Depression Is Associated With Decreased 25-Hydroxyvitamin D and Increased Parathyroid Hormone Levels in Older Adults | Depressive Disorders | JAMA Psychiatry | JAMA Network
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Serum levels of 25-hydroxyvitamin D [25(OH)D] (A) and parathyroid hormone (PTH) (B). MDD indicates major depressive disorder. Values are given as mean (SD). To convert PTH to nanograms per liter, multiply by 1; 25(OH)D to nanomoles per liter, multiply by 2.496.

Serum levels of 25-hydroxyvitamin D [25(OH)D] (A) and parathyroid hormone (PTH) (B). MDD indicates major depressive disorder. Values are given as mean (SD). To convert PTH to nanograms per liter, multiply by 1; 25(OH)D to nanomoles per liter, multiply by 2.496.

Table 1. 
Study Variables Across Depression Status
Study Variables Across Depression Status
Table 2. 
Results of Regression Analyses for the Association Between Serum Levels of 25(OH)D and PTH With Depression Severity Before and After Adjustment
Results of Regression Analyses for the Association Between Serum Levels of 25(OH)D and PTH With Depression Severity Before and After Adjustment
Original Article
May 2008

Depression Is Associated With Decreased 25-Hydroxyvitamin D and Increased Parathyroid Hormone Levels in Older Adults

Author Affiliations

Author Affiliations: Research Institute Neurosciences and the Center for Neurogenomics and Cognitive Research (Dr Hoogendijk), Institute for Research in Extramural Medicine (Drs Dik, Deeg, Beekman, and Penninx), and Departments of Endocrinology (Dr Lips) and Psychiatry (Drs Hoogendijk, Deeg, Beekman, and Penninx), VU University Medical Center, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.

Arch Gen Psychiatry. 2008;65(5):508-512. doi:10.1001/archpsyc.65.5.508

Context  Depression has incidentally been related to altered levels of 25-hydroxyvitamin D [25(OH)D] and parathyroid hormone (PTH), but this relation has never been studied systematically.

Objective  To determine in a large population-based cohort whether there is an association between depression and altered 25(OH)D and PTH levels.

Design  Population-based cohort study (Longitudinal Aging Study Amsterdam).

Participants  One thousand two hundred eighty-two community residents aged 65 to 95 years.

Setting  The Netherlands.

Main Outcome Measure  Depression was measured using self-reports (Center for Epidemiologic Studies–Depression scale) and diagnostic interviews (Diagnostic Interview Schedule). Levels of 25(OH)D and PTH were assessed. Potentially confounding factors (ie, age, sex, smoking status, body mass index, number of chronic conditions, and serum creatinine concentration) and explanatory factors (ie, season of data acquisition, level of urbanization, and physical activity) were also measured.

Results  Levels of 25(OH)D were 14% lower in 169 persons with minor depression and 14% lower in 26 persons with major depressive disorder compared with levels in 1087 control individuals (P < .001). Levels of PTH were 5% and 33% higher, respectively (P = .003). Depression severity (Center for Epidemiologic Studies Depression Scale) was significantly associated with decreased serum 25(OH)D levels (P = .03) and increased serum PTH levels (P = .008).

Conclusion  The results of this large population-based study show an association of depression status and severity with decreased serum 25(OH)D levels and increased serum PTH levels in older individuals.

Significant depressive symptoms are highly prevalent in older persons (13%)1 and result in high morbidity and mortality.2 Schneider et al3 suggested that psychiatric disorders, in particular depression, may be associated with low serum concentrations of 25-hydroxyvitamin D [25(OH)D]. Underlying causes of vitamin D deficiency such as less sun exposure as a result of decreased outdoor activity, different housing or clothing habits, and decreased vitamin intake4 may be secondary to depression, but depression may also be the consequence of poor vitamin D status. Moreover, poor vitamin D status causes an increase in serum parathyroid hormone (PTH) levels. Primary hyperparathyroidism, in turn, is frequently accompanied by depressive disorders, and mood usually normalizes after treatment of hyperparathyroidism.5,6

Serum 25(OH)D and PTH abnormalities, while common, are highly treatable, which may enable prevention of depression. Therefore, it is surprising that there have been few studies of these abnormalities in relation to depression. Only a few small studies have been performed, with conflicting data in persons with major depressive disorder (MDD).3-5,7,8 To our knowledge, the association of 25(OH)D and PTH abnormalities with minor depression or with the severity of depression have not been assessed. Therefore, the present study assesses the association between both major and minor depression and depression severity and serum 25(OH)D and PTH levels in a large population-based study of older adults.


The Longitudinal Aging Study Amsterdam is an ongoing cohort study of the predictors and consequences of changes in mood, autonomy, and well-being in an aging population in the Netherlands. A random sample of older men and women (age, 55-85 years), stratified by age, sex, urbanization, and expected 5-year mortality, was drawn from the population registers of 11 municipalities in areas in the west, south, and northeast of the Netherlands. A total of 3107 subjects, 99% white, participated in the baseline examination (1992-1993). The sampling and data collection procedures have been previously described in detail.9,10

The present study was limited to those participants aged 65 or older (ie, born during or before 1930) (n = 2525) who participated in the first follow-up in 1995-1996 (n = 1720) and from whom blood could be obtained (n = 1285) and 25(OH)D and PTH levels were available (n = 1282). Between the first and second cycles, attrition (n = 805 [51.7%]) was primarily because of death. Respondents in 1995-1996 who did not participate in the blood-drawing procedure were older (P < .000), more often women (P = .003), and more often depressed (P = .008). Informed consent was obtained from all respondents, and the study was approved by the medical ethics committee of Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.

At the first follow-up in 1995-1996, depression status and depression severity were assessed using the Center for Epidemiologic Studies–Depression (CES-D) scale.11 Persons scoring above the generally accepted cut-off point for clinically relevant symptoms (CES-D score ≥16) were approached to undergo a diagnostic psychiatric evaluation using the Diagnostic Interview Schedule.12

Blood samples were obtained and centrifuged in the morning. Subjects were allowed to have tea and toast but no dairy products. The serum samples were stored at −25°C until assays were performed in 1997-1998. Repeating some of the measurements in 2005 yielded similar results. The serum 25(OH)D concentration was determined using a competitive binding protein assay (Nichols Institute Diagnostics Inc, San Juan Capistrano, California), with an interassay coefficient of variation of 10% and a normal range of 10 to 40 ng/mL (to convert to nanomoles per liter, multiply by 2.496). The serum PTH level was measured using an immune-radiometric assay (Incstar Corp, Stillwater, Minnesota) as described by Pluijm et al,13 with an interassay coefficient of variation of 7% and a normal range of 0.7 to 7 pg/mL (to convert to nanograms per liter, multiply by 1).

Potentially confounding factors were also measured. Smoking status was classified as current smoker or nonsmoker. We controlled for body mass index (BMI) because Wortsman et al14 showed that the increase in serum vitamin D3 after sun exposure was 57% less in obese compared with nonobese subjects. The most common chronic physical illnesses, including stroke, cancer, lung disease, cardiac disease, diabetes mellitus, osteoarthritis, and peripheral artery disease, were measured using self-reports and data from general practitioners.15 Because mild renal impairment could affect vitamin D and PTH homeostasis, we adjusted for serum creatinine concentration.

Several possible explanatory factors that may explain a link between depression and vitamin D and PTH levels were determined. Because vitamin D status is dependent in part on sunlight exposure, it was recorded whether data were collected in winter, spring, summer, or fall. In addition, the levels of physical activity (total activity or outdoor activities only in minutes per day) and urbanization (number of inhabitants per square kilometer) were assessed as described by Snijder et al.10 The use of antidepressants was determined because Zhou et al16 described enhancement of vitamin D catabolism with medication.

All analyses were performed using commercially available software (SPSS for Windows version 14.0; SPSS Inc, Chicago, Illinois). χ2 Tests were performed to determine differences in age, sex, BMI, smoking status, physical activity, number of chronic conditions, serum creatinine concentration, season when data were collected, and level of urbanization between persons with no depression, minor depression, or MDD. Multiple linear regression analyses were performed to study the associations between depression variables (independent variables) and serum 25(OH)D or PTH levels (dependent variables). Because the distribution of serum PTH was skewed, we used logarithmically transformed values. In addition, we adjusted the regression models for potential confounding variables and, in a separate step, for those potential explanatory variables that were univariately associated with depression status. Potential effect modification by sex was examined by additionally including product terms of hormone levels × sex in the adjusted regression analyses.


Twenty-six persons had a current (1-month recency) diagnosis of MDD according to the Diagnostic Interview Schedule, 169 had minor depression (defined as CES-D score ≥16 but Diagnostic Interview Schedule negative for MDD), and 1087 persons were not depressed (Table 1). Compared with nonpressed persons, depressed persons were significantly (P < .05) older, were more often women, were more often smokers (MDD only), had higher BMI (MDD only), had more chronic conditions, and more often lived in highly urbanized areas, which underscores the need to consider these factors in the analyses. Creatinine concentration, season of assessment, and physical activity levels did not differ significantly between depressed and nondepressed persons. Only 1% of the participants used low-dose vitamin D or calcium supplements. According to the serum 25(OH)D and PTH levels, this did not influence our results. Less than 1% of the participants (ie, 7 persons with minor depression and 4 with MDD) used antidepressants, which did not influence our results when added to the model (data not shown).

The mean (SD) serum 25(OH)D level was 21 (10) ng/mL (Figure, A), and the mean serum PTH level was 3.6 (1.7) pg/mL (Figure, B). The Pearson correlation coefficient between serum 25(OH)D and PTH levels was −0.30 (P < .001). In 4.5% of the men and 7.7% of the women, the serum 25(OH)D level was less than 10 ng/mL, indicating a deficient status as defined by Lips.17 In 38.8% of the men and 56.9% of the women, the serum 25(OH)D level was less than 20 ng/mL, indicating an insufficient status.

The 25(OH)D levels were 14% lower in the 169 persons with minor depression (mean, 19 ng/mL) and 14% lower in the 26 persons with MDD (mean, 19 ng/mL) compared with those in the 1087 nondepressed persons (mean, 22 ng/mL) (P < .001). The PTH levels were 5% higher in persons with minor depression (mean, 3.72 pg/mL) and 33% higher in persons with MDD (mean, 4.69 pg/mL) compared with those in nondepressed persons (mean, 3.53 pg/mL) (P = .003).

Depression severity (CES-D scale score) was associated with decreased serum 25(OH)D levels (P < .001) and increased serum PTH levels according to quartiles of 25(OH)D and PTH levels (P < .001; Table 2). After adjustment for age, sex, BMI, smoking status, and number of chronic conditions, CES-D scale scores were still associated with decreased 25(OH)D (P = .01) and increased PTH levels (P = .002). After additional adjustment for level of urbanization, which was the only explanatory variable that differed across depression status, these associations remained significant (P = .03 and .008, respectively). Insofar as the link with depressive symptoms, no significant interaction terms were found for sex × 25(OH)D (P = .70) or sex × PTH (P = .82), indicating that associations were consistent across sex. Additional adjustment for PTH levels did not weaken the association between the CES-D scale score and 25(OH)D level, whereas PTH remained significantly associated with the CES-D scale score after adjustment for the 25(OH)D level.


This large population-based study shows, for the first time, an association of depression status and depression severity with decreased serum 25(OH)D levels and increased serum PTH levels in older subjects. This association was adjusted for the potentially confounding factors of age, sex, BMI, smoking status, and number of chronic conditions and is not explained by differences in season of data acquisition, level of physical activity, or use of antidepressants. Only the level of urbanization had a small explanatory effect, which confirms that decreased light exposure contributes to a decreased serum 25(OH)D level and depression. That the PTH level was also associated with depression after adjustment for the 25(OH)D level suggests that PTH may also have a role in the pathogenesis of depression. This is in accord with the high prevalence of depression in primary hyperparathyroidism.

Low levels of 25(OH)D could be involved in the pathogenesis of depression in several ways. Autoradiography and immunohistochemistry in rodents showed that the target tissues of 25(OH)D are related to exocrine and endocrine secretory and somatotrophic processes rather than to calcium metabolism alone. Moreover, the distribution of target neurons of 25(OH)D suggests an influence of synthesis levels of nerve growth factor,18 acetylcholine acetylase, serotonin, testosterone, thyroid hormone, and tyrosine hydroxylase messenger RNA,19,20 which have all been implicated in the pathogenesis of depression in human beings. Recently, vitamin D deficiency restricted to late gestation was found to result in hyperlocomotion in the adult rat, suggesting a role in the pathogenesis of neuropsychiatric disorders.21 In human beings, the distribution of the vitamin D receptor seems to be similar to that in rodents, with the strongest staining occurring in the hypothalamus,22 suggesting a role in neuroendocrine functioning. In earlier work, we found that the human hypothalamus is likely implicated in the pathogenesis of depression because a number of neuron types show altered levels of neuropeptides and corresponding gene expression in postmortem brain tissue from depressed patients compared with control subjects.112326 However, more pathophysiologic research on the vitamin D receptor in the human hypothalamus and eventual alterations in depression is needed to confirm its relevance for the pathogenesis of the disorder.

From the patient’s perspective, our findings may be of clinical relevance because the prevalence of minor depression in older persons is high (13%)1 and both decreased serum 25(OH)D levels and increased serum PTH levels can, in theory, be treated with higher dietary intake of vitamin D3 or calcium and increased exposure to daylight.27 Moreover, vitamin D status was found to predict physical performance and its decline in older persons.28 Vitamin D and PTH status may also be improved indirectly by adequate antidepressant treatment, resulting in increased food intake and activity patterns.4 Moreover, the clinical relevance of the present study is underscored by our finding that 38.8% of men and 56.9% of women in our community-based cohort had an insufficient vitamin D status.

To date, no reliable data are available on the outcome of vitamin D or light intervention studies in persons with minor depression or MDD, and results in subjects with seasonal affective disorder or healthy subjects with seasonal mood changes are conflicting.29,30 We did not find an effect of season on 25(OH)D level. Only one trial31 has shown a significant positive effect of phototherapy on 25(OH)D. In this study, vitamin D medication had a positive effect on both 25(OH)D level and depression severity, but the number of subjects receiving vitamin D was small (n = 8) and the data deserve follow-up. Therefore, we suggest that future large-scale intervention studies on, for example, osteoporosis32 in older persons, use of vitamin D3, and exposure to daylight, also use mood as an outcome measure.

In conclusion, we found that depression and depression severity, as measured with the CES-D scale, is strongly associated with lower serum 25(OH)D levels and higher PTH levels, even after adjustment for age, sex, BMI, smoking status, health status, level of physical activity, and level of urbanization. Long-term longitudinal studies with repeated assessments should be performed to explore the question of whether decreased 25(OH)D levels and increased PTH levels precede depression or follow it. In other words, are these biological changes a cause or a consequence of depression?

Correspondence: Witte J. G. Hoogendijk, MD, PhD, VU University Medical Center, Vrije Universiteit Amsterdam, A. J. Ernststraat 887, 1081 HL, Amsterdam, the Netherlands (

Submitted for Publication: July 24, 2007; final revision received December 5, 2007; accepted December 5, 2007.

Financial Disclosure: This study is based on data collected in the context of the Longitudinal Aging Study Amsterdam, funded by the Netherlands Ministry of Health, the Hague.

Funding/Support: This study was supported by ZonMw clinical fellow grant 907-00-012 (W.J.G.H.) from the Netherlands Organisation for Scientific Research.

Role of the Sponsor: The Netherlands Organisation for Scientific Research had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.

Beekman  ATCopeland  JRPrince  MJ Review of community prevalence of depression in later life.  Br J Psychiatry 1999;174307- 311PubMedGoogle ScholarCrossref
Penninx  BWBeekman  ATHonig  ADeeg  DJSchoevers  RAvan Eijk  JTvan Tilburg  W Depression and cardiac mortality: results from a community-based longitudinal study.  Arch Gen Psychiatry 2001;58 (3) 221- 227PubMedGoogle ScholarCrossref
Schneider  BWeber  BFrensch  AStein  JFritz  J Vitamin D in schizophrenia, major depression and alcoholism.  J Neural Transm 2000;107 (7) 839- 842PubMedGoogle ScholarCrossref
Michelson  DStratakis  CHill  LReynolds  JGalliven  EChrousos  GGold  P Bone mineral density in women with depression.  N Engl J Med 1996;335 (16) 1176- 1181PubMedGoogle ScholarCrossref
Petersen  P Psychiatric disorders in primary hyperparathyroidism.  J Clin Endocrinol Metab 1968;28 (10) 1491- 1495PubMedGoogle ScholarCrossref
Watson  LCMarx  CE New onset of neuropsychiatric symptoms in the elderly: possible primary hyperparathyroidism.  Psychosomatics 2002;43 (5) 413- 417PubMedGoogle ScholarCrossref
Herrán  AAmado  JAGarcia-Unzueta  MTVázquez-Barquero  JLPerera  LGonzález-Macias  J Increased bone remodeling in first-episode major depressive disorder.  Psychosom Med 2000;62 (6) 779- 782PubMedGoogle ScholarCrossref
Wilkins  CHSheline  YIRoe  CMBirge  SJMorris  JC Vitamin D deficiency is associated with low mood and worse cognitive performance in older adults.  Am J Geriatr Psychiatry 2006;14 (12) 1032- 1040PubMedGoogle ScholarCrossref
Deeg  DJvan Tilburg  TSmit  JHde Leeuw  ED Attrition in the Longitudinal Aging Study Amsterdam: the effect of differential inclusion in side studies.  J Clin Epidemiol 2002;55 (4) 319- 328PubMedGoogle ScholarCrossref
Snijder  MBvan Dam  RMVisser  MDeeg  DJDekker  JMBouter  LMSeidell  JCLips  P Adiposity in relation to vitamin D status and parathyroid hormone levels: a population-based study in older men and women.  J Clin Endocrinol Metab 2005;90 (7) 4119- 4123PubMedGoogle ScholarCrossref
Alkemade  AUnmehopa  UABrouwer  JPHoogendijk  WJWiersinga  WMSwaab  DFFliers  E Decreased thyrotropin-releasing hormone gene expression in the hypothalamic paraventricular nucleus of patients with major depression.  Mol Psychiatry 2003;8 (10) 838- 839PubMedGoogle ScholarCrossref
Robins  LNHelzer  JECroughan  JRadcliff  KS National Institute of Mental Health Diagnostic Interview Schedule: its history, characteristics, and validity.  Arch Gen Psychiatry 1981;38 (4) 381- 389PubMedGoogle ScholarCrossref
Pluijm  SMFVisser  MSmit  JHPopp-Snijders  CRoos  JCLips  P Determinants of bone mineral density in older men and women: body composition as mediator.  J Bone Miner Res 2001;16 (11) 2142- 2151PubMedGoogle ScholarCrossref
Wortsman  JMatsuoka  LYChen  TCLu  ZHolick  MF Decreased bioavailability of vitamin D in obesity [published correction appears in Am J Clin Nutr. 2003;77(5):1342].  Am J Clin Nutr 2000;72 (3) 690- 693PubMedGoogle Scholar
Kriegsman  DMDeeg  DJStalman  WA Comorbidity of somatic chronic diseases and decline in physical functioning: the Longitudinal Aging Study Amsterdam.  J Clin Epidemiol 2004;57 (1) 55- 65PubMedGoogle ScholarCrossref
Zhou  CAssem  MTay  JCWatkins  PBBlumberg  BSchuetz  EGThummel  KE Steroid and xenobiotic receptor and vitamin D receptor crosstalk mediates CYP24 expression and drug-induced osteomalacia.  J Clin Invest 2006;116 (6) 1703- 1712PubMedGoogle ScholarCrossref
Lips  P Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss and fractures and therapeutic implications.  Endocr Rev 2001;22 (4) 477- 501PubMedGoogle ScholarCrossref
Wion  D MacGrogan  DNeveu  IJehan  FHoulgatte  RBrachet  P 1,25-Dihydroxyvitamin D3 is a potent inducer of nerve growth factor synthesis.  J Neurosci Res 1991;28 (1) 110- 114PubMedGoogle ScholarCrossref
Stumpf  WE Vitamin D sites and mechanisms of action: a histochemical perspective. Reflections on the utility of autoradiography and cytopharmacology for drug targeting.  Histochem Cell Biol 1995;104 (6) 417- 427PubMedGoogle ScholarCrossref
Stumpf  WEO'Brien  LP 1,25 (OH)2 vitamin D3 sites of action in the brain: an autoradiographic study.  Histochemistry 1987;87 (5) 393- 406PubMedGoogle ScholarCrossref
O'Loan  JEyles  DWKesby  JKo  PMcGrath  JJBurne  TH Vitamin D deficiency during various stages of pregnancy in the rat: its impact on development and behaviour in adult offspring.  Psychoneuroendocrinology 2007;32 (3) 227- 234PubMedGoogle ScholarCrossref
Eyles  DWSmith  SKinobe  RHewison  MMcGrath  JJ Distribution of the vitamin D receptor and 1 alpha-hydroxylase in human brain.  J Chem Neuroanat 2005;29 (1) 21- 30PubMedGoogle ScholarCrossref
Meynen  GUnmehopa  UAHofman  MASwaab  DFHoogendijk  WJ Hypothalamic oxytocin mRNA expression and melancholic depression.  Mol Psychiatry 2007;12 (2) 118- 119PubMedGoogle ScholarCrossref
Purba  JSHoogendijk  WJHofman  MASwaab  DF Increased number of vasopressin- and oxytocin-expressing neurons in the paraventricular nucleus of the hypothalamus in depression.  Arch Gen Psychiatry 1996;53 (2) 137- 143PubMedGoogle ScholarCrossref
Raadsheer  FCHoogendijk  WJStam  FCTilders  FJSwaab  DF Increased numbers of corticotropin-releasing hormone expressing neurons in the hypothalamic paraventricular nucleus of depressed patients.  Neuroendocrinology 1994;60 (4) 436- 444PubMedGoogle ScholarCrossref
Zhou  JNRiemersma  RFUnmehopa  UAHoogendijk  WJvan Heerikhuize  JJHofman  MASwaab  DF Alterations in arginine vasopressin neurons in the suprachiasmatic nucleus in depression.  Arch Gen Psychiatry 2001;58 (7) 655- 662PubMedGoogle ScholarCrossref
Stumpf  WEPrivette  TH Light, vitamin D and psychiatry: role of 1,25-dihydroxyvitamin D3 (soltriol) in etiology and therapy of seasonal affective disorder and other mental processes.  Psychopharmacology (Berl) 1989;97 (3) 285- 294PubMedGoogle ScholarCrossref
Wicherts  ISvan Schoor  NMBoeke  AJVisser  MDeeg  DJSmit  JKnol  DLLips  P Vitamin D status predicts physical performance and its decline in older persons.  J Clin Endocrinol Metab 2007;92 (6) 2058- 2065PubMedGoogle ScholarCrossref
Harris  SDawson-Hughes  B Seasonal mood changes in 250 normal women.  Psychiatry Res 1993;49 (1) 77- 87PubMedGoogle ScholarCrossref
Oren  DASchulkin  JRosenthal  NE 1,25(OH)2 vitamin D3 levels in seasonal affective disorder: effects of light.  Psychopharmacology (Berl) 1994;116 (4) 515- 516PubMedGoogle ScholarCrossref
Gloth  FM  IIIAlam  WHollis  B Vitamin D vs broad spectrum phototherapy in the treatment of seasonal affective disorder.  J Nutr Health Aging 1999;3 (1) 5- 7PubMedGoogle Scholar
Jackson  RD LaCroix  AZGass  MWallace  RBRobbins  JLewis  CEBassford  TBeresford  SABlack  HRBlanchette  PBonds  DEBrunner  RLBrzyski  RGCaan  BCauley  JAChlebowski  RTCummings  SRGranek  IHays  JHeiss  GHendrix  SLHoward  BVHsia  JHubbell  FAJohnson  KCJudd  HKotchen  JMKuller  LHLanger  RDLasser  NLLimacher  MCLudlam  SManson  JEMargolis  KLMcGowan  JOckene  JKO’Sullivan  MJPhillips  LPrentice  RLSarto  GEStefanick  MLVan Horn  LWactawski-Wende  JWhitlock  EAnderson  GLAssaf  ARBarad  DWomen's Health Initiative, Calcium plus vitamin D supplementation and the risk of fractures [published correction appears in N Engl J Med. 2006;354(10):1102].  N Engl J Med 2006;354 (7) 669- 683PubMedGoogle ScholarCrossref