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.