Association between the use of serotonin receptor 2A–blocking antidepressants and joint disorders

Abstract

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.

INTRODUCTION

Arthritis and arthralgia as adverse drug reactions (ADRs) caused by the use of medical drugs is a fairly unexplored field. However, there are certain drugs or groups of drugs that have been shown in clinical studies to be connected with ADRs in the joints, e.g., bisphosphonates (1, 2).

The serotonin system has mainly been studied in relation to neuroscience and to psychiatric diseases, but it has widespread functions and is distributed within several tissue types of the human body. Seven main groups of serotonin receptors with their corresponding subgroups have been identified (3). Serotonin receptor subtype 2A (5-HT_2A) is located on neurons, but also on platelets, vascular smooth muscle (3), and probably also on immune cells (4, 5).

From published case reports and case series, it has been suggested that 5-HT_2A–blocking antidepressant drugs may cause joint disorders (6–9). These reports could be a signal of a true ADR, but could also simply be a result of coincidence because arthritis and arthralgia, even without established rheumatic disease, are common in general populations. It is therefore difficult to judge in individual cases whether or not the symptoms are caused by the use of a drug. However, the subject of 5-HT_2A–blocking antidepressant drugs and joint disorders has not been thoroughly investigated, and it is difficult to find an appropriate study design to detect a small increase in joint disorders caused by a certain drug when the frequency of these disorders is relatively high in the population. When randomized controlled trials for practical reasons would be hard to carry out, retrospective epidemiologic studies have been used to generate hypotheses emanating from national registers of ADRs (10).

The World Health Organization (WHO) Adverse Reactions Database is the largest international database of case reports of spontaneous reporting of suspected ADRs, with almost 4 million total records of ADRs (11). The disadvantage of this database is that the reporting culture differs very much between the many countries sending reports to this database. In some big countries no evaluation is performed, and since both the health care system and drug companies have the possibility to report, double reporting is an enormous problem for the WHO database (12). Because the reports entering the WHO database are deidentified, no routine check for double reporting could be performed. Another problem is that it is difficult to get reliable sales figures from all of the countries reporting to the WHO. The reports in the WHO database very seldom provide a case history or information about age, sex, time at onset of the ADR, clinical outcome, and possible concomitant medications. Quality assessments or evaluation of causality and seriousness are also seldom provided.

Sweden has had a reporting system for ADRs where only health care providers entitled to prescribe drugs, i.e., physicians, dentists, and some special nurses, have to report all new, serious, uncommon, or otherwise unexpected ADRs. Physicians, nurses, and pharmacists employed by the Medical Products Agency (MPA) handle these ADR reports, summarize the clinical data, and perform quality assessments, including an evaluation of causality and seriousness, and add all of the reports to a national database (SWEDIS). The ADRs are classified into reactions by organ system and specific reactions terms in accordance with guidelines from the WHO and MPA (13, 14). Most of the reports also contain more information, e.g., about age, sex, time at onset of the ADR, clinical outcome, concomitant medication, and a case history. In Sweden, all of the drugs are centrally distributed through the National Corporation of Swedish Pharmacies (Apoteket), which is also responsible for the collection of all of the sales data. Annual sales data can be shown as the number of defined daily doses (DDDs) sold. Briefly, the “DDD is the assumed average maintenance dose per day for a drug used for its main indication in adults” (15). The advantage of the Swedish database is that the robustness of the organization of the spontaneous reporting system gives a material handled under homogenous conditions. In addition, although there is substantial underreporting, Sweden is usually one of the countries with the highest reporting frequencies (16). Furthermore, since there is only one national distributor of drugs, the prerequisites for receiving reliable data of annual sold DDDs are good.

In the present study, we assessed reports of joint disorders as possible ADRs of 5-HT_2A–blocking atypical antidepressants with the use of a retrospective epidemiologic model.

MATERIALS AND METHODS

Cases.

In this study, we have assessed ADR reports concerning joint disorders where the suspected drug was any of the three 5-HT_2A–blocking atypical antidepressants used in Sweden, i.e., mianserin, mirtazapine, and nefazodone. Because the propensity to report ADRs may have varied during different periods of time, we limited the analysis to reports added to the databases between January 1, 1990 and December 31, 2006. In the Swedish material, ADRs with a causality assessment classified as at least “possible” were included in the analysis, whereas ADRs classified as “unlikely” or “unclassifiable” were not taken into consideration. The following specific reactions terms concerning joints were identified in the Swedish database: arthritis, arthralgia, joint swelling, and arthropathy. Demographic data of the patients described in these reports are shown in Table 1. In the WHO database, arthralgia, arthritis, arthritis aggravated, arthropathy, and synovitis were used.

Table 1. Demographic data of the patients in the Swedish ADR reports concerning joint disorders*

Drug group	Age, mean ± SD years	Men/women	Cases with debut of joint ADR within 1 month, %
* There were no significant differences in demographics between the 5-HT2A–blocking substances and the SSRIs. The ADR reports concerning bisphosphonates included more women and the patients were older compared with the 5-HT2A antagonists (P < 0.001). ADR = adverse drug reaction; 5-HT2A = serotonin receptor 2A; SSRIs = selective serotonin reuptake inhibitors.
5-HT2A antidepressants	49.9 ± 15.2	21/39	69.2
SSRIs	48.4 ± 20.9	2/10	72.7
Bisphosphonates	69.4 ± 8.5	1/35	83.3

Selection of control groups.

To compare the number of joint disorders as reported ADRs of the 5-HT_2A–blocking atypical antidepressants, the selective serotonin reuptake inhibitors (SSRIs) were used as a main control group. The SSRIs are considered to be a relatively homogenous group of substances prescribed on the same indications as the studied 5-HT_2A antagonists.

In addition to the SSRIs, we also examined the amount of joint ADRs for bisphosphonates to further evaluate the magnitude of joint disorders as reported ADRs of 5-HT_2A–blocking antidepressants. The bisphosphonates were chosen because clinical studies have indicated that joint disorders are common ADRs caused by these drugs (1, 2).

Statistical analysis.

A ratio between reports of joint ADRs and the total amount of ADR reports for the same drug was calculated. In the Swedish material, we also calculated a ratio between ADRs from the joints and annual sales data during the study period. In the WHO material, all of the joint ADRs and the ADRs with the specific reaction term arthritis were respectively related to all of the ADRs for the same drug.

For comparison between the different drug groups, the chi-square test was used with Statcalc, EpiInfo version 6 (Centers for Disease Control and Prevention, Atlanta, GA) to analyze the relationship between joint ADRs and all ADRs, and a Poisson regression model was used with Stata, version 9.0 (StataCorp, College Station, TX) to analyze the relationship between joint ADRs and DDDs. Incidence rate ratios with 95% confidence intervals were calculated when appropriate. An evaluation of possible differences in demographic data between the different groups of drugs in the Swedish material was performed using SPSS, version 12.0 (SPSS, Chicago, IL).

RESULTS

Joint ADRs in relation to DDDs.

Approximately 1.5 billion DDDs of SSRIs, 170 million 5-HT_2A–blocking antidepressants, and 136 million bisphosphonates were sold in Sweden during the study period. When quotients were made between the ADR reports concerning joint disorders and the DDDs, the ratio for the 5-HT_2A antagonists was 45 times that of the SSRIs (P < 0.001) (Table 2), whereas the ratio for the bisphosphonates was on the same level as the 5-HT_2A antagonists.

Table 2. Reports of joint ADRs in the Swedish database in relation to DDDs for the same drug during the study period January 1, 1990 to December 31, 2006*

Drug group	Joint ADR reports	DDD ×10^6	Joint ADR/DDD ×10^6	Incidence rate ratio (95% CI) vs. the SSRI group
* ADR = adverse drug reaction; DDD = defined daily dose; 95% CI = 95% confidence interval; SSRI = selective serotonin reuptake inhibitor; 5-HT2A = serotonin receptor 2A.
5-HT2A antagonists	60	170	0.35	45.6 (24.5–84.8)
Mianserin	36	38	0.96
Mirtazapine	17	124	0.14
Nefazodone	7	88	0.80
SSRI	12	1,552	0.0077
Citalopram	3	791	0.0038
Fluvoxamine	1	13	0.076
Fluoxetine	1	136	0.0074
Paroxetine	3	193	0.016
Sertraline	3	375	0.0080
Zimeldine	0	0.2	0
Escitalopram	1	44	0.023
Bisphosphonates	36	136	0.26	34.4 (17.9–66.1)
Alendronate	26	94	0.28
Risedronate	8	23	0.35
Etidronate	1	8	0.13
Clodronate	1	7	0.14
Pamidronate	0	0.2	0
Tiludronate	0	0.007	0
Ibandronate	0	3	0
Zoledronic acid	0	0.2	0

Joint ADRs in relation to all ADRs.

The Swedish database.

During the study period, the numbers of ADR reports that had a causality assessment of at least “possible” were 906, 2,540, and 417 for the 5-HT_2A–blocking antidepressants, SSRIs, and bisphosphonates, respectively. Of these, there were 60 ADR reports of joint disorders for the 5-HT_2A–blocking substances, representing 6.6% of the ADR reports for these drugs. The corresponding figures for the SSRIs and bisphosphonates were 12 (0.5%) and 36 (8.6%), respectively (Table 3). Therefore, joint disorders were significantly more common ADR terms for the 5-HT_2A substances when compared with the SSRIs (P < 0.001), while being on the same level as the bisphosphonates (P = 0.22). A comparison within the group of 5-HT_2A antagonists showed that mianserin had a significantly higher proportion of joint-related ADRs than mirtazapine (P < 0.001), but not when compared with nefazodone (P < 0.22).

Table 3. Reports in the Swedish and WHO databases of joint ADRs in relation to all ADR reports for the same drug during the study period January 1, 1990 to December 31, 2006*

Drug	All ADR reports	Joint ADR reports	Joint reports, % of all	Incidence rate ratio (95% CI) vs. the SSRI group
* WHO = World Health Organization; ADR = adverse drug reaction; 95% CI = 95% confidence interval; SSRI = selective serotonin reuptake inhibitor; 5-HT2A = serotonin receptor 2A.
Mianserin
Swedish	365	36	9.86	20.88 (10.96–39.75)
WHO	3,939	110	2.79	4.42 (3.66–5.34)
Mirtazapine
Swedish	426	17	3.99	8.45 (4.06–17.56)
WHO	14,160	194	1.37	2.20 (1.90–2.55)
Nefazodone
Swedish	115	7	6.09	12.88 (5.17–32.11)
WHO	18,069	152	0.84	1.36 (1.15–1.60)
Total 5-HT2A antagonists
Swedish	906	60	6.62	14.02 (7.58–25.93)
WHO	36,168	456	1.26	2.03 (1.83–2.24)
SSRIs
Swedish	2,540	12	0.48
WHO	315,010	1,948	0.62
Bisphosphonates
Swedish	417	36	8.63	18.27 (9.59–34.83)
WHO	63,084	1,776	2.82	4.46 (4.18–4.75)

There was information that the suspected joint ADRs disappeared upon discontinuation of the SSRI, the 5-HT_2A antagonist, or the bisphosphonate in 67%, 68%, and 86% of the cases, respectively. The differences between the different groups of drugs were not significant.

The WHO database

The same result was found in the WHO material, where joint ADRs constituted 1.3%, 0.6%, and 2.8% of all ADRs for the 5-HT_2A–blocking antidepressants, SSRIs, and bisphosphonates, respectively (Table 3). The difference between the 5-HT_2A antagonists and the SSRIs was significant (P < 0.001). The bisphosphonates had a significantly higher proportion of joint ADRs when compared with the group of 5-HT_2A–blocking antidepressants (P = 0.001), but compared with mianserin taken alone, there was no difference (P = 0.94). Mianserin had a significantly higher proportion of joint-related ADRs than both mirtazapine and nefazodone (P < 0.001).

The same pattern of associations was found when only arthritis was related to all ADRs for the investigated drugs (Table 4), although not for nefazodone taken alone.

Table 4. Specific reaction term arthritis in the WHO database in relation to all ADRs for the same drug during the study period January 1, 1990 to December 31, 2006*

Drug	All ADRs	Arthritis	Arthritis, % of all	Incidence rate ratio (95% CI) vs. the SSRI group
* See Table 3 for abbreviations.
Mianserin	3,939	14	0.36	2.92 (1.71–4.97)
Mirtazapine	14,160	27	0.19	1.57 (1.06–2.31)
Nefazodone	18,069	20	0.11	0.91 (0.58–1.43)
Total 5-HT2A antagonists	36,168	61	0.17	1.39 (1.06–1.82)
SSRIs	315,010	383	0.12
Bisphosphonates	63,084	300	0.48	3.90 (3.35–4.53)

DISCUSSION

The present study suggests an association between the use of the 5-HT_2A–blocking antidepressant substances mianserin, nefazodone, and mirtazapine, and joint disorders as ADRs. In addition to our primary study based on the material in the Swedish database of ADRs, we replicated part of the analysis and found similar results in the WHO database.

There are some obvious limitations to the study. First, it is known that there is a substantial underreporting of ADRs (17). In this perspective, it is interesting to notice that 2 bisphosphonates have been reported to have an incidence of 12.6% of joint disorders in one major clinical study (2). Despite significantly younger patients and less women, the 5-HT_2A group in our study had the same level of joint ADRs as the bisphosphonates. Second, the propensity to report ADRs could vary with time and between different drugs. However, there are reasons to believe that the reporting frequency for the three 5-HT_2A–blocking antidepressant substances mianserin, nefazodone, and mirtazapine are on the same level as the frequency for the SSRIs because they were introduced on the market during the same period of time and used for similar indications (Table 5). In addition, the approach where the number of reports with joint disorders was related to the number of all other ADR reports for a certain drug will compensate at least in part for bias as a result of differences in propensity to report ADRs between different substances. Of course, with this approach, a relatively higher tendency to report other types of ADRs will attenuate the percentage part of joint disorders, and if this is the case for only some drugs, it may give bias. However, the combination of relating to both sales figures and non–joint-related ADRs will increase the reliability of the results. Third, some of the ADR terms included in joint disorders, e.g., arthralgia, are more nonspecific and difficult to interpret, but also the more stringent diagnostic term arthritis showed the same association to the 5-HT_2A antagonists. The ADRs were mostly not examined and evaluated by a rheumatologist. This would have been desirable, but since the ADRs often disappeared upon discontinuation, patients seldom were referred to a specialist clinic. However, in this respect, the situation was the same for all of the drugs included in the study. Fourth, one must take into consideration that the frequency of joint disorders increases with increasing age and they are more common among women. In our study, however, there were no significant differences in age and sex between the 5-HT_2A antagonists and the SSRIs.

Table 5. Approval dates for the selective serotonin reuptake inhibitors (SSRIs) and serotonin receptor 2A (5-HT_2A) antagonists on the Swedish market

Drug	Approval date
SSRIs
Citalopram	October 23, 1992
Escitalopram	December 7, 2001
Fluoxetine	September 5, 1995
Fluvoxamine	June 15, 1990
Paroxetine	June 20, 1991
Sertraline	January 19, 1995
Zimeldine	March 12, 1982
5-HT2A antagonists
Mianserin	February 2, 1990
Mirtazapine	February 28, 1996
Nefazodone	December 20, 1995

There are some pathophysiologic findings from previous studies suggesting that 5-HT_2A antagonism may constitute one of many etiologic factors promoting the development of arthralgia and arthritis. A result from a previous study suggests that patients with rheumatoid arthritis have a lower density of 5-HT_2A compared with age- and sex-matched controls (18). This seems, at least in part, to be related to constitutional differences in certain single-nucleotide polymorphism genotypes in the HTR2A gene (19) that have been suggested to give a lower expression of 5-HT_2A (20).

What could be the mechanism of joint disorders as ADRs of 5-HT_2A antagonists? The 5-HT_2A is linked to cell signaling through the JAK-2/STAT pathway (21), and there are studies suggesting that 5-HT_2A is present on activated T lymphocytes (4, 5). One possible explanation, therefore, is that these joint ADRs could be of inflammatory origin. Another possibility is some sort of direct mediation through neurotransmission, since 5-HT_2A receptors seem to be present on sympathetic ganglia innervating synovium of the joints (22). Among the 3 studied 5-HT_2A–blocking antidepressants, mianserin had the highest percentage of joint ADRs. There might be a biologic reason for that because mianserin not only blocks the 5-HT_2A receptor, but also has been reported to down-regulate the HTR2A gene expression on a transcriptional level (23). Although further studies are needed, the result from this study might support an idea that not only constitutional factors, but also acquired factors that give lower levels of 5-HT_2A receptors, are associated with joint disorders.

In conclusion, based on this retrospective epidemiologic study, we found a signal for an association between the use of the 5-HT_2A–blocking atypical antidepressants and joint-related ADRs.

AUTHOR CONTRIBUTIONS

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Kling had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Kling, Danell-Boman, Dahlqvist.

Acquisition of data. Kling, Danell-Boman.

Analysis and interpretation of data. Kling, Stenlund, Dahlqvist.

Acknowledgements

We thank Anders Viklund, MScPharm, Uppsala Monitoring Centre, WHO Collaborating Centre for International Drug Monitoring, for providing us with some of the information from the WHO database.