no matter how serious or intractable their condition may be. And that may well have been her intention. Injustice can be administratively very convenient.
(I've banged on about this personal example, mostly because it's still a wound I'm trying to get over. Apologies for going on about it.)
There are many people of this type in managerial control of our institutions now: they will never be convinced, I don't think, of the thuggishness of their views.
La Rochefoucauld has a wonderful epigram about people of this type; it diagnoses their worship of "toughness" as essentially a function of their vanity:
"We all have stength enough to endure the misfortunes of others".
Pretty damning, I'd say.
> Take care, and good luck.
>
Thanks, Scott, I will. Same to you. And, no, I won't give up.> ----------------------------------------------
>
>
> > > > I found this study of Parnate vs. a combo of Effexor and Mirtazapine which seems to indicate that the combo is twice as effective for MOST treatment resistant patients.> >
> >
> >
> > > This particular arm of the STAR*D study is meaningless.
> >
> > "The mean daily dose at exit for tranylcypromine was 36.9"
> >
> > The low dosage of Parnate used was woefully inadequate to treat depression. Most people don't respond to Parnate until a dosage of 40 - 80 mg/day is reached.>
> >
> > - Scott
> >
> > Scott, this is so well-said, well-spotted, and well-deserving of repeated emphasis.
> >
> > Your observation is instructive because it prompts all of us who are "treatment-refactory" to pay very close attention to the protocols which are appplied in studies purporting to demonstrate the relative superiority of x strategy over y strategy.
> >
> > Last year I was also, foolishly, excited by the discovery of this paper on ven + mirtaz v. tranyl. The excitement was aroused because I simply could not convince, at that time, any psychiatrist to prescribe parnate. (For one psychiatrist, I printed out and indexed a number recent research papers on the drug published since 2000, by eminent and rigorous psychopharmacologists, which supported its efficacy and corrected misconceptions as to its intrinsic "dangers", but to no avail). Rather, the efforts I went to in order to demonstrate the sincerity of my motivation, my desperation, to overcome my depressive illness were interpreted as evidence of a discreditable belief that there exists a "magic bullet" in the form of a mythical drug which will "cure" this illness once and for all. The particular psychiatrist who delivered this assessment (not the same one to whom I had given all the papers mentioned above), quite a senior and apparently reputable one, remarked that I had done more solid research into possible treatments than any patient he had seen before. It was clear that his remark was not intended as a compliment.
> >
> > So my next strategy was to press the merits of the combination studied in this paper. And he was perfectly happy to prescribe the ven + mirtaz combo, though without any understanding of the mechanisms by which it was claimed to have such an effective, and extraordinarily positive, action in treatment-resistant cases. This same psychiatrist refused to consider an MAOI, on reasons which recent research, which should have been known to him if he were scientifically conscientious, has proven to be entirely erroneous.
> >
> > The lesson I learnt from this experience is that, for psychiatrists, while all forms of ignorance may be equal, some are more equal than others.
> >
> > The effect of this combination was (on me) negligble. The (posited) increase in noradrenergic neuro-transmission may have contributed to an acute, and very unpleasant, episode of troublesome anger I went through. Not wholly unsurprisingly given his deficient learning, the psychiatrist who prescribed this very combination refused to offer any constructive advice about this side-effect ("I don't treat side-effects"); I was simply advised to address my concerns to my GP.
> >
> > The idea that this combo's appeal as an efficacious psychotropic with superb anti-depressant properties should be publicised popularly by the moniker "Californian rocket fuel" may well be some evidence for its source as a marketing ploy. I would, however, not wish to dismiss the positive experiences of people who have benefited from it.
> >
> > Any "anti-depressant" benefit from Mirtazapine may in any case arise predominantly as a result of its extremely potent H1 antagonism. The supposition that it is "dual-action" has been pretty much exploded. But I don't possess sufficient learning to draw any conclusion.
> >
> > Scott, you mention the Star*D trials. I agree that no competent psychopharmacologist could possibly assent to the proposition that their outcome has any clinical bearing on the relative efficacy of parnate. The only point I'd make in response is that the majority of psychiatrists, in my experience, are incompetent or barely competent psychopharmacologists; and the supposed definitiveness of the Star*D outcomes is routinely invoked in a knee-jerk and uncritical way whenever MAOIs are raised.
> >
> > I was informed unequivocally by the same psychiatrist whose "advice" I was subject to for eight months last year that, given the trials of medication to which I had been non-responsive or only partially responsive in the past, there was (if I recall correctly) only a 6 - 10% chance (i.e., a pretty negligible chance) that I'd be responsive to anything else. This ex cathedra declaration was made in full awarenesss of, and must therefore have been taken to have incorporated due consideration of, my desire to trial an MAOI. But the idea that Star*D (or any trial using a similar a protocol as regards MAOIs) has anything at all to say about tranylcypromine is unsupportable; indeed, risible.
> >
> >
> >
>
>
Posted by ed_uk2010 on February 14, 2015, at 9:35:12
In reply to Re: Effexor + Mirtazapine MORE effective than PARNATE!, posted by burial on February 14, 2015, at 8:54:45
>According to this study, venlafaxine occupies 60% of NET and it may be that the metabolite, desvenlafaxine gives even more NET.
With venlafaxine, occupancy of NET appears to be a function of the dose. Occupancy is significant at high doses. Occupancy of SERI is high across the entire dose range, and very high at high doses.
>it may be that the metabolite, desvenlafaxine gives even more NET.
The 60% figure should refer to the total occupancy/inhibtion, I would imagine, not occupancy only by venlafaxine itself. Unfortunately, a blood test was used in this study as an estimate of NET occupancy. PET scans provide a better estimate.
>I once read a study that desipramine occupied 80% of NET so it isn't that huge of a difference
I think that's about right. The difference could well be significant though. For SSRIs, as an example, 60% SERT occupancy may be right at the bottom end of clinically effective inhibition. In fact, some studies have suggested that effective SSRI doses usually produce around 80% occupany, with 85-90%+ at high doses. Whether similar percentages apply to NET occupancy is unclear.
Posted by Robert_Burton_1621 on February 24, 2015, at 10:58:12
In reply to Re: Effexor + Mirtazapine MORE effective than PARNATE! » vanvog, posted by SLS on March 12, 2013, at 8:36:26
>this particular arm of the STAR*D study is meaningless.
>
> "The mean daily dose at exit for tranylcypromine was 36.9"
>
> The low dosage of Parnate used was woefully inadequate to treat depression. Most people don't respond to Parnate until a dosage of 40 - 80 mg/day is reached.
>
> http://ajp.psychiatryonline.org/article.aspx?articleID=98116
>> - Scott
Note that the citation in the AJP which Scott links to includes both a letter from critics attributing the cause of the 'disappointing' results regarding tranylcypromine to the sub-therapeutic mean dosage used, and a reply by the authors (McGrath et al) of the venlafaxine plus mirtazapine vs tranylcypromine study, which entirely *endorses* the critical observations contained in that letter.
McGrath explains that the study was not permitted to use dosages beyond the maximum recommended by the FDA, thus they were stuck with a clinically negligible comparator of 36.9 mg of tranylcypromine against a clinically sufficient regime of ven + mirtazapine. It's hardly surprising, then, that a clinical regime was found in its therapeutic effects to be superior to a sub-clinical one. Scott's description of the study as "meaningless" is therefore entirely accurate, as the authors themselves concede (but in a separate, brief note written only subsequent to the publication of their paper).
Posted by FredPotter on April 2, 2015, at 11:24:28
In reply to Re: Effexor + Mirtazapine MORE effective than PARNATE! » Robert_Burton_1621, posted by SLS on February 14, 2015, at 7:10:34
Robert You describe your situation so articulately. I contacted Dr Ken Gillman a few years ago, he of psychotropical research (sic). He's an expert in serotonin toxicity and has had more success prescribing tranylcypromine (Parnate) than anything else. He KNOWS what is safe and effective and finds it frustrating that so much misinformation abounds. Many doctors are afraid to prescribe MAOIs because they think they cause hypertension, whereas in reality they cause hypotension at the effective dose, unless you eat blue cheese spread with Marmite or Icelandic fermented shark, sleuced down with Black Death. I'm about to start mirtazapine after being on Nardil for years. My reason is: while Nardil worked for dep and anx better than anything else I've tried, it didn't quite cut it. The NZ guidelines that my Dr follows have a red square beside the Nardil/mirtazapine combo, meaning very dangerous, so he won't let me do it. Ken KNOWS the combo is safe and effective, but if I want to try it I would have to lie to my Dr until the supply of Nardil ran out. Polypharmacy gives so many opportunities not available in monopharmacy, if there be such a word. About 1 in 4 people will suffer dep and/or anx, in their life so I think my Dr should be more conscientious. He should read the literature like we do. This is not a rare condition we're talking about, and the suffering is very great. I thought a doctor had a calling to save lives and alleviate suffering. Instead doctors are opting for an easier life-style so that they can avoid stress ... rant ... rant
Best wishes
Fred
Posted by FredPotter on April 2, 2015, at 11:54:51
In reply to Re: Effexor + Mirtazapine MORE effective than PARNATE! » vanvog, posted by SLS on March 12, 2013, at 8:36:26
> > I found this study of Parnate vs. a combo of Effexor and Mirtazapine which seems to indicate that the combo is twice as effective for MOST treatment resistant patients.
> >
> > Free full article:
> > http://ajp.psychiatryonline.org/data/Journals/AJP/3775/06aj1531.PDF
>
> This particular arm of the STAR*D study is meaningless.
>
> "The mean daily dose at exit for tranylcypromine was 36.9"
>
> The low dosage of Parnate used was woefully inadequate to treat depression. Most people don't respond to Parnate until a dosage of 40 - 80 mg/day is reached.
>
> http://ajp.psychiatryonline.org/article.aspx?articleID=98116
>
>
> - ScottHi Scott The guide for MAOI dosage seems to be that which causes orthostatic hypotension which gets more pronounced 2 minutes later. I don't know why this should be so. Also some people have said of Nardil that the dosage should be approximately 1mg per Kg body weight per day. I'm 90Kg so I'm lucky. It's tough on people who weigh 120Kg as doctors willing to prescribe 120mg per day are as rare as rocking horse sh*t
Fred
Fred
Posted by FredPotter on April 2, 2015, at 11:55:42
In reply to Re: Effexor + Mirtazapine MORE effective than PARNATE! » vanvog, posted by SLS on March 12, 2013, at 8:36:26
> > I found this study of Parnate vs. a combo of Effexor and Mirtazapine which seems to indicate that the combo is twice as effective for MOST treatment resistant patients.
> >
> > Free full article:
> > http://ajp.psychiatryonline.org/data/Journals/AJP/3775/06aj1531.PDF
>
> This particular arm of the STAR*D study is meaningless.
>
> "The mean daily dose at exit for tranylcypromine was 36.9"
>
> The low dosage of Parnate used was woefully inadequate to treat depression. Most people don't respond to Parnate until a dosage of 40 - 80 mg/day is reached.
>
> http://ajp.psychiatryonline.org/article.aspx?articleID=98116
>
>
> - ScottHi Scott The guide for MAOI dosage seems to be that which causes orthostatic hypotension which gets more pronounced 2 minutes later. I don't know why this should be so. Also some people have said of Nardil that the dosage should be approximately 1mg per Kg body weight per day. I'm 90Kg so I'm lucky. It's tough on people who weigh 120Kg as doctors willing to prescribe 120mg per day are as rare as rocking horse sh*t
Fred
Fred
This is the end of the thread.
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