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Harvey, 2003 Neurobiology of antidepressant withdrawal

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Altostrata

This paper describes the neurological activity that leads to withdrawal syndrome. The authors conclude:
 

The distress that potentially accompanies antidepressant withdrawal has not always been sufficiently appreciated. As alluded to earlier, missed doses, abrupt dose reduction, or abrupt discontinuation of some antidepressants may be associated with an antidepressant discontinuation syndrome. Although the severity of withdrawal symptoms may vary with the type of antidepressant and between patients, all too often not enough emphasis is placed on the possible neurobiological effects and possible longer-term risks associated with inappropriate withdrawal or discontinuation.

As emphasized here, antidepressant discontinuation may involve a stress response accompanied by a set of specific biochemical responses that cause further neuronal dysfunction and that may compromise long-term outcome. This is not to say that clinicians should continue antidepressants indefinitely; it is, however, to emphasize that the decision to discontinue antidepressants should be made judiciously and on an individualized basis.


Biol Psychiatry. 2003 Nov 15;54(10):1105-17.
Neurobiology of antidepressant withdrawal: implications for the longitudinal outcome of depression.
Harvey BH, McEwen BS, Stein DJ.


Source

Division of Pharmacology, School of Pharmacy, Potchefstroom University for Christian Higher Education, Potchefstroom, South Africa.

Abstract at http://www.ncbi.nlm.nih.gov/pubmed?term=neurobiology%20withdrawal%20harvey Full text here.

Inappropriate discontinuation of drug treatment and noncompliance are a leading cause of long-term morbidity during treatment of depression. Increasing evidence supports an association between depressive illness and disturbances in brain glutamate activity, nitric oxide synthesis, and gamma-amino butyric acid. Animal models also confirm that suppression of glutamate N-methyl-D-aspartate receptor activity or inhibition of the nitric oxide-cyclic guanosine monophosphate pathway, as well as increasing brain levels of gamma-amino butyric acid, may be key elements in antidepressant action. Imaging studies demonstrate, for the most part, decreased hippocampal volume in patients with depression, which may worsen with recurrent depressive episodes. Preclinical models link this potentially neurodegenerative pathology to continued stress-evoked synaptic remodeling, driven primarily by the release of glucocorticoids, glutamate, and nitric oxide. These stress-induced structural changes can be reversed by antidepressant treatment. In patients with depression, antidepressant withdrawal after chronic administration is associated with a stress response as well as functional and neurochemical changes. Preclinical data also show that antidepressant withdrawal evokes a behavioral stress response that is associated with increased hippocampal N-methyl-D-aspartate receptor density, with both responses dependent on N-methyl-D-aspartate receptor activation. Drawing from both clinical and preclinical studies, this article proposes a preliminary molecular perspective and hypothesis on the neuronal implications of adherence to and discontinuation of antidepressant medication.

Edited by Altostrata
Emphasized "inappropriate discontinuation"

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Maybe

Well, they all talk about the discontinuation of antidepressants. But what if people had an adverse reaction? There was no way for me to taper or go on. And because ads change neurochemistry over a certain period, what did they do when I only took them for 4 days?

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Altostrata

Maybe, some people are stuck and have to make awful decisions.

 

As we've discussed before, some people have violent adverse reactions to very little exposure to SSRIs. They have a serotonin sensitivity. There is a genetic basis for this. It's a natural variation. You are apparently one of those people.

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cinephile

But what if people had an adverse reaction?

KEY POINT! We must not forget this unfortunate segment of the withdrawal population either! Indeed there are some people who have terrible toxic reactions to SSRIs and other psych meds which are, of course, misdiagnosed as "unmasked disorders" which leads to more meds.

 

I honestly think this is what happened to "Jasmine" in Robert Whitaker's ANATOMY OF AN EPIDEMIC. Hers is an extreme case, of course, but a powerful cautionary tale of just how devastating an adverse reaction can be and how we MUST find ways of screening for this.

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compsports

But what if people had an adverse reaction?

KEY POINT! We must not forget this unfortunate segment of the withdrawal population either! Indeed there are some people who have terrible toxic reactions to SSRIs and other psych meds which are, of course, misdiagnosed as "unmasked disorders" which leads to more meds.

 

I honestly think this is what happened to "Jasmine" in Robert Whitaker's ANATOMY OF AN EPIDEMIC. Hers is an extreme case, of course, but a powerful cautionary tale of just how devastating an adverse reaction can be and how we MUST find ways of screening for this.

 

Totally agree about not forgetting this population group.

 

While I taking psych meds, I had an averse reaction to 5mg of Celexa which caused severe agiatation. I am totally convinced that if I had heeded my psychiatrist's advice to stay on the med, I would have been in big time trouble.

 

CS

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Maybe

I just hope that a nervous system that had an adverse reaction to a medication is still able to heal. What makes me wonder is that many symptoms are the same like in withdrawl. So an adverse reaction might not be that different from "normal" withdrawl.

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Altostrata

Right, Maybe, you had one of these rare adverse reactions AND you have withdrawal syndrome.

 

I've gotten a report of another case very like yours, but the person has not registered on this site.

 

Clearly, your nervous system can heal, as it's demonstrated already, with better windows.

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Maybe

But those who had symptoms for 4 or even 6 years, don't they have waves and windows as well? It somehow seems to me that this pattern is not really a sign of recovery, but maybe a part of a biochemistry cycle?

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Altostrata

Yes, Maybe, just about everyone has waves or windows. Nobody gets better all at once.

 

What do you mean a biochemistry cycle? Every operation in our bodies is a biochemistry cycle.

 

Please stop looking for the worst. Some day even you will be unable to deny you've improved, that the windows have gotten longer and more frequent.

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Maybe

There surely will be this day. I am just afraid that it might take longer than I thought. I hope so much that I will be better at the 2 year mark...

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Altostrata

Dr. Harvey sent me this in correspondence:

 

I am very glad to see you are recovering from your own nasty experience. I find it especially interesting that you are showing this recovery using lamotrigine, which is a very effective inhibitor of glutamate release. Our studies have strongly implicated altered glutamatergic activity following antidepressant discontinuation/withdrawal, with especially overt activity at NMDA receptors acting to perpetuate the illness via a kindling-like action. One could even consider this to be a useful case report in support of the argument.

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Altostrata

I've come to the point where my system does not need the lamotrogine anymore and I'm tapering off it. I'm down to .42mg today, from 5.4mg for the last 1.5 years.

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alexjuice

Alto,

 

If you'd care to share, can you talk about how you came to feel comfortable with the decision to taper? That your system no longer needed the Lamictal?

 

Alex

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Altostrata

Sure. I started sleeping better, my autonomic nervous system stabilized -- many pesky symptoms went away, particularly the autonomic dumping and palpitations -- and I got "signals" from the lamotrigine that it was time to decrease.

 

The signals are a tiny headache in the front of my head, long gaps in sleep, or queasiness. I tend to get the headache and sleep gaps.

 

Last night, for example, I woke up about 2:30 a.m. with the tiny headache. I'd been at .45mg for maybe a week, so this morning I went down to .42mg. (I keep the drops at 10% or less in proportion to the current dosage to keep from destabilizing the whole ball o' wax. It usually takes a couple of days for the decrease to take effect. I might have a tiny headache tonight.)

 

Headache and queasiness or nausea are signs lamotrigine dosage is too high.

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alexjuice

That's interesting. I talked with a new doctor recently and we discussed how best to conduct my benzo taper.

 

It seems right now that I am still too hypersensitive so some other interventions have been recommended. I've specifically been fanatical about avoiding caffeine and walking daily. I'm feeling on the upswing, but I still have gastro issues that affect vocal strength and these make me so leery of reducing the benzos.

 

Some speculate that the benzos could make GI issues worse, while others speculate that the w/d syndrome is responsible and that the benzos tame it...

 

Anyway, these things will work out in time, I believe.

 

Alex

 

ps - What do you mean by autonomic dumping?

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Altostrata

Autonomic dumping is a sudden wave of a bunch of autonomic symptoms all at once. For example, for a long time I had frequent palpitations, feeling hot, dizziness, and belching, all together.

 

The combination of benzo withdrawal syndrome with antidepressant withdrawal syndrome is a more complicated beast than either one by itself, and may not respond to lamotrigine, since lamotrigine has an indirect effect on the benzo system (increases GABA).

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BinxBolling

I'm wondering, given the glutamatergic dysregulation theory of SSRI withdrawal, if anyone thinks that in addition to microdosing of lamotrigine, an NMDA antagonist like Ketamine (or new drugs in development, like GLYX-13, that apparently work on glutamate) could be useful in withdrawal. I realize that taking any such drug would then put one in the position of having to taper something else. (But I knew nothing about tapering when I quit my SSRI cold turkey, and would welcome the opportunity to taper something that put a dent in my withdrawal syndromes.) I, like many who have protracted, severe withdrawal (2 years in my case), am hypersensitive to any psychotropic drugs, so the question may be moot or silly. I'm just curious.

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Altostrata

Psychiatry is prone to fads. Ketamine is the fad du jour.

 

Every "promising" molecule is reported in breathless terms. The SSRIs received the same hype.

 

I talked to a doctor who investigated ketamine; he found its effects inconsistent and whatever benefits it had were temporary. Same as it ever was.

 

Whatever medicine knows (or doesn't know) about treating depression in people with stable nervous systems emphatically does not apply to those whose nervous systems have become destabilized by withdrawal syndrome. Withdrawal syndrome is not relapse, it cannot be treated as depression.

 

In general, psychiatric drugs are far too strong for the hypersensitive nervous systems in people who have prolonged withdrawal syndrome. Even lamotrigine has to be carefully titrated so as not to trigger paradoxical reactions.

 

The prevalence of paradoxical reactions to drugs in people sensitized by withdrawal makes treatment of withdrawal syndrome very tricky. Doctors who have tried it have not seen much success because they think in terms of "therapeutic" dosages that tend to make withdrawal syndrome worse.

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Barbarannamated

Alto wrote: "Withdrawal syndrome is not relapse, it cannot be treated as depression."

 

Withdrawal syndrome, especially protracted w/d as in my case, makes 'depression' look like a walk in the park. I'm in severely rough shape at ~18 months after last dose of Pristiq. I'm open to any suggestions. Hydrocortisone (for autoimmune/adrenals) made the morning dread of life far worse and i tapered off after a few months. My endocrinologist thought Wellbutrin might help but it messed with my sleep, my only escape from this hell.

 

There was a comment in Harvey about glucocorticoids being a possible CAUSE of neurodegenerative process..?

 

"Preclinical models link this potentially neurodegenerative pathology to continued stress-evoked synaptic remodeling, driven primarily by the release of glucocorticoids, glutamate, and nitric oxide."

But SSRIs increase cortisol, correct? Is withdrawal of SSRIs causing a steroid/cortisol-type w/d and rebound also? I'm very fuzzy today so excuse if this is tangential or has been covered.

 

The LOW cortisol symptoms flared badly after several months off of Pristiq. Very low pulse, low blood pressure, low energy, depressed state. During taper and early w/d, i had more typical symptoms of anxiety, hypomania, cortisol dumping in early morning. Adding hydrocortisone (a glucocorticoid) to this while still in dysautonomia seems counterintuitive.

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Altostrata

I believe that refers to the current thinking that stress is neurodegenerative. Kind of saying that life is neurodegenerative.

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Sparrow

FWIW: I was taking the NMDA antagonist memantine (Namenda) for an unrelated reason prior to and during my initial bungled attempts at withdrawing from psych drugs, including an SSRI. Didn't help a bit.

 

Sparrow

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BinxBolling

Has anyone else besides Alto been helped by micro dosing lamotrigine?

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FeelingAlone

I have been...I'm currently on 5mg of Lamictal. At my docs advice he cold turkeyed me off both Celexa and Lexapro. I was in horrible horrible withdrawal. So after 2 weeks of no medication I tried low dose lamictal at 2.5 mg. The Lamictal has helped me sleep better, tremors almost gone, and cut my anxiety and depression in half. It has also helped me with DP/DR symptoms. All in all, I feel calmer and more sure of recovery. It's given me hope.

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cmusic

I just found this paper and to be honest I'm not sure if it makes me feel better or worse. In my case I stopped Prozac abruptly in 2010, got severe withdrawal, and since then have tried several SSRI's and SNRI's (including Prozac again) with no success. This article seems to imply that once the damage is done, things change and it becomes impossible to go back. So the argument is 'don't stop'.

 

But what do people like me do that have stopped, have suffered the effects, and are now looking for some way to fix things? Clearly based on all the info here (and my last three years of trying), I don't think it's recommended to go back on SSRI's. So is the only option to wait it out? The article doesn't seem to imply that people heal naturally, it actually implies the opposite.

 

How do we reconcile this conclusion with the fact that people do seem to get better over time?

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Altostrata

Dr. Harvey actually is very concerned about withdrawal risks. As with most papers on antidepressants, his includes some boilerplate blather about their value, etc.

 

He is describing the process that causes nervous system dysregulation, not the recovery process, which is based on neuroplasticity.

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Lilu

Sure. I started sleeping better, my autonomic nervous system stabilized -- many pesky symptoms went away, particularly the autonomic dumping and palpitations -- and I got "signals" from the lamotrigine that it was time to decrease.The signals are a tiny headache in the front of my head, long gaps in sleep, or queasiness. I tend to get the headache and sleep gaps.Last night, for example, I woke up about 2:30 a.m. with the tiny headache. I'd been at .45mg for maybe a week, so this morning I went down to .42mg. (I keep the drops at 10% or less in proportion to the current dosage to keep from destabilizing the whole ball o' wax. It usually takes a couple of days for the decrease to take effect. I might have a tiny headache tonight.)Headache and queasiness or nausea are signs lamotrigine dosage is too high.

Alto,

Is Lamictal used to help withdrawal insomnia?  I'm wondering if this is something I should suggest to my doctor. I've tried Lamictal before but at a much higher dose, and had all sorts of symptoms.  But maybe it's something I should revisit, since it seems that even a small reduction (4.2%) is giving me insomnia.

 

Also, how were you able to measure .45 and .42 mgs? 

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btdt

Dr. Harvey sent me this in correspondence:

 

I am very glad to see you are recovering from your own nasty experience. I find it especially interesting that you are showing this recovery using lamotrigine, which is a very effective inhibitor of glutamate release. Our studies have strongly implicated altered glutamatergic activity following antidepressant discontinuation/withdrawal, with especially overt activity at NMDA receptors acting to perpetuate the illness via a kindling-like action. One could even consider this to be a useful case report in support of the argument.

 

I was looking at causes and treatment for mcs multiple chemical sensitivity which some of us seem to have post AD use. I found an article NO searched here think this applies here

 

 

Martin Pall asserts that MCS is initially triggered by volatile organic solvent exposure, organophosphorus/carbamate pesticide exposure, organochlorine pesticide exposure, and/or pyrethroid pesticide exposure.   These initiating triggers act to increase the levels of nitric oxide (NO) in the body.  Nitric oxide then acts through its oxidant product, peroxynitrite (ONOO-), to maintain a vicious cycle mechanism which is responsible for the resulting chronic illness (MCS).  This cycle is called the NO/ONOO- Cycle (pronounced “no oh no”).  In Summary,

 

· Short term triggers initiate MCS by raising nitric oxide synthesis and consequent levels of nitric oxide and its oxidant product peroxynitrite.

· Initiation is converted into a chronic illness through the action of a vicious cycle mechanism in which chronic elevation of nitric oxide and peroxynitrite and is produced and maintained.

· Symptoms of MCS are generated by elevated levels of nitric oxide and elevated levels of peroxynitrite or inflammatory cytokines, oxidative stress and elevated NMDA and vanilloid receptor activity. This is called “up-regulation”.

· Treatment should focus on down-regulating NO/ONOO- cycle biochemistry. 

 

Pall first developed a nutritional protocol for down-regulating the NO/ONOO– cycle with Dr. Grace Ziem and later developed his own variation.

http://mcs-america.org/index_files/mcsmedicaltreatment.htm

I am not recommending any of the suggested treatments btw. 

I of course had to look up the vanilloid receptor 

 

The vanilloid receptor: a molecular gateway to the pain ...
www.ncbi.nlm.nih.gov/pubmed/11283319
  •  
by MJ Caterina - ‎2001 - ‎Cited by 1346  - ‎Related articles

The vanilloid receptor: a molecular gateway to the pain pathway. Caterina MJ(1), Julius D. Author information: (1)Department of Biological Chemistry, Johns 

 

For me wd was very painful

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Altostrata

Going way off-topic. Please don't do this.

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Sheri755

@Alto. I just read Psychology Today's article 7-17-11, referencing your journey. After reading the below, how can we regrow/sprout new neural pathways? Thanks!

 

"Several receptors—including 5-HT1A—aren't especially malleable, moreover, and take longer to sprout anew after drug treatment ends, delaying the patient's return to neuronal health. Indeed, some studies I consulted found that in certain patients those receptors fail to grow back at all, in effect leaving the patients worse off than before. (See for instance "Dissociation of the Plasticity of 5-HT1A Sites and 5-HT Transporter Sites" in Paxil Research Studies 19.3 [1994], 311-15.)"

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Altostrata

This is not the last word on 5-HT1A receptors, or any receptors. Much is not known about them.

 

The nervous system has many ways to create alternative routes around any area that's not working right. That's what neuroplasticity is all about.

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Sheri755

I love researching and find Neuroplasicity intriguing. Dr. Carolyn Leaf's work is one of several that I've been following.

I want to thank you for your tireless efforts in helping others. I'm so very grateful.

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Altostrata

You're welcome!

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fema4psychiatrists

drugs are just poisons that create imbalances percieved as theraputic. disrupting natural enzyme activity. mono amine oxidadise INHIBITOR. selective serotonin re-uptake INHIBITOR. no drugs are curing anything. our bodies are fantasticly designed to survive large amounts of malnutritions and multi-generational habits, damage and poisions. 

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