Differences in blood pregnenolone and
dehydroepiandrosterone levels between
schizophrenia patients and healthy subjects
Michael Ritsnera,b,⁎, Rachel Maayanc, Anatoly Gibela, Abraham Weizmanc,d
aSha'ar Menashe Mental Health Center, Mobile Post Hefer 38814, Israel
bBruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
cLaboratory of Biological Psychiatry, Felsenstein Medical Research Center, Beilinson Campus, Petah Tikva, Israel
dResearch Unit, Geha Psychiatric Hospital, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Received 4 May 2006; received in revised form 15 September 2006; accepted 5 October 2006
Background and objective: Contradictory and confusing reports on serum dehydroepiandroster-
one (DHEA) levels in schizophrenia led us to compare the serum concentration of its precursor,
pregnenolone (PREG), between medicated schizophrenia patients and healthy subjects. The
neurosteroid levels were monitored for two months and the relationship of these neurosteroids
with schizophrenic symptomatology, emotional distress, and anxiety was examined.
Method: We determined blood levels of PREG, and DHEA in 15 schizophrenia patients and 12
healthy controls at four time points: at the start of the study, after 2, 4 and 8 weeks. Analysis of
covariance and canonical correlations across four time points were applied.
Results: Controlling for age, serum concentrations of PREG were lower, while the DHEA level and
the molar ratio values of DHEA/PREG were higher in schizophrenia patients compared to healthy
controls. Both levels of PREG and DHEA and their molar ratio did not change significantly during
the study's period either among schizophrenia patients or healthy controls. The blood levels of
PREG appear to be associated with trait-anxiety scores in the schizophrenia patients, while
associations of clinical symptoms with two neurosteroids did not reach a significant level when
the confounding effect of emotional distress, and anxiety scores was controlled.
Conclusion: Low serum pregnenolone concentrations in schizophrenia appear to be associated
with trait-anxiety scores independent of symptoms. Further research into the role of
pregnenolone in schizophrenia is warranted.
© 2006 Elsevier B.V. and ECNP. All rights reserved.
Pregnenolone (PREG) and its principal metabolite dehydroe-
piandrosterone (DHEA) are neurosteroids: they have
⁎ Corresponding author. Sha'ar Menashe Mental Health Center,
Mobile Post Hefer 38814, Hadera, Israel. Tel.: +972 4 6278750; fax:
+972 4 6278045.
E-mail address: firstname.lastname@example.org (M. Ritsner).
0924-977X/$ - see front matter © 2006 Elsevier B.V. and ECNP. All rights reserved.
European Neuropsychopharmacology (2007) 17, 358—365
allosteric modulatory effects on the GABAA, NMDA and sigma
receptors (Holsboer et al., 1994; Baulieu, 1997; Rupprecht,
1997). Because disturbances of neurotransmission mediated
by GABA and NMDA are prominently implicated in the
pathophysiology of schizophrenia and other major psychiat-
ric disorders, a strong rational exists for examining differ-
ences in levels of neurosteroids between patients and
appropriately matched control subjects. Further, recent
evidence shows that neurosteroids modulate hippocampal
neurogenesis (Mayo et al., 2001), consistent with a neuro-
developmental lesion affecting the normal lamination of the
brain in schizophrenia; thus, neurosteroids may be involved
in the neurodevelopmental lesion.
Current knowledge concerning PREG metabolism, the
enzymes mediating these reactions, and their localization
has been summarized in recent publications (Compagnone
and Mellon, 2000; Stoffel-Wagner, 2003). Briefly, PREG is
derived from cholesterol in which the side chain is cleaved
by cytochrome P450scc (Le Goascogne et al., 1987), now
referred to as CYP11A1 (Flier and Foster, 1998). Cyto-
chrome P45017a (17a-hydroxylase/17,20-desmolase) cata-
lyzes the synthesis of DHEA from PREG. PREG is present in
human post-mortem brain tissue at considerably higher
concentrations than typically observed in serum or plasma
(Marx et al., 2006). Furthermore, PREG was found in the
brain, at concentrations of about 1 order of magnitude
larger than those of DHEA, as might be expected from a
precursor-to-product relationship. The concentrations of
PREG and of its sulfate ester (PREGS) were of the same
order of magnitude, and about 10-fold larger than in
Therapeutic use of PREG has been considered in neuro-
degenerative diseases, peripheral nerve damage, epilepsy
and substance dependence (Akhondzadeh and Stone, 1998;
Gasior et al., 1999; Rupprecht, 1997). PREG treatment
appears to be safe and well-tolerated (Pincus and Hoagland,
1944; McGavack et al., 1951; Meieran et al., 2004).
Previous clinical studies demonstrated low levels of PREG
in the elderly, including those with dementia (Roberts and
Fitten, 1990), and in individuals with major depression
(George et al., 1994), while depressed women suffering
from anxiety-depressive disorder treated with fluoxetine
showed significantly higher values of plasma PREG levels
compared to the control group (Bicikova et al., 2000).
Reported findings demonstrate that male patients (n=8)
with generalized anxiety disorder have significantly lower
Similarly, PREGS levels were significantly lower in 12 non-
medicated male patients with generalized social phobia than
2002). Serum concentrations of PREGS were significantly
matched 43 healthy controls. By contrast, in 22 patients with
hyperthyroidism, serum PREGS concentrations were signifi-
cantly higher (Tagawa et al., 2000). Among schizophrenia
patients previous studies have demonstrated either low
(Tourney and Hatfield, 1972; Oertel et al., 1974; Harris et
al., 2001), elevated (di Michele et al., 2005; Strous et al.,
2004; Ritsner et al., 2006) or no differences in DHEA levels
(Brophy et al., 1983; Ritsner et al., 2004) compared to
matched healthy controls. Since the biological activity of
of both these neurosteroids among schizophrenia patient is
To the best of our knowledge, no study has been
conducted assessing blood PREG levels among schizophrenia
patients in comparison with healthy controls. Therefore, the
aim of this study was, firstly, to compare blood PREG and
DHEA levels in schizophrenia patients with healthy controls
over two months, and, secondly, to test the relationship
between the level of these neurosteroids and psychopatho-
logy, emotional distress and anxiety measures within the
2. Experimental procedures
2.1. Data collection
We tested serum from medicated patients meeting the DSM-IV
criteria for schizophrenia, recruited from Sha'ar Menashe Mental
Health Center, and stabilized enough to provide informed consent
for participation in the study. The patients were treated with stable
doses of antipsychotics for the 8-week duration of the study. The
control group consisted of healthy volunteers with a similar age
distribution. Patients who had received antidepressants up to one
month prior to the investigation and patients who suffered from
major physical illness, drug or alcohol abuse, epilepsy and other
organic brain syndromes were excluded from the study. All patients
underwent physical and neurological examinations including ECG
and EEG, as well as routine laboratory tests to rule out physical
illness. Blood collection and assessments of patients and controls
were performed at baseline, after 2, 4 and 8 weeks (end-of-study).
The Institutional Review Board approved the study. All participants
provided written informed consent for participation in the study
after having received a detailed explanation of the study
Fifteen schizophrenia patients (13 men, 2 women) and 12 healthy
volunteers (8 men, 4 women) matched for age (37.9±10.3 vs. 37.4+
9.5 years, respectively) and weight (73.2±5.1 vs. 71.4±4.6 kg,
respectively, z=1.1, p=0.23), body mass index (22.1±1.9 vs. 21.5±
1.1 kg/m2, respectively, z=1.3, p=0.18), and menstrual history,
participated in this study. A total of 3 out of 15 schizophrenic
patients were married, 11 were single, and 1 was divorced. Twelve
patients met DSM-IV criteria for paranoid type, 2 residual type, and 1
disorganized type. Demographic background, and clinical informa-
tion for the patient sample is provided in Table 1.
Patients were treated with one or more antipsychotics, and
were allowed to receive benzodiazepines, and anti-parkinsonian
medications. Overall, 7 patients received first-generation antipsy-
chotic agents (FGAs; haloperidol, perphenazine, zuclopenthixol,
haloperidol decanoate, zuclopenthixol decanoate, and flu-
penthixol decanoate), 3 patients received second generation
antipsychotics (SGAs; olanzapine=15 mg/day, risperidone=4 mg/
day, and clozapine=350 mg/day), and 5 received both types of
antipsychotics (CAs; combined agents) foratleast onemonth priorto
and for the entire duration of this investigation. Patients were
treated with stable doses of antipsychotics at least 2 weeks prior to
entering the study and during the course of the study. All patients
were physically healthy, with normal physical examinations, blood
and urine laboratory tests in the normal range; they did not receive
The control group consisted of 12 healthy male and female
volunteers mean age 37.4 years (SD=9.5), who had no current
medical or psychiatric illness. Subjects with personal or family
359 Serum pregnenolone and DHEA in schizophrenia
history of psychiatric illness or personal history of substance abuse
were excluded. Patients and controls were cigarette smokers and
closely matched for age (37.9±10.3 vs. 37.4±9.5 years, respective-
ly; t=0.1, p=0.87).
Patients were diagnosed with DSM-IV schizophrenia following
interviews with senior psychiatrists (A.G., M.R.), using the
Structured Clinical Interview for DSM-IV Axis I Disorders, Patients
Edition (First et al., 1995). Clinical evaluation of patients was
performed using the Positive and Negative Symptom Scale (PANSS)
(Kay et al., 1987). The PANSS five-factor model was used for
analysis: positive, negative, activation, dysphoric mood and
autistic preoccupations (White et al., 1997). Raters were trained
and reached an acceptable level of inter-rater reliability for the
primary diagnosis, and PANSS (kappa: 0.92, and 0.87, respective-
ly). Psychometric evaluation was performed with the following
self-report questionnaires: the State-Trait Anxiety Inventory (STAI;
Speilberger, 1977), and the Talbieh Brief Distress Inventory (TBDI;
Ritsner et al., 2002). For the present study self-report instruments
demonstrated high reliability (Cronbach's α): STAI (α=0.79−0.82),
and TBDI index (α=0.89).
2.4. Hormone assays
Patients and healthy controls were controlled for time of
awakening, morning activity, caffeine consumption and smoking,
factors that can affect morning neurosteroid levels. Serum
samples were collected from all participants between 8.00 and
9.00 a.m. to avoid possible diurnal rhythm variations, after 20 min
of rest, before smoking a cigarette. Subjects were instructed to
abstain from unusual physical activity or stress for a period of
24 hours prior to blood sampling. DHEA was determined using the
DHEA-DSL 9000 Active TM DHEA coated tube radioimmunoassay
(RIA) kit (Diagnostic Systems Laboratories, Webster, Texas, USA).
The detection limit of the assay is 0.02 ng/ml; assay variability is
10.2% between runs and 5.6−10.6% within runs according to the
level of DHEA in the sample; cross-reactivity with other steroids is
PREG was measured using a modification of the commercial ICN
RIA kit (Biochemical, Inc., CA, USA). 0.1 ml 1:10 3H-PREG from the
RIA kit were added to 0.6 ml serum as an internal standard and were
extracted with 6.0 ml hexane. The hexane phase, which included
free PREG, was separated, evaporated, and the free steroids were
dissolved in 0.5 ml isooctane (2,2,4 trimethyl pentane; Sigma, USA.).
PREG was separated from other similar steroids by chromatography
using microcolumns (150×8 mm; volume 4.5 ml) packed with 1.0 ml
lipidex-5000 (Sigma,USA)whichhadbeensoakedinmethanol forthe
several preceding days. The columns were washed twice with
isooctane before the samples were added. After the addition of
each sample, 3 ml of isooctane, followed by 2 ml of 5% ethyl acetate
in isooctane were infused through the column and discarded. An
additional 7 ml were collected and vaporized, and the residue was
dissolved in 1.2 ml steroid diluent (provided by the RIA kit). 0.5 ml
were used for recovery and 0.5 ml were assayed according to the RIA
protocol (recovery of extraction and chromatography was about
65%). Before assaying the samples, the volume of extraction and the
point at which PREG is extracted were rechecked using two serum
samples containing 500–1000 cpm 3H-PREG and the radioactivity
count of each ml extraction was determined separately. Lowest level
variability 15% between runs, 10% within runs, according to level.
clinical characteristics of schizophrenia patients (N=15)
Sociodemographic, background and baseline
Age of onset, years
Number of admissions
Length of stay in hospital, months
Duration of illness, years
DHEA concentration (nmol/L)
Pregnenolone concentration (nmol/L)
patients and healthy controls over time (mean±SE). A. Pregneno-
lene. B. Serum DHEA levels.
Serum pregnenolone and DHEA levels in schizophrenia
360 M. Ritsner et al.
2.5. Data analysis
In addition to serum concentrations of the steroid hormones studied,
their product/precursor DHEA/PREG molar ratio was calculated.
Doses for antipsychotic agents were converted into Defined Daily
Dose (DDD) defined by the WHO Collaborating Center for Drug
Statistics (WHO, 2000). On the first step, the two-sample Hotelling's
test was applied to compare differences between patients and
healthy subjects in the mean values of three hormonal variables
(PREG, DHEA, and molar ratio) across four time points. This test is
used when the number of response variables are two or more. After
that, the general linear model of three-way analysis of covariates
(ANCOVA) was applied to assess the main effect of the mental health
state (first factor: membership to patients or healthy controls) by
time (second factor: four time points) and sex (third factor) on
hormonal measures controlling for age. Next, two-way ANCOVA
model was used to test differences in hormonal concentrations and
molar ratio among three subgroups of patients received various
types of antipsychotic agents. Finally, in order to avoid the effect of
multiple statistical comparisons, canonical correlations or the
multivariate extension of correlation analysis for study the linear
relations between two sets of variables, was used. It provides the
most general multivariate framework. For example, canonical
correlation finds a weighted average of five PANSS factor ratings
and correlates this with a weighted average of the serum hormone
concentrations across four time points. The weights are constructed
to maximize the correlation between these two averages. Thus, we
evaluated canonical correlations across four time points as follow-
ing: (a) between five PANSS factor ratings (White et al., 1997) and
serum hormone concentrations (PREG and DHEA) before and after
controlling distress and anxiety scores, and (b) between distress and
anxiety scores and serum hormone concentrations (PREG and DHEA)
before and after controlling for five PANSS factor ratings. Canonical
correlation finds canonical variates of the variables, and their
correlates with canonical variates. The term variate is used to refer
to variables that are constructed as weighted averages of the
original variables. Canonical correlation analysis assumes linear
relations among the variables, but does not make strong normality
assumptions. A rule of thumb is for variables with correlations of
0.30 or above to be interpreted as being part of the canonical
variate, and those below not to be considered part of the canonical
variate. Differences between groups on continuous variables were
evaluated with two-tailed t-tests. NCSS-2000 PC program (Hintze,
1998) was used for all analyses.
According to Hotelling's test schizophrenia patients had
significantly decreased PREG (1.26±0.7), increased serum
DHEA (52.1±27.9) levels, and DHEA/PREG molar ratio (51.9±
34.7) compared to healthy subjects across four time points
(1.64±1.0, t=4.6, p=0.033; 39.8±21.2, t=6.0, p=0.016;
and 34.2±23.6, t=8.6, p=0.004, respectively). In three-way
ANCOVA model with controlling for age and sex serum PREG
levels remain significantly and stably decreased, while the
serum levels of DHEA and ratio of DHEA to PREG were
significantly and stably elevated over the four time points:
PREG (F=4.6, df=1,104, p=0.035), DHEA (F=5.7, df=1,104,
p=0.019) levels, and DHEA/PREG molar ratio (F=6.3,
df=1,104, p=0.014) (Fig. 1). No significant ‘group×time’
interactions (F=0.01−0.39, df=3,104, all pN0.05) or main
gender effect (F=0.01−0.70, df=1,104, all pN0.05) were
found. A confounding effect ofage was noted regarding DHEA
concentrations (F=13.8, df=1,104, pb0.001), and DHEA/
PREG ratio (F=6.4, df=1,104, p=0.013).
Psychometric properties were compared between
patients and controls as depicted in Table 2. As expected,
during the two-month period of the study schizophrenia
patients reported higher emotional distress, and anxiety (all
pb0.001) compared to healthy subjects, with significant
improvement in the state-anxiety scale (pb0.05). Symptom
severity as measured by five PANSS factor scores did not
change significantly from baseline to the end-of-study
(F=0.4−2.1, df=3,60, all pN0.05).
As can be noted in Table 3, before controlling for
emotional distress and anxiety scores the association of
PANSS dysphoric mood, positive and activation symptoms
with PREG and DHEA on the first pair canonical variate was
Table 2 Psychometric properties in the schizophrenia patients and healthy controls
Weeks MeanSD MeanSDFpFpFpFp
42.2 0.0011.6 0.196.20.01013.8 0.001
State-anxiety 13.4 0.0012.9 0.0462.5 0.12 0.80.37
Trait-anxiety 21.3 0.0011.2 0.333.1 0.0870.4 0.51
aThree-way ANCOVA model: first factor — between-group comparison (membership to patients or healthy controls), second factor —
time effect (across four time points), third factor — sex, and confounding variable — age (years).
361Serum pregnenolone and DHEA in schizophrenia
significant (R2=0.46, F=4.2, df=10,98, pb0.001). However,
when the confounding effect of distress and anxiety scores
was controlled, correlations of these symptoms were below
0.30, and, thus, they not to be considered as significant part
of the canonical variate.
On the other hand, emotional distress (r=0.58) and state-
and trait-anxiety scores (r=0.44 and 0.39) together with
serum DHEA (r=0.60), but not PREG (r=0.12) levels were
positively associated with canonical first variate (R2=0.37,
F=5.0, df=9,96, pb0.001; Table 4). After controlling for
symptom severity ratings, only trait-anxiety and serum PREG
concentrations remand correlated with first canonical
variate (R2=0.19, F=2.4, df=6,86, p=0.034).
Lastly, two-way ANCOVA was performed to test differ-
ences in hormonal concentrations and molar ratio among
three subgroups of patients (7 patients received FGAs, 3
patients received SGAs, and 5 received CAs) across four time
points controlling for two variables (dosage as DDD and age).
Dosage of antipsychotic agents (DDD) was FGAs=2.0±1.7,
SGAs=0.9±0.6, and CAs=2.4±1.4 (F=1.6, df=2,60, p=0.27).
DHEA/PREG molar ratio (F=1.1, df=2,60, p=0.93), serum
concentrations of PREG (F=1.3, df=2,60, p=0.64) and DHEA
(F=1.8, df=2,60, p=0.17) did not reach a significant level
between patients who received FGAs, SGAs, and both types of
To the best of our knowledge, this is the first report
associating serum PREG levels and DHEA/PREG molar
ratio with schizophrenia. During the two-month study
period, improvement on the state-anxiety scale was
observed while severity of symptoms did not change
significantly. The main results of this study are that: (a)
serum concentrations of PREG are significantly lower in
schizophrenia patients compared with healthy controls,
while the levels of DHEA and the DHEA/PREG molar ratio
are higher; (b) within-and between-groups hormonal
differences remained stable throughout the study; (c)
serum pregnenolone concentrations appear to be associ-
ated with trait-anxiety scores independent of schizophre-
nia symptoms; and (d) correlation between serum DHEA
levels and severity of symptomatology is related to
emotional distress and anxiety scores.
Low levels of serum PREG, as observed in our
schizophrenia patients were reported previously in
patients with dementia (Roberts and Fitten, 1990),
generalized anxiety disorder (Semeniuk et al., 2001)
and social phobia (Heydari and Le Melledo, 2002). Our
finding of elevated serum DHEA levels among schizophre-
nia patients is in accord with previous similar observa-
tions in first-episode, and chronic schizophrenia patients
(Strous et al., 2004; di Michele et al., 2005). Inconsis-
tency in studies investigating DHEA serum levels (un-
changed or decreased) in schizophrenia (Tourney and
Hatfield, 1972; Oertel et al., 1974; Brophy et al., 1983;
Harris et al., 2001; Ritsner et al., 2004) may be related
to wide clinical polymorphism, variability of psychometric
properties (distress, anxiety), drug treatment (typicals,
atypicals and combinations), clinical responsivity of
schizophrenia patients to their antipsychotic treatment,
small sample sizes, or differences in age, gender, drug
abuse/smoking and duration of illness of patients enrolled
in the studies (Ritsner et al., 2005, 2006).
A further important finding of the study demonstrates that
correlation between serum DHEA levels and severity of
hormones' concentrations with severity of symptoms across
four time points
Summary of canonical correlation analysis of
Canonical variates Correlation of PANSS factors
Canonical R2 a
aThe R2of the canonical correlation coefficient gives the R2
value of fitting the PANSS, distress, and anxiety canonical
variate to the corresponding neurosteroid canonical variate.
hormones' concentrations with emotional distress, and
anxiety across four time points
Summary of canonical correlation analysis of
Canonical variatesCorrelation of distress and
anxiety with neurosteroids
First SecondFirst Second
Canonical R2 a
aThe R2of the canonical correlation coefficient gives the R2
value of fitting the PANSS, distress, and anxiety canonical
variate to the corresponding neurosteroid canonical variate.
362M. Ritsner et al.
and anxiety scores that may explain the discrepency between
reports (Harris et al., 2001; Shirayama et al., 2002; Ritsner et
al., 2004, 2005, 2006; Strous et al., 2001). The possible
involvement of PREG and DHEA in depression, anxiety
disorders, and responses to different stress stimuli are well
documented (see Dubrovsky, 2005). It is still possible that
antipsychotic medication may affect neurosteroids levels
levels (Nechmad et al., 2003; Ugale et al., 2004). However,
we did not find main effect of type (second vs. first
generations) and dosage of antipsychotic agents on PREG and
The molecular mechanisms underlying the regulation of
PREG conversion to DHEA in schizophrenia are still unclear.
There could be an increase in P450-17alpha-hydroxylase
activity (DHEA/PREG molar ratio) converting PREG to DHEA.
A growing body of evidence indicates that PREG can
influence neuronal activity and behavior. Both PREG and
DHEA improve posttraining memory when injected into
limbic structures of the mouse brain (Flood et al., 1995).
PREG displays mixed modulatory effect (positive and
negative) on the GABAAreceptor (Majewska, 1992; Bitran
et al., 1995) and neuromodulatory effects on NMDA (Monnet
et al., 1995), sigma-1 (Bergeron et al., 1996) receptors. The
antiglucocorticoid properties of DHEA (Bradlow et al., 1999)
combined with the neuromodulatory effects on brain GABAA,
NMDA and sigma-1 receptors (Debonnel et al., 1996;
Rupprecht, 1997; Wen et al., 2001) may contribute to
symptom severity, response to stress, anxiety, aggressive
behavior, learning and memory (Rupprecht and Hoelsboer,
Studies in animals have suggested that PREG has anti-
depressive (Reddy et al., 1998) and anxiolytic (Melchior and
Ritzmann, 1994) effects. Thus it is possible that the
combination of decreased PREG (a negative GABAAmodula-
tor; Meieran et al., 2004) and elevated DHEA (a weak
negative GABAAmodulator, Deuster et al., 2005) levels may
result in decreased GABAergic tone, contributing to dyspho-
ria and anxiety.
Systemic or intra-cerebral administration of PREG and
PREGS enhance memory in rodents by increasing the animal's
natural performance, or by antagonizing pharmacologically-
induced amnesia (Melchior and Ritzmann, 1996). PREG
treatment during the neonatal period influences the cortical
dopaminergic and adenosinergic systems as well as behav-
ioral responses of rats (Muneoka et al., 2002). Thus, these
neurosteroids may play a significant role in schizophrenia
due to PREG and DHEA effects on excitatory and inhibitory
Limitations of the study include the relatively small
sample size of patients and use of polypharmacotherapy and
benzodiazepine, a relatively small number of healthy control
subjects, the lack of a parallel group of untreated schizo-
phrenia patients as well as the short duration of the follow-
up (two months). Since schizophrenia is a chronic disorder
with various different clinical signs and symptoms and a
fluctuating course, a long-term follow-up is needed to
substantiate our findings.
In conclusion, altered serum PREG and DHEA levels appear
to be associated with anxiety and emotional distress scores,
but not with schizophrenia symptoms. PREG and DHEA/PREG
ratio may represent a trait-like marker of impaired hormonal
response to stress in schizophrenia. Although, the role of
PREG and DHEA in non-specific response to distress and
anxiety or in the pharmacotherapy of schizophrenia is as yet
unclear, this report adds evidence to the assumption that, for
example PREG and DHEA concentrations, are not related to
specific diagnoses, but to more general psychological states,
like anxiety, that can occur in various disorders. A further
longitudinal large-scale case-control comparison ofPREG and
DHEA levels in treated and an untreated, as well as, in
washed-out schizophrenia patient is warranted.
The authors acknowledge the dedicated editorial assistance
of Sara Dominitz.
Statement of interest: None of the authors has a conflict
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