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Worried that the next one won't work either....Immunity to SSRI's?


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Is it possible that a brain becomes immune to working mechanism SSRI's for long time users? So there can be side effects but no effect on thing you are taking it for?
I can't find anything on this on the internet. I know individual SSRI's have different properties,  but I wonder if they could also do some kind of 'damage' (I'm not talking about withdrawal and recovery). Like insensitive / insusceptible? 

I've been using Luvox(2/3 years) and Lexapro (6/7 years) and now Zoloft, which I have been on for 6 months (200 mg for almost about 1,5 months). But Zoloft doesn't like the other two, not much effect on my intrusive thoughts.

I've read from a lot of people that SSRI's don't work as good when you restart the same one. I had this experience with Luvox, when I took it for the third time in two years time. I then switched to Lexapro and it worked great! But now I'm not so lucky and I wonder WHY my brain isn't responding the way I like. Apart from mild side effects I'm not getting the same relief from Zoloft.

If anyone has more (indepth) info that would be AWESOME! :-)
 

Edited by Catwoman
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As far as I know there isn't any veritable proof that these medications cause a permanent change in the brain that would require you to continue taking them for your brain to function normally for the rest of your life. The brain is very elastic and it bounces back. Perhaps it does so more easily when you're younger and neurogenesis is still at its peak but the brain "flexes".

Now I have read some studies about antipsychotics causing oxidative stress on the brain and potentially having negative effects in the long term. I have even heard of antipsychotics potentially reducing brain matter, but I don't think those studies were very conclusive. In reality most of that is propaganda.

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Thanks Browri....I can't find any studies or other articles on it, so maybe immunity to SSRI's doesn't really excist.

What I gathered from coming off SSRI's is that you need to do it gradually in order to reduce the withdrawal symptoms.
The brain adapts to the SSRI and when you stop cold turkey it is like a plant (like a creeper) pulled off a trellis. It can't grow without the support of the trellis.  This makes sense and I think there's research to support this comparison.

Last year I came off Lexapro. I started tapering in June or July and was med free in October. I thought my brain needed some time without medications. It didn't make me worse but it didn't make anything better either, so in January I started with Zoloft. In hind sight I could have started Lexapro again...but I was still worried about the initial poop-out/tachyphylaxis. So starting something entirely new made more sense to me. After 6 months of not getting better with Zoloft I just really worry that Lexapro 'did' something that caused my brain not responding.

But there's no research that confirms my fear....No one seems to know why one SSRI works and why another one doesn't. It bothers me, I can't help wondering why this is.

I probably need to let it go and just go for the next SSRI. Two of them worked wonders for me in the past.

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I seriously doubt it, and then even the PDoc could try different combinations of ADs with other drugs.  I would often always need a combination when I had major issue.  Seroquel/Ativan together have helped me for over a decade now to get back in place.

One good thing about our modern world is we do have a lot of medications/drugs available to help with depression/anxiety.

You'll find something that works, there's always hope.  =)

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An important part of the "flexing" that I talked about though is in fact the reason for the withdrawal and also the reason antidepressants take so long to start working. Brain imaging shows that administering a single dose of an SSRI to someone who has never taken one does in fact increase serotonin levels in the brain immediately, but the actual antidepressant effect of SSRIs isn't felt for weeks. This is because receptors have to be desensitized to the higher levels of serotonin in the synapse. So effectively the medication makes your receptors used to having higher levels of serotonin available. Then when you withdrawal the antidepressant, those neurotransmitters plummet. Then you have receptors previously over-stimulated and desensitized now have no serotonin to speak of for proper neurotransmission. Thus the withdrawal.

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5 hours ago, browri said:

An important part of the "flexing" that I talked about though is in fact the reason for the withdrawal and also the reason antidepressants take so long to start working. Brain imaging shows that administering a single dose of an SSRI to someone who has never taken one does in fact increase serotonin levels in the brain immediately, but the actual antidepressant effect of SSRIs isn't felt for weeks. This is because receptors have to be desensitized to the higher levels of serotonin in the synapse. So effectively the medication makes your receptors used to having higher levels of serotonin available. Then when you withdrawal the antidepressant, those neurotransmitters plummet. Then you have receptors previously over-stimulated and desensitized now have no serotonin to speak of for proper neurotransmission. Thus the withdrawal.

This is interesting and a bit complicated. So if SSRIs desensitize & overstimulate the receptors and you come off - will your brain ever go back to a normal pre-med state? OR will this cause your brain to be even more depleted & then you get more severe symptoms of serotonin deficiency, until you resume treatment?

If so, on average, I wonder how long it takes for the brain to regulate again by itself? I know as you get older you have less neuroplasticity. Afterwards, like with @Catwoman will it always take a higher dosage or a different drug the next time around for any noticeable effect? I too wonder if loading the brain up with meds longterm causes a situation where you are forever dependent on many meds & eventually higher doses to function minimally.

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3 hours ago, Blahblah said:

This is interesting and a bit complicated. So if SSRIs desensitize & overstimulate the receptors and you come off - will your brain ever go back to a normal pre-med state? OR will this cause your brain to be even more depleted & then you get more severe symptoms of serotonin deficiency, until you resume treatment?

If so, on average, I wonder how long it takes for the brain to regulate again by itself? I know as you get older you have less neuroplasticity. Afterwards, like with @Catwoman will it always take a higher dosage or a different drug the next time around for any noticeable effect? I too wonder if loading the brain up with meds longterm causes a situation where you are forever dependent on many meds & eventually higher doses to function minimally.

Your serotonin won't be depleted per se. It's simply that without the SSRI, there becomes less serotonin in the synapse, and eventually the receptors on the receiving end will down-regulate themselves and "resensitize" if you will. However, the time that process would take would be almost as unique as a fingerprint. There may be some commonalities, but it would be very different from person to person. I suppose it could even depend on how well you take care of yourself during that process and some good ole genetics. Theoretically speaking.

EDIT: Additionally, it would depend on the binding profile of the medication that you were coming off of as well as the half-life and the dose.

Edited by browri
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There are some people who need supratherapeutic doses of SSRIs for treatment-refractory OCD. For instance, sertraline can be pushed up to 400 mg, escitalopram up to 40 mg, paroxetine up to 100 mg, fluvoxamine up to 450 mg, and fluoxetine in the 100's mg. There have been case reports of venlafaxine ER and duloxetine (120 mg) helping OCD.

I would also look into antiglutamatergic meds as an adjunct to your SSRI. Most are anticonvulsants, some are not. Riluzole, lamotrigine, topiramate, zonisamide, memantine, amantadine, the SNRI milnacipran, and haloperidol are some to name a few.

You may consider trying supplements like L-theanine, magnesium, zinc, and huperzine A, which are also antiglutamatergic (huperzine A has the added effect of being an acetylcholinesterase inhibitor, thereby improving cognition; magnesium has an anxiolytic and calming effect and is good to take right before bedtime; and zinc is a natural antidepressant).

The anticonvulsants like pregabalin, gabapentin, carbamazepine (and therefore probably oxcarbazepine and Aptiom), and levetiracetam may be helpful.

Even consider going on the ketogenic diet because it causes kynurenic acid to form in the brain which is a natural AMPA and kainate antagonist.

Also, antipsychotics can be helpful, including risperidone, olanzapine, aripiprazole, thioridazine, (and haloperidol already mentioned).

The benzodiazepine clonazepam is helpful for OCD.

There's also the tricyclics, of course, the golden standard clomipramine is a good way to go either monotherapy or as an adjunct in low doses to an SSRI, as well as imipramine and desipramine.

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Thanks Mik!

Yeah...augmenting could be the next step, or switching to a TCA. I will discuss that with my doctor.
I've already lowered the sertraline a bit to 175 mg. That 250 mg was causing way too much tinnitus en restless legs. I don't think I could handle 400 mg :blink:

Still, is there anything in literature of research about my initial question?

In order to give my brain a break from medication (and I was only on 1 SSRI and a low dose as well) I decided to taper and I've been off them entirely for about 4 months. 
I thought it might also help with the next SSRI (it might do its work more effectively). I have no idea if I gave my brain enough time to reset.

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This is about all I could find.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4008298/

Quote

It has been reported that patients with "true" antidepressant tachyphylaxis may be less responsive to new treatment interventions.

Quote

Fava et al found that 26 of 77 depressed patients (33.7%) who had achieved full remission of symptoms on fluoxetine 20 mg daily experienced a recurrence of symptoms (ADT tachyphylaxis) between 14 and 54 weeks despite maintenance treatment. In another small study, 15 patients who had lost their response to antidepressants failed multiple treatment strategies including augmentation with mood stabilizers and, in some cases, electroconvulsive therapy. Therefore, it appears that patients who experience ADT tachyphylaxis may be less responsive to subsequent treatment interventions.

 

 

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36 minutes ago, mikl_pls said:

This is about all I could find.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4008298/

 

Thanks so much Mik!
The studies mentioned were quite small (77 and 15 persons) so it seems like the issue that I'm worried about isn't considered a big thing in the medical research world. 

And apparantly researchers are still not sure why tachypylaxis happens either or what is causing it.
Or, why chronic antidepressant use can result in lower response rates....I guess I won't find any definitive answer to why or what is causing my non-response to sertraline.

Quote

It has been suggested that the etiology of ADT tachyphylaxis is due to evolving pharmacokinetic and/or pharmacodynamic tolerance resulting from chronic exposure to antidepressants.

There are still numerous strategies I can try and I am not even bipolar or depressed. My low moods are a result from having intrusive thoughts all the time.
 

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I tried every single SSRI out there and only citalopram (Celexa) worked for me. While they are all SSRIs, they do have different mechanisms of action and are distinct chemicals, and you have to find the one(s) that fits your brain chemistry. It's funny because citalopram was the last SSRI I had tried and I was about to completely give up, but I got positive results from it more so than any other antidepressant that I took. I'm guessing that Lexapro would work for me, but I didn't like the way I felt on it and asked to be put back on citalopram.

What I'm saying is that I don't think you are immune. You just have to find another one that fits your brain chemistry. So if the next one you try doesn't work, keep looking.

Edited by jt07
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Have you taken paroxetine? It has no sigma receptor affinity but it does have an indication for OCD.

I seem to remember you have an aversion to the SNRIs.

Sigma receptor agonists: citalopram, escitalopram, fluoxetine, fluvoxamine, memantine, methamphetamine, methylphenidate, quetiapine, amitriptyline, desipramine, imipramine, tramadol, venlafaxine

Sigma receptor antagonists: haloperidol, sertraline, lamotrigine, naltrexone

Unknown/unsorted: chlorpromazine, selegiline

I forget what all you've tried, but polypharmacy definitely looks like it would be in your best interest.

This is a cocktail I just kinda threw together that would seem synergistic...

  • Citalopram/Escitalopram/Fluoxetine/Fluvoxamine/(Sertraline)/Amitriptyline/Desipramine/Imipramine/Venlafaxine/Clomipramine
  • Lamotrigine (doses used for OCD typically lower than for bipolar)
  • Quetiapine
  • Memantine
  • (Methylphenidate)
  • (Naltrexone?)
     

 

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11 minutes ago, mikl_pls said:

Have you taken paroxetine? It has no sigma receptor affinity but it does have an indication for OCD.

I seem to remember you have an aversion to the SNRIs.

Sigma receptor agonists: citalopram, escitalopram, fluoxetine, fluvoxamine, memantine, methamphetamine, methylphenidate, quetiapine, amitriptyline, desipramine, imipramine, tramadol, venlafaxine

Sigma receptor antagonists: haloperidol, sertraline, lamotrigine, naltrexone

Unknown/unsorted: chlorpromazine, selegiline

I forget what all you've tried, but polypharmacy definitely looks like it would be in your best interest.

This is a cocktail I just kinda threw together that would seem synergistic...

  • Citalopram/Escitalopram/Fluoxetine/Fluvoxamine/(Sertraline)/Amitriptyline/Desipramine/Imipramine/Venlafaxine/Clomipramine
  • Lamotrigine (doses used for OCD typically lower than for bipolar)
  • Quetiapine
  • Memantine
  • (Methylphenidate)
  • (Naltrexone?)
     

 

Seems like a lot tho 

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1 hour ago, Iceberg said:

It's interesting ur a namenda fan that's pretty left field for many pdocs, although mine has one patient he gives it too. Have you tried/had success with it?

Lol I wouldn't really call myself a Namenda fan. No, but I've read studies that it does well with OCD. 

Any other antiglutamatergic drug would do, especially if it had sigma receptor binding, like maybe quetiapine?

I'm kinda trying to stick with the sigma receptor agonists since @Catwoman doesn't seem to be doing well with sertraline which is an antagonist. The original cocktail I proposed did have naltrexone, supposedly an antagonist, but it has implications in impulse control that may be helpful. But I'm certainly no expert, so I could just be blowing smoke unintentionally.

Other good ones would be some anticonvulsants like topiramate and zonisamide, but lamotrigine was already in there; it's not unheard of to be on two anticonvulsants at once—I'm on three... lol—but I just figured minimizing it would be helpful.

N-Acetylcysteine is also supposed to be helpful. Perhaps that could be added to the cocktail.

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Well my visit to my general doctor this morning wasn't very satisfying.

First, here's my frustration (don't read it if you're just interested in the medication-part :P)

He proposed I stay on sertraline for another 3 weeks, but that I would taper to 125 mg and then evaluate again (AGAIN :angry:)
I tried to explain that sertraline doesn't do much for me and that I want to switch to something else. 
He said: so taking medication doesn't make a difference? Why don't you quit taking it then? 

Right.

It's not that I need medication in order to function. I like my job, I love my friends and family, I have a good relationship....I do struggle with daily life but it doesn't make me depressed or anxious. 
I've tried to stop the urge to get rid of the intrusive thought. My goal has always been to get rid of it. Mindfulness and therapy learned me that you can't get rid of intrusive thoughts. And the harder you try, the more frequent they will become. It's OK to have weird stuff in your head. But I haven't managed this. It still bothers me. It's with me all day. I  cherish these short moments when it's not in my head.

Medication helped me so much.  What I couldn't achieve with 4 years of therapy happened after 5 weeks on Luvox. It was incredible (untill it pooped out....but I took the next one and it was incredible again, untill it pooped out).  I'm not considering going on a drug holiday again, like my doctor advised me last year 

Medication part:

Doctor thinks I might not react to sertraline because I have been on this type of med before. Or, he said, it could have been a placebo-effect. 
Thanks you for the encouragement....

His next suggestion: a TCA, not clomipramine (like us dummes think, who don't have a medical degree) but nortriptyline. It has a better side effect profile. 

What I didn't say to him but what I was thinking: "consider a new gdoc and FIND YOURSELF A PDOC"

 

Quote

I tried every single SSRI out there and only citalopram (Celexa) worked for me. While they are all SSRIs, they do have different mechanisms of action and are distinct chemicals, and you have to find the one(s) that fits your brain chemistry. It's funny because citalopram was the last SSRI I had tried and I was about to completely give up, but I got positive results from it more so than any other antidepressant that I took. I'm guessing that Lexapro would work for me, but I didn't like the way I felt on it and asked to be put back on citalopram.

What I'm saying is that I don't think you are immune. You just have to find another one that fits your brain chemistry. So if the next one you try doesn't work, keep looking.

Thanks @jt07! That's why I would still like to try Prozac / fluoxetine. SSRI's did work for me, and now the current one doesn't. I tried to explain this to my doctor this morning, but he wants me to try a TCA (or quit medication all together). I really think I should give another SSRI a try, it could fit my brain chemistry and if it doesn't I'll keep searching for something else. I don't understand why my gdoc wants me off medication when I had such good results with it.

Edited by Catwoman
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