2006 Correspondence from Dr. Richard Shelton about prolonged withdrawal syndrome
Subject: RE: Antidepressant discontinuation syndrome
Date: Sat, 22 Jul 2006 14:31:17 -0500
From: "Shelton, Richard" <richard.shelton@[e-mail]
Sorry for the delay - I have been away at a scientific meeting.
I actually think the discontinuation syndrome is pretty bad in some situations and truly horrible in others.
Hence, why participated in a scientific focus group that wrote a series of papers teaching docs about the problem (appeared in the Journal of Clinical Psychiatry).
First, let's acknowledge one thing: there is a great deal of variability in response, with a lot of people experiencing bad symptoms and others little at all, but almost all resolve; that is, except for a very small group, where the symptoms become persistent.
At the core, the variability is related to genetic (actually, more correctly, genomic) differences between people (one of our areas of research).
The receptors do down-regulate. In fact, the reaction of the majority of people is consistent with down-regulation. That is, there is an adaptation that occurs in the receptor (actually phosphorylation) that makes it less responsive to serotonin. This, by the way, is probably the serotonin 2A type receptors. When the adaptation occurs, it takes about 10-14 days to re-equilibrate (to de-phosphorylate). The receptor returns to normal, along with related proteins (like the serotonin transporter protein). That is how they work.
The variation between people is probably due to genomic variations in the genes coding for proteins involved in this process. However, regardless of the situation, in the average circumstance, the re-adaptation eventually occurs. This is why it can be protracted in some situations. However, even in that situation, there is a limit in time.
So, why do some people have these very long effects? There may be several potential causes. For example, it is possible that something has happened to destroy some neurons - either the ones containing serotonin or the others that they connect to.
In fact, there is a research literature that says exactly that. However, all the studies have been in cells in culture and have one essential problem that invalidate them (sorry for being so direct). The concentrations used to achieve the toxic effects are a two orders of magnitude above what can ever be found in human tissue - that is, the concentration is 100 times as much as can ever be achieved in humans. Typical concentrations don't do that. This, then, falls into the category that too much of anything is toxic (first postulated by Paracelsus in the 16th century, I think). So, too much water, salt, sun, etc., etc.
In fact, a strong effect of antidepressants (including paroxetine) is the opposite - that is, preservation of neurons by stimulating the production of brain derived neurotrophic hormone, and another hormone, bcl-2. Both stimulate the growth of new tissue and preserve the health of the living cells.
So, what then? Let's go back to our premise: The discontinuation effect is truly horrific in some people. The direct mechanisms involved in the genesis of the problem can't really be involved in it's persistance. So, what's up with that?
In fact, there are long-standing adaptations that can take place in the nervous system. However, as with most things in the body, the problem is a variation of a normal process (otherwise, it wouldn't be there in the first place).
There appear to be lots of variation in this reaction in people who develop persistent symptoms, but one salient feature that seems almost invariably present: They become intensely afraid during the experience. People may describe this in different ways, but the way the brain is reacting is an exaggeration of what the brain does during threat. The physical symptoms are consistent with that.
So the "threat" systems are "turned on" and don't "turn off" easily. This can happen in a few ways, but has to occur pretty fast.
In fact, it is a normal response. Think of a mouse living in a field somewhere. If there is an acute threat that occurs (e.g., chased by a cat) and the mouse escapes, the mouse's brain has to remember that and react. There are a couple of ways to do that. One is to synthesize proteins to "remember." That, actually, is slow (but happens). The second is to actually do something to the genes controlling the system itself: to induce chemical modifications to the genes or the supporting structure to activate some genes and inactivate others. The net effect is for the system to stay "on" so to speak. However, in this situation, it is purely adaptive.
Going by the principle, then, that people vary in their response, some people seem particularly prone to have this to occur. That is why when people are exposed to a life threatening situation, some go on to develop post-traumatic stress disorder, and others don't. Now, one important thing is that most people develop trauma related symptoms immediately after an event (e.g., insomnia, dreams of the event, anxiety, etc., etc.). In the normal situation, these symptoms resolve within a month. But some people develop long-standing responses, in which the system is turned "on" and they can't turn it "off." I think that is what is at play here.
People might ask, "why then do I still have some of the same symptoms?" The answer is related to the longer-term synthesis of new proteins. What happens is that the brain activates the pathways associated with that symptom (e.g., electrical sensations in the body), and it stays on. It is like a kind of memory, so to speak. But one that reactivates the sensations.
That is the basic story. The question, then, is what's next? There are a few ways to potentially deal with the problem. First, you could use something to directly suppress the symptoms - really not great, but often effective. Drugs related to Valium (e.g., Xanax) activate neurons related to a chemical in the brain called gamma amino butyric acid (GABA). That is an inhibitory transmitter, which can suppress the symptoms. However, it only works when it is present, and the body adapts to it with time, producing physical dependency - not ideal.
Another way is to use another serotonin uptake inhibitor antidepressant (probably one with a long half life). Most people don't want to do that since they believe that the first one was toxic (which, as I've described, is untrue). Serotonin is a regulatory chemical in the body, and in the stress-emotional system its primary role is inhibitory. So, it suppresses the activity of the neurons that are "turned on," suppressing the symptoms. In most (but not all) people that will work. It is an acceptible alternative.
Given that the mechanism involves "memory," then information processing is important. So, certain forms of cognitive behavioral therapy seem to be effective in reducing the symptoms, at least to a manageable degree. I like that option. It has to start with several ideas - your brain has not actually been "damaged;" the symptoms are not life-threatening; etc. However, a good cognitive therapy may be able to help.
A lot of therapists say they do cognitive therapy; however, most who do so are not really compent at the treatment. I'd advise going to the Center for Cognitive Therapy website at the University of Pennsylvania (http://www.uphs.upenn.edu/psycct/
). There is a referral list at the bottom of the page (it goes to this site: http://www.uphs.upen...rral/states.htm
, where you can look up your state to try to find a therapist). If you have the choice, someone that specializes in anxiety disorders is the place to start.
Best of luck,
Richard C. Shelton, M.D.
James G. Blakemore Research Professor
Department of Psychiatry
Vanderbilt University School of Medicine