Serum methylarginines and incident depression in a cohort of older adults.
BACKGROUND
Methylarginines are endogenous nitric oxide synthase inhibitors that have been implicated in depression. This study measured serum concentrations of l-arginine, asymmetric (ADMA) and symmetric (SDMA) dimethylarginine in a representative sample of older community-dwelling adults and determined their association with incident depression over 6-years of follow-up.


METHODS
Data on clinical, lifestyle, and demographic characteristics, methylated arginines, and l-arginine (measured using LC-MS/MS) were collected from a population-based sample of older Australian adults (Median age=64 years; IQR=60-70) from the Hunter Community Study. Clinical depression was defined as a Centre for Epidemiological Studies Depression Scale (CES-D) score ≥16 or use of antidepressant medications.


RESULTS
In adjusted analyses ADMA (Q3), SDMA (Q2), l-arginine (Q2), gender, and asthma remained statistically significant predictors of incident depression at follow-up. Quartile 3 of ADMA concentration was associated with 3.5 times the odds of developing depression compared with Q1 (OR=3.54; 95% CI: 1.25-9.99).


CONCLUSIONS
Limitations of our study include the use of a subjective self-reported questionnaire tool using a dichotomous cut-off, together with use of antidepressant medications, as proxies for clinical depression. Moreover, similarly to most population studies on methylated arginines, the measurement of ADMA and SDMA from blood does not necessarily reflect intracellular concentrations of these compounds. Finally, there were no measures of nitric oxide metabolites to determine if these levels were altered in the presence of elevated methylarginines and depression.


CONCLUSIONS
After adjusting for clinical, demographic, biochemical, and pharmacological confounders, higher serum ADMA was independently associated with incident depression at 6-years follow-up.
Centre for Clinical Epidemiology & Biostatistics, Hunter Medical Research Institute, School of Medicine & Public Health, University of Newcastle, Callaghan, Newcastle, New South Wales 2308, Australia. Electronic address: mark.mcevoy@newcastle.edu.au.
Mark A
MA
McEvoy
Centre for Translational Neuroscience and Mental Health, University of Newcastle, Callaghan, Newcastle, New South Wales 2308, Australia. Electronic address: peter.schofield@hnehealth.nsw.gov.au.
Peter
P
Schofield
Environmental Health Branch, New South Wales Department of Health, 73 Miller Street, North Sydney, New South Wales 2060, Australia. Electronic address: WSMIT@doh.health.nsw.gov.au.
Wayne
W
Smith
Science of Mental Health & Adversity unit, School of Medicine, University of Western Sydney, Parramatta, New South Wales, Australia. Electronic address: K.Agho@uws.edu.au.
Kingsley
K
Agho
Department of Clinical Pharmacology, Flinders Medical Centre and Flinders University, Flinders Drive, Bedford Park, South Australia 5042, Australia. Electronic address: a.a.mangoni@abdn.ac.uk.
Arduino A
AA
Mangoni
Division of Applied Medicine, Section of Translational Medical Sciences, School of Medicine and Dentistry, University of Aberdeen, Polwarth Building, Foresterhill, Aberdeen AB25 2ZD, United Kingdom; Department of Medicine for the Elderly, Woodend Hospital, NHS Grampian, Aberdeen AB15 6XS, United Kingdom. Electronic address: roy.soiza@nhs.net.
Roy L
RL
Soiza
Centre for Clinical Epidemiology & Biostatistics, Hunter Medical Research Institute, School of Medicine & Public Health, University of Newcastle, Callaghan, Newcastle, New South Wales 2308, Australia. Electronic address: Roseanne.peel@newcastle.edu.au.
Roseanne
R
Peel
Centre for Clinical Epidemiology & Biostatistics, Hunter Medical Research Institute, School of Medicine & Public Health, University of Newcastle, Callaghan, Newcastle, New South Wales 2308, Australia. Electronic address: Stephen.hancock@newcastle.edu.au.
Stephen
S
Hancock
Centre for Translational Neuroscience and Mental Health, University of Newcastle, Callaghan, Newcastle, New South Wales 2308, Australia. Electronic address: Brian.Kelly@newcastle.edu.au.
Brian
B
Kelly
Centre for Translational Neuroscience and Mental Health, University of Newcastle, Callaghan, Newcastle, New South Wales 2308, Australia; Hunter Institute of Mental Health, Newcastle, New South Wales, Australia. Electronic address: Kerry.Inder@newcastle.edu.au.
Kerry
K
Inder
Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43/b, Sassari 07100, Italy. Electronic address: carru@uniss.it.
Ciriaco
C
Carru
Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43/b, Sassari 07100, Italy. Electronic address: angelozinellu@gmail.com.
Angelo
A
Zinellu
Centre for Clinical Epidemiology & Biostatistics, Hunter Medical Research Institute, School of Medicine & Public Health, University of Newcastle, Callaghan, Newcastle, New South Wales 2308, Australia; Department of General Medicine, John Hunter Hospital, Newcastle, New South Wales, Australia. Electronic address: john.attia@newcastle.edu.au.
John
J
Attia
D000368:Aged; D000369:Aged, 80 and over; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood*; D003863:Depression / Q000097:blood / Q000453:epidemiology*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009517:New South Wales / Q000453:epidemiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors
C024917:symmetric dimethylarginine; C018524:N,N-dimethylarginine; D001120:Arginine; D019001:Nitric Oxide Synthase
Cohort study; Depression; Methylarginines