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Schlep

Help. Need advice for switching off Nortriptyline.

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Okay, now after 26 years nortriptyline is starting to affect me adversely and it looks as though I might need to switch antidepressents. I think my problem is a sensitivity to dopamine (I've read that nortriptyline is a dopamine agonist on a certain part of the brain, and I'm having the same problems as I had with benzos and Abilify.)

So the first criteria would be that the new med doesn't alter dopamine. Second criteria would be something I could make an easy switch to. I tried amitriptyline a few years ago and couldn't handle it, so that's out. Are there any drugs very close to nortriptyline that don't affect dopamine? What would be the next logical choice?

As far as the second criteria, I've been looking at http://wiki.psychiatrienet.nl/index.php/SwitchAntidepressants, and see these as possibilities:

 fluoxetine, bupropion, citalopram, clomipramine, dosulepine, doxepine, imipramine, maprotiline, sertraline. venlafaxine.

I'm not sure how many meet the first criteria yet. 

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Posted (edited)
1 hour ago, Schlep said:

 So the first criteria would be that the new med doesn't alter dopamine. 

I'm not sure how many meet the first criteria yet. 

Bupropion (Wellbutrin) would definitely not meet your first criteria......

It is a norepinephrine-dopamine reuptake inhibitor. (NDRI)

The others on your list I'm not sure about....I would have to do some research first.

Hopefully someone else will respond who knows a bit more than I do.

 
Edited by CrazyRedhead

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Benzos do not hit dopamine at all. I think you are chasing the wrong med.

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I think the point the OP is trying to make is that GABA agonism can lead to downstream dopamine release which provides chemical reinforcement for their use leading to potential addiction in susceptible populations.

However, notloki makes a fair point. You may be chasing the wrong meds. Nortriptyline's affinity for the dopamine transporter is ~1140nM which is a really low affinity. That being said it is the highest of the TCAs aside from amineptine. It acts at D2 receptors as an antagonist with ~2570nM affinity. So I'm curious where you read nortriptyline was a dopamine receptor agonist.

Keep in mind that if nortriptyline is affecting you adversely, you may want to look for something completely different altogether. What makes nortriptyline distinct is its higher affinity for the norepinephrine transporter relative to serotonin. If you wanted to stick with TCAs and stick to predominantly noradrenergic ones, your next step would be desipramine. It has an affinity for the dopamine transporter of ~3190nM which would satisfy your requirement, but it may not be the ultimate fix. In the process, you would lose significant serotonergic effect. The other option is protriptyline but it isn't as often prescribed anymore because of a modest abuse potential. Additionally, it would have a higher affinity for the dopamine transporter than nortriptyline, which would rule this one out entirely.

 

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1 hour ago, browri said:

I think the point the OP is trying to make is that GABA agonism can lead to downstream dopamine release which provides chemical reinforcement for their use leading to potential addiction in susceptible populations.

However, notloki makes a fair point. You may be chasing the wrong meds. Nortriptyline's affinity for the dopamine transporter is ~1140nM which is a really low affinity. That being said it is the highest of the TCAs aside from amineptine. It acts at D2 receptors as an antagonist with ~2570nM affinity. So I'm curious where you read nortriptyline was a dopamine receptor agonist.

 

One source was here; "agonsut" was probably the wrong term.

https://books.google.com/books?id=KKlVf-L5DSkC&pg=PA137&lpg=PA137&dq="dopamine+transporters+nortriptyline"&source=bl&ots=XxhftESEv4&sig=h_f_jwp9QqzFPtGy3b-UqIbthkg&hl=en&sa=X&ved=2ahUKEwjA8oTy5eHfAhWhd98KHfpuB7QQ6AEwAHoECAUQAQ#v=onepage&q="dopamine transporters nortriptyline"&f=false

Another user elsewhere remarked that nortriptyline's  5HT2C antagonism also increased dopamine.

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14 hours ago, Schlep said:

Ah yes now that would be correct. Nortriptyline itself is not an agonist but you could technically call it an indirect agonist because all of the activity at dopamine receptors is mediated through other pathways. Norepinephrine and dopamine are both catecholamines, and the body does interconvert the two between each other.

I actually have the book you referenced. Stephen Stahl is great. He's suggesting that the increased noreadrenergic neurotransmission in the frontal cortex via norepinephrine reuptake inhibition and 5HT2C antagonism (which causes norepinephrine and dopamine release in the frontal cortex) leads to a net increase in dopaminergic signaling.

This mechanism is somewhat the same for most norepinephrine reuptake inhibitors and isn't specific to nortriptyline though. If you think that increased dopamine signaling is your problem, then you'll want to stay away from most medications that inhibit norepinephrine reuptake as well as dopamine reuptake. This rules out desipramine, protriptyline, nortriptyline, bupropion, duloxetine, venlafaxine, desvenlafaxine, sertraline, and quite possibly fluoxetine (which doesn't itself inhibit dopamine reuptake, but its major metabolite norfluoxetine does when you reach higher doses).

However, this truly begs the question why you think increased dopamine signaling is your problem. I don't see in the thread where you've indicated what symptoms you are experiencing that lend to that hypothesis. A lot of people on the boards here have taken several of these meds and we may be able to correlate the symptoms you are experiencing on nortriptyline to experiences that we've had on nortriptyline or other medications with similar mechanisms of action. Do you feel too stimulated? If so, then I would recommend trying perhaps paroxetine or escitalopram as SSRI options. If you wanted to stick with TCAs or TeCAs, you could also look at mirtazapine or amoxapine. Both have strong sedative action. All 4 of those options are known for being exceptional in anxious depression for many people.

However, like I indicated earlier, if you generally do respond well to nortriptyline and would like to keep close to that pharmacological profile, desipramine would likely be your next stop. Or if you wanted to switch from a TCA to an SNRI, desvenlafaxine and duloxetine would do it. Additionally, venlafaxine at higher doses can have an affinity for the dopamine transporter where desvenlafaxine does not appear to have such an affinity.

Can you describe what you're going through right now and perhaps we can provide experiences of what worked for us in those situations?

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4 hours ago, browri said:

Can you describe what you're going through right now and perhaps we can provide experiences of what worked for us in those situations?

Well, one thing is not noticing when I make such awful typing mistakes. Ugh. The original topic actually came from another thread which I reposted here verbatim because it swung so sharply towards ADs. I actually have a copy of that book which a former Pdoc gave me several years ago.

My problems started about three months ago with unexplained mild anxiety after being very stable for seven years (I did not have access to a pdoc at this time). At the time I was on 150mg of nortriptyline and about .25mg of clonazepam. Of course the first thing I did was raise the clonazepam, and things only got worse, reaching the point where I felt physically ill with bouts of nausea, not to mention severe depression and anhedonia, which were very atypical symptoms for me. It took me a month it was the clonazepam that was making me ill. I admitted myself to a psyche ward a few days after stopping the clonazepam and without extra medication much of the anxiety and physical symptoms lifted, though  not the depression. I finally tried some Ativan (.5mg), which I was initially reluctant to because it was another benzo, and at first felt an anxiety that gradually turned into a kind of euphoria that helped lift the depression (dopamine?). I knew this wasn't a real solution, but apparently it was enough for them to discharge me.

So I ended on on .25mg of Ativan 3X a day (the euphoria from .5mg was a bit strong), and would always get a bit nauseous the first dose, but it wouldn't persist. I should add that the euphoria was all I felt from the Ativan, and not any of the anti anxiolytic effects I was familiar with from clonazepam. But after a few weeks I started reacting to it the same way I was from the clonazepam, so I ended up in the psyche ward again. I first tried gabapentin, which made me anxious, then Zyprexa (2.5mg -0 5mg) for about a week, which made me slightly sedated and kind of emotionally flat. I tried Abilify (5mg) next, and responded well to it, possibly more due to its lack of side effects than anything it did in itself (no euphoria). Either way I got a bit stable and was discharged.

Maybe a week after getting home I started having the same bad reactions to the Abilify (though the anhedonia was initially not as bad, but some new symptoms were a kind of stiff feeling in my hands and feet, as well as leg cramps). It persisted for about four days, during which time I reduced my dosage to about a crumb that I took in the evening so I could stave off any withdrawal until I could see a Pdoc. I felt just as crappy on that little piece as I did a full pill (which was also the case with Ativan), but it was tolerable for a few hours and dissipated by the morning. I was actually feeling pretty stable until last friday night, and then the whole business started again. It began not long after my nightly dose of nortriptyline (reduced to 125mg because high levels were detected a few months ago), with the onset of a warm feeling that I felt strongly in my stomach and spread to the rest of my body, dry mouth (which I've often experienced with nortriptyline, but never at night right after having taken it), ear ringing (also unusual) and then insomnia, anxiety, and anhedonic depression the next day. I immediately stopped the Abilify, and carefully noted how things transpired the next few nights. It all followed the same pattern, and I was forced to conclude it was nortriptyline. By night four I tried reducing it to 100mg, and then came brain-on-fire anxiety (though I can't rule out Abilify withdrawel as the cause.) I was able to get my Pdoc to call in some Zyprexa (2.5mg) by Tuesday, which I felt was my best chance at temporary relief, and it immediately started helping the anxiety (the reduction of the nortriptyline to 75mg could be helping too.) I'm on day two now, and things on the anxiety side at least are slightly better.  

I'm largely thinking a dopamine imbalance due to the benzos, especially in regards to the euphoria being the only thing I experienced from Ativan. Maybe excess dopamine is destroying GABA production, and the benzos brought dopamine up to some critical point that resulted in illness. Maybe this is somewhat supported by my so far positive reaction to Zyprexa's dopamine antagonism? It's the only neurotransmitter imbalance theory I can come up with, though it might not explain the depression and anhedonia. I'm curious about which plays a larger role in anhedonia: dopamine or serotonin. 

But what I'd really like to go after are possible physiological conditions that might be causing this. My first Pdoc seemed to regularly test my thyroid, as she had me on synthroid my first year. I believe it affects dopamine production and a lot of gut developments that affect neurotransmitters. Metabolism could be some kind of issue too, perhaps reflected by the recent immediate onset of side effects from the nortriptyline. During this whole period I've noticed a kind of "vapor" that produced a taste and smell from medications affecting me adversely that I've never experienced in the past. But at this point, as far as I know, no one treating me has considered anything other than brain chemical imbalances.   

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38 minutes ago, Schlep said:

Well, one thing is not noticing when I make such awful typing mistakes. Ugh. The original topic actually came from another thread which I reposted here verbatim because it swung so sharply towards ADs. I actually have a copy of that book which a former Pdoc gave me several years ago.

My problems started about three months ago with unexplained mild anxiety after being very stable for seven years (I did not have access to a pdoc at this time). At the time I was on 150mg of nortriptyline and about .25mg of clonazepam. Of course the first thing I did was raise the clonazepam, and things only got worse, reaching the point where I felt physically ill with bouts of nausea, not to mention severe depression and anhedonia, which were very atypical symptoms for me. It took me a month it was the clonazepam that was making me ill. I admitted myself to a psyche ward a few days after stopping the clonazepam and without extra medication much of the anxiety and physical symptoms lifted, though  not the depression. I finally tried some Ativan (.5mg), which I was initially reluctant to because it was another benzo, and at first felt an anxiety that gradually turned into a kind of euphoria that helped lift the depression (dopamine?). I knew this wasn't a real solution, but apparently it was enough for them to discharge me.

So I ended on on .25mg of Ativan 3X a day (the euphoria from .5mg was a bit strong), and would always get a bit nauseous the first dose, but it wouldn't persist. I should add that the euphoria was all I felt from the Ativan, and not any of the anti anxiolytic effects I was familiar with from clonazepam. But after a few weeks I started reacting to it the same way I was from the clonazepam, so I ended up in the psyche ward again. I first tried gabapentin, which made me anxious, then Zyprexa (2.5mg -0 5mg) for about a week, which made me slightly sedated and kind of emotionally flat. I tried Abilify (5mg) next, and responded well to it, possibly more due to its lack of side effects than anything it did in itself (no euphoria). Either way I got a bit stable and was discharged.

Maybe a week after getting home I started having the same bad reactions to the Abilify (though the anhedonia was initially not as bad, but some new symptoms were a kind of stiff feeling in my hands and feet, as well as leg cramps). It persisted for about four days, during which time I reduced my dosage to about a crumb that I took in the evening so I could stave off any withdrawal until I could see a Pdoc. I felt just as crappy on that little piece as I did a full pill (which was also the case with Ativan), but it was tolerable for a few hours and dissipated by the morning. I was actually feeling pretty stable until last friday night, and then the whole business started again. It began not long after my nightly dose of nortriptyline (reduced to 125mg because high levels were detected a few months ago), with the onset of a warm feeling that I felt strongly in my stomach and spread to the rest of my body, dry mouth (which I've often experienced with nortriptyline, but never at night right after having taken it), ear ringing (also unusual) and then insomnia, anxiety, and anhedonic depression the next day. I immediately stopped the Abilify, and carefully noted how things transpired the next few nights. It all followed the same pattern, and I was forced to conclude it was nortriptyline. By night four I tried reducing it to 100mg, and then came brain-on-fire anxiety (though I can't rule out Abilify withdrawel as the cause.) I was able to get my Pdoc to call in some Zyprexa (2.5mg) by Tuesday, which I felt was my best chance at temporary relief, and it immediately started helping the anxiety (the reduction of the nortriptyline to 75mg could be helping too.) I'm on day two now, and things on the anxiety side at least are slightly better.  

I'm largely thinking a dopamine imbalance due to the benzos, especially in regards to the euphoria being the only thing I experienced from Ativan. Maybe excess dopamine is destroying GABA production, and the benzos brought dopamine up to some critical point that resulted in illness. Maybe this is somewhat supported by my so far positive reaction to Zyprexa's dopamine antagonism? It's the only neurotransmitter imbalance theory I can come up with, though it might not explain the depression and anhedonia. I'm curious about which plays a larger role in anhedonia: dopamine or serotonin. 

But what I'd really like to go after are possible physiological conditions that might be causing this. My first Pdoc seemed to regularly test my thyroid, as she had me on synthroid my first year. I believe it affects dopamine production and a lot of gut developments that affect neurotransmitters. Metabolism could be some kind of issue too, perhaps reflected by the recent immediate onset of side effects from the nortriptyline. During this whole period I've noticed a kind of "vapor" that produced a taste and smell from medications affecting me adversely that I've never experienced in the past. But at this point, as far as I know, no one treating me has considered anything other than brain chemical imbalances.   

Okay this makes sense. To answer your question about anhedonia, we aren't totally sure. At this point though, we can draw the hypothesis that dopamine is the culprit because it is the center of our pleasure system. Anhedonia is prominent on partial responders to serotonergic antidepressants like SSRIs but doesn't seem to be an issue for those taking dopamine enhancing medications like bupropion.

In regards to the relation of GABA and dopamine, yes, GABA release encourages a downstream release of dopamine. However, increased dopamine signaling also leads to increased glutamate signaling, which is GABA's opposite. With increasing glutamate there will be decreasing GABA. This is the feedback loop. GABA signaling increases, followed by dopamine, then glutamate, and then GABA signaling decreases. It's one of the brain's balancing acts. However, you also can see how this feedback loop can be dangerous and reinforces the use of benzos. If the dopamine release results in a reduction in GABA signaling, this then encourages the user to consume more of the GABAergic agent (benzo or otherwise) to maintain GABA signaling and the pleasurable dopamine release. This is likely where the euphoria came from when you took Ativan and it's why people so easily become dependent on benzo's.

Interesting to note that your nortriptyline levels were high. Do you normally have serum levels taken?

Speaking to the olanzapine (Zyprexa), keep in mind that the activities at serotonin receptors encourage downstream dopamine release. The dopamine antagonism balances that out. At 2.5mg, you haven't entirely saturated the 5HT2A or H1 (histamine) receptors, hence why you're still experiencing the sedative effects, which can dissipate with higher dosing where olanzapine will saturate those receptors. This makes low dose olanzapine a common anxiolytic agent. Also keep in mind that its potent anticholinergic effects can increase the body temp and make you sleepy as well.

Which leads into another possibility, that maybe for anxiety you would respond well to an older antihistamine like hydroxyzine or the tetracyclic antidepressant mirtazapine (Remeron), which is also an antihistamine.

If you want to delve into deeper physiological roots to these issues, one thing you could look at is if you have the MTHFR mutation. This mutation will reduce your body's ability to produce neurotransmitter precursors from folate. Those who have the genetic mutation benefit from supplementation with L-5-methylfolate (not your retail pharmacy folic acid, which can make things infinitely worse). Another more "esoteric" approach is to get either Ancestry or 23andMe's DNA tests done, download your data, and plug it into a methylation analysis tool like Genetic Genie to see if you have any common dysfunctions in the body's methylation processes, which can contribute significantly to mental illness. I've found that I'm an underproducer of MAO-A (monoamine oxidase A) which metabolizes serotonin, norepinephrine, and dopamine (with preference to serotonin) and I'm also an under-producer of COMT (catechol-O-methyltransferase) which metabolizes norepinephrine, epinephrine, and dopamine. The net result is NO shortage of neurotransmitters in my brain to the point that dampening signaling is what I want to do. This may be why I respond well to Depakote. It increases MAO-A and it reduces the synthesis of more catecholamines like dopamine to make up for my brain's deficient ability to do break down these neurotransmitters on its own. Additionally, I have multiple short alleles for the serotonin transporter, which would mean I have lower amounts of the transporter and higher levels of serotonin. I also may have over-expressed pre-synaptic 5HT1A receptors, which combined with low SERT and high serotonin would actually REDUCE serotonin signaling. And this may be why I've never gotten by without some sort of serotonergic antidepressant. And I've done better on ones that activate the 5HT1A receptor like vortioxetine (Trintellix) and vilazodone (Viibryd). Although with the latter I had insomnia, vivid dreaming, and chronic diarrhea unfortunately. But it was still quite a kick for my depression.

You mentioned that your pdoc tested your thyroid, and maybe it's time to test it again. I would encourage testing TSH, T4, and T3. This is important because TSH may be normal but T4 could be low, meaning the brain isn't releasing more TSH to increase the thyroid's T4 output. Alternatively, T4 could be normal, but T3 could be low, which would mean there is an issue with the internal bodily process which converts T4 into T3, the more active form. If your T4 and T3 are both low, you start with Synthroid (levothyroxine, T4). If your T4 normalizes but your T3 does not, then you might need to switch to Cytomel (liiothyronine, T3). There are also other thyroid medications that are a combination of the two in controlled ratios.

Also, if you responded well to Abilify while inpatient but experienced side effects after release, that isn't surprising. It takes Abilify about 2-3 weeks to reach steady state once you reach a specific dose, so it's not unusual for side effects to not show up until a week or two into it on a steady dose. For those that initially respond well to Abilify but can't tolerate the side effects, Rexulti is generally regarded as more tolerable for those people with similar to better efficacy. I personally couldn't tolerate Abilify any longer than 10 days before I gave up. Rexulti, by contrast, has been a DREAM.

Would you say you've ever had mood swings?

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2 hours ago, browri said:

Okay this makes sense. To answer your question about anhedonia, we aren't totally sure. At this point though, we can draw the hypothesis that dopamine is the culprit because it is the center of our pleasure system. Anhedonia is prominent on partial responders to serotonergic antidepressants like SSRIs but doesn't seem to be an issue for those taking dopamine enhancing medications like bupropion.

In regards to the relation of GABA and dopamine, yes, GABA release encourages a downstream release of dopamine. However, increased dopamine signaling also leads to increased glutamate signaling, which is GABA's opposite. With increasing glutamate there will be decreasing GABA. This is the feedback loop. GABA signaling increases, followed by dopamine, then glutamate, and then GABA signaling decreases. It's one of the brain's balancing acts. However, you also can see how this feedback loop can be dangerous and reinforces the use of benzos. If the dopamine release results in a reduction in GABA signaling, this then encourages the user to consume more of the GABAergic agent (benzo or otherwise) to maintain GABA signaling and the pleasurable dopamine release. This is likely where the euphoria came from when you took Ativan and it's why people so easily become dependent on benzo's.

Interesting to note that your nortriptyline levels were high. Do you normally have serum levels taken?

Speaking to the olanzapine (Zyprexa), keep in mind that the activities at serotonin receptors encourage downstream dopamine release. The dopamine antagonism balances that out. At 2.5mg, you haven't entirely saturated the 5HT2A or H1 (histamine) receptors, hence why you're still experiencing the sedative effects, which can dissipate with higher dosing where olanzapine will saturate those receptors. This makes low dose olanzapine a common anxiolytic agent. Also keep in mind that its potent anticholinergic effects can increase the body temp and make you sleepy as well.

Which leads into another possibility, that maybe for anxiety you would respond well to an older antihistamine like hydroxyzine or the tetracyclic antidepressant mirtazapine (Remeron), which is also an antihistamine.

If you want to delve into deeper physiological roots to these issues, one thing you could look at is if you have the MTHFR mutation. This mutation will reduce your body's ability to produce neurotransmitter precursors from folate. Those who have the genetic mutation benefit from supplementation with L-5-methylfolate (not your retail pharmacy folic acid, which can make things infinitely worse). Another more "esoteric" approach is to get either Ancestry or 23andMe's DNA tests done, download your data, and plug it into a methylation analysis tool like Genetic Genie to see if you have any common dysfunctions in the body's methylation processes, which can contribute significantly to mental illness. I've found that I'm an underproducer of MAO-A (monoamine oxidase A) which metabolizes serotonin, norepinephrine, and dopamine (with preference to serotonin) and I'm also an under-producer of COMT (catechol-O-methyltransferase) which metabolizes norepinephrine, epinephrine, and dopamine. The net result is NO shortage of neurotransmitters in my brain to the point that dampening signaling is what I want to do. This may be why I respond well to Depakote. It increases MAO-A and it reduces the synthesis of more catecholamines like dopamine to make up for my brain's deficient ability to do break down these neurotransmitters on its own. Additionally, I have multiple short alleles for the serotonin transporter, which would mean I have lower amounts of the transporter and higher levels of serotonin. I also may have over-expressed pre-synaptic 5HT1A receptors, which combined with low SERT and high serotonin would actually REDUCE serotonin signaling. And this may be why I've never gotten by without some sort of serotonergic antidepressant. And I've done better on ones that activate the 5HT1A receptor like vortioxetine (Trintellix) and vilazodone (Viibryd). Although with the latter I had insomnia, vivid dreaming, and chronic diarrhea unfortunately. But it was still quite a kick for my depression.

You mentioned that your pdoc tested your thyroid, and maybe it's time to test it again. I would encourage testing TSH, T4, and T3. This is important because TSH may be normal but T4 could be low, meaning the brain isn't releasing more TSH to increase the thyroid's T4 output. Alternatively, T4 could be normal, but T3 could be low, which would mean there is an issue with the internal bodily process which converts T4 into T3, the more active form. If your T4 and T3 are both low, you start with Synthroid (levothyroxine, T4). If your T4 normalizes but your T3 does not, then you might need to switch to Cytomel (liiothyronine, T3). There are also other thyroid medications that are a combination of the two in controlled ratios.

Also, if you responded well to Abilify while inpatient but experienced side effects after release, that isn't surprising. It takes Abilify about 2-3 weeks to reach steady state once you reach a specific dose, so it's not unusual for side effects to not show up until a week or two into it on a steady dose. For those that initially respond well to Abilify but can't tolerate the side effects, Rexulti is generally regarded as more tolerable for those people with similar to better efficacy. I personally couldn't tolerate Abilify any longer than 10 days before I gave up. Rexulti, by contrast, has been a DREAM.

Would you say you've ever had mood swings?

Okay, something here really stands out, and it's glutamate. Some cursory research shows that it can be responsible for anxiety, restlessness, and an inability to focus, which sort of covers what I'm going through. Perhaps it was high glutamate that kept the benzos from working the way that they should. Can glutamate be tested (I have a bunch of test results from the last few months and it could be on there), and are there drugs that lower it? I'd also like to add that my anxiety condition was triggered by caffeine almost three decades ago, which is partly why I suspected dopamine. I vaguely knew already that GABA and dopamine exclude eachother, but didn't know the mechanism. So maybe I react to dopamine normally, but not the glutamate. Does the brain naturally rid itself of excess glutamate? 

The doctor in my last stay at the psyche ward wanted to increase the dosage of Zyprexa to 7.5mg, but I assumed more Zyprexa woukd be more sedating, and that's when I decided to try Abilify. Is Olanazipine one of those weird  drugs that acts differently at different doses. As far as visteral, I was given 50mg after I had stopped the clonazepam and had a negative reaction to it that included brief problems with memory. I really never want to take it again. I was considering remeron, but there are some major contraindications with nortriptyline.

As far as I know, I had no thyroid testing done since that first psychiatrist, who retired almost twenty years ago. One of my previous medical doctors used to check my nortriptyline levels fanatically, but I think over the past ten years it was only tested once as an outpatient, and that was by request. The levels were tested as an inpatient (I think again at my suggestion), with a result of 220; thus my dosage was lowered to 125mg.

I was taking Abilify about a month in total, and once the negative effects started I was suffering them right until the end. I was thinking of Rexulte, but am concerned it might be too much like Abilify and I'll just react badly to it eventually. No psychiatrists in my area seem to offer genetic testing, so I would have to do it independently. 

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If you are thinking of the glutamate angle (reducing/modulating glutamate)

1. lamictal - onlabel mood stabilizer. has known antidepressant qualities

2. topamax - off label mood stabilizer, questionable efficacy

Supplement

1. NAC - Might help, least it's OTC..cheap enough to roll the dice at any rate.

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13 hours ago, Schlep said:

Okay, something here really stands out, and it's glutamate. Some cursory research shows that it can be responsible for anxiety, restlessness, and an inability to focus, which sort of covers what I'm going through. Perhaps it was high glutamate that kept the benzos from working the way that they should. Can glutamate be tested (I have a bunch of test results from the last few months and it could be on there), and are there drugs that lower it? I'd also like to add that my anxiety condition was triggered by caffeine almost three decades ago, which is partly why I suspected dopamine. I vaguely knew already that GABA and dopamine exclude eachother, but didn't know the mechanism. So maybe I react to dopamine normally, but not the glutamate. Does the brain naturally rid itself of excess glutamate? 

The doctor in my last stay at the psyche ward wanted to increase the dosage of Zyprexa to 7.5mg, but I assumed more Zyprexa woukd be more sedating, and that's when I decided to try Abilify. Is Olanazipine one of those weird  drugs that acts differently at different doses. As far as visteral, I was given 50mg after I had stopped the clonazepam and had a negative reaction to it that included brief problems with memory. I really never want to take it again. I was considering remeron, but there are some major contraindications with nortriptyline.

As far as I know, I had no thyroid testing done since that first psychiatrist, who retired almost twenty years ago. One of my previous medical doctors used to check my nortriptyline levels fanatically, but I think over the past ten years it was only tested once as an outpatient, and that was by request. The levels were tested as an inpatient (I think again at my suggestion), with a result of 220; thus my dosage was lowered to 125mg.

I was taking Abilify about a month in total, and once the negative effects started I was suffering them right until the end. I was thinking of Rexulte, but am concerned it might be too much like Abilify and I'll just react badly to it eventually. No psychiatrists in my area seem to offer genetic testing, so I would have to do it independently. 

Unfortunately, glutamate cannot be tested. It is a neurotransmitter and isn't something we can really quantify (without splitting your skull open) especially because glutamate supply doesn't always translate to glutamate signaling. As for me, I have high serotonin levels, but low serotonin signaling, at least according to some genetic studies. Glutamate is responsible for cognition, but in high amounts it can cause depression and anxiety. For some people, depression and anxiety COULD be the result of an overactive glutamate system. And for some people the glutamate system is underactive. One of the ways the Trintellix is thought to mediate some of its antidepressant and pro-cognitive effects is through enhancement of glutamate signaling via antagonism of 5HT3 receptors, which also results in increased signaling of acetylcholine (cognition as well), histamine (alertness), serotonin (emotions), norepinephrine (fight-or-flight/vigilance), and dopamine (pleasure). 5HT3 is a very multi-faceted receptor.

As for olanzapine, I never went higher than 5mg on it. It was always sedating for me. I know that quetiapine goes from sedating to activating at around 200mg, but that's because it is also a norepinephrine reuptake inhibitor similarly to nortriptyline. Olanzapine on the other hand is not. Theoretically at higher doses when 5HT2A and H1 are saturated, there may be less sedation, but I would need someone who has taken olanzapine at doses of 10mg and above to second that.

And as for brexpiprazole (Rexulti), I can assure you that it is very different from aripiprazole. Lower propensity for agitation and akathisia, slightly higher propensity for weight gain than aripiprazole. However, brexpiprazole has shown a lot of positive results in anxious depression and PTSD as well as agitation in Alzheimer's disease. It's much more calming. Having personally taken both olanzapine and brexpiprazole, I can say from experience that they are more similar in their antidepressant and anxiolytic effects than brexpiprazole and aripiprazole. I found aripiprazole to be way too agitating and that was after increasing to 7.5mg on it over the course of 10 days. I just couldn't hack aripiprazole at all.

If there's one thing I can certainly encourage, it's that going into brexpiprazole you should expect that it will be different from aripiprazole. Brexpiprazole will be sedating at lower doses and activating at higher ones, whereas aripiprazole is activating at lower doses and sedating (sometimes) at higher ones. The reason for this is their difference in receptor affinities and intrinsic activities. Brexpiprazole has a higher affinity and near 100% intrinsic activity at 5HT1A receptors (it's almost a full agonist) unlike aripiprazole, whose intrinsic activity is lower making it a partial agonist. Brexpiprazole also has a higher affinity for the 5HT2A receptor than aripiprazole making it a stronger blocker there. Combined, the increased effect at these two receptors improves brexpiprazole's tolerability (against akathisia or agitation) as well as its antidepressant and anxiolytic effects. Brexpiprazole is also a stronger blocker of alpha adrenergic receptors similarly to mirtazapine and -pine atypical antipsychotics. And finally, but most importantly, where aripiprazole has an intrinsic activity (agonist effect) at D2 receptors of about 60% or so, brexpiprazole only has an intrinsic activity of about 40-45%, so more balanced dopamine signaling, which also contributes to less akathisia and agitation in combination with adrenergic antagonism.

When it comes to genetic testing, nowadays that's pretty much a foray you have to make on your own using the raw data from Ancestry and 23andMe tests and tools like Genetic Genie and SelfDecode (love this site). The latter site is actually where I do most of my discovery work using both my Ancestry and 23andMe data. The reason I review both is because each company doesn't test your entire genome, just what they need to in order to make an ethnic profile, but there are some key differences. For example, 23andMe tests mitochondrial DNA, which is only inherited from the mother. The mitochondrial DNA happens to be the locus for monoamine oxidase A, which is most interesting because my mother hasn't struggled with clinical depression in her lifetime, at least none that she's taken medication for, yet she clearly passed on genes to me that have the potential to be dysfunctional when combined with other dysfunctional genes.

There are genetic tests that a pdoc can order like Genesight, but it's a 50/50 toss-up that the report will make recommendations that are valid. More often than not, pdocs say that because we aren't very far along in psychogenomics and pharmacogenetics that those reports are better at telling what you SHOULDN'T use rather than what you SHOULD use.

12 hours ago, argh said:

If you are thinking of the glutamate angle (reducing/modulating glutamate)

1. lamictal - onlabel mood stabilizer. has known antidepressant qualities

2. topamax - off label mood stabilizer, questionable efficacy

Supplement

1. NAC - Might help, least it's OTC..cheap enough to roll the dice at any rate.

@argh pretty much nailed it. If you want to reduce glutamate and keep to the books, lamotrigine (Lamictal) is what you're looking for. Topiramate (Topamax) is also a glutamate reducing agent, but it has less evidence in its favor when it comes to treating mood disorders. If you wanted to go really off the beaten path, riluzole has some evidence in its favor for the treatment of mood disorders and modulates glutamate signaling. Although it's indicated for amyotrophic lateral sclerosis (ALS / Lou Gehrig's), it is generic now and might be considered if your pdoc is adventurous and lamotrigine doesn't work out. Additionally, they are working on a prodrug of riluzole called troriluzole which will supposedly be more effective at treating mental conditions allowing riluzole as a compound to be appropriately re-purposed and properly approved for those indications.

I believe @notloki would be able to comment on NAC as well. It supposedly is effective at reducing glutamate toxicity caused by amphetamines and I believe reduces amphetamine tolerance as well from what I understand? So I suppose it may be helpful in this case if glutamate is in fact the problem.

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Schlep. FWIW. I’m convinced that my personal issue stems from the glutamate/gaba system.

reason being, gabapentin has been my miracle drug for depression. It is a gaba analogue, so think of it as balancing the other side of the glutamate system.

while very early in, I have also been taking NAC. For me it is a supplement with an actual tangible effect. I find it calming, better focused and ability to stop thinking about things that wreck my proverbial shit when they pop up. Could totally be placebo however as I’m only 3 weeks in.

never been on lamictal or topamax, so I can’t say for sure if they would help. Logically they might, due  to the response to the NAC via glutamate modulation 

 

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10 hours ago, browri said:

Unfortunately, glutamate cannot be tested. It is a neurotransmitter and isn't something we can really quantify (without splitting your skull open) especially because glutamate supply doesn't always translate to glutamate signaling. As for me, I have high serotonin levels, but low serotonin signaling, at least according to some genetic studies. Glutamate is responsible for cognition, but in high amounts it can cause depression and anxiety. For some people, depression and anxiety COULD be the result of an overactive glutamate system. And for some people the glutamate system is underactive. One of the ways the Trintellix is thought to mediate some of its antidepressant and pro-cognitive effects is through enhancement of glutamate signaling via antagonism of 5HT3 receptors, which also results in increased signaling of acetylcholine (cognition as well), histamine (alertness), serotonin (emotions), norepinephrine (fight-or-flight/vigilance), and dopamine (pleasure). 5HT3 is a very multi-faceted receptor.

As for olanzapine, I never went higher than 5mg on it. It was always sedating for me. I know that quetiapine goes from sedating to activating at around 200mg, but that's because it is also a norepinephrine reuptake inhibitor similarly to nortriptyline. Olanzapine on the other hand is not. Theoretically at higher doses when 5HT2A and H1 are saturated, there may be less sedation, but I would need someone who has taken olanzapine at doses of 10mg and above to second that.

And as for brexpiprazole (Rexulti), I can assure you that it is very different from aripiprazole. Lower propensity for agitation and akathisia, slightly higher propensity for weight gain than aripiprazole. However, brexpiprazole has shown a lot of positive results in anxious depression and PTSD as well as agitation in Alzheimer's disease. It's much more calming. Having personally taken both olanzapine and brexpiprazole, I can say from experience that they are more similar in their antidepressant and anxiolytic effects than brexpiprazole and aripiprazole. I found aripiprazole to be way too agitating and that was after increasing to 7.5mg on it over the course of 10 days. I just couldn't hack aripiprazole at all.

If there's one thing I can certainly encourage, it's that going into brexpiprazole you should expect that it will be different from aripiprazole. Brexpiprazole will be sedating at lower doses and activating at higher ones, whereas aripiprazole is activating at lower doses and sedating (sometimes) at higher ones. The reason for this is their difference in receptor affinities and intrinsic activities. Brexpiprazole has a higher affinity and near 100% intrinsic activity at 5HT1A receptors (it's almost a full agonist) unlike aripiprazole, whose intrinsic activity is lower making it a partial agonist. Brexpiprazole also has a higher affinity for the 5HT2A receptor than aripiprazole making it a stronger blocker there. Combined, the increased effect at these two receptors improves brexpiprazole's tolerability (against akathisia or agitation) as well as its antidepressant and anxiolytic effects. Brexpiprazole is also a stronger blocker of alpha adrenergic receptors similarly to mirtazapine and -pine atypical antipsychotics. And finally, but most importantly, where aripiprazole has an intrinsic activity (agonist effect) at D2 receptors of about 60% or so, brexpiprazole only has an intrinsic activity of about 40-45%, so more balanced dopamine signaling, which also contributes to less akathisia and agitation in combination with adrenergic antagonism.

When it comes to genetic testing, nowadays that's pretty much a foray you have to make on your own using the raw data from Ancestry and 23andMe tests and tools like Genetic Genie and SelfDecode (love this site). The latter site is actually where I do most of my discovery work using both my Ancestry and 23andMe data. The reason I review both is because each company doesn't test your entire genome, just what they need to in order to make an ethnic profile, but there are some key differences. For example, 23andMe tests mitochondrial DNA, which is only inherited from the mother. The mitochondrial DNA happens to be the locus for monoamine oxidase A, which is most interesting because my mother hasn't struggled with clinical depression in her lifetime, at least none that she's taken medication for, yet she clearly passed on genes to me that have the potential to be dysfunctional when combined with other dysfunctional genes.

There are genetic tests that a pdoc can order like Genesight, but it's a 50/50 toss-up that the report will make recommendations that are valid. More often than not, pdocs say that because we aren't very far along in psychogenomics and pharmacogenetics that those reports are better at telling what you SHOULDN'T use rather than what you SHOULD use.

@argh pretty much nailed it. If you want to reduce glutamate and keep to the books, lamotrigine (Lamictal) is what you're looking for. Topiramate (Topamax) is also a glutamate reducing agent, but it has less evidence in its favor when it comes to treating mood disorders. If you wanted to go really off the beaten path, riluzole has some evidence in its favor for the treatment of mood disorders and modulates glutamate signaling. Although it's indicated for amyotrophic lateral sclerosis (ALS / Lou Gehrig's), it is generic now and might be considered if your pdoc is adventurous and lamotrigine doesn't work out. Additionally, they are working on a prodrug of riluzole called troriluzole which will supposedly be more effective at treating mental conditions allowing riluzole as a compound to be appropriately re-purposed and properly approved for those indications.

I believe @notloki would be able to comment on NAC as well. It supposedly is effective at reducing glutamate toxicity caused by amphetamines and I believe reduces amphetamine tolerance as well from what I understand? So I suppose it may be helpful in this case if glutamate is in fact the problem.

What was your personal experience in evaluating olanzapine and brexpiprazole; e.g differences in their main effect, side effects, etc. Which one did you think was better? I've also seen amisulpride and sulpride suggested, but their not available in the US. What APs are they most similar to?

On a more esoteric note, do you know anything about the effects of mold (toxic or otherwise) on neurotransmitters? I've had incidients with mold directly affecting my condition in the past, and it could be a factor this time.

6 hours ago, argh said:

Schlep. FWIW. I’m convinced that my personal issue stems from the glutamate/gaba system.

reason being, gabapentin has been my miracle drug for depression. It is a gaba analogue, so think of it as balancing the other side of the glutamate system.

while very early in, I have also been taking NAC. For me it is a supplement with an actual tangible effect. I find it calming, better focused and ability to stop thinking about things that wreck my proverbial shit when they pop up. Could totally be placebo however as I’m only 3 weeks in.

never been on lamictal or topamax, so I can’t say for sure if they would help. Logically they might, due  to the response to the NAC via glutamate modulation 

 

I tried gabapentin and it immediately made me anxious. Would that indicate anything as far as glutamate is concerned?  

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Just now, Schlep said:

What was your personal experience in evaluating olanzapine and brexpiprazole; e.g differences in their main effect, side effects, etc. Which one did you think was better?

On a more esoteric note, do you know anything about the effects of mold (toxic or otherwise) on neurotransmitters? I've had incidients with mold directly affecting my condition in the past, and it could be a factor this time.

I tried gabapentin and it immediately made me anxious. Would that indicate anything as far as glutamate is concerned?  

Not something you should worry about imo. Just might not have been the right drug for you. 

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On 1/11/2019 at 6:58 PM, Schlep said:

What was your personal experience in evaluating olanzapine and brexpiprazole; e.g differences in their main effect, side effects, etc.

Main effect was very similar, which is what I liked about brexpiprazole. It had the anxiolytic/calming efficacy of olanzapine and also produced an antidepressant effect when combined with Trintellix at doses of just 0.25mg and 0.5mg. Like olanzapine, it does cause weight gain, but the mechanisms are slightly different.

Olanzapine has a super high affinity for 5HT2C, H1, and several of the muscarinic acetylcholine receptors, particularly M1 and M3. The M3 antagonism dramatically increases olanzapine's risk for type 2 diabetes, and broad anticholinergic effects cause other side effects like urinary retention and blurred vision. The 5HT2C inverse agonism and H1 antagonism also contribute, the former by reducing satiety (i.e. making you more hungry), and the latter by making you more sedentary.

By contrast, brexpiprazole does have affinity for 5HT2C and H1 like olanzapine, but much lower affinities. Additionally, at the 5HT2C receptor, it is a partial agonist, which may allow more normal modulation of satiety. Brexpiprazole also has very little, if any, anticholinergic effect which means that while Rexulti might cause some weight gain and increase your appetite, it likely will not disturb metabolic parameters like blood glucose or triglycerides/cholesterol as greatly as olanzapine.

In my experience, both have caused weight gain. Rexulti, half as much. And where olanzapine even at 5mg did somewhat elevate my lipids and blood glucose, brexpiprazole has not, and I have been taking it now since September or October of 2017. I think I took olanzapine for maybe 6-9 months.

On 1/11/2019 at 6:58 PM, Schlep said:

Which one did you think was better? I've also seen amisulpride and sulpride suggested, but their not available in the US. What APs are they most similar to?

I think brexpiprazole feels a bit "cleaner". But really it's hard to say. All I know is it gave me the strong effect of olanzapine with fewer side effects. And I don't think Rexulti is like any other AAP I've tried, even Abilify.

On 1/11/2019 at 6:58 PM, Schlep said:

On a more esoteric note, do you know anything about the effects of mold (toxic or otherwise) on neurotransmitters? I've had incidients with mold directly affecting my condition in the past, and it could be a factor this time.

Funny you say that, in the story the Crucible, and the Salem witch trials in general, they believe that because the rye fields were wet, the growth of ergot mold (which was used to synthesize LSD) is likely what caused a lot of the paranoia and possibly hallucinations in some of those people. Not to mention psilcybin...so there is the possibility I suppose.

On 1/11/2019 at 6:58 PM, Schlep said:

I tried gabapentin and it immediately made me anxious. Would that indicate anything as far as glutamate is concerned?  

Question is have you taken gabapentin regularly or did you just take it that one time? Sometimes there are lasting changes that need to happen. GABA analogues like gabapentin, pregabalin, and vigabatrin all bind to GABA receptors in place of GABA to calm the suppress nerve signaling. It may be that repeated gabapentin administration may have had anxiolytic effects after a period of time.

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Browri has a point. For me gabapentin would be pretty worthless as a prn. At least in my doses. Took a good 4 days before any anxiolytic or antidepressant effects kicked in. To note of course, that it generally doesn’t work as an ad for most.

what was your dose, schlep? I felt nothing under 200, a tiny bit at 300. Didn’t notice much until 500. These are still low doses however. Many here need much higher doses to get any benefit.

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36 minutes ago, argh said:

Browri has a point. For me gabapentin would be pretty worthless as a prn. At least in my doses. Took a good 4 days before any anxiolytic or antidepressant effects kicked in. To note of course, that it generally doesn’t work as an ad for most.

what was your dose, schlep? I felt nothing under 200, a tiny bit at 300. Didn’t notice much until 500. These are still low doses however. Many here need much higher doses to get any benefit.

Just one dose of whatever the lowest dosage was, since I'm very sensitive to meds (that's why the pdoc originally suggested Zyprexa due to it's low dosage range.) I was still getting sick from Ativan at that time, and had taken my last crumbbs of Ativan on that day. The anxiety was definitely from the gabapentin though, since I felt it kick in after taking it.

Hey browri, what different kinds of factors predispose one to be sensitive to psychiatric medications? Are there a lot of biological ones?

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That would be about 100mg.

You could be a slow metabolizer of medications due to genes. I.E. your body takes longer to clear medicines out of your body.

https://www.snpedia.com/index.php/Drug_Metabolism

There is also the consideration of inhibitors to metabolism, such as CYP2D6. For example, bupropion is a CYP2D6 inhibitor, which beyond inhibiting itself, could cause high levels of prozac as CYP2D6 is involved in the metabolism of prozac.

That said, gabapentin is not metabolized. Sensitivity..in that case good question. FWIW, there are some people on this board who are also super sensitive to gabapentin at 100mg..while there are others on 3600mg/day with barely an effect.

What do you mean by favoring zyprexa due to the low dosing range? Like low mgs?

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