title: Purinergic system dysfunction in mood disorders: a key target for developing improved therapeutics.
abstract: Uric acid and purines (such as adenosine) regulate mood, sleep, activity, appetite, cognition, memory, convulsive threshold, social interaction, drive, and impulsivity. A link between purinergic dysfunction and mood disorders was first proposed a century ago. Interestingly, a recent nationwide population-based study showed elevated risk of gout in subjects with bipolar disorder (BD), and a recent meta-analysis and systematic review of placebo-controlled trials of adjuvant purinergic modulators confirmed their benefits in bipolar mania. Uric acid may modulate energy and activity levels, with higher levels associated with higher energy and BD spectrum. Several recent genetic studies suggest that the purinergic system - particularly the modulation of P1 and P2 receptor subtypes - plays a role in mood disorders, lending credence to this model. Nucleotide concentrations can be measured using brain spectroscopy, and ligands for in vivo positron emission tomography (PET) imaging of adenosine (P1) receptors have been developed, thus allowing potential target engagement studies. This review discusses the key role of the purinergic system in the pathophysiology of mood disorders. Focusing on this promising therapeutic target may lead to the development of therapies with antidepressant, mood stabilization, and cognitive effects.
authors.affiliation: Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, Division of Intramural Research Programs, National Institutes of Health, Bethesda, MD, USA. Electronic address: robinortiz.mail@gmail.com.
authors.forename: Robin
authors.initials: R
authors.lastname: Ortiz
authors.affiliation: Departament of Biochemistry, University of Sao Paulo, Sao Paulo, Brazil. Electronic address: henning@iq.usp.br.
authors.forename: Henning
authors.initials: H
authors.lastname: Ulrich
authors.affiliation: Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, Division of Intramural Research Programs, National Institutes of Health, Bethesda, MD, USA. Electronic address: zaratec@mail.nih.gov.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Zarate
authors.affiliation: Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, Division of Intramural Research Programs, National Institutes of Health, Bethesda, MD, USA; Laboratory of Neuroscience, LIM27, University of Sao Paulo, Sao Paulo, Brazil. Electronic address: machadovieirar@mail.nih.gov.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Machado-Vieira
mesh_terms: D000241:Adenosine / Q000502:physiology; D000255:Adenosine Triphosphate / Q000502:physiology; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D006151:Guanosine / Q000502:physiology; D006801:Humans; D008959:Models, Neurological; D058990:Molecular Targeted Therapy; D019964:Mood Disorders / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D059906:Neuroimaging; D011619:Psychotropic Drugs / Q000494:pharmacology / Q000627:therapeutic use; D011983:Receptors, Purinergic / Q000235:genetics / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D011619:Psychotropic Drugs; D011983:Receptors, Purinergic; D006151:Guanosine; D000255:Adenosine Triphosphate; D000241:Adenosine
keywords: Bipolar disorder; Depression; Mania; Purines; Treatment; Uric acid