Association of clinical correlates, metabolic parameters, and thyroid hormones with suicide attempts in first-episode and drug-naïve adolescent depression comorbid with anxiety: a large-scale cross-sectional study

doi:10.21203/rs.3.rs-4941266/v1

Background

The prevalence of youth depression is rising, making the identification of reliable biomarkers for early detection increasingly challenging. This study explores potential biomarkers in youth experiencing their first depressive episode, with comorbid anxiety, and metabolic or thyroid imbalances.

Methods

We recruited 399 participants and measured thyroid stimulating hormone (TSH), triiodothyronine (FT3), free thyroxine (FT4), fasting blood glucose (FBG), cholesterol levels, body mass index (BMI), and blood pressure.

Results

Participants with abnormal TSH levels exhibited longer durations of depression, higher rates of suicidal behavior, increased anxiety, and more severe psychotic symptoms. Significant differences were observed in FBG, cholesterol levels, blood pressure, and BMI. Suicidal behavior was associated with higher TSH levels, anti-thyroglobulin antibodies (A-TG), and total cholesterol (TC), as well as lower high-density lipoprotein cholesterol (HDL-C) and BMI.

Conclusions

Our findings indicate a higher incidence of suicidal behaviors in youth with major depressive disorder (MDD) and comorbid anxiety symptoms. Elevated TSH levels, abnormal TC and HDL-C levels, and metabolic dysfunctions are significant risk factors. These findings underscore the importance of monitoring these biomarkers in managing youth with MDD.

Adolescent Depression

Suicidal Behavior

Thyroid Stimulating Hormone

Biomarkers

Metabolic dysfunctions

The prevalence of major depressive disorder (MDD) among adolescents has significantly increased in recent years, making it a critical public health concern[1, 2]. Despite this rise, early detection and intervention remain challenging, particularly in identifying reliable risk factors[3, 4]. Most existing studies focus on adult populations, leaving a gap in our understanding of the physiological factors associated with adolescent depression[5, 6]. Furthermore, MDD often co-occurs with anxiety disorders, a comorbidity that elevates the risk of suicidal behavior[7, 8].

Previous research has suggested correlations between physiological factors—such as thyroid-stimulating hormone (TSH), blood glucose levels, cholesterol levels, body mass index (BMI), blood pressure, and imbalances inflammation resolution—and depressive symptoms [9–11]. However, the role of these biomarkers in predicting suicide risk among adolescents experiencing their first depressive episode, especially those with comorbid anxiety symptoms, remains unclear[12]. This study aims to address this gap by exploring the relationship between these physiological biomarkers and the severity of depressive symptoms and suicidal behaviors in this population.

This research is novel in its focus on the biomarkers of metabolic function and thyroid hormone imbalances in adolescents experiencing their first depressive episode with comorbid anxiety symptoms. We hypothesize that abnormal levels of TSH, metabolic dysfunctions (e.g., abnormal cholesterol levels), and other physiological factors are significantly associated with the severity of depressive symptoms and the incidence of suicidal behaviors. Our comprehensive assessment of 399 participants includes measurements of TSH, triiodothyronine (FT3), free thyroxine (FT4), fasting blood glucose (FBG), cholesterol levels, BMI, and blood pressure.

The findings from this study will contribute to improving early detection and intervention strategies for adolescent depression, reducing the negative impact of MDD on young individuals.

Participants

This study was reviewed and approved by the Institutional Review Boards of the First Hospital of Shanxi Medical University. Written informed consent was obtained from all participants or their guardians. From 2015 to 2017, 399 patients were enrolled in the Department of Psychiatry at the First Clinical Medical College of Shanxi Medical University.

Participants had to be 10 to 22 years old, diagnosed with major depressive disorder (MDD) per DSM-V criteria, experiencing their first episode, drug-naive, and have a Hamilton Rating Scale for Depression (HAMD) score of 24 or higher. Exclusion criteria included the presence of other major Axis I disorders, severe physical illnesses, substance abuse or dependence, or pregnancy. Participants were recruited from Shanxi Medical University and the study protocol was reviewed by the Shanxi and Shanghai ethics committees.

Clinical interviews and assessments

Demographic information, including sex, highest education level, and marital status, was collected from the participants through structured interviews. Participants also reported any history of suicidal attempts, with additional details on frequency, dates, and methods recorded for those with such a history. Depressive, anxiety, and psychotic symptoms were assessed using the Chinese version of the 17-item Hamilton Rating Scale for Depression (HAMD-17), the Hamilton Rating Scale for Anxiety (HAMA), and the Positive and Negative Syndrome Scale (PANSS), respectively.

The PANSS evaluation specifically targeted items related to delusions, conceptual disorganization, hallucinations, excitement, suspiciousness/persecution, and hostility, as well as the total scores of positive syndromes. The Clinical Global Impressions Scale (CGI) was also used for participant evaluation. These well-established assessment tools are recognized for their high validity and reliability in the field.

Structured clinical interviews were conducted by trained psychiatrists at the mental health center. The threshold for comorbid anxiety symptoms in MDD patients was set at a HAMA score of 18, based on established guidelines.

Physical and biochemical parameters measurements

Metabolic and hormonal conditions were assessed through measurements of biochemical and metabolic markers, including TSH, antithyroglobulin antibody (A-TG), FT3, FT4, FBG, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and BMI (calculated as weight [in kilograms]/height [in meters] squared). Fasting blood samples were collected for these measurements, following standard laboratory procedures. Physiological parameters such as systolic blood pressure (SBP) and diastolic blood pressure (DBP) were also evaluated, with measurements taken multiple times and averaged to ensure accuracy.

Statistical analysis

We used Chi-square tests for categorical data, ANOVA for continuous variables, Mann-Whitney U test for non-normally distributed variables, and Kolmogorov-Smirnov test to check for normal distribution. Bonferroni correction was applied for multiple testing. Risk factors for suicide attempts in MDD patients with anxiety were assessed through univariate analysis and logistic regression. The AUCROC, with an acceptable range of 0.7–0.8, evaluated parameter discrimination[13, 14]. Multivariate regression analyzed the link between suicide attempt frequency and clinical/biochemical factors. Data was analyzed in SPSS 23.0 and visualized in GraphPad Prism 6.0, with a significance level of 0.05 for two-tailed p-values.

Clinical and Biochemical Differences Between Participants with Normal and Abnormal TSH Levels

Based on their TSH (Thyroid Stimulating Hormone) levels, participants were initially divided into two groups: those with abnormal TSH levels (defined as outside the normal reference range) and those with normal levels. Univariate analysis, specifically independent T-tests and chi-square tests was employed to investigate potential differences in clinical characteristics between the two groups. The analysis indicated that individuals with a longer duration of MDD tended to have higher abnormal TSH levels.

Notably, a significantly higher incidence of suicidal behavior was observed in participants with abnormal TSH levels (p< 0.001). Moreover, both the Hamilton Rating Scale for Depression (HAMD) and the Hamilton Rating Scale for Anxiety (HAMA) scores were significantly higher in participants with abnormal TSH levels compared to those with normal levels (p< 0.001). Differences in anxiety levels, psychotic symptoms, and other psychopathological characteristics such as delusions, hostility, and disorganized thinking were also observed between the two groups (all p< 0.001).

Furthermore, there were significant differences in physiological and biochemical indices, including antithyroglobulin antibody (A-TG), cholesterol levels, body mass index (BMI), fasting blood glucose (FBG), and blood pressure (BP), between the groups (allp < 0.05). Individuals with abnormal TSH levels exhibited higher levels of A-TG, FBG, TC, LDL-C, BMI, and BP while showing lower high-density lipoprotein cholesterol (HDL-C) levels (all p< 0.05; see Table 1).

Table 1

Demographic, Psychopathological, Biochemical, and Physiological Characteristics of Participants Stratified by Thyroid Stimulating Hormone (TSH) Levels
Item	Category	Total Cohort	TSH Normal Group	TSH Abnormal Group	P Value
Actual Age		19.00 (18.00–21.00)	19.00 (18.00–20.00)	19.00 (18.00–21.00)	0.1738
Disease Duration (Month)		3.50 (2.50–5.50)	3.00 (2.50–4.50)	4.00 (2.50–6.00)	0.0139
Age of Onset		19.00 (18.00–21.00)	19.00 (18.00–20.00)	19.00 (18.00–21.00)	0.0887
Sex	Male	170 (42.61)	74 (41.57)	96 (43.44)	0.7079
	Female	229 (57.39)	104 (58.43)	125 (56.56)
	Total	399 (100.00)	178 (100.00)	221 (100.00)
Education	Junior High	10 (2.51)	6 (3.37)	4 (1.81)	0.6443
	High School	248 (62.16)	111 (62.36)	137 (61.99)
	University	131 (32.83)	55 (30.90)	76 (34.39)
	Graduate	10 (2.51)	6 (3.37)	4 (1.81)
	Total	399 (100.00)	178 (100.00)	221 (100.00)
Marriage	Single	360 (90.23)	154 (86.52)	206 (93.21)	0.0252
	Married	39 (9.77)	24 (13.48)	15 (6.79)
	Total	399 (100.00)	178 (100.00)	221 (100.00)
Suicidal Behavior	No Suicidal Behavior	336 (84.21)	166 (93.26)	170 (76.92)	< .0001
	Suicidal Behavior	63 (15.79)	12 (6.74)	51 (23.08)
	Total	399 (100.00)	178 (100.00)	221 (100.00)
Anxiety	Without Severe Anxiety	364 (91.23)	171 (96.07)	193 (87.33)	0.0022
	Severe Anxiety	35 (8.77)	7 (3.93)	28 (12.67)
	Total	399 (100.00)	178 (100.00)	221 (100.00)
Psychotic Symptom	Without Psychotic Symptom	357 (89.47)	169 (94.94)	188 (85.07)	0.0014
	Psychotic Symptom	42 (10.53)	9 (5.06)	33 (14.93)
	Total	399 (100.00)	178 (100.00)	221 (100.00)
HAMD Score		30.00 (28.00–32.00)	28.00 (26.00–30.00)	31.00 (29.00–33.00)	< .0001
HAMA Score		21.00 (18.00–22.00)	19.00 (17.00–22.00)	21.00 (19.00–23.00)	< .0001
Delusion	Level 1	357 (89.47)	169 (94.94)	188 (85.07)	0.0017
	Level 3	2 (0.50)	0 (0.00)	2 (0.90)
	Level 4	20 (5.01)	3 (1.69)	17 (7.69)
	Level 5	14 (3.51)	5 (2.81)	9 (4.07)
	Level 6	6 (1.50)	1 (0.56)	5 (2.26)
	Total	399 (100.00)	178 (100.00)	221 (100.00)
Disorganized Thinking	Level 1	342 (85.71)	166 (93.26)	176 (79.64)	0.0001
	Level 2	26 (6.52)	4 (2.25)	22 (9.95)
	Level 3	17 (4.26)	5 (2.81)	12 (5.43)
	Level 4	11 (2.76)	2 (1.12)	9 (4.07)
	Level 5	3 (0.75)	1 (0.56)	2 (0.90)
	Total	399 (100.00)	178 (100.00)	221 (100.00)
Hallucinatory Behavior	Level 1	357 (89.47)	169 (94.94)	188 (85.07)	0.0017
	Level 3	6 (1.50)	0 (0.00)	6 (2.71)
	Level 4	21 (5.26)	5 (2.81)	16 (7.24)
	Level 5	11 (2.76)	3 (1.69)	8 (3.62)
	Level 6	4 (1.00)	1 (0.56)	3 (1.36)
	Total	399 (100.00)	178 (100.00)	221 (100.00)
Excitement	Level 1	396 (99.25)	176 (98.88)	220 (99.55)	0.4428
	Level 2	3 (0.75)	2 (1.12)	1 (0.45)
	Total	399 (100.00)	178 (100.00)	221 (100.00)
Suspicion and Persecution	Level 1	306 (76.69)	159 (89.33)	147 (66.52)	< .0001
	Level 2	31 (7.77)	7 (3.93)	24 (10.86)
	Level 3	25 (6.27)	4 (2.25)	21 (9.50)
	Level 4	27 (6.77)	7 (3.93)	20 (9.05)
	Level 5	10 (2.51)	1 (0.56)	9 (4.07)
	Total	399 (100.00)	178 (100.00)	221 (100.00)
Hostility	Level 1	319 (79.95)	160 (89.89)	159 (71.95)	< .0001
	Level 2	46 (11.53)	13 (7.30)	33 (14.93)
	Level 3	32 (8.02)	5 (2.81)	27 (12.22)
	Level 4	2 (0.50)	0 (0.00)	2 (0.90)
	Total	399 (100.00)	178 (100.00)	221 (100.00)
Positive Score		7.00 (7.00–7.00)	7.00 (7.00–7.00)	7.00 (7.00–9.00)	< .0001
CGI Score	Level 5	136 (34.09)	70 (39.33)	66 (29.86)	< .0001
	Level 6	167 (41.85)	92 (51.69)	75 (33.94)
	Level 7	96 (24.06)	16 (8.99)	80 (36.20)
	Total	399 (100.00)	178 (100.00)	221 (100.00)
TSH Score		4.60 (3.15–6.57)	2.94 (1.85–3.65)	6.30 (5.15–7.87)	< .0001
A-TG Score		19.63 (13.73–32.17)	17.44 (13.15–25.25)	22.25 (15.28–57.62)	0.0001
FT3 Score		4.97 (4.41–5.49)	4.96 (4.42–5.48)	4.98 (4.41–5.55)	0.8211
FT4 Score		16.53 (14.52–18.78)	16.86 (14.95–18.79)	16.21 (14.10–18.73)	0.1272
FBG Score		5.26 (4.87–5.76)	5.01 (4.70–5.33)	5.55 (5.15–5.97)	< .0001
TC Score		4.99 (4.28–5.89)	4.43 (3.89–4.97)	5.59 (4.78–6.26)	< .0001
HDL-C Score		1.26 (1.03–1.44)	1.31 (1.22–1.47)	1.18 (0.87–1.39)	< .0001
TG Score		1.92 (1.40–2.82)	1.84 (1.28–2.72)	1.94 (1.54–2.87)	0.0559
LDL-C Score		2.80 (2.27–3.49)	2.42 (2.10–3.00)	3.14 (2.51–3.70)	< .0001
BMI Score		24.13 (23.14–25.48)	23.78 (23.01–25.40)	24.23 (23.20–25.87)	0.0369
SBP Score		110.00 (104.00–117.00)	103.50 (98.00–108.00)	116.00 (112.00–120.00)	< .0001
DBP Score		72.00 (68.00–76.00)	68.00 (65.00–70.00)	75.00 (72.00–78.00)	< .0001

A-TG, antithyroglobulin antibody; BMI, body mass index; CGI, Clinical Global Impressions Scale; DBP, diastolic blood pressure; FBG, fasting blood glucose; FT3, triiodothyronine; FT4, free thyroxine; HAMA, Hamilton Anxiety Rating Scale; HAMD, Hamilton Rating Scale for Depression; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; SBP, systolic blood pressure; TC, total cholesterol; TG, triglyceride; TSH, thyroid stimulating hormone.

Risk Factors and Markers in Participants with Abnormal TSH Levels Exhibiting Suicidal Behavior

Within the group exhibiting abnormal TSH levels, we conducted a detailed analysis of psychopathological, physiological, and biochemical markers, differentiating those with and without suicidal behavior. The median TSH level among individuals exhibiting suicidal behavior was 8.21 (interquartile range [IQR] 6.35–9.45), which was significantly higher compared to the median of 5.94 (IQR 4.90–7.29) in the group without suicidal attempts (p< 0.0001).

The median HAMD score was significantly higher in the suicide group (32.00; IQR 32.00–34.00) compared to the non-suicide group (31.00; IQR 29.00–32.00), indicating more severe depression in the former group (p< 0.0001). Similarly, the median HAMA score was notably higher in the suicide group (23; IQR 21–24) relative to the non-suicide group (21; IQR 18–22), suggesting greater anxiety severity among those with suicidal behavior.

Further analysis revealed significant differences in metabolic indicators between groups, including FBG, total cholesterol (TC), HDL-C, and BMI scores. Specifically, the suicide group had a higher median FBG score (5.89; IQR 5.53–6.38) compared to the non-suicide group (5.47; IQR 5.12–5.85) (p= 0.0002), a higher TC score (6.16; IQR 5.24–6.97) than the non-suicide group (5.43; IQR 4.63–6.20) (p= 0.0008), a lower HDL-C score (0.94; IQR 0.85–1.25) in comparison with the non-suicide group (1.23; IQR 0.92–1.46) (p= 0.0029), and a lower BMI (23.56; IQR 22.38–25.16) compared to the non-suicide group (24.38; IQR 23.45–26.14) (p= 0.0017). See Table 2 for detailed statistics.

Table 2

Demographic, Psychopathological, Biochemical, and Physiological Characteristics Stratified by Suicidal Behavior in the TSH Abnormal Cohort
Item	Category	Total Cohort	No Suicidal Behavior	Suicidal Behavior	P Value
Actual Age		19.00 (18.00–21.00)	19.00 (18.00–21.00)	20.00 (18.00–21.00)	0.6680
Disease Duration (month)		4.00 (2.50–6.00)	4.00 (2.50–6.00)	3.50 (2.50–5.00)	0.3071
Onset Age		19.00 (18.00–21.00)	19.00 (18.00–21.00)	19.00 (18.00–21.00)	0.6211
Sex	Male	96 (43.44)	77 (45.29)	19 (37.25)	0.3097
	Female	125 (56.56)	93 (54.71)	32 (62.75)
	Total	221 (100.00)	170 (100.00)	51 (100.00)
Education	Junior High	4 (1.81)	2 (1.18)	2 (3.92)	0.3253
	High School	137 (61.99)	104 (61.18)	33 (64.71)
	University	76 (34.39)	61 (35.88)	15 (29.41)
	Graduate	4 (1.81)	3 (1.76)	1 (1.96)
	Total	221 (100.00)	170 (100.00)	51 (100.00)
Marriage	Single	206 (93.21)	157 (92.35)	49 (96.08)	0.3536
	Married	15 (6.79)	13 (7.65)	2 (3.92)
	Total	221 (100.00)	170 (100.00)	51 (100.00)
Anxiety Score	Without Severe Anxiety	193 (87.33)	153 (90.00)	40 (78.43)	0.0294
	Severe Anxiety	28 (12.67)	17 (10.00)	11 (21.57)
	Total	221 (100.00)	170 (100.00)	51 (100.00)
Psychotic Symptom	Without Psychotic Symptom	188 (85.07)	151 (88.82)	37 (72.55)	0.0042
	With Psychotic Symptom	33 (14.93)	19 (11.18)	14 (27.45)
	Total	221 (100.00)	170 (100.00)	51 (100.00)
HAMD Score		31.00 (29.00–33.00)	31.00 (29.00–32.00)	32.00 (32.00–34.00)	< .0001
HAMA Score		21.00 (19.00–23.00)	21.00 (18.00–22.00)	23.00 (21.00–24.00)	< .0001
Delusion	Level 1	188 (85.07)	151 (88.82)	37 (72.55)	0.0040
	Level 3	2 (0.90)	0 (0.00)	2 (3.92)
	Level 4	17 (7.69)	12 (7.06)	5 (9.80)
	Level 5	9 (4.07)	5 (2.94)	4 (7.84)
	Level 6	5 (2.26)	2 (1.18)	3 (5.88)
	Total	221 (100.00)	170 (100.00)	51 (100.00)
Disorganized Thinking	Level 1	176 (79.64)	145 (85.29)	31 (60.78)	< .0001
	Level 2	22 (9.95)	14 (8.24)	8 (15.69)
	Level 3	12 (5.43)	8 (4.71)	4 (7.84)
	Level 4	9 (4.07)	3 (1.76)	6 (11.76)
	Level 5	2 (0.90)	0 (0.00)	2 (3.92)
	Total	221 (100.00)	170 (100.00)	51 (100.00)
Hallucinatory Behavior	Level 1	188 (85.07)	151 (88.82)	37 (72.55)	0.0023
	Level 3	6 (2.71)	4 (2.35)	2 (3.92)
	Level 4	16 (7.24)	12 (7.06)	4 (7.84)
	Level 5	8 (3.62)	2 (1.18)	6 (11.76)
	Level 6	3 (1.36)	1 (0.59)	2 (3.92)
	Total	221 (100.00)	170 (100.00)	51 (100.00)
Excitement	Level 1	220 (99.55)	169 (99.41)	51 (100.00)	0.5913
	Level 2	1 (0.45)	1 (0.59)	0 (0.00)
	Total	221 (100.00)	170 (100.00)	51 (100.00)
Suspicion or Victimization	Level 1	147 (66.52)	123 (72.35)	24 (47.06)	0.0005
	Level 2	24 (10.86)	17 (10.00)	7 (13.73)
	Level 3	21 (9.50)	13 (7.65)	8 (15.69)
	Level 4	20 (9.05)	12 (7.06)	8 (15.69)
	Level 5	9 (4.07)	5 (2.94)	4 (7.84)
	Total	221 (100.00)	170 (100.00)	51 (100.00)
Hostility	Level 1	159 (71.95)	130 (76.47)	29 (56.86)	0.0056
	Level 2	33 (14.93)	22 (12.94)	11 (21.57)
	Level 3	27 (12.22)	17 (10.00)	10 (19.61)
	Level 4	2 (0.90)	1 (0.59)	1 (1.96)
	Total	221 (100.00)	170 (100.00)	51 (100.00)
Positive Score		7.00 (7.00–9.00)	7.00 (7.00–9.00)	9.00 (7.00–18.00)	0.0002
CGI Score	Level 5	66 (29.86)	63 (37.06)	3 (5.88)	< .0001
	Level 6	75 (33.94)	65 (38.24)	10 (19.61)
	Level 7	80 (36.20)	42 (24.71)	38 (74.51)
	Total	221 (100.00)	170 (100.00)	51 (100.00)
TSH Score		6.30 (5.15–7.87)	5.94 (4.90–7.29)	8.21 (6.35–9.45)	< .0001
A-TG Score		22.25 (15.28–57.62)	21.39 (14.12–38.54)	34.12 (16.18–188.62)	0.0082
FT3 Score		4.98 (4.41–5.55)	5.09 (4.45–5.55)	4.63 (4.25–5.39)	0.1840
FT4 Score		16.21 (14.10–18.73)	16.19 (13.65–18.84)	16.51 (15.19–18.13)	0.4463
FBG Score		5.55 (5.15–5.97)	5.47 (5.12–5.85)	5.89 (5.53–6.38)	0.0002
TC Score		5.59 (4.78–6.26)	5.43 (4.63–6.20)	6.16 (5.24–6.97)	0.0008
HDL-C Score		1.18 (0.87–1.39)	1.23 (0.92–1.46)	0.94 (0.85–1.25)	0.0029
TG Score		1.94 (1.54–2.87)	1.93 (1.54–2.80)	1.97 (1.50–2.97)	0.4418
LDL-C Score		3.14 (2.51–3.70)	3.09 (2.50–3.67)	3.30 (2.78–3.96)	0.0609
BMI Score		24.23 (23.20–25.87)	24.38 (23.45–26.14)	23.56 (22.38–25.16)	0.0017
SBP Score		116.00 (112.00–120.00)	115.00 (112.00–120.00)	118.00 (112.00–125.00)	0.0287
DBP Score		75.00 (72.00–78.00)	75.00 (70.00–78.00)	76.00 (72.00–80.00)	0.1724

A-TG, antithyroglobulin antibody; BMI, body mass index; CGI, Clinical Global Impressions Scale; DBP, diastolic blood pressure; FBG, fasting blood glucose; FT3, triiodothyronine; FT4, free thyroxine; HAMA, Hamilton Anxiety Rating Scale; HAMD, Hamilton Rating Scale for Depression; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; SBP, systolic blood pressure; TC, total cholesterol; TG, triglyceride; TSH, thyroid stimulating hormone.

Correlation Analysis of Mental Status and Physiological Measures

The correlation analysis explored the relationship between mental status and physiological condition. The findings revealed that total cholesterol (TC) was associated with all mental status scores, including HAMD, HAMA, Positive Score, and Clinical Global Impressions Scale (CGI) (all p< 0.001).

Additionally, HAMD scores were positively correlated with free thyroxine (FT4), low-density lipoprotein cholesterol (LDL-C), and fasting blood glucose (FBG), and negatively correlated with high-density lipoprotein cholesterol (HDL-C) (all p< 0.05). HAMA scores showed positive correlations with LDL-C, systolic blood pressure (SBP), and DBP (diastolic blood pressure), and a negative correlation with HDL-C. CGI scores were positively associated with FBG, triglycerides (TG), LDL-C, and SBP, and negatively associated with HDL-C (see Table 3).

Table 3

Correlational Analysis of Mental Status Scores and Physiological Measures
		A-TG Score	FT3 Score	FT4 Score	FBG	TC Score	HDL-C Score	TG Score	LDL-C Score	BMI Score	SBP Score	DBP Score
HAMD Score	r	0.019	0.082	0.142	0.163	0.538	-0.199	0.129	0.280	-0.050	0.112	0.079
	p	0.781	0.225	0.035	0.015	< 0.001	0.003	0.056	< 0.001	0.462	0.096	0.242
HAMA Score	r	0.110	-0.005	0.129	0.081	0.320	-0.137	0.127	0.179	0.005	0.144	0.153
	p	0.102	0.939	0.055	0.231	< 0.001	0.042	0.059	0.008	0.940	0.033	0.022
Positive Score	r	0.031	0.035	0.097	0.150	0.226	-0.104	0.091	0.087	0.040	0.116	0.120
	p	0.651	0.606	0.151	0.026	< 0.001	0.124	0.177	0.200	0.558	0.084	0.074
CGI Score	r	0.047	-0.024	0.110	0.178	0.454	-0.225	0.149	0.247	-0.025	0.141	0.116
	p	0.483	0.719	0.102	0.008	< 0.001	< 0.001	0.026	< 0.001	0.711	0.036	0.084

A-TG, antithyroglobulin antibody; BMI, body mass index; CGI, Clinical Global Impressions Scale; DBP, diastolic blood pressure; FT3, triiodothyronine; FT4, free thyroxine; HAMA, Hamilton Anxiety Rating Scale; HAMD, Hamilton Rating Scale for Depression; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; SBP, systolic blood pressure; TC, total cholesterol; TG, triglyceride.

Logistic Regression Analysis

A logistic regression analysis was conducted to further investigate these associations. Psychotic symptoms were found to be associated with a threefold increase in the odds of suicidal behavior (odds ratio [OR] = 3.01 [95% CI: 1.38–6.55], p= 0.0056). Higher HAMD and HAMA scores, indicating more severe symptoms of depression and anxiety respectively, were also significantly associated with an increased risk of suicide, with ORs of 1.45 (p< 0.0001) and 1.23 (p< 0.0001), respectively. Additionally, elevated TSH levels were significantly associated with a higher suicidal risk, showing an OR of 1.69 (p< 0.0001). The CGI score exhibited a strong association, with an OR of 4.90 (p< 0.0001), and the severity measured by the CGI showed an adjusted OR of 3.96 (p< 0.0001). Conversely, a lower BMI was correlated with suicidal behavior, with an OR of 0.82 (p= 0.0138) and an adjusted OR of 0.80 (p= 0.0192), suggesting a potential protective effect against suicidal risk (see Table 4).

Table 4

Multifactorial and Single-Factor Analysis Outcomes for Predictors of Suicidal Behavior
Variable Name	Single-Factor OR Value	Single-Factor P Value	Multi-Factor OR Value	Multi-Factor P Value
Psychotic Symptoms	3.01 (1.38–6.55)	0.0056		.
HAMD Score	1.45 (1.24–1.69)	< .0001		.
HAMA Score	1.23 (1.11–1.36)	< .0001		.
Actual Age	1.04 (0.85–1.28)	0.7081		.
Positive Score	1.11 (1.05–1.18)	0.0005		.
CGI Score	4.90 (2.80–8.56)	< .0001	3.96 (2.13–7.36)	< .0001
TSH Score	1.69 (1.40–2.04)	< .0001	1.43 (1.17–1.75)	0.0006
A-TG Score	1.00 (1.00–1.00)	0.0806		.
FT3 Score	0.78 (0.50–1.22)	0.2740		.
FT4 Score	1.04 (0.94–1.15)	0.4456		.
FBG Score	2.33 (1.44–3.77)	0.0006		.
TC Score	1.72 (1.25–2.38)	0.0009		.
Disease Duration (month)	0.95 (0.84–1.07)	0.3957		.
HDL-C Score	0.20 (0.07–0.60)	0.0042		.
TG Score	1.19 (0.86–1.65)	0.2898		.
LDL-C Score	1.43 (1.00–2.04)	0.0485		.
BMI Score	0.82 (0.70–0.96)	0.0138	0.80 (0.67–0.96)	0.0192
SBP Score	1.07 (1.02–1.12)	0.0074		.
DBP Score	1.04 (0.98–1.10)	0.2246		.
Onset Age	1.07 (0.87–1.30)	0.5251		.
Female	1.39 (0.73–2.65)	0.3108		.
Education	0.74 (0.41–1.33)	0.3170		.
Married	0.49 (0.11–2.26)	0.3626		.
Severe Anxiety	2.48 (1.07–5.70)	0.0333		.

A-TG, antithyroglobulin antibody; BMI, body mass index; CGI, Clinical Global Impressions Scale; DBP, diastolic blood pressure; FBG, fasting blood glucose; FT3, triiodothyronine; FT4, free thyroxine; HAMA, Hamilton Anxiety Rating Scale; HAMD, Hamilton Rating Scale for Depression; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; SBP, systolic blood pressure; TC, total cholesterol; TG, triglyceride; TSH, thyroid stimulating hormone.

Diagnostic Power and Predictive Models

The area under the curve (AUC) for the CGI condition was 0.77 (95% CI: 0.71–0.84), indicating a high diagnostic power of CGI in predicting MDD in adolescents. The AUC for the TSH condition was 0.75 (95% CI: 0.67–0.83), demonstrating the validity of TSH as a single predictor in diagnosing MDD. The AUC of 0.64 (95% CI: 0.56–0.73) for the BMI condition was low, suggesting a weaker diagnostic power of BMI alone as a predictor. Finally, the AUC for the combined prediction of CGI and TSH was 0.82 (95% CI: 0.76–0.89), the highest of all the predictive models, showing that the combination of these indicators significantly outperformed each one used alone.

As shown in Fig. 1, different curves exhibit varying diagnostic capabilities. The CGI condition (blue curve) shows high speCIficity at higher sensitivity, indicating superior overall diagnostic ability. The TSH condition (red curve) in the graph shows some fluctuation at different sensitivities and specificities but still maintains considerable diagnostic power. The AUC of the BMI situation (cyan curve) is slightly lower than the other curves, indicating weak diagnostic ability. The Combined CGI and TSH prediction (purple curve) have the largest AUC, indicating that the combined prediction has the best overall diagnostic ability.

This study is among the first to investigate the relationship between physiological factors and suicidal behavior in adolescents with major depressive disorder (MDD) and comorbid anxiety symptoms, utilizing a substantial sample of 399 participants[15, 16]. Our findings reveal several important insights into how endocrine and metabolic imbalances can influence depression severity and suicide risk among youth.

Our study shows that adolescents with abnormal TSH levels experience more severe depressive symptoms, higher rates of suicidal behavior, and increased anxiety and psychotic symptoms compared to those with normal TSH levels. This finding aligns with previous research indicating that thyroid dysfunction, particularly abnormal TSH levels, is associated with greater severity of depressive symptoms and an increased risk of suicidal behavior[17, 18]. For example, earlier studies have suggested that elevated TSH levels correlate with both the onset and progression of depressive disorders in various populations[19]. Our research extends these findings to a youth population, emphasizing that endocrine imbalances can significantly impact mental health outcomes in adolescents.

Additionally, our results highlight that adolescents exhibiting suicidal behavior also present with distinct metabolic profiles characterized by elevated TSH, A-TG, FBG, and TC levels, alongside decreased HDL-C and BMI. These findings suggest a complex interplay between thyroid function, metabolic health, and suicidal behavior[20]. Prior research has shown that metabolic dysregulation, including altered cholesterol and glucose levels, can influence the severity of depressive symptoms and the risk of suicide[21, 22]. Our study supports these conclusions and points to the potential role of metabolic biomarkers in identifying adolescents at higher risk for suicide.

The correlation analysis highlighted significant associations between psychological status and physiological factors. Multiple linear regression models identified the Clinical Global Impressions Scale (CGI), TSH, and BMI as significant predictors of suicidal intent[23]. Notably, the ROC curve analysis revealed that the combined predictive value of CGI and TSH was superior, with the AUC for the combined prediction being the largest[24]. This indicates that combining CGI and TSH is more effective for prediction than using any single indicator alone.

The observed associations between increased TSH levels and higher rates of suicidal behavior and anxiety in our sample support the hypothesis that endocrine and metabolic disruptions are critical factors in the pathophysiology of MDD with comorbid anxiety[25]. This extends findings from studies in adult populations, where similar associations have been noted [26]. Our study contributes to the growing body of evidence suggesting that monitoring thyroid function and metabolic markers could be beneficial in assessing suicide risk among depressed adolescents.

However, there are several limitations to consider. First, the cross-sectional design of our study limits our ability to infer causality between physiological factors and suicidal behavior. Future longitudinal studies are needed to establish causal relationships and explore how changes in TSH levels and metabolic biomarkers over time might impact depression severity and suicide risk. Second, the participants in our study were primarily from an outpatient clinic in a specific geographic region, which may affect the generalizability of our findings to other populations or settings. Subsequent research should include more diverse samples from different regions and clinical backgrounds to validate our results across varied contexts.

Despite these limitations, our study provides crucial insights into how physiological and metabolic factors are related to depression and suicide risk among adolescents. Our findings suggest that integrating assessments of TSH levels, metabolic health, and anxiety symptoms into clinical evaluations could enhance the early detection of at-risk individuals and inform targeted interventions. This approach could be pivotal in developing more effective strategies for managing and preventing suicide in youth with MDD and comorbid anxiety.

This study highlights the importance of endocrine and metabolic biomarkers as indicators of depression severity and suicide risk in adolescents. Specifically, abnormal TSH levels, A-TG, FBG, TC, HDL-C, and BMI are associated with increased suicidal behavior. These findings provide a basis for future research to further explore these associations and improve clinical interventions for adolescent mental health.

TSH

Thyroid Stimulating Hormone

FT3

Triiodothyronine

FT4

Free Thyroxine

FBG

Fasting Blood Glucose

TC

Total Cholesterol

HDL-C

High-Density Lipoprotein Cholesterol

LDL-C

Low-Density Lipoprotein Cholesterol

TG

Triglycerides

BMI

Body Mass Index

SBP

Systolic Blood Pressure

DBP

Diastolic Blood Pressure

A-TG

Anti-Thyroglobulin Antibodies

MDD

Major Depressive Disorder

HAMD

Hamilton Rating Scale for Depression

HAMA

Hamilton Anxiety Rating Scale

PANSS

Positive and Negative Syndrome Scale

CGI

Clinical Global Impressions Scale

AUC

Area Under the Curve

Ethics approval and consent to participate

The present study was reviewed and approved by the Institutional Review Boards of First Hospital of Shanxi Medical University. Written informed consents were obtained from participants or their guardians. Patients were recruited from the Department of Psychiatry, First Clinical Medical College of Shanxi Medical University, during 2015–2017.

Consent for publication

Not Applicable.

Competing interests

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Funding

This study was supported by the Medical Discipline Construction Project of Pudong Health Committee of Shanghai: (Grant No. PWZzb2022-09), Medical discipline Construction Project of Pudong Health Committee of Shanghai: (Grant No. PWYgy2021-02).

Author Contribution

XZ is responsible for the conceptualization and methodology of the article. XF is responsible for the software, validation, and visualization parts of the article, including writing, reviewing, and editing. XL, RZ, CZ, JL, YZ, are responsible for data management, resource sorting, experimental verification, formal analysis, and article editing.

Acknowledgement

The authors thank the First Clinical Medical College, Shanxi Medical University for the supports. This study was supported by the medical discipline Construction Project of Pudong Health Committee of Shanghai: (Grant No. PWZzb2022-09), Medical discipline Construction Project of Pudong Health Committee of Shanghai: (Grant No. PWYgy2021-02).

Data availability

The original contributions presented in the study are included in the article/supplementary materials, further inquiries can be directed to the corresponding author/s.

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No competing interests reported.

Association of clinical correlates, metabolic parameters, and thyroid hormones with suicide attempts in first-episode and drug-naïve adolescent depression comorbid with anxiety: a large-scale cross-sectional study

Status:

Version 1

Abstract

Background

Methods

Results

Conclusions

Figures

Background

Methods

Participants

Clinical interviews and assessments

Physical and biochemical parameters measurements

Statistical analysis

Results

Clinical and Biochemical Differences Between Participants with Normal and Abnormal TSH Levels

Risk Factors and Markers in Participants with Abnormal TSH Levels Exhibiting Suicidal Behavior

Correlation Analysis of Mental Status and Physiological Measures

Logistic Regression Analysis

Diagnostic Power and Predictive Models

Discussion

Conclusions

Abbreviations

Declarations

Funding

Author Contribution

Acknowledgement

Data availability

References

Additional Declarations

Status:

Version 1