Effect of vitamin D deficiency on depressive symptoms in child and adolescent psychiatric patients: results of a randomized controlled trial

Abstract

PurposeWhile observational studies revealed inverse associations between serum vitamin D levels [25(OH)D] and depression, randomized controlled trials (RCT) in children and adolescents are lacking. This RCT examined the effect of an untreated vitamin D deficiency compared to an immediate vitamin D3 supplementation on depression scores in children and adolescents during standard day and in-patient psychiatric treatment.Methods
Patients with vitamin D deficiency [25(OH)D ≤ 30 nmol/l] and at least mild depression [Beck Depression Inventory II (BDI-II) > 13] (n = 113) were 1:1 randomized into verum (VG; 2640 IU vitamin D3/d) or placebo group (PG) in a double-blind manner. During the intervention period of 28 days, both groups additionally received treatment as usual. BDI-II scores were assessed as primary outcome, DISYPS-II (Diagnostic System for Mental Disorders in Childhood and Adolescence, Self- and Parent Rating) and serum total 25(OH)D were secondary outcomes.ResultsAt admission, 49.3% of the screened patients (n = 280) had vitamin D deficiency. Although the intervention led to a higher increase of 25(OH)D levels in the VG than in the PG (treatment difference: + 14 ng/ml; 95% CI 4.86–23.77; p = 0.003), the change in BDI-II scores did not differ (+ 1.3; 95% CI − 2.22 to 4.81; p = 0.466). In contrast, DISYPS parental ratings revealed pronounced improvements of depressive symptoms in the VG (− 0.68; 95% CI − 1.23 to − 0.13; p = 0.016).Conclusion
Whereas this study failed to show a vitamin D supplementation effect on self-rated depression in adolescent in- or daycare patients, parents reported less depressive symptoms in VG at the end of our study. Future trials should consider clinician-rated depressive symptoms as primary outcome.Trial registration“German Clinical Trials Register” (https://www.drks.de), registration number: DRKS00009758

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European Journal of Nutrition (2020) 59:3415–3424
https://doi.org/10.1007/s00394-020-02176-6
ORIGINAL CONTRIBUTION
Eect ofvitamin D deciency ondepressive symptoms inchild
andadolescent psychiatric patients: results ofarandomized
controlled trial
LarsLibuda1,2 · NinaTimmesfeld3,4· JochenAntel1· RaphaelHirtz1,5· JensBauer5· DagmarFührer6·
DeniseZwanziger6· DanaÖztürk1· GinaLangenbach1· DeniseHahn1· StefanieRing1· TriinuPeters1·
AnkeHinney1· JudithBühlmeier1· JohannesHebebrand1· CorinnaGrasemann5,7· ManuelFöcker1,8
Received: 23 July 2019 / Accepted: 3 January 2020 / Published online: 27 February 2020
© The Author(s) 2020
Abstract
Purpose While observational studies revealed inverse associations between serum vitamin D levels [25(OH)D] and depres-
sion, randomized controlled trials (RCT) in children and adolescents are lacking. This RCT examined the effect of an
untreated vitamin D deficiency compared to an immediate vitamin D3 supplementation on depression scores in children and
adolescents during standard day and in-patient psychiatric treatment.
Methods Patients with vitamin D deficiency [25(OH)D ≤ 30nmol/l] and at least mild depression [Beck Depression Inventory
II (BDI-II) > 13] (n = 113) were 1:1 randomized into verum (VG; 2640IU vitamin D3/d) or placebo group (PG) in a double-
blind manner. During the intervention period of 28days, both groups additionally received treatment as usual. BDI-II scores
were assessed as primary outcome, DISYPS-II (Diagnostic System for Mental Disorders in Childhood and Adolescence,
Self- and Parent Rating) and serum total 25(OH)D were secondary outcomes.
Results At admission, 49.3% of the screened patients(n=280) had vitamin D deficiency. Although the intervention led
to a higher increase of 25(OH)D levels in the VG than in the PG (treatment difference: + 14ng/ml; 95% CI 4.86–23.77;
p = 0.003), the change in BDI-II scores did not differ (+ 1.3; 95% CI − 2.22 to 4.81; p = 0.466). In contrast, DISYPS parental
ratings revealed pronounced improvements of depressive symptoms in the VG (− 0.68; 95% CI − 1.23 to − 0.13; p = 0.016).
Conclusion Whereas this study failed to show a vitamin D supplementation effect on self-rated depression in adolescent in-
or daycare patients, parents reported less depressive symptoms in VG at the end of our study. Future trials should consider
clinician-rated depressive symptoms as primary outcome.
Trial registration “German Clinical Trials Register” (https ://www.drks.de), registration number: DRKS00009758
Keywords Vitamin D· Vitamin D deficiency· Supplementation· Depressive symptoms· Depressive disorder· Mood
* Lars Libuda
lars.libuda@uni-due.de
1 Department ofChild andAdolescent Psychiatry, University
Hospital Essen, University ofDuisburg-Essen, Virchowstr.
174, 45147Essen, Germany
2 Research Institute forthePrevention ofAllergies
andRespiratory Diseases inChildhood, Department
ofPediatrics, Marien-Hospital Wesel, Wesel, Germany
3 Institute ofMedical Biometry andEpidemiology,
Philipps-University Marburg, Marburg, Germany
4 Department ofMedical Informatics, Biometrics
andEpidemiology, Ruhr University Bochum, Bochum,
Germany
5 Pediatric Endocrinology andDiabetology, Klinik für
Kinderheilkunde II, University Hospital Essen, University
ofDuisburg-Essen, Essen, Germany
6 Department ofEndocrinology, Diabetes andMetabolism,
Division ofLaboratory Research, University Hospital Essen,
University ofDuisburg-Essen, Essen, Germany
7 Children’s Hospital, St. Josef-Hospital, Ruhr University
Bochum, Bochum, Germany
8 Department ofChild andAdolescent Psychiatry, University
Hospital Münster, Münster, Germany
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3416 European Journal of Nutrition (2020) 59:3415–3424
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Introduction
The term vitamin D subsumes a group of secosterols, with
vitamin D2 and vitamin D3 being the most relevant forms
[1]. Vitamin D has been classified as fat soluble, but in
contrast to other nutrients of this group, vitamin D sta-
tus is not mainly determined by its dietary intake, but by
endogenous synthesis from cholesterol precursors in the
skin through UVB exposition [2, 3]. Another particular-
ity of vitamin D is the high prevalence of insufficiency in
large parts of the general population worldwide [4]. Con-
sidering the Institute of Medicine (IoM) cutoffs classifying
25(OH) vitamin D [25(OH)D] levels of 30–50nmol/l as
“potentially at risk for inadequacy” and levels < 30nmol/l
as “at risk for deficiency” [1], vitamin D status seems to be
critical in children and adolescents in Germany: accord-
ing to data from a representative study more than 60% of
children and adolescents had 25(OH)D < 50nmol/l [5].
While the IoM cutoffs primarily refer to the observed
effects of vitamin D on bone health and calcium absorption
[1], more recent research has raised the question whether
vitamin D inadequacy could also have detrimental effects
on mental health. A potential role in mental disorders is
plausible since the vitamin D receptor as well as vitamin
D metabolizing enzymes are expressed in various brain
regions [6, 7]. Additionally, a modulation of neuroimmune
processes has been postulated as one explanation for a
potential role in diverse neurological and mental disor-
ders [8]. Most recently, findings in serotonergic neuronal
cell lines of cultured rats indicated that treatment with
1,25(OH)2D, i.e., the physiological active metabolite of
vitamin D, enhanced serotonin concentrations [9].
In childhood and adolescence, the vast majority of stud-
ies examining the association between vitamin D and men-
tal health focused on autism spectrum disorders [10]. First
evidence regarding the role of vitamin D in depressive
disorders derives from single observational studies [11].
A prospective analysis of the Avon Longitudinal Study for
Parents and Children (ALSPAC) cohort revealed that par-
ticipants with total 25(OH)D < 50nmol/l at age 10years
had a 20% increased risk of self-reported depressive symp-
toms at age 14years, but not at age 11years [12]. Results
from a representative cross-sectional analysis in Germany
confirmed these findings, as an inverse association was
observed between 25(OH)D levels and emotional prob-
lems as indicated by the Strengths and Difficulties Ques-
tionnaire (SDQ) [13, 14].
Although a recent uncontrolled intervention study
in 940 Iranian adolescent girls showed a significant
reduction in depression scores after 9weeks of vitamin
D supplementation [15], randomized controlled trials
(RCTs) examining the antidepressant effect of vitamin
D supplementation have not been conducted to date in
children and adolescents. In adults, systematic reviews
and meta-analyses of existing RCTs revealed conflicting
results which might be explained by limitations in the
study design of the included RCTs. In a meta-analysis,
Spedding reported that a beneficial effect was confirmed
in six out of seven studies “without biological flaws”, i.e.,
those studies considering only participants with vitamin
D deficiency at baseline and using an adequate dose to
achieve vitamin D sufficiency [16]. In contrast, six out of
eight RCTs with “biological flaws” did not show an effect
[16]. Reviewing common limitations in adult RCTs, we
recently concluded that future RCTs in adolescence should
consider only patients with baseline vitamin D deficiency,
apply a sufficient dose of vitamin D, and focus on a well-
defined risk group [10].
Considering these key requirements pertaining to the
study design, the aim of the present RCT was to examine
the effects of an untreated vitamin D deficiency (placebo)
versus an immediately supplemented vitamin D deficiency
[with 2640 IU vitamin D3 per day (verum)] on depressive
symptoms in child and adolescent psychiatric patients with
at least mild depression. The main hypothesis was that in
unsupplemented patients with vitamin D deficiency [pla-
cebo group (PG)], the standard psychiatric treatment would
result in significantly lower improvement of BDI-II scores
compared to the group with immediate vitamin D3 supple-
mentation [verum group (VG)].
Methods
Study design andparticipants
This two-armed, parallel group, double-blind RCT was con-
ducted at the University Hospital Essen between 2016 and
2018 (first patient first assessment: June 2016, last patient
last assessment: May 2018). The study was registered at the
“German Clinical Trials Register” (https ://www.drks.de,
registration number: DRKS00009758). Details of the study
design are provided elsewhere [17].
Participants were in- or daycare patients aged
11.0–18.9years with hypovitaminosis D and concurrent (at
least) mild depressive symptoms recruited upon admission
to the Department of Child and Adolescent Psychiatry, Psy-
chosomatics and Psychotherapy (LVR-Klinikum Essen) at
the University Hospital Essen, Germany. A screening assess-
ment (T0) for study eligibility was conducted within the first
2 days after hospital admission. Inclusion criteria were a
vitamin D deficiency, i.e., 25(OH)D ≤ 30nmol/l [equiva-
lent to ≤ 12ng/ml] and a BDI–II sum score > 13 indicating
at least mild depression. Exclusion criteria were a concur-
rent diagnosis of a severe somatic disease, renal disease,
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3417European Journal of Nutrition (2020) 59:3415–3424
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hypocalcemia and/or elevated blood plasma parathyroid
hormone (PTH) > 130ng/ml), and/or mental retardation
(IQ < 70). Patients with vitamin D deficiency and established
hypocalcemia or PTH level > 130ng/ml were excluded and
referred to pediatric endocrinology for further treatment.
Children and adolescents meeting all eligibility criteria were
allocated to receive placebo or verum for a period of 28days
at the latest on the 5th day after admission.
Intervention andrandomization
All participants were treated according to best clinical prac-
tice and existing treatment guidelines for their respective
mental disorders, i.e., treatment as usual (TAU). Participants
were 1:1 randomized into one of two study groups. Group
1 (VG) received TAU and oral vitamin D3 supplementation
at a dose of 2640IU/day, i.e., 66mg/day, while group 2
(PG) received placebo during the intervention period besides
TAU. The selected dose of vitamin D supplementation is
substantially higher than the minimum effective dose of
600–800IU/day described in the meta-analysis of Sped-
ding [16] and also higher than the minimum dose used in
the RCTs included in the major depressive disorder (MDD)
meta-analysis of adult patients (i.e., 1500IU/day) [18, 19].
Considering the mean length of hospitalization of inpatient
adolescents at our clinic, as well as previous research on
pharmacokinetics of vitamin D which indicates the reach of
a plateau concentration after 1month of supplementation
[20], the intervention period was set to 28days. Participants
who were discharged from hospital prior to day 28 were
asked to continue supplementation in the scheduled man-
ner, followed up weekly by phone, and scheduled for the
end-of-study examination on day 28 after randomization
(n = 18). A vitamin D supplementation with 1000IU daily
was recommended to all participants with persistent vitamin
D deficiency at the end of the study.
Vitamin D or placebo was administered orally as pills
(880IU vitamin D3/pill), delivered by the same manufac-
turer (Dr. B. Scheffler Nachf. GmbH & Co. KG, Bergisch
Gladbach, Germany) in identical dispensers, labeled with
the randomization number. Participants in both groups were
advised to take three pills per day in the morning after break-
fast. Participants, parents, therapists, and outcome assessors
were blinded regarding study allocation.
Randomization was conducted by the Institute of Medical
Biometry and Epidemiology [(IMBE), Philipps-University
Marburg, Marburg, Germany] using computer-generated
random number lists with random block sizes of lengths
2, 4 and 6. The randomization lists were stratified for two
BDI-II strata (total score values 14–23 and ≥ 24), respec-
tively [21], and two 25(OH)D strata (low stratum: 25(OH)
D < 12.5nmol/l, high stratum: 25(OH)D between 12.5 and
30nmol/l) to guarantee an equal distribution in both study
groups.
Prior to the study start, randomization lists (numbers and
treatment allocations) generated by the IMBE were sent to
the company providing the vitamin D/placebo supplements
for an appropriate labeling of the pill dispensers. Upon
recruitment of a patient, a fax was sent to the IMBE, which
then provided information on the individual randomization
number of the participant to the study center where the cor-
responding pill dispenser was assigned.
Outcome andcovariate assessments
The Beck Depression Inventory (BDI)-II [22] sum score at
the end of the study was defined as the primary outcome
and 25(OH)D concentrations and DISYPS-II DES (Diag-
nostic System for Mental Disorders in Children and Ado-
lescents according to ICD-10 and DSM-IV, [23]) depression
scores—all at the end of study—as secondary outcomes.
BDI-II was used to assess depressive symptom severity
at T0 and after 28 interventional days (T1). The BDI-II is
a self-reported questionnaire including 21 items covering
DSM-IV diagnostic criteria for MDD. Using a four-point
Likert scale (0–3 points) with higher scores indicating a
greater degree of depression, the BDI-II asks how much
these statements describe the participant’s symptoms in
the preceding 2 weeks. Kumar and colleagues stated that
the items of BDI-II address all nine DSM-IV criteria for a
major depressive episode [22]. These are depressed mood,
diminished interest or pleasure in most activities, significant
weight change or change in appetite, insomnia or hypersom-
nia, psychomotor agitation or retardation, fatigue or loss of
energy, feelings of worthlessness or excessive or inappropri-
ate guilt, diminished ability to think or concentrate, and sui-
cidality. In an adolescent sample of 105 male and 105 female
outpatients between 12 and 18years, Steer etal. observed
a high internal consistency of the BDI-II (Cronbach’s
alpha = 0.92) [24]. Total BDI-II scores > 13 indicate at least
mild depression [22]. The above-mentioned BDI strata were
a priori defined considering mean values observed in a Ger-
man sample of adolescent psychiatric patients [21].
Depressive symptoms at T0 and T1 were additionally
assessed using DISYPS-II DES (self- and parent rating). In
general, DISYPS-II is a German diagnostic system includ-
ing self-rating (SBB) and rating by parent and/or teacher
(FBB) to support the diagnosis of psychiatric disorders in
children and adolescents according to ICD-10 and DSM-IV
[23]. The parent-reported questionnaire DISYPS-II FBB and
the self-rated version DISYPS-II SBB, respectively, include
29 items covering the ICD-10/DSM-IV criteria for MDD.
Using a four-point Likert scale (0–3 points) with higher
scores indicating a greater degree of the respective symp-
tom, the questionnaire probes how much these statements
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3418 European Journal of Nutrition (2020) 59:3415–3424
1 3
describe the participant’s symptoms. Examples for these
items are “seems sad most of the time”, “seems grumpy,
irritable and cranky most of the time”, “is not interested
or derives no pleasure from nearly anything or anybody”,
and “seems tired, without energy and exhausted most of
the time”. Analyses of internal consistency of DISYPS-II
DES revealed a Cronbach’s alpha of 0.89 for the depression
scale of both DISYSPS-II SBB and FBB [23]. Total scores
were transferred to stanine scores using age- and sex-spe-
cific reference values. A stanine score ≥ 7 indicates at least
borderline abnormality. Psychiatric diagnoses at T0 were
assessed via the semi-structured interview “Kiddie Schedule
for Affective Disorders and Schizophrenia for School Aged
Children—Present and Lifetime Version” aged 6–18years
(K-SADS-PL) according to DSM-IV [25].
At T0 and T1, blood samples were obtained from an ante-
cubital vein through a short catheter in Monovettes (Sarstedt,
Germany) at early morning after an overnight fast. The
blood samples were transferred within an hour after blood
sampling to the central laboratory of the University Hospi-
tal Essen for analyses of serum 25(OH)D, calcium levels
and plasma PTH.Whole blood was centrifuged(3350 × g,
10 min, 4˚C) after coagulation and serum/plasma was dis-
tributed in small aliquots. The study protocol envisaged the
same procedure—if possible—in case of a study dropout
for any reason.
Serum total 25(OH)D and plasma PTH concentrations
were determined with the Siemens ADVIA Centaur®
Immunoassay-system (Siemens Healthineers, Erlangen,
Germany). The ADVIA Centaur® Vitamin D Total Assay
is a competitive immunoassay and according to the product
insert the intra-assay variation was < 11.9%, the inter-assay
variation was < 5.3%, the functional sensitivity was 4.2ng/
ml (10.5nmol/l) and the limit of detection was 3.2ng/ml
(8.0mmol/l). The ADVIA Centaur® Vitamin D Total Assay
is a standardized laboratory measurement of 25(OH)D of the
NIST (National Institute of Standards and Technology). The
ADVIA Centaur® PTH Test is a two-side sandwich chemi-
luminescence immunoassay and, according to the product
insert, the intra-assay variation was < 6.8%, the inter-assay
variation was < 5.2%, the functional sensitivity was 4.6pg/
ml (0.488pmol/l) and the limit of detection was 3.2pg/
ml (0.339pmol/l). Serum calcium was analyzed with the
ADVIA2400 (Siemens Healthineers, Erlangen, Germany)
using the colorimetric o-cresolphthalein method with an
intra-assay variation < 2.4%, an inter-assay variation < 2.0%
and a functional sensitivity of 1.0mg/dl (0.25mmol/l). The
controls were performed according to the product inserts
(quality control advice of the manufacturer). Serum 25(OH)
D, plasma PTH and serum calcium analyses are accredited
according to DIN EN ISO 15189:2014.
Clinical assessments at admission included assessments
of general health and parameters such as current body
weight and pubertal status.
Statistical analysis
Sample size calculation with a two-sided Student’s t test
resulted in a required size of 81 patients per group to detect
a difference of 4 points in the BDI-II, assuming an SD of 9
points, to attain an 80% statistical power, at a two-sided α of
0.05. The detectable difference for the BDI-II of four points
corresponds to the observed effect in an RCT of vitamin D
supplementation in depressed adults [26]. Information on
standard deviations of the BDI-II in adolescents was derived
from RCTs in adolescents with MDD, irrespective of vita-
min D as the treatment item [27, 28]. Since a dropout/loss
to follow-up rate of approximately 20% was assumed, 100
patients per group should be recruited into the study.
The recruitment period was a priori scheduled to be com-
pleted within 2years. In practice recruitment turned out to
be less successful as planned, resulting in a sample of 113
participants (including 13 participants who were “lost to
follow-up”) after 2years of recruitment. Therefore, it was
decided to perform an unplanned interim analysis. Before
conducting this analysis, it was scheduled to stop the study
for futility if the observed difference in the BDI-II reduction
was below two points. In addition, sample size modification
would be allowed at the interim analysis, where control of
the type I error rate would be ensured through the use of the
CRP principle [29]. Recruitment of patients was stopped
and end of follow-up was awaited for all recruited patients
before interim analysis was performed. At the analysis an
estimated difference in the BDI-II reduction below 0 was
observed, which led to a futility stopping of the trial and
therefore recruitment of patients was terminated. Here, we
provide results from this interim analysis.
The main analysis considered subjects with complete data
and examined all participants within their randomized group
(i.e., modified intention-to-treat (ITT) population). Interven-
tion effects for primary and secondary outcomes were ana-
lyzed using a linear model (ANCOVA) with the respective
outcome variable at the end of the study as dependent varia-
ble, and the individual study group, age, sex, 25(OH)D level
at baseline and the value of the outcome variable at baseline
as independent (co-)variables. Besides BDI-II sum scores at
the end of the study, separate ANCOVA models considered
the secondary outcomes serum 25(OH)D concentrations,
DISYPS-FBB and DISYPS-SBB depression scores at the
end of the study as dependent variables to evaluate whether
the dietary intervention resulted in significant differences
between study groups.
Sensitivity analysis for the primary outcome was con-
ducted with missing values (n = 13) imputed via a linear
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3419European Journal of Nutrition (2020) 59:3415–3424
1 3
regression model, which predicted the missing BDI-II val-
ues from the variables age, sex, BDI and 25(OH)D level
at admission [30]. Furthermore, explorative analyses were
performed to examine whether antidepressant effects depend
on severity of depressive symptoms at baseline. For this pur-
pose, an interaction term (group×BDI-II at baseline) was
included as an additional co-variable in the above-mentioned
ANCOVA model for BDI-II. An additional exploratory anal-
ysis examined the association between the change in BDI-II
between T0 and T1 (outcome) and the concomitant change
in 25(OH)D levels (exposure) by linear regression, consider-
ing 25(OH)D at baseline, BDI at baseline, and age and sex
as independent (co-)variables.
Analysis of the data was conducted after database locking
with “R” (www.r-proje ct.org, version 3.5.1). For all analy-
ses, two-sided tests were used and p values < 0.05 were con-
sidered significant.
Results
Sample characteristics
While a vitamin D deficiency was diagnosed in 138 of 280
screened patients (49.3%), 113 (40.4%) participants ful-
filled all inclusion criteria and were randomized to VG or
PG (Fig.1). During the intervention period, 13 participants
were “lost to follow-up” resulting in a sample of 100 par-
ticipants with complete data sets for the modified intent-
to-treat analysis. Baseline characteristics of randomized
patients revealed a similar distribution in both study groups
(Table1): In both, 75% of the participants were females,
more than 95% were in the higher vitamin D stratum and
nearly 70% were in the higher BDI-II stratum, indicating a
moderate to severe depressive episode at T0. Over 90% of
the randomized subjects had a KIDDIE-SADS diagnosis of
MDD.
Excluded (n=167)
•BDI-II Score<14 & 25(OH)D≤30nmol/l (n=25)
•BDI-II Score<14 & 25(OH)D>30 nmol/l (n=36)
•BDI-II Score>13 & 25(OH)D>30 nmollL (n=104)
•BDI-II Score not assessed & 25(OH)D≥30nmol/l (n=2)
Analysed (n=52)
Participated in follow-up assessment (n=52)
Allocated to receive 2640 IU Vitamin D3 (n=56)
Participated in follow-up assessment (n=48)
Allocated to receive Placebo (n=57)
Analysed (n=48)
Allocation
Analysis
Follow-Up
Enrollment Assessed for eligibility
at clinical admission (n=331)
Declined to participate (n=51)
Randomly assigned to
parallel group design (n=113)
Complete Screening with BDI-
II and 25(OH)D serum
assessment (n=280)
Lost to follow-up (n=9)
Not available (n=9)
Lost to follow-up (n=4)
Not available (n=4)
Excluded from analysis
(n=0)
Excluded from analysis
(n=0)
Fig. 1 Flowchart of study enrollment, randomization and loss to follow-up during the intervention period
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3420 European Journal of Nutrition (2020) 59:3415–3424
1 3
Eects ofvitamin D supplementation onprimary
andsecondary outcomes
Mean 25(OH)D concentrations substantially increased
during the intervention in VG, resulting in a higher mean
serum 25(OH)D at T1 in VG than in PG (estimated dif-
ference verum-placebo: + 14ng/ml; 95% CI 4.9to23.8;
p = 0.003, Table2). However, BDI-II scores improved
similarly in both groups (PG: − 5.2 ± 8.8; VG: − 4.3 ± 8.5,
Table2) and did not differ between groups at T1 (esti-
mated difference: + 1.3; 95% CI − 2.2 to 4.8; p = 0.466,
Table2). Sensitivity analysis yielded similar results with
the imputed data set (estimated difference = 0.49; 95% CI
− 2.52 to 3.58; p = 0.75). The exploratory analysis revealed
no evidence for effect modification according to BDI-II
scores at T0 [interaction term (group×BDI): β = − 0.003;
95% CI − 0.36 to 0.35; p = 0.985]. Additionally, no linear
association was observed between the change in 25(OH)
D between T0 and T1 and the concomitant BDI change
(β = 0.049; 95% CI − 0.16 to 0.2; p = 0.6415).
In accordance with the results for the self-rated BDI-II,
the self-reported DISYPS-SBB also revealed no group dif-
ferences in depressive symptoms at T1. In contrast, parent-
reported DISYPS-FBB stanine scores at T1 were lower in
VG compared to PG (estimated difference: − 0.68; 95% CI
− 1.23 to − 0.13; p = 0.016; Table2).
Discussion
This study is the first RCT on the effect of an untreated
vitamin D deficiency on depressive symptoms in children
and adolescents and considered several intensively dis-
cussed limitations of previous RCTs: As postulated, our
study focused on participants who were both vitamin D
deficient and at least mildly depressed at baseline [31]. The
main finding of this RCT was that an immediate vitamin D3
supplementation in depressed child and adolescent psychi-
atric patients with vitamin D deficiency did not result in a
significant decrease of self-reported depressive symptoms,
but in a significant decrease of parent-reported depressive
symptoms after 4weeks of in- or day-patient treatment com-
pared to placebo.
These findings are in line with the overall equivocal
results from previous studies: observational studies in ado-
lescents indicate an inverse association between 25(OH)
D levels and emotional problems [13, 14] or depressive
symptoms [12]. Pooled data from observational studies in
Table 1 Baseline characteristics
of randomized participants
BDI-II Beck Depression Inventory-II, DISYPS Diagnostic System for Mental Disorders in Childhood and
Adolescence, MDD major depressive disorder
a Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) major depression disor-
der diagnosis based on KIDDIE-SADS Present and Lifetime Version (KIDDIE-SADS not available: VG:
n = 2, PG: n = 1)
b 1ng/ml 25(OH) vitamin D equates to 2.5nmol/l
Placebo group (n = 57) Verum group (n = 56)
nMean (± SD) or % nMean (± SD) or %
Age [years] 57 15.8 ± 1.65 56 16.1 ± 1.41
Females [N, %] 43 75.4% 42 75.0%
Body height [cm] 57 167 ± 8.50 56 167 ± 9.54
Body weight [kg] 57 63.7 ± 18.2 56 67.1 ± 18.9
BMI [kg/m2] 57 22.8 ± 5.5 56 23.8 ± 5.9
MDD diagnosis [%]a54 96.4% 51 94.4%
Serum 25 (OH) vitamin D
Absolute concentration [ng/ml]b57 8.56 ± 2.05 56 8.66 ± 1.97
Stratum 1 (0–5ng/ml) [N; %] 2 3.51% 1 1.79%
Stratum 2 (5–12ng/ml) 55 96.5% 55 98.2%
BDI-II
Total scores 57 29.2 ± 9.38 56 31.1 ± 11.3
Stratum 1 (14–23) 18 31.6% 17 30.4%
Stratum 2 (24–64) 39 68.4% 39 69.6%
DISYPS-stanine depression
Self-report 56 8.54 ± 1.13 54 8.46 ± 1.02
Parent report 54 8.37 ± 1.23 55 8.65 ± 0.82
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3421European Journal of Nutrition (2020) 59:3415–3424
1 3
adults confirmed this association: While nine cross-sectional
studies revealed a moderately higher risk of depression for
the lowest compared to the highest vitamin D category (OR
1.31; 1.0–1.71 95% CI), three cohort studies even showed
more definite associations between vitamin D categories at
baseline and the risk of developing depression over time
(lowest vs. highest vitamin D category: pooled HR 2.21;
1.40–3.49 95% CI) [32]. These cohort studies did not reveal
a definite cutoff for 25(OH)D concentrations which might
be required to experience beneficial effects on depression
[32]. In contrast, Mendelian randomization studies did not
indicate a causal relationship between 25(OH)D concentra-
tions and depression [33, 34].
Meta-analyses of RCTs in adults also revealed no general
impact of vitamin D supplementation on depression scores
or depressive symptoms [31, 35, 36]. Spedding argued that
these null effects might result from “biological flaws” in
the design of included RCTs [16]. In the current study we
considered the limitations depicted by Spedding [16], e.g.,
focusing on patients with diagnosed vitamin D deficiency
and depressive symptoms as indicated by BDI-II.
While the present study failed to show a significant effect
of vitamin D on the primary outcome parameter (BDI,
i.e., self-reported depressive symptoms), parent reports of
depressive symptoms revealed beneficial effects of vitamin
D supplementation. Whereas we cannot dismiss this effect as
a spurious finding, we in retrospect and upon review of phar-
macological and/or psychotherapeutic RCTs to treat depres-
sion in children, adolescents and adults deem it important
to point out that our use of the BDI-II as primary outcome
could well represent the main reason for the observed
conflicting results. Although the BDI-II is commonly used
in depression research and served as primary outcome in
three of four studies [26, 37, 38] included in the most recent
MDD meta-analysis of vitamin D effects on depression [19],
self-reports might be less appropriate as primary outcome
measure in RCTs focusing on antidepressant effects. Indeed,
using the parent-rated DISYPS-FBB as outcome variable we
detected a beneficial effect of vitamin D supplementation of
0.7 stanine scores on parent-reported depressive symptoms.
As the negative results of the self-rated DISYPS-SBB were
in accordance with those for the BDI-II, these conflicting
findings seem to rely on the differing raters.
In general, only moderate correlations have been
observed between self- and parental-rated mental health of
adolescents; furthermore, differences between informants
increase with age in particular for internalizing problems
[39]. In adults, the depression severity assessed via BDI
also correlates only moderately with clinicial ratings using
Hamilton Depression Rating Scale [40]. RCTs focussing on
the effects of pharmacological antidepressants and/or psy-
chotherapy have revealed larger effect sizes for both verum
and placebo when clinician-based ratings were considered
in comparison to self-ratings [41-43]. Accordingly, we rec-
ommend that future RCTs should include a clinician rating,
ideally as the primary outcome as usual in pharmacotherapy
trials, to answer the question whether vitamin D supplemen-
tation has antidepressant effects.
Another explanation for our negative primary outcome
relies on the intervention period of only 4weeks. This time
frame represents the mean hospitalization duration of ado-
lescents in our clinic and, thus, reflects real-life conditions
Table 2 Changes in primary
and secondary outcomes
during study participation and
treatment effect of 4weeks
vitamin D supplementation
(verum) compared to placebo
BDI-II Beck Depression Inventory-II, DISYPS Diagnostic System for Mental Disorders in Childhood and
Adolescence, DISYPS parent report at T0 not available for n = 1 in PG
a Linear model (ANCOVA) adjusted for age, sex, baseline vitamin D and baseline value
b 1ng/ml 25(OH) vitamin D equates to 2.5nmol/l
Placebo group Verum group Difference
verum–pla-
ceboa
95% CIat value p valuea
N = 48 N = 52
BDI-II
T1 24.4 ± 12.6 27.1 ± 14.0 1.29 − 2.22 to 4.81 0.731 0.466
T1–T0 − 5.21 ± 8.78 − 4.33 ± 8.51
25(OH) Vitamin D [ng/ml]b
T1 10.4 ± 4.31 23.9 ± 6.11 14.3 4.86 to 23.77 3.005 0.003
T1–T0 1.84 ± 4.24 15.1 ± 6.16
DISYPS-stanine depression
Parent report
T1 8.23 ± 0.95 7.65 ± 1.74 − 0.68 − 1.23 to − 0.13 − 2.458 0.016
T1–T0 − 0.17 ± 1.11 − 0.98 ± 1.69
self-report
T1 8.21 ± 1.18 7.96 ± 1.36 − 0.20 − 0.70 to 0.31 − 0.781 0.437
T1–T0 − 0.33 ± 1.55 − 0.48 ± 1.43
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3422 European Journal of Nutrition (2020) 59:3415–3424
1 3
in child and adolescent psychiatry. Anyhow, this time frame
might have been too short to cause substantial modifica-
tions in brain metabolism and, thus, antidepressant effects.
Indeed, a meta-analysis indicated differences in pooled
effect sizes for depression between RCTs with follow-ups
less than 8weeks and those with at least 8weeks [31]. Also
in the most recent meta-analysis showing a significant ben-
eficial effect of vitamin D supplementation on MDD, only
RCTs with follow-up between 8 and 52weeks were included
[19]. In comparison, RCTs including pharmacological anti-
depressants were able to show a treatment response after
2–4weeks [44]. As there is currently no rationale for defin-
ing a minimal duration needed for significant antidepressant
effects of vitamin D, our study only allows to draw conclu-
sions regarding missing short-term effects of vitamin D sup-
plementation on self-rated depression, but it is not suited to
exclude beneficial longer-term effects. Additionally, it has
to be kept in mind that vitamin D supplementation was not
used as monotherapy in our study, but in addition to TAU
which has a separate effect on depressive symptoms. An
unbiased examination of the vitamin D supplementation
effect was achieved by using TAU in both study groups.
However, our study only allows to draw conclusions regard-
ing vitamin D supplementation as adjunctive therapy, but not
as monotherapy for depressive symptoms.
The heterogeneity of depression and depressive symp-
toms as well as of their specific underlying pathophysiologic
mechanism could represent another explanation for the lack
of a positive finding in our studies. Furthermore, the antide-
pressant effects of vitamin D supplementation may be par-
ticularly apparent at more severe stages of depression. In line
with this hypothesis, Shaffer and colleagues observed statis-
tically significant effects only in a subgroup analysis of two
studies in participants with clinically significant depressive
symptoms, while five studies without clinically significant
depressive participants did not show significant effects [36].
We, therefore, examined whether the intervention effect
differed according to BDI scores at baseline, but did not
observe a significant interaction. Accordingly, we cannot
confirm differing vitamin D effects according to baseline
depression severity in our study sample.
An alarming finding was the high prevalence of vitamin
D deficiency (and potential consequences especially for cal-
cium metabolism and bone health) in all patients screened
for this study. A direct comparison with the prevalence in the
general adolescent population in Germany is hampered by
the fact that a slightly lower cutoff for vitamin D deficiency
was used in the most recent representative study KIGGS
in Germany (i.e., 25nmol/l). Although both studies used
chemiluminescence immunoassay technology (DiaSorin
in KiGGS), differences in vitamin D analytics also make a
direct comparison difficult. With these limitations in mind,
the prevalence of vitamin D deficiency in our study was
high, since nearly 50% of all screened patients had 25(OH)
D levels ≤ 30nmol/l. In fact, 98 of the 280 screened patients
(35.0%) were below the cutoff of 25nmol/l applied in the
representative KiGGS study, which applied to only 20% of
the participants from the general population [5]. Likewise,
117 adult psychiatric outpatients in Sweden were exam-
ined with considerable lower median 25(OH)D levels than
reported in samples from healthy Swedish populations [45].
Further studies are needed to confirm whether patients from
psychiatric clinics might be a specifically vulnerable group
for vitamin D deficiency to draw conclusions whether analy-
sis of 25(OH)D levels should be integrated in psychiatric
clinical routine diagnostic.
In conclusion, results on potential antidepressant effects
of vitamin D supplementation remain conflicting. While
self-rated depression improved similarly in both the verum
and the placebo groups of this study, the observed differ-
ences in parent-reported depressive symptoms in favor of
vitamin D supplementation warrant attention. Therefore,
further RCTs in children and adolescents are needed which
should include a blinded clinician rating as the primary
instrument to assess depressive symptoms. Furthermore, a
study duration of more than 4 weeks would appear helpful
to allow detection of potential longer-term antidepressant
effects of vitamin D supplementation. Considering the fact
that almost 50% of the patients were found to be vitamin D
deficient, a routine screening in child and adolescent psychi-
atric patients needs to be debated further.
Acknowledgements Open Access funding provided by Projekt DEAL.
The authors thank the participants and their parents for their efforts
and the clinic and laboratory personnel for their support in conducting
the study.
Compliance with ethical standard
Conflict of interest The authors declare no conflict of interest. Dr. B.
Scheffler Nachf. GmbH & Co. KG provided vitamin D supplements as
well as placebo free of charge. The company was neither involved in
designing and conducting the study nor in data analysis, interpretation
and manuscript preparation.
Ethical approval and consent to participate This study was conducted
in accordance with the Declaration of Helsinki and with written
informed consent of the patients. For participants below 18years of
age, written informed consent was additionally obtained by parents or
assigned foster parents, respectively. All patients were informed that
participation was completely voluntary. The study was approved by
the local Ethics Committee of the University of Duisburg-Essen (No.
15–6363-BO).
Open Access This article is licensed under a Creative Commons Attri-
bution 4.0 International License, which permits use, sharing, adapta-
tion, distribution and reproduction in any medium or format, as long
as you give appropriate credit to the original author(s) and the source,
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were made. The images or other third party material in this article are
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3423European Journal of Nutrition (2020) 59:3415–3424
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