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Association between the use of serotonin receptor 2A-blocking antidepressants and joint disorders
Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Public Health Sciences.
Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
2009 (English)In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 61, no 10, 1322-1327 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: There are case reports about antidepressants causing arthritis and arthralgia, and the majority of these reports deal with atypical antidepressants, which are serotonin receptor 2A (5-HT(2A))-blocking substances. The aim of this study was to examine a possible association between joint disorders and the use of 5-HT(2A)-blocking atypical antidepressants.

METHODS: We performed a retrospective study using reports of adverse drug reactions (ADRs) of 5-HT(2A)-blocking atypical antidepressant substances concerning joint disorders reported to the Swedish Adverse Drug Reactions Committee and the World Health Organization (WHO) Adverse Reactions Database during the period January 1, 1990 to December 31, 2006. The reports of joint disorders were related to sales figures measured as defined daily doses and to the total number of ADR reports.

RESULTS: In the Swedish material, the 5-HT(2A) antagonists were 45 times more often reported to give joint ADRs when related to sales figures and compared with the selective serotonin reuptake inhibitors (SSRIs; P < 0.001). Joint disorders constituted 6.6% of the total number of reports of possible ADRs for the three 5-HT(2A)-blocking substances mianserin, mirtazapine, and nefazodone compared with 0.5% for the SSRIs (P < 0.001). In the WHO material, the joint disorders constituted 1.3% of all ADRs for the 5-HT(2A)-blocking antidepressants and 0.6% for the SSRIs (P < 0.001).

CONCLUSION: In this study, joint disorders were considerably more frequently reported ADRs of 5-HT(2A)-blocking antidepressants than of other comparable drugs, suggesting a possible association between the use of 5-HT(2A)-blocking antidepressants and joint disorders.

Place, publisher, year, edition, pages
2009. Vol. 61, no 10, 1322-1327 p.
National Category
Social and Clinical Pharmacy
URN: urn:nbn:se:umu:diva-30604DOI: 10.1002/art.24673PubMedID: 19790123OAI: diva2:284862
Available from: 2010-01-08 Created: 2010-01-08 Last updated: 2013-01-14Bibliographically approved
In thesis
1. 5-HT2A: a serotonin receptor with a possible role in joint diseases
Open this publication in new window or tab >>5-HT2A: a serotonin receptor with a possible role in joint diseases
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]


Serotonin (5-HT), an amino acid derivative and neurotransmitter, has for long been studied in relation to inflammation. It is an endogenous ligand for several different types of serotonin receptors. The serotonin receptor 5-HT2A has been reported to have a role in the pathophysiology of arthritis in animal experiment models. However, no studies into this subject have been reported in man.


The objectives of this project were firstly, to examine possible associations for the 5-HT2A receptor and also for the gene (HTR2A) encoding for the receptor with arthritis in man and secondly, to explore possible mechanisms underlying such associations.


The density and affinity of platelet 5-HT2A receptors were determined in 43 patients with a common inflammatory joint disease, i. e., rheumatoid arthritis (RA), in comparison with matched controls using a radio-ligand assay. The effects of treatment with prednisolone on 5-HT2A density and affinity were also examined in 27 individuals diagnosed with polymyalgia rheumatica before and after start of treatment. In addition, possible candidate HTR2A genes were studied in relation to RA in two Swedish cohorts incorporating a total of 2450 RA patients. Furthermore, a register study using reports of joint symptoms as adverse drug reactions (ADRs) in the Swedish and the WHO ADR databases was undertaken. The proportion of reports concerning joint symptoms in relation to all ADR reports and to sales figures was analysed for 5-HT2A blocking atypical antidepressant substances compared with another group of antidepressants, i. e., selective serotonin re-uptake inhibitors (SSRIs), used for similar clinical indications.


The mean density of 5-HT2A receptors in RA patients was significantly lower than in controls, 45.3 versus 57.4 fmol/mg protein (p = 0.004). There was no significant difference in affinity. Variation of four single nucleotide polymorphisms (SNPs) (rs6314, rs1328674, rs6313 and rs6311) in the HTR2A gene was associated with RA, although not significantly so for all SNPs after testing for multiple comparisons. The proportion of joint symptoms reported as ADRs, relative to all ADRs was significantly higher for the 5-HT2A blocking antidepressants compared with the SSRIs in both databases (p< 0.001). In the Swedish material the comparison of ADRs was also related to sales figures, showing a considerable higher frequency of joint symptoms for the 5-HT2A antagonists (p< 0.001). The density of 5-HT2A receptors increased after treatment with prednisolone in 23 out of 27 individuals. The mean density at baseline was 45.2 versus 64.9 fmol/mg protein at the end of the study (p=0.001). There were no significant differences in affinity during the treatment period, although a low affinity at baseline was a predictor for higher density following treatment with prednisolone.


The density of 5-HT2A receptors, reflecting the number of receptors, was markedly reduced in a cohort of patients with RA from Northern Sweden. This may depend, at least in part, on an association between RA and certain HTR2A SNPs. Genetically determined or acquired low levels of accessible 5-HT2A receptors may contribute to susceptibility for development of joint symptoms, not only in RA but more generally, e. g., joint ADRs caused by 5-HT2A blocking atypical antidepressants. The benefits of treatment with glucocorticoids may, at least partially, be mediated by an effect on 5-HT2A receptors.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet, 2013. 79 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 1547
5-HT2A serotonin receptor, serotonin, rheumatoid arthritis, adverse drug reaction, HTR2A, glucocorticoids
National Category
Pharmacology and Toxicology
Research subject
Clinical Pharmacology
urn:nbn:se:umu:diva-64013 (URN)978-91-7459-549-9 (ISBN)
Public defence
2013-01-28, Vårdvetarhusets aula, Vårdvetarhuset, Umeå, 13:00 (Swedish)
Available from: 2013-01-14 Created: 2013-01-11 Last updated: 2013-01-14Bibliographically approved

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Kling, AndersDanell-Boman, MaritStenlund, HansDahlqvist, Rune
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