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.
Highlights
Side 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
The thickness of the edges represents the cosine correlation coefficient as determined by formula 1, which represents the degree of side effect similarity between drugs. a Different type of antidepressants formed different clusters according to their side effect profiles
The similarities between these 217 drugs are depicted as a network shown in Fig. 1, in which each node represents a drug and edges between the nodes represent pair-wise side effect similarities, with the thickness of the edge corresponding to the degree of similarities
Summary
The adverse effects of drugs, contain important clinical phenotypic information that may be useful in predicting novel or unknown targets of a drug. 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. It may be possible to exploit similarities in clinical readouts to better understand the antidepressant effects of immune-related drugs. Multiple studies have shown that some MDD patients have elevated serum levels of pro-inflammatory biomarkers, such as Interleukin 1 (IL-1), Interleukin 6 (IL-6), Tumor Necrosis Factor alpha (TNF-α), and C-reactive Protein (CRP) compared to healthy controls [4,5,6]. MDD patients resistant to treatment with selective serotonin re-uptake inhibitors (SSRI) were shown to have higher IL-6 and TNF-α levels than healthy controls and euthymic patients who were formerly SSRI-resistant [8]
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