Murata 2010 Effects of the Serotonin 1A, 2A, 2C, 3A, and 3B and Serotonin Transporter Gene Polymorphisms

[lupe]

An excellent research paper. Great biostatistical analysis, cutting edge laboratory techniques, literature references and discussion.... but very difficult to understand without a lot of background.

Edited July 20, 2011 by Altostrata
added date and title of paper to heading

[lupe]

I thought I added attachment but I don't see it. I will try again.

serotonin transporter gene discont.syn.pdf

[Altostrata]

lupe, what's your interpretation of this regarding why some people get withdrawal syndrome and others do not?

[summer]

Some of it was obvious... like going CT versus tapering. The rest... well, I never went to medical school.

 

xo Blueberry

[lupe]

This paper is very difficult...I know!!! But my take on this is that they did discover a statistical difference in one of the polymorphism's in the 1A(?) receptor. They refer to it as<1019G, an allele (a location for a gene on a chromosome) They are talking about snips (SNP's) or single nucleotide polymorphism's., where there is a single nucleotide difference in the DNA of a gene. We have 2 copies of our chromosomes so you can have a change on one of them (makes you a heterozygote for that gene) and not the other or you can have a change on both (makes you a homozygote for that gene). If you have it on both the change can have a profound effect on the organism and if it is only on one it will be less or not effect it at all.

In the future we will have the ability to test for these types of genetic differences in individuals in a clinical setting and have the ability to treat people on the basis of their individual genetic makeup... so somebody who will be genetically predisposed to discontinuation syndrome would not be given these types of medications.

I am not a doctor and do not have a doctoral degree and also found this paper very difficult... but also was excited to see some research into the mechanisms behind the differences in people who get this syndrome and those who don't.

[Altostrata]

J Clin Psychopharmacol. 2010 Feb;30(1):11-7.

Effects of the serotonin 1A, 2A, 2C, 3A, and 3B and serotonin transporter gene polymorphisms on the occurrence of paroxetine discontinuation syndrome.

Murata Y, Kobayashi D, Imuta N, Haraguchi K, Ieiri I, Nishimura R, Koyama S, Mine K.

 

Source

 

Department of Psychosomatic Medicine, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan.

 

Abstract at http://www.ncbi.nlm.nih.gov/pubmed/20075642 Full text here.

 

Paroxetine discontinuation symptoms can at times be severe enough to reduce the quality of life. However, it is currently not possible to predict the occurrence of discontinuation syndrome before the initiation or discontinuation of paroxetine treatment. In this study, we investigated the effects of genetic polymorphisms in the serotonin 1A, 2A, 2C, 3A, and 3B receptor, the serotonin transporter, and the cytochrome P450 2D6 (CYP2D6) genes on the occurrence of paroxetine discontinuation syndrome. A consecutive series of 56 Japanese patients who had a diagnosis of major depressive or anxiety disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, were treated with paroxetine. Paroxetine discontinuation syndrome was found in 35.7% of the patients by direct interview. Patients who stopped taking paroxetine abruptly experienced paroxetine discontinuation syndrome significantly more often than patients who had a tapering off of the dosage of medication. Patients who had the -1019C allele experienced paroxetine discontinuation syndrome more frequently than patients who had the -1019G homozygote (nominal P = 0.0423) of the serotonin 1A receptor gene. However, this result did not remain significant after the Bonferroni correction for multiple comparisons. The findings suggest that the abrupt stoppage of medication is a major risk factor for the occurrence of paroxetine discontinuation syndrome and that C(-1019)G polymorphism of the serotonin 1A receptor gene may be related to the occurrence of the syndrome.

 

 

 

(lupe, I like to post the abstract and link to the PubMed entry in the initial post.)

[Altostrata]

Here are the major points of the paper for me (no doctorate for me, either; however, usually there are flaws in study design you can spot a mile away). While its genetic findings were not significant, it is a fairly readable overview of the literature on antidepressant withdrawal syndrome.

 

- The paper was published in the Journal of Clinical Psychopharmacology, a high-quality medical journal that every so-called psychopharmacologist reads (or should read).

 

- It has a good citation list for further documentation of withdrawal syndrome.

 

- The study did not find a "smoking gun" for paroxetine discontinuation syndrome among the genes they studied. This is no surprise to me because I don't believe it's due to a single gene. Also, it's across medications.

 

"Although the exact mechanism and the pathogenesis of SSRI discontinuation syndrome remain unclear, many studies have suggested that serotonergically mediated neural systems may be involved in the development of the syndrome."

 

My guess is withdrawal is related to a characteristic of serotonin receptors that controls their repopulation, or individual variations in neuroplasticity in general, which would be controlled by a web of genes so complex, reductionism will never figure it out.

 

- "Paroxetine discontinuation syndrome was found in 35.7% of the patients by direct interview." This is as good a measurement as any and adds to the evidence that withdrawal syndrome is fairly common.

 

- "Discontinuation symptoms are usually mild to moderate but can at times be severe enough to impair the quality of life of the patient."

 

- "....clinical studies have reported that the occurrence of discontinuation syndrome is extremely higher in patients treated with paroxetine (ranging 29%-66%) in comparison with other SSRIs."

 

For which we should be grateful prescriptions of paroxetine are declining, as its bad reputation has gotten around.

 

- "Selective serotonin reuptake inhibitor discontinuation symptoms do not occur in all patients who stop taking medications; however, abrupt stoppage of SSRI is considered an important risk factor. Although individual differences are known to exist in the occurrence of SSRI discontinuation syndrome, it is currently not possible to predict its occurrence."

 

- "Coupland et al reported that after the stoppage of clomipramine and SSRIs, the most common discontinuation symptom was dizziness. It is of interest that this frequent symptom, dizziness, resembles the characteristic symptom of motion sickness, which can be inhibited in animals by serotonin 1A (5-HT1A) receptor agonists,14 and that dizziness or light-headedness is an adverse effect reported commonly with 5-HT1A receptor agonists.15 Therefore, it is possible that genetic polymorphisms of the 5-HT1A receptor gene are associated with the occurrence of SSRI discontinuation syndrome."

 

This is why the researchers are looking at variations in 5-HT1A receptors. They are extrapolating from the symptom of dizziness. While this may have been sufficient to get their research grant, it is not a very complete description of withdrawal syndrome. In the real world, focusing on dizziness as the key symptom is faulty reasoning.

 

Again, here's the problem with diagnosis of subjective symptoms, which undermines all psychiatric studies -- who knows what Coupland et al called dizziness? The subjects may have had heterogenous symptoms they all called dizziness for the sake of convenience.

 

- "The participants were a series of 56 consecutive Japanese outpatients who were treated with oral paroxetine for 8 weeks or longer and who underwent an abrupt discontinuation or a dosage reduction of medication during treatment. Written informed consent was obtained from each participant....Patients taking tandospirone, benzodiazepines, or nonbenzodiazepines (zolpidem or zopiclone) were included."

 

Very curious that patients taking benzos and z-drugs were included; this could definitely affect their experience of withdrawal symptoms -- a confounding factor.

 

- "Assessment of possible paroxetine discontinuation-emergent events was made according to the modified methods proposed by Black et al. The patients were directly asked if they had experienced any symptoms after the abrupt stoppage or tapering off of the dosage of paroxetine. The items queried were symptoms such as dizziness, vertigo, gait instability, light-headedness, nausea, vomiting, loss of appetite, diarrhea, insomnia, increased dreaming, vivid dreams, anxiety, fatigue, headache, irritability, tremor, paresthesia, feeling faint, visual disturbances, muscle aches, chills, and fever. Patients with at least one qualitatively new symptom within 7 days of stopping the medication or after a dose reduction of paroxetine were identified as having experienced discontinuation syndrome."

 

This is a checklist.

 

- "For 33 patients, the dosage of paroxetine was gradually reduced under the direction of a psychiatrist, and the remaining 23 patients stopped taking paroxetine for a mean of 3.4 plus or minus 2.2 days (range, 0-7 days). The reasons for the discontinuation of medication were "forgetting to take medications" (9/23; 39%), "no need for an antidepressant, by their own judgment" (6/23; 26%), "drugs used up" (6/23; 26%), and "advice from others" (2/23; 9%). Of the patients with psychotropic comedication, 42 used tandospirone, 40 used benzodiazepines, and 25 used nonbenzodiazepines."

 

42 of the 56 subjects were taking other psych medications with paroxetine. (I'm really disgusted about this being permitted in the study design.)

 

- "Of the 20 patients with paroxetine discontinuation syndrome, 12 (60%) had experienced 2 or more of these symptoms and 5 (25%) had experienced very distressing symptoms. All patients with the syndrome had restarted paroxetine at the same dosage just before stoppage of the medication and recovered within a few days."

 

5 of the 56 subjects experienced "very distressing symptoms." Since, mercifully, patients showing withdrawal symptoms were reinstated on the medication, we don't know how many might have gone on to prolonged withdrawal syndrome.

 

- Table 1 is interesting; it shows 23 subjects quit abruptly and 33 "tapered" (no details given about the tapering method). Of the 23 who quit abruptly, 18 had serious discontinuation symptoms, 5 got away with "no" symptoms. Of the 33 who tapered, 31 had "no" symptoms; 2 had more serious symptoms.

 

"Discontinuation syndrome occurred significantly more frequently in patients who stopped taking paroxetine abruptly than in patients who had a tapering off of the dosage of medication (90% [18/20] in the group with paroxetine discontinuation syndrome had stopped abruptly compared with 14% [5/36] in the group without the syndrome...."

 

- From the Discussion:

 

"In the present study, paroxetine discontinuation syndrome was found by direct interview in 36% of our patients who abruptly stopped taking medication or who had the dosage of paroxetine tapered off. Rosenbaum et al reported that 66% of their paroxetine-treated patients experienced discontinuation syndrome in a prospective placebo-substitution study. van Geffen et al reported in a study using direct telephone interview that the incidence of discontinuation syndrome was 59% for SSRI-treated patients. The incidence of SSRI discontinuation syndrome in our study is considerably different from the findings of these studies. Both reports, obtained by direct interview, show a fairly high incidence of paroxetine discontinuation syndrome in whites. Our findings from a Japanese population are inconsistent with these reports. The difference might possibly be explained by ethnic and genetic variations....."

 

A finding of differences among ethnic groups would be very interesting indeed. But the small sample sizes in all of these studies probably explains the variation in reported incidence.

 

However

 

"....Of note, in our study, 75% of the subjects were treated with tandospirone (5-HT1A receptor partial agonist), which is the potential major flaw of the study design. The 5-HT1A receptor agonist may have decreased the discontinuation syndrome-like symptoms, as data from an animal study have suggested...."

 

Right, they wasted their grant money.

 

"Our results indicate that the most frequent discontinuation symptom was dizziness, which is consistent with reports by Michelson et al and Bogetto et al. Based on our observation, the symptoms are fairly distressing and uncomfortable. This is in good agreement with reports by Judge et al, van Geffen et al, and Hindmarch et al. However, it is currently not possible to predict the occurrence of SSRI discontinuation syndrome before stoppage of the medication."

 

So much for the clinicians who say they've never seen withdrawal syndrome.

 

- "In our study, paroxetine discontinuation syndrome occurred more frequently in patients who suddenly stopped taking medication than in those whose treatment was gradually tapered. Our finding is consistent with reports by van Geffen et al and Himei and Okamura, which confirmed that abrupt stoppage of medication is the most important causal factor of paroxetine discontinuation syndrome. Lejoyeux and Ades and Schatzberg et al suggested that tapering off of the dosage of an SSRI could be considered as a strategy for reducing the incidence of discontinuation syndrome. However, interestingly, 2 patients experienced discontinuation syndrome while the dosage of paroxetine was slowly tapered in the present study. Recently, Fava et al reported that 9 (45%) of 20 patients experienced discontinuation syndrome during a slow tapering of SSRIs. Tint et al reported that tapering for 14 days compared with 3 days did not reduce the incidence of discontinuation syndrome in patients treated with SSRIs. Considering the previous, the occurrence of SSRI discontinuation syndrome might be related not only to pharmacokinetic factors but to individual differences in susceptibility to SSRI discontinuation syndrome."

 

I'm quoting this here to show the information on this site conforms to evidence from medical research.

 

- "Our results showed that all the patients with paroxetine discontinuation syndrome recovered within a few days by reinstitution of the drugs. Rosenbaum et al speculated that the prompt readministration of SSRI therapy would be useful for the treatment of SSRI discontinuation syndrome. However, Fava et al and Chouinard and Chouinard suggested that adjunctive therapy with benzodiazepines or anticonvulsants can be effective for patients who experience persistent discontinuation syndrome. Thus, the most optimal treatment of SSRI discontinuation syndrome is controversial."

 

Controversial is a polite word for it. No one knows anything. To suggest that reinstatement is a "treatment" for withdrawal syndrome is typical of logic in psychiatry.

[summer]

Whenever I come across the word Paxil, or its other names, I immediately toss out the word Paxil and substitute any other AD in its place. Does this make sense? Is it a good idea??

[Altostrata]

Yes, this studies look at, say, Paxil in agoraphobia because they have to define their focus. But you can substitute any antidepressant for Paxil and "being human" for the mental disorder and you'll get the gist.

[cinephile]

Amazingly thorough (and authoritative!) postmortem of this study Alto! You have such a unique insight into these studies as a patient that I just know that eventually the researchers will be coming to you (well, they already are, considering Fava's study) asking for your input on future withdrawal study designs. I just know it. No SSRI patient is more qualified than you to do this! And your big plug on the Psychology Today blog is a great start for you to get more attention.

 

You deserve all the success and future healing you can get!