Side effect profile similarities shared between antidepressants and immune-modulators reveal potential novel targets for treating major depressive disorders

Abstract

BackgroundSide effects, or the adverse effects of drugs, contain important clinical phenotypic information that may be useful in predicting novel or unknown targets of a drug. It has been suggested that drugs with similar side-effect profiles may share common targets. The diagnostic class, Major Depressive Disorder, is increasingly viewed as being comprised of multiple depression subtypes with different biological root causes. One ‘type’ of depression generating substantial interest today focuses on patients with high levels of inflammatory burden, indicated by elevated levels of C-reactive proteins (CRP) and pro-inflammatory cytokines such as interleukin 6 (IL-6). It has been suggested that drugs targeting the immune system may have beneficial effect on this subtype of depressed patients, and several studies are underway to test this hypothesis directly. However, patients have been treated with both anti-inflammatory and antidepressant compounds for decades. It may be possible to exploit similarities in clinical readouts to better understand the antidepressant effects of immune-related drugs.MethodsHere we explore the space of approved drugs by comparing the drug side effect profiles of known antidepressants and drugs targeting the immune system, and further examine the findings by comparing the human cell line expression profiles induced by them with those induced by antidepressants.ResultsWe found 7 immune-modulators and 14 anti-inflammatory drugs sharing significant side effect profile similarities with antidepressants. Five of the 7 immune modulators share most similar side effect profiles with antidepressants that modulate dopamine release and/or uptake. In addition, the immunosuppressant rapamycin and the glucocorticoid alclometasone induces transcriptional changes similar to multiple antidepressants.ConclusionsThese findings suggest that some antidepressants and some immune-related drugs may affect common molecular pathways. Our findings support the idea that certain medications aimed at the immune system may be helpful in relieving depressive symptoms, and suggest that it may be of value to test immune-modulators for antidepressant-like activity in future proof-of-concept studies.

Comparative Efficacy and Acceptability of Anti-inflammatory Agents on Major Depressive Disorder: A Network Meta-Analysis

“…Glucocorticoid receptor may be a therapeutic target for MDD patients because it is involved in both immune regulation and depression. Corticosteroids possibly restore the negative feedback loop on the hypothalamic–pituitary–adrenal axis to exhibit their antidepressive effects ( Sun et al, 2016 ). In a previous trial, the response rate of dexamethasone group could achieve 37%, while that of placebo group was only 6% ( Arana et al, 1995 ).…”

Immune targets for therapeutic development in depression: towards precision medicine

“…A noteworthy study in this regard profiled drugs for their similarity across 4,201 side effects, and found that cytokine inhibitors were closest in the high-dimensional side effect space to drugs with a dopaminergic effect, but were distant from other antidepressants 148 . This finding suggests that dopaminergic compounds that influence reward-guided behaviours may be more effective in patients with an inflammatory component to their depression.…”

Diagnostic Issues in Early-Onset Obsessive-Compulsive Disorder and their Treatment Implications

“…One study analyzing drug-similarity based on side effect profiles indicates indeed that some antidepressants and some immune-related drugs may affect common molecular pathways, such as cytokines levels and glucocorticoid signaling [85].…”