Tardive dyskinesia-depression association in Chinese patients with chronic schizophrenia: The mediating role of insomnia and gender differences

Abstract

BACKGROUND

There is growing evidence linking tardive dyskinesia (TD) - a prevalent iatrogenic movement disorder among chronic schizophrenia patients - to the development of depressive symptomatology. However, two critical gaps remain in the existing literature on Chinese individuals diagnosed with chronic schizophrenia: (1) The potential mediating role of insomnia in the association between TD and depression has not been systematically explored; and (2) Gender-specific differences in this relationship remain understudied.

AIM

To examine the association between TD and depressive severity in Chinese individuals diagnosed with chronic schizophrenia and to explore the mediating role of insomnia and gender differences.

METHODS

This study, conducted across two psychiatric hospitals in China, recruited 669 chronic schizophrenia inpatients (68% male) using a multicenter design: Guangzhou Huiai Hospital and Wuhan Mental Health Center. Demographic and clinical data were collected. Psychopathology and symptom severity were assessed using the Positive and Negative Syndrome Scale, Hamilton Depression Rating Scale (HAMD), Insomnia Severity Index, and Abnormal Involuntary Movement Scale.

RESULTS

The prevalence of TD in this cohort was 46.6%. Compared to patients without TD, those with TD had more severe insomnia (Insomnia Severity Index score: 2 vs 1; Z = 3.262, P = 0.001) and depression (HAMD total score: 7 vs 6; Z = 2.042, P = 0.041). Insomnia was found to partially mediate the TD-depression relationship in the subsequent mediation analysis: Total effect (TD-depression) = 0.480 (P < 0.001), direct effect = 0.298 (P < 0.001; 62%), and indirect effect (via insomnia) = 0.183 (P < 0.001; 38%), with 95% confidence intervals: 0.099, 0.276, excluding zero. Gender-stratified analyses revealed that: (1) Among males, TD patients differed from non-TD patients only in HAMD diurnal variation (Z = 3.259, P = 0.001); and (2) Among females, TD patients had higher HAMD total scores (10 vs 7; Z = 2.034, P = 0.042), greater diurnal variation (Z = 4.906, P < 0.001), and more severe psychomotor retardation (Z = 2.496, P = 0.013) compared with non-TD females.

CONCLUSION

TD is associated with greater depressive severity in Chinese patients with chronic schizophrenia. Notable gender differences were observed, with females exhibiting a broader and more severe depressive symptom profile. Routine screening for insomnia and depression in patients with TD, along with gender-tailored interventions, may improve clinical outcomes.

Key Words: Tardive dyskinesia; Depression; Chronic schizophrenia; Insomnia; Mediation effect; Gender differences

Core Tip: This study of 669 Chinese patients with chronic schizophrenia demonstrates that tardive dyskinesia (TD) is associated with increased depressive severity, with insomnia partially mediating this relationship (accounting for 38% of the total effect). Gender differences were identified: Female patients with TD exhibited more severe overall depression, greater diurnal variation, and increased psychomotor retardation, whereas male patients with TD differed from non-TD males only in diurnal variation. These findings point to the critical need for systematic evaluation of insomnia and depression in the TD patient population and highlight the need for gender-specific interventions to optimize care in this vulnerable population.

INTRODUCTION

Schizophrenia is a severe, chronic psychiatric disorder accompanied by multiple comorbidities that adversely affect prognosis and quality of life[1]. Among these comorbidities, depressive symptoms are highly prevalent in patients with chronic schizophrenia and are associated with greater subjective distress, functional impairment, and increased suicide risk[2-4]. Tardive dyskinesia (TD) is another major clinical concern and remains a common, potentially disabling adverse effect of long-term antipsychotic treatment, manifesting as involuntary abnormal movements[5]. TD is typically defined as an iatrogenic movement disorder characterized by repetitive, involuntary choreoathetoid movements involving the mouth, tongue, and perioral region, as well as the extremities[6]. Although prevalence estimates vary across studies, meta-analytic evidence indicates a global mean prevalence of approximately 25.3%[7]. Notably, studies in Chinese patients with schizophrenia have reported even higher rates, ranging from 35.9% to 41.1%[8-11], suggesting that TD constitutes a particularly important yet often under-recognized clinical burden in Chinese psychiatric settings.

The co-occurrence of TD and depressive symptoms presents a complex clinical problem. TD is associated with psychosocial stigma, social withdrawal, functional impairment, and reduced quality of life, all of which may precipitate or exacerbate depressive symptomatology[12-14]. Several lines of evidence further support a potentially bidirectional relationship. A cross-sectional study of neuroleptic-free chronic schizophrenic inpatients found that individuals with TD were more likely to exhibit depressive and negative symptoms than those without TD[15]. In addition, TD has been associated with increased healthcare utilization, higher economic burden, and greater medical comorbidity[12,13], factors that may indirectly contribute to depression. Shared biological mechanisms may also underlie this association, including dysregulation of the hypothalamic-pituitary-adrenal axis[16] and neuroinflammatory alterations such as increased interleukin-6 activity[17]. Despite these indications, prior studies have rarely examined the relationship between TD and depression within a single, clinically homogeneous sample of patients with chronic schizophrenia.

Insomnia may represent an important mechanistic pathway linking TD and depressive symptoms in schizophrenia, based on both empirical and theoretical grounds. First, insomnia is highly prevalent in schizophrenia. It has been shown to mediate the association between various clinical risk factors - such as childhood maltreatment - and adverse outcomes, including suicidal ideation[18,19], highlighting its role as a transdiagnostic risk amplifier. Second, strong evidence indicates that insomnia is a causal risk factor for depression; meta-analyses demonstrate an approximately two-fold increased risk[20], and both conditions share neural substrates involving the salience network[21]. Third, chronic insomnia is associated with rapid eye movement sleep instability, impaired emotional regulation, and increased vulnerability to affective disturbances[22]. Although direct research on the TD-insomnia relationship remains limited, it is biologically plausible that TD could disrupt sleep through physical discomfort, social stigma, or shared neurobiological alterations (e.g., dopaminergic dysfunction involving basal ganglia circuits that also regulate sleep-wake processes). Accordingly, insomnia may serve as a key intermediary through which TD contributes to depressive symptoms.

Gender differences may further modify these relationships. Epidemiological studies in Chinese patients with schizophrenia have consistently reported higher TD prevalence among males[8,10]. In contrast, depressive symptoms in schizophrenia often display gender-specific patterns, with female patients tending to show different correlates and greater severity of affective symptoms[3,23]. Preliminary data also suggest that the association between TD and cognitive impairment varies by gender[24], implying that gender could influence the TD-depression relationship as well. However, to the best of our knowledge, no study has systematically examined whether gender moderates the association between TD and depressive symptoms in Chinese patients with chronic schizophrenia. Previous research in this population has focused primarily on cognitive impairment[8,24], while comparatively little attention has been paid to affective outcomes, particularly from a gender-informed perspective. This gap is clinically important because depression strongly influences quality of life and predicts future outcomes in schizophrenia.

Accordingly, the present study had three objectives: (1) To examine the association between TD and depressive symptoms in a large sample of Chinese patients with chronic schizophrenia; (2) To evaluate whether insomnia mediates this association; and (3) To determine whether gender moderates the TD-depression relationship. We hypothesized that insomnia would partially mediate the relationship between TD and depressive symptoms and that gender differences would be present, based on prior evidence of sex-related variation in TD vulnerability and depressive symptom expression. Clarifying the mediating role of insomnia and gender-specific pathways may facilitate more precise screening, monitoring, and targeted interventions for this vulnerable population in Chinese psychiatric services.

MATERIALS AND METHODS

Methods

Participants: This study included 669 patients with chronic schizophrenia: 457 males (TD/non-TD = 202/255) and 212 females (TD/non-TD = 110/102). The sample size was a priori estimated via G*Power 3.1 software. This study explored TD-depression association, gender differences, and mediating effects in chronic psychiatric patients, using χ² test, U-test, and mediating effect analysis, with nonparametric tests adopted due to non-normal data. For key analyses (|r| = 0.30, d = 0.50, α = 0.05, 1-β = 0.80), the minimum required sample was 128. We finally included 669 valid patients, ensuring sufficient statistical power and result reliability. All participants were recruited during the same period in 2019 from two psychiatric hospitals in China - Guangzhou Huiai Hospital and Wuhan Mental Health Center. Anonymous data were used in this study. The study protocol was approved by the Institutional Ethics Review Board of the Institute of Psychology, Chinese Academy of Sciences (No. H18031).

The inclusion criteria were as follows: (1) Age 17-70 years and of Han Chinese ethnicity; (2) Diagnosis of schizophrenia confirmed independently by two psychiatrists according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; (3) Illness duration of at least 1 year; (4) Treatment with a stable dose of antipsychotic medication for more than 6 months; and (5) Competent to provide informed consent, as determined by evaluation of comprehension of the consent form. Exclusion criteria were as follows: (1) History of neurological disorders, severe physical illness, or head injury; (2) Pregnancy or lactation; and (3) A history of alcohol or substance abuse. Sociodemographic and clinical information was collected through structured interviews, including age, sex, marital status, years of education, family psychiatric history, smoking history, suicidal ideation, diabetes status, hypertension status, and age at first onset of mental illness. Height and weight were measured by nursing staff, and body mass index was calculated as weight (kg) divided by height (m²).

Survey questionnaire

TD assessment: The Abnormal Involuntary Movement Scale (AIMS) was used to evaluate the severity of TD. The AIMS comprises seven items, each scored on a 4-point Likert scale. Items 1-4 were summed to generate the orofacial AIMS score, whereas the remaining three items assessed limb and trunk movements. TD was diagnosed according to the following criteria: (1) An AIMS score ≥ 3 (moderate severity) in any single body region; or (2) AIMS scores ≥ 2 (mild severity) in at least two body regions. Participants meeting these criteria were reassessed after a minimum interval of 1 month using the AIMS, and a TD diagnosis was confirmed only if the two assessments were consistent[24].

Depressive symptoms: The Hamilton Depression Rating Scale (HAMD) was used to assess the severity of depressive symptoms. Total scores range from 0 to 52, with higher scores indicating more severe depressive symptomatology[25].

Insomnia symptoms: Insomnia severity was evaluated using the Insomnia Severity Index (ISI). The ISI yields a total score ranging from 0 to 28, with higher scores reflecting more severe insomnia[26].

Psychotic symptoms: Psychotic symptoms were assessed using the Positive and Negative Syndrome Scale. This instrument comprises three subscales - positive symptoms, negative symptoms, and general psychopathology - with total scores ranging from 30 to 210; higher scores indicate more severe psychopathology[27].

Cognitive functioning: Cognitive performance was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). The RBANS includes 12 subtests that generate scores across five cognitive index domains, and the total score reflects overall cognitive functioning[28].

Statistical analysis

Statistical analyses were performed using Statistical Package for Social Sciences version 27.0. Descriptive statistics were used to summarize demographic and clinical variables. Because the Kolmogorov-Smirnov test indicated non-normal distributions for all continuous variables (P < 0.05), nonparametric statistical methods were applied throughout the analyses. Continuous data are presented as medians with interquartile ranges [M (P25, P75)], and between-group comparisons were conducted using the Mann-Whitney U test. Categorical variables are presented as n (%) and were compared using the χ² test; when the expected cell count was < 5, Fisher’s exact test was used. The χ² tests were specifically applied to examine gender differences in demographic and clinical characteristics between patients with schizophrenia and without TD. To further examine the relationship between TD and depression in Chinese patients with chronic schizophrenia, mediation analysis was conducted with insomnia as the mediator, and the indirect and direct effects were estimated. All statistical tests were two-tailed with a significance level of α = 0.05, and P < 0.05 was considered statistically significant.

RESULTS

Demographic and clinical characteristics

The demographic and clinical characteristics of patients with chronic schizophrenia with and without TD are presented in Table 1. The prevalence of TD in this cohort was 46.6% (312/669). Significant differences were observed between TD and non-TD patients across several variables. Patients with TD were significantly older than those without TD (Z = 4.028, P < 0.001). The proportion of patients with diabetes was significantly higher in the TD group than in the non-TD group (16.7% vs 8.1%; χ² = 11.420, P < 0.001). Additionally, patients with TD had slightly more years of education (Z = 2.282, P = 0.023).

Table 1 Demographic and clinical characteristics of chronic schizophrenia patients with or without tardive dyskinesia, n (%).

		TD (n = 312)	Non-TD (n = 357)	χ2/Z	P value
Gender	Male	202 (64.7)	255 (71.4)	3.438	0.064
	Female	110 (35.3)	102 (28.6)
Marital status	Unmarried	186 (59.8)	233 (65.3)	2.604	0.272
	Married	74 (23.8)	68 (19.0)
	Others (divorced or widowed)	51 (16.4)	56 (15.7)
Smoking history	No	187 (59.9)	201 (56.1)	0.298	0.585
	Yes	186 (40.1)	157 (43.9)
Diabetes	No	260 (83.3)	328 (91.9)	11.420	< 0.001
	Yes	52 (16.7)	29 (8.1)
Hypertension	No	301 (96.5)	345 (96.6)	0.014	0.907
	Yes	11 (3.5)	12 (3.4)
Family history	No	248 (80.3)	286 (80.6)	0.010	0.921
	Yes	61 (19.7)	69 (19.4)
Suicidal ideation	No	243 (82.4)	270 (84.4)	0.445	0.505
	Yes	52 (17.6)	50 (15.6)
Age		48 (37, 56)	41 (30, 53)	4.028	< 0.001
Education (years)		8 (8, 11)	8 (8, 11)	2.282	0.023
Age of onset		23 (19, 28.3)	23 (19, 28)	0.948	0.343
BMI		23.6 (20.9, 27.0)	23.8 (21.1, 26.8)	0.646	0.518
Positive symptoms		18 (12, 23)	15 (10, 21)	3.704	< 0.001
Negative symptoms		25 (19, 29)	22 (16, 28)	3.616	< 0.001
General psychopathology		38 (29.8, 49)	35 (28, 42)	5.393	< 0.001
Total scores		81.5 (64, 99)	72 (60, 86)	5.465	< 0.001
RBANS		61 (52.8, 72)	64 (54, 76)	2.328	0.020
ISI		2 (0, 5)	1 (0, 4)	3.262	0.001
HAMD total score		7 (3, 12)	6 (2, 10)	2.042	0.041
Anxiety somatization		2 (1, 3)	2 (1, 3)	2.229	0.026
Weight loss		0 (0, 0)	0 (0, 0)	0.685	0.493
Cognitive disturbances		1 (0, 3)	1 (0, 2)	2.682	0.007
Diurnal variation		0 (0, 0)	0 (0, 0)	5.781	< 0.001
Psychomotor retardation		2 (0.75, 3)	1 (0, 3)	2.002	0.045
Insomnia		0 (0, 1)	0 (0, 2)	0.856	0.392
Hopelessness		1 (0, 2)	0 (0, 2)	1.939	0.053

TD: Tardive dyskinesia; BMI: Body mass index; RBANS: Repeatable Battery for the Assessment of Neuropsychological Status; ISI: Insomnia Severity Index; HAMD: Hamilton Rating Scale for Depression.

Regarding psychopathology, as measured by the Positive and Negative Syndrome Scale, TD patients showed significantly greater severity of positive symptoms (Z = 3.704, P < 0.001), negative symptoms (Z = 3.616, P < 0.001), general psychopathology symptoms (Z = 5.393, P < 0.001), and total scores (Z = 5.465, P < 0.001) compared to non-TD patients. In terms of cognitive and depressive symptoms, TD patients had significantly lower RBANS scores, indicating poorer neurocognitive functioning (Z = 2.328, P = 0.020). They also reported greater insomnia severity (ISI: Z = 3.262, P = 0.001) and more severe depressive symptoms, reflected by higher total HAMD scores (Z = 2.042, P = 0.041). Specifically, TD patients scored significantly higher on the HAMD subitems of anxiety (Z = 2.229, P = 0.026), cognitive impairment (Z = 2.682, P = 0.007), diurnal variation (Z = 5.781, P < 0.001), and psychomotor retardation (Z = 2.002, P = 0.045). However, no significant differences were observed between the groups in sex distribution, marital status, smoking history, hypertension, family history of mental disorders, suicidal ideation, age at onset, body mass index, or the HAMD items of weight loss and sleep disturbance (all P > 0.05). The difference in the HAMD item assessing hopelessness did not reach statistical significance (P = 0.053).

Mediating effect of insomnia on the relationship between TD and depression

As shown in Table 2 and Figure 1, mediation analysis indicated that TD significantly predicted insomnia (path a: Coefficient = 0.245, P < 0.001), and insomnia significantly predicted depression (path b: Coefficient = 0.744, P < 0.001). The total effect of TD on depression was also significant (path c: Coefficient = 0.480, P < 0.001). Insomnia partially mediated this relationship (indirect effect c-c’ = 0.183, 95% confidence intervals: 0.099-0.276).

Figure 1 Mediation model for the relationship between tardive dyskinesia and depression, with insomnia as a mediator. a: The effect of tardive dyskinesia on insomnia; b: The effect of insomnia on depression; c: The total effect of tardive dyskinesia on depression; c’: The direct effect of tardive dyskinesia on depression after controlling for insomnia; TD: Tardive dyskinesia.

Table 2 Mediating effect of insomnia on the relationship between tardive dyskinesia and depression.

	Effect1	Coefficient	SE	t	P value	95%CI
						LL	UL
DV: Depression; IV: Tardive dyskinesia; mediator: Insomnia	a	0.245	0.049	5.031	< 0.001	0.150	0.341
	b	0.744	0.059	12.581	< 0.001	0.628	0.860
	c	0.480	0.080	5.994	< 0.001	0.323	0.638
	c’	0.298	0.073	4.081	< 0.001	0.154	0.441
	c-c’	0.183	0.045	-	-	0.099	0.276

¹Coefficients are unstandardized regression coefficients.

a: The effect of tardive dyskinesia on insomnia; b: The effect of insomnia on depression; c: The total effect of tardive dyskinesia on depression; c’: The direct effect of tardive dyskinesia on depression after controlling for insomnia; c-c’: The indirect effect of tardive dyskinesia on depression through insomnia; SE: Standard error; CI: Confidence interval; LL: Lower limit; DV: Upper limit; IV: Independent variable; UL: Dependent variable.

Sex differences in depressive symptoms in schizophrenia with and without TD

To examine potential sex differences, depressive symptoms measured by the HAMD were analyzed separately in male and female schizophrenia patients with and without TD (Table 3). Among male patients, a significant difference between TD and non-TD groups was observed only for the diurnal variation item (Z = 3.259, P = 0.001). No significant differences were found between male TD and non-TD patients in anxiety, weight, cognitive impairment, retardation, sleep disturbance, feeling of hopelessness, or total HAMD scores (all P > 0.05).

Table 3 Comparison of Hamilton depression total and index scores in male and female schizophrenia patients with and without tardive dyskinesia.

	Male				Female
	TD	Non-TD	Z	P value	TD	Non-TD	Z	P value
Anxiety somatization	2 (0, 3)	2 (0, 3)	1.091	0.275	2 (2, 4)	2 (1, 3.75)	1.803	0.071
Weight loss	0 (0, 0)	0 (0, 0)	0.91	0.927	0 (0, 0)	0 (0, 0)	0.718	0.473
Cognitive disturbances	1 (0, 2)	0 (0, 2)	1.729	0.084	2 (0, 3)	1 (0, 3.75)	1.544	0.123
Diurnal variation	0 (0, 0)	0 (0, 0)	3.259	0.001	0 (0, 1)	0 (0, 0)	4.906	< 0.001
Psychomotor retardation	1 (0, 3)	1 (0, 3)	0.732	0.464	3 (1, 4)	1 (0, 3)	2.496	0.013
Insomnia	0 (0, 1)	0 (0, 2)	0.420	0.674	0 (0, 1)	0 (0, 1)	0.971	0.332
Hopelessness	0 (0, 1.5)	0 (0, 1.75)	1.340	0.180	1 (0, 2.5)	0.5 (0, 2)	1.253	0.210
HAMD total score	6 (3, 11)	6 (2, 10)	0.670	0.503	10 (5, 14)	7 (2, 13)	2.034	0.042

TD: Tardive dyskinesia; HAMD: Hamilton Rating Scale for Depression.

In contrast, among female patients, those with TD exhibited significantly more severe symptoms than those without TD in several domains. Significant differences were found in diurnal variation (Z = 4.906, P < 0.001), retardation (Z = 2.496, P = 0.013), and total HAMD scores (Z = 2.034, P = 0.042). No significant differences were observed between female TD and non-TD patients in anxiety, weight, cognitive impairment, sleep disturbance, or feeling of hopelessness (all P > 0.05). These findings suggest that the association between TD and depressive symptoms varies by sex, with a more pronounced effect observed in female patients.

DISCUSSION

This study elucidates the complex relationships among TD, depressive symptoms, insomnia, and sex differences in patients with chronic schizophrenia. Our principal findings indicate that: (1) TD is highly prevalent (46.6%) and is associated with more severe psychopathology, poorer cognitive functioning, and higher depressive symptom scores; (2) Insomnia partially mediates the relationship between TD and depression; and (3) The association between TD and depressive symptoms is more pronounced in female patients. These findings have important implications for both clinical practice and future research.

The high prevalence of TD (46.6%) in our chronic inpatient cohort is consistent with previous meta-analytic findings reporting similar rates among antipsychotic-treated patients[7]. The observed sex difference in TD prevalence, with higher rates in males, is also consistent with previous epidemiological studies of schizophrenia. A recent large-scale study from Germany reported a higher standardized incidence proportion of treated schizophrenia in men (45.3/100000) than in women (37.1/100000)[29], suggesting potential sex-related differences in disease manifestation or treatment response that may extend to TD vulnerability. This substantial prevalence underscores TD as a common and clinically significant adverse effect of long-term antipsychotic treatment, particularly in chronic schizophrenia patients. Our findings further corroborate the existing literature indicating that TD is associated with older age and more severe negative symptoms[30]. Moreover, the association between TD and diabetes observed in our study is consistent with findings by Caroff et al[12], who identified diabetes as a significant correlate of TD, suggesting shared pathophysiological mechanisms or a role for metabolic dysregulation in TD vulnerability.

The central finding of this study concerns the mediating role of insomnia in the TD-depression relationship. Our mediation analysis demonstrated a significant indirect effect, indicating that the impact of TD on depression is partially explained by insomnia severity. High-quality research directly examining the association between TD and insomnia remains limited, with only a few case reports available. For example, in cases in which quetiapine was prescribed for depressive insomnia[31], insomnia may indirectly increase TD risk by prompting the use of low-dose antipsychotics, which are the primary causative agents. Furthermore, the increased frequency and amplitude of involuntary movements associated with TD can significantly impair sleep quality[32]. Subsequently, chronic insomnia is a well-established risk factor for the development and exacerbation of depressive episodes[2]. Based on our findings, insomnia plays a prominent mediating role in extending previous research on sleep disturbances in schizophrenia. While insomnia is widely recognized as a common comorbidity in schizophrenia, our study positions it as a potential mechanistic link between a specific iatrogenic condition (TD) and a major psychiatric comorbidity (depression). This interpretation is consistent with broader literature indicating that sleep disruption contributes significantly to affective symptom exacerbation in psychiatric disorders[33].

Although our mediation analysis suggests a pathway from TD to depression through insomnia, the cross-sectional design warrants caution in inferring causality. Alternative directional relationships cannot be excluded. For example, depression - particularly its somatic and motivational symptoms - may exacerbate insomnia, and sleep disturbance may heighten awareness of or distress related to involuntary movements, thereby amplifying perceived TD severity[33]. Such reciprocal interactions may create a self-reinforcing cycle among TD, insomnia, and depression. In addition, unmeasured confounders may simultaneously influence all three variables. Neuroinflammation, for example, has been implicated in the pathogenesis of TD[34], the regulation of sleep-wake cycles[35], and mood disorders[36]. Future longitudinal studies with repeated measurements and objective sleep assessments are therefore needed to clarify temporal sequencing and test the directionality proposed in our model.

A clear sex-specific pattern was observed in TD-related depressive symptomatology. Whereas male patients with TD differed from non-TD patients only in diurnal variation, female patients exhibited significantly higher scores for psychomotor retardation, diurnal variation, and total HAMD scores, indicating greater vulnerability to clinically significant depression. This finding is consistent with the literature showing that women with schizophrenia often present more prominent affective symptoms[3,24] and have approximately twice the lifetime risk of major depression compared with men[37]. Our results extend this observation to TD-associated depression in schizophrenia, suggesting that female patients experience a greater affective burden when TD is present. Potential mechanisms may involve hormonal, psychosocial, and pharmacodynamic factors[16,24]. These findings underscore the importance of careful monitoring of mood symptoms in female schizophrenia patients with TD.

Several mechanisms may explain the observed sex differences in TD-associated depression. From a neurobiological perspective, sexual dimorphism in brain organization and function may contribute to differential symptom expression. Studies have shown that females demonstrate stronger connectivity in amygdala projection networks involved in emotion regulation[38]. Psychosocial factors may also contribute to the observed sex differences. Women with schizophrenia often face distinct challenges, including higher rates of poverty and trauma history, which may increase the psychological burden of TD[39]. Additionally, cultural influences on gender roles may affect symptom expression and reporting, with women potentially more likely to report affective symptoms[40].

The clinical implications of these findings are substantial. First, the high prevalence of TD and its association with greater psychopathology and depression highlight the need for regular, systematic screening using standardized instruments such as the AIMS in chronic schizophrenia populations[9,14]. Second, the identified insomnia-depression pathway suggests a potential therapeutic target. For female patients with TD, proactive assessment and management of depressive symptoms are particularly important.

Several limitations should be acknowledged. First, the cross-sectional design precludes definitive causal inferences regarding the relationships among TD, insomnia, and depression. Longitudinal studies are required to confirm the temporal sequence suggested by the mediation model. Second, the sample consisted of chronic inpatients from a single center, which may limit generalizability to outpatient or community-dwelling populations and to other ethnic groups. Finally, insomnia was assessed using a clinical rating scale; future studies would benefit from incorporating objective sleep measures such as actigraphy or polysomnography.

CONCLUSION

This study demonstrates that TD in chronic schizophrenia is not merely a motor disorder but is closely associated with affective morbidity. Insomnia was identified as a significant mediator in the pathway linking TD to depression, and a more severe depressive phenotype was observed in female patients with TD. These findings support an integrated treatment approach that addresses both the motor symptoms of TD and the associated sleep and mood disturbances, with particular attention to female patients. Future longitudinal and interventional studies are warranted to clarify these complex relationships further and to develop targeted strategies aimed at improving the quality of life in this vulnerable patient population.