A tricky Question that my Prof. can't give the exact answer

[Davevanza]

Hi,

We all know, that, part of Depression is caused by Chemical imbalance.

Now, There are several Neurotransmitters which are responsible for it.
( Serotonin, Noradrenaline, Dopamine, Phenylethylamine, etc)


Now, it just come across my mind that one day I might ask my doc, that, Brain's Chemical imbalance can not be measured, unlike Diabetes ( where blood sample can show the Glucose level, etc)


Now, Chemical imbalance means, our Neurotransmitters in our brain are lacking or not functioning properly, that's how, antidepressants are used to correct this.


Now, I am thinking, SSRIs ( Fluoxetine, Paroxetine, Escitalopram, etc) only affect Serotonin.

SNRI's ( Cymbalta, Effexor-XR, Milnacipran) affect 2 Neurotransmitters, that being Serotonin and Noradrenaline.

Bupropion only affect Noradrenaline and Dopamine.

Edronax ( Reboxetine) is a NARI, only affeting Noradrenaline.

TCAs.....well, some of them, ( like Amitriptyline, Imipramine) affect at least 3 of the Neurotransmitters.

MAOIs do the same, but with different mechanism.

So, why, do some people with Chemical imbalance, improved ( called Remission, medically), while only taking SSRI?

Or only taking NARI which affects only Noradrenaline?

or Bupropion which affects Dopamine and Noradrenaline only?


I asked, once, to a Professor, as I'm working in Hospital as a Researcher about this.

My main duty there is mainly to give docs info about new meds' Pharmacokinetics, and report to them about the possible drug interactions that the patients are taking, as well as a bit of Counselling to to Elderly patients, as I am put to take care of the Elderlies suffering from (Dementia, Paranoia, Parkinson Disease, Alzheimer's etc),

.......Doctors are so busy, they rarely have time to do any research, and sometimes, accidentally, wrong meds are given ( this involves nurses as in a Hospital, the shift/work schedule are rotating 24 hours. I can't blame anyone.)

So it's my job there to monitor, check carefully, do the research, and during the weekly meeting, I , then explain to the Docs if there happen to be a drug interactions or worsening conditions of the Elderly Patients.

So , as the Professor could not really give me an exact answer, I need an input from different opinion of this forum members.

I appreciate any input,

Kind regards,
David

 

[I NUK3D U]

Because most anti-depressants attempt to counter-act symptoms, and not repair the cause?

 

[footscrazy]

As far as I knew, noone is at all sure what causes depression. The exact brain states that give rise to certain emotions or feelings includes a lot of unknowns at this point, I thought. This is one of the reasons I think anti depressants are a bit dodgy. They're not sure how exactly the work, which should be reason enough to treat them with a lot more caution. One of the more interesting hypotheses I've seen on them is that SSRI's actually cause downregulation of serotonin receptors, as artificially increasing the amount of serotonin available will cause the brain to downregulate to reachieve homeostasis. This could explain why it takes 2-4 weeks for SSRI's to take effect, and why the risk of suicide is increased during those 2-4 weeks. This theory takes into account that neurotransmitters have very different effects in different areas of the brain. In certain parts of the brain, it's thought it's actually too much serotonin that causes depression or anxiety in some people.

 

[Divine Moments]

When any effect is temporally associated with taking a drug, it's generally due to one of 3 main things:
1) the drug's effect
2) the placebo effect
3) the natural course of the disease

To apply to this situation, if somebody takes antidepressants and gets better then it could be due:
1) the antidepressant "curing" the depression
2) the placebo effect (well-documented for mood altering substances)
3) the disease getting better 'on its own' and not actually being related to the antidepressant

I would also add a fourth, being that other treatment or lifestyle modalities (e.g. counselling/CBT, diet and exercise, spirituality, life changes, etc.) helped with or without additional beneficial effect of the antidepressant.

With regards to why SSRIs/SNRIs/TCAs/NRIs/MAOIs/etc. have different efficacies from person to person, I would say that the same essentially applies to any drug or treatment. There is a huge amount of variation between people's bodies and minds. As such, people can respond differently for innumerable reasons, e.g. different receptor composition, different levels of neurotransmitters, different psychological responses to events, different perceptions of how life should be, different co-morbidities,and so on.

Add to that what footscrazy said that nobody really knows what causes depression, and that depression is probably a wide array of different processes which manifest similarly, and you can see some of the reasons why there is such variation in which antidepressants are effective

 

[tommy34]

I'm not 100% sure what exactly your question is but, if a specific neurotransmitter is deficient and thus causing depression. In the rare case that a drug is taken to fix the specific problem then a temporary cure is found. This, in theory, allows the patent to return to a normal state of life without copping the full below of depression or preventing harm. If only we knew my friend, if only we knew.

 

[grugz]

Tbh doctors as in medically trained, are horrible at research and writing academic scientific journals. Dr who done a PhD, are good at research and know their stuff, maybe you are asking the wrong channels, maybe shoot a email off to a researcher at the psychology dept at any university, who has research in that area

 

[Davevanza]

When any effect is temporally associated with taking a drug, it's generally due to one of 3 main things:
1) the drug's effect
2) the placebo effect
3) the natural course of the disease

To apply to this situation, if somebody takes antidepressants and gets better then it could be due:
1) the antidepressant "curing" the depression
2) the placebo effect (well-documented for mood altering substances)
3) the disease getting better 'on its own' and not actually being related to the antidepressant

I would also add a fourth, being that other treatment or lifestyle modalities (e.g. counselling/CBT, diet and exercise, spirituality, life changes, etc.) helped with or without additional beneficial effect of the antidepressant.

With regards to why SSRIs/SNRIs/TCAs/NRIs/MAOIs/etc. have different efficacies from person to person, I would say that the same essentially applies to any drug or treatment. There is a huge amount of variation between people's bodies and minds. As such, people can respond differently for innumerable reasons, e.g. different receptor composition, different levels of neurotransmitters, different psychological responses to events, different perceptions of how life should be, different co-morbidities,and so on.

Add to that what footscrazy said that nobody really knows what causes depression, and that depression is probably a wide array of different processes which manifest similarly, and you can see some of the reasons why there is such variation in which antidepressants are effective

Hi,
I quite agree with your opinion.

I appreciate it so much.

Kind regards,
David

 

[Divine Moments]

^ I disagree that most doctors are horrible at research and journal writing, but obviously someone with a PhD will be more experienced and generally more skilled at it. The majority of medical doctors who actually do significant amounts of research, and the majority of professorial doctors (usually one and the same), have a PhD anyway - partly because you can obtain a PhD by publication (i.e. a certain number of first-authored papers in reputable journals).

I may be misinterpreting what you mean, but it sounds like you're saying that a non-medical doctor (i.e. someone with a PhD and no MBBS/MD) is better at research than a 'double doctor' (i.e. someone with both a PhD and an MBBS/MD). I don't think there are all that many medical doctors who are professors yet don't have a PhD, so I would assume that's the case here.

 

[Davevanza]

I'm not 100% sure what exactly your question is but, if a specific neurotransmitter is deficient and thus causing depression. In the rare case that a drug is taken to fix the specific problem then a temporary cure is found. This, in theory, allows the patent to return to a normal state of life without copping the full below of depression or preventing harm. If only we knew my friend, if only we knew.

Hi,

Yes, I agree with you, too.
As at this time of moment, noone knows the EXACT cause of Depression.

There could be Exogenously ( Family problems, life events, work problems, etc)

There could also be Endogenously ( That involves our Neurotransmitters. Whether be because of congenital-born with, or, it could also be caused by stimulants, that actually depletes our Neurotransmitters.)

So, talking about Endogenous Depression, if it is caused by overused of Stimulants, our Neurotransmitters are released from the Cytoplasmic pools. Leading to a decreased amount of them, in the Synaptic Clefts. ( It is kind of a gap, of how our cells which has Axons and dendrites/branches, connecting from each other.)

In other words, One cell in our brain has Axon and Dendrites ( it's like branches), and each cell actually communicates with the other cells via the end-points of Dendrites.

The End-point of Dendrite that releases the Neurotransmitters ( Serotonin, Noradrenaline, Dopamine etc) is called Pre-synaptic, and the other End-point of Dendrites that receives them is called Post-Synaptics.
And in between those 2, there is a gap called Synaptic Cleft, where only Neurotransmitters are transferred from cells to other cells.

That is why, Antidepressants work, by inhibiting the re-uptake/re-absoption from the pre-synaptic, causing more Neurotransmitters in the Synaptic Gaps.

That is with TCA's, SSRIs ( Only works to increase Serotonin), SNRIs ( both Serotonin and Noradrenaline) except Venlafaxine which at a low dose 37.5mg only affects Serotonin, at moderate dose greater than 75mg affects both Serotonin and Noradrenaline, and above 150mg affects Dopamine as well.


So, at this point of time, those Pharmacologists, are trying to further explore about this.

I would say, WE CAN BE RECOVERED FROM DEPRESSION, BUT NOT CURED.

Anyway, i appreciate your input, as everyone sees things from different angles, and noone of us is PERFECT.


Kind Regards,
David

 

[DeathDomokun]

I think someone needed to clarify how they work.
Here's another extremely simple explanation of how Selective Serotonin REUPTAKE Inhibitors work
A neuron has these 2 things sticking out, an axon and dendrite. Axons usually send information and dendrites detect and receive information. So there's A, he's a Serotonin axon.
Axons kind of chill at the end of the neurons up in your brain. Your brain is like
"Hey man, listen the fuck up, A! Look man, I need some Serotonin over at B, lets cheer this fucker up, hook him up"
So A sends it's Serotonin out to this faggot, B, whose got receptors for that Serotonin. In this gap, between the two, let's call it an "inter-synaptic" gap for fun (and also thats what its called).
But A has more than B needs, so he just kind of tosses it out there, and theres a bunch of this Serotonin floating around in that space. B takes what he needs and some of the left overs are destroyed and a large amount, I forget how much, are sucked back up into A.
SSRI's prevent that reuptake, so there would be more of that Serotonin floating around in the middle, in that synaptic gap between A and B, and it can't get back into A like usual, at least for a while. It just chills there and A can't get it back because the SSRI stops that shit and B is just chilling for a bit and then he's like "Fuck! Theres Serotonin all over this bitch!" so B grabs some more up. Now B has extra, and if it was a lack of Serotonin that was fucking shit up in this brain, he now has more. This obviously is for a short time, your brain doesn't just go INFINITY SEROTONIN MODE!
They don't produce any serotonin, they slow down the process of it getting back into A so hard that B gets extra.

Now MAOI's, first off there are reversible maoi's and irreversible maoi's. Shit like tobacco and harmaline, the shit syrian rue for example is reversible; basically this means that most of the dietary restrictions involved with maoi's and what not don't matter as much. Just thought I'd mention that because thats a huge myth around taking harmaline to potentiate psychedelics, that "if you have a beer or eat Parmesan cheese YOU WILL DIE". If you're on an maoi for depression purposes or anxiety, I'm pretty sure a majority of them are irreversible, so make sure you learn what you can and cannot take food and drug wise.
The idea here is different to SSRI's. The idea is that depression is related to Serotonin, but instead of leaving it in the synaptic gap and preventing it from going back into our old friend A the axon, it prevents the things that break it down. Monoamine oxidase is what nerds call MAO. This is the mother fucker that destroys the left overs in there when that serotonin (and others! dopamine and a bunch ofthers!) are in that synaptic gap.
Theres MAO-A and MAO-B, iirc MAO-A is the cool, important one generally, in terms of 'feeling happy' because that one deals with Serotonin and a most others, dopamine is both, i don't remember if its equal between MAO-B and MAO-A but its at least close.
MAO-B does some shit, I forget what. Fuck MAO-B, I think it mainly is just helpful because it helps with the Dopamine and some other shit but I totally forget what thats related to. Maybe PEA? I forget how to spell it, phenethylalamine? Maybe? I know it has something to do with mood, but I forget how significantly.
Now, MAOI's! The I stands for 'Inhibitor.' The idea is to stop MAO-A and/or MAO-B (lets say A and B for this) from fucking up all that serotonin and all the other nice neurotransmitters.
MAOI's can inhibit A or B equally, or some are designed to target one over the other.
A is a cool guy because now theres more serotonin and friends, but he also is kind of fucking us because he also breaks down this shit called Tyramine. Tyramine is in foods and stuff, like, a lot of fucking foods, and delicious ones too. When A isn't around so much, that tyramine builds up and then you fucking die. [don't do that]
B helps with dopamine but isn't even touching the tyramine, so if the medication only involves B, dietary problems are gone totally.
Now, generally, MAOI's are shitty, don't work as well as SSRI's, and have dangerous side effects.
I know it was a shitty explanation but I felt it need to be said.

Also, by increasing the Serotonin the brain may be able to balance itself out, or the affect on the Serotonin on your mood could increase it enough to stop the depression, so the brain would produce different amounts of other chemicals because of the mood. I'm no professor though, in fact I know barely anything I'm just throwing around an idea.

 

[Mr Blonde]

Pretty much everything I wanted to say has already been said. Depression, like all mental illness and the CNS in general, is not completely understood. The theory of low serotonin levels led to the development of the serotonin acting drugs, which can lead to improvements in many patients (particularly those with clinical depression, not minor-moderate depression). Those who do not experience improvements may benefit from an SNRI, or a DARI, or some other type of medication. Until we have the ability to look into the brains of those with mental illness and pinpoint exactly what their problem is, treatment of mental illness is going to remain hit and miss.

 

[DeathDomokun]

What's to say we'll ever be able to pinpoint the problem and fix it with chemicals?
I'd say Divine is right, that while drugs can help people if it'll help you combining it with positive steps like CBT or counselling as well as a change for the better with your diet and exercising more, as well as changing things that may be attributing to your mood [e.g if you're lonely make a new friend] and just changing your life, or not even changing the physical situation at all and just changing the way you perceive it. I personally think it's all about surrendering to the way things are and accepting the present moment, trying to be aware and making steps towards whatever you want.
Our perception and the physical environment/surrounding obviously make an impact on our mood.

 

[tyrael]

Very good info Divine Moments and Mr Blonde! I very much enjoy reading both your posts (not only here but through BL!).

With repeating what everyone has already said here, I find the area of pharmacogenetics very interesting yet don't hear a lot about it (whether that's in the media or newspaper articles, or the like).

I ask in reference to why TCA's might work for one, as opposed to SSRI's, SNRI's, SNDRI's, etc.

 

[grugz]

^ I disagree that most doctors are horrible at research and journal writing, but obviously someone with a PhD will be more experienced and generally more skilled at it. The majority of medical doctors who actually do significant amounts of research, and the majority of professorial doctors (usually one and the same), have a PhD anyway - partly because you can obtain a PhD by publication (i.e. a certain number of first-authored papers in reputable journals).

I may be misinterpreting what you mean, but it sounds like you're saying that a non-medical doctor (i.e. someone with a PhD and no MBBS/MD) is better at research than a 'double doctor' (i.e. someone with both a PhD and an MBBS/MD). I don't think there are all that many medical doctors who are professors yet don't have a PhD, so I would assume that's the case here.

The way I see it is, mbbs, ~7yrs(i think), intern work etc(few years), specialise, then start research.generally by starting with case studies, n drug trials. They prolly get a honorable doctorate fm a university if they done significant work, n get partnerships with uni, get given prof title by uni. In short, Many years before they start research. (doesnt always have to be like this)

Reseaecher, does undergrad in science, biomedical science or some other health science, 3-4 years, extra year in honours (majority) or 2 yrs in masters (if ur not as smart, but can buy your way in). Either one can bet into phd, 3 yrs (if u can afford or scholarship). Become dr. get fellowships, advance to senior fellow depending on research, eventually if you get results n good funding, get your own lab. Not all lab heads are profs. Eventually u get given associate prof, and prof as you advance your career.

So as you can see someone who isnt medically trained, starts writing thesis at honours stage, real experiments and real research. In undergraduatr years they are trained to research and write in science. Mbbs dont get that, they have alot more other things to learn than how to research n write scientific articles. So when I read journals u can notice the difference. Not saying that there isnt good mbbs writers, I guess it attains to experience, and the lower number of them. With that there are also shocker writers in non-mbbs backgrounds. But they usually publish in obscuer journals in a random non english speaking country

 

[Mr Blonde]

Very good info Divine Moments and Mr Blonde! I very much enjoy reading both your posts (not only here but through BL!).

With repeating what everyone has already said here, I find the area of pharmacogenetics very interesting yet don't hear a lot about it (whether that's in the media or newspaper articles, or the like).

I ask in reference to why TCA's might work for one, as opposed to SSRI's, SNRI's, SNDRI's, etc.

Pharmacogenetics is a tricky field, and most of my knowledge of the subject has to do with phenotypes and polymorphism among liver enzymes and non-microsomal enzymes. I guess right now it just comes to 'it works for some folks, not for others'.

I think I just read something about pharmacogenetics in my text book, I'll see if I can pull out some information for you.

 

[shoo-bop]

As alluded to in some other posts, there may be several different "kinds" of depression. But I actually think the "exogenous/endogenous" dichotomy is problematic, both philosophically (because it assumes a distinct line can be drawn between our bodies and the rest of the world) and scientifically (because external events alter our neurochemistry and neuroanatomy, which in turn affects what kinds of experiences we may be drawn to, and certain biological vulnerabilities may require environmental stressors, or vice versa, to manifest as depression). Psychiatrists have, and continue to debate, various subtypes of depression such as melancholic (marked anhedonia and a range of "physical" symptoms), atypical (deceptive name because its generally considered the most common type of major depression, but characterised by interpersonal sensitivity, sparing of hedonic response, and some sleep and appetite symptoms that are opposite those found in melancholia), dysthymia (long-term low level depression), and "adjustment disorder with depressed mood" (when they reckon it's really just shit going on in your life that you'll get over when things improve)

Each kind (and other potential unidentified kinds, if you even believe this classification) probably has different neurobiological profiles. Intuitively, for example, the complete consummatory anhedonia of melancholia, combined with the severe agitation, insomnia, loss of appetite, etc, suggests a more likely role of opioidergic dysfunction than other types. I recently reead an older paper (from the '80s), where the author was commenting on his impression that atypicals did better with dexamphetamine and MAOIs, whereas giving dexies to melancholics just made their agitation worse, and that they did better with tricyclics (or ECT, if they didn't mind forgetting several months of their life).

Keep a few other things in mind: firstly these "specific" medications aren't as specific as you might think - i.e. a range of effects on histamine, cholinergic, adrenergic, NMDA, and other receptor types is rather common. Also, it's probably not the immediate effects on monoamine transporters or receptors that's usually or largely responsible for the effect, as the effects often take weeks to emerge, which is more consistent with the time course of changes in receptor sensitisation, recruitment of neurotrophins like BDNF that mediate synaptic plasticity, etc.

 

[Mr Blonde]

Intuitively, for example, the complete consummatory anhedonia of melancholia, combined with the severe agitation, insomnia, loss of appetite, etc, suggests a more likely role of opioidergic dysfunction than other types.

I agree the endorphin system could play a role here, but so could malfunction of the norepinephrine, epinephrine and dopamine systems (all could lead to anhedonia, agitation, insomnia, anorexia, etc...). Not to mention the role that the body's corticosteroid system could play as well.

Well, this thread has certainly become rather academic.

 

[shoo-bop]

Totally good point. I only mentioned it because I had recently read some other thread on here where there was discussion about past (i.e. early-mid 20th century) prescription of, and also contemporary off-label/illicit self-medication with, opiates for depression, and because I recently met someone who, for this very reason, was planning to research whether fentanyl analogues would be a superior anaesthetic to use during ECT compared to the standard anaesthetics usually used.

... and that's definitely academic!

 

[Mr Blonde]

^ Electro convulsive therapy? To be honest, the only advantage the fentanyl analogues offer is potency and that isn't an advantage unless the dose of the original compound is so large as to be a burden to take. Doctors back in the day (and maybe even today) seemed to have this notion that 'greater potency means better in general', without considering things like the efficacy or therapeutic index of a new compound.

 

[shoo-bop]

Yep, that's what I meant by ECT. Can't say I expect it to be a particularly promising project even if it ever gets through the various approval processes!

Another thing to consider is the possible dissociation between anticipatory anhedonia and consummatory anhedonia. We tend to assume that we look forward to what we find pleasurable, and vice versa, but this is not actually always the case - recent schizophrenia research for example suggests that schizophrenics have impaired expectancy of pleasure and/or ability to take pleasure in the expectancy of something good, but normal pleasure when something good actually happens (this may be as much do to the meds as due to the illness, as this research was conducted only in medicated patients, and most of those medications block dopamine receptors). My impression is that this may also apply to so-called "atypical" depression - not feeling like anything's going to be good, not deriving pleasure from knowing of something good coming up, but still being able to take pleasure when it happens. Anhedonia in melancholia, however, is much more profound: it's both anticipatory and consummatory anhedonia.

There's at least a few people out there who will say dopaminergic dysfunction is involved in anticipatory anhedonia and opioid and/or serotonergic dysfunction is involved in consummatory anhedonia. That's probably a massive over-simplification, perhaps to the point of being largely incorrect, but if it even vaguely approximates reality, it also adds to the explanation of why some medications that help some people with depression don't help others. Last I heard, though, around a third of people treated for depression with the "standard" classes of antidepressants don't have an adequate response even after multiple trials of different classes of those medications.