Orexinergic Dysregulation in Major Depressive Disorder: Insights from a Prospective Cohort Study Evaluating MADRS,PSQI,and MoCA Scores

Abstract

Background:

Major depressive disorder (MDD) is a complex psychiatric condition characterized by affective, cognitive, and somatic symptoms. Disturbances in sleep and cognition are common yet underexplored features of MDD. Orexin, a hypothalamic neuropeptide, plays key roles in arousal, sleep–wake regulation, and cognition. This was a prospective, observational study with longitudinal follow-up investigating the correlation between serum orexin-A levels and depression symptom severity, sleep quality, and cognitive status, as assessed with standard psychometric tools.

Methods:

A total of 113 patients with MDD and 60 age- and sex-matched healthy controls were assessed in this study. Patients were followed up after 6–12 weeks of antidepressant therapy. Symptom severity, sleep quality, and cognitive status were assessed using the Montgomery–Åsberg Depression Rating Scale (MADRS), the Pittsburgh Sleep Quality Index (PSQI), and the Montreal Cognitive Assessment (MoCA), respectively. Serum orexin-A was quantified using an enzyme-linked immunosorbent assay (ELISA). The correlation between changes in serum orexin-A levels and clinical scale scores was assessed.

Results:

The median (Q1–Q3) serum orexin levels in patients and healthy controls were 192.6 (183.2–209.3) pg/mL and 207.4 (203.8–218.7) pg/mL, respectively, with a statistically significant difference (p < .001). Serum orexin-A levels in the patient group at baseline and follow-up were not statistically significant. Changes in various score components of the questionnaires were statistically significant. However, serum orexin-A levels were correlated only with the apparent sadness component of MADRS. No correlation was observed between orexin-A levels and PSQI or MoCA questionnaire components.

Conclusions:

Serum orexin-A showed potential as a biomarker for MDD, exhibiting correlation with a MADRS score component. However, no correlation was observed with sleep quality and cognitive status, necessitating validation in larger cohorts.

Keywords

Orexin Montgomery–Åsberg Depression Rating Scale (MADRS)Montreal Cognitive Assessment (MoCA)major depressive disorder (MDD)Pittsburgh Sleep Quality Index (PSQI)

Key Messages:

Question: Does serum orexin-A differ between MDD patients and healthy controls, and is it linked to changes in depression severity, sleep quality, or cognitive performance after antidepressant therapy?

Findings: Patients with MDD had lower serum orexin-A levels than healthy controls. It was linked to a MADRS component but not sleep quality or cognition.

Meaning: Reduced serum orexin-A appears characteristic of MDD, but short-term antidepressant treatment may not change orexin levels. Orexin-A relates to certain depressive symptoms but does not signal sleep or cognitive changes.

Mood disorders are among the most common psychiatric disorders worldwide.¹ Major depressive disorder (MDD) ranks among the leading causes of global disability, affecting more than 300 million people and contributing significantly to years lived with disability and economic burden.^2,3 By 2030, MDD is projected to become the second leading cause of the global burden of disease.⁴ The COVID-19 pandemic further intensified this burden, resulting in a 27.6% increase in the prevalence of depressive disorders.⁵ In India, the burden of MDD is considerable yet often under-recognized due to stigma, inadequate mental health resources, and prioritization of physical illnesses. According to the National Mental Health Survey (2015–2016), the lifetime prevalence of MDD in India is 5.25%.⁶

MDD is a heterogeneous disorder arising from biological, psychological, social, and environmental factors. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) defines MDD as the presence of ≥5 symptoms within two weeks, including depressed mood, or loss of interest, accompanied by disturbances in weight, sleep, psychomotor activity, concentration, energy, feelings of worthlessness, or suicidal ideation.⁷ Beyond affective symptoms, cognitive impairments such as deficits in attention, memory, executive function, and processing speed are increasingly recognized as integral to the disorder.⁸

While multiple pathophysiological hypotheses have been proposed, including monoaminergic imbalance, neuroplasticity deficits, and immune dysregulation, emerging evidence suggests a significant role for the orexin (hypocretin [HCRT]) system. Orexin-A (HCRT-1) and orexin-B (HCRT-2), derived from prepro-orexin, are neuropeptides produced in the lateral hypothalamus and play essential roles in sleep–wake regulation, arousal, appetite, mood, and reward pathways.^9,10 Dysregulation of the orexinergic system has been reported in neuropsychiatric and neurodegenerative conditions, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and multiple sclerosis, where impaired sleep architecture and neuroinflammation are prominent features.^11–13 Given its involvement in mood regulation and sleep, the orexin pathway is increasingly viewed as a promising biomarker and therapeutic target in MDD. Standard treatment for MDD includes psychotherapy and pharmacotherapy, primarily with selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs).¹⁴ SSRIs such as citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline are commonly used first-line agents due to their favorable safety profile and efficacy.¹⁵ However, limited data exist regarding how antidepressant therapy influences orexin levels in Indian patients. Additionally, limited evidence assesses the relationship between orexin levels and key clinical dimensions of MDD, namely symptom severity, sleep quality, and cognitive status. Therefore, the present study investigated serum orexin-A levels in patients with MDD compared with healthy controls, examined changes following 6–12 weeks of antidepressant therapy, and evaluated correlations with depression severity, sleep disturbances, and cognitive performance.

Rationale for the Study

MDD involves disruptions across mood, sleep, and cognitive domains, yet the biological mechanisms underlying these symptoms remain incompletely understood, especially in Indian populations. The orexin (hypocretin) system, central to sleep–wake regulation, arousal, and emotional processing, has been implicated in the pathophysiology of mood disorders, but existing evidence is derived largely from Western cohorts, uses small sample sizes, or relies on cerebrospinal fluid rather than peripheral blood samples.

There is a major knowledge gap regarding (a) whether serum orexin-A differs between Indian patients with MDD and healthy controls, (b) whether antidepressant therapy alters orexin levels, and (c) whether orexin changes correlate with symptom severity, sleep quality, or cognition when assessed through validated clinical scales.

Novelty

This is one of the first Indian longitudinal studies to evaluate serum orexin-A levels before and after antidepressant therapy while simultaneously correlating changes with Montgomery–Åsberg Depression Rating Scale (MADRS), Pittsburgh Sleep Quality Index (PSQI), and Montreal Cognitive Assessment (MoCA), providing a multidimensional understanding of orexin physiology in MDD.

Hypothesis

It was hypothesized that patients with MDD would have significantly lower serum orexin-A levels compared to healthy controls, that antidepressant therapy would produce measurable changes in serum orexin-A levels over 6–12 weeks, and that changes in orexin-A concentrations would correlate with changes in depressive symptom severity, sleep quality, and cognitive performance.

Aim

The study aimed to evaluate the role of serum orexin-A as a potential biomarker associated with depressive symptoms, sleep quality, and cognitive status in patients with MDD.

Objectives

The objectives of the study were to compare serum orexin-A levels between patients with MDD and age- and sex-matched healthy controls, to assess changes in serum orexin-A levels after 6–12 weeks of antidepressant therapy, and to examine the association of orexin-A levels with depressive symptom severity assessed using the MADRS, sleep quality assessed using the PSQI, and cognitive function assessed using the MoCA at baseline and follow-up.

Methods

Study Design

This prospective observational study was conducted at a tertiary-care center in India. Data collection was carried out from September 2022 to January 2024. The Institutional Ethics Committee approved the study. Written informed consent was obtained from all adult participants. Participants who were found to have significant clinical abnormalities such as severe depressive symptoms, suicidal ideation, cognitive impairment, or sleep dysfunction were appropriately counseled and referred to psychiatric services for further evaluation and treatment as per institutional protocols.

A total of 120 patients with MDD and 60 age and sex-matched healthy controls were assessed in this study. Of the 120 enrolled patients, seven were lost to follow-up. Thus, 113 patients were included in the final analysis (i.e., pre–post comparisons). The baseline characteristics of 120 patients with MDD are presented in Table 1.

Table 1.

Sociodemographic and Clinical Characteristics of Patients with MDD and Healthy Controls at Baseline.

Variables	Patients with MDD (n = 120)	Healthy Controls (n = 60)	p Value
Age (years)	29.03 ± 10.95	27.53 ± 5.36	.67
Gender: Male/female	55 (45.8%)/65 (54.2%)	28 (46.6%) / 32 (53.4%)	.60
Marital status: Unmarried/married/divorced-Widow	40 (33.3%)/75 (62.5%)/5 (4.1%)	35 (58.3%) / 25 (41.7%) / 0	.06
Education: Up to high school/graduate/postgraduate	53 (44.2%)/57 (47.5%)/10 (8.3%)	18 (30.0%) / 24 (40.0%) / 18 (30.0%)	.62
Occupation: Homemaker/professional/self-employed/student	52 (43.3%)/21 (17.5%)/25 (20.8%)/22 (18.3%)	8 (13.3%) / 22 (36.7%) / 6 (10.0%) / 24 (40.0%)	.17
Total duration of illness (months)	11.89 ± 5.53	—	—
Antidepressants prescribed during the treatment period (n)	Escitalopram (n = 92); Sertraline (n = 15); Fluoxetine (n = 8); Paroxetine (n = 5)	—	—
Benzodiazepines prescribed (clonazepam), n	104	—	—
Total MADRS score (Median Q1–Q3)	26 (21.5–29)	—	—
Total PSQI score (median Q1–Q3)	11 (8–14)	—	—
Total MoCA score (median Q1–Q3)	24 (20.5–27)	—	—

MDD = Major depressive disorder, MADRS = Montgomery–Åsberg Depression Rating Scale, PSQI = Pittsburgh Sleep Quality Index, MoCA = Montreal Cognitive Assessment.

This study follows the Strengthening the Reporting of Observational Studies in Epidemiology guidelines for a longitudinal prospective cohort study, and is uploaded as Supplementary Online Material.

Participants and Diagnostic Criteria

Adults aged 18–65 years attending the psychiatry outpatient services were screened. Patients diagnosed with MDD as per DSM-5 criteria (American Psychiatric Association, 2013) were included. Patients were either treatment-naive or had received antidepressants for ≤2 weeks at enrollment. They were followed up after 6–12 weeks of antidepressant therapy. Adults aged 18–65 years who met the DSM-5 diagnostic criteria for MDD and were willing to provide written informed consent were included in the study. Participants were excluded if they had neurological, medical, or psychiatric disorders known to cause secondary depression, if they had any other psychiatric diagnosis or a substance use disorder, or if they were pregnant or lactating. These exclusion criteria applied to both the patient and healthy control groups.

Healthy controls aged 18–65 years without personal or family history of psychiatric illness were recruited in a 2:1 ratio to minimize unnecessary venipuncture. Sample size was estimated to detect a large effect size with >80% power, accounting for 20% attrition.¹⁶

Study Tools

A semi-structured clinical form was prepared to collect sociodemographic and clinical details from participants. Patients were assessed for depression symptom severity using the MADRS, which is a 10-item clinician-rated diagnostic questionnaire to measure the severity of depressive episodes in patients with mood disorders. The symptoms included in the questionnaire are: (a) Apparent sadness, (b) reported sadness, (c) inner tension, (d) reduced sleep, (e) reduced appetite, (f) concentration difficulties, (g) lassitude, (h) inability to feel, (i) pessimistic thoughts, and (j) suicidal thoughts. Each component has a score of 0–6, and the overall score ranges from 0 to 60. A higher MADRS score indicates more severe depression.¹⁷ The MADRS severity score is as follows: 0–6 indicates normal/ absence of symptoms, 7–19 indicates mild, 20–34 indicates moderate, and >34 indicates severe depression.

The PSQI was used to assess sleep quality in patients with MDD. The PSQI is an effective questionnaire for assessing sleep quality in adults. It differentiates poor from good sleep quality by measuring seven areas/components over the past one month: (a) Subjective sleep, (b) sleep latency, (c) sleep duration, (d) habitual sleep efficiency, (e) sleep disturbances, (f) use of sleep medications, and (g) daytime dysfunction. Each component score ranges from 0 to 3, and the scores for all seven components are summed to obtain the global PSQI score, which ranges from 0 to 21.¹⁸ A global PSQI score > A score of five indicates poor sleep quality relative to clinical symptoms, whereas a score of <5 indicates good sleep quality.

Cognitive status in patients with MDD was assessed using the MoCA. MoCA is a screening tool to detect mild cognitive impairment developed by Nasreddine et al. in 1996.¹⁹ MoCA is performed in seven steps. It is a 30–point, one-page test administered in 10 minutes. The test has the following components: (a) Visuospatial/executive, (b) naming, (c) attention, (d) language, (e) abstraction, (f) delayed recall, and (g) orientation. Each scoring component is assigned different points ranging from 0 to 6. The points for each component are summed to obtain the total MoCA score, which ranges from 0 to 30. A total MoCA score of ≥26 is generally considered normal, and a score of <26 may indicate some degree of cognitive impairment, relative to clinical symptoms.

Pharmacotherapy

Patients received antidepressants, including SSRIs and SNRIs, as prescribed by the treating psychiatrist. Mean daily dosages (mg/day) for each medication were: Escitalopram, 10 mg/day; sertraline, 50 mg/day; fluoxetine, 20 mg/day; and paroxetine, 20 mg/day. Benzodiazepines, such as clonazepam, were used when clinically indicated, and the daily dosage was 0.5 mg/day.

Serum Orexin-A Estimation

Approximately 3 mL of venous blood was collected, centrifuged, and serum aliquots were stored at −80°C until analysis. Serum orexin-A levels were measured using a human orexin-A enzyme -linked immunosorbent assay (ELISA) kit (Elabsciences, USA) according to the manufacturer’s protocols. Absorbance was read using an ELISA microplate reader (BioTek Cytation 5, Agilent, USA). All assays were performed in duplicate with internal quality-control standards.

Statistical Analysis

All statistical analyses were performed using International Business Machines Corporation (IBM) Statistical Package for the Social Sciences (SPSS) Statistics for Windows, version 30.0.0 (IBM Corp., Armonk, NY, USA). Continuous variables were presented as median and interquartile range (Q1–Q3), and categorical variables were expressed as frequency with percentage. Data normality was assessed using the Shapiro–Wilk test. To test the statistical significance of changes in baseline and follow-up findings for numerical variables, the Wilcoxon signed-rank test was used. To test the statistical significance of the difference in the changes in baseline and follow-up serum orexin-A between patients and healthy controls, the Mann–Whitney U test was used. To assess the correlation between baseline and follow-up changes in different variables and changes in serum orexin, the Spearman rank correlation coefficient was computed, and its statistical significance was tested. A p value of < .05 was statistically significant.

Results

Of the 168 patients screened, 44 did not meet the selection criteria, and four declined to be sampled. 120 patients were enrolled in the study; seven were lost to follow-up, leaving 113 patients with MDD in the final analysis. Of the 72 healthy controls screened, seven individuals did not meet the selection criteria, and five did not consent to be sampled. Thus, 60 healthy controls were enrolled and included in the final analysis.

Sociodemographic and Clinical Characteristics

Both patients with MDD and the healthy control groups were comparable in sociodemographic characteristics, including age, gender, marital status, education, and occupation (Table 1). There was no statistically significant difference between the groups in terms of these factors. Considering the clinical characteristics of patients with MDD, the mean total illness duration was 11.89 ± 5.53 months. In terms of the antidepressants given to the patients, 92 patients were treated with escitalopram, and paroxetine was the least commonly prescribed SSRI for the patients, with five of them receiving paroxetine during the treatment period. 104 patients received benzodiazepines such as clonazepam during the treatment period. The MADRS, PSQI, and MoCA scores at baseline were 26 (21.5–29), 11.0 (8–14), and 24 (20.5–27), respectively.

Serum Orexin-A Levels

Serum orexin-A levels were estimated in patients with MDD at baseline and at follow-up after antidepressant therapy, and in healthy controls at baseline. The results showed that in patients with MDD, serum orexin-A had almost identical median (Q1–Q3) values at baseline [192.8 (182.0–209.3) pg/mL] and at follow-up [189.2 (174.7–211.6) pg/mL], which was not statistically significant (p = 0.67) (Figure 1). Serum orexin-A levels at baseline were compared between patients with MDD and healthy controls. The median (Q1–Q3) serum orexin-A levels among patients were 192.6 (183.2–209.3) pg/mL, whereas healthy controls showed a higher median of 207.4 (203.8–218.7) pg/mL, and the values were significantly different (p < .001) (Figure 2).

Figure 1.

Boxplot Showing Serum Orexin-A Levels at Baseline and at Follow-up in Patients With MDD.

Serum orexin pre and serum orexin post refer to the serum orexin levels at baseline and at follow-up, respectively, in patients with MDD.

Figure 2.

Boxplot Showing Serum Orexin-A at Baseline between Patients With MDD and Healthy Controls. Serum orexin pre refers to the serum orexin levels at baseline in the cases (patients with MDD) and controls (healthy controls) group, respectively.

Correlation of Serum Orexin-A with Symptom Severity Using MADRS

The median (Q1–Q3) value of total MADRS score dropped sharply from 26 (21.5–29.0) at baseline to 14 (13.0–18.0) at follow-up (Table 2). The median (Q1–Q3) value of severity score decreased from 2 (2.0–2.0) at baseline to 1 (1.0–1.0) at follow-up. All other components of the questionnaire showed considerable improvement in scores at follow-up compared with baseline. The correlation analysis between changes in serum orexin-A levels and various variables showed mostly weak and statistically nonsignificant relationships. Among all, only apparent sadness showed a statistically significant negative correlation with change in serum orexin (r = −0.20, p = .03), implying that as serum orexin increases, apparent sadness tends to decrease slightly, albeit with a weak correlation (Figure 3).

Table 2.

Correlation of Change in Serum Orexin-A Levels With Montgomery–Åsberg Depression Rating Scale Components.

Variable	Baseline (Median, Q1–Q3)	Follow-up (Median, Q1–Q3)	p Value	Correlation Coefficient (ρ)	p Value (Correlation)
Total MADRS score	26 (21.5–29)	14 (13–18)	<.001*	−0.03	.68
Severity	2 (2–2)	1 (1–1)	<.001*	−0.007	.94
Apparent sadness	3 (2–3)	2 (1–2)	<.001*	−0.20	.03*
Reported sadness	4 (3–4)	2 (2–3)	<.001*	0.08	.36
Inner tension	4 (3–4)	2 (2–3)	<.001*	0.14	.13
Reduced sleep	3 (2.5–4)	2 (2–3)	<.001*	−0.04	.63
Reduced appetite	2 (2–3)	1 (0–2)	<.001*	0.07	.41
Concentration difficulties	3 (2–4)	2 (2–2)	<.001*	0.05	.56
Lassitude	2 (1–3)	1 (1–2)	<.001*	0.02	.76
Inability to feel	2 (1–2)	1 (1–2)	<.001*	0.06	.51
Pessimistic thoughts	2 (1–3)	1 (0–2)	<.001*	−0.09	.31
Suicidal thoughts	0 (0–1)	0 (0–0)	<.001*	0.01	.91

MADRS = Montgomery–Åsberg Depression Rating Scale, ρ = Spearman correlation coefficient.

Statistical tests: Wilcoxon signed-rank test for baseline and follow-up comparison; Spearman’s rank correlation for associations.

Figure 3.

Scatter Plot of Apparent Sadness Score With Change in Serum Orexin.

Correlation of Serum Orexin-A with Sleep Quality Using PSQI

The median (Q1–Q3) of total PSQI score fell from 11 (8.0–14.0) at baseline to 8.0 (5.0–10.0) at follow-up and showed statistically significant improvement (p < .001) (Table 3). All components, except the sleep medication component, showed statistical significance between baseline and follow-up scores. Across the seven variables examined, changes in serum orexin-A showed no statistically significant correlation with the PSQI score components.

Table 3.

Correlation of Change in Serum Orexin-A Levels With PSQI Components.

Variable	Baseline (Median, Q1–Q3)	Follow-up (Median, Q1–Q3)	p Value	Correlation Coefficient (ρ)	p Value (Correlation)
Total PSQI score	11 (8–14)	8 (5–10)	<.001*	0.12	.20
Subjective quality	2 (1–3)	1 (1–2)	<.001*	−0.01	.87
Sleep latency	2 (1–3)	1 (1–2)	<.001*	0.09	.29
Sleep duration	1 (0–2)	1 (0–2)	<.001*	0.09	.32
Sleep efficiency	1 (0–2)	0 (0–1)	<.001*	0.10	.28
Sleep disturbance	2 (1–2)	1 (1–2)	<.001*	0.13	.16
Use of sleep medication	1 (0–3)	2 (1–2)	.30	−0.02	.83
Daytime dysfunction	2 (1–2)	1 (1–2)	<.001*	−0.04	.65

PSQI = Pittsburgh Sleep Quality Index, ρ = Spearman correlation coefficient.

Statistical tests: Wilcoxon signed-rank test for baseline and follow-up comparison; Spearman’s rank correlation for associations.

Correlation of Serum Orexin-A with Cognitive Status Using MoCA

The results revealed statistically significant increases in the median scores of most variables following antidepressant therapy (Table 4). The median (Q1–Q3) of total MoCA score rose notably from 24 (20.5–27.0) to 28 (26.0–29.0), reflecting a substantial upward shift across the patients. The correlation analysis between changes in serum orexin-A and various variables revealed no statistically significant or meaningful associations. All correlation coefficients (ρ values) were weak, ranging from −0.12 to 0.06, with all p values well above the .05 threshold.

Table 4.

Correlation of Change in Serum Orexin-A Levels With MoCA Components.

Variable	Baseline (Median, Q1–Q3)	Follow-up (Median, Q1–Q3)	p Value	Correlation Coefficient (ρ)	p Value (Correlation)
Total MoCA score	24 (20.5–27)	28 (26–29)	<.001*	0.03	.72
Visuospatial/ Executive	3 (2–4)	4 (3–5)	<.001*	0.06	.52
Naming	3 (2–3)	3 (3–3)	<.001*	0.03	.69
Attention	4 (3–6)	6 (4–6)	<.001*	0.01	.87
Language	1 (1–3)	3 (2–3)	<.001*	−0.006	.94
Abstraction	2 (2–2)	2 (2–2)	.13	−0.04	.60
Delayed recall	4 (2–5)	5 (4–5)	<.001*	0.01	.99
Orientation	6 (6–6)	6 (6–6)	.53	−0.12	.19

MoCA = Montreal Cognitive Assessment, ρ = Spearman correlation coefficient.

Statistical tests: Wilcoxon signed-rank test for baseline and follow-up comparison; Spearman’s rank correlation for associations.

Discussion

This longitudinal study reports the correlation of serum orexin-A levels with symptom severity, sleep quality, and cognitive status in patients with MDD from northern India. This article adds to the limited literature on the effect of antidepressant therapy on the orexinergic pathway in MDD among Indian subjects.

A significant finding of this study was a marked reduction in baseline serum orexin levels in MDD patients compared to healthy controls. This aligns with prior reports indicating that orexin-A levels are diminished in individuals with MDD, particularly in those experiencing fatigue, hypersomnia, and motivational deficits.^20,21 Theorexinergic system, originating in the lateral hypothalamus, plays a pivotal role in arousal, stress regulation, and monoaminergic modulation. The observed hypoactivity may be attributed to chronic hyperactivation of the Hypothalamic-Pituitary-Adrenal axis (HPA) axis and glucocorticoid-induced suppression of orexin neurons.^22,23 Interestingly, although orexin levels increased at follow-up after antidepressant therapy, the change was not statistically significant. This may reflect inter-individual variability in antidepressant response, the duration of treatment, or potential receptor-level alterations not captured by serum concentrations. Previous studies have reported that SSRIs and SNRIs may modulate orexin levels indirectly through serotonergic and noradrenergic feedback on hypothalamic circuits.²⁴

Clinically significant reductions in MADRS scores from baseline to follow-up affirm the efficacy of standard antidepressant therapy in symptom amelioration in our study population. This aligns with previous literature.²⁵ These changes in MADRS scores were paralleled by improvements in sleep quality (PSQI scores) and cognitive function (MoCA scores), suggesting that the biochemical and clinical changes were interconnected. Sleep disturbances are a core symptom of MDD, and the orexin system plays a crucial role in maintaining sleep–wake architecture.²⁶ Recent work has expanded the literature on peripheral orexin (hypocretin) measures in mood disorders, but results remain mixed. Some studies report increased plasma/hypocretin-1 (orexin-A) in affective disorders, while others find no difference or even reductions in suicidal patients, suggesting heterogeneity by sample, assay, and clinical features. A small adolescent study found no relationship between serum orexin-A and depressive symptom severity. At the same time, larger recent syntheses highlight inconsistent peripheral findings but growing clinical interest in targeting the orexin system for comorbid insomnia and depression (and for pharmacologic modulation using orexin-receptor antagonists). These discrepancies underline the need to report assay methods, sample timing (circadian effects), and concurrent sleep or medication status when interpreting peripheral orexin measures.^27,28

Addressing possible age-dependent orexinergic changes, we recommend pre-specifying clinically meaningful age strata (for example: Adolescents 12–17, young adults 18–39, middle-aged 40–64, older adults ≥65) and performing subgroup analyses comparing mean serum orexin-A and its correlations with MADRS, PSQI, and MoCA across these groups. Age stratification helps detect developmental or neurodegenerative shifts in orexin signaling, identify whether sleep-related effects mediate orexin–mood associations in older versus younger people, and improve translational relevance for age-targeted interventions.²⁹ Although the correlations between serum orexin-A and MADRS components were weak, small effect sizes are common in psychiatric research due to the multifactorial nature of depression. These findings suggest that orexin may play a modest, indirect role in specific symptom domains rather than strongly influencing overall severity. Peripheral orexin levels may also not fully reflect central activity, and factors such as sleep, circadian rhythm, and medication could attenuate associations. Thus, the weak correlations should be interpreted cautiously but not dismissed as clinically irrelevant. Animal studies have shown that orexin enhances prefrontal cortex activation and hippocampal long-term potentiation, processes that are central to cognition.^30,31 In terms of cognitive performance, our study found no significant correlation between orexin levels and MoCA scores, suggesting that while antidepressants can improve cognitive symptoms, the orexinergic pathway may serve as an indirect modulator and a potential target for pro-cognitive adjunct therapies.

The study’s limitations include the collection of samples from a single center, which limits the generalizability of the findings. Feasibility constraints limited the sample size, and a larger sample would have increased the study’s power. Nonetheless, this study provides valuable information about the effect of antidepressant therapy on the orexinergic pathway in MDD, along with the association of orexin with mood symptoms, sleep patterns, and cognitive status in the Indian population. This is the first study of its kind conducted in India.

Conclusions

Statistically significant differences in serum orexin-A levels were observed between patients with MDD and healthy controls. However, the duration of antidepressant therapy may not have been sufficient to cause a significant increase in orexin-A levels post-treatment compared to baseline. Given that India is a large country, we recommend conducting multicenter studies in the future with a longer treatment period to assess the effects of antidepressant therapy on the orexin pathway and to investigate further the association between orexin and symptom severity, sleep quality, and cognitive status in MDD.

Supplemental Material

Supplemental material for this article is available online.

Supplemental Material

Supplemental material for this article is available online.

Footnotes

Acknowledgements

Not applicable.

Reporting Guidelines

STROBE guidelines for a longitudinal prospective cohort study.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Declaration Regarding the Use of Generative AI

We have checked the grammar of the manuscript draft using the free version of Grammarly software. The authors take full responsibility for the accuracy, integrity, and originality of the published article.

Ethical Approval

Name of the Institutional Ethics Committee/Independent Review Board: Institute Ethics Committee, All India Institute of Medical Sciences, New Delhi

Approval Ref. No.: IEC-762/07.10.2022

Date: October 7, 2022

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The authors received financial support for this research from the Department of Health Research, Indian Council of Medical Research, Government of India, vide sanction no. F.No. R. 11012/01/2023-GIA-HR.

Informed Consent

Written informed consent was obtained from all adult participants before their enrollment in the study.

PROSPERO/CTRI Details

CTRI Ref. No.: CTRI/2024/05/06684.

Trial registry name: Clinical Trials Registry–India (CTRI)

URL: http://ctri.nic.in

Registration No.: CTRI/2024/05/06684

Citation Diversity Statement

We recognize that citation practices may reflect systemic biases. We therefore made a good-faith effort to include scholarship from a diverse range of authors and perspectives in the references cited.

References

Barr

, Bigdeli

, Meyers

, . Prevalence, comorbidity, and sociodemographic correlates of psychiatric disorders reported in the all of us research program. JAMA Psychiatry, 2022; 79(6): 622–628. DOI: 10.1001/jamapsychiatry.2022.0685.

Cui

, Li

, Wang

, . Major depressive disorder: Hypothesis, mechanism, prevention and treatment. Signal Transduct Target Ther, 2024; 9(1): 30. DOI: 10.1038/s41392-024-01738-y.

Jiao

, Lin

, Deng

, . The immunological perspective of major depressive disorder: Unveiling the interactions between central and peripheral immune mechanisms. J Neuroinflammation, 2025; 22(1): 10. DOI: 10.1186/s12974-024-03312-3.

Mathers

and Loncar

Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med, 2006; 3(11): e442. DOI: 10.1371/journal.pmed.0030442.

COVID-19 Mental Disorders Collaborators. Global prevalence and burden of depressive and anxiety disorders in 204 countries and territories in 2020 due to the COVID-19 pandemic. Lancet, 2021; 398(10312): 1700–1712. DOI: 10.1016/S0140-6736(21)02143-7.

Rockson

, Girish

, Harivenkatesh

, . Prevalence of major depression and dysthymia among outpatient attendees at a tertiary healthcare psychiatric facility in South India. Clin Epidemiol Glob Health, 2024; 26(101536). DOI: 10.1186/s12974-024-03312-3.

Tolentino

and Schmidt

. DSM-5 criteria and depression severity: Implications for clinical practice. Front Psychiatry 2018; 9: 450. DOI: 10.3389/fpsyt.2018.00450.

Perini

, Cotta

Ramusino M

, Sinforiani

, . Cognitive impairment in depression: Recent advances and novel treatments. Neuropsychiatr Dis Treat 2019; 15: 1249–1258. DOI: 10.2147/NDT.S199746.

Sakurai

. The neural circuit of orexin (hypocretin): Maintaining sleep and wakefulness. Nat Rev Neurosci, 2007; 8(3): 171–181. DOI: 10.1038/nrn2092.

10.

Tsunematsu

, Ueno

, Tabuchi

, . Optogenetic manipulation of activity and temporally controlled cell-specific ablation reveal a role for MCH neurons in sleep/wake regulation. J Neurosci, 2014; 34(20): 6896–6909. DOI: 10.1523/JNEUROSCI.5344-13.2014.

11.

Liu

, Xue

, Liu

, . Orexin-A exerts neuroprotective effects via OX1R in Parkinson’s disease. Front Neurosci 2018; 12: 835. DOI: 10.3389/fnins.2018.00835.

12.

Petersén

, Gil

, Maat-Schieman

, . Orexin loss in Huntington’s disease. Hum Mol Genet, 2005; 14(1): 39–47. DOI: 10.1093/hmg/ddi004.

13.

Mander

, Winer

, Jagust

, . Sleep: A novel mechanistic pathway, biomarker, and treatment target in the pathology of Alzheimer’s disease?. Trends Neurosci, 2016; 39(8): 552–566. DOI: 10.1016/j.tins.2016.05.002.

14.

Dobson

and Scherrer

. Major depressive disorder. In: Hersen

, Thomas

, eds Handbook of clinical interviewing with adults. USA: Sage Publications Ltd., 2007, pp.134–152.

15.

Goldstein

and Goodnick

. Selective serotonin reuptake inhibitors in the treatment of affective disorders-III. Tolerability, safety and pharmacoeconomics. J Psychopharmacol, 1998; 12(3 Suppl B): S55–S87. DOI: 10.1177/0269881198012003041.

16.

Browne

. On the use of a pilot sample for sample size determination. Stat Med, 1995; 14(17): 1933–1940. DOI: 10.1002/sim.4780141709.

17.

Quilty

, Robinson

, Rolland

, . The structure of the Montgomery-Åsberg depression rating scale over the course of treatment for depression. Int J Methods Psychiatr Res, 2013; 22(3): 175–184. DOI: 10.1002/mpr.1388.

18.

Buysse

, Reynolds

3rd , Monk

, . The Pittsburgh Sleep Quality Index: A new instrument for psychiatric practice and research. Psychiatry Res, 1989; 28(2): 193–213. DOI: 10.1016/0165-1781(89)90047-4.

19.

Nasreddine

, Phillips

, Bédirian

, . The Montreal Cognitive Assessment, MoCA: A brief screening tool for mild cognitive impairment. J Am GeriatrSoc, 2005; 53(4): 695–699. DOI: 10.1111/j.1532-5415.2005.53221.x.

20.

Brundin

, Björkqvist

, Petersén

, . Reduced orexin levels in the cerebrospinal fluid of suicidal patients with major depressive disorder. EurNeuropsychopharmacol, 2007; 17(9): 573–579. DOI: 10.1016/j.euroneuro.2007.01.005.

21.

Tsuchimine

, Hattori

, Ota

, . Reduced plasma orexin-A levels in patients with bipolar disorder. Neuropsychiatr Dis Treat 2019; 15: 2221–2230. DOI: 10.2147/NDT.S209023.

22.

Grafe

and Bhatnagar

Orexins and stress. Front Neuroendocrinol 2018; 51: 132–145. DOI: 10.1016/j.yfrne.2018.06.003.

23.

Mazzocchi

, Malendowicz

, Gottardo

, . Orexin A stimulates cortisol secretion from human adrenocortical cells through activation of the adenylate cyclase-dependent signaling cascade. J ClinEndocrinolMetab, 2001; 86(2): 778–782. DOI: 10.1210/jcem.86.2.7233.

24.

Nollet

and Leman

Role of orexin in the pathophysiology of depression: Potential for pharmacological intervention. CNS Drugs, 2013; 27(6): 411–422. DOI: 10.1007/s40263-013-0064-z.

25.

Borentain

, Gogate

, Williamson

, . Montgomery-Åsberg depression rating scale factors in treatment-resistant depression at onset of treatment: Derivation, replication, and change over time during treatment with esketamine. Int J Methods Psychiatr Res, 2022; 31(4): e1927. DOI: 10.1002/mpr.1927.

26.

Nishino

, Ripley

, Overeem

, . Hypocretin (orexin) deficiency in human narcolepsy. Lancet, 2000; 355(9197): 39–40. DOI: 10.1016/S0140-6736(99)05582-8.

27.

, Lu

, Li

, . Increased hypocretin (orexin) plasma level in depression, bipolar disorder patients. Front Psychiatry 2021; 12: 676336. DOI: 10.3389/fpsyt.2021.676336.

28.

Meshkat

, Kwan

ATH

, Le

, . Efficacy of orexin antagonists for the management of major depressive disorder: A systematic review of randomized clinical trials. J Affect Disord 2025; 372: 409–419. DOI: 10.1016/j.jad.2024.12.008.

29.

Blume

, Nam

, Luz

, . Sex- and age-dependent effects of orexin 1 receptor blockade on open-field behavior and neuronal activity. Neuroscience 2018; 381: 11–21. DOI: 10.1016/j.neuroscience.2018.04.005.

30.

Abounoori

, Maddah

and Ardeshiri

. Orexin neuropeptides modulate the hippocampal-dependent memory through basolateral amygdala interconnections. CerebCircCognBehav 2021; 3: 100035. DOI: 10.1016/j.cccb.2021.100035.

31.

Song

, Kim

, . The role of orexin in post-stroke inflammation, cognitive decline, and depression. Mol Brain 2015; 8: 16. DOI: 10.1186/s13041-015-0106-1.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.02 MB

0.00 MB

0.03 MB