The total numbers of subjects with high anxiety (HADS-A ≥ 8) or depression (HADS-D ≥ 8) levels were 929 (15.7%) and 550 (9.3%), respectively. 1979;5(2):157-169. Objective: We examined the cross-sectional association between plasma choline concentrations and scores of anxiety and depression symptoms in a general population sample. Works cited [1] Fioravanti M, Buckley AE. Stoll AL, Sachs GS, Cohen BM, Lafer B, Christensen JD, Renshaw PF. > Sources : 1. Current smoking was more common among the middle-aged (29.5%) than among the older (12.2%) subjects, with only minor sex differences. Keywords: Citicoline, CDP-Choline, nootropics, depression. By Hara Estroff Marano published January 3, 2017 - … This can happen at normal doses. It's strange, cdp choline is known to raise dopamime receptors number and it's a quite good antidepressant. Univariate associations of anxiety and depression with sex, age group, time since last meal, educational level, smoking habit, and plasma choline concentration: the Hordaland Health Study (n = 5918). Probable Nootropicinduced Psychiatric Adverse Effects: A Series of Four Cases. 2006;1(3):247-251. In animal models (rats), dorsal hippocampal cholinergic transmission mediates an anxiolytic effect (23). There was a negative association between choline concentrations and anxiety symptoms (P < 0.001) but not depression symptoms (P = 0.622). Adjusted for sex, age group (46–49 and 70–74 y), and time since last meal. Today, I am using Phenylpiracetam to soak up the CDP Choline, and it's already helping me to normalize. Hence, selection bias cannot be ruled out. Generalized additive logistic regression was used to provide a graphic representation of the dose-response relation between choline and high anxiety and depression levels. An updated literature review, Determination of choline, betaine, and dimethylglycine in plasma by a high-throughput method based on normal-phase chromatography-tandem mass spectrometry, Divergent associations of plasma choline and betaine with components of metabolic syndrome in middle age and elderly men and women, Choline transporters, cholinergic transmission and cognition, The association between depression, anxiety, and cognitive function in the elderly general population—the Hordaland Health Study, The role of the dorsal hippocampal serotonergic and cholinergic systems in the modulation of anxiety, Effect of nicotine and nicotinic receptors on anxiety and depression, Neurotransmitters and CNS disease: depression, Folate, vitamin B12, homocysteine, and the MTHFR 677C->T polymorphism in anxiety and depression: the Hordaland Homocysteine Study, Ultra-processed food consumption is associated with increased risk of all-cause and cardiovascular mortality in the Moli-sani Study, Dietary cholesterol and egg intake in relation to incident cardiovascular disease and all-cause and cause-specific mortality in postmenopausal women, The effect of bovine colostrum/egg supplementation compared with corn/soy flour in young Malawian children: a randomized, controlled clinical trial, Associations of prenatal methylmercury exposure and maternal polyunsaturated fatty acid status with neurodevelopmental outcomes at 7 years of age: results from the Seychelles Child Development Study Nutrition Cohort 2, A prospective study of waist circumference trajectories and incident cardiovascular disease in China: the Kailuan Cohort Study, About The American Journal of Clinical Nutrition, http://www.acnp.org/g4/GN401000095/CH.html, Nutritional epidemiology and public health, Receive exclusive offers and updates from Oxford Academic, Effect of fish-oil supplementation on mental well-being in older subjects: a randomized, double-blind, placebo-controlled trial. Renshaw PF, Lafer B, Babb SM, et al. The study population included 5918 subjects with valid data on anxiety and depression symptoms, plasma choline, educational level, and smoking habits. Adjusted for sex, age group (46–49 and 70–74 y), time since last meal, educational level, and smoking habit. The precision of the OR estimates was expressed with 95% CIs. SH Zeisel et KA da Costa, Choline: An Essential Nutrient for Public Health, Nutr Rev., Novembre 2009;67(11): 615–623. In addition, citicoline elevates the levels of a few hormones that can be effective for attention deficit disorder (ADD) and depression. EDTA plasma was stored at −80°C. However, in a substudy of the oldest age group (n = 1930) in whom cognitive function was assessed, we found no association between cognitive function and anxiety symptoms (22). Further adjustment for smoking and educational level somewhat weakened the association (β = −0.027, P = 0.045). Nanostructured Diamond for Biomedical Applications. Biringer E, Mykletun A, Dahl AA, et al. I take a fasoracetam/phenylpiracetam stack when I have to focus on heavy tasks as a designer. Despite the presence of a pathway for endogenous synthesis of choline, a choline-deficient diet impairs growth, memory, and hepatic, renal, and pancreatic functions in mammals (2). In the world of biochemistry, it is known as cytidine 5’-diphosphocholine, and this molecule is an intermediate. However, we found no associations between components of one-carbon metabolism and anxiety symptoms in a previous study of the same population (26). spectroscopy. Stress, an anxiety component, induces an increase in adrenal catecholamines, which increases the demand for methylation reactions required in norepinephrine and adrenaline synthesis (25). Artery. La prise de choline est déconseillée chez les personnes atteintes de dépression ou de maladie de Parkinson, pour éviter une possible aggravation des symptômes. United States, © 2020 International Journal of Environmental Science & Technology (IJEST.org). NMR Biomed. In summary, results from this large population-based study suggest a role of choline in anxiety disorders. Choline plays an important role in the central nervous system, both for the synthesis of membrane phosphatidylcholine and for acetylcholine (3). On the basis of animal studies and drug effects, Janowsky et al (6) postulated that there is relative or actual cholinergic hyperactivity in depression and the opposite in mania. Picciotto MR, Brunzell DH, Caldarone BJ. Citicoline (Cognizin) in the treatment of cognitive impairment. Test for trends in proportions (chi-square test). HADS-A contains items mainly related to restlessness and worry and one item that reflects panic attacks. CDP-Choline, Cognizin, and Other Names for Citicoline. The withdrawal is a sign your dopamine stores are depeleted, so they are running on fumes without the amphetamine. Among subject with the shortest time (<2 h) since the last meal, mean plasma choline was highest (10.15 μmol/L) and gradually decreased in the next groups (2–3 h 59 min: 9.85 mol/L; 4–5 h 59 min: 9.42 μmol/L) to the lowest concentration (9.20 μmol/L) in subjects with the longest time (≥6 h) since the last meal. 2008;21(10):1066-1075. Quintile 1: 4.09–7.96 μmol/L; quintile 2: 7.97–9.08 μmol/L; quintile 3: 9.09–10.10 μmol/L: quintile 4: 10.11–11.58 μmol/L; quintile 5: 11.60–24.70 μmol/L. Associations between plasma choline concentrations and anxiety and depression symptoms by logistic regression analyses: the Hordaland Health Study (n = 5918). Choline is an essential nutrient found in animal products such as liver, egg, and meat, but also in some vegetable products, including wheat germ and soy beans (1). The trend tests for these models were significant (P = 0.004 and P = 0.007 for models 1 and 2, respectively). Number of cases with high anxiety or depression levels. The effect measure β is the standardized regression coefficient of choline concentration predicting either HADS-A or HADS-D scores. Specifically, many people have become concerned that citicoline may cause lethargy, loss of motivation, and depression. The Research. [2] Fioravanti M, Buckley AE. HADS-D focuses mainly on the reduced pleasure response aspect (anhedonia) of depression but also on psychomotor retardation and impaired mood. In the logistic regression models predicting high depression levels, no significant associations were found for either separate choline quintiles or trend through the choline quintiles. Also, the trend test in the anxiety model was significant (P = 0.007). Tests were recorded after 28 days of supplementation. The journal is dedicated to research into environmental technology and the innovative use of biotechnology in the advancement of health. In an open-label clinical trial, patients (n = 13) with Alzheimer disease showed no significant change in the mean Geriatric Depression Scale score after treatment with tetrahydroaminoacridine (an acetylcholine-esterase inhibitor) and lecithin (phosphatidylcholine) for 10 wk (8). There is mounting evidence for choline's place in therapy for stroke, brain and spinal cord injury, cognitive deficits, and glaucoma; however, results in clinical trials have been inconsistent. In the brains of non-depressed mice—and people—an enzyme called acetyl- cholinesterase (AChE) is produced to lower acetylcholine levels. 2015;12(11-12):21-25. The present study has a cross-sectional design. The Hospital Anxiety and Depression Scale (HADS) (16) is a self-administered questionnaire consisting of 14 items, 7 for anxiety (HADS-A subscale) and 7 for depression (HADS-D subscale). For example, studies link dopamine dysregulation with a wide range of major depressive disorders. CDP-Choline appears to have dopaminergic activity as assessed by its efficacy in animal models of Parkinson's disease, which is likely related to the uridine component of CDP-choline, as the augmentation of potassium-evoked dopamine release seen with uridine is also seen with CDP-Choline (250mg/kg oral intake causing a 59% increase in dopamine release), with one study noting that CDP-Choline … [2] Fioravanti M, Buckley AE. There was no significant effect modification of age (P = 0.525) or of the methylenetetrahydrofolate reductase 677 C→T polymorphism (P = 0.944) on the association. Citicoline reduced depression in 60 methamphetamine (meth) addicts but didn’t impact drug use (2,000 mg/day for 3 … Los Angeles, A 2-sided P value <0.05 was chosen to indicate statistical significance. Citicoline enhances frontal lobe bioenergetics as measured by phosphorus magnetic resonance International Journal of Environmental Science & Technology, Author: Paul Tardner                       Date published: 25/08/2020, Originally published at: IJEST     Pull test PDF: View PDF. Clinical Overview Use. La choline est synthétisée ou encore extraite d’aliments qui en sont riches, tels que le foie, le jaune d’œuf, le soja ou le chou-fleur. Synthesis of biogenic amines may increase the demand for one-carbon units for methionine synthesis, derived from choline, as well as folate-dependent pathways. [3] Silveri MM, Dikan J, Ross AJ, et al. Adderall alternatives. Although the primary participation rate of the present study was relatively high (77%), the recruitment might have been affected by mental disorders themselves, because persons with high levels of anxiety and depression symptoms may have been less likely to participate. With CDP-choline vs choline, both are produced by the body; however, necessary levels are rarely sufficient for good brain health and supplements are necessary. Conclusion: In this large population–based study, choline concentrations were negatively associated with anxiety symptoms but not with depression symptoms. It greatly improves motivation and anxiety issues that I have. The total number of participants and cases is somewhat lower because of missing data. CDP Choline: Becoming Citicoline . This technique is based on the generalized additive model (19) and allowed adjustment for age, sex, time since last meal, smoking status, and educational level. Thus helping prevent brain fog and mental fatigue. Information on health behaviors, subjective health, current or former diseases, use of medications, and demographic, socioeconomic, and psychosocial variables was obtained with a self-administered questionnaire. Owing to the commonality of its use, people have become increasingly concerned about the safety of citicoline use, particularly when it is used on a daily basis for prolonged periods. From its name — acetyl choline — and as shown on the right of the same figure, choline is a part of the molecular structure of acetylcholine. 2006;1(3):247-251. The educational level was higher among the middle-aged subjects, and this difference was most pronounced among women. 3. Alpha-GPC (L-alpha-glycerylphosphorylcholine or choline alphoscerate) is a Origine, formes et dosage de la choline. Thus, it has been experimentally proven that CDP-choline increases noradrenaline and dopamine levels in the CNS. Meth and Cocaine Addiction. Publications Dosing. Citicoline (Cognizin) in the treatment of cognitive impairment. You may have seen citicoline in on and offline health food stores under names like CDP-choline, alpha GPC (A-GPC), choline, or even as some form of bitartrate, which is choline plus a salt. Supported by the Foundation to Promote Research into Functional Vitamin B-12 Deficiency. To evaluate the possible effect modification of age, sex, and methylenetetrahydrofolate reductase 677 C→T polymorphism, product terms were added separately to the models. In the equivalent fully adjusted linear regression model, a significant inverse association was found between choline quintiles and anxiety levels (standardized regression coefficient = −0.027, P = 0.045). Tamminga C, Smith RC, Chang S, Haraszti JS, Davis JM. Associations between plasma choline concentrations and anxiety and depression symptoms by linear regression: the Hordaland Health Study (n = 5918). IJEST is an independent academic journal, and one of the leading research organizations in its field. CDP Choline, also known as citicoline, is a health supplement ingredient which, when orally taken, breaks down into cytidine and choline. Plasma free choline, betaine, and dimethylglycine were measured by using a method based on normal-phase chromatography–tandem mass spectrometry (18). Keywords: Citicoline, CDP-Choline, nootropics, depression. Impaired cognitive function might cause problems with the management of daily life tasks, which in turn might increase the level of anxiety symptoms. The team showed that when depressed mice were given Prozac®, AChE levels were raised, and abnormally high levels of acetylcholine … Galeone F, Salvadorini F Guarguaglini M Saba P. Effect of intravenous injection of CDP-choline, S-adenosyl-methionine and citiolone in subjects with hyperlipemia. Despite the presence of a pathway for endogenous synthesis of choline, a choline-deficient diet impairs growth, memory, and hepatic, renal, and pancreatic functions in mammals (2). We studied free circulating choline, which is a precursor of brain acetylcholine. In the linear regression models predicting depression symptoms, no significant associations were found. This supplement is catered towards preventing or treating memory impairments associated with aging due to the fact that both of the molecules it confers are neuroprotective and potentially enhance learning. It is a building block of cell membranes and is instrumental in affecting the brain’s ability to produce acetylcholine, a neurotransmitter important for memory. Blandina P, Efoudebe M, Cenni G, Mannaioni P, Passani MB. None of the authors had any conflicts of interest. However, our results are preliminary, and prospective studies need to be conducted. Copyright © 2020 American Society for Nutrition. In a case report of 2 patients with tardive dyskinesia, large doses of choline induced depressive symptoms in both patients (7). Oxford University Press is a department of the University of Oxford. This is what I did last time I had too much CDP Choline in my system, and it worked great :) Caffeine and Amphetamine based stimulants didn't help, so I'm sure any racetam will help burn up the CDP Choline, and reverse the depression. Dose-response relations between plama choline and high levels of anxiety and depression symptoms from generalized additive regression analyses (19) adjusted for sex, age group, time since last meal, smoking habit, and educational level in the Hordaland Health Study (n = 5918). Innov Clin Neurosci. We investigated the association between plasma choline concentrations and anxiety and depression symptoms in a cohort of 5918 community-dwelling subjects and found that choline was inversely related to anxiety, but not to depression symptoms. And you may even ease the fatigue associated with clinical depression by using CDP-Choline. The proportion of participants with high levels of anxiety or depression symptoms according to sex, age group, time since last meal, educational level, smoking habit, and choline quintiles is shown in Table 1. The subjects underwent a brief physical examination (height, weight, and blood pressure). It is highly bioavailable in oral doses, such that it is as available to the body for use as when it is introduced intravenously. Know Amazing Health Benefits of CDP Choline Supplements that helps in Cognition boost, Prevention of deterioration of brain function, can help in Drug addiction or depression, Aids in Stroke Recovery, Improves eyesight, Improved messages sent to the brain and many more. Higher educational levels (negatively) and current smoking (positively) were associated with both anxiety (P = 0.003 and P < 0.001, respectively) and depression (P < 0.001 and P < 0.001, respectively) symptom levels. [4] Talih F, Ajaltouni J. Phone: ‪+1 707-633-3769‬, Editorial Inquiries Two linear regression models were used, corresponding to the logistic regression models regarding explanatory variables. Acetylcholine is of great importance in cognitive function and diseases, including Alzheimer disease (21). ... dopamine and serotonin imbalances are known for causing depression in people. In a study at the University of Utah, 75 healthy males were given 250 mg, 500 mg of CDP-Choline, or a placebo. Uses . The dotted lines indicate 95% pointwise CIs. Blood samples used for the preparation of plasma were drawn into evacuated tubes containing EDTA, placed in a refrigerator (4–5°C) within 15–30 min, and centrifuged, usually within 1 h (always within 3 h). Janowsky DS, el-Yousef MK, Davis JM, Sekerke HJ. A significant inverse association was also found by linear regression analyses, only between choline and anxiety levels (Table 3), after adjustment for sex, age group, and time since last meal [standardized regression coefficient (β) = −0.030, P = 0.028]. Disturbed cholinergic tran… As it stands, citicoline is one of the most commonly used ingredients in pre-made natural nootropic supplements. During the past decade, there has been an interest in choline as a marker of neuronal activity in imaging studies with magnetic resonance spectroscopy. Subjects with plasma choline concentrations in the lowest (first) quintile [compared with the highest (fifth)] had an OR of 1.36 (95% CI: 1.08, 1.72) in the model that adjusted for sex, age group, and time since the last meal (model 1), which was similar to the results in the fully adjusted model 2 (OR: 1.33; 95% CI: 1.06, 1.69). You’ll … Large amounts (about 20 g) of choline may cause other side effects. Adjustments for coffee consumption, physical exercise, body mass index, cardiovascular disease, and serum creatinine were performed as well and had essentially no effect on the associations between plasma choline and anxiety. Steingard RJ, Yurgelun-Todd DA, Hennen J, et al. The Hordaland Health Study was conducted from 1997 to 1999 as a collaboration between the National Health Screening Service, the University of Bergen, and local health services. CDP-choline, a form of choline, is shown to increase ATP production in your brain cells. Citicoline, also known as CDP-Choline (or less frequently Cognizin in its branded form) is a widely-used nootropic substance known for its ability to acutely increase acetylcholine availability in the brain. Konstantinova SV, Tell GS, Vollset SE, Nygard O, Bleie O, Ueland PM. Stability of free choline in the presence of EDTA and at a low temperature was previously documented (18) and is corroborated by the mean choline concentration (9.87 μmol/L) of the study population not exceeding the concentration previously measured in fresh EDTA samples from nonfasting healthy subjects (18). However, I think the Choline may be causing anxiety/depression. The CDP-choline pathway, first identified by Eugene Kennedy in 1956, is the predominant mechanism by which mammalian cells synthesize phosphatidylcholine (PC) for incorporation into membranes or lipid-derived signalling molecules. Zeisel SH, Mar MH, Howe JC, Holden JM. Clin Interv Aging. Choline may cause a stomach ache, diarrhea, or loose stools. The most common synonym for citicoline is CDP-choline. Citicoline (Cognizin) in the treatment of cognitive impairment. Nicotine, an acetylcholine receptor agonist, affects anxiety in both animal and human studies (24). For full access to this pdf, sign in to an existing account, or purchase an annual subscription. CDP-choline is one of the three choline-containing phospholipids that can be orally supplemented (the other two being Alpha-GPC and phosphatidylcholine). 2012;143(1- 3):257-260. I take CDP-Choline to prevent loss of Choline. Clin Interv Aging. CDP Choline and Your Brain. Citicoline (Cognizin) in the treatment of cognitive impairment. So that individuals do not feel as though they are being tested for mental disorders, symptoms of severe psychopathology are not included. You should not use choline if you have bipolar disorder. In the logistic regression analyses (Table 2), significant associations were found only between choline and high anxiety levels. In this article, we examine the available clinical literature on citicoline use as it related to mental illness, with a particular focus on depression. General Inquiries In a crossover, double-blind, placebo-controlled trial, patients (n = 11) with mania showed a significant improvement after 1 wk of treatment with lecithin, but not with placebo (9). 2006;1(3):247-251. They can also include depression and heart rhythm problems. A higher proportion of women than men reported anxiety symptoms (P < 0.001), whereas no sex differences were seen for depression. Design: We studied a subsample (n = 5918) of the Hordaland Health Study, including both sexes and 2 age groups of 46–49 and 70–74 y who had valid information on plasma choline concentrations and symptoms of anxiety and depression measured by the Hospital Anxiety and Depression Scale—the latter 2 as continuous measures and dichotomized at a score ≥8 for both subscales. J Affect Disord. Because high levels of anxiety and depression may influence dietary habits, it is conceivable that these mental conditions may alter choline status through dietary changes. CDP choline (cytidine diphosphate-choline) is also known as Citicoline. Background: Despite its importance in the central nervous system as a precursor for acetylcholine and membrane phosphatidylcholine, the role of choline in mental illness has been little studied. Clinical and Radiological Characteristics of Neuromyelitis Optica Spectrum Disorder: The Experience from Saudi Arabia. Although this design allows the assessment of associations between variables, causality could not be determined. [3] Silveri MM, Dikan J, Ross AJ, et al. Stochastic models of systems for Nanotechnology: from micro to macro scale. Background: Despite its importance in the central nervous system as a precursor for acetylcholine and membrane phosphatidylcholine, the role of choline in mental illness has been little studied. [1] Fioravanti M, Buckley AE. Email: admin@ijest.org Case reports suggest that choline (a vitamin in the B family) reduces the severity of mania.Choline is required for … Clin Interv Aging. Two logistic regression models were used, one with adjustment for age group, sex, and time since last meal (model 1) and one with additional adjustments for smoking status (smokers compared with nonsmokers and ex-smokers) and educational level (<10, 10–12, and >12 y) (model 2). There has probably been no or only minor change in free choline during storage of the EDTA samples before analysis. Therapy-Related Imaging Findings in Patients with Sarcoma. Ingvar Bjelland, Grethe S Tell, Stein E Vollset, Svetlana Konstantinova, Per M Ueland, Choline in anxiety and depression: the Hordaland Health Study, The American Journal of Clinical Nutrition, Volume 90, Issue 4, October 2009, Pages 1056–1060, https://doi.org/10.3945/ajcn.2009.27493. We found no significant associations in the corresponding analyses of the relation between plasma choline and depression symptoms. Moore CM, Breeze JL, Gruber SA, et al. Results: The lowest choline quintile was significantly associated with high anxiety levels (odds ratio: 1.33; 95% CI: 1.06, 1.69) in the fully adjusted (age group, sex, time since last meal, educational level, and smoking habits) logistic regression model. The analyses of blood samples were completed in 2006; thus, plasma was stored for 7 to 9 y. Best nootropics Some use CDP-Choline as an alternative to the stimulants prescribed for ADHD. While it’s found in every cell in the body, our primary concern here is its role in the brain. An inverse dose-response association between plasma choline concentrations and high anxiety symptom levels and a possible inverse dose-response association between plasma choline concentrations and high depression symptom levels were indicated by the generalized additive model analyses (Figure 1). Common Name(s): CDP-choline, Citicoline. All participants signed a consent form. The authors’ responsibilities were as follows—IB: analyzed the data and primarily responsible for writing the manuscript; GST: Principal Investigator of the Hordaland Health Study, responsible for the design of the study and data collection; and provided significant advice and consultation concerning the writing of the manuscript; SEV: involved in the design of the Hordaland Health Study, provided significant advice and consultation concerning the analysis of the data, and critically read and commented on the manuscript; SK: performed the plasma choline assessments in the blood samples and critically read and commented on the manuscript; and PMU: involved in the design of the Hordaland Health Study, in charge of the plasma choline assessments, and provided significant advice and consultation concerning the writing process of the manuscript. The study protocol was approved by the Regional Committee for Medical Research Ethics and the Norwegian Data Inspectorate. A randomized, double-blind, placebo- controlled trial of citicoline for bipolar and unipolar depression and methamphetamine dependence. This means that it is synthesized in the process of phosphatidylcholine generation from choline, which occurs in cell membranes naturally, with both animals and humans. Privacy Policy It’s a natural chemical compound produced by the body, but it’s also a dietary supplement. The mean (±SD) plasma choline concentration was 9.87 ± 2.30 μmol/L, was lower in women than in men, and was lower in younger than in older subjects (20). 2. Choline is an essential nutrient found in animal products such as liver, egg, and meat, but also in some vegetable products, including wheat germ and soy beans (1). Oral dosages of 250 to 2,000 mg daily have been evaluated in adolescents and adults in clinical trials. Supplementing with this compound can increase cognitive function and memory performance, protect the brain from damage and disease, and reduce inflammation. Defined as a Hospital Anxiety and Depression Scale anxiety subscale score ≥8. High anxiety levels were most prevalent among middle-aged women (19.9%) and high depression levels were most prevalent among older men (10.1%). Ueland PM, Nygard O, Vollset SE, Refsum H. Bjelland I, Dahl AA, Haug TT, Neckelmann D. Holm PI, Ueland PM, Kvalheim G, Lien EA. Data on the role of acetylcholine in other mental disorders and in emotional regulation in humans in particular are sparse (5). Clin Interv Aging. Because of increasing widening of the 95% pointwise CIs, the results from the tails of the distribution are not shown. I've tried many things and I know that many of them can cause depression to some extent depending on the individual, but conversely, I've felt cdp choline … Disturbed cholinergic transmission affects cognitive function (4); however, its influence on emotional regulation is less known (5). The statistical analyses were conducted by using the software package SPSS 15.0 and S-Plus 6.1 (SPSS Inc, Chicago, IL). However, the number of studies has been few (11–14), and it is difficult to draw specific conclusions other than that choline concentrations in the central nervous system may be disturbed in mental illness. The representation of the choline quintiles as indicator variables was used to allow for assessment of nonlinear dose-response relations, whereas a linear (1 df) representation was used to test for linear trends.

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