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Neurochemicals most intimately involved with cognitive and executive function?

Cotcha Yankinov said:
Psychomotor retardation is a term people tend to use in the context of major depression, when you don't have the energy/motivation to carry out some physically oriented task, "I can't go get the mail, it's so exhausting" sort of thing.

Johnny boy, norepinephrine and dopamine play big roles in combatting fatigue and increasing concentration (if only by dopamine increasing the activity of NMDA) but SSRIs can help with whatever because serotonin regulates a lot of neural activity and helps the brain cells (it's a good idea to look beyond just receptors). I think specifically more norepinephrine was found to help with psychomotor retardation and some depression symptoms and an NRI like Atomexetine has use in ADHD, but SSRIs/SNRIs are probably better agents for MDD long term.
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Just out of curiousity - atomoxetine - why raise that as an option to treat a noradrenaline imbalance, when it's not licensed for that purpose?
Do some people use it off license for depression.

It would seem to me that the go to options for treating noradrenaline would be, bupropion or desipramine, particularly for those that do not respond to SSRI/SNRI's, or have somewhat adverse reactions to serotonin.


I suppose to jump back a step and examine the cause from a further distance - what would be considered the most effective medications, specifically in terms of treating cognitive dysfunction and reduced executive function, associated with low mood.

I understand the point of view - well, if it's related to, let's say parkinsons, by example, dopaminergics will improve cognitive dysfunction.

But, for the purposes of my question, we're assuming that particular ailment stems exclusively from low mood.

https://clinicaltrials.gov/ct2/show/...lt=With&rank=5


Going back to this, their hypothesis seems to be, serotonin implicated in low mood is relative to "sadness", ruminating thoughts, OCD tendencies etc.
Where as, they consider, noradrenaline to be implicated more so with, energy levels, fatigue etc.
The latter being my interpretation of cognitive dysfunction in this context.
 
There was also a study done, hypothesizing that, noradrenergics were better suited to those with active lifestyles, goal orientated individuals etc.
Serotonergics, more so, again, for sadness, ruminating thoughts.
 
Well, SSRI have kind of a generally misunderstood action due to the common knowledge that it increases serotonin in the synaptic clef. But the reason why they take some time to make their ''theraputic effect'' is because what makes them work with MDD and some other psychiatric conditions is actually a receptor response to irrationnaly high levels of serotonin.

When the brain gets high amount of serotonin and can't reuptake it some excitatory receptors such as 5HT2a, 5-HT2c, and well im not going to list em all, are being downregulated which decrease their activity while inhibitory receptors such as 5HT1a, 5HT7 are being flooded with serotonin but downregulate alot less since their overexcitation can't be as harmful as excitatory 5HT receptors.
The result being a decrease in serotonin related stimulation and increased serotonin related inhibition. So yes it is partly caused by increased serotonin but most of the theraputic effects come from downregulation of excitatory receptor which are responsible for emotive intensity.
But I gotta say that in regard to perceptual cognition, SSRI have normally a negative effect since Serotonin related inhibition is known to reduce cognitive abilities. So mabe mood elevation and increased motivation makes a person more active/productive, but the purely computational cognition is downregulated.
 
Mracid said:
Well, SSRI have kind of a generally misunderstood action due to the common knowledge that it increases serotonin in the synaptic clef. But the reason why they take some time to make their ''theraputic effect'' is because what makes them work with MDD and some other psychiatric conditions is actually a receptor response to irrationnaly high levels of serotonin.

When the brain gets high amount of serotonin and can't reuptake it some excitatory receptors such as 5HT2a, 5-HT2c, and well im not going to list em all, are being downregulated which decrease their activity while inhibitory receptors such as 5HT1a, 5HT7 are being flooded with serotonin but downregulate alot less since their overexcitation can't be as harmful as excitatory 5HT receptors.
The result being a decrease in serotonin related stimulation and increased serotonin related inhibition. So yes it is partly caused by increased serotonin but most of the theraputic effects come from downregulation of excitatory receptor which are responsible for emotive intensity.
But I gotta say that in regard to perceptual cognition, SSRI have normally a negative effect since Serotonin related inhibition is known to reduce cognitive abilities. So mabe mood elevation and increased motivation makes a person more active/productive, but the purely computational cognition is downregulated.
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Super information.

Where did you learn it?
 
NCBI is a nice source of informations, altho on this website they usually give the information without really explaining, more just stating, so gotta build up the knowledge to integrate new information instead of just reading what they have to say.
 
Mracid said:
NCBI is a nice source of informations, altho on this website they usually give the information without really explaining, more just stating, so gotta build up the knowledge to integrate new information instead of just reading what they have to say.
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I think I should mention that NCBI (Pubmed) is only a source of abstracts (hence why there is little explanation) and is not meant to be used as a primary reference. The papers it links to are supposed to be what you read to learn about the topic of interest. I don't mean to state the obvious, but I suspect that some people don't understand the purpose of Pubmed (especially if there is no link to the full text). The primary literature has to be read with a critical eye, and there is no way to do that if you just read the abstracts.
 
serotonin2A said:
I think I should mention that NCBI (Pubmed) is only a source of abstracts (hence why there is little explanation) and is not meant to be used as a primary reference. The papers it links to are supposed to be what you read to learn about the topic of interest. I don't mean to state the obvious, but I suspect that some people don't understand the purpose of Pubmed (especially if there is no link to the full text). The primary literature has to be read with a critical eye, and there is no way to do that if you just read the abstracts.
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A lot of the full text articles, well, it seems you have to pay for them.
The abstracts are free.

To the other poster - you didn't read any neuropharmacology books to make that determination?
Was that something you deduced personally (I doubt it but...)
Or are you quoting from a source?

If so, can you link that source?

I really want to give it to my psychiatrist at out next meeting, as well as file a written complaint as regards their course of treatment for me, and I need to be able to back up thoroughly all my assertions so, that info, being comprehensively familiar with it, would be great.

A lot of the full text articles on pubmed are also full of trial measures etc - and not so much actual pharmacodynamic mechanics...?
 
I would definitely not file a complaint against them. Getting treated properly in the future will be a hazard. Maybe it's hard to believe, but there's a strong probability that they know a lot more of what they're doing than you think. It's a lot more than just pure science that they work with. And they will have read the appropriate studies with a critical eye.

I mean, for instance that norepinephrine is just another word for noradrenaline, right?

College students usually have database access, if that pertains.
 
They want to take me off all medication, refuse further prescription etc.

I'm getting all meds through my GP.

They dispute my having depressive symptoms, period.

I don't see the point of going into it but, "negligence" springs to mind when I consider their treatment approach.

I'm fairly sure they have formed an opinion of my being OCD with these meds, or possibly a hypochondriac.
Either way, they don't take me seriously.
 
Have you tried CBT, practicing mindfulness and regular cardio thoroughly? Typically it's unwise to go straight for meds. And just as a combo of drugs might be more effective from treatment refractory cases, you typically want to use the minimum amount of pharmacotherapy necessary to achieve remission. Of course that's usually pharmacotherapy combined with CBT.

So essentially you think you have MDD or a similar depressive disorder while your provider may think you're OCD/hypochondriac?

Sorry please remind me, what meds are you currently on and what are your symptoms?
 
Cotcha Yankinov said:
Have you tried CBT, practicing mindfulness and regular cardio thoroughly? Typically it's unwise to go straight for meds. And just as a combo of drugs might be more effective from treatment refractory cases, you typically want to use the minimum amount of pharmacotherapy necessary to achieve remission. Of course that's usually pharmacotherapy combined with CBT.

So essentially you think you have MDD or a similar depressive disorder while your provider may think you're OCD/hypochondriac?

Sorry please remind me, what meds are you currently on and what are your symptoms?
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I've tried CBT, extensive psychology, with two different PhD's in psychology, occupational therapy.
None of these therapies made even the SLIGHTEST impact on my symptoms.
I mean, zero, nothing.
I never experienced a life event that would precipitate my condition.

By trade I'm an athlete.
My life revolves around cardio, working out, being in shape.
Diet etc, is excellent.

I've had every physical health screening under the sun, blood tests, endocrinologist exams, gastroentrologist exams etc.
Thyroid - all that stuff - everything, has been thoroughly screened, and there is zero problems physically.

I'm currently on mirtazapine 45mg, which made an impact where prozac and lexapro did nothing, and very little.
Effexor, did a little - thus my deduction noradrenaline must be implicated in my condition.

So a month ago I started 300 mg bupropion, which as been the best AD I've tried so far apart from mirtazapine.

I've also tried seroquel, risperadrone and olanzapine - all of which did nothing (they initially though I was delusional, a psychotic condition).

They've displayed complete lack of thoroughness in terms of analyzing my condition, and treatment has been poor as a result.

Only when I started taking treatment into my own hands, did I begin to see real progress.
 
I don't think Effexor is very selective, thought it had other effects aside from SNRI. Cymbalta might be something to talk to your doc about then, or amitryptyline.

Care to give an overview of your symptoms?

Mindfulness meditation is definitely worth a thorough try.
 
Tried mindfulness also.
It's not applicable to me.

Chronic fatigue is the most prevalent symptom.
Confined to bed. Extremely poor concentration, to the point of not being able to pick up a book and read it.
Followed by low/non-existent appetite, and irritable bowl syndrome, severe weight loss as a result.

Then we have insomnia of course.
No sleep without meds.

Then, due to complete absence of functionality, quite severe social withdrawal (people don't feel comfortable around a sullen skelator looking poorly presented recluse with bad personal hygiene - go figure....).

And then, when I can't move sufficiently to lift my head off the pillow, or table, or whatever I happen to collapse upon, persistent unending crying spells, distress to the point where I pray for death.
This has descended into convulsions on occasions where the distress has become too intense to bear.

At that point I moved back in with my parents and they basically treated me like a baby with a fever, until I found meds that worked.

The only reason I started on meds, aws to attempt to make a vegetable out of myself; anything to alleviate the distress.
Low and behold, with the meds, my energy began to come back (anti-depressants, that is. Not anti-psychotics).
 
Have you tried amitryptyline? It's used in IBS I believe, and it is very effective as an antidepressant. It has some unique properties. It is also more of a norepinephrine boosting antidepressant. If I were you I would try amitriptyline and hopefully get your malnutrition sorted out as well.

Don't rule out mindfulness, especially for sleep. What makes you say it's not applicable?
 
Amitryptiline??

lol - did you miss the part where I said chronic-fatigue was the main symptom I'm trying to alleviate, not exacerbate.

I do believe it is used for IBS, but the other side effects.... just no.

If I was going to try a tricyclic, I'd go for Desipramine.
Though, that's not actually available here.... which sucks.
The suppliers can't even import it.

Serotonergics make me drowsy, well, reuptake inhibitors anyways.
Rather exclude them.

I was thinking either

- Reboxetine
- Vilazodone (Brintellix)
- Agomelatine (though the potency on NA I do not yet know)
- Moclobimide - but this impact serotonin in the reuptake sense - which I'd rather avoid.
 
The acutely sedating histaminergic effects will desensitize at some point, and you may also feel less fatigue with better sleep and less IBS. It does also have significant NRI properties.

Also, fundamentally these antidepressants have a lot more action than their acute action - that's very important to realize. Antidepressants can take months to work, or at least couple weeks. Amitriptyline has really good efficacy for MDD compared to other antidepressants. Attenuation of brain inflammation and fundamentally altering neuroplasticity with amitriptyline is going to outweigh the temporary fatigue you may get from serotonergics.
 
Yeah well, urinary retention is enough to turn me off, no matter how efficacious it could be.
 
And I'll never take another AD that has the potential to induce sexual dysfunction.

I can't live like that.

Amitriptyline can cause that, being a SRI.

I'd prefer to stick to the newer formulations.

Steven Stahl suggested a combination of bupropion and reboxetine can potentiate the NA effect.

Something to consider, after I spend a month on 450mg bupropion.
Titrating up tomorrow from 300.
 
Cotcha Yankinov said:
The acutely sedating histaminergic effects will desensitize at some point, and you may also feel less fatigue with better sleep and less IBS. It does also have significant NRI properties.

Also, fundamentally these antidepressants have a lot more action than their acute action - that's very important to realize. Antidepressants can take months to work, or at least couple weeks. Amitriptyline has really good efficacy for MDD compared to other antidepressants. Attenuation of brain inflammation and fundamentally altering neuroplasticity with amitriptyline is going to outweigh the temporary fatigue you may get from serotonergics.
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And I definitely did not find this to be the case with mirtazipine.
If anything, the sedation level increased.
 
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