Hello,
I turned to the peer-reviewed medical journals for an answer to your
question. There are very few papers with a bearing on this topic,
which suggests that it is not arousing concern in the medical
profession at the moment. If serotonin inhibitors did delay tissue
repair, I would expect to find some case reports and studies reporting
this.
The results of my search are not 100% conclusive, but would tend to
argue that serotonin uptake inhibitors have a beneficial effect on
wound healing and tissue repair.
I found eight article in total. Two of them, from the same Ukrainian
laboratory, claim that the presence of serotonin reduces inflammation
and assists healing of experimental skin wounds and stomach ulcers in
rats. From this, one might expect that inhibitors would inhibit
healing. However, a larger number of other papers which report
studies in humans claim the oppposite. One paper did not find any
effect either way when a serotonin inhibitor was applied to surgical
wounds, but other studies found such treatment helped healing of
diabetic and leprosy ulcers, and also promoted healing by decreasing
the swelling caused by fluid leakage in burn wounds. Serotonin causes
constriction of blood vessels. Inhibitors of serotonin uptake may
help wound healing by increasing the flow of oxygen-carrying blood to
the wound area, thus stimulating repair processes and antibacterial
activity.
Finally, some circumstantial evidence. St John’s Wort, which has
serotonin-inhibitory properties, has also been used traditionally to
accelerate wound healing.
The articles I found are listed below.
1. Fiziol Zhurnal 2000;46(4):52-7
[The effect of serotonin on the healing of an experimental stomach
ulcer following vagotomy]
Klymenko MO, Lupal'tsov VI, Iahniuk AI, Tatarko SV.
Kharkov State Medical University, Ministry of Public Health of
Ukraine.
Presence of serotonin helps to reduce inflammation and optimise
healing of experimentally-induced stomach ulcers in rats.
2. Fiziol Zhurnal 1997;43(1-2):78-82
[Intercellular interactions during the healing of an experimental skin
wound]
Lipshits' RU, Zviahintseva TV.
Serotonin levels higher during healing of experimental skin wound in
rats.
3. Arch Med Res 1997 Spring;28(1):95-9 Randomized single-blind trial
of topical ketanserin for healing acceleration of diabetic foot
ulcers.
Martinez-de Jesus FR, Morales-Guzman M, Castaneda M, Perez-Morales A,
Garcia-Alonso J, Mendiola-Segura I.
Division de Cirugia, Centro Medico Nacional Adolfo Ruiz Cortines,
Instituto Mexicano del Seguro Social, Veracruz, Mexico.
Ketanserin, a serotonin antagonist, helped the healing of foot ulcers
in diabetics.
4. Br J Dermatol 1995 Apr;132(4):580-6 Related Articles, Books,
LinkOut
The effect of ketanserin on healing of fresh surgical wounds.
Lawrence CM, Matthews JN, Cox NH.
Department of Dermatology, Royal Victoria Infirmary, Newcastle upon
Tyne, U.K.
Topical ketanserin had no effect on the healing of wounds after
surgery.
5. J Cardiovasc Pharmacol 1994 Apr;23(4):664-8
Tetrachlorodecaoxygen, a wound healing agent, produces vascular
relaxation through hemoglobulin-dependent inactivation of serotonin
and norepinephrine.
Wolin MS, Kleber E, Mohazzab KM, Elstner EF.
Department of Physiology, New York Medical College, Valhalla 10595.
Serotonin causes constriction of blood vessels. Inhibitors of
serotonin uptake may contribute to wound healing by increasing
nutrient blood flow and oxygen delivery needed for repair processes
and bactericidal activity.
6. Indian J Lepr 2001 Apr-Jun;73(2):103-10
Use of topical ketanserin for the treatment of ulcers in leprosy
patients.
Salazar JJ, Serrano GG, Leon-Quintero GI, Torres-Mendoza BM.
Dermatologic Institute Guanajuatense, Viveros Revolucion S/N Irapuato,
Gto, Mexico.
Ketanserin applied to leprosy ulcers promoted their healing.
7. Pharmacopsychiatry 1997 Sep;30 Suppl 2:108-12
In vitro receptor binding and enzyme inhibition by Hypericum
perforatum extract.
Cott JM.
Pharmacologic Treatment Research Program, National Institute of Mental
Health (NIMH), National Institutes of Health, Rockville, Maryland,
USA.
Hypericum (St John’s Wort), which has serotonin-inhibitory properties,
has also been used traditionally for wound healing (although this is
only circumstantial evidence, and the healing effect could be due to
another constituent).
8. Acta Chir Plast 1999;41(1):25-32
Therapeutical aspects of using citalopram in burns.
Blaha J, Svobodova K, Kapounkova Z.
Klinika popaleninove mediciny FNKV Praha.
Citalopram, a serotonin inhibitor, accelerated recovery from burns by
decreasing the amount of edema (swelling). |
Clarification of Answer by
tehuti-ga
on
02 Jun 2002 18:40 PDT
Hello again,
Perhaps I should clarify my credentials for taking up your question.
I have a PhD in biomedical science and a postgraduate diploma in
library and information studies. I have extensive experience in
Internet and database searching, and lecture to scientists, editors
and indexers about these topics in the UK and abroad. In order to
find an answer to your question, I availed myself of the Medline
database at the National Library of Medicine:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi I used a variety of
search terms, defining serotonin and serotonin uptake inhibitors via
the MeSH thesaurus, and combining these with phrases such as "wound
healing", "tissue repair". Medline includes references to articles in
medical and scientific journals dating back to 1966. I did search
within the complete time range and scanned all the references that I
retrieved, however I limited myself to evaluating references which
provided abstracts of the content.
|
Clarification of Answer by
tehuti-ga
on
03 Jun 2002 02:08 PDT
Bad comment qwerty6400-ga, you do not document any of your statements.
I already explained in my answer that there was very little in the
literature that dealt with this topic. I searched on all aspects of
serotonin, serotonin inhibition and serotonin reuptake inhibition in
connection with tissue repair and wound healing in order to obtain a
full story and only found the eight papers I cited.
"Are you saying that SSRIs are equivalent to the presence of
serotonin?
Nice try, but I don't think so. This could be true, but you need to
point to a source that gives credibility to your blind inference."
No I'm not saying that, nor am I making any inferences. I'm trying to
find out whether serotonin itself affects wound healing. If it has no
effects, it is less likely that compounds which act on serotonin
and/or its receptors will have any effects. It is impossible to prove
there is nothing in the literature, because there may always be some
material which has not been retrieved by the search strategy.
Therefore, in a situation like this, where I found only one paper
dealing with the specific question and only dealing with it partially
(only in relation to burn wounds not to surgical wounds), it is wise
to broaden out the search as much as possible.
There are two papers from the same laboratory claiming serotonin
promotes healing. There are four papers from four different
laboratories claiming that serotonin antagonists promote wound
healing, ie the exact opposite (i.e. 4 to 1 in favour of the
antagonists. There is one paper claiming a serotonin reuptake
inhibitor promotes healing.
"Those studies used a serotonin antagonist, which is actually the
opposite of certain SSRIs."
Ketanserin and tetrachlorodecaoxygen are serotonin antagonists,
citalopram is a serotonin reuptake inhibitor. Agreed that ketanserin
and citalopram have opposite effects from a neurological point of view
(eg as reported in Liechti ME, Saur MR, Gamma A et al. (2000),
Psychological and physiological effects of MDMA (Ecstasy) after
pretreatment with the 5-HT(2) antagonist ketanserin in healthy humans.
Neuropsychopharmacology 23(4):396-404), however both are reported in
the papers I found to promote tissue healing. The question was about
tissue healing, not about neurobiology.
As for St John's Wort, the jury is still out on that. There is no
consensus in the medical literature on its mechanism of action, except
that it does affect serotonin responses in some way. A number of
researchers do believe that it acts as a serotonin reuptake inhibitor,
a number of others do not. It would take several hours of searching
and analysing the literature to make any more detailed comment on the
question. For this reason, I presented hypericum as circumstantial
evidence and said so.
Depending on whether you do or do not believe hypericum to have SSRI
activity, there are either two or one SSRIs which have been found to
promote wound healing, either in clinical studies (citalopram) or
through traditional use (hypericum). There are zero papers which
claim that SSRIs inhibit healing.
Therefore, as I said right at the start of my answer, there is no
evidence that serotonin reuptake inhibitors have a negative effect on
tissue repair, there is
slight evidence that they might have a positive effect.
|
Request for Answer Clarification by
xxxxxxxxxxxxxx-ga
on
06 Jun 2002 03:22 PDT
Thanks for your answer. It would both from your answer and the comment
that different SSRIs may have different effects. The one I am talking
about in particular is sertraline (also seroxat). Two people - a
surgeon and a chriporactor have independantly suggested that the
medication is thought to inhibit repair from a back operation. I would
appreciate any further comment you may have - one possibility would be
to search through sites dealing with surgery.
|
Clarification of Answer by
tehuti-ga
on
07 Jun 2002 06:42 PDT
Hello,
Apologies for the delayed response, but I was abroad and did not
return home until late last night. The additional information on drug
names has enabled me to search more extensively. I still have not
found any evidence that these drugs affect wound healing to an extent
that has caused clinicians to take notice of such an effect in
patients. However, there are some pointers that seroxat (one of the
trade names for paroxetine), in particular, could affect wound healing
processes through its effect on nitric oxide synthesis. In addition,
sertraline and paroxetine both have an effect on platelets, and
platelets are responsible for the release of certain cell mediators
and for blood clotting which are important in early wound healing. I
will go through the various bits of information I have found in turn:
Firstly, there is a paper (see ref. 1) about the use of sertraline in
car accident victims with severe brain injury. This study was carried
out in 11 patients, of whom some were given sertraline and some were
given placebo for 2 weeks, starting within 2 weeks of injury. The
study was concerned with
behavioural symptoms. However, the report does mention that
sertraline did
not have any negative effects on recovery in general and that no
complications were associated with its use. On the other hand, if
wound healing was not a specific point of observation, small
differences in this respect might not have been noticed.
Secondly, both sertraline and paroxetine affect platelet activity.
This effect has been reported as a favourable effect of these drugs
for the following reason: depressed people have been found to show
increased platelet activity compared to non-depressed controls.
Platelet activity is responsible for blood clotting, so that their
increased activity will make the blood “stickier”. This is considered
to be one of the risk factors for coronary disease (coronary
thrombosis). Therefore, sertraline and paroxetine are considered to
reduce this risk. The studies I found (see refs 2 and 3) showed that
sertraline and paroxetine reduced the increased plaetelet activity in
depressed people. The effects on platelets were not related to
effects on depression, suggesting that different mechanisms are
involved. However, the studies did not look at whether these drugs
affect normal levels of platelet activity, or whether they simply
bring increased activity down to normal levels. If they do decrease
activity to below normal, then this would make the blood “thinner” and
reduce clotting ability. Reduced clotting ability could slow down the
process of wound healing.
I did however find a report suggesting that the use of sertraline in
children and adolescent patients could possibly be associated with
increased bleeding and bruising, which suggests that sertraline can
reduce platelet activity to below normal levels (see ref 4). A study
on 26 heart attack patients also found that sertraline increased
bleeding time in 12 patients (see ref 5).
I then looked for other articles by the authors of the papers I have
quoted so far, and this gave me a new lead to follow:
Paroxetine has been reported to inhibit the activity of nitric oxide
synthase (see ref 6).
Following up the nitric oxide story, I found a review (see ref 7) on
the role of nitric oxide in wound repair which states that the
inducible form of nitric oxide synthase is produced by inflammatory
cells in the early stages of wound repair. It also states that nitric
oxide is known to improve wound healing. Therefore, something which
inhibits an enzyme responsible for nitric oxide synthesis could
possibly delay wound healing.
I found a further article which also states that nitric oxide has an
important role in wound healing (see ref 8), and an article on the
role of nitric oxide and nitric oxide synthase in wound healing (see
ref 9). The authors of ref 9 refer to a previous paper in which they
showed that blocking the synthesis of nitric oxide impairs wound
healing, especially by inhibiting the production of collagen. In the
paper listed here, they looked at collagen-producing cells from mice
in which the gene for inducible nitric oxide synthase had been knocked
out and found these produced less collagen.
I then looked to see whether sertraline can have an effect on nitric
oxide synthase. One letter has appeared in a journal asking whether
the increased bleeding associated with selective serotonin reuptake
inibitors could be due to them inhibiting nitric oxide synthase (see
ref 10), which suggests the authors think this a possibility.
However, I found no studies that investigated this question with
respect to sertraline. I did find that fluoxetine and amitryptiline
inhibit nitric oxide release (see ref 11).
Thus, I still have not found any direct clinical reports that
sertraline or seroxat affect wound healing and tissue repair in
patients. However, both have a potential to affect this process if
they do decrease platelet activity to below normal levels. I also
think that the inhibitory activity of paroxetine on nitric oxide
synthase could be an important factor, perhaps more relevant than its
effect on platelets, but I have not found reports of such an effect
with sertraline.
References:
1. Brain Injury 2001 Apr;15(4):321-31
Sertraline to improve arousal and alertness in severe traumatic brain
injury secondary to motor vehicle crashes.
Meythaler JM, Depalma L, Devivo MJ, Guin-Renfroe S, Novack TA.
University of Alabama at Birmingham Model Traumatic Brain Injury
System;
Spain Rehabilitation Center, Department of Physical Medicine and
Rehabilitation, University of Alabama School of Medicine, Birmingham,
AL
2. American Journal Psychiatry 2000 June; Vol 157(6):1006-8
Platelet activation in depression and effects of sertraline treatment:
An open-label study.
Markovitz JH, Shuster JL, Chitwood WS, May RS, Tolbert LC.
Department of Medicine, University of Alabama at Birmingham, 35205,
USA.
3. Clinical Psychopharmacology 2000 Apr;20(2):137-40
Evaluation of platelet activation in depressed patients with ischemic
heart disease after paroxetine or nortriptyline treatment.
Pollock BG, Laghrissi-Thode F, Wagner WR.
Department of Psychiatry, University of Pittsburgh School of Medicine,
University of Pittsburgh Medical Center, Pennsylvania, USA.
4. J Child Adolescent Psychopharmacology 2000 Spring;10(1):35-8
Bleeding and selective serotonin reuptake inhibitors in childhood and
adolescence.
Lake MB, Birmaher B, Wassick S, Mathos K, Yelovich AK.
Department of Child Psychiatry, Western Psychiatric Institute and
Clinic,
University of Pittsburgh School of Medicine, Pennsylvania 15213, USA.
5. American Heart Journal 1999 Jun;137(6):1100-6
An open-label preliminary trial of sertraline for treatment of major
depression after acute myocardial infarction (the SADHAT Trial).
Sertraline Anti-Depressant Heart Attack Trial.
Shapiro PA, Lesperance F, Frasure-Smith N, O'Connor CM, Baker B, Jiang
JW, Dorian P, Harrison W, Glassman AH.
Department of Psychiatry, Columbia University College of Physicians
and Surgeons, New York, NY 10032, USA.
6. Psychopharmacological Bulletin 1996;32(4):653-8
Paroxetine is a novel nitric oxide synthase inhibitor.
Finkel MS, Laghrissi-Thode F, Pollock BG, Rong J.
Department of Medicine (Cardiology), University of Pittsburgh School
of Medicine, University of Pittsburgh Medical Center, PA, USA.
7. American Journal of Surgery 2002 Apr;183(4):406-12
Role of nitric oxide in wound repair.
Witte MB, Barbul A.
Department of Surgery, the Sinai Hospital of Baltimore, and the Johns
Hopkins Medical Institutions, Baltimore, MD 21215, USA.
8. Kidney International 2002 Mar;61(3):882-8
Nitric oxide drives skin repair: novel functions of an established
mediator.
Frank S, Kampfer H, Wetzler C, Pfeilschifter J.
Pharmazentrum Frankfurt, Klinikum der Johann Wolfgang
Goethe-Universitat, Frankfurt/Main, Theodor-Stern-Kai, D-60590
Frankfurt am Main, Germany.
9. Surgery 2001 Aug;130(2):225-9
The role of iNOS in wound healing.
Shi HP, Most D, Efron DT, Tantry U, Fischel MH, Barbul A.
Department of Surgery, Sinai Hospital of Baltimore, MD 21215, USA.
10. Shen WW, Swartz CM, Calhoun JW.
Is inhibition of nitric oxide synthase a mechanism for SSRI-induced
bleeding?
Psychosomatics. 1999 May-Jun;40(3):268-9
11. Arthritis Rheumatism 1999 Dec;42(12):2561-8
Fluoxetine and amitriptyline inhibit nitric oxide, prostaglandin E2,
and hyaluronic acid production in human synovial cells and synovial
tissue cultures.
Yaron I, Shirazi I, Judovich R, Levartovsky D, Caspi D, Yaron M.
Ichilov Hospital, Tel Aviv University, Israel.
|
Clarification of Answer by
tehuti-ga
on
07 Jun 2002 07:21 PDT
After doing the above searches on nitric oxide, etc, I did attempt a
specific search on the two drug names combined with the search "back
surgery" and "spinal surgery". This did not provide me with anything
of relevance either in Medline or in an Internet search using Google.
I also searched separately the web sites of the American Academy of
Orthopaedic Surgeons (http://www.aaos.org/), American College of
Surgeons (http://www.facs.org/), British Orthopaedic Association
(http://www.boa.ac.uk), Espine.com, OrthoGate, the international
orthopaedic gateway (http://www.orthogate.com/), and the archives of
OrthNorth, a discussion list for orthopaedic surgeons in the North of
England (http://mailbase.ncl.ac.uk/lists/orthnorth/), but again did
not find anything of relevance to the query.
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