Alpha 2 adrenergic receptor blockade - saturation??

[JohnBoy2000]

How exactly would it be possible to tell how to fully saturate this receptor?

The two clinically available alpha 2 blockers are - remeron, and it's sister, Mianserin.

As it happens - Mianserin does have a weak NRI base also, so, I've found, for me - when combined with a potent NRI in reboxetine, it's exaggerates this.

Only problem is, I take Mianserin at night, as it's also a hypnotic, so - activation plus sedation.
I sleep restlessly for three hours, wide awake - then by morning - I'm totally wasted for the next day.

I don't ever recall getting that whilst taking mirtazapine so, I'm attributing the activation to the NRI property.

Though, it may also be the negation of the auto inhibition feedback loop - but - like I said, I never got that on remeron so...


In any case - my concern is raising the NE levels as high as possible so, I would theoretically like the auto inhibition feedback loop cut completely - via alpha2 receptor blockade saturation.

Now - in terms of the dosing of Mirtazapine vs Mianserin - Mianserin goes twice as high at 90 mg.
Though I could only ever tolerate 60mg, and more recently - just 30 mgs.

So, 30 mgs is the starter dose - I'm assuming saturation is gonna be a ways off there.

However - Mianserin is reputed to be a stronger noradrenergic that remeron - due to its alpha 1 blockade also, negate 5 HT release.


I suppose my question here is - how potent is Remeron on the alpha 2 receptor blockade, at its maximum dose of 45 mgs??

Saturation potent?

Are there any academic papers that would yield such information - and where might I find them?

 

[Cotcha Yankinov]

Max dose of Mirtazapine is 45mg? I thought it was at least double that.

But you could look at radioligand PET studies to determine receptor occupation, that won't necessarily tell you that much about the physiological response though. At some point the physiological response will be saturated, or a biphasic effect will take over.

 

[JohnBoy2000]

I had difficulty getting studies with the keywords "PET radioligands" - however - micro dialysis does seem did yield some info:


The effects of three compounds with alpha-2 adrenoceptor antagonistic properties, mirtazapine (Org 3770; Remeron), mianserin and idazoxan, were measured on hippocampal noradrenergic and serotonergic transmission in freely moving rats by using microdialysis.
Dihydroxyphenylacetic acid (DOPAC) was measured as a correlate of noradrenergic presynaptic activity. Infusing 1 microM tetrodotoxin decreased extracellular serotonin (5-HT) and DOPAC by 65 and 40%, respectively. 5-Hydroxytryptophan (25 mg/kg s.c.) increased extracellular 5-HT by 500%, whereas 8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (0.5 mg/kg s.c.) decreased 5-HT release by 60%.
Prazosin decreased 5-HT release to 60% of base-line in agreement with an alpha-1-mediated control of 5-HT transmission, whereas it increased DOPAC release with 80%.

Both mirtazapine (2 and 5 mg/kg s.c.) and idazoxan (1 mg/kg s.c.) caused a rapid increase in DOPAC by up to 80%. Mianserin slowly increased DOPAC, reaching a maximal increase of 30 and 60% at 2 and 5 mg/kg s.c., respectively. Only mirtazapine caused a concurrent increase in 5-HT, reaching up to 80% above base-line within 60 min, whereas mianserin and idazoxan failed to change 5-HT levels significantly.

Mirtazapine (5 mg/kg s.c.) only slightly affected DOPAC and homovanillic acid levels in the striatum, hardly affected 5-HT release, but clearly increased 5-hydroxyindole acetic acid.

Thus, the antidepressants mirtazapine and mianserin markedly differ in their effects on noradrenergic and serotonergic transmission in vivo as measured with microdialysis in freely moving rats.
These differences are explained by their different modulatory effects on noradrenergic transmission.


Apparently - Mirtazapine raises noradrenergic levels more profoundly than Mianserin - which is surprising but - concerningly, does not seem to increase noradrenergic levels in the striatum.

The lack of increase in striatal monoamines - what it means?
Reduced efficacy?

I'm not particularly familiar with the variations in effects depending on brain areas implicated.

Mianserin increases NA to 60% at 5 mg/kg, slowly.
Mirtazpaine increases NA to 80% at 5 mg/kg, rapidly.

Which would indicate that, 45 mg remeron is prob significantly stronger at increasing NA at 45 mg, than Mianserin at 30 mg - which is not really what I would have thought, given Mianserin act exclusively on noradrenaline.
I though I did read somewhere though, that it does have a lower bioavailability than remeron, which possibly explains why it's dosed that much higher.

Does that sound/look about right?

 

[Cotcha Yankinov]

Mirtazapine's 5-HT2C inverse agonism can also have effects on the midbrain, I believe even by binding the PFC it can alter activity in the midbrain (although 5-HT2C is expressed everywhere). 5-HT2C is supposedly the most populous 5-HT receptor.

Another thing to consider is that a2 is not entirely pre-synaptic, I believe it's also expressed post synaptically on pyramidal cells in the cortex where it plays some role in executive function. Which is part of the theory for clonidine for ADHD.

So even though clonidine will be acting to decrease neurotransmitter release when it is binding to autoreceptors, at some point that won't matter as much because it can just bind directly post synaptically. There could be a biphasic effect there, a certain threshold that needs to be reached before the post synaptic binding outweighs the autoreceptor binding that inhibits cell firing.

 

[JohnBoy2000]

Yes I believe alpha 2 is post synaptic or "central" also - but I browsed a study that mentions remeron having a much lower, to null affinity, for post synaptic alpha 2 receptors, in contrast to high affinity for pre-synaptic.
How that works - I'd love to know.

If it did block this potently - wouldn't that negate the positive implications of increased synaptic noradrenaline?
I mean cause, it can't exert downstream effects without binding to a post-synaptic receptor.
So it's either alpha 1, or 2 - or one of the 3 subtypes for each.
But - I haven't come across mention regarding which subtype activated relates to it's AD properties - unlike most recent, as yourself Cotcha posted - 5HT2B, seems specifically the subtype responsible for serotonergic AD properties.

 

[JohnBoy2000]

Mianserin increases NA to 60% at 5 mg/kg, slowly.
Mirtazpaine increases NA to 80% at 5 mg/kg, rapidly.

But at the moment anyways I'm depending on this piece of information, as a means to determine which drug would be more potent.
As I can tolerate only 30 mg mianserin.
As oppose to 45 mg mirtazapine.

At similar doses, Mirtazapine seems to raise NA levels by an additional 20% - so with another 50% to that dose (45 mg vs 30 mg) - it should be quite a bit stronger than mianserin.
You know - theoretically.

After a month or six weeks - I'm thinking I might just throw the 30 mg mianserin back into the mix, to see what effect it might have.

I believe, as I mentioned, it's NRI property induces stimulation, at night time - re-activated or reinforced, as it were, by the strong NRI property of reboxetine (but not in mono therapy).
So - I haven't found any academic data on anything remotely like that - so I'll be conducting my own one man clinical trial to make a determination.

 

[Cotcha Yankinov]

I found a PET occupancy study for you, for whatever it's worth https://www.ncbi.nlm.nih.gov/m/pubmed/17653532/

The issue with using a non-specific ligand like mirtazapine to test against radiolabeled mirtazapine is that we don't know whether it's occupying a2 vs. 5-HT2C vs. histamine, so I couldn't find anything specific to a2 occupation (assuming there is a ligand selective for a2?)

RE: mirtazapine preferentially binding to pre synaptic autoreceptors - many of these receptors that are both pre and post synaptically expressed like 5-HT1A may appear to be predominantly presynaptic, but there seem to be situations where different receptor populations are in the low affinity state (not coupled to G-proteins) vs. high affinity state, which will give rise to preferential binding pre vs. post synaptically

This could create another situation where binding occupancy doesn't = physiological response, and decoupling of post synaptic e.g. 5-HT1A receptors can be a problem in MDD apparently. Another example here is pindolol which "preferentially" blocks 5-HT1A autoreceptors (somatodendritic)

The other thing to consider is that the post synaptic a2 may be positioned to create a much stronger response or categorically different response when activated or blocked, so we may not be able to go off of pure concentration of NTs here if we're talking about post synaptic a2 in the cortex.

 

[JohnBoy2000]

Yeah it seems using them search tools is an artwork in itself.

I was also looking forever for a paper on the comparison between noradrenergic enhancement in NRI application, versus, NRI with the autoinhibitory feedback loop nullified - i.e. with an alpha 2 blocker.

In the course of things, I happened to find a study like this in the past but, didn't bookmark it at the time and now - I can't for the life of me find it.

I do recall the information was something to the effect of, "NA levels increase 200% with the NRI, but 1500% with at addition of the alpha 2 blocker".

There's loads of material, in books etc - that claims this; "stepping on the accelerator, cutting the break cable etc", but not much in the way of giving actual percentiles of the NA increase.

 

[Cotcha Yankinov]

I think in vivo microdialysis studies are expensive.

But there could be more to NRI and a2 antagonism than NE. As an example we have NRI affecting dopamine in the PFC, and a2 receptors post synaptically on non-adrenergic cells, and a2 blockade presynaptically also increasing 5-HT concentrations.

Mirtazapine further complicates things because 5-HT2C can inhibit NE/DA cell firing.

But re: search engine, you'll probably have more luck searching through PubMed about a2 receptor physiology rather than e.g. Mirtazapine

https://www.ncbi.nlm.nih.gov/m/pubmed/12670699/

I know you love to tunnel vision on NE, but a2 receptors regulate other things and NE would be relatively useless unless NE could affect other cell types, thus adrenergic receptors have to be expressed on other cell types.

 

[JohnBoy2000]

I know this isn't the exact purpose of bluelight, but if I may - I'm just gonna do a temporary blog here cause, this combination is so up and down - just to keep track of things.

Yesterday, combo was

8 mg reboxetine
45 mg remeron

Insomnia bad, and woozy feeling the next day.
I had started the remeron 7 days previous, so its therapeutic effect was probably still coming into play, thus, the days previous, the NA levels were not such to induce insomnia etc.

Last night, down to

30 mg remeron.

Insomnia still - took a zopiclone - but a better feeling today.
That would indicate to me that, NA levels may still be too high.

Given that I felt, probably best, within the first two/three days of commencing remeron - it was primarily an anti histamine whicih assisted sleep, and the alpha 2 mediated noradrenergic enhancement had not taken hold.

Thus, as it's therapeutic effect kicks in, the excess NA proves a hindrance.
Thus, I taper to maintain the anti-histamine effect, but reduce the alpha 2 block/NA enhancement - and hopefully get the necessary balance of NA.


Now, the issue is, I don't have specific figures to rely on but - that would kind of infer that 8 mg reboxetine raises NA levels sufficient to alleviate my symptoms, without further augmentation.
Possibly.

Would 15 mg mirtazapine really induce any kind of noradrenergic enhancement??

 

[Cotcha Yankinov]

For me 15mg Mirtazapine is mostly an antihistamine, and histamine can inhibit the wakeful NE projections like the tuberomammillary nucleus. But I imagine there is some appreciable 5-HT2 blockade/inverse agonism that becomes more and more noticeable at 30mg+

I guess I wouldn't undervalue the 5-HT2C inverse agonism aspect of Mirtazapine

See
https://bmcneurosci.biomedcentral.com/articles/10.1186/1471-2202-13-65

"For example, systemic administration of the 5-HT2C inverse agonist SB 206553 (SB206) enhances dopamine (DA) efflux in the nucleus accumbens and striatum in rats [8], whereas an agonist either decreases or has no effect on accumbal and striatal DA [8, 23, 24, 25, 26, 27]. Supporting a role of constitutive activity in this effect, the SB206-induced effects were verified to occur independent of endogenous 5-HT [8].

We previously revealed that the atypical antidepressant, mirtazapine, attenuates methamphetamine (meth)-induced sensitization [28], place conditioning [29, 30, 31], and seeking [31] in rodent models of human substance abuse. Mirtazapine historically has been considered to be an antagonist at 5-HT2C and other receptors [32, 33, 34]; however, more recent studies indicate its action as an inverse agonist at constitutively active 5-HT2C receptors [35, 36].

 

[JohnBoy2000]

In terms of 5HT2C inverse agonism, I will say - well, one of it's properties is supposedly an increase in appetite - and at 90 mg mianserin, it was noticeably stronger than Mirtazapine in that sense - but not necessarily more activating or, inducing effect synonymous with noradrenergic enhancement.
At least not more than mirtazapine.

In that sense - whilst I'm sure they are relevant, personally - I would prioritize effects on the transporter etc.

From that point of view - I did try 15 mg of mirtazapine - and a marked reduction in somnolence and restfulness was very apparent.
i.e. not the desired effect, as I had thought reducing the alpha 2 blockade would reduce noradrenergic levels such that they would not incite sleep disturbance.


Studies seem to show that, or insinuate at least, via other experimental alpha2 blockers, that they don't exert huge noradrenergic enhancement on their own - but in tandem with a transporter blocker - vastly enhance NE levels.

One such study:

http://onlinelibrary.wiley.com/doi/10.1038/sj.bjp.0702926/full

outlines the percentage increases clearly - with and without the alpha 2 blocker.

It postulates that, alpha2 desensitization may occur with prolonger NRI use, further enhancing efficacy.


In any case, the next step to take for myself is, maintain the strong alpha 2 blockade via 30 mg mirtazpine - and tailor back the NRI from 8 mg, to perhaps, 6, or 4 mg.

The objective being - trying to strike the balance between sufficient enhancement for symptom alleviation, but not so much as to incite sleep disturbance (which ruins me energy wise and counters any symptom alleviation).


But them percentages -

250% increase with NRI alone, to

1500% increase, NRI with alpha 2 blocker - certainly highlight it being an essential mechanism.

Unfortunately it doesn't elaborate how exactly to tailor the % increase, re: proportional dosages of the NRI based drug, vs alpha 2 based drug.

I'm thinking though - if alpha 2 mediated NE enhancement in monotherapy is negligible - then perhaps the NRI dose will be the controlling factor.

 

[JohnBoy2000]

Curious also that, desipramines NRI effect - seems markedly different from reboxetines NRI effect - on myself at least.
In that the latter, being - more effective, better symptom alleviation.
Perhaps that's more relative to reboxetines selectivity but - it's definitely more activating, less sedating - and more pure in terms of the characteristic effect or noradrenergic enhancement - as oppose to desipramine, which is a contradiction; activating and sedating etc.

 

[Cotcha Yankinov]

A lot of the older tricyclic era drugs also have antihistamine/anticholinergic/adrenolytic actions too

But definitely prioritize your sleep. One possibility is that you could take adrenolytics at night, if it's not the 5-HT keeping you awake. E.g. Propranolol

Have you tried Amitriptyline? Sorry I forget

 

[JohnBoy2000]

Adrenolytics?
Does amitriptyline fall into that class??
Adrenoceptor blockade, enhancing noradrenaline.

Beta blockers to counter adrenergic enhancement?
Is that a clinically tested route?

Never tried either.
The only tricyclic I've ever been on is Lofepramine (desipramine pro-drug).
Possibly Mianserin - but more of a tetracyclic.

I've tapered the Reboxetine to half, at 4 mg, today.
So, how my somnolence is affected tonight, will be interesting.

When I was on lofepramine and mianserin - I introduced Reboxetine at 2 mg for a week, and within a couple of days, my sleep had definitely improved.
Only, when I upped the dose more so, then it went to hell.

That would possibly allude to some middle ground being there.

I tend to "load" early, to try and speed along the therapeutic effect, as oppose to the normal psychiatric advice to slowly increasing the dose after several weeks.
Then reach a point where I have to tailor back.
I guess I'm at that point now.

30 mg mirtazapine
4 mg reboxetine.

Although, regardless of the outcome, a beta blocker is something i wouldn't mind trying.
I get CRAZY high blood pressure, heartbeat etc, when I have to do public speaking etc.

 

[Cotcha Yankinov]

Well amitriptyline is classically known as a better AD for people with insomnia, it can be sedating. It supposedly has the highest average efficacy for MDD

It has some sympatholytic actions, particularly blocking a1 adrenergic receptors. But there would also be something like Prazosin for a1 antagonism.

I'm not sure about propranolol being used to treat NRI related insomnia (most clinicians would probably adjust the medications so that wasn't a problem) but people have used it to come down and sleep after amphetamines


Have you tried any of the mood stabilizers, like Lamotrigine or Depakote?

 

[JohnBoy2000]

Anticonvulsant indicated agents would for sure be something that I would have sidestepped.

But they put me through the ringer of a-typical anti psychotics initially - all of which were effectively useless to me.
Mild and short lived 5ht2c blockade with olanzapine, fractionally beneficial perhaps.

Lofepramine accelerated my heart rate, so I shudder to think what amitriptyline would do.


Sci hub really came through for me, got the full text article:

http://jpet.aspetjournals.org.sci-hub.cc/content/277/2/852

Last paragraph on page 7 has the scoop.

Which seems to strongly suggest that, certainly at equal doses - mirtazapine is significantly more potent at NE enhancement.
Mianserin is dosed higher - but I could only tolerate 60 mg.
According to the percentages - 45 mg remeron, would raise NE the same as 60 mg mianserin....


However, the increase was modest and by no means comparable to the effects of mirtazapine or idazoxan, suggesting that the autoreceptors are not fully blocked after treatment with mianserin. Because both mirtazapine and mianserin are equipotent as antagonists of these receptors, the weak effect of mianserin on extracellular DOPAC cannot be explained by poor affinity for atpha-2 autoreceptors (de Boor et at. , 1988). Thus, mianserin only moderately enhances noradrenergic transmission both in terms of increases in extracellular NE as shown by Itoh et at. (1990) and presynaptic noradrenergic activity (measured as DOPAC level) as shown in this study.


Basically seems to infer that - "we don't really know how it works", what with them both having full alpha 2 occupancy, yet yielding different results.

 

[Cotcha Yankinov]

Are they both full antagonists? It's common for some antagonists to be really weak partial agonists. This would add another dimension to the equation, in addition to the dimension of affinity/occupancy. One could also be more of a silent antagonist while another could be more of an inverse agonist.

Affinity is also boiled down to Ki but I wouldn't be surprised if exact binding mechanics yield different results, the non a2 targets aside (which will certainly affect results even if there is maximal a2 blockade).

There is also the issue of a2 subtypes. It appear 90% of a2 is a2c, and this is the predominantly relevant receptor for Mirtazapine's action.


I'm not quite sure why you dismiss mood stabilizers so quickly - lamotrigine sees great use in depression, especially particular subtypes. They are a unique class of drugs - your responses to any other class of drugs could not predict your response to mood stabilizers. Lamotrigine in particular is very unique.

 

[JohnBoy2000]

Regarding the Alpha focus being primarily alpha 2c subtype - did you get that info from a paper or book or such?

I haven't happened across any papers that go into the alpha 2 subtypes, apart from illustrating they're there, but regarding which in particular would mediate the bio/physiologic/anti-depressant effect etc - not so much.

I had just assumed that mianserin/mirtazapine were both simple antagonists at alpha2(they both have similar occupancy levels) - again, I would be very much open to modifying this understanding, but google scholar hasn't been good to me in terms of yielding that type of information.

But yeah, I mean obviously it makes sense.
If there is full occupancy but they yield varying results, their mode of action, one being perhaps a partial agonist, would certainly offer an explanation as to why that's the case.
My whole understanding of how they get insight into the nature of the ligand, whether an agonist, PA etc - is limited.
I didn't come across anything in Stahl or Nestlers books anyways.
But in some papers - there seems to be this push to analyse the libraries of ligands using more modern analytical techniques, high performance chromatography etc, to determine potential applications or effects on subtypes etc - so I assume it's related to some assay technique like that?

There was actually another tetracyclic noradrenergic agent - Aptazapine - with apparently 10x the affinity for alpha 2 as mianserin/mirtazapine, but it was never marketed - bummer.


Lamotragine - GABA agent.

The real reason I overlook agents other than NA agents is, first - nothing has ever had the remotest effect apart from NA enhancers.
And secondly - before medicinal treatment, I sustained myself for years, sometimes to quite a high functioning level, on self induced alternate realities or delusions, which would incite a sense of euphoria, and thus an adrenergic response.
I would actually feel the adrenal glands going to work.

Shortly thereafter, symptom alleviation would occur, and I would have temporary remission - until the delusion wore off - then I'd have to conjure up another one.

The point being - this process indicated to me that, catacholamines specifically, are the implicated neurotransmitter - as during intense delusions, like I said, I would achieve almost full remission - albeit it short lived, and rapidly go into decline.

I believe adrenaline is unique among catecholamines in that, a small molecule neurotransmitter - it can cross the blood brain barrier, and does actually activate, or can work on - noradrenergic receptors.
I think it was Nestlers book I read that in.

Now, adrenaline cannot be administered - so that is not a practical medical treatment.
Noradrenergic agents seem to work and act similarly to the self induced delusions, in terms of degree of symptom alleviation - and for that reason, I hope to achieve with pharmaco-agents, what I could not do via the alternate reality approach - which is, a long term sustainable solution.

But between transporter blockade and alpha 2 antagonism, synergistic effects, insomnia, striking the correct balance, and finding an doctor to prescribe the agents I request - it's a tricky solution to achieve.

But in any case - that is primarily why I am preoccupied with noradrenergic agents - and overlook other agents, especially those that potentially downregulate noradrenergic activity - such as GABA enhancers, as I feel ultimately they would be counterproductive to me ends.

Albeit - Z drugs, which do just that, did prove useful when I overdid the NE enhancement with too much reboxetine + mirtazapine/mianserin.
But that was a retrieval from excess, as oppose to a move toward sustained balance.
Indeed, when I would take a Z drug WITHOUT insomnia being caused by noradrenergic excess - it would not really be effective - but was hella effective when insomnia was caused by TOO MUCH NE, which again, leads me to believe - it's a matter of striking the balance.

 

[Cotcha Yankinov]

Regarding the Alpha focus being primarily alpha 2c subtype - did you get that info from a paper or book or such?

From a paper on pubmed, but sure enough I can't find it now

My whole understanding of how they get insight into the nature of the ligand, whether an agonist, PA etc - is limited.
I didn't come across anything in Stahl or Nestlers books anyways.
But in some papers - there seems to be this push to analyse the libraries of ligands using more modern analytical techniques, high performance chromatography etc, to determine potential applications or effects on subtypes etc - so I assume it's related to some assay technique like that?

To test intrinsic efficacy you would use an assay like GTPgammaS incorporation

Lamotragine - GABA agent.

The real reason I overlook agents other than NA agents is, first - nothing has ever had the remotest effect apart from NA enhancers.
And secondly - before medicinal treatment, I sustained myself for years, sometimes to quite a high functioning level, on self induced alternate realities or delusions, which would incite a sense of euphoria, and thus an adrenergic response.
I would actually feel the adrenal glands going to work.

Shortly thereafter, symptom alleviation would occur, and I would have temporary remission - until the delusion wore off - then I'd have to conjure up another one.

The point being - this process indicated to me that, catacholamines specifically, are the implicated neurotransmitter - as during intense delusions, like I said, I would achieve almost full remission - albeit it short lived, and rapidly go into decline.

Noradrenergic agents seem to work and act similarly to the self induced delusions, in terms of degree of symptom alleviation - and for that reason, I hope to achieve with pharmaco-agents, what I could not do via the alternate reality approach - which is, a long term sustainable solution.

But between transporter blockade and alpha 2 antagonism, synergistic effects, insomnia, striking the correct balance, and finding an doctor to prescribe the agents I request - it's a tricky solution to achieve.

1. Lamotrigine is not really a GABA agent, it has complex effects and is categorically different from any e.g. monoamine drug
2. Its commonly used in bipolar depression, and you are starting to sound more and more bipolar if I may say so

If you self-induce delusions and have some sort of maladaptive daydreaming disorder, and actively daydreaming induces temporary relief by increasing NE (I don't think adrenaline really crosses the BBB), then increasing NE and mimicking the effects of daydreaming pharmacologically is not a long term solution.

Its about as feasible of a treatment as amphetamine for depression. One of the issues is homeostatic compensation - the hedonic treadmill can always run faster than we can, and eventually there will be side effects to NE medications that don't appear right away (to say nothing of dependence).

The hedonic treadmill is particular good at countering euphoria from catecholamines and stimulation. Achieving genuine wellbeing by correcting pathology should be the real goal. There was probably some underlying pathology, and the daydreaming probably only exacerbated this pathology.


But I'm not quite sure why we would narrow down abstract happiness/euphoria induced via daydreaming to NE. I think it would be more important to consider the gross brain structures and circuits involved to treat a maladaptive daydreaming disorder patient. See for example the cingulate's role in abstract happiness and depression, and mindfulness meditation's effects on the cingulate. Mindfulness is essentially antithetical to daydreaming.

I think I've mentioned mindfulness to you before and you said something like "yeah... no..." - I hear from a lot of people like yourself that seem to take a really odd approach to their wellbeing.

1. They will be misdiagnosed and not attempt to correct this - a primary diagnosis like bipolar depression/maladaptive daydreaming disorder is more important than just treating a downstream symptom like depression, but diagnosis can be very difficult with complex patients, especially when they themselves are playing a large role in their treatment (they cannot get an outside perspective)

2. They like to trial specific pharmacological agents while ignoring others and especially ignoring non-pharmacological treatments like mindfulness

3. They will tunnel vision upon something - in this case NE - even if it may not hold the key to their sustained wellbeing


Be very aware of the acute effects of treatments and mindsets vs. their chronic effects.