289 replies to this topic

[EBB]

EBB - I am on the bipolar spectrum so Lexapro would not be enough to manage my depression and anxiety.  However, it has been a miracle drug in managing my withdrawl from Cymbalta.

 

I would try the Zoloft.  Nothing to lose.

Thanks Juli, I'm actually leaning towards Lexapro - what does did you start on?

[juli]

I started at 5mg for a week, then upped it 10mg the second week.  I increased it to 15mg on the fourth week and am holding steady at that dose for now.

[fishinghat]

I am convinced drs are idiots. As you can see by the title of this article dopamine increases in the extracellular fluid around the nerves with the use of Zoloft (sertraline). These ssri/snri/nri etc decrease the activity of a specific neurotransmitter by blocking the protein that transports that neurotransmitters from one nerve cell to the next. If these transport proteins are blocked than the dopamine is NOT transported from one nerve cell to the next and therefore it builds up in the fluid around the outside of the nerves (extracellular) because the dopamine is not being used. The same principle applies to serotonin. You take an ssri because you have anxiety from too much serotonin and the ssri blocks the transporters so the serotonin builds up outside the nerve cells because it is no longer being used. There are hundred of research papers from drs who say 'WOW, serotonin is increasing how come this drug works. The patient started with high serotonin and now that he/she is on an ssri the serotonin increases. That shouldn't happen.' A lot of other drs try to argue with them and explain it is because the serotonin is not being used so of course it builds up in the fluid OUTSIDE the nerve cells instead of attached to the next nerve cell.

 

Be back in a minute.

 

When drs go to school I think they eat their books.

[fishinghat]

I do agree with one thing, Seroquel and Abilify would probably work better. Instead of blocking the protein transporter of dopamine they block the synapse so the dopamine can not react with the nerve cell. (which by the way also increases extracellular brain dopamine concentrations*. I bet they didn't think of that.

*Relationship between daily dose, plasma concentrations, dopamine receptor occupancy, and clinical response to quetiapine: a review.
Sparshatt A, Taylor D, Patel MX, Kapur S.
J Clin Psychiatry. 2011 Aug;72(8):1108-23. doi: 10.4088/JCP.09r05739yel. Epub 2011 Jan 25. Review.
PMID: 21294996

I would consider the Seroquel. It is much more effective than Abilify in controlling dopamine use, has less of a withdrawal and Abilify withdrawal is considered as bad as Cymbalta withdrawal by many.

Abilify has also been associated with obsessive/compulsive activities like gambling, sex, changes in sexual orientation etc.

https://www.ncbi.nlm...pubmed/26923999
Encephale. 2016 Jun;42(3):281-3. doi: 10.1016/j.encep.2016.01.003. Epub 2016 Feb 26.
[Aripiprazole, gambling disorder and compulsive sexuality].
[Article in French]
Mété D1, Dafreville C2, Paitel V2, Wind P2.

[EBB]

AAAAAAHHH! Super confused now. My doc is not the brightest, but she said she likes Lexapro for anxiety. I really want to understand this. I don't see and article - maybe you meant to post and forgot? So what does it mean that Zoloft is "dopaminergic"? Sounds like you're saying the dopamine builds up around the nerves but then it's blocked?

[EBB]

I was reading this thinking Lexapro helps block dopamine: https://www.ncbi.nlm...les/PMC2674976/

[EBB]

FH,

I am not saying you are wrong, it's just that everything I read says Wellbutrin, for example, BOOSTS dopamine. The gene issue I have creates EXCESS dopamine right? So... that means Wellbutrin would be bad.

[fishinghat]

EBB

Your close. in the case of Zoloft dopamine builds up around the nerves but isn't transported into the nerve synapse to be used. In the case of Seroquel dopamine builds up around the nerves but is transported into the nerve synapse but is then blocked from use.

dopaminergic - applies to dopamine, relates to dopamine.

Zoloft is dopaminergic - Zoloft has an effect on dopamine.

What subject are you saying I did not reference an article? Was it drs being idiots. lol I can probably find a lot of articles on that.

[EBB]

This below is from Wikipedia - and they call it dopaminergic neurotransmission - doesn't that mean increased dopamine? Don't I need LESS dopamine transmission??

 

This is from Wikipedia: For this reason, sertraline has sometimes been described as a serotonin–dopamine reuptake inhibitor (SDRI).^[110] This is relevant as dopamine is thought to be involved in the pathophysiology of depression, and increased dopaminergic neurotransmission by sertraline in addition to serotonin may have additional benefits against depression.^[109]

[EBB]

You referenced 

 

EBB

Your close. in the case of Zoloft dopamine builds up around the nerves but isn't transported into the nerve synapse to be used. In the case of Seroquel dopamine builds up around the nerves but is transported into the nerve synapse but is then blocked from use.

dopaminergic - applies to dopamine, relates to dopamine.

Zoloft is dopaminergic - Zoloft has an effect on dopamine.

What subject are you saying I did not reference an article? Was it drs being idiots. lol I can probably find a lot of articles on that.

You referenced an article in the post above

[fishinghat]

Effects of sustained serotonin reuptake inhibition on the firing of dopamine neurons in the rat ventral tegmental area
Eliyahu Dremencov, PhD, Mostafa El Mansari, PhD, and Pierre Blier, MD, PhD

There is a theory that the higher a persons seroton9n the lower their dopamine. This theory is highly debated. This article you mentioned states that Lexapro may reduce dopamine levels by raising the serotonin. A lot of research being done on this now. I really have no opinion on if this theory is true or not. Not enough evidence yet to convince me one way or another.

[EBB]

FH,

Did you see the article above about Lexapro and dopamine? What are your thoughts? I'm still concerned because everything I read makes it sound like Wellbutrin and Zoloft increase dopamine. Wikipedia makes it sound like Zoloft is a double winner SSRI because it increases dopamine as well as serotonin. Lexapro on the other hand in the article I posted above seems to have a reputation for sometimes NOT being effective for people because it lowers dopamine transmission.

[fishinghat]

"I am not saying you are wrong, it's just that everything I read says Wellbutrin, for example, BOOSTS dopamine. The gene issue I have creates EXCESS dopamine right? So... that means Wellbutrin would be bad."

It doesn't increase the rate of dopamine production but because the dopamine is not being used as much it accumulates around the nerve cells. Your gene on the other hand actually causes the production of dopamine. With no medicine to control it the use of all that dopamine can happen as fast as the transporter can move it to the nerve cells and trust me that can be extremely fast. Transporters are capable of moving neurotransmitters dozens of times per second. Think about how rapidly adrenaline is used during an emergency. Almost instantly the heart pounds, head spins, knees weaken, etc. Wellbutrin actually blocks the transporters of the dopamine the impact of the dopamine is reduced.

[fishinghat]

"This is from Wikipedia: For this reason, sertraline has sometimes been described as a serotonin–dopamine reuptake inhibitor (SDRI)."

Zoloft is a reuptake inhibitor. That means it inhibits or slows down the protein transporters for both serotonin and dopamine.

"This is relevant as dopamine is thought to be involved in the pathophysiology of depression, and increased dopaminergic neurotransmission by sertraline in addition to serotonin may have additional benefits against depression."

Lack of dopamine is linked to depression while too much dopamine is linked to anxiety. Zoloft is believed to increase the activity of dopamine and serotonin and thus may help fight depression. When reading the article from 109 it is one of those articles that state well when taking Zoloft dopamine levels outside the nerve cells rise so dopamine activity must increase. Now you can understand the confusion because many think the levels rise because the transporters are blocked allowing the dopamine to collect to high levels around the nerve cells. But because of the block of the transporters dopamine is not used as much.

[EBB]

So you are saying that Zoloft does this same thing - blocks the transmission of dopamine? Why do all these sources like Wikipedia (not the strongest I know) say that Zoloft DOES transport dopamine? I'm trying to understand here, so forgive me for the continued questions. Does Zoloft perhaps have a "regulating" effect on dopamine? So in theory if it's too low, it would make it the "right amount" transported. And  in my case, if it's too high, it would transport the "correct" amount?

[fishinghat]

Did you see the article above about Lexapro and dopamine? What are your thoughts? I'm still concerned because everything I read makes it sound like Wellbutrin and Zoloft increase dopamine. Wikipedia makes it sound like Zoloft is a double winner SSRI because it increases dopamine as well as serotonin. Lexapro on the other hand in the article I posted above seems to have a reputation for sometimes NOT being effective for people because it lowers dopamine transmission."

My post #161 references that article. SO much of this is confused because the drs and researchers are mislead by the fact dopamine increases OUTSIDE the nerve cells and they think that means there is MORE dopamine activity. The dopamine is simply building up OUTSIDE the nerve cells because the synapses or dopamine transporters can't function due to the medicine. You are still producing dopamine but you are not using it so it has to build up somewhere. If it can't attach to the nerve cells then it builds up in the fluid around the cells.

[fishinghat]

"...blocks the transmission of dopamine?"

Yes it does that is why it is called a reuptake inhibitor. A reuptake inhibitor interers with the protein that transports a particular neurotransmitter.

"Why do all these sources like Wikipedia (not the strongest I know) say that Zoloft DOES transport dopamine?"

That is based on the report by author 109. His assumption is based on the fact that dopamine levels increase so dopamine must be transported and used more. He does not consider the blocking of the transporter by Zoloft. He makes some assumptions that are not true. I can produce a dozen articles that show Zoloft interferes with the dopamine transport to the nerve cells and inhibits dopamine activity.

Now you understand the confusion about the functions of these medicines. Even the drs and researchers get confused. When a researcher misstates something and draws a wrong conclusion it is accepted b y fact by many drs and researchers which only continues the confusion.

[fishinghat]

"Does Zoloft perhaps have a "regulating" effect on dopamine? So in theory if it's too low, it would make it the "right amount" transported. And in my case, if it's too high, it would transport the "correct" amount?"

Ahh, wouldn't that be nice if it did. I am afraid all it does is block the transporter lowering dopamine usage.

[fishinghat]

Now, let me say this. I hope everyone reads this thread. It highlights the complexity of determining what medicine will work for a patient. You have conflicting medical research articles. Why? Well yes some is from misunderstanding but much is from their sampling. They collect a number of people, say 100, who have anxiety. The give a placebo to 50 and a new medicine to 50 and see what the results are. Sounds fine right. Wrong. Some of these people will have no genetic polymorphs, others may have 3 like you or even 10. There are over 30 genetic variations that have been found that effect anxiety/depression. Each genetic variation has a different effect than the others. Do they test the patients in these trials first to see what kind of genetic polymorphs they have? NO. So one set of research shows one result and a similar research shows another result. To further complicate this issue is around 20 mineral and vitamins that effect these processes as well. Do they test these patients for those 20 items? NO.

SO what you are left with is the intuition of the drs and flipping a coin. With so many variables in the effectiveness of a medicine it is no wonder things vary so much from one person to another.

[EBB]

Ok, this is very interesting. Just wish it wasn't me. So Zoloft DOES make more dopamine, but it blocks the transport to the nerve cells and that is why it's called a "dopamine inhibitor"? Same with Wellbutrin? It raises dopamine, but the transport is blocked? And if so, why would someone take it? Are you saying people like me should take Wellbutrin, not people with LOW dopamine?

[EBB]

Found this:

Sertraline blocks both serotonin and dopamine reuptake transporters, effectively increasing the synaptic activity of both neurotransmitters. So no, it does not “increase dopamine” because it does not increase the actual production of dopamine. But it does increase dopaminergic signalling by increasing the length of time that dopamine hangs out in the synaptic junction and interacts with its receptors.

Note that sertraline has a high affinity for the serotonin reuptake transporter, and is not widely used to inhibit the dopamine transporter. This suggests that sertraline’s actions on the dopamine transporter are secondary, and that most of sertraline’s effects can be attributed to changes in serotonergic signalling.

[EBB]

FH, I'm so sorry I just can't find anything that says Zoloft blocks transport of dopamine to the nerve cells and inhibits dopamine activity. Everything makes it sound like Zoloft is a better SSRI because it has the added feature of dopaminergic effects - better mood, relaxation, etc. Please don't run out of patience with me. What am I missing?

[fishinghat]

Ok, this is very interesting. Just wish it wasn't me. So Zoloft DOES make more dopamine, but it blocks the transport to the nerve cells and that is why it's called a "dopamine inhibitor"? Same with Wellbutrin? It raises dopamine, but the transport is blocked? And if so, why would someone take it? Are you saying people like me should take Wellbutrin, not people with LOW dopamine?

Zoloft does NOT increase the production of dopamine but allows dopamine to collect in the fluid around nerve cells because it is used less. The rest is true. Wellbutrin should be considered for people with depression because it blocks the use of dopamine. Because it the dopamine is not used then it builds up in the fluid around the nerve cells.

[fishinghat]

Found this:
Sertraline[/size] blocks both serotonin and dopamine reuptake transporters, effectively increasing the synaptic activity of both neurotransmitters. So no, it does not “increase dopamine” because it does not increase the actual production of dopamine. But it does increase dopaminergic signalling by increasing the length of time that dopamine hangs out in the synaptic junction and interacts with its receptors.[/size]
Note that sertraline has a high affinity for the serotonin reuptake transporter, and is not widely used to inhibit the dopamine transporter. This suggests that sertraline’s actions on the dopamine transporter are secondary, and that most of sertraline’s effects can be attributed to changes in serotonergic signalling.

Sertraline blocks both serotonin and dopamine reuptake transporters (true), effectively increasing the synaptic activity of both neurotransmitters. (False) (If it blocks the transporter to the synapse then how could it increase the activity?)

"So no, it does not “increase dopamine” because it does not increase the actual production of dopamine."
True. Dopamine production is not increased but remains the same but because it is not being used it collects in the fluid around the nerve cells.

"But it does increase dopaminergic signalling by increasing the length of time that dopamine hangs out in the synaptic junction and interacts with its receptors."

OK, lets complicate the issue, LOL. Some (like me) believe that the transporter collects a dopamine from one nerve cell and transports it to the next nerve cell for use. Others believe that the dopamine finds its own way across to the next nerve cell and the transporter simply removes it from the second nerve cell and brings it back to the original nerve cell to be reused (This author believes this.

"Note that sertraline has a high affinity for the serotonin reuptake transporter, and is not widely used to inhibit the dopamine transporter."
For the most cases I would agree.

"This suggests that sertraline’s actions on the dopamine transporter are secondary, and that most of sertraline’s effects can be attributed to changes in serotonergic signalling."

Sort of. There are a couple theories about that.

[fishinghat]

FH, I'm so sorry I just can't find anything that says Zoloft blocks transport of dopamine to the nerve cells and inhibits dopamine activity. Everything makes it sound like Zoloft is a better SSRI because it has the added feature of dopaminergic effects - better mood, relaxation, etc. Please don't run out of patience with me. What am I missing?

"FH, I'm so sorry I just can't find anything that says Zoloft blocks transport of dopamine to the nerve cells and inhibits dopamine activity."

I have a drs appointment soon (routine) so when I get back I will address that statement. Actually what you are missing is that these drs and researchers don't know.

Which way the transporter moves the dopamine? Two theories.
Does the collecting dopamine increase or decrease dopamine activity. Two theories.

And none of these articles mention the changes in synapse structure so the "medicine" can react with the synapse. If that happens how can dopamine react with the nerve cell if the attachment site is altered? When I get back I will explain that comment.

Talk to you soon.

[EBB]

Thanks FH,

I guess at this point, I'm wondering how I do the med process. Whether I do Lexapro or Zoloft, I will start at a low dose and then what? What do I do if I feel bad? Do I then have to do a long taper? Do I then switch to a different med from the one that's not good? Luvox was also reck to try bc I metabolize it, along with Paxil, but Paxil has so many problems...

[fishinghat]

Well, it is interesting. I saw my psychologist today and told her about my discussion with you today and we ere trying to figure out how these SSRI/SNRI work. She said 'Oh, lord, don't try to figure out who is right on that. It will drive you crazy.'

She did bring up one point that I new but had not mentioned in our discussion. All this research is done on dead brain tissue. Who know what effect that has on the actual mechanism.

[fishinghat]

You might want to look at this article EBB. Apparently there are several types of transport inhibitor. Each with its own mechanism of attaching to a medication and different mechanisms associated with it. Bo wonder this is so confusing.

https://en.wikipedia...anism_of_action

[fishinghat]

Interesting read.

https://en.wikipedia...herapeutic_uses


"A dopamine reuptake inhibitor (DRI) is a class of drug which acts as a reuptake inhibitor of the monoamine neurotransmitter dopamine by blocking the action of the dopamine transporter (DAT). Reuptake inhibition is achieved when extracellular dopamine not absorbed by the postsynaptic neuron is blocked from re-entering the presynaptic neuron. This results in increased extracellular concentrations of dopamine and increase in dopaminergic neurotransmission.[1]"

OK, if you look at the various forms of reuptake inhibitors and go back to the research on dopamine reuptake inhibitor and their effects you can see why the confusion.

"Selective dopamine reuptake inhibitors
4-Hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidyl 4-methylphenyl ketone
Altropane (O-587)
Amfonelic acid (WIN 25978)
Amineptine (has a reasonable degree of selectivity for dopamine over norepinephrine reuptake inhibition)
BTCP (GK-13)
3C-PEP (extremely potent and selective for dopamine transporter)
DBL-583
Difluoropine (O-620)
GBR-12783
GBR-12935
GBR-13069
GBR-13098
GYKI-52895
Iometopane (β-CIT, RTI-55)
Methylphenidate (has a mild degree of selectivity for dopamine over norepinephrine reuptake inhibition, although it significantly affects both)
Ethylphenidate (more selective for DA vs NE reuptake inhibition compared to methylphenidate, but still has a marked effect on both)
Modafinil (relatively weak but very selective for the dopamine transporter, with little to no effect on the norepinephrine or serotonin transporters)
Armodafinil (R-enantiomer of modafinil; somewhat more potent at inhibiting DAT than racemic modafinil, with equally negligible action on NET and SERT)
RTI-229
Vanoxerine (GBR-12909)

DRIs with substantial activity at other sites[edit]
Adrafinil (weak, possibly stressful on liver)
Benztropine (also muscarinic antagonist)
Bupropion
Fluorenol (extremely weak)
Medifoxamine (relatively weak)
Metaphit (irreversible; depletes dopamine)
Rimcazole
Venlafaxine (weak)

Other DRIs[edit]
Chaenomeles speciosa (Flowering Quince)[13]
Oroxylin A (found in Oroxylum indicum and Scutellaria baicalensis (Skullcap))[14]"

Some of the reuptake transporters are Active site transporter substrates, some
Allosteric site transporter substrates, some Vesicular transporter substrates and others have mechanisms unknown. Some of these types increase neurotransmitter function and some retard it depending on how the medicine binds to the transporters and how that combination reacts with the nerve cell synapses.

[fishinghat]

EBB, I am so glad you pushed this subject with me. I have learned a lot today because of you. What a complex issue but because Zoloft is an active site transporter substrate it DOES increase dopamine activity and I stand corrected. If it was an allosteric site transporter substrate it would decrease dopamine activity. I think I need to reread this every day for a couple weeks to get my head around it. WHEW!!!

 

Thanks again EBB.