
==== Front
BMC Psychiatry
BMC Psychiatry
BMC Psychiatry
1471-244X
BioMed Central London

6023
10.1186/s12888-024-06023-4
Research
Psychotic symptoms in Chinese adolescent patients with major depressive disorder: prevalence and related endocrine clinical factors
Sun Shiyu 8
Jin Wei 1
Hou Tianle 1
Tong Siyu 7
Zhou Siyao 2
Hong Lan 13
Yao Keqing KQKangning@gmail.com

45
Zhao Ke cocozk1986@163.com

7
Zheng Tiansheng sky.tsh@163.com

6
1 https://ror.org/00rd5t069 grid.268099.c 0000 0001 0348 3990 School of Mental Health, Wenzhou Medical University, Wenzhou, China
2 https://ror.org/00a2xv884 grid.13402.34 0000 0004 1759 700X Zhejiang University, Hangzhou, China
3 The Third Hospital of Quzhou, Quzhou, China
4 Shenzhen Mental Health Center, Shenzhen, Guangdong China
5 https://ror.org/02skpkw64 grid.452897.5 0000 0004 6091 8446 Shenzhen Kangning Hospital, 77 Zhenbi Road, Pingshan District, Shenzhen, Guangdong China
6 grid.268099.c 0000 0001 0348 3990 The Affiliated Kangning Hospital of Wenzhou Medical University Zhejiang Provincial Clinical Research Center for Mental Disorder, Wenzhou, China
7 grid.268099.c 0000 0001 0348 3990 Lishui Second People’s Hospital, Wenzhou Medical University, Lishui, China
8 https://ror.org/04dzvks42 grid.412987.1 0000 0004 0630 1330 Department of Mental Health, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
5 9 2024
5 9 2024
2024
24 59824 3 2023
16 8 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Objective

Major depressive disorder (MDD) is often accompanied by psychotic symptoms. However, few studies have examined the relationship between psychotic symptoms and endocrine factors in adolescent patients with MDD. Therefore, this study aimed to investigate the prevalence and related endocrine clinical factors of psychotic symptoms in Chinese adolescent patients with MDD.

Methods

In total, 601 patients (aged 12–18) with MDD were recruited. The Patient Health Questionnaire – 9 items (PHQ – 9) was utilized for assessing depressive symptoms. Psychotic symptoms were assessed through clinical interviews. Prolactin (PRL), thyroid-stimulating hormone (TSH), triiodothyronine (T3), free triiodothyronine (FT3), thyroxine (T4), and free thyroxine (FT4) were also measured.

Results

The incidence of psychotic symptoms in adolescent patients with MDD was 22.6%. The findings demonstrated that age, self-harming behavior, PHQ-9 score, FT4, and normalized PRL were independently associated with psychotic symptoms in patients with MDD (All p < 0.05).

Conclusions

PRL and FT4 levels are more likely to be abnormally elevated in major depressive adolescents with psychotic symptoms. Prolactin and thyroid hormones in patients with MDD should be paid more attention.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12888-024-06023-4.

Keywords

Major depressive disorder
Psychotic symptom
Prevalence
Prolactin
Thyroid hormones
Shenzhen Fund for Guangdong Provincial High-level Clinical Key SpecialtiesNo.SZGSP013 Shenzhen Science and technology research and Development Fund for Sustainable development projectNo.KCXFZ20201221173613036 Zhejiang Provincial Natural Science Foundation of ChinaNO. LY22H090022 Zhejiang Provincial Medical health ProjectNO. 2022RC256 issue-copyright-statement© BioMed Central Ltd., part of Springer Nature 2024
==== Body
pmcIntroduction

Major depressive disorder (MDD) is a prevalent mental disorder characterized by significantly diminished interest, depressed mood, and fatigue [1]. Psychotic symptoms, mainly hallucinations and/or delusions, frequently occur in all stages of MDD and are considered the distinct and the most severe subtype of MDD. Previous epidemiological studies have illustrated that 5.3–42% of patients with MDD exhibited psychotic symptoms [2–4]. The prevalence of psychotic symptoms was even higher among hospitalized patients with MDD. Patients with psychotic MDD presented more severe depressive symptoms, higher suicide attempts, worse disease duration, higher recurrence rates, greater social dysfunction, and worse response to depression treatment [2, 5, 6], suggesting that the co-occurrence of MDD and psychotic symptoms predicts poorer clinical outcomes. These psychotic symptoms (delusions and/or hallucinations) appear more commonly in children and adolescents than in adults [7, 8]. Therefore, in order delay the progression of severe illness and reduce the incidence of adverse outcomes, it is necessary to investigate the prevalence of psychotic symptoms in patients with MDD, especially among adolescents.

Hallucinations and delusions are common clinical psychotic symptoms of MDD. However, the mechanism of hallucinations and delusions was unclear. Some previous investigations suggested that psychotic symptoms were closely related to endocrine changes, such as the HPA axes. For example, recent research has focused on hyperprolactinemia in antipsychotic-free patients with first-episode psychosis [9–11]and patients with an at-risk mental state for psychosis [10]. Those finding revealed that compared with the normal control group, the patients diagnosed with first-episode schizophrenia and who have never used any antipsychotic drug have relatively elevated prolactin (PRL) levels. Abnormal level of PRL maybe associated with psychiatric symptoms, thus antipsychotic drugs which may induce increased PRL levels should be carefully selected while treating these patients [10]. It is worth noting that hyperprolactinemia (where serum levels of PRL are higher than the nor mal range) can be caused by many physiological processes which are common in patients with depression, such as psychological distress, sex, stress [12]. Therefore, hyperprolactinemia may be associated with psychiatric symptoms and depressive symptoms. Hyperprolactinemia may result in numerous unfavorable clinical outcomes such as irregular menses or amenorrhea, hypogonadism, subfertility, osteoporosis, and fracture risk [12, 13]. Hence, the consequences cannot be underestimated.

Meanwhile, the thyroid hormone was also believed to share a close relationship with psychiatric symptoms. Clinically relevant hyperthyroidism might manifest in people with psychotic symptoms, whereas hypothyroidism may cause mood symptoms that resemble negative symptoms of schizophrenia [14, 15]. Do people with MDD, who also have psychotic symptoms such as hallucinations and delusions, have similar mechanisms of psychotic symptoms resembling schizophrenia and involve similar abnormal level of endocrine levels?

The onset of psychotic symptoms in children or adolescents with depression or anxiety disorders may indicate a more severe course of an illness or more clinically important behavior, such as the possibility of suicidal thoughts or self-harm [5, 16, 17]. As we all know, adolescence is a period of rapid development, both physically and mentally. In this special period, thyroid hormones and PRL are crucial for early neurocognitive development and growth and development in childhood and adolescence [18, 19]. Simultaneously, adolescents are surrounded by many psychological stress problems, such as academic pressure, peer bullying, and parental relations [20, 21]. Studies have revealed that psychotic depression at the age of 12 is associated with poorer educational, occupational, and social outcomes at the age of 16–20 [22]. This means that adolescents with depression and psychiatric symptoms have more difficulty returning to society. Given the differences in age at onset and the incidence of psychotic symptoms, psychotic symptoms may play a different role in depression in adolescents than in adults [23]. Thyroid hormones and PRL are crucial for neurocognitive development and growth in early childhood and adolescence [18, 19]. However, the effects of psychotic symptoms on depressive symptom outcomes in adolescents have not been well studied, especially in the endocrine direction.

In conclusion, adolescent patients with MDD having psychotic symptoms face more difficulty achieving ideal treatment outcomes and may have more severe adverse outcomes. More importantly, they may have endocrine disorders similarly to schizophrenia. This hidden and undetected clinical condition can be quite dangerous, especially for adolescents who are undergoing necessary physical and mental development [18, 19, 24]. To reduce the incidence of adverse outcomes, it is crucial to investigate the relationship between psychotic symptoms and endocrine factors in patients with MDD, especially among adolescents. Therefore, this study will take Chinese adolescent patients as subjects to explore the incidence of psychotic symptoms in MDD and the related influencing factors.

This study hypothesized that significant differences were present in PRL and thyroid hormone between psychotic MDD and non-psychotic MDD groups. Moreover, PRL, thyroid hormone, and self-harming behavior were risk factors for psychotic symptoms of patients with MDD.

Methods

Subjects

This national multi-center and cross-sectional study was based on a cohort study of Chinese adolescent depression (CADC). The study proposal was approved by the Institutional Review Board (IRB) of the Shenzhen Kangning Hospital (IRB:2020-k021-02). The data was collected from January to December 2021. A total of 601 inpatients were recruited from the inpatient department of cooperative hospitals. The inclusion criteria of this study are as follows: (1) patients belonging to age group: 12–18 years; (2) patients meeting the criteria of the fifth edition of the Diagnostic and Statistical Manual (DSM-5) for MDD; (3) patients achieving the score of PHQ-9 ≥ 10; (4) the patients must have never received psychotropic medications (e.g., risperidone, paliperidone, among others) (5) years of education ≥ five years; (6) patients must be right-handed; and (7) Each participant obtained informed consent from their legal guardian before approving to participate in the study. Participants and their legal guardians received a full study description and voluntarily signed written informed consent. The exclusion criteria were as follows: (1) patients having complications from severe somatic diseases, infectious diseases, or immune system diseases, or have a previous history of the thyroid-related disease; (2) patients with brain trauma, epilepsy, or other known severe nervous system diseases or brain organic diseases; (3) patients having a previous history of severe mental disorders such as schizophrenia or mental retardation. After receiving informed consent for enrollment, all participants underwent comprehensive interview assessments conducted by two experienced psychiatrists. These assessments covered clinical diagnosis, the presence of psychotic symptoms, and details regarding the content and frequency of such symptoms. Prior to the study, all research team members at each center underwent identical training and passed a consistency test. Clinical diagnoses were made based on the observations and evaluations conducted during these assessments.

Demographic characteristics

The following demographic and clinical data of all patients were collected in this study: sex, age, years of education, and self-harming behavior. Self-harm was defined as the deliberate act of injuring one’s own body, such as intentionally cutting the skin, hitting oneself, or biting. If participants self-reported engaging in self-harming behavior in the past year, and the frequency of such incidents was five or more, researchers identified the participant as having self-harm behavior. Otherwise, it be considered non-existent.

Clinical measurements

In this study, depressive symptoms were evaluated by the Patient Health Questionnaire – 9 items (PHQ – 9) [25], which has nine items and one function of general evaluation. The PHQ – 9 is recognized as an effective tool for assessing the depressive status of adolescents [26, 27]. PHQ-9 ≥ 10 is often used as the dividing point of major depression [28].

Psychotic symptoms were assessed through interviews by two experienced psychiatrists where each participant was questioned about the content and frequency of delusions (excluding delusions of grandeur) and hallucinations experienced in the past 7 days. In cases where responses were ambiguous, supplementary information was gathered from interviews with their family members or friends to reach a conclusion. Each item is rated on a five-point Likert scale: 0 = never, 1 = occur occasionally or suspiciously, 2 = definitely present (with emotional background), 3 = definitely present (without emotional background), 4 = accompanied by hallucinations. To reduce false positive rates and ensure consistency in the study, patients were included in the psychotic symptoms group only if one of the symptoms, such as hallucinations or delusions, was clearly present (a score of 2 or more for any of these was considered positive).

Measurement of PRL and thyroid hormones

Fasting blood samples were collected at the sub-center between 6 a.m. and 8 a.m., centrifuged and stored in a -80℃ refrigerator. Finally, all blood samples were mailed to the headquarters of Shenzhen Mental Health Center. PRL, thyrotropin (TSH), triiodothyronine (T3), free triiodothyronine (FT3), thyroxine (T4) and free thyroxine (FT4) were determined in the headquarters.

Statistical analysis

The incidence of psychotic symptoms in patients with MDD was expressed as a proportion (percentage). The normal distribution of data was examined by the Shapiro-Wilk test. The t test and χ² test were used to compare demographic and clinical variables, which were normally distributed between psychotic MDD and non-psychotic MDD groups. Continuous variables of normal distribution are expressed as mean ± standard deviation (M ± SD). The ordered rank variables of non-normal distribution were described by median (lower quartile, upper quartile) and compared with the Mann-Whitney U test. PRL values analyzed on a continuous variable were first log-transformed (to accommodate positive skew) and then normalized for men and women separately based on the log-transformed reference ranges for healthy men and women. For this assay, the normal PRL range is 63.6–318mIU/L for males and 84.8–487.6mIU/L for females [29]. The means and SDs of the log-transformed normative samples for men and women were calculated by taking the means of log-transformed upper and lower bounds of the reference ranges and dividing the differences between log-transformed upper and lower bounds of the reference ranges by 3.92, respectively. Thus, the normal sex difference in PRL observed in healthy individuals was partially removed from the continuous PRL measurement before inclusion in the models [30].

Binary logistic regression analyses (forward stepwise method) were conducted for risks related to adolescent MDD patients with psychotic symptoms, together with odds ratios (OR) and 95% confidence intervals (CIs), after controlling for the related variables. All statistical analyses were performed by SPSS version 26.0. A two-tailed p-value less than 0.05 was considered statistically significant.

Results

Demographic and clinical characteristics of patients with psychotic MDD and non-psychotic MDD

Table 1 shows that the percentage of the psychotic MDD study sample was 22.6% (136/601). More women (23.6%, 118 of 500) had psychotic symptoms compared to men (17.8%, 18 of 101). Significant differences were observed with respect to age (p < 0.001), education (p = 0.005), and PHQ-9 score (p < 0.001) between psychotic MDD and non-psychotic MDD. The incidence of self-harming behavior in the psychotic MDD group (83.8%) was higher than that in the non-psychotic MDD group (70.8%). Additionally, there was no significant difference in TSH levels between patients with MDD who had comorbid psychotic symptoms and those who did not (p > 0.05) (Table 1). However, TSH levels were slightly higher in the patients of the psychotic MDD group. The serum levels of FT3, FT3, T4, and FT4 in the psychotic MDD group were significantly higher than those in the non-psychotic MDD group (all p < 0.001).

Table 1 Demographic and clinical variables in psychotic MDD group and non-psychotic MDD group

Characteristics	MDD without psychotic symptoms
(n = 465, 77.4%)	MDD with psychotic symptoms
(n = 136, 22.6%)	t/χ2	P-Value	
Age (years), M (SD)	14.77(0.08)	14.20(0.13)	3.923	< 0.001	
Sex, (n, %)			1.602	0.206a	
Female	382(82.2)	118(86.8)			
Male	83(17.8)	18(13.2)			
Education(years), M (SD)	9.10(0.08)	8.64(0.13)	2.801	0.005	
Self-harming behavior, (n, %)			9.277	0.002a	
No	136(29.2)	22(16.2)			
Yes	329(70.8)	114(83.8)			
PHQ-9 score, M (SD)	18.80(0.23)	21.16(0.38)	−5.035	< 0.001	
TSH (mIU/L), M (SD)	2.12(0.10)	2.18(0.23)	−0.267	0.790	
T3 (mIU/L), M (SD)	1.51(0.02)	1.69(0.03)	−4.123	< 0.001	
FT3 (pmol/L), M (SD)	4.62(0.07)	5.01(0.07)	−4.091	< 0.001	
T4 (pmol/L), M (SD)	73.96(1.57)	86.01(1.72)	−5.183	< 0.001	
FT4 (pmol/L), M (SD)	10.73(0.23)	13.48(0.26)	−7.935	< 0.001	
PRL (mIU/L), M (SD)	601.20 (26.98)	713.22 (46.84)	−2.002	0.045	
PRL normalized, M (SD)	1.35(0.14)	2.23(0.17)	−3.992	< 0.001	
Note: PHQ-9 = Patient Health Questionnaire-9; a Chi-square test for categorical variables

The analysis of PRL as a continuous variable (PRL normalized by sex) revealed that that PRL levels were significantly higher in patients having both MDD and psychotic symptoms than in those without psychotic symptoms (p < 0.001). Table 2 depicts the mean and standard deviation of the normalized PRL values by group (patient/control) and sex (male/female).

Table 2 Prolactin normalized in MDD with psychotic symptoms and without psychotic symptoms

	MDD with psychotic symptoms	MDD without psychotic symptoms	
	Men
(n = 18)	Women
(n = 118)	Men
(n = 83)	Women
(n = 382)	
Prolactin normalized					
Mean ± SD.	1.57 ± 0.85	1.57 ± 0.29	-1.07 ± 0.46	−0.53 ± 0.20	
Median	2.67	2.31	−0.79	−0.93	
Range	−6.08–5.26	−11.70–5.82	−8.43–5.46	−9.30–6.83	
SD, standard deviation

Factors associated with psychotic symptoms of MDD

The binary logistic regression model was used to determine the relevant factors for psychotic symptoms in patients with MDD. The results demonstrated that age (OR = 0.820; 95%CI: 0.715–0.942), self-harming behavior (OR = 1.986; 95%CI: 1.157–3.410), PHQ-9 score (OR = 1.103; 95%CI: 1.053–1.157), normalized PRL (OR = 1.220; 95%CI: 1.108–1.343), and FT4 (OR = 1.215; 95%CI: 1.145–1.289) were independently associated with psychotic symptoms of MDD (Table 3).

Table 3 Logistic regression analyses for factors related to psychotic symptoms in patients with MDD a

Variables	B	Waldχ2	OR (95%CI)	P-value	
Age	–0.198	7.944	0.820(0.715–0.942)	0.005	
Self-harming behavior					
No	-	-	reference	-	
Yes	0.686	6.190	1.986(1.157–3.410)	0.013	
PHQ-9	0.098	16.775	1.103(1.053–1.157)	< 0.001	
FT4	0.195	41.456	1.215(1.145–1.289)	< 0.001	
PRL normalized	0.199	16.355	1.220(1.108–1.343)	< 0.001	
a Variables in the model: (Age, Education, Suicide attempt, PHQ-9, normalized PRL, T3, FT3, T4, FT4)

Note: OR = odds ratio; CI = confidence interval

Discussion

This is a large sample based clinical study to investigate the incidence of psychotic symptoms in Chinese patients (aged 12–18) with MDD, and to explore the association of psychotic symptoms with endocrine factors such as PRL and thyroid hormone. This cross-sectional study found that the prevalence of psychotic symptoms in patients with MDD was 22.6%. Normalized PRL and FT4, self-harming behaviors, and depressive symptoms might be the risk factors for psychotic symptoms in patients with MDD. This is basically consistent with our hypothesis.

Combined with previous epidemiological studies, there are some differences in the reported incidence of depression with psychotic symptoms. This may be due to factors such as the age range of participants, the severity of depression, and the method of assessment. First, adolescents with depression seem to be more likely to develop psychotic symptoms [8]. The prevalence of psychotic symptoms among MDD adolescents in this study was 22.6%, which is higher than among Chinese adults with major depression [31]. Second, the incidence of psychotic depression was much higher in the sample of patients with MDD. In a European study of patients who met the criteria for MDD, 18.5% also met the criteria for an episode of major depressive disorder with psychotic features [32]. By contrast, Xin et al. study found that the prevalence of psychotic features in depressed patients was about 9.2%, and it did not place a specific limit on the severity of depression [33]. Other previous studies have also reported that patients with psychotic symptoms have more severe depressive symptoms [34]. In addition, a previous study of MDD adolescents in China reported an incidence of up to 52% of psychotic symptoms. Their relatively broad definition of psychotic symptoms may be the main reason why the results are significantly higher than in other studies [35]. In summary, patients with MDD seem to have more psychotic symptoms, which should cause more clinical attention.

Patients with MDD and psychotic symptoms were more likely to report an earlier age of illness onset and have lower educational attainment than those without psychotic symptoms [2, 36]. This result is basically consistent with the findings of this study.

This study showed that the psychotic MDD group had a higher PRL level (PRL normalized by sex) than the non-psychotic MDD group. Although little evidence has been reported on PRL levels in patients with MDD and psychotic symptoms, the finding is agreed with previous research works that documented the positive correlations between PRL levels and psychiatric symptoms in adult patients with MDD and other prominent psychoses [37–40]. For instance, Asmahan Elgellaie’s study on adult patients with MDD reported that the plasma PRL was associated with psychiatric symptoms, such as psychoticism, paranoid ideation, and hostility [40]. Furthermore, some studies were inconsistent with the finding of this study. An investigation of 18 inpatients with delusional depression and 22 with non-delusional depression found no difference in PRL levels between the two groups [41]. However, their sample size was small and similar results are rarely reported. Patients with MDD and psychotic symptoms have higher levels of PRL, especially adolescents, which may be caused by a series of physiological and psychological factors. Hormonal fluctuations during adolescence often cause higher stress levels in adolescents. Many authors have argued that enhanced PRL secretion in early psychosis may be secondary to the increased stress reactivity at the onset of psychosis [42, 43]. Stress activates the HPA axis, thereby stimulating the pituitary gland to release stress hormones such as ACTH [44, 45]. In contrast, PRL release is also enhanced in response to stressors against the damage caused by stress and inhibiting the HPA axis reactivity as a protective role [46, 47]. Different from drug-induced hyperprolactinemia, Riecher-Rössler et al. have suggested that increased levels of PRL could directly enhance dopamine release by the feedback loop, thus triggering psychotic symptoms in patients [48, 49]. This result may explain why this study found that increased PRL was a risk factor for psychotic symptoms. However, some authors have suggested that no causal link may exist between PRL and the onset of psychiatric symptoms. Hyperprolactinemia could be just a simple stress-related phenomenon, and other stress-related hormones really play an essential role [42, 50]. Although the physiological importance of stress-induced PRL in psychotic depression remains unclear, considering the inflammation responses and cognitive impairment caused by hyperprolactinemia [51–53], more attention should be directed toward the side effects such as hyperprolactinemia in antidepressant–antipsychotic combinations therapies.

In this study, patients with MDD and psychotic symptoms had higher levels of T3, FT3, T4, and FT4 compared to those without psychotic symptoms. In addition, there was no significant difference in TSH levels between the two groups, which was inconsistent with previous studies [54]. Differences in thyroid levels at different ages may have contributed to the differences in inconsistent outcomes [55–57].There was no statistically significant difference between serum TT3 and TT4 levels in Chinese adult depression samples, and TSH level was considered to an independent risk factor for psychotic symptoms [31]. Based on hypotheses of previous research, TSH levels may increase the severity of psychotic symptoms and the risk of suicide in MDD through underlying mechanisms [58, 59], but our study did not verify this result (a positive correlation between TSH levels and psychotic symptoms). It is worth noting that a systematic review of thyroid hormones suggested that thyroid hormone levels, especially FT4 levels, seemed to correlate more strongly with clinical parameters than TSH levels [60]. This is basically consistent with our findings.

To date, only a limited number of studies explored the association between thyroid dysfunction and psychotic symptoms in patients with MDD, and the findings from these studies have been inconsistent. A recent Chinese study conducted in patients with MDD and psychotic symptoms found higher levels of T3 in female [61]. Yang et al. found increased FT4 level was negatively correlated with adolescence psychotic symptoms [35]. The inconsistencies in results could be attributed to variations in inclusion and exclusion criteria, methods of calculating thyroid hormone levels, and other related data across studies. The unique role of altered hormone levels during adolescence in adolescent-onset depression should be noted [62–64]. This study found that increased FT4 levels were independent risk factors for psychotic symptoms in patients with MDD. This result may be attributed to the fact that the thyroid hormone can promote the growth of dopamine neurons and increase dopamine synthesis [65–67], leading to psychotic symptoms such as hallucinations and delusions. In summary, the thyroid hormone may be a potential biological indicator to distinguish between non-psychotic MDD and psychotic MDD. The correlation between thyroid hormones and psychotic symptoms remains controversial. Future literature should further examine the possible relationship between thyroid levels and the development of psychotic symptoms in patients with MDD.

Several limitations are present in this study. First, psychotic symptoms should be assessed using a proprietary scale. In addition to examining the presence of hallucinations or delusions, additional psychopathological characteristics such as grandiosity, hostility, or excitement should be further explored in the future, which may imply different dimensions beyond psychotic depression (e.g., mixed properties). It was an important limitation that the Short Psychiatric Rating Scale (BPRS), the Psychiatric Depression Assessment Scale (PDAS) and the Hamilton Depression Scale (HAMD) were not be used in this study. In subsequent studies, we will be more rigorous and use more professional scales simultaneously to further improve accuracy and reduce limitations. Therefore, this study’s findings should be considered preliminary because they need to be confirmed in other studies before making any definitive conclusions. Second, this study does not prohibit the use of antidepressants. The subjects in this study were patients with MDD, and the researchers did not prevent them from using antidepressants from the perspective of severe disease course and life safety, which may have affected this study’s results. A long-term follow-up of patients with MDD should be conducted in the future. Third, the samples were the inpatients. Hence, this study’s findings cannot be extended to other patients in different settings, such as outpatients and community patients. Finally, stress may be involved in endocrine disorders and psychiatric symptoms in patients with MDD and psychotic symptoms. Future studies should also assess individual perceived stress levels using, for example, the perceived stress scale [68].

In conclusion, this study found psychotic symptoms in approximately two out of ten patients with MDD, implying that psychotic symptoms are relatively common among patients with MDD in the adolescent population, especially among the youngest and less educated. More importantly, this study demonstrated that the levels of normalized PRL and FT4, self-harming behaviors, and depressive symptoms might be the risk factors for patients with MDD and psychotic symptoms. It is suggested that clinicians should pay more attention to the psychotic symptoms, thyroid function and PRL level in patients with MDD.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material 1

Acknowledgements

We would like to thank all patients who participated in the study. We are grateful to all the physicians and nurses that participated in our current study and those research staff that contributed to the diagnosis of the subjects and clinical assessments.

Author contributions

SYS and WJ led the study design, and were the major contributor in writing the manuscript. KQY, KZ, TSZ, conceived the idea for the study. SYS, WJ, TLH, SYT, SYZ and LH analyzed and interpreted the patient data, and all co-authors critically revised the manuscript. All the authors approved the final version of the manuscript.

Funding

This study was supported by Zhejiang Provincial Natural Science Foundation of China (NO. LY22H090022), Shenzhen Fund for Guangdong Provincial High-level Clinical Key Specialties (No.SZGSP013), Shenzhen Science and technology research and Development Fund for Sustainable development project (No.KCXFZ20201221173613036), Zhejiang Provincial Medical health Project (NO. 2022RC256).

Data availability

The data used and analyzed during the study are available from the corresponding author if the request is reasonable.

Declarations

Ethics approval and consent to participate

The study protocol was reviewed and approved by the Institutional Review Board (IRB) of the Shenzhen Kangning Hospital (IRB:2020-k021-02) before the research was carried out. The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 200. Each participant obtained informed consent from their legal guardian before approving to participate in the study. Participants and their legal guardians received a full study description and voluntarily signed written informed consent.

Consent for publication

Not applicable.

Conflict of interest

The authors report no conflicts of interest in this work.

Abbreviations

MDD Major depressive disorder

PHQ-9 Patient Health Questionnaire-9

PRL Prolactin

TSH Thyroid-stimulating hormone

T3 Triiodothyronine

FT3 Free triiodothyronine

T4 Thyroxine

FT4 Free thyroxine

CADC A cohort study of Chinese adolescent depression

IRB The study proposal was approved by the Institutional Review Board

OR Odds ratio

CI Confidence interval

SD Standard deviation

CIs Confidence intervals

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Shiyu Sun, Wei Jin these authors have contributed equally to this work and share first authorship.
==== Refs
References

1. Kendler KS The genealogy of major depression: symptoms and signs of melancholia from 1880 to 1900 Mol Psychiatry 2017 22 11 1539 53 10.1038/mp.2017.148 28785109
Kendler KS. The genealogy of major depression: symptoms and signs of melancholia from 1880 to 1900. Mol Psychiatry. 2017;22(11):1539–53.28785109 10.1038/mp.2017.148
2. Gaudiano BA Dalrymple KL Zimmerman M Prevalence and clinical characteristics of psychotic versus nonpsychotic major depression in a general psychiatric outpatient clinic Depress Anxiety 2009 26 1 54 64 10.1002/da.20470 18781658
Gaudiano BA, Dalrymple KL, Zimmerman M. Prevalence and clinical characteristics of psychotic versus nonpsychotic major depression in a general psychiatric outpatient clinic. Depress Anxiety. 2009;26(1):54–64.18781658 10.1002/da.20470
3. Jääskeläinen E Juola T Korpela H Lehtiniemi H Nietola M Korkeila J Miettunen J Epidemiology of psychotic depression - systematic review and meta-analysis Psychol Med 2018 48 6 905 18 10.1017/S0033291717002501 28893329
Jääskeläinen E, Juola T, Korpela H, Lehtiniemi H, Nietola M, Korkeila J, Miettunen J. Epidemiology of psychotic depression - systematic review and meta-analysis. Psychol Med. 2018;48(6):905–18.28893329 10.1017/S0033291717002501
4. Shen Y Wei Y Yang XN Zhang G Du X Jia Q Zhu X Ma Y Lang X Luo X Psychotic symptoms in first-episode and drug naïve patients with major depressive disorder: prevalence and related clinical factors Depress Anxiety 2020 37 8 793 800 10.1002/da.23026 32383260
Shen Y, Wei Y, Yang XN, Zhang G, Du X, Jia Q, Zhu X, Ma Y, Lang X, Luo X, et al. Psychotic symptoms in first-episode and drug naïve patients with major depressive disorder: prevalence and related clinical factors. Depress Anxiety. 2020;37(8):793–800.32383260 10.1002/da.23026
5. Wigman JT van Nierop M Vollebergh WA Lieb R Beesdo-Baum K Wittchen HU van Os J Evidence that psychotic symptoms are prevalent in disorders of anxiety and depression, impacting on illness onset, risk, and severity–implications for diagnosis and ultra-high risk research Schizophr Bull 2012 38 2 247 57 10.1093/schbul/sbr196 22258882
Wigman JT, van Nierop M, Vollebergh WA, Lieb R, Beesdo-Baum K, Wittchen HU, van Os J. Evidence that psychotic symptoms are prevalent in disorders of anxiety and depression, impacting on illness onset, risk, and severity–implications for diagnosis and ultra-high risk research. Schizophr Bull. 2012;38(2):247–57.22258882 10.1093/schbul/sbr196
6. Zaninotto L Guglielmo R Calati R Ioime L Camardese G Janiri L Bria P Serretti A Cognitive markers of psychotic unipolar depression: a meta-analytic study J Affect Disord 2015 174 580 8 10.1016/j.jad.2014.11.027 25560194
Zaninotto L, Guglielmo R, Calati R, Ioime L, Camardese G, Janiri L, Bria P, Serretti A. Cognitive markers of psychotic unipolar depression: a meta-analytic study. J Affect Disord. 2015;174:580–8.25560194 10.1016/j.jad.2014.11.027
7. van Os J Linscott RJ Myin-Germeys I Delespaul P Krabbendam L A systematic review and meta-analysis of the psychosis continuum: evidence for a psychosis proneness-persistence-impairment model of psychotic disorder Psychol Med 2009 39 2 179 95 10.1017/S0033291708003814 18606047
van Os J, Linscott RJ, Myin-Germeys I, Delespaul P, Krabbendam L. A systematic review and meta-analysis of the psychosis continuum: evidence for a psychosis proneness-persistence-impairment model of psychotic disorder. Psychol Med. 2009;39(2):179–95.18606047 10.1017/S0033291708003814
8. Kelleher I Connor D Clarke MC Devlin N Harley M Cannon M Prevalence of psychotic symptoms in childhood and adolescence: a systematic review and meta-analysis of population-based studies Psychol Med 2012 42 9 1857 63 10.1017/S0033291711002960 22225730
Kelleher I, Connor D, Clarke MC, Devlin N, Harley M, Cannon M. Prevalence of psychotic symptoms in childhood and adolescence: a systematic review and meta-analysis of population-based studies. Psychol Med. 2012;42(9):1857–63.22225730 10.1017/S0033291711002960
9. Kahn RS Fleischhacker WW Boter H Davidson M Vergouwe Y Keet IP Gheorghe MD Rybakowski JK Galderisi S Libiger J Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomised clinical trial Lancet 2008 371 9618 1085 97 10.1016/S0140-6736(08)60486-9 18374841
Kahn RS, Fleischhacker WW, Boter H, Davidson M, Vergouwe Y, Keet IP, Gheorghe MD, Rybakowski JK, Galderisi S, Libiger J, et al. Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomised clinical trial. Lancet. 2008;371(9618):1085–97.18374841 10.1016/S0140-6736(08)60486-9
10. Aston J Rechsteiner E Bull N Borgwardt S Gschwandtner U Riecher-Rössler A Hyperprolactinaemia in early psychosis-not only due to antipsychotics Prog Neuro-psychopharmacol Biol Psychiatry 2010 34 7 1342 4 10.1016/j.pnpbp.2010.02.019
Aston J, Rechsteiner E, Bull N, Borgwardt S, Gschwandtner U, Riecher-Rössler A. Hyperprolactinaemia in early psychosis-not only due to antipsychotics. Prog Neuro-psychopharmacol Biol Psychiatry. 2010;34(7):1342–4.10.1016/j.pnpbp.2010.02.019
11. Garcia-Rizo C Fernandez-Egea E Oliveira C Justicia A Parellada E Bernardo M Kirkpatrick B Prolactin concentrations in newly diagnosed, antipsychotic-naïve patients with nonaffective psychosis Schizophr Res 2012 134 1 16 9 10.1016/j.schres.2011.07.025 21831600
Garcia-Rizo C, Fernandez-Egea E, Oliveira C, Justicia A, Parellada E, Bernardo M, Kirkpatrick B. Prolactin concentrations in newly diagnosed, antipsychotic-naïve patients with nonaffective psychosis. Schizophr Res. 2012;134(1):16–9.21831600 10.1016/j.schres.2011.07.025
12. Prabhakar VK Davis JR Hyperprolactinaemia Best Pract Res Clin Obstet Gynaecol 2008 22 2 341 53 10.1016/j.bpobgyn.2007.08.002 17889620
Prabhakar VK, Davis JR. Hyperprolactinaemia. Best Pract Res Clin Obstet Gynaecol. 2008;22(2):341–53.17889620 10.1016/j.bpobgyn.2007.08.002
13. Melmed S Casanueva FF Hoffman AR Kleinberg DL Montori VM Schlechte JA Wass JA Diagnosis and treatment of hyperprolactinemia: an endocrine Society clinical practice guideline J Clin Endocrinol Metab 2011 96 2 273 88 10.1210/jc.2010-1692 21296991
Melmed S, Casanueva FF, Hoffman AR, Kleinberg DL, Montori VM, Schlechte JA, Wass JA. Diagnosis and treatment of hyperprolactinemia: an endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(2):273–88.21296991 10.1210/jc.2010-1692
14. MacDonald AW Schulz SC What we know: findings that every theory of schizophrenia should explain Schizophr Bull 2009 35 3 493 508 10.1093/schbul/sbp017 19329559
MacDonald AW, Schulz SC. What we know: findings that every theory of schizophrenia should explain. Schizophr Bull. 2009;35(3):493–508.19329559 10.1093/schbul/sbp017
15. Snabboon T Khemkha A Chaiyaumporn C Lalitanantpong D Sridama V Psychosis as the first presentation of hyperthyroidism Intern Emerg Med 2009 4 4 359 60 10.1007/s11739-009-0259-y 19452134
Snabboon T, Khemkha A, Chaiyaumporn C, Lalitanantpong D, Sridama V. Psychosis as the first presentation of hyperthyroidism. Intern Emerg Med. 2009;4(4):359–60.19452134 10.1007/s11739-009-0259-y
16. Nishida A Tanii H Nishimura Y Kajiki N Inoue K Okada M Sasaki T Okazaki Y Associations between psychotic-like experiences and mental health status and other psychopathologies among Japanese early teens Schizophr Res 2008 99 1–3 125 33 10.1016/j.schres.2007.11.038 18248792
Nishida A, Tanii H, Nishimura Y, Kajiki N, Inoue K, Okada M, Sasaki T, Okazaki Y. Associations between psychotic-like experiences and mental health status and other psychopathologies among Japanese early teens. Schizophr Res. 2008;99(1–3):125–33.18248792 10.1016/j.schres.2007.11.038
17. Wigman JT van Os J Abidi L Huibers MJ Roelofs J Arntz A Kelleher I Peeters FP Subclinical psychotic experiences and bipolar spectrum features in depression: association with outcome of psychotherapy Psychol Med 2014 44 2 325 36 10.1017/S0033291713000871 23651602
Wigman JT, van Os J, Abidi L, Huibers MJ, Roelofs J, Arntz A, Kelleher I, Peeters FP. Subclinical psychotic experiences and bipolar spectrum features in depression: association with outcome of psychotherapy. Psychol Med. 2014;44(2):325–36.23651602 10.1017/S0033291713000871
18. Correll CU Effect of hyperprolactinemia during development in children and adolescents J Clin Psychiatry 2008 69 8 e24 10.4088/JCP.0808e24 18816151
Correll CU. Effect of hyperprolactinemia during development in children and adolescents. J Clin Psychiatry. 2008;69(8):e24.18816151 10.4088/JCP.0808e24
19. Yao C Wu M Liu M Chen X Zhu H Xiong C Wang D Xiang Y Suo G Wang J Age- and sex-specific reference intervals for thyroid hormones in a Chinese pediatrics: a prospective observational study of 1,279 healthy children Transl Pediatr 2021 10 10 2479 88 10.21037/tp-21-389 34765471
Yao C, Wu M, Liu M, Chen X, Zhu H, Xiong C, Wang D, Xiang Y, Suo G, Wang J, et al. Age- and sex-specific reference intervals for thyroid hormones in a Chinese pediatrics: a prospective observational study of 1,279 healthy children. Transl Pediatr. 2021;10(10):2479–88.34765471 10.21037/tp-21-389
20. Riglin L Hammerton G Heron J Collishaw S Arseneault L Thapar AK Maughan B O’Donovan MC Thapar A Developmental contributions of Schizophrenia risk alleles and childhood peer victimization to early-onset Mental Health trajectories Am J Psychiatry 2019 176 1 36 43 10.1176/appi.ajp.2018.18010075 30486671
Riglin L, Hammerton G, Heron J, Collishaw S, Arseneault L, Thapar AK, Maughan B, O’Donovan MC, Thapar A. Developmental contributions of Schizophrenia risk alleles and childhood peer victimization to early-onset Mental Health trajectories. Am J Psychiatry. 2019;176(1):36–43.30486671 10.1176/appi.ajp.2018.18010075
21. Ierago L Malsol C Singeo T Kishigawa Y Blailes F Ord L Florsheim P Phillips L Kuartei S Tiobech J Adoption, family relations and psychotic symptoms among Palauan adolescents who are genetically at risk for developing schizophrenia Soc Psychiatry Psychiatr Epidemiol 2010 45 12 1105 14 10.1007/s00127-009-0154-x 19885633
Ierago L, Malsol C, Singeo T, Kishigawa Y, Blailes F, Ord L, Florsheim P, Phillips L, Kuartei S, Tiobech J, et al. Adoption, family relations and psychotic symptoms among Palauan adolescents who are genetically at risk for developing schizophrenia. Soc Psychiatry Psychiatr Epidemiol. 2010;45(12):1105–14.19885633 10.1007/s00127-009-0154-x
22. Davies J Sullivan S Zammit S Adverse life outcomes associated with adolescent psychotic experiences and depressive symptoms Soc Psychiatry Psychiatr Epidemiol 2018 53 5 497 507 10.1007/s00127-018-1496-z 29556667
Davies J, Sullivan S, Zammit S. Adverse life outcomes associated with adolescent psychotic experiences and depressive symptoms. Soc Psychiatry Psychiatr Epidemiol. 2018;53(5):497–507.29556667 10.1007/s00127-018-1496-z
23. Kehinde F Bharmal AV Goodyer IM Kelvin R Dubicka B Midgley N Fonagy P Jones PB Wilkinson P Cross-sectional and longitudinal associations between psychotic and depressive symptoms in depressed adolescents Eur Child Adolesc Psychiatry 2022 31 5 729 36 10.1007/s00787-020-01704-3 33432401
Kehinde F, Bharmal AV, Goodyer IM, Kelvin R, Dubicka B, Midgley N, Fonagy P, Jones PB, Wilkinson P. Cross-sectional and longitudinal associations between psychotic and depressive symptoms in depressed adolescents. Eur Child Adolesc Psychiatry. 2022;31(5):729–36.33432401 10.1007/s00787-020-01704-3
24. Thapar A Collishaw S Pine DS Thapar AK Depression in adolescence Lancet 2012 379 9820 1056 67 10.1016/S0140-6736(11)60871-4 22305766
Thapar A, Collishaw S, Pine DS, Thapar AK. Depression in adolescence. Lancet. 2012;379(9820):1056–67.22305766 10.1016/S0140-6736(11)60871-4
25. Spitzer RL Kroenke K Williams JB Validation and utility of a self-report version of PRIME-MD: the PHQ primary care study. Primary care evaluation of Mental disorders Patient Health Questionnaire Jama 1999 282 18 1737 44 10568646
Spitzer RL, Kroenke K, Williams JB. Validation and utility of a self-report version of PRIME-MD: the PHQ primary care study. Primary care evaluation of Mental disorders. Patient Health Questionnaire Jama. 1999;282(18):1737–44.10568646
26. Leung DYP Mak YW Leung SF Chiang VCL Loke AY Measurement invariances of the PHQ-9 across gender and age groups in Chinese adolescents Asia Pac Psychiatry 2020 12 3 e12381 10.1111/appy.12381 32011101
Leung DYP, Mak YW, Leung SF, Chiang VCL, Loke AY. Measurement invariances of the PHQ-9 across gender and age groups in Chinese adolescents. Asia Pac Psychiatry. 2020;12(3):e12381.32011101 10.1111/appy.12381
27. Guo W Zhao Y Chen H Liu J Chen X Tang H Zhou J Wang X The bridge symptoms of childhood trauma, sleep disorder and depressive symptoms: a network analysis Child Adolesc Psychiatry Ment Health 2023 17 1 88 10.1186/s13034-023-00635-6 37403102
Guo W, Zhao Y, Chen H, Liu J, Chen X, Tang H, Zhou J, Wang X. The bridge symptoms of childhood trauma, sleep disorder and depressive symptoms: a network analysis. Child Adolesc Psychiatry Ment Health. 2023;17(1):88.37403102 10.1186/s13034-023-00635-6
28. Accuracy of Patient Health Questionnaire-9 (PHQ-9) for screening to detect major depression: individual participant data meta-analysis BMJ 2019 365 l1781 30979729
Accuracy of Patient Health. Questionnaire-9 (PHQ-9) for screening to detect major depression: individual participant data meta-analysis. BMJ. 2019;365:l1781.30979729
29. Migliardi G Spina E D’Arrigo C Gagliano A Germanò E Siracusano R Diaz FJ de Leon J Short- and long-term effects on prolactin of risperidone and olanzapine treatments in children and adolescents Prog Neuro-psychopharmacol Biol Psychiatry 2009 33 8 1496 501 10.1016/j.pnpbp.2009.08.009
Migliardi G, Spina E, D’Arrigo C, Gagliano A, Germanò E, Siracusano R, Diaz FJ, de Leon J. Short- and long-term effects on prolactin of risperidone and olanzapine treatments in children and adolescents. Prog Neuro-psychopharmacol Biol Psychiatry. 2009;33(8):1496–501.10.1016/j.pnpbp.2009.08.009
30. Studerus E Ittig S Beck K Del Cacho N Vila-Badia R Butjosa A Usall J Riecher-Rössler A Relation between self-perceived stress, psychopathological symptoms and the stress hormone prolactin in emerging psychosis J Psychiatr Res 2021 136 428 34 10.1016/j.jpsychires.2020.06.014 32948308
Studerus E, Ittig S, Beck K, Del Cacho N, Vila-Badia R, Butjosa A, Usall J, Riecher-Rössler A. Relation between self-perceived stress, psychopathological symptoms and the stress hormone prolactin in emerging psychosis. J Psychiatr Res. 2021;136:428–34.32948308 10.1016/j.jpsychires.2020.06.014
31. Peng P Wang Q Ren H Zhou Y Hao Y Chen S Wu Q Li M Wang Y Yang Q Association between thyroid hormones and comorbid psychotic symptoms in patients with first-episode and drug-naïve major depressive disorder Psychiatry Res 2023 320 115052 10.1016/j.psychres.2023.115052 36645990
Peng P, Wang Q, Ren H, Zhou Y, Hao Y, Chen S, Wu Q, Li M, Wang Y, Yang Q, et al. Association between thyroid hormones and comorbid psychotic symptoms in patients with first-episode and drug-naïve major depressive disorder. Psychiatry Res. 2023;320:115052.36645990 10.1016/j.psychres.2023.115052
32. Ohayon MM Schatzberg AF Prevalence of depressive episodes with psychotic features in the general population Am J Psychiatry 2002 159 11 1855 61 10.1176/appi.ajp.159.11.1855 12411219
Ohayon MM, Schatzberg AF. Prevalence of depressive episodes with psychotic features in the general population. Am J Psychiatry. 2002;159(11):1855–61.12411219 10.1176/appi.ajp.159.11.1855
33. Xin LM Su YA Yan F Yang FD Wang G Fang YR Lu Z Yang HC Hu J Chen ZY Prevalence, clinical features and prescription patterns of psychotropic medications for patients with psychotic depression in China J Affect Disord 2022 301 248 52 10.1016/j.jad.2022.01.063 35038478
Xin LM, Su YA, Yan F, Yang FD, Wang G, Fang YR, Lu Z, Yang HC, Hu J, Chen ZY, et al. Prevalence, clinical features and prescription patterns of psychotropic medications for patients with psychotic depression in China. J Affect Disord. 2022;301:248–52.35038478 10.1016/j.jad.2022.01.063
34. Dold M, Bartova L, Kautzky A, Porcelli S, Montgomery S, Zohar J, Mendlewicz J, Souery D, Serretti A, Kasper S. Psychotic features in patients with major depressive disorder: a Report from the European Group for the study of resistant depression. J Clin Psychiatry 2019, 80(1).
35. Yang R Zhu F Yue Y Lu X Zhu P Li Z Zhao X Yang X Zhou Y Du X Association between thyroid function and psychotic symptoms in adolescents with major depressive disorder: a large sample sized cross-sectional study in China Heliyon 2023 9 6 e16770 10.1016/j.heliyon.2023.e16770 37303557
Yang R, Zhu F, Yue Y, Lu X, Zhu P, Li Z, Zhao X, Yang X, Zhou Y, Du X. Association between thyroid function and psychotic symptoms in adolescents with major depressive disorder: a large sample sized cross-sectional study in China. Heliyon. 2023;9(6):e16770.37303557 10.1016/j.heliyon.2023.e16770
36. Zalpuri I Rothschild AJ Does psychosis increase the risk of suicide in patients with major depression? A systematic review J Affect Disord 2016 198 23 31 10.1016/j.jad.2016.03.035 26998793
Zalpuri I, Rothschild AJ. Does psychosis increase the risk of suicide in patients with major depression? A systematic review. J Affect Disord. 2016;198:23–31.26998793 10.1016/j.jad.2016.03.035
37. Tsuchiya K Studies on prolactin in major psychoses–with reference to prolactin response to stress in schizophrenia Folia Psychiatr Neurol Jpn 1984 38 1 53 6 6537392
Tsuchiya K. Studies on prolactin in major psychoses–with reference to prolactin response to stress in schizophrenia. Folia Psychiatr Neurol Jpn. 1984;38(1):53–6.6537392
38. Reavley A Fisher AD Owen D Creed FH Davis JR Psychological distress in patients with hyperprolactinaemia Clin Endocrinol (Oxf) 1997 47 3 343 8 10.1046/j.1365-2265.1997.2701073.x 9373457
Reavley A, Fisher AD, Owen D, Creed FH, Davis JR. Psychological distress in patients with hyperprolactinaemia. Clin Endocrinol (Oxf). 1997;47(3):343–8.9373457 10.1046/j.1365-2265.1997.2701073.x
39. Tharoor H Mohan G Gopal S Title of the article: sex hormones and psychopathology in drug naïve Schizophrenia Asian J Psychiatry 2020 52 102042 10.1016/j.ajp.2020.102042
Tharoor H, Mohan G, Gopal S. Title of the article: sex hormones and psychopathology in drug naïve Schizophrenia. Asian J Psychiatry. 2020;52:102042.10.1016/j.ajp.2020.102042
40. Elgellaie A Larkin T Kaelle J Mills J Thomas S Plasma prolactin is higher in major depressive disorder and females, and associated with anxiety, hostility, somatization, psychotic symptoms and heart rate Compr Psychoneuroendocrinol 2021 6 100049 10.1016/j.cpnec.2021.100049 35757357
Elgellaie A, Larkin T, Kaelle J, Mills J, Thomas S. Plasma prolactin is higher in major depressive disorder and females, and associated with anxiety, hostility, somatization, psychotic symptoms and heart rate. Compr Psychoneuroendocrinol. 2021;6:100049.35757357 10.1016/j.cpnec.2021.100049
41. Lykouras E Markianos M Malliaras D Stefanis C Neurochemical variables in delusional depression Am J Psychiatry 1988 145 2 214 7 10.1176/ajp.145.2.214 2449085
Lykouras E, Markianos M, Malliaras D, Stefanis C. Neurochemical variables in delusional depression. Am J Psychiatry. 1988;145(2):214–7.2449085 10.1176/ajp.145.2.214
42. Labad J The role of cortisol and prolactin in the pathogenesis and clinical expression of psychotic disorders Psychoneuroendocrinology 2019 102 24 36 10.1016/j.psyneuen.2018.11.028 30503781
Labad J. The role of cortisol and prolactin in the pathogenesis and clinical expression of psychotic disorders. Psychoneuroendocrinology. 2019;102:24–36.30503781 10.1016/j.psyneuen.2018.11.028
43. Tost M Monreal JA Armario A Barbero JD Cobo J García-Rizo C Bioque M Usall J Huerta-Ramos E Soria V Targeting hormones for improving Cognition in Major Mood disorders and Schizophrenia: thyroid hormones and prolactin Clin Drug Investig 2020 40 1 1 14 10.1007/s40261-019-00854-w 31612424
Tost M, Monreal JA, Armario A, Barbero JD, Cobo J, García-Rizo C, Bioque M, Usall J, Huerta-Ramos E, Soria V, et al. Targeting hormones for improving Cognition in Major Mood disorders and Schizophrenia: thyroid hormones and prolactin. Clin Drug Investig. 2020;40(1):1–14.31612424 10.1007/s40261-019-00854-w
44. Zorn JV Schür RR Boks MP Kahn RS Joëls M Vinkers CH Cortisol stress reactivity across psychiatric disorders: a systematic review and meta-analysis Psychoneuroendocrinology 2017 77 25 36 10.1016/j.psyneuen.2016.11.036 28012291
Zorn JV, Schür RR, Boks MP, Kahn RS, Joëls M, Vinkers CH. Cortisol stress reactivity across psychiatric disorders: a systematic review and meta-analysis. Psychoneuroendocrinology. 2017;77:25–36.28012291 10.1016/j.psyneuen.2016.11.036
45. Turner AI Smyth N Hall SJ Torres SJ Hussein M Jayasinghe SU Ball K Clow AJ Psychological stress reactivity and future health and disease outcomes: a systematic review of prospective evidence Psychoneuroendocrinology 2020 114 104599 10.1016/j.psyneuen.2020.104599 32045797
Turner AI, Smyth N, Hall SJ, Torres SJ, Hussein M, Jayasinghe SU, Ball K, Clow AJ. Psychological stress reactivity and future health and disease outcomes: a systematic review of prospective evidence. Psychoneuroendocrinology. 2020;114:104599.32045797 10.1016/j.psyneuen.2020.104599
46. Torner L Toschi N Nava G Clapp C Neumann ID Increased hypothalamic expression of prolactin in lactation: involvement in behavioural and neuroendocrine stress responses Eur J Neurosci 2002 15 8 1381 9 10.1046/j.1460-9568.2002.01965.x 11994132
Torner L, Toschi N, Nava G, Clapp C, Neumann ID. Increased hypothalamic expression of prolactin in lactation: involvement in behavioural and neuroendocrine stress responses. Eur J Neurosci. 2002;15(8):1381–9.11994132 10.1046/j.1460-9568.2002.01965.x
47. Torner L Actions of Prolactin in the brain: from physiological adaptations to stress and neurogenesis to psychopathology Front Endocrinol (Lausanne) 2016 7 25 10.3389/fendo.2016.00025 27065946
Torner L. Actions of Prolactin in the brain: from physiological adaptations to stress and neurogenesis to psychopathology. Front Endocrinol (Lausanne). 2016;7:25.27065946 10.3389/fendo.2016.00025
48. Riecher-Rössler A Oestrogens, prolactin, hypothalamic-pituitary-gonadal axis, and schizophrenic psychoses Lancet Psychiatry 2017 4 1 63 72 10.1016/S2215-0366(16)30379-0 27856396
Riecher-Rössler A. Oestrogens, prolactin, hypothalamic-pituitary-gonadal axis, and schizophrenic psychoses. Lancet Psychiatry. 2017;4(1):63–72.27856396 10.1016/S2215-0366(16)30379-0
49. Lally J Ajnakina O Stubbs B Williams HR Colizzi M Carra E Fraietta S Gardner-Sood P Greenwood KE Atakan Z Hyperprolactinaemia in first episode psychosis - A longitudinal assessment Schizophr Res 2017 189 117 25 10.1016/j.schres.2017.07.037 28755878
Lally J, Ajnakina O, Stubbs B, Williams HR, Colizzi M, Carra E, Fraietta S, Gardner-Sood P, Greenwood KE, Atakan Z, et al. Hyperprolactinaemia in first episode psychosis - A longitudinal assessment. Schizophr Res. 2017;189:117–25.28755878 10.1016/j.schres.2017.07.037
50. Demarest KT Moore KE Comparison of dopamine synthesis regulation in the terminals of nigrostriatal, mesolimbic, tuberoinfundibular and tuberohypophyseal neurons J Neural Transm 1979 46 4 263 77 10.1007/BF01259333 528998
Demarest KT, Moore KE. Comparison of dopamine synthesis regulation in the terminals of nigrostriatal, mesolimbic, tuberoinfundibular and tuberohypophyseal neurons. J Neural Transm. 1979;46(4):263–77.528998 10.1007/BF01259333
51. Montalvo I Gutiérrez-Zotes A Creus M Monseny R Ortega L Franch J Lawrie SM Reynolds RM Vilella E Labad J Increased prolactin levels are associated with impaired processing speed in subjects with early psychosis PLoS ONE 2014 9 2 e89428 10.1371/journal.pone.0089428 24586772
Montalvo I, Gutiérrez-Zotes A, Creus M, Monseny R, Ortega L, Franch J, Lawrie SM, Reynolds RM, Vilella E, Labad J. Increased prolactin levels are associated with impaired processing speed in subjects with early psychosis. PLoS ONE. 2014;9(2):e89428.24586772 10.1371/journal.pone.0089428
52. Labad J Stojanovic-Pérez A Montalvo I Solé M Cabezas Á Ortega L Moreno I Vilella E Martorell L Reynolds RM Stress biomarkers as predictors of transition to psychosis in at-risk mental states: roles for cortisol, prolactin and albumin J Psychiatr Res 2015 60 163 9 10.1016/j.jpsychires.2014.10.011 25466832
Labad J, Stojanovic-Pérez A, Montalvo I, Solé M, Cabezas Á, Ortega L, Moreno I, Vilella E, Martorell L, Reynolds RM, et al. Stress biomarkers as predictors of transition to psychosis in at-risk mental states: roles for cortisol, prolactin and albumin. J Psychiatr Res. 2015;60:163–9.25466832 10.1016/j.jpsychires.2014.10.011
53. Montalvo I Llorens M Caparrós L Pamias M Torralbas J Giménez-Palop O Caixàs A Palao DJ Labad J Improvement in cognitive abilities following cabergoline treatment in patients with a prolactin-secreting pituitary adenoma Int Clin Psychopharmacol 2018 33 2 98 102 10.1097/YIC.0000000000000199 29035904
Montalvo I, Llorens M, Caparrós L, Pamias M, Torralbas J, Giménez-Palop O, Caixàs A, Palao DJ, Labad J. Improvement in cognitive abilities following cabergoline treatment in patients with a prolactin-secreting pituitary adenoma. Int Clin Psychopharmacol. 2018;33(2):98–102.29035904 10.1097/YIC.0000000000000199
54. Contreras F Menchon JM Urretavizcaya M Navarro MA Vallejo J Parker G Hormonal differences between psychotic and non-psychotic melancholic depression J Affect Disord 2007 100 1–3 65 73 10.1016/j.jad.2006.09.021 17098292
Contreras F, Menchon JM, Urretavizcaya M, Navarro MA, Vallejo J, Parker G. Hormonal differences between psychotic and non-psychotic melancholic depression. J Affect Disord. 2007;100(1–3):65–73.17098292 10.1016/j.jad.2006.09.021
55. da Costa VM Moreira DG Rosenthal D Thyroid function and aging: gender-related differences J Endocrinol 2001 171 1 193 8 10.1677/joe.0.1710193 11572803
da Costa VM, Moreira DG, Rosenthal D. Thyroid function and aging: gender-related differences. J Endocrinol. 2001;171(1):193–8.11572803 10.1677/joe.0.1710193
56. Samuels MH Subclinical hypothyroidism and depression: is there a link? J Clin Endocrinol Metab 2018 103 5 2061 4 10.1210/jc.2018-00276 29481656
Samuels MH. Subclinical hypothyroidism and depression: is there a link? J Clin Endocrinol Metab. 2018;103(5):2061–4.29481656 10.1210/jc.2018-00276
57. Kerp H Gassen J Führer D Age and sex influence thyroid hormone effects in Target tissues with organ-specific responses Exp Clin Endocrinol Diabetes 2020 128 6–07 469 72 31931531
Kerp H, Gassen J, Führer D. Age and sex influence thyroid hormone effects in Target tissues with organ-specific responses. Exp Clin Endocrinol Diabetes. 2020;128(6–07):469–72.31931531
58. Lang X Hou X Shangguan F Zhang XY Prevalence and clinical correlates of subclinical hypothyroidism in first-episode drug-naive patients with major depressive disorder in a large sample of Chinese J Affect Disord 2020 263 507 15 10.1016/j.jad.2019.11.004 31759671
Lang X, Hou X, Shangguan F, Zhang XY. Prevalence and clinical correlates of subclinical hypothyroidism in first-episode drug-naive patients with major depressive disorder in a large sample of Chinese. J Affect Disord. 2020;263:507–15.31759671 10.1016/j.jad.2019.11.004
59. Liu W Wu Z Sun M Zhang S Yuan J Zhu D Yan G Hou K Association between fasting blood glucose and thyroid stimulating hormones and suicidal tendency and disease severity in patients with major depressive disorder Bosn J Basic Med Sci 2022 22 4 635 42 35238287
Liu W, Wu Z, Sun M, Zhang S, Yuan J, Zhu D, Yan G, Hou K. Association between fasting blood glucose and thyroid stimulating hormones and suicidal tendency and disease severity in patients with major depressive disorder. Bosn J Basic Med Sci. 2022;22(4):635–42.35238287
60. Fitzgerald SP Bean NG Falhammar H Tuke J Clinical parameters are more likely to be Associated with thyroid hormone levels than with thyrotropin levels: a systematic review and Meta-analysis Thyroid 2020 30 12 1695 709 10.1089/thy.2019.0535 32349628
Fitzgerald SP, Bean NG, Falhammar H, Tuke J. Clinical parameters are more likely to be Associated with thyroid hormone levels than with thyrotropin levels: a systematic review and Meta-analysis. Thyroid. 2020;30(12):1695–709.32349628 10.1089/thy.2019.0535
61. Tan BF Lu XJ Yao JW Qin X Comparison of thyroid hormone levels in depressive adolescent patients with or without psychotic symp- toms J Clin Psychiatry 2022 32 3 224 6
Tan BF, Lu XJ, Yao JW, Qin X. Comparison of thyroid hormone levels in depressive adolescent patients with or without psychotic symp- toms. J Clin Psychiatry. 2022;32(3):224–6.
62. Botteron KN Editorial: it’s complicated: Adrenarcheal and Pubertal Hormonal Influence on Brain Development J Am Acad Child Adolesc Psychiatry 2020 59 6 699 700 10.1016/j.jaac.2020.04.007 32311474
Botteron KN. Editorial: it’s complicated: Adrenarcheal and Pubertal Hormonal Influence on Brain Development. J Am Acad Child Adolesc Psychiatry. 2020;59(6):699–700.32311474 10.1016/j.jaac.2020.04.007
63. Flach E Koenig J van der Venne P Parzer P Resch F Kaess M Hypothalamic-pituitary-thyroid axis function in female adolescent nonsuicidal self-injury and its association with comorbid borderline personality disorder and depression Prog Neuro-psychopharmacol Biol Psychiatry 2021 111 110345 10.1016/j.pnpbp.2021.110345
Flach E, Koenig J, van der Venne P, Parzer P, Resch F, Kaess M. Hypothalamic-pituitary-thyroid axis function in female adolescent nonsuicidal self-injury and its association with comorbid borderline personality disorder and depression. Prog Neuro-psychopharmacol Biol Psychiatry. 2021;111:110345.10.1016/j.pnpbp.2021.110345
64. Hirtz R Libuda L Hinney A Föcker M Bühlmeier J Antel J Holterhus PM Kulle A Kiewert C Hebebrand J Lack of evidence for a relationship between the hypothalamus-pituitary-adrenal and the hypothalamus-pituitary-thyroid Axis in Adolescent Depression Front Endocrinol (Lausanne) 2021 12 662243 10.3389/fendo.2021.662243 34108936
Hirtz R, Libuda L, Hinney A, Föcker M, Bühlmeier J, Antel J, Holterhus PM, Kulle A, Kiewert C, Hebebrand J, et al. Lack of evidence for a relationship between the hypothalamus-pituitary-adrenal and the hypothalamus-pituitary-thyroid Axis in Adolescent Depression. Front Endocrinol (Lausanne). 2021;12:662243.34108936 10.3389/fendo.2021.662243
65. Chen C Ma Q Deng P Yang J Yang L Lin M Yu Z Zhou Z Critical role of TRPC1 in thyroid hormone-dependent dopaminergic neuron development Biochim Biophys Acta Mol Cell Res 2017 1864 10 1900 12 10.1016/j.bbamcr.2017.07.019 28779972
Chen C, Ma Q, Deng P, Yang J, Yang L, Lin M, Yu Z, Zhou Z. Critical role of TRPC1 in thyroid hormone-dependent dopaminergic neuron development. Biochim Biophys Acta Mol Cell Res. 2017;1864(10):1900–12.28779972 10.1016/j.bbamcr.2017.07.019
66. Lee EH Kim SM Kim CH Pagire SH Pagire HS Chung HY Ahn JH Park CH Dopamine neuron induction and the neuroprotective effects of thyroid hormone derivatives Sci Rep 2019 9 1 13659 10.1038/s41598-019-49876-6 31541140
Lee EH, Kim SM, Kim CH, Pagire SH, Pagire HS, Chung HY, Ahn JH, Park CH. Dopamine neuron induction and the neuroprotective effects of thyroid hormone derivatives. Sci Rep. 2019;9(1):13659.31541140 10.1038/s41598-019-49876-6
67. Hassan WA Rahman TA Aly MS Shahat AS Alterations in monoamines level in discrete brain regions and other peripheral tissues in young and adult male rats during experimental hyperthyroidism Int J Dev Neurosci 2013 31 5 311 8 10.1016/j.ijdevneu.2013.03.003 23501473
Hassan WA, Rahman TA, Aly MS, Shahat AS. Alterations in monoamines level in discrete brain regions and other peripheral tissues in young and adult male rats during experimental hyperthyroidism. Int J Dev Neurosci. 2013;31(5):311–8.23501473 10.1016/j.ijdevneu.2013.03.003
68. Cohen S Kamarck T Mermelstein R A global measure of perceived stress J Health Soc Behav 1983 24 4 385 96 10.2307/2136404 6668417
Cohen S, Kamarck T, Mermelstein R. A global measure of perceived stress. J Health Soc Behav. 1983;24(4):385–96.6668417 10.2307/2136404
