Science of the Total Environment 882 (2023) 163303

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Science of the Total Environment

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Estimating the prevalence of depression using wastewater-based

epidemiology: A case study in Qinghai Province, West China
Haijian Lu 1, Jingpu Fan 1, Changsheng Guo, Jiangtao Yang, Heng Zhang, Miao Chen, Yang Liu,
⁎
Wenxiu Liu, Jian Xu
State Key Laboratory of Environmental Criteria and Risk Assessment, Chinese Research Academy of Environmental Sciences, Beijing 100012, China
State Environmental Protection Key Laboratory of Ecological Effect and Risk Assessment of Chemicals, Chinese Research Academy of Environmental Sciences, Beijing 100012, China

H I G H L I G H T S G R A P H I C A L A B S T R A C T

• Antidepressant consumption and preva-

lence were estimated using wastewater-
based epidemiology.
• The prevalence of depression in Qinghai
Province in Northwest China was 17.8 %.
• SSRIs and SNRIs were the most commonly
used antidepressants in the study area.

A R T I C L E I N F O A B S T R A C T

Editor: Jay Gan Wastewater-based epidemiology (WBE) is considered a cost-effective alternative approach capable of determining the
consumption and prevalence of drug use in communities, however, the application of WBE for estimating the preva-
Keywords: lence of depression has seldom been reported. In this study, the prevalence of antidepressants was estimated in five
Antidepressants cities in Qinghai Province, west China to examine the feasibility of using WBE to estimate the depression prevalence.
Wastewater-based epidemiology
Residual concentrations of the drugs varied from different wastewater treatment plants (WWTPs) in five cities.
Depression
Prevalence
Venlafaxine (0.06–720 ng/L), O-desmethylvenlafaxine (1.31–1659 ng/L), paroxetine (<LOD-69.9 ng/L), sertraline
Qinghai Province (0.20–3.36 ng/L), and nortriptyline (<LOD-50.8 ng/L) were in the top concentrations quartile in the influent samples
of 17 WWTPs. Back-calculation estimated venlafaxine (538 mg/1000 inh/d) as the most consumed antidepressant in
Qinghai Province, followed by paroxetine (159 mg/1000 inh/d), sertraline (150 mg/1000 inh/d) and amitriptyline
(97.2 mg/1000 inh/d). The prevalence of depression was 17.8 % based on antidepressant usage (2.50 %), which
was consistent with the data conducted by traditional survey (16.7 %). Risk assessment showed that fluoxetine,
citalopram and venlafaxine in effluents might cause ecological risks to aquatic environment. This study provided a
promising way for monitoring antidepressant usage and depression prevalence through WBE, which would improve
the understanding of depression disease and provide guidance for public health care.

1. Introduction
⁎ Corresponding author at: State Key Laboratory of Environmental Criteria and Risk
Assessment, Chinese Research Academy of Environmental Sciences, Beijing 100012, China.
Depression is one of the most common psychological disorders that can
E-mail address: xujian@craes.org.cn (J. Xu). lead to suicide in severe cases. According to the World Health Organization,
1
The first two authors contributed equally to this study. depression was the third cause of disease burden globally in 2008, and it is

http://dx.doi.org/10.1016/j.scitotenv.2023.163303
Received 4 February 2023; Received in revised form 31 March 2023; Accepted 1 April 2023
Available online 11 April 2023
0048-9697/© 2023 Elsevier B.V. All rights reserved.
H. Lu et al.
predicted to become the first cause by 2030 (Malhi and Mann, 2018). Cur-
rently, approximately 350 million people worldwide are suffering from de-
pression (World Health Organization, 2017). The China Mental Health
Survey shows that the lifetime prevalence of depression among adults is
6.8 %, which means that the number of people suffering from depression
is currently over 95 million in China (Lu et al., 2021). The prevalence of
depression among children and adolescents in China was reported to be
22.2 % (Li et al., 2019).
Traditionally, data related to depression is derived from questionnaire-
based surveys (The Nine-item Patient Health Questionnaire PHQ-9, the Self-
rating Depression Scale SDS, and the depression subscale of the Symptom
Checklist-90-Revised SCL-90-R) or clinical cases and reports. However, these
approaches are usually costly, and the results may suffer from update latency
and survey biases, resulting in the underestimation of actual prevalence of de-
pression. By analyzing the parent drugs and metabolites of legal or illegal sub-
stances and other chemicals in domestic wastewater, the patterns of human
consumption of drugs and chemicals can be obtained by wastewater-based ep-
idemiology (WBE). WBE has many advantages, including more frequently col-
lected data (Wang et al., 2020a, b), more objective, accurate, and real-time
data (van Nuijs et al., 2011; Zuccato et al., 2005), and the avoidance of biases
caused by self-reporting in traditional survey method. WBE can also describe
national-level temporal and spatial consumption trends to investigate the con-
sumption patterns of drugs (Daglioglu et al., 2021; Du et al., 2015), and even
further reveal the prevalence of diseases (Hou et al., 2020; Xiao et al., 2019).
In recent years, the abuse or consumption of methamphetamine (Zheng et al.,
2021), cocaine (Zuccato et al., 2005), alcohol (Kuloglu Genc et al., 2021), to-
bacco (Asicioglu et al., 2021), metformin (Xiao et al., 2019), lamivudine (Hou
et al., 2020), and phthalate (Du et al., 2018) have been estimated using WBE.
Antidepressants are a large class of psychoactive pharmaceuticals with sig-
nificant therapeutic effects on the clinical symptoms of depression. Currently,
selective serotonin reuptake inhibitors (SSRIs) represented by sertraline and
citalopram, and serotonin and norepinephrine reuptake inhibitors (SNRIs)
represented by venlafaxine, are widely used in patients with depressive disor-
ders (Guo et al., 2020). Antidepressants are not completely metabolized and
absorbed by humans, and eventually enter the sewage as drugs or active me-
tabolites excreted from the body (Niu et al., 2022). A variety of antidepres-
sants and their metabolites can be found in the sewage and show high in-
sample stability, which can be used as biomarkers of WBE (Baker et al.,
2014; Boogaerts et al., 2019). WBE has been employed to estimate the con-
sumption of antidepressant drugs in US (Skees et al., 2018), UK (Baker
et al., 2014), and some other countries. However, the application of WBE for
estimating the prevalence of depression has seldom been reported. Addition-
ally, antidepressants in the surface water environment may exert adverse im-
pact to the ecosystem (Lei et al., 2017; Liang et al., 2021). For instance,
environmentally relevant concentrations of citalopram and venlafaxine
caused freshwater snails' foot detachment from the substrate (Fong and Hoy,
2012). Amitriptyline significantly inhibited the growth and development of
zebrafish embryos (Yang et al., 2014). The secondary sex characteristics of
adult male fathead minnows were significantly impacted by exposure to fluox-
etine, sertraline, and venlafaxine (Schultz et al., 2011).
In this study we selected Qinghai Province in west China as the target area,
because Qinghai Province is located in the Tibetan Plateau, and its environ-
ment is characterized by low temperature, low oxygen and strong ultraviolet
radiation, which are all proven risk factors for depression (Ma et al., 2016;
Yang et al., 2016). The objective of this research were to (1) determine the
levels of 18 antidepressants and metabolites in wastewater samples in five cit-
ies from Qinghai Province; (2) estimate the consumption of antidepressants
and the prevalence of antidepressants and depression using WBE, and (3) eval-
uate the ecological risks of antidepressants with risk quotient (RQ) method.
2. Materials and methods
2.1. Chemicals and materials
HPLC-grade acetonitrile (ACN) and methanol (MeOH) were purchased
from Fisher Scientific (Poole, UK). Formic acid (FA) (99 %) was purchased
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Science of the Total Environment 882 (2023) 163303
from Sigma-Aldrich (Steinheim, Germany). Concentrated hydrochloric acid
(HCl (aq)) and ammonium hydroxide (NH3·H2O) were purchased from J&K
Scientific (Beijing, China). Ultrapure water was produced by a Milli-Q ultra-
pure water system (Millipore, Bedford, USA). Waters Oasis MCX (150 mg,
6 cc) and HLB (500 mg, 6 cc) cartridges were purchased from Waters
(Milford, MA, USA). Glass microfiber filters (GF/F 0.7 mm) were purchased
from Whatman (Kent, UK) and polytetrafluoroethylene syringe filters
(0.22 μm) were purchased from Jinteng (Tianjin, China).
Eighteen antidepressants were investigated in this study, which were
mainly divided into 5 categories, including tricyclic antidepressants
(TCAs), SSRIs, SNRIs, noradrenergic and specific serotonergic antidepres-
sants (NaSSAs), and dopamine reuptake inhibitors (DRIs). Standards of
imipramine, clomipramine, trimipramine, amitriptyline, nortriptyline,
doxepin, melitracen, fluoxetine, fluvoxamine, paroxetine, sertraline,
citalopram, venlafaxine, O-desmethylvenlafaxine (desvenlafaxine), trazo-
done, hydroxybupropione, mianserin and mirtazapine, internal standards
(IS) of fluoxetine-D5 and fluvoxamine-D3 were purchased from Alta
Scientific Co., Ltd. (Tianjin, China), in ACN or MeOH (100 μg/mL).
Desvenlafaxine, nortriptyline and hydroxybupropione are metabolites of
venlafaxine, amitriptyline and bupropion, respectively. The basic proper-
ties of the selected drugs were listed in Table S1.
2.2. Sample collection and preparation
In September and October of 2021, both influent and effluent samples
in 17 wastewater treatment plants (WWTPs) were collected from five cities
in Qinghai Province (i.e. Xining (XN), Haidong (HD), Hainan (HN), Guoluo
(GL), and Haixi (HX)) using a JC-8000D automatic water sampler at a sam-
pling frequency of 50 mL/0.5 h for 24 h (Fig. S1). Information on the ser-
vice population and daily water inflow of the wastewater treatment plant
was listed in Table S2. All samples were placed into 4 L brown glass bottles,
stored at 4 °C and extracted within 24 h.
400 mL wastewater was vacuum filtered through glass microfiber filters
after adding 50 μL internal standards (100 ng/mL). Samples were adjusted
to pH 2 using HCl and loaded onto cartridges at a flow rate of 10 mL/min,
which were equilibrated with 5 mL of MeOH and 5 mL of Milli-Q water.
HLB and MCX cartridges were washed with 5 mL of 5 % MeOH in water
and 5 mL of Milli-Q water respectively. Target substances in HLB were eluted
with 8 mL of 2 % formic acid in MeOH, and in MCX with 8 mL of 2 % ammo-
nia in MeOH. The extract was concentrated under a weak nitrogen stream at
40 °C to nearly dryness, and reconstituted to 1 mL with 15 % ACN in water.
Samples were ready for analysis by ultra-high performance liquid chromatog-
raphy tandem mass spectrometry (UPLC-MS/MS) after being filtered with
0.22 μm polytetrafluoroethylene syringe filter. The peak areas of blank ultra-
pure water and influent wastewater with all target substances spiked at
100 ng/L pre- and post-SPE were compared to estimate the recovery (Fig. S2).
2.3. Analysis by UPLC-MS/MS
Sample analysis was accomplished by an ultra-performance liquid
chromatography tandem triple quadrupole mass spectrometer system
(Waters, Milford, MA, USA). The analytes were separated with a C18 column
(1.7 μm, 50 mm × 2.1 mm, Waters, MA, USA) at a flow rate of 400 μL/min.
Mobile phases were ACN (phase A) and ultrapure water with 0.1 % FA (phase
B). The composition of the mobile phase was programmed as follows: 0 min,
15 % A; 0–0.5 min, 15 % A; 0.5–1.0 min, 15–25 % A; 1.0–6.2 min, 25–55 % A;
6.2–6.4 min, 55–98 % A; 6.4–7.4 min, 98 % A; 7.4–7.6 min, 98–15 % A;
7.6–9.1 min, 15 % A. The oven temperature was 40 °C. The injection volume
was 5 μL. After every four samples, ACN was injected to wash away residues.
Samples were analyzed by a triple quadrupole mass spectrometer (Xevo TQ-S
micro IVD system, Waters, Manchester, UK) equipped with an electrospray
ionization source. Samples were quantitatively analyzed by using the positive
electrospray ionization (ESI+) ion source. The source and desolvation tem-
peratures were 150 °C and 500 °C, respectively. Nitrogen was used as the neb-
ulizing and desolvation gas, and the collision gas was argon. The cone gas flow
was 50 L/h. The desolvation gas flow was 1000 L/h.
H. Lu et al.
2.4. Calculation of antidepressants consumption and prevalence
The antidepressant consumption was estimated with Eq. (1) (Du et al.,
2015).
Ci  F j  RDW MWDrug 1 were used to ensure the accuracy of the results.
m¼    10−6 ð1Þ
Pj MWBiomarker Ei
where m is the daily antidepressant consumption per thousand people (mg/
1000 inh/d, the drug usage per 1000 inhabitants in one day); Ci is the con-
centration of antidepressants in influent of WWTP (ng/L); Fj is the flow rate
of WWTP (L/day); RDW is the proportion of domestic wastewater (%); Pj is
the population served by WWTP (×103 inhabitants); MWDrug is the molec-
ular weight of the target drug (g/mol); MWBiomarker is the molecular weight
of the biomarker (g/mol); Ei is the excretion rate of target drug excreted as
biomarker (%). Data are shown in Table S2 and S3. The antidepressants'
consumption in city was calculated from the weighted average of the pop-
ulation served by the WWTPs, as shown in Eq. (2).
mWWTP1  PWWTP1 mWWTP2  PWWTP2 mWWTPn  PWWTPn
mCity ¼ þ þ⋯þ
PTotal PTotal PTotal
ð2Þ
Antidepressants can increase the risk of suicidal ideation and suicidal
behavior in children, adolescents, and young adults (Hengartner, 2020;
Spielmans et al., 2020). The population over 15 years old was used to esti-
mate the prevalence of antidepressants in this study. Prevalence of antide-
pressants was calculated by Eq. (3) (Hou et al., 2020).
m to 96.4 % (HD1), with an average removal rate of 64.9 % (Fig. S3). SSRIs
PRover 15 ¼  100 (3)
Rover 15  D  1000
where PRover 15 is the prevalence of antidepressants in people over 15 years
old (%); Rover 15 is the percentage of people over the age of 15 in a city (%);
D is the average daily dose of antidepressants (mg/d). The calculation pa-
rameters mentioned above are shown in Table S2 and Table S3.
PRover 15
PRDepression ¼ (4)
RT
where PRDepression is the prevalence of depression (%); RT is the proportion
of depressive disorders currently receiving treatment, which was selected
as 14.5 % in western China (Qi et al., 2019).
2.5. Ecological risk characterization
The effluent from WWTPs in the study area was directly discharged into
nearby surface water, therefore RQ method was used to assess the ecologi-
cal risks to the freshwater ecosystem (Silva et al., 2014; Zhang et al., 2017).
The ecological risk was classified as high if RQ ≥ 10, moderate if
1 ≤ RQ < 10, low if 0.1 ≤ RQ < 1, and insignificant if RQ < 0.1 (Liu
et al., 2020). RQs were calculated as follows:
C among which the concentrations detected in XN1 and XN2 were higher,
RQ ¼ (5)
PNEC
where C is the concentration of antidepressants in effluent (ng/L); PNEC is
the predicted no effect concentration (ng/L) and is calculated as quotient of
the most sensitive toxicity concentration divided by assessment factors
(AF). The most sensitive toxicity data was searched from ECOTOX
Knowledgebase (https://cfpub.epa.gov/ecotox/search.cfm) developed by
the US EPA.
2.6. Quality control and statistical analysis
The target substances were identified based on the parent ion and the
most intensive ion production. Calibration solution concentrations were
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Science of the Total Environment 882 (2023) 163303
set to 13 concentration levels in the range of 0.01–100 ng/mL in 15 % aque-
ous solution of ACN, and the internal standard method was used for quan-
tification (Table S4). The limit of detection (LOD) and the limit of
quantification (LOQ) were determined based on a signal-to-noise ratio of
3 and 10, respectively. Procedure blanks and QC samples (10 ng/mL)
2.7. Uncertainty analysis
Considering that the calculated estimations are performed based on the
average of the input parameters, there is a certain degree of uncertainty in
the results. The uncertainty in this study was simulated by Monte Carlo
using Oracle Crystal Ball software (11.1.2.4). The final result was the distri-
bution of antidepressant and depression prevalence. The concentration of
antidepressants in sewage was taken from the actual measured data and
set as lognormal distribution. The uncertainty of the WWTPs flow and the
population were assumed to be 10 % of the mean value and set as normal
distribution. The excretion rate of drug was set to lognormal distribution.
The daily dose of drugs was set as lognormal distribution and the propor-
tion of the population over 15 years old was set as normal distribution.
3. Results and discussion
3.1. Occurrence of antidepressants in influents and effluents
Concentrations of the antidepressants in wastewater of 17 WWTPs were
illustrated in Fig. 1, Table S5 and Table S6. The concentration of antidepres-
sants ranged from 0.03 to 1659 ng/L with an average value of 25.8 ±
139 ng/L. The removal rate of antidepressants ranged from 16.0 % (GL2)
and SNRIs were the dominant antidepressant drugs in wastewater
(Fig. 2). Citalopram (3.38 ± 2.82 ng/L) and venlafaxine (56.2 ±
134 ng/L) were detected in all influents and effluents samples. Mirtazapine
(DF = 11.8 %, detection frequency), trimipramine (DF = 5.9 %) and imip-
ramine (DF = 5.9 %) were the pharmaceuticals only detected in influents.
The negative removal of venlafaxine, citalopram and sertraline occurred in
a few WWTPs, similar to the results of a WWTP in Beijing (Bian et al.,
2021), which may be due to the enhanced transformation of drug precur-
sors and metabolites by wastewater treatment plants (Subedi and Kannan,
2014). Combining the total population and economic data of five cities, it
was found that cities with larger populations and higher economies had
higher concentrations of antidepressants in wastewater samples.
3.1.1. TCAs
TCAs are typical antidepressants that have been used extensively in the
past. Their main pharmacological action is to block the reuptake of mono-
amine transmitters. Common TCAs include amitriptyline, imipramine,
and doxepin. Because of the adverse reactions of TCAs, it is no longer the
first choice for treating depression.
As shown in Tables S5 and S6, 7 TCAs (trimipramine, amitriptyline, nor-
triptyline, clomipramine, imipramine, doxepin, and melitracen) presented
concentrations varying from <LOD to 50.8 ng/L in WWTP influents,
while XN4 and GL1 were lower. Nortriptyline (6.36 ± 11.8 ng/L) and am-
itriptyline (2.37 ± 2.41 ng/L) were the main TCAs detected in influent
samples. In the effluents, 7 TCAs were all detected with concentrations
ranging from <LOD to 47.9 ng/L. The low concentration of TCAs could
be likely related to the low infrequency of use in clinics. TCAs concentra-
tions in Xining City (25.1 ± 16.7 ng/L) were higher than that in the
other four cities (0.72–6.58 ng/L). By contrast, the influent TCAs
concentrations of the 17 WWTPs were significantly lower than those re-
ported in WWTPs in Beijing (nortriptyline 35.0–47.8 ng/L, imipramine
10.6–10.9 ng/L, clomipramine 77.5–102 ng/L) (Sheng et al., 2014),
Santorini, Greece (amitriptyline 30.7–98.2 ng/L, doxepin 262–670 ng/L)
(Borova et al., 2014), and São Paulo State, Brazil (amitriptyline ND-
200 ng/L, nortriptyline ND-159 ng/L) (Pivetta et al., 2020).
H. Lu et al. Science of the Total Environment 882 (2023) 163303

Fig. 1. Concentration of TCAs, SSRIs, SNRIs, NaSSAs and DRIs in wastewater of 17 WWTPs.

3.1.2. SSRIs and SNRIs
SSRIs are new antidepressants used in the clinic, including fluoxetine,
paroxetine, sertraline and citalopram. Because of their high selectivity, single
target, low adverse reactions and high safety, SSRIs have become the first-
line drugs for the treatment of depression, accounting for nearly half of the
antidepressant market in China (Chen et al., 2018; Zhong et al., 2015).
SNRIs have dual effects of 5-hydroxytryptamine (5-HT) and noradrenaline
(NA) reuptake inhibition, and the representative drug is venlafaxine. SNRIs
have quick effects, a wide antidepressant spectrum and few adverse reactions
(Liu and Tong, 2016). Due to their rapidly expanding use in clinics, SSRIs and
SNRIs have drawn growing attention and concern.
Both SSRIs and SNRIs were ubiquitous in the influent and effluent
of the 17 WWTPs. Venlafaxine (ND-719 ng/L) and desvenlafaxine
(0.05–1658 ng/L) were the main components of antidepressants in waste-
water (accounting for 72.7 %) (Fig. 1), the concentration levels of which
were similar to those reported in WWTPs in Beijing (venlafaxine:
408 ng/L in influent, 165 ng/L in effluent), Canada (venlafaxine:
788–2982 ng/L in influent and 600–2563 ng/L in effluent; desvenlafaxine:
1850–4166 ng/L in influent and 1311–4042 ng/L in effluent) and Greece
(venlafaxine: 191–418 ng/L, average 289 ng/L) (Duan et al., 2018;
Lajeunesse et al., 2012; Thomaidis et al., 2016). In WWTP-HN2, the concen-
tration of venlafaxine and desvenlafaxine in wastewater was relatively low,

Fig. 2. Composition of antidepressants in influent and effluent samples.

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H. Lu et al. Science of the Total Environment 882 (2023) 163303

accounting for about 20 % of the total concentrations, which was different
from other WWTPs.
The concentrations of SSRIs in sewage (influent: ND-69.9 ng/L, effluent:
ND-9.75 ng/L, mainly paroxetine, sertraline and citalopram) were lower
than those in other studies, such as ND-173 ng/L for fluoxetine in Beijing,
China (Duan et al., 2018) and Sao Paulo State, Brazil (Pivetta et al.,
2020); ND-435 ng/L for fluvoxamine in Canada (Lajeunesse et al., 2012)
and Beijing (Yuan et al., 2013); ND-632 ng/L for paroxetine and ND-
716 ng/L for sertraline globally (Singh et al., 2019); ND-754 ng/L for
citalopram in Leiria, Portugal (Paiga et al., 2019) and Athens, Greece
(Thomaidis et al., 2016).
3.1.3. NaSSAs and DRIs
NaSSAs are a new class of antidepressants, which can promote the re-
lease of noradrenalin (NA) and 5-HT neurotransmitters and has a dual anti-
depressant mechanism. Mirtazapine, mianserin, and trazodone are three
representative NaSSAs. Bupropion (its metabolite is OH-bupropione) be-
longs to DRIs, and its main mechanism is to inhibit the reuptake of dopa-
mine and norepinephrine. In this study, DF of NaSSAs and DRIs in the
influent were 76.5 % and 82.4 %, respectively, and their concentrations
were in the range of ND-5.05 ng/L (trazodone) and ND-3.05 ng/L in influ-
ents, which were lower than the influent concentrations of WWTPs in
Germany (Gurke et al., 2015; Schluesener et al., 2015), Portugal (Paiga
et al., 2019) and Shanghai, China (Wu et al., 2015; Xiang et al., 2018).
This reflected the low use of NaSSAs and DRIs in the region.
3.2. Estimation of antidepressants' daily consumption
Table 1 showed the per capita consumption of antidepressants in Qing-
hai Province. Information on the excretion rate of some antidepressants
(mianserin, mirtazapine, trimipramine, clomipramine, and melitracen) is
lacking, and their consumption was not able to be estimated. In this
study, trazodone, venlafaxine, paroxetine, and sertraline had the highest es-
timated per capita consumption with mean values of 112, 538, 159 and
150 mg/1000 inh/d, respectively. The average consumption of citalopram,
fluoxetine, bupropion and fluvoxamine in Qinghai Province was <10 mg/
1000 inh/d. Antidepressant consumption was higher in Xining than in the
other four cities, and venlafaxine consumption was much higher than
other drugs. Additionally, venlafaxine consumption is twice as high when
calculated using venlafaxine as biomarker compared to desvenlafaxine. Ac-
cording to previous study, venlafaxine excretion rate was low, and if actual
values significantly differed from reference values, the results would be sig-
nificantly impacted (Baker et al., 2014). A more appropriate biomarker was
likely to be desvenlafaxine.
Generally, venlafaxine, citalopram, fluoxetine and sertraline are more
reported substances (Table 2). Antidepressant consumption in this study
was much lower than in the US (venlafaxine 351–6230 mg/1000 inh/d,
citalopram 263–1160 mg/1000 inh/d, fluoxetine 33.5–349 mg/1000
inh/d, sertraline 56.2–17,800 mg/1000 inh/d, and fluvoxamine
210–787 mg/1000 inh/d) (Croft et al., 2020; Montgomery et al., 2021;
Skees et al., 2018), UK (venlafaxine 1276 mg/1000 inh/d, amitriptyline
2153.6 mg/1000 inh/d, and fluoxetine 98 mg/1000 inh/d) (Baker et al.,
2014) and Portugal (citalopram 17.1 mg/1000 inh/d and fluoxetine
14.6 mg/1000 inh/d) (Silva et al., 2014). During the Corona Virus Disease
2019 (COVID-19) epidemic, the use of antidepressants in Turkey increased
significantly (Yavuz-Guzel et al., 2022), with venlafaxine as the drug with
the highest consumption (104 ± 112 mg/1000 inh/d), and its use rate in-
creased the most during the pandemic. The consumption for amitriptyline
(12.5–18.5 mg/1000 inh/d), bupropion (4.7–13.5 mg/1000 inh/d) and
fluvoxamine (ND-2.0 mg/1000 inh/d) found in four WWTPs in Belgium
(Boogaerts et al., 2019) was similar to this study. The results indicated
that antidepressants were widely used among the general population in
all regions.
3.3. Prevalence of antidepressants and depression
Many antidepressants are not allowed for use in children, so in this
study people over 15 years old were selected to estimate the prevalence
of antidepressants. The daily dose of antidepressants and the proportion
of the population over 15 years old in the study area were obtained from
the drug manual, New Materia Medica and the demographic yearbook
(Table S3).
Based on Eq. (3), the prevalence of antidepressants usage among inhab-
itants aged over 15 years was in the range of 0.0002 % (bupropion in Hai-
nan and Guoluo, and doxepin in Guoluo) to 1.58 % (venlafaxine in Xining)
(Table 3). In Xining, Haidong, Hainan and Haixi City, paroxetine, sertraline
and venlafaxine were the top three drugs in terms of prevalence. The prev-
alence of various antidepressants was added up, and the total prevalence
of antidepressants in Xining was the highest (3.81 %), and in Qinghai
Province was 2.50 %.
The prevalence of depressive disorders was estimated based on the
prevalence of antidepressants usage (Eq. (4)), with an average value of

Table 1
The mean consumption of antidepressants in the area served by WWTPs and city (mg/1000 inh/d).
Site AMI AMIa IMI DOX FLV FLX PAR SER CIT VEN VENa TRA BUP

XN1 44.6 466 2.7 38.0 7.6 2.2 427 242 3.6 3760 1311 115 1.5
XN3 7.1 12.7 – 6.9 – – – 26.1 1.2 41.9 19.2 – 1.5
XN4 – 1.8 – 2.7 2.0 – – 14.7 0.3 5.1 1.4 38.8 0.8
XN5 69.0 106 – 19.4 12.0 3.1 249 494 2.3 2003 1659 418 21.0
HD1 90.9 6.2 – 17.7 3.0 – 89.3 119 9.2 545 282 81.1 1.3
HD2 18.6 3.5 – 6.2 2.2 – 214 57.9 2.3 410 196 20.0 0.9
HD3 2.6 3.2 – 14.0 2.7 – – 40.7 2.9 71.6 83.0 70.7 0.5
HD4 19.2 – – – – – 0.8 10.0 0.3 15.7 8.1 – 0.6
HD5 16.5 99.6 – 4.5 – – 24.7 61.1 5.4 179 217 – –
HN1 11.7 25.1 – – 1.6 – 7.3 29.0 2.1 201 53.4 80.4 0.7
HN2 3.6 – – 0.3 – – 6.5 11.1 0.2 0.1 0.3 – –
GL1 – 0.7 – 1.3 – – – 17.1 0.6 1.6 0.8 – 1.0
GL2 – 6.0 – 0.6 – – – 7.8 0.3 1.1 1.3 9.4 0.4
HX1 61.6 50.5 – 7.7 – 0.7 396 106 2.6 397 311 203 1.0
HX2 7.5 18.5 – 49.9 8.8 1.1 19.8 106 5.0 123 78.3 73.3 7.1
Region
Xining 37.4 181 0.8 19.9 6.5 1.7 211 241 2.2 1810 940 176 7.7
Haidong 34.2 11.0 – 8.4 2.0 – 132 65.2 3.9 354 187 32.8 0.9
Hainan 7.6 12.5 – 0.2 0.8 – 6.9 20.1 1.1 100 26.8 40.2 0.3
Guoluo – 5.2 – 0.7 – – – 9.2 0.4 1.2 1.2 8.0 0.5
Haixi 30.2 32.0 – 32.2 5.1 0.9 178 106 4.0 238 176 128 4.5
Qinghai Province 31.6 97.2 0.4 15.3 4.3 0.9 159 150 2.6 1029 538 112 4.5
a
Consumption of the drug was calculated from the concentration of metabolite. Amitriptyline-nortriptyline; venlafaxine-desvenlafaxine. AMI: amitriptyline; IMI: imipramine;
DOX: doxepin; TRA: trazodone; BUP: bupropion; FLV: fluvoxamine; FLX: fluoxetine; PAR: paroxetine; SER: sertraline; CIT: citalopram; VEN: venlafaxine. - not detected.

5
H. Lu et al. Science of the Total Environment 882 (2023) 163303

Table 2
Consumption (mg/1000 inh/d) of antidepressants in various parts of the world.
Area Time MIA VEN TRI CIT PAR AMI DOX FLX CLO MEL TRA OHB SER FLV ODV Reference

Qinghai Province 2021 1029 2.6 159 97.2 15.3 0.9 112 150 4.3 538 This study
US 2018 (Croft et al., 2020)
Kentucky 4750 916 11,700 581
6230 1080 14,300 787
5450 1160 4030 210
Tennessee 2020 4995 789 297 7005 (Montgomery et al., 2021)
Kentucky 6068 979 349 17,800
US 2017 351 263 33.5 56.2 (Skees et al., 2018)
Belgium 2017 19.3 217 48.1 14.8 3.3 1.5 3.9 35.7 13.5 3.8 ND 553 (Boogaerts et al., 2019)
15.4 136 34.8 18.5 2.4 1.3 3.0 20.0 5.7 5.9 2.0 437
16.1 160 40.0 14.6 4.1 1.1 3.2 41.4 4.7 8.6 0.2 340
18.4 190 43.8 12.5 3.4 0.1 8.4 36.7 7.0 15.1 1.8 384
Turkey 2020 (Yavuz-Guzel et al., 2022)
Adana 5.5 123 9.7 25.1 0.5 9.0
Ankara 3.4 80.6 6.5 117 0.4 5.7
Diyarbakır 2.8 27.9 3.3 10.0 0.3 11.4
Erzurum 4.5 91.3 4.6 14.0 0.5 7.0
Gaziantep 4.8 106 15.4 29.9 0.5 10.3
Kayseri 5.0 361 17.0 28.4 0.6 9.1
Konya 3.8 104 10.0 34.8 0.9 9.2
Mersin 6.8 145 15.0 42.0 0.7 23.0
Şanlıurfa 3.1 41.7 2.1 10.0 0.3 4.5
Trabzon 3.3 70.0 10.6 43.5 0.6 12.1
Van 2.9 25.1 2.2 6.1 0.3 3.7
Slovakia 2013 (Mackul'ak et al., 2016)
Bratislava 86 21
Petržalka 72 29
Košice 61 34
Prešov 59 22
B. Bystrica 68 45
Zvolen 120 55
Trenčín 100 31
Piešťany 91 45
UK 2011 1276 2154 98.0 (Baker et al., 2014)
Portuguese 2014 17.1 17.5 14.6 1.4 (Silva et al., 2014)

TRI: trimipramine; AMI: amitriptyline; NOR: nortriptyline; CLO: Clomipramine; IMI: imipramine; DOX: doxepin; MEL: melitracen; TRA: trazodone; MIR: mirtazapine; MIA:
mianserin; OHB: OH-Bupropione; FLV: fluvoxamine; FLX: fluoxetine; PAR: paroxetine; SER: sertraline; CIT: citalopram; VEN: venlafaxine; ODV: desvenlafaxine.

17.7 % in Qinghai Province. The prevalence of depressive disorders in the
five surveyed cities was 27.0 % (Xining), 10.3 % (Haidong), 1.5 %
(Hainan), 0.3 % (Guoluo) and 13.2 % (Haixi), respectively. Due to the
low economic status of Hainan and Guoluo, the treatment rate for depres-
sion was lower than the average value of 14.5 %, as the drug concentration
in sewage was lower than LOQ. The RT was 9.5 % according to China's na-
tional survey in 2013–2015 (Lu et al., 2021; The Lancet, 2022), while the
population weight of Hainan and Guoluo was small, and it had little impact
on the prediction of the average prevalence of depressive disorders in Qing-
hai Province.
The Institute of Health Metrics and Evaluation counted the prevalence
of depressive disorders from 1990 to 2019, and reported that the preva-
lence of depressive disorders in China increased from 3.20 % to
3.67 % year by year (https://ghdx.healthdata.org/). The China National
Mental Health Development Report (2019–2020) released in 2021 pointed
out that the high-risk detection rate of depressive disorders in the western
region was 20.1 % (Fu et al., 2021), and in a cross-sectional study in
north-west China, 16.7 % of the participants were diagnosed (Guo et al.,
2017). According to a national survey on psychological distress during
the COVID-19 epidemic in China in 2020, 35 % of respondents experienced
anxiety and depression (The Lancet, 2022). The prevalence of depressive
disorders among the elderly in China's pension institutions was 41 %
(Ran et al., 2021). The overall prevalence of depressive disorders among
Chinese college students in the past decade was 31.2 % (Wang et al.,
2020a, b), and 15 %–26 % during the COVID-19 pandemic (Chang et al.,
2021; Deng et al., 2021; Luo et al., 2021). Although different investigator
age ranges and diagnostic criteria were used, these data documented a
large burden of depressive disorders in China.
3.4. Uncertainty analysis
The input parameters for Monte Carlo simulation were shown in
Table S7, and the probability distribution density was presented in Fig. S4
and Table 4. Prevalence of antidepressants and depressive disorders all fit

Table 3
Prevalence (%) of antidepressants in Qinghai Province.
City Amitriptyline⁎ Imipramine Doxepin Fluvoxamine Fluoxetine Paroxetine Sertraline Citalopram Venlafaxine⁎ Trazodone Bupropion Total
② ③ ①
Xining 0.216 0.001 0.024 0.008 0.010 1.262 0.577 0.025 1.579 0.105 0.003 3.81
Haidong 0.014 – 0.011 0.003 – 0.852① 0.169③ 0.050 0.340② 0.021 0.0004 1.46
Hainan 0.017 – 0.0002 0.001 – 0.045③ 0.053① 0.015 0.050② 0.027 0.0002 0.21
Guoluo 0.008② – 0.001 – – – 0.026① 0.005 0.002 0.006③ 0.0002 0.05
Haixi 0.039 – 0.040 0.006 0.006 1.092① 0.261③ 0.049 0.304② 0.078 0.002 1.88
Qinghai 0.117 0.001 0.019 0.005 0.005 0.969① 0.364③ 0.032 0.913② 0.068 0.002 2.50

-: no detected in samples.
The drugs marked with ①, ② and ③ are the prevalence top three in the region.
⁎ Consumption of the drug was calculated from the concentration of metabolite.

6
H. Lu et al. Science of the Total Environment 882 (2023) 163303

Table 4 mianserin at all sampling sites were <0.1, indicating a negligible risk.
Uncertainty analysis of the prevalence of depression in Qinghai Province. Citalopram and venlafaxine showed potential low or moderate risks in
Prevalence of depression Unit Probability Median Range CI several effluents. Only effluent from the WWTP-XN1 indicated a high eco-
distribution logical risk for nortriptyline, and the remaining effluents showed no risk.
Xining City % Lognormal 27.0 20.2–36.5 95 % Although the detection rate of fluoxetine in effluent was low (24 %), the
Haidong City % Lognormal 10.3 7.6–14.5 95 % ecological risks of fluoxetine were all at moderate level (1 ≤ RQ < 10),
Hainan City % Lognormal 1.46 1.07–2.04 95 % based on experimental LOEC data for zebrafish (Crago and Klaper, 2018).
Guoluo City % Lognormal 0.34 0.24–0.48 95 %
Fluvoxamine was only detected in the effluent of WWTP-HD3 with a mod-
Haixi City % Lognormal 13.2 9.49–19.0 95 %
Qinghai Province % Lognormal 17.8 13.6–22.9 95 % erate ecological risk (0.1 ≤ RQ < 1). Our research showed that venlafaxine
and citalopram have moderate or low risk, consistent with other studies
that high or moderate risk of these drugs occurred (Bian et al., 2021;
the lognormal distribution. The prevalence of antidepressants in Qinghai Fernández-Rubio et al., 2019; Lopez et al., 2022). Results in this study indi-
Province was ranging from 2.0 % to 3.3 % (CI: 95 %), with an average cated that the ecological risks of fluoxetine, citalopram and venlafaxine in
value of 2.6 %. The prevalence of depression in Qinghai Province was rang- the water environment deserved attention, and the combined effect of anti-
ing from 13.9 % to 22.9 % (CI: 95 %), with an average value of 17.7 %. The depressants to aquatic organisms required further study.
results were consistent with the estimation in Section 3.3.
The results of sensitivity analysis were presented in Fig. S5. The main 3.6. Limitations
sources of uncertainty for estimating depressive disorders prevalence
were daily dose (19.1 %), Rover 15 (18.9 %), population served by WWTPs There are a few limitations in the present study. Firstly, data from the
(18.7 %), excretion rate of drugs (18.6 %) and flow rate of WWTPs medical sector, such as the proportion of drugs used in clinical treatment
(18.6 %). Meanwhile, concentration of antidepressants contributed 6.0 % and drug excretion rates, are not available. The percentage of the dose
of total uncertainty to the final results. that was excreted in the urine as the excretion rate of drugs in this study
largely ignored the degradation and absorption of urine in the sewerage
3.5. Ecological risk assessment system. The chemical, physicochemical and biological degradation in the
actual sewer should be taken into consideration in further research for ac-
The most sensitive toxicity data of 11 antidepressants on non-target curate estimation of drug consumption. Secondly, estimates of depression
organisms were retrieved from the ECOTOX, and the RQ value of each sub- prevalence are based on total consumption of antidepressants; in the future,
stance at each sampling site was calculated according to the corresponding the percentage of clinical drug use should be identified so that estimates of
PNEC (Table S8). The antidepressant concentrations were calculated using depression prevalence can be made using a class of antidepressants, such as
measured values if greater than LOQ, 1/2 LOQ if <LOQ, 1/2 LOD if <LOD, SSRIs. Thirdly, depression treatment rate varies greatly in different regions
and 0 if not detected (Liu et al., 2020). As shown in Fig. 3, the RQ values for and populations in China. The treatment rate used in this study was 14.5 %,
amitriptyline, clomipramine, imipramine, paroxetine, sertraline, and which was an estimated average of the treatment rate of depression in

Fig. 3. RQ values of antidepressants in effluent of WWTPs.

7
H. Lu et al.
western China (Qi et al., 2019) and the value may differ significantly be-
tween cities, for example, in Guoluo City and Hainan City in this study.
Therefore, more research is needed to obtain abundant data such as the
treatment rate of depression, which requires joint efforts from multiple
parties.
4. Conclusions
In this study, the prevalence of depression was successfully estimated by
WBE in Qinghai Province in west China, which is located in Qinghai-
Tibetan Plateau where potential high risk for depression may occur. The
predicted prevalence of depression was consistent with results from con-
ventional survey method. This study proved that WBE provided a feasible
method for assessing the real-time trend of depression and could be used
to implement a national monitoring program for depression. Additionally,
the parameters such as the treatment rate of depression, the clinical usage
of antidepressants, the degradation rate of antidepressants, and the drug ex-
cretion rates, should be optimized through a more thorough survey, and the
use of one or several drugs to estimate the prevalence of depression should
be taken into consideration. Relevant departments should promote mental
health knowledge more vigorously, increase resident mental health liter-
acy, and protect resident mental health.
CRediT authorship contribution statement
Haijian Lu: Investigation, Sampling, Experiments and Manuscript writ-
ing. Jingpu Fan: Investigation, Correction and Review. Changsheng Guo:
Methodology, Correction and Validation. Jiangtao Yang & Heng Zhang:
Investigation and Sampling. Miao Chen: Experiments and Methodology.
Yang Liu: Software and Study design. Wenxiu Liu: Investigation and Meth-
odology. Jian Xu: Study design, Conceptualization, Review & Editing and
Supervision.
Data availability
Data will be made available on request.
Declaration of competing interest
The authors declare that they have no known competing financial inter-
ests or personal relationships that could have appeared to influence the
work reported in this paper.
Acknowledgments
This work was supported by the Second Tibetan Plateau Scientific
Expedition and Research Program (STEP) (Grant No. 2019QZKK0608),
and National Natural Science Foundation of China (42177382).
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.scitotenv.2023.163303.
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