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Genome-wide association study in HK highlights value of drug repositioning in treatment of psychiatric disorders

Dr. Joseph Delano Fule Robles
04 Sep 2017

A recent genome-wide association study (GWAS) performed by investigators from the Chinese University of Hong Kong (CUHK) has found potential new indications for existing drugs for the treatment of various psychiatric disorders.

In this study, expression profiles of 1,309 drugs from the Connectivity Map database were compared with GWAS summary statistics corresponding to seven psychiatric disorders, including schizophrenia, major depressive disorder, bipolar disorder, Alzheimer’s disease, anxiety disorders, autistic spectrum disorders and attention deficit hyperactivity disorder, in 10 brain regions. [Nat Neurosci 2017, doi: 10.1038/nn.4618]

“Drug discovery in the field [of psychiatry] has largely been stagnant in the past two decades. By employing computational drug repositioning, we hope to provide more choices of medications for the treatment of psychiatric disorders and diseases with few known treatment options,” said investigator Professor Hon-Cheong So of the School of Biomedical Sciences, CUHK.

Bumetanide, a sodium-potassium-chloride cotransporter-1 inhibitor ordinarily indicated for heart failure, is recently shown in a randomized control trial to improve positive symptoms of schizophrenia (ie, hallucinations). In the current study, bumetanide showed a significant repositioning hit for schizophrenia (p=8.57 x 10−4). [Schizophr Res 2017:184;145-146]

A few NSAIDs, notably aspirin (p=2 x 10−3), the cyclooxygenase-2 inhibitor SC-58125 (p=1.12 x 10−3), the cardiovascular drug simvastatin (p=5.59 x 10−3) and the antidiabetic drug metformin (p=3.9x 10−3) also showed possible clinical use in bipolar disorder.

“The findings support the neuroinflammatory hypothesis of bipolar disorders… Some studies also revealed a higher risk for cardiovascular disease amongst patients with bipolar disorder and a probable shared pathophysiology between the two disease entities,” the authors explained. [Psychiatry Investig 2016:13;18-33; Lancet Psychiatry 2015:2;452-464]

Repositioning hits for major depressive disorders with diverse mechanisms include the phosphodiesterase inhibitor papaverine (p=2.93 × 10−4), the muscarinic antagonist scopolamine (p=4.44 × 10−3), and the cortisol-lowering agent ketoconazole (p=2.75 × 10−3).

For anxiety disorders, the loop diuretic bumetanide and the antiparasitic agent ivermectin also showed significant repositioning hits.

In Alzheimer’s disease where intensive research is currently ongoing, the vasodilatory agent naftidrofuryl, the alkaloid vinpocetine, and the NSAIDs meclofenamic acid, ketorolac, celecoxib, naproxen and acemetacin ranked among the top 15 in repositioning hits.

Significant hits were also shown with the anticonvulsant carbamazepine, where preliminary evidence has shown its effect for the treatment of attention deficit hyperactivity disorder, and with the antiviral medication ribavirin, for management of autism spectrum disorders.

“To our knowledge, this is the first systematic analysis of drug repositioning covering major psychiatric disorders… Our repositioning framework is ‘hypothesis-free’, immune to confounding by medication effects, intuitive and computationally simple to implement,” the authors commented.

“It can also be applied to any chemicals as long as the expression profile is available, such as traditional Chinese medicine or drugs shelved after unsuccessful trials,” they added.

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