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Major depressive disorder; MDD

Disease ID:583
Name:Major depressive disorder; MDD
Associated with:4 targets
1 immuno-relevant ligand
Database Links
Disease Ontology: DOID:1470
OMIM: 608516

Targets

5-HT2A receptor
5-HT3B
Role:  5-HT3B has been associated with major female depression in genetic analyses.
Comments:  This polymorphism occurs at a significantly reduced frequency in female patients suffering from major depression and also patients with bipolar disorder, consistent with a protective influence of the variant allele.
References:  9
Mutations:  5-HT3B is associated with 1 mutation. Click here for details
KCa2.3
Drugs:  Apamin has positive effects in a mouse model of depression.
Side effects:  High doses of apamin induce seizures and lead to Purkinje cell degeneration in the cerebellum.
Therapeutic use:  KCa2.3 blockers have been proposed for the treatment of depression.
References:  1,3,5
Kir4.1
Role:  K+ buffering. There is a putative link between Kir4.1 and depression
Drugs:  Tricyclic anti-depressants.
Side effects:  Seizure.
References:  8

Ligands

Key to terms and symbols Click ligand name to view ligand summary Click column headers to sort
Ligand References Clinical and Disease comments
sirukumab
Immuno Disease Comments: Phase 2 clinical candidate for MDD (see NCT02473289).
Clinical Use: Phase 3 clinical trials assessing sirukumab for RA have been completed or are still ongoing (Oct 2017). Click here to link to ClinicalTrials.gov's listing of Phase 3 sirukumab trials. Other trials are collecting data in additional inflammatory conditions including lupus nephritis [7], cutaneous lupus erythematosus, systemic lupus erythematosus and giant cell arteritis.
Research is beginning to indicate that the disease pathophysiology of depression may have an immune component [2,4,6], and reviewed in [10]. In particular, IL-6 has been identified as a susceptibility gene for major depressive disorder (MDD), with the promoter polymorphism rs1800797 showing a marginally significant correlation with cortical IL-6 expression [11]. This and other work (including [6]) has led to clinical trial of sirukumab as an adjunct to conventional antidepressant therapy in patients with MDD (see Phase 3 trial NCT02473289). | View clinical data

References

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1. Blank T, Nijholt I, Kye MJ, Spiess J. (2004) Small conductance Ca2+-activated K+ channels as targets of CNS drug development. Curr Drug Targets CNS Neurol Disord, 3 (3): 161-7. [PMID:15180477]

2. Du Preez A, Leveson J, Zunszain PA, Pariante CM. (2016) Inflammatory insults and mental health consequences: does timing matter when it comes to depression?. Psychol Med, 46 (10): 2041-57. [PMID:27181594]

3. Galeotti N, Ghelardini C, Caldari B, Bartolini A. (1999) Effect of potassium channel modulators in mouse forced swimming test. Br. J. Pharmacol., 126 (7): 1653-9. [PMID:10323599]

4. Hepgul N, Cattaneo A, Agarwal K, Baraldi S, Borsini A, Bufalino C, Forton DM, Mondelli V, Nikkheslat N, Lopizzo N et al.. (2016) Transcriptomics in Interferon-α-Treated Patients Identifies Inflammation-, Neuroplasticity- and Oxidative Stress-Related Signatures as Predictors and Correlates of Depression. Neuropsychopharmacology, 41 (10): 2502-11. [PMID:27067128]

5. Lam J, Coleman N, Garing AL, Wulff H. (2013) The therapeutic potential of small-conductance KCa2 channels in neurodegenerative and psychiatric diseases. Expert Opin. Ther. Targets, 17 (10): 1203-20. [PMID:23883298]

6. Money KM, Olah Z, Korade Z, Garbett KA, Shelton RC, Mirnics K. (2016) An altered peripheral IL6 response in major depressive disorder. Neurobiol. Dis., 89: 46-54. [PMID:26804030]

7. Rovin BH, van Vollenhoven RF, Aranow C, Wagner C, Gordon R, Zhuang Y, Belkowski S, Hsu B. (2016) A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Treatment With Sirukumab (CNTO 136) in Patients With Active Lupus Nephritis. Arthritis Rheumatol, 68 (9): 2174-83. [PMID:27110697]

8. Su S, Ohno Y, Lossin C, Hibino H, Inanobe A, Kurachi Y. (2007) Inhibition of astroglial inwardly rectifying Kir4.1 channels by a tricyclic antidepressant, nortriptyline. J. Pharmacol. Exp. Ther., 320 (2): 573-80. [PMID:17071817]

9. Yamada K, Hattori E, Iwayama Y, Ohnishi T, Ohba H, Toyota T, Takao H, Minabe Y, Nakatani N, Higuchi T et al.. (2006) Distinguishable haplotype blocks in the HTR3A and HTR3B region in the Japanese reveal evidence of association of HTR3B with female major depression. Biol. Psychiatry, 60 (2): 192-201. [PMID:16487942]

10. Young JJ, Bruno D, Pomara N. (2014) A review of the relationship between proinflammatory cytokines and major depressive disorder. J Affect Disord, 169: 15-20. [PMID:25128861]

11. Zhang C, Wu Z, Zhao G, Wang F, Fang Y. (2016) Identification of IL6 as a susceptibility gene for major depressive disorder. Sci Rep, 6: 31264. [PMID:27502736]