| Article Access Statistics|
| Viewed||1654 |
| Printed||33 |
| Emailed||0 |
| PDF Downloaded||178 |
| Comments ||[Add] |
Click on image for details.
|Year : 2017
: 59 | Issue : 1 | Page
|Long noncoding RNAs: New evidence for overlapped pathogenesis between major depressive disorder and generalized anxiety disorder
Xuelian Cui1, Wei Niu2, Lingming Kong3, Mingjun He3, Kunhong Jiang3, Shengdong Chen4, Aifang Zhong5, Wanshuai Li6, Jim Lu7, Liyi Zhang3
1 Department of Health Care, Changzhou Maternity and Child Health Care Hospital Affiliated with Nanjing Medical University, Changzhou, People's Republic of China
2 Department of Rehabilitation, No. 102 Hospital of Chinese People's Liberation Army, Changzhou, People's Republic of China
3 Prevention and Treatment Center for Psychological Diseases, No. 102 Hospital of Chinese People's Liberation Army, Changzhou, People's Republic of China
4 Department of Neurology, No. 102 Hospital of Chinese People's Liberation Army, Changzhou, People's Republic of China
5 Department of Clinical Laboratory, No.102 Hospital of Chinese Liberation Army, Changzhou, People's Republic of China
6 Gopath Diagnostic Laboratory Co. Ltd., Changzhou, People's Republic of China
7 Gopath Diagnostic Laboratory Co. Ltd., Changzhou, People's Republic of China; Gopath Laboratories LLC, 1351 Barclay Blvd, Buffalo Grove, USA
Click here for correspondence address and
|Date of Web Publication||12-Apr-2017|
| Abstract|| |
Background: About half of patients with major depressive disorder (MDD) have clinically meaningful levels of anxiety. Greater severity of depressive illness and functional impairment has been reported in patients with high levels of anxiety accompanying depression. The pathogenesis for the comorbidity was still unsure.
Aim: This study aimed to determine whether there would be molecular link for overlapped pathogenesis between MDD and anxiety disorder.
Materials and Methods: Using long noncoding RNA (lncRNA) microarray profiling and reverse transcription polymerase chain reaction, six downregulated lncRNAs and three upregulated lncRNAs had been identified to be the potential biomarkers for MDD and generalized anxiety disorder (GAD), respectively. Then, the lncRNAs were cross-checked in forty MDD patients, forty GAD patients, and forty normal controls.
Results: Compared with normal controls, six downregulated MDD lncRNAs also had a significantly lower expression in GAD (P < 0.01), and there was no significant difference between GAD and MDD (P > 0.05). In addition, three upregulated GAD lncRNAs had no different expression in MDD (P > 0.05), but there was remarkable difference between MDD and GAD (P < 0.01).
Conclusions: These results indicated that lncRNAs in peripheral blood mononuclear cells could be potential molecular link between MDD and GAD, which added new evidence to the overlapped pathogenesis and suggested that anxious depression could be a valid diagnostic subtype of MDD.
Keywords: Comorbidity, generalized anxiety disorder, long noncoding RNA, major depressive disorder
|How to cite this article:|
Cui X, Niu W, Kong L, He M, Jiang K, Chen S, Zhong A, Li W, Lu J, Zhang L. Long noncoding RNAs: New evidence for overlapped pathogenesis between major depressive disorder and generalized anxiety disorder. Indian J Psychiatry 2017;59:83-7
|How to cite this URL:|
Cui X, Niu W, Kong L, He M, Jiang K, Chen S, Zhong A, Li W, Lu J, Zhang L. Long noncoding RNAs: New evidence for overlapped pathogenesis between major depressive disorder and generalized anxiety disorder. Indian J Psychiatry [serial online] 2017 [cited 2019 Oct 23];59:83-7. Available from: http://www.indianjpsychiatry.org/text.asp?2017/59/1/83/204436
| Introduction|| |
Psychiatric comorbidity is defined as the presence, either simultaneously or in succession, of two or more specific disorders in an individual within a specified period. The Epidemiologic Catchment Area study and the National Comorbidity Study, both in the United States, found that 54% and 56%, respectively, of respondents with a lifetime history of at least one Diagnostic and Statistical Manual of Mental Disorders, 3rd Edition (DSM-III)/DSM-III-Revision disorder also met criteria for some other mental disorder. A large number of studies conclude that generalized anxiety disorders (GADs) occur in patients with major depressive disorder (MDD) far more frequently than expected by chance. Studies conducted in Europe and the USA have shown that comorbidity between MDD and anxiety disorders is the most prevalent comorbid condition among both genders (especially in women) and associated with younger age, lower educational attainment, and unemployment. A community-based epidemiological survey in mainland China also reported that 63% of individuals with mood disorder had at least one type of anxiety disorder. Comorbidity induces harmful consequences, such as more severe symptoms,, greater functional disability,, longer illness course, higher rates of neuroticism, earlier onset age, greater suicidal risk and poorer treatment response, lower social competence, and worse prognosis.
In view of the prevalence and consequences of psychiatric comorbidity, identifying individuals at the greatest risk for comorbidity early becomes a public health priority. There was a key unanswered question related to the cause of comorbidity: the direction and mechanisms underlying causal links, as well as the potential spurious nature of such links. Common genetic predisposition to MDD and anxiety ,,, is well known, but the genetic factors explain only part of the co-occurrence of illness, and nonshared environment explains 40% covariance between MDD and GAD for female twins. The relative contribution of genetic and nongenetic/environmental factors to this comorbidity has been examined in a series of population-based twin studies, indicating that the interaction between genetic and environmental determinants plays an important role in the onset of comorbidity MDD and GAD, but they did not know the reason. With the development of RNA deep sequencing technology and bioinformatics, epigenetics can help to explain the interaction between genetic and environment. Epigenetics is defined as inheritable and reversible phenomena that affect gene expression without altering the underlying base-pair sequence  that environmental events and behavioral experience induce epigenetic changes at particular gene loci, and these changes help shape neuronal plasticity, function, and behavior, hence contributed to the pathogenesis of MDD.
Long noncoding RNA (lncRNA), one major mechanism of epigenetics, is more than 200nt in length, not encoding proteins itself, but regulating gene expression in multilevel form of RNA, such as epigenetic regulation, transcriptional regulation, and posttranscriptional regulation. LncRNAs have been implicated in neurodevelopmental disorders such as Rett syndrome, autism,, schizophrenia (SZ), and fragile X syndrome. Using LncRNA microarray profiling and reverse transcription polymerase chain reaction (RT-PCR), the differentially expressed lncRNAs in MDD (downregulated TCONS_00019174, ENST00000566208, NONHSAG045500, ENST00000517573, NONHSAT034045, and NONHSAT142707) and GAD (upregulated ENST00000505825, NONHSAG017299, and NONHSAT078768) compared with the normal control. In this study, all of the lncRNAs in MDD and in GAD were cross-checked again in another disease and controls, respectively, to ascertain whether there is the same lncRNAs expression both in MDD and GAD.
| Materials and Methods|| |
Forty MDD patients and forty GAD patients who met the criteria of the DSM-IV were enrolled from Changzhou Maternity and Child Health Care Hospital and No. 102 Hospital of the Chinese People's Liberation Army from May 2014 to February 2015. Diagnoses were independently made by two psychiatry attending doctors using the Chinese version of the modified Structured Clinical Interview for DSM-IV, patient version (SCID-I/P). Both MDD patients and GAD patients were assessed using the 24-item Hamilton Depression Scale (HAMD-24) and 14-item Hamilton Anxiety Scale (HAMA). All the patients were first visitors or before any clinical treatment, drug naïve from any antidepressant for at least 3 months before study enrollment, no previous history of organic disease (such as heart disease, diabetes, and Parkinson's disease), and no other psychiatric disorders.
The forty healthy controls were recruited from the community nearby, having no family history of major psychiatric disorders (SZ, bipolar disorder, mania, anxiety, and substance abuse), without any history of severe traumatic events within 6 months. Controls were also assessed through the modified SCID-I/P, HAMD, and HAMA to rule out prior incidence of mental disease. MDD patients, GAD patients, and healthy controls were matched in gender, age, and ethnicity at a ratio of 1:1. The study was approved by the Ethical Committee for Medicine of Changzhou Maternity and Child Health Care Hospital and No. 102 Hospital of Chinese People's Liberation Army. All patients or their legal guardians provided written informed consent.
Reverse transcription polymerase chain reaction
Whole blood (5 ml) was collected in ethylenediaminetetraacetic acid tube, and peripheral blood mononuclear cells (PBMCs) were isolated from forty MDD patients, forty GAD patients, and forty controls. Total RNAs were extracted from the PBMCs using TRIzol (Invitrogen, Carlsbad, CA, USA) and the RNeasy kit (Qiagen, Hilden, Germany) according to the manufacturer's protocol, quantified by NanoDrop ND-2000 (Thermo Scientific, Delaware, ME, USA), DNase treated (TURBO DNase, Life Technologies), and reverse transcribed (Superscript III; Invitrogen). Then, six downregulated lncRNAs in GAD, three upregulated lncRNAs in MDD, and both of them in controls were performed through RT-PCR using Applied Biosystems 7900HT Real-Time PCR System (Applied Biosystems, Inc., USA). The method and process can be referred to our previous article. Data were collected using the SDS 2.3 software (Applied Biosystems, Foster City, CA, USA) and DataAssist version 3.0 Software (Thermo Fisher Scientific, MA, USA). After normalized to α-actin, the expression levels of lncRNAs were calculated using the 2-ΔΔCt method.
All statistical analyses were carried out using DataAssist version 3.0 Software (Thermo Fisher Scientific, MA, USA), SPSS version 20.0 Software (Chicago, IL, USA), and GraphPad Prism 5 (Graphad Software Inc., San Diego, CA, USA). Demographic variables were compared between patients and matched controls with Chi-square test for qualitative variables and ANOVA for quantitative variables. The difference of six lncRNAs in GAD and three lncRNAs in MDD with healthy controls was analyzed by Wilcoxon rank sum test. P< 0.05 (two-tailed) was considered with statistical significance.
| Results|| |
Demographic data of the major depressive disorder patients, generalized anxiety disorder patients, and normal controls
Using Chi-square test and ANOVA, there were no significant differences between patients and control group in age and sex distribution, but HAMD and HAMA scores were significantly different, as shown in [Table 1].
|Table 1: Clinical characteristics of MDD patients, GAD patients and normal controls|
Click here to view
Differentially expressed long noncoding RNAs in major depressive disorder and generalized anxiety disorder
Using lncRNA microarray profiling and quantitative RT-PCR, six downregulated lncRNAs in MDD (TCONS_00019174, ENST00000566208, NONHSAG045500, ENST00000517573, NONHSAT034045, and NONHSAT142707) and three upregulated lncRNAs in GAD (ENST00000505825, NONHSAG017299, and NONHSAT078768) were found to be differentially expressed, as shown in [Table 2].
|Table 2: Six down-regulated lncRNAs in MDD and three up-regulated lncRNAs in GAD|
Click here to view
Comparison of six downregulated major depressive disorder long noncoding RNAs in generalized anxiety disorder and controls
As shown in [Figure 1], using Wilcoxon rank sum test, six downregulated lncRNAs in MDD were also significantly lower expressed comparing with normal controls (P < 0.01), and there was no significant difference between GAD and MDD (P > 0.05).
|Figure 1: Comparison of the six downregulated long noncoding RNAs expression in generalized anxiety disorder and normal controls. NC = Normal control, GAD = Generalized anxiety disorder, MDD = Major depressive disorder|
Click here to view
Comparison of the three upregulated generalized anxiety disorder long noncoding RNAs in major depressive disorder and controls
Using Wilcoxon rank sum test, there was no significant difference between three upregulated lncRNAs in MDD and in controls (P > 0.05). On the contrary, there was a significant difference between MDD and GAD (P < 0.01) [Figure 2].
|Figure 2: Comparison of the three downregulated long noncoding RNAs expression in major depressive disorder and normal control. NC = Normal control, GAD = Generalized anxiety disorder, MDD = Major depressive disorder|
Click here to view
| Discussion|| |
Previous studies indicate that high levels of comorbidity existed between major depression and GAD, and anxiety symptoms can fluctuate over time. A follow-up study of individuals with uncomplicated GAD at baseline found that at the end of 3 years, the diagnosis of 24% of the participants had changed to depressive disorders and that of a further 16% had changed to depressive disorders comorbid with GAD. Scholars had tried to find whether there were some unique genetic effects on anxiety or depressive disorders. Maron et al. screened 90 SNPS in genes associated with the neurobiology of anxiety and found that polymorphisms in cholecystokinin-related genes and the serotonin 1A receptor (5-hydroxytryptamine receptor 1A) were associated with affective disorders. In a sample of Caucasian Vietnam veterans in Australia, the TaqI A allele of the dopamine receptor gene was associated with comorbid anxiety and depression. PLXNA2 gene, which encodes for plexin 2A, had been implicated in comorbidity between depression and anxiety. These studies also demonstrate that the genetic factors explain only part of the co-occurrence of illnesses. The paths from DNA to psychopathology were long and tortuous, involved the action, interaction, and correlation of many genes and environmental factors, so-called genotype × environment interaction and genotype-environment correlation, whose effects change and/or accumulate through development as a result of endogenous mechanisms and the interplay between the person and the environment. Early studies about the interaction between genes and environment are based on multivariate twin modeling,, no further molecular biology research. With the development of RNA deep sequencing technology and bioinformatics, epigenetics became to fill the gaps in this area. Its molecular mechanism includes methylation of DNA, RNA interference, noncoding RNA (ncRNA), protein modification, and histone acetylation.
A significant number of brain-enriched or brain-specific lncRNAs are found adjacent to genes encoding transcriptional regulators and key drivers of neural development, including those involved in the regulation of stem cell pluripotency, neuronal differentiation, and synaptogenesis.,,, In the present study, we found that the six downregulated lncRNAs expressed the same both in MDD and GAD, which illustrated that there could be overlapped pathogenesis between depression and anxiety, also directly providing evidence why part of anxiety patients would eventually transform into depression. Using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, our previous paper showed that the lncRNAs in this study were all involved in the following pathways: (1) Translational elongation, (2) protein transport, (3) ribosome activities, (4) RNA degradation, (5) DNA replication. Besides, the ncRNAs expression in psychiatric disorders had a significant change after standard treatment, even returned to normal levels when symptoms remised,,, indicating lncRNAs could be objective molecular index to evaluate the therapeutic effect. In clinical treatment, antidepressants (paroxetine, sertraline, fluoxetine, venlafaxine hydrochloride, etc.,) can have therapeutic effect both in anxiety and depressive symptoms, but single use of anxiolytics or sedative/hypnotics (alprazolam, buspirone, etc.) has nothing to do with the core symptoms of depression. Thus, we speculated that when doctors are confused about the diagnosis and therapy, testing the lncRNAs expression in PBMCs can provide advice for them.
Comorbid mental disorders are so common that the rigid application of a diagnostic hierarchy will not adequately identify clinically important differences between patients. To improve the clinical characterization of depression and the effectiveness of treatments for anxiety disorders, clinicians must simultaneously assess the severity of both depressive and anxiety symptoms. If both two types of symptoms are prominent, revising their treatment regimens accordingly is needed. Based on this concept, although DSM-IV  did not recognize anxious depression as a diagnostic subtype, but in DSM-V, in the chapter on bipolar and related disorders and the chapter on depressive disorders, a specifier for anxious distress is delineated, the specifier is intended to identify patients with anxiety symptoms that are not part of the bipolar diagnostic criteria. This study provided a theoretical support for the alteration.
| Conclusions|| |
In conclusion, this study found that lncRNAs in PBMCs might be molecular link between MDD and GAD, and the results were supportive of the view that anxious depression could be a valid diagnostic subtype of MDD and suggested the need for additional emphasis on the depression measurement of patients with anxiety disorder.
We sincerely thank the patients, their families, and the healthy volunteers for their participation as well as the medical staff involved in collecting specimens.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Kessler RC, McGonagle KA, Zhao S, Nelson CB, Hughes M, Eshleman S, et al.
Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey. Arch Gen Psychiatry 1994;51:8-19.
Gorwood P. Generalized anxiety disorder and major depressive disorder comorbidity: An example of genetic pleiotropy? Eur Psychiatry 2004;19:27-33.
de Graaf R, Bijl RV, Smit F, Vollebergh WA, Spijker J. Risk factors for 12-month comorbidity of mood, anxiety, and substance use disorders: findings from the Netherlands Mental Health Survey and Incidence Study. Am J Psychiatry 2002;159:620-9.
Phillips MR, Zhang J, Shi Q, Song Z, Ding Z, Pang S, et al.
Prevalence, treatment, and associated disability of mental disorders in four provinces in China during 2001-05: An epidemiological survey. Lancet 2009;373:2041-53.
Andrade L, Eaton WW, Chilcoat H. Lifetime comorbidity of panic attacks and major depression in a population-based study. Symptom profiles. Br J Psychiatry 1994;165:363-9.
Roy-Byrne PP, Stang P, Wittchen HU, Ustun B, Walters EE, Kessler RC. Lifetime panic-depression comorbidity in the National Comorbidity Survey. Association with symptoms, impairment, course and help-seeking. Br J Psychiatry 2000;176:229-35.
Bijl RV, Ravelli A. Current and residual functional disability associated with psychopathology: Findings from the Netherlands Mental Health Survey and Incidence Study (NEMESIS). Psychol Med 2000;30:657-68.
Kessler RC, Frank RG. The impact of psychiatric disorders on work loss days. Psychol Med 1997;27:861-73.
Howland RH, Rush AJ, Wisniewski SR, Trivedi MH, Warden D, Fava M, et al.
Concurrent anxiety and substance use disorders among outpatients with major depression: Clinical features and effect on treatment outcome. Drug Alcohol Depend 2009;99:248-60.
Brown TA, Campbell LA, Lehman CL, Grisham JR, Mancill RB. Current and lifetime comorbidity of the DSM-IV anxiety and mood disorders in a large clinical sample. J Abnorm Psychol 2001;110:585-99.
Cerdá M, Sagdeo A, Johnson J, Galea S. Genetic and environmental influences on psychiatric comorbidity: A systematic review. J Affect Disord 2010;126:14-38.
Lamers F, van Oppen P, Comijs HC, Smit JH, Spinhoven P, van Balkom AJ, et al.
Comorbidity patterns of anxiety and depressive disorders in a large cohort study: The Netherlands Study of Depression and Anxiety (NESDA). J Clin Psychiatry 2011;72:341-8.
Kendler KS, Gardner CO, Gatz M, Pedersen NL. The sources of co-morbidity between major depression and generalized anxiety disorder in a Swedish national twin sample. Psychol Med 2007;37:453-62.
Khan AA, Jacobson KC, Gardner CO, Prescott CA, Kendler KS. Personality and comorbidity of common psychiatric disorders. Br J Psychiatry 2005;186:190-6.
Middeldorp CM, Cath DC, Van Dyck R, Boomsma DI. The co-morbidity of anxiety and depression in the perspective of genetic epidemiology. A review of twin and family studies. Psychol Med 2005;35:611-24.
Rhebergen D, Batelaan NM, de Graaf R, Nolen WA, Spijker J, Beekman AT, et al.
The 7-year course of depression and anxiety in the general population. Acta Psychiatr Scand 2011;123:297-306.
Choi SW, Claycombe KJ, Martinez JA, Friso S, Schalinske KL. Nutritional epigenomics: A portal to disease prevention. Adv Nutr 2013;4:530-2.
Vialou V, Feng J, Robison AJ, Nestler EJ. Epigenetic mechanisms of depression and antidepressant action. Annu Rev Pharmacol Toxicol 2013;53:59-87.
Bernard D, Prasanth KV, Tripathi V, Colasse S, Nakamura T, Xuan Z, et al.
A long nuclear-retained non-coding RNA regulates synaptogenesis by modulating gene expression. EMBO J 2010;29:3082-93.
Williams JM, Beck TF, Pearson DM, Proud MB, Cheung SW, Scott DA. A 1q42 deletion involving DISC1, DISC2, and TSNAX in an autism spectrum disorder. Am J Med Genet A 2009;149A: 1758-62.
Ziats MN, Rennert OM. Aberrant expression of long noncoding RNAs in autistic brain. J Mol Neurosci 2013;49:589-93.
Barry G, Briggs JA, Vanichkina DP, Poth EM, Beveridge NJ, Ratnu VS, et al.
The long non-coding RNA Gomafu is acutely regulated in response to neuronal activation and involved in schizophrenia-associated alternative splicing. Mol Psychiatry 2014;19:486-94.
Pastori C, Peschansky VJ, Barbouth D, Mehta A, Silva JP, Wahlestedt C. Comprehensive analysis of the transcriptional landscape of the human FMR1 gene reveals two new long noncoding RNAs differentially expressed in Fragile X syndrome and Fragile X-associated tremor/ataxia syndrome. Hum Genet 2014;133:59-67.
Cui X, Sun X, Niu W, Kong L, He M, Zhong A, et al.
Long non-coding RNA: Potential diagnostic and therapeutic biomarker for major depressive disorder. Med Sci Monit 2016;22:5240-8.
Williams JB, Gibbon M, First MB, Spitzer RL, Davies M, Borus J, et al.
The Structured Clinical Interview for DSM-III-R (SCID). II. Multisite test-retest reliability. Arch Gen Psychiatry 1992;49:630-6.
Zheng YP, Zhao JP, Phillips M, Liu JB, Cai MF, Sun SQ, et al.
Validity and reliability of the Chinese Hamilton Depression Rating Scale. Br J Psychiatry 1988;152:660-4.
Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol 1959;32:50-5.
Schoevers RA, Deeg DJ, van Tilburg W, Beekman AT. Depression and generalized anxiety disorder: Co-occurrence and longitudinal patterns in elderly patients. Am J Geriatr Psychiatry 2005;13:31-9.
Maron E, Nikopensius T, Kõks S, Altmäe S, Heinaste E, Vabrit K, et al.
Association study of 90 candidate gene polymorphisms in panic disorder. Psychiatr Genet 2005;15:17-24.
Lawford BR, Young R, Noble EP, Kann B, Ritchie T. The D2 dopamine receptor (DRD2) gene is associated with co-morbid depression, anxiety and social dysfunction in untreated veterans with post-traumatic stress disorder. Eur Psychiatry 2006;21:180-5.
Wray NR, James MR, Mah SP, Nelson M, Andrews G, Sullivan PF, et al.
Anxiety and comorbid measures associated with PLXNA2. Arch Gen Psychiatry 2007;64:318-26.
Eaves L, Silberg J, Erkanli A. Resolving multiple epigenetic pathways to adolescent depression. J Child Psychol Psychiatry 2003;44:1006-14.
Kendler KS, Prescott CA, Myers J, Neale MC. The structure of genetic and environmental risk factors for common psychiatric and substance use disorders in men and women. Arch Gen Psychiatry 2003;60:929-37.
Ponjavic J, Oliver PL, Lunter G, Ponting CP. Genomic and transcriptional co-localization of protein-coding and long non-coding RNA pairs in the developing brain. PLoS Genet 2009;5:e1000617.
Lin M, Pedrosa E, Shah A, Hrabovsky A, Maqbool S, Zheng D, et al.
RNA-Seq of human neurons derived from iPS cells reveals candidate long non-coding RNAs involved in neurogenesis and neuropsychiatric disorders. PLoS One 2011;6:e23356.
Mercer TR, Qureshi IA, Gokhan S, Dinger ME, Li G, Mattick JS, et al.
Long noncoding RNAs in neuronal-glial fate specification and oligodendrocyte lineage maturation. BMC Neurosci 2010;11:14.
Ng SY, Johnson R, Stanton LW. Human long non-coding RNAs promote pluripotency and neuronal differentiation by association with chromatin modifiers and transcription factors. EMBO J 2012;31:522-33.
Song HT, Sun XY, Zhang L, Zhao L, Guo ZM, Fan HM, et al.
A preliminary analysis of association between the down-regulation of microRNA-181b expression and symptomatology improvement in schizophrenia patients before and after antipsychotic treatment. J Psychiatr Res 2014;54:134-40.
Zhang QL, Lu J, Sun XY, Guo W, Zhao L, Fan HM, et al
. A preliminary analysis of association between plasma microRNA expression alteration and symptomatology improvement in Major Depressive Disorder (MDD) patients before and after antidepressant treatment. Eur J Psychiatry 2014;28:252-64.
Gopath Diagnostic Laboratory Co. Ltd., No. 801, Changzhou, People's Republic of China; Gopath Laboratories LLC, 1351 Barclay Blvd, Buffalo Grove, USA
Prevention and Treatment Center for Psychological Diseases, No. 102 Hospital of Chinese People's Liberation Army, North Peace Road 55, Changzhou
People's Republic of China
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2]
[Table 1], [Table 2]