Hyperadrenergic

[fighting4health]

I was told I don't have hyperadrenergic POTS, but my standing norepinephrine test was over 700. The lab paper did say that I was in the normal range so I don't know if it got overlooked because of that.

I take Welbutrin (SNRI) and it seems to help my symptoms. A couple years ago I weaned myself off of Welbutrin by lowering the dose every 2 weeks. Each time I lowered it I had less fatigue, but then the fatigue would come back. Once I was completely off of it the fatigue came back and stayed. I'm back on it now.

My doctor told me to take the drug in the morning so that I would sleep better, but I've found that I sleep much better when taking it right before bed. If I miss two or more days of Welbutrin I have really bad fatigue and I hobble around and have trouble getting the strength to do anything especially standing. If hyperadrenergic gives you an increase in norepinephrine wouldn't an SNRI make the levels even higher, or does it actually help regulate it?

Has anyone else experienced similar reactions to an SNRI? Does this sound like hyperadrenergic? How is hyperadrenergic treated?

[erik]

Wellbutrin, a dopamine-norepinephrine reuptake inhibitor (DNRI) is on one of Grubb's published lists associated with H-POTS (Table 2 in here)... along with two SNRI's. I heard indirectly of one of his patients being incredibly improved by an SNRI plus aripiprazole (a neuroleptic but also used to augment anti-depressant effects). It is surprising on the surface for sure.

One might speculate that more global reuptake inhibition could prompt counter-regulations that mitigate even an existing inhibited reuptake (as with NET deficiency)... for example, down-regulation of calcium-ion channels that just as critical to neural signals as the neurotransmitters. Some say that prolonged elevation of neurotransmitter presence (activity in the synaptic cleft) can result in long term reduction or antagonization of the receptors that the neurotransmitter binds with (a very direct counter regulation). Maybe whatever makes that happen (if it does) is triggered more centrally rather than in peripheral sympathetic nervous system synapses.

Another way they could theoretically help is by applying a consistent pervasive "pressor" response... perhaps lessening the need for the "overreaction" during orthostatic stress in the first place. Or just as mysteriously as the SSRI's, they might just kind of "shift the regulation" of the autonomic system to partly correct it's misresponse. If one has partial denervation involved in their POTS, maybe they are helped with strengthening the signals in remaining nerves... even at the cost of overexciting some others (but I don't know if the denervation POTS causes would typically give a hyper-adrenergic presentation or not???).

Also, many of these meds effects are shaped by their variable affinity for specific receptors. "Selective" is the first "S" in SSRI... and NRI or DRI or DNRI should be called SNRI, SDRI, SDNRI respectively except for the fact that it would then get confused with SNRI where "S" is seretonin (which should be SSNRI). I'm just trying to say that they tend to be "Selective"... like some beta-blockers are cardio-selective (leaving lungs & brain alone) whereas others are non-selective (and give anxiolytic effect in brain and can aggrivate asthma and such). I don't know how much this selectivity affects wellbutrin and the like, but it is another way they could have this paradoxical benefit amid an already goofed NET situation.

Just some speculations... my pseudo-science... I wouldn't know which, if any, are plausible in reality (or substantiated by much research).

This study might be informative too:

Norepinephrine Transporter Blockade With Atomoxetine Induces Hypertension in Patients With Impaired Autonomic Function

Indeed, blockade of norepinephrine reuptake would be expected to increase neurotransmitter concentrations in the neuro-effector junction, and in the periphery this effect would lead to a pressor response. This mechanism, however, seems to be counteracted by a central sympatholytic action through activation of {alpha}-2 adrenoreceptors (a "clonidine-like" effect).

So theoretically, if the patients' existing disorder involves a NET deficiency specific to beta receptors (which is a finding in some research I think)... an NRI (or DNRI) that also inhibits NET in other adrenergic receptors (or centrally) could arguably bring "balance" even while also mildly exacerbating the original problem.

[firewatcher]

I'm gonna throw a monkey wrench in your thinking: when I had my single horrid day of endocrine testing (it was supposed to be three days) they gave me L-dopa. Almost magically the tremors I'd been having all day were gone and my headache lessened considerably. Then, when this same endo wanted me to start Pristiq (SNRI) for fatigue, my Vandy cardiologist adamantly said "NO WAY!" If I wanted a SSRI that was fine, but no N. Would it be because of the hypertension I exhibit on standing that he said this? Why would a Parkinson's drug that increases dopamine, assist me?

[avidita]

http://www.ncbi.nlm.nih.gov/pmc/articles/P...?tool=pmcentrez

According to this article (see page 4 on Central Hyperadrenergic POTS), POTS patients often exhibit norephinephrine levels of over 600, however, to be considered H-POTS they have to be way higher. Usually over 1000, sometimes as high as 2000.

[kayjay]

I am adding my 2 cents here. My thought is that if your testing showed you were in the "normal" range you really may not have hyperadergenic POTS.

I do and I think regardless of meds in my case there is no doubt. My 24 hour urine collection ( on 3 occasions) showed enough of those hormones that at first I was diagnosed with an adrenal gland tumor.

"Regular POTS" people also can have adrenal surges when your body feels stress, but I just have to stand up. At mayo clinic the neuro had me do 3 squats in his office. I was sweaty, could not breathe, my pulse went sky high- also don't know what my bp was. (I was sorta fit, not over weight). he said I had the typical hyper presentation. My blood test was not in the normal range.

With hyper POTS I think your blood test ( if done properly would show this clearly).

I am with firewatcher- can't have something like wellbutrin- I am on lexapro. I think Avidita is right.

I have wondered if hyper POTS people have larger swings in heart rate? mine has gone from 28 to 90 and also from 60's to 201. We may be more likely to have high blood pressure swings also. I know I do.

[janiedelite]

My supine norepinephrine was 250 and standing was 1089, and the mayo neuro called my mildly hyperadrenergic just to let you know. My heartrate usually doesn't go above 150 when I stand. When my BP spikes, my heartrate is often 60 lying and standing strangely enough, but it's during these times that I feel absolutely horrible.

[Guest tearose]

They need to do the blood testing on you to see the numbers and preferably when you have been off meds for awhile. Also, keep off your compression garments for 72 hours.

My supine norepinepherine was 260 and my standing was in the 1400's. I get spikes of surges and I am use to these. I do a lot of behavior modification. I manage without medications.

I pace myself, wear compression and sit when I feel the surge starting to build.

My surges usually precede an SVT and I don't want to go there. I feel fortunate that I have been able to learn how to manage without medication because I have terrible side effects. I don't have to deal with meds wearing off, becoming tolerant to them or having damage of any sort from them.

[erik]

It is an interesting point of contention between experts (if that's what's going on, I'm not really sure). Using my "dissociative skills" as a tool rather than a deficit, and projecting myself to an out-of-body experience (an extreme derealized state)... I can place myself carefully as a fly-on-the-wall in Dr. Raj's lab and perhaps even read the minds of the Vandy folks (a little "remote viewing" a. la. staring at goats). I am doing this now and this is what I hear them saying:

Both we and others have found that pharmacological NET inhibition can recreate an orthostatic tachycardia phenotype in susceptible healthy volunteer subjects. Yohimbine, a central alpha-2 antagonist that will also increase synaptic norepinephrine, can also cause orthostatic tachycardia.

An I'm getting the "vibe" that this makes them leery of prescribing anything that can induce in "healthy" what is already present in a patient... on assumption that it will exacerbate it.

I also hear them saying something about regular pots being plasma NE >600 and Hyperadrenergic being >1200 or so...

As I fly through space & time and eavesdrop on the Cleveland folks, it seems they're saying H-POTS is indicated by NE >600 (hmm, a different definition it seems), urinary urge from prolonged standing, significant tremor, anxiety, cold sweaty hands, and such. And that after being so bold as to still try NRIish meds (after all, most POTS meds are paradoxical or mixed-result sort anyway) actually found success with them.

This latter conclusion about clinical success is mostly my mind-reading, which quite error prone to say the least... whereas the former just happens to coincide with some references (Raj and Grubb basics) also available via the internet... which sadly put me and my "remote viewing" skills to the redundancy-bin some years back. Oh well.

[ramakentesh]

Every research body has a different definition and none of them really mean anything. Ultimately hyperadrenergic POTS is simply where the pressor response to standing is considered the primary problem rather than a hyperadrenergic response to abnormal pooling or vasomotor failure.

According to this article (see page 4 on Central Hyperadrenergic POTS), POTS patients often exhibit norephinephrine levels of over 600, however, to be considered H-POTS they have to be way higher. Usually over 1000, sometimes as high as 2000.

Actually, no they just have to be above 600pmol according to Blair Grubb at Toledo and Robertson, Raj et al at Vandy. But this is a pretty arbitrary amount given the evidence and mechanisms involved in hyperadrenergic POTS are speculative and as one doctor recently said 'there is certainly room for other theories.'

As examples:

Postural Tachycardia Syndrome - the MAYO experience:

'RESULTS: We identified 152 patients (86.8% female; mean ? SD age, 30.2?10.3 years) with a mean duration of symptoms of 4.1 years. The mean orthostatic heart rate increment was 44 beats/min. Half the patients had sudomotor abnormalities (apparent on both the quantitative sudomotor axon reflex test and thermoregulatory sweat test), and 34.9% had significant adrenergic impairment, indicating that at least half of the patients had a neuropathic pattern of POTS. In 13.8% of patients, onset was subacute, and ganglionic acetylcholine receptor antibody was detected in 14.6%, suggesting an autoimmune origin in at least 1 in 7 patients. Hyperadrenergic status was documented in 29.0% of patients (standing plasma norepinephrine level ≥600 pg/mL), and at least 28.9% were presumably hypovolemic (24-hour urinary sodium level <100 mEq/24h). The lack of correlation between urinary sodium and standing norepinephrine levels suggests that mechanisms other than hypovolemia accounted for the hyperadrenergic state.

CONCLUSION: Our findings suggest a neuropathic basis for at least half the cases of POTS and that a substantial percentage of cases may be autoimmune. Hyperadrenergic and hypovolemic correlates are likely compensatory or exacerbating.'

In other words Hyperadrenergic states in POTS may just be another coping mechanisms for abnormal venous or circulatory control.

[ramakentesh]

deleted.

[erik]

"Actually, no they just have to be above 600pmol according to Blair Grubb at Toledo and Robertson, Raj et al at Vandy."

Hey, wait a minute! From Raj article:

While we require the upright norepinephrine level to be >600 pg/ml for the diagnosis of POTS, the hyperadrenergic subgroup often has upright norepinephrine level >1000 pg/ml and it is occasionally >2000 pg/ml. These patients sometimes have large increases in blood pressure on standing, indicating that baroreflex buffering is somehow impaired.

At that time at least, Raj said >600 for any POTS, even higher is associated with H-POTS, just as avidita said.

From Grubb article:

A second (and less frequent) form of POTS is termed the "hyperadrenergic" form. These patients often describe a more gradual and progressive emergence of symptoms over time rather then an abrupt onset. Patients with hyperadrenergic POTS often complain of significant tremor, anxiety, and cold sweaty extremities while upright. Over half of these patients experience migraine headaches as well as a significant increase in urinary output after being upright for only a short period of time. A characteristic of this form of POTS is that patients will often display orthostatic hypertension in addition to orthostatic tachycardia. Many will also have an exaggerated response to intravenous isoproterenol, as well as significantly elevated serum norepinephrine levels (>600 ng/mL) on standing. The disorder often has a strong family history. A study by Shannon et al found that some patients have a single point mutation that produces a poorly functioning reuptake transporter protein that recycles norepinephrine within the intrasynaptic cleft. This process leads to an excessive degree of norepinephrine serum spillover in response to a number of sympathetic stimuli, producing a "hyperadrenergic" state (similar to that seen in pheochromocytoma).

So in that case, the bar of for H-POTS is just 600... which had been the bar for regular POTS in the Raj (a.k.a. Vandy) article. Are these superseded by new publications? Even if so, probably plenty of GP's & Cardios are going to have varying perspectives, based on what they "happen to read", what fits their general style, how they feel about contravening insurance provider policies or peer scrutiny or liability issues (or FDA scrutiny), blah blah. Not to mention (perhaps last of all), their personal medical opinion on the complexities!

"As for SNRIs - ive never heard of Dr Grubb recommending them."

Hey again. Note the acknowledgment in prior citation of the NET issue. An autonomic specialist would be aware that overstimulation (with or without compounding NET inhibition and hence extra clearance from cleft) means more spillover (one presumed cause for serum elevations). In that very same Grubb article, in the list of pharma options associated with "H" variety... 3 of the 5 drugs are NRI's+ (including Wellbutrin). The NRI recommendation was not made in ignorance of (nor prior to) the over-stim & under-reuptake issues. Why it was made isn't clear in things I have thusfar managed to find via the web (or my "remote viewing" This fits your situation reasonably well, right fighting4health?

Perhaps this jibes with trends of clinical successes that Grubb has observed from his unique vantage point??? One would like to assume this was key when publishing a "clinical guidelines" document. (As always, individual patients vary greatly, particularly in the POTS population) I tend to be encouraged by "diversity of ideas" across experts... I think it is how complex things are resolved by complex systems... a top-down unified policy would shut down research progress (as would too much sheltering from peer scrutiny).

Take the "simple case" of prozac. It is an SRI, which means the serotonin is left in the cleft (it's active region) longer giving more umph (an 5-HT "up" regulation of sorts). Over the course of a few weeks, the body counters and down-regulates... which is "coincidentally" when the therapeutic effect comes in... in the resultant "down" regulation, not the initial & continual "up". The initial dosing phase is ironically more associated with aggravation of the targeted symptoms (sometimes even calling for a temporary use of a benzo, or concomitant use of buspirone or who knows what... just extreme patience to bridge this unfortunate gap). It gives a peek at behind the scenes complexity (and enthusiasm for even better future meds though RI's tend to strike the best overall balance, currently).

It would make sense that other reuptake inhibitors (of different neurotransmitters and with different selectivity profiles) like NRI's & DRI's (and maybe even loosely similar things like Mestinon... sort of like an acetylcholine-RI, right) could have similar "paradoxical" effect.

Some of these things might explain how wellbutrin could help even in light of existing "adrenergic" excitement & spillover (no matter what extent). Your "sleep enhancing" rather than "insomnia inducing" reaction (prompting you to have better result with night dose rather than morning) might be a clue that your body, for whatever reason, is one that enjoys the paradoxical more than the direct. Seems to be "the norm" with POTS in many cases! I don't think I'd be surprised to hear one day that even a vasodilator or a diuretic could be simultaneously helpful somehow... hmm.

It is a wild world in the body!

[ramakentesh]

its confusingly common for research bodies to contradict one another.

here is another interesting read:

http://www.mc.vanderbilt.edu/root/vumc.php...dc&doc=4788

The hyperadrenergic subgroup of OI is characterized by a clinical spectrum including attenuated plasma renin activity and aldosterone, reduced supine blood volume coupled with dynamic orthostatic hypovolemia, elevated plasma norepinephrine and epinephrine, impaired clearance of norepinephrine from the circulation and evidence of partial dysautonomia. When the upright posture is assumed, there is a loss of plasma volume from the blood into the surrounding tissue. In normal subjects, about 14% of the plasma volume may leave the blood within 30 minutes of standing. This loss of plasma volume into interstitial tissues is greatly enhanced in patients with OI; occasional patients will lose more than twice this amount of fluid. It is little wonder such patients with supine hypovolemia to begin with develop symptoms in a setting of this excessive dynamic orthostatic hypovolemia. Normal subjects reduce urinary sodium excretion on assumption of upright posture, but patients with OI do so ineffectively. This probably contributes to the severity of their hypovolemia. In patients with florid symptoms of orthostatic intolerance in a setting of hypovolemia and increased plasma norepinephrine, several interesting findings emerge. The plasma renin activity and aldosterone are generally slightly reduced in proportion to the degree of the hypovolemia. This suggests that the reduced renin level may be responsible for the hypovolemia. It is possible that impaired sympathetic innervation of the juxtoglomerular apparatus in the kidney may underlie this renin deficit.

Work out what that means...

[erik]

Boy, I don't know. Dopamine happens to be key to leaky vein processes though. Just a tidbit. No rule to say that Wellbutrin would do anything specific with that. A surface temptation would be to say "enhance dopamine" --> "reduce vascular permeability"... but as always there's little reliability to "surface" analysis like that. Might be meaningful clue nonetheless. Elsewhere, like in key dopaminergic pathways of the brain, one gets enhanced dopamine effect by manipulating other things (serotonin, GABA, opioids, and such). But maybe in the endothelium this is not so in matters of permeability regulation... maybe things are more simple & direct there.

Not sure what to say about renin-angiotensin-et.al. stuff. Like with SSRI's one is tempted to focus on things in top-level regulatory centers of the brain, trunk, hypothalmic stuff, etc. The generic concept of "resetting autonomic processes" can apply to D & N just as it can to SRI use. In the Medula Inna Godda da Vida and whatnot... Iron Butterfly would probably know a thing or two about this

I'm tempted to view the "spillover" excess as though it is a misbehaving endocrine gland or secreting tumor. This is the neurohormone turning from the neurotransmitter into the hormone (in levels & timings not normally present)... as opposed to being mostly secreted in proper regulatory cycle from a well controlled gland. I'd call it a neuropseudopheochromocytoma or pseudoneuroparaneoplasticism perhaps! A cute idea... a different angle on what is commonly mentioned, but with different phrasing that helps one draw analogy & help "Work out what that means"! Interesting that POTSies can "look a bit" clinically like some of these more direct endocrine disorders. I do better playing with the "big blocks", the baby LEGO's... since that's where I'm at compared to a researcher, who has the cool big-boy LEGO kits to play with (knowledge & tool wise)!

Your description of the weening & night dosing are neat to contemplate, fighting4health. There's always room for counter-intuitive things, like "Low Dose Naltrexone" which is theorized to boost opioids by blocking them (temporarily, since a low dose is cleared quickly). Things that get boosted by a med can then go lower later. A night dose of Wellbutrin might set up a day with less sympathetic activity. Hard to say... just fun to speculate about. Bottom line is clinical effect, especially since one is treating symptoms and not going for cure. That can mean a drug need have nothing directly to do with an underlying pathology, theory, body part, etc.

The "weening" pattern that you note happens to match the timing of the "adaptive" phase of reuptake inhibitors in general. Like SSRI's take a couple weeks for the body to "counter the drug" it is likely to be similar with SNRI & DNRI... and apply to escalating and dropping alike. Maybe your night dosing is setting up a "mini ween" during the day... and that's the "benefit period for you" just as your longer "ween" indicates. So maybe you've found a "working cycle" as opposed to a working "steady state". A cycle shift like that would be finicky to dosage... too much or too little might mask such potential benefit easily.

I have some "natural cycles" in which I operate best and balanced. Losing weight cycle (steady slight caloric deficit) and warming body cycle (being in moderately cool weather). Both of those make simple sense as far as when the body would "permit activity" and when it would "impede it" and they are my best "fatigue correlating factors" I've found to date. They feel like "my body metabolism shifting itself" and getting functional rather than bogged. Neither of those can be maintained forever. I'd like to be able to trick my hypothalmus (or whatever) into keeping that cycle steady and remove my heat & metabolic intolerance phases. Maybe a med could do that for me.

[prettyinpink]

I'm gonna throw a monkey wrench in your thinking: when I had my single horrid day of endocrine testing (it was supposed to be three days) they gave me L-dopa. Almost magically the tremors I'd been having all day were gone and my headache lessened considerably. Then, when this same endo wanted me to start Pristiq (SNRI) for fatigue, my Vandy cardiologist adamantly said "NO WAY!" If I wanted a SSRI that was fine, but no N. Would it be because of the hypertension I exhibit on standing that he said this? Why would a Parkinson's drug that increases dopamine, assist me?

I did some research for you and found that snri increases the release of norepinephrine and people with hyperadrenic pots have way too much norepinephrine being released. Also, the L-dopa and tremors issue seems more complicated. Significant loss of dopamine or decreased sensitivity to the dopamine receptors can cause tremors and L-Dopa can help. In hyperadrenic pots tremors are caused by excess adrenalin and noradrenalin. maybe the L-Dopa is able to make dopamine that can inhibit the tremor despite its cause??

[erik]

That's a good point. Norepinephrine is "made from" dopamine. One way to "lose dopamine" is for the body to be way to busy pumping out norepinephrine instead of leaving as much of the dopamine alone to just be dopamine. Since so much norepi is washing away from synapse into the blood the body has motive to do this... and to "work the adrenals" harder on a regular basis making the precursors (unless endogenously supplemented).

Dopamine could be underpresent it select places it seems. I wonder if this is an observation in any studies? If it were underpresent in spots that regulate motor control (perhaps influencing ion channel thresholds) it seems like a tremor inducer. If underpresent in endothelium neuroregulation, it would cause leaky veins by failing to inhibit Vascular Permeability Factor.

Is this indicated/contradicted in any some studies or facts out there?

[firewatcher]

That's a good point. Norepinephrine is "made from" dopamine. One way to "lose dopamine" is for the body to be way to busy pumping out norepinephrine instead of leaving as much of the dopamine alone to just be dopamine. Since so much norepi is washing away from synapse into the blood the body has motive to do this... and to "work the adrenals" harder on a regular basis making the precursors (unless endogenously supplemented).

Dopamine could be underpresent it select places it seems. I wonder if this is an observation in any studies? If it were underpresent in spots that regulate motor control (perhaps influencing ion channel thresholds) it seems like a tremor inducer. If underpresent in endothelium neuroregulation, it would cause leaky veins by failing to inhibit Vascular Permeability Factor.

Is this indicated/contradicted in any some studies or facts out there?

Am J Physiol Heart Circ Physiol. 2007 Jul;293(1):H684-90.

Dopamine-beta-hydroxylase in postural tachycardia syndrome.

Garland EM, Black BK, Harris PA, Robertson D.

Autonomic Dysfunction Center, AA3228 Medical Center North, Vanderbilt University, Nashville, TN 37232-2195, USA. emily.garland@vanderbilt.edu

Norepinephrine is frequently elevated in postural tachycardia syndrome (POTS), a syndrome of heterogeneous etiology characterized by a >30 beats/min increase in heart rate with standing. Norepinephrine is synthesized from dopamine by dopamine-beta-hydroxylase (DBH). The results of a preliminary study suggested that the T allele frequency of the DBH -1021C-->T polymorphism is elevated in POTS. This allele correlates with low DBH activity and might predict reduced serum DBH activity in patients with POTS. To test the hypothesis that low DBH activity and the underlying -1021C-->T polymorphism are associated with increased susceptibility to POTS, we measured serum DBH activity in POTS and determined its relationship to the DBH genotype and plasma norepinephrine. Serum DBH was similar for 83 normal volunteers and 42 patients with POTS: median (range) = 22.5 (0.5-94.2) and 19.6 (0.1-68.8) nmol.min(-1).ml(-1), respectively (P = 0.282). The genotype frequencies for 254 control and 157 POTS patients were not different between groups ( approximately 63% CC genotype and approximately 5% TT genotype, P = 0.319). The T allele associated with lower serum DBH in both groups [control serum DBH = 15.7 (SD 12.3) and 35.1 nmol.min(-1).ml(-1) (SD 18.6) for T carriers and noncarriers, respectively; POTS serum DBH = 8.2 (SD 5.6) and 28.5 nmol.min(-1).ml(-1) (SD 14.7) for T carriers and noncarriers, respectively]. High DBH in POTS was linked to elevated plasma levels of norepinephrine. Although DBH activity and genotype are unlikely to be primary determinants of susceptibility to POTS, differences in DBH activity in POTS may reflect differences in the level of sympathetic activation.

PMID: 17625104

Chicken or egg?

[ramakentesh]

presumably from NET disfunction as it is partially responsible for dopamine reuptake. The author of that study is currently examining dopamine activity in the kidney of pots patients.