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Depression in those who are ill is 5–10 times more common than in the general population. Increasing evidence implicates bidirectional biological mechanisms linking mood disorders and medical conditions.1 Depressive symptoms are significantly more common in rheumatoid arthritis (RA) than in the general population. Conservative estimates suggest major depressive disorder in between 13% and 17% of patients with RA. However, prevalence exceeding 40% has been reported in a recent study, with up to 11% of patients experiencing suicidal ideation.1 Major depressive disorder is an independent risk factor for both work disability and mortality in patients with RA.2
Cytokine dysregulation is central to the pathogenesis of RA with functional implications for breach of tolerance and autoimmunity, subsequent inflammation and articular dysfunction.3 Tumour necrosis factor (TNF), in particular, appears to be of pivotal importance in pathogenesis, based on plausible bioactivities and successful clinical targeting. Cytokines can directly modulate monoaminergic neurotransmitter systems.4 The density and activity of the serotonin transporter (SERT), a key target of conventional antidepressant treatment, are increased by proinflammatory cytokines, leading to an increase in 5HT uptake from the synapse, thereby decreasing 5HT transmission.5 6
We used single photon emission CT (SPECT) to test the hypothesis that TNF blockade is associated with altered SERT activity in the brain in patients with RA.
Six patients with seropositive RA (meeting American College of Rheumatology diagnostic criteria) were recruited from the Centre for Rheumatic Diseases in Glasgow Royal Infirmary. After tuberculosis screening patients received adalimumab 40 mg by subcutaneous injection every other week. Patients were assessed using the Hamilton Rating Scale for Depression, the Social Functioning 36-item scale (SF36) and the Hospital Anxiety and Depression Scale. RA activity was measured using the composite 28-joint count Disease Activity Score (DAS28) (table 1).
SPECT with the radioligand [123I]β-carbomethoxy-3-β-(4- iodophenyl)tropane allows in vivo measurement of SERT density within the midbrain structures and was performed up to 14 days before the start of adalimumab treatment and repeated within 4 days of the last treatment. A well-validated region of interest analysis method7 was used and changes in the SERT density were tested using a Wilcoxon matched pairs, signed rank test using Minitab version 15.
Adalimumab induced an overall improvement in measures of physical and mental functioning as measured by SF36. Improvements in DAS28 were seen in all recipients. There was a significant decrease in the SERT density (figure 1; p=0.03), with five of the patients exhibiting a decrease of around 20%.
These data suggest that one consequence of TNF blockade in patients with RA is modulation of SERT expression. Our analysis provides some of the first in vivo evidence in humans of functional effects on the brain following blockade of a single cytokine, thereby strongly suggesting a direct link between cytokine-mediated events and brain function.
Whether this is a disease-specific finding or one that relates to cytokine action in general can only be answered by studying another group of patients for whom TNF blockade is indicated– for example, those with psoriatic arthritis. Similarly, whether disease-modifying antirheumatic drug treatment other than TNFα blockade would produce similar effects, requires a longer study. These pilot results do, however, fit with the extant literature.8
If these findings relating to the SERT can be corroborated in a larger cohort this would provide invaluable insight into the biological link between clinical depression and inflammatory processes and would inform more holistic therapeutic strategies, dealing with both the inflammatory and affective components of RA. It might also lead to the closer investigation of anti-inflammatory agents as treatments for clinical depression in patients with, and without, major inflammatory symptoms.
We thank the Chief Scientist Office of the Scottish Government and the Mortimer & Theresa Sackler Foundation for funding and to the patients who gave of their time and energy during their treatment for rheumatoid arthritis.
Competing interests None.
Patient consent Obtained.
Ethics approval This study was conducted with the approval of the local NHS ethics committee.
Provenance and peer review Not commissioned; externally peer reviewed.