The investigators seek clinically actionable understanding of the mechanisms that underlie depression in the context of immune mediated inflammatory diseases (IMIDs), delivered by a focused immune intervention study examining brain circuitry using state of the art imaging in the context of exquisitely specific therapeutic immune interception in human immune disease. Glutamate concentration in the NAcc will be positively correlated with the magnitude of the inflammatory response and will be attenuated by IL-17A inhibition. Ultimately, this will be associated with an improvement in depressive symptoms. The strength of coupling between early and late systems will be attenuated in the context of IL-17A-driven inflammation and will be correlated with less frequent switching behaviour following negative outcomes and ultimately depressive symptoms. This coupling will be re-established following IL-17 antagonism. Patients whose depressive symptoms benefit most from IL-17A antagonism will exhibit greatest resting-state and task-specific functional connectivity between Th-NAcc.
Approximately 30-40% of patients with immune-mediated inflammatory diseases (IMIDs), such as psoriatic disease, experience depression. These symptoms negatively affect clinical outcomes, quality of life and treatment adherence. There is accumulating evidence that peripheral inflammation may contribute to the origins of depression. In particular, a) stimulation of active phase inflammation results in remitting-relapsing depressive symptoms b) abnormal neural connectivity linked to this depression is correlated with peripheral inflammation and c) biologic therapies targeting specific peripheral inflammation components (cytokines) improve depressive symptoms. In this proposal, psoriatic disease (PsD), encompassing both psoriasis and PsA, will be our IMID exemplar. In this condition, the IL-23/IL-17 cytokine axis is central to pathogenesis, as proven by successful application of inhibitors to this pathway. Moreover, this axis has also recently been implicated in the neurobiology of depression in both preclinical and clinical studies. The investigators aim to uncover the mechanisms that underlie depression in the context of IMIDs, delivered by a focused immune intervention study examining brain circuitry using state of the art imaging in the context of exquisitely specific therapeutic immune interception in human immune disease. The rationale for this study is to use this specific therapeutic immune intervention to leverage mechanistic understanding of brain changes that drive depressive symptoms. Prior animal studies have clearly demonstrated the deleterious effects of proinflammatory cytokines on neural functioning. The investigators will integrate current therapy with innovative neuroimaging technologies to obtain data for the first time in humans that have hitherto only been possible in animal studies. The intervention tools proposed herein (secukinumab, bimekizumab or Ixekizumab) are IL-17 inhibitors licensed for treatment of active PsO and PsA. Secukinumab, bimekizumab and Ixekizumab are widely used in clinical practice globally and across the UK as a first/second-line biologic disease modifying antirheumatic drug (DMARD), in line with national/international NICE (TA350, TA445, TA723, TA916, TA442, TA537) treatment recommendations. Secukinumab is given by self-administered subcutaneous injection weekly for the first five weeks of treatment and thereafter by monthly maintenance injections. Bimekizumab is given by self-administered subcutaneous injection 4 weekly, Ixekizumab is given by self -administered subcutaneous injection either 2 or 4 weekly. Typically, depressive symptoms are attenuated within weeks of therapeutic initiation. Prior study data indicate a beneficial effect of IL17 antagonism on depressive symptoms, but the mechanism of action has not yet been explored.
Study Type
OBSERVATIONAL
Enrollment
50
Initial dosing of Secukinimab at week 0, 1, 2, 3, 4 and maintenance doses will be determined by the standard care team. This will be 150mg or 300mg. This will be administered by the study team once confirmed and randomisation has occurred for secukinimab/ placebo allocation.
Initial dosing of bimkizumab at week 0 \& 4 and maintenance doses will be determined by the standard care team. This will be 160mg or 320mg. This will be administered by the study team once confirmed and randomisation has occurred for bimekizumab/ placebo allocation.
Initial dosing of Ixekizumab at week 0 \& 4 or week 0, 2 \& 4, maintenance doses will be determined by the standard care team. The initial dose will be 160mgs then 80mg dose will either be given 2 or 4 weekly. This will be administered by the study team once confirmed and randomisation has occurred for Ixekizumab/ placebo allocation.
Sodium chloride 0.9% for injection will be used as a placebo. A 1ml volume will be drawn up into a suitable sized syringe and labelled in accordance with standard practice at site. The dose will be administered as a subcutaneous injection in line with the Secukinumab/ Bimekizumab/ Ixekizumab dosing regimen. No dose adjustments are permitted.
Queen Elizabeth University Hospital
Glasgow, Scotland, United Kingdom
RECRUITINGChanges in glutamate concentration in the NAcc as measured by 7T MRS.
Changes in glutamate concentration in the NAcc as measured by 7T MRS, from Week 0 to Week 6 (before and after IL17 antagonism).
Time frame: Week 0 to Week 6
Differences in the EEG amplitude during positive and negative response outcomes.
Changes in the EEG amplitude between the thalamic and NAcc learning systems before and after IL-17 antagonism.
Time frame: Week 0 to Week 6
Correlating fMRI signals with differences in EEG amplitude.
fMRI signals that correlate with the changing EEG amplitude, before and after IL17 antagonism.
Time frame: Week 0 to Week 6
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