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

Show »

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, Detera-Wadleigh SD, Yoshikawa T. (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]