Clinical implications of admission anemia for electroconvulsive therapy planning in adolescent major depressive disorder: identifying vulnerable subgroups with poorer response

Background: Major depressive disorder (MDD) represents a grave worldwide concern, particularly afflicting the adolescent population. Electroconvulsive therapy (ECT) is widely regarded as a gold-standard intervention for severe forms of MDD, although treatment response varies considerably among individuals. Growing evidence suggests that hematological parameters may influence therapeutic outcomes. This study sought to examine the link between admission anemia and response to ECT treatment.

Methods: We analyzed 381 adolescent MDD patients who underwent ECT, comparing demographic and hematological indicators between responders and non-responders. Subgroup analyses were conducted based on gender and depressive subtypes.

Results: Among the 381 patients treated with ECT, 272 (71.4%) were classified as responders. Non-responders showed significantly lower baseline hemoglobin levels compared to responders (mean ± SD: 119.0 ± 9.7 vs. 128.7 ± 13.1, p < 0.001). Analysis identified a significant link between hemoglobin levels at admission and the percentage improvement on the HAMD-17 (r = 0.231, p < 0.001). Following confounder adjustment in a binary logistic regression model, anemia at admission was correlated with a lower probability of ECT response [OR (95% CI): 4.051 (2.399-6.840), p < 0.001]. Females and patients with psychotic depression were particularly more susceptible to the impact of admission anemia.

Conclusion: Admission anemia is associated with poorer ECT efficacy in adolescent MDD patients. Assessing baseline hemoglobin levels may help optimize ECT treatment planning, especially in female patients and those with psychotic depression.

1 Introduction

Major depressive disorder (MDD) constitutes a leading cause of mental health disease in adolescents across the world, with a global prevalence of approximately 6.2% (1). Studies indicate that up to 67% of adolescents with depressive symptoms face a significantly higher risk of developing full-syndrome depression or anxiety disorders in adulthood. Additionally, this age group is more prone to suicidal ideation and self-harm behaviors (2–5). Electroconvulsive therapy (ECT) is widely regarded as one of the most potent therapeutic options for MDD (6, 7), achieving a remission rate of 70%-80% (8). One study reported an 80.9% response rate in adolescent MDD patients treated with ECT (9). However, due to the unclear mechanisms underlying ECT’s therapeutic effects, variability in treatment outcomes, and potential side effects, its widespread use among adolescent MDD patients remains limited. Identifying objective biomarkers predictive of ECT efficacy thus holds significant clinical importance.

In recent years, peripheral blood cell parameters have gained attention in depression research due to their association with inflammation and metabolic status (10–12). Anemia is defined as a condition where the red blood cell (RBC) count or hemoglobin concentration in peripheral blood falls below the normal threshold (13). Hemoglobin, essential for maintaining tissue oxygen metabolism, may influence neuroplasticity by regulating brain energy metabolism, thereby playing a role in various neuropsychiatric conditions, especially Alzheimer’s disease, autism, and depression (14–16). A large cross-sectional study of 44,173 healthy adults revealed a significant and robust association between depression and anemia (17). Furthermore, a 4-year prospective study in older adults demonstrated that depression was independently and positively correlated with both admission anemia and a higher likelihood of anemia at the 4-year follow-up, with this association being more pronounced in MDD (16).

While extensive research over past decades has examined the link between anemia and depression, literature directly investigating the relationship between anemia and the clinical efficacy of ECT remains limited, especially among adolescents. Given that hemoglobin is crucial for cerebral oxygen supply and energy metabolism and may influence neuroplasticity, which is a key mechanism in both depression pathophysiology and ECT treatment (18, 19), we hypothesize that admission anemia may serve as an important modulator of ECT clinical outcomes. This research specifically examines three aspects (1): the correlation between admission anemia and ECT response rates (2); the predictive potential of various blood cell parameters for treatment efficacy; and (3) differential associations between admission anemia and ECT response across demographic and clinical subgroups. To our knowledge, this is the first study specifically designed to investigate the predictive value of admission anemia status for ECT outcomes in adolescent MDD patients. This research aims to address a critical knowledge gap and may provide an easily accessible biomarker for personalized treatment strategies in this challenging patient population.

2 Methods

2.1 Participants

A retrospective study was conducted on MDD patients admitted to the Department of Psychiatry at the First Affiliated Hospital of Chongqing Medical University between May 2023 and February 2025. Inclusion criteria were (1): patients aged 13–18 years (2); meeting DSM-5 diagnostic criteria for major depressive disorder (3); complete blood count tested within 24 hours of admission; and (4) completion of ECT treatment. Exclusion criteria included (1): inability to complete ECT (2); substance dependence or drug abuse (within the past 6 months) (3); prior ECT treatment (within the past 6 months) (4); history of brain disorders or severe traumatic brain injury (5); recent blood transfusion (within 1 month); and (6) missing laboratory data or assessment scale results. The study protocol was approved by the Ethics Committee of the First Affiliated Hospital of Chongqing Medical University (K2023-676). Written informed consent was obtained from all participants or their legal guardians.

2.2 Clinical data acquisition

Clinical characteristics were recorded, such as age, gender, number of ECT sessions, and concomitant medications. Pharmacological treatments were categorized into antidepressants [selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), mirtazapin, and trazodone], antipsychotics (risperidone, olanzapine, quetiapine, or aripiprazole), and anxiolytics (benzodiazepines and Z-drugs). The baseline fasting blood samples were collected from all patients within 24 hours after admission and prior to the initiation of ECT. The first ECT session was administered within 1–2 days following the blood draw, ensuring a consistent pre-treatment baseline assessment across the entire cohort. Complete blood count was analyzed using Sysmex XN-1500 automated hematology analyzer. Anemia was diagnosed according to WHO criteria: hemoglobin <120 g/L for females and males aged 12–14 years; <120 g/L for females and <130 g/L for males aged 15–18 years (20).

The 17-item Hamilton Depression Rating Scale (HAMD-17) was utilized to evaluate depression severity and treatment response. A positive response to ECT was defined as ≥ 50% reduction in HAMD-17 scores from baseline (21).

2.3 ECT procedure

All ECT sessions were delivered via the Thymatron DGx system (Somatics LLC, Lake Bluff, IL, USA), employing brief-pulse stimulus with bitemporal electrode application. A standardized formula (age × 0.7) defined the initial electrical charge administered, with subsequent adjustments based on seizure duration. Induction of anesthesia was achieved with succinylcholine (0.5–1 mg/kg) and propofol (1.5–2 mg/kg). We obtained written informed consent from all patients and their legal guardians prior to treatment, after comprehensively explaining the procedures, risks, and benefits of ECT.

2.4 Statistical analysis

Categorical variables were assessed between groups with chi-square, as appropriate, and are expressed as frequencies and percentages. Analysis of continuous variables was conducted using t-tests or Mann-Whitney U tests, reported as mean ± SD or median (IQR). Correlation analyses used Pearson/Spearman tests. We constructed receiver operating characteristic (ROC) curves to assess the ability of blood cell indices to predict ECT outcomes. Logistic regression was performed to calculate odds ratios (OR) with 95% confidence intervals (CI) for the association between anemia and ECT response. Formal testing for interaction effects between admission anemia and categorical covariates, including age, gender, and depressive subtype, was performed by introducing product terms into binary logistic regression models containing the main effects of both variables. The significance of these interaction terms was assessed using the Wald test, and the resulting p-values are reported as p-interaction. To illustrate the association between anemia and ECT response within each subgroup, we subsequently performed stratified analyses and reported the stratum-specific OR and p-values. Statistical significance was established at the p < 0.05 level. Analyses were carried out utilizing IBM-SPSS 23.0 and Prism 10.0.

3 Results

3.1 Patient demographic characteristics

From May 2023 to February 2025, we recruited a cohort of 713 adolescents diagnosed with MDD. Following the screening process, 332 patients were excluded due to failure to meet one or more of the following criteria: 152 cases due to inability to complete ECT treatment (comprising 65 patients who withdrew consent due to concerns about anesthesia or cognitive side effects after initial sessions; 40 patients who discontinued due to significant adverse effects such as severe headache or prolonged confusion; 32 patients discharged against medical advice for non-medical reasons including financial constraints or family decisions; and 15 patients who developed intercurrent physical illnesses unrelated to hematological issues requiring ECT cessation), 34 cases with substance dependence or drug abuse (within the past 6 months), and 91 cases with prior ECT treatment (within the past 6 months). Ultimately, 381 adolescent MDD patients were enrolled in the study, with 272 responders (71.4%) and 109 non-responders (28.6%) (Figure 1). The study cohort comprised 245 female participants (64.3%), with mean values of 14.7 ± 1.3 years for age and 20.7 ± 3.7 kg/m² for BMI, respectively (Table 1).

Figure 1

Figure 1. Study population recruitment flow chart. MDD, major depressive disorder; ECT, electroconvulsive therapy; HAMD-17, Hamilton depression rating scale, 17-item version.

Table 1

Table 1. Baseline characteristics of the analyzed participants.

3.2 Differences in clinical characteristics between ECT responders and non-responders

Comparative analysis of clinical characteristics between response groups is summarized in Table 1. The baseline hemoglobin level was significantly lower in non-responders than in responders (mean ± SD: 119.0 ± 9.7 vs. 128.7 ± 13.1, p < 0.001) (Table 1, Figure 2A). Anemia was present in 56% of non-responders, compared to only 23.5% in responders (p < 0.001). Additionally, non-responders had lower RBC counts (mean ± SD: 4.4 ± 0.3 vs. 4.5 ± 0.3, p = 0.012) but higher WBC counts (mean ± SD: 6.2 ± 1.6 vs. 5.9 ± 1.4, p = 0.043). Notably, psychotic depression was more prevalent in non-responders (29.4% vs. 19.9%, p = 0.045). However, analysis revealed no significant differences in age, gender, BMI, antidepressants, antipsychotics, or other factors (p > 0.05) (Table 1).

Figure 2

Figure 2. The association between baseline hemoglobin levels with ECT treatment outcomes in adolescent MDD patients. (A) Baseline hemoglobin levels in ECT responders and non-responders; (B) Correlation between baseline hemoglobin levels and percentage change in HAMD-17 scores; (C) Receiver operating characteristic analysis of blood cell parameters for predicting ECT response. MDD, major depressive disorder; ECT, electroconvulsive therapy; AUC, area under the curve; WBC, white blood cell; RBC, red blood cell. ***p < 0.001.

Correlation analysis revealed that baseline hemoglobin levels were positively associated with the percentage improvement on the HAMD-17 (r = 0.231, p < 0.001) (Figure 2B). Furthermore, ROC curve analysis showed that hemoglobin had greater predictive power for ECT response in adolescent MDD patients (AUC = 0.730, sensitivity = 77.1%, specificity = 59.6%) compared to other blood cell markers, such as WBC [AUC = 0.609, 95% CI (0.545–0.673), p < 0.001] and RBC [AUC = 0.570, 95% CI (0.510–0.631), p = 0.030] (Figure 2C).

3.3 Baseline characteristics of anemia and non-anemia stratified by admission hemoglobin levels

All adolescent MDD patients were divided into anemia (32.8%) and non-anemia (67.2%) groups based on hemoglobin levels at admission. Compared to the non-anemia patients, patients with anemia had a higher likelihood of experiencing adverse effects from ECT, including increased risks of memory impairment (8.8% vs. 3.5%, p = 0.030), headache (9.6% vs. 2.7%, p = 0.004), and haziness (4.0% vs. 0.8%, p = 0.028). Additionally, the anemia group exhibited higher post-ECT HAMD-17 scores [median (IQR): 15.0 (10.0–21.0) vs. 11.0 (8.0–16.0), p < 0.001] and a lower proportion of ECT responders (51.2% vs. 81.3%, p < 0.001) (Table 2). These findings suggest that admission anemia is significantly associated with both ECT-related side effects and treatment efficacy.

Table 2

Table 2. Baseline profiles of MDD patients categorized by anemia status at admission.

3.4 Predictors of ECT response

In binary logistic regression analysis after adjusting for potential confounders (including age, gender, BMI, antipsychotics, antidepressants, anxiolytics and variables with p < 0.1 in univariate analysis), we found that anemia [OR (95% CI): 4.051 (2.399-6.840), p < 0.001] significantly reduced the likelihood of ECT response (Table 3). This indicates that anemia is independently associated with ECT treatment outcomes.

Table 3

Table 3. Binary logistic regression analysis of admission anemia and ECT response.

3.5 Subgroup differences in the association between anemia and ECT response

We investigated potential interactions between admission anemia and various demographic and clinical factors. As shown in Table 4, after stratifying by age, gender, and depressive subtype, a significant interaction effect was observed between anemia and gender [female vs. male, OR (95% CI): 29.292 (11.644–73.687) vs. 0.513 (0.180–1.461), p for interaction < 0.001]. These findings suggest gender-specific effects - anemia was independently associated with poor ECT response in female patients but not in males. Additionally, an interaction effect was also found in patients with psychotic depression [none vs. yes, OR (95% CI): 3.388 (1.868–6.143) vs. 21.560 (6.588–70.552), p for interaction = 0.027], indicating that individuals with psychotic depression may be more sensitive to anemia at admission (Table 4).

Table 4

Table 4. Subgroup analysis indicating the association between adm. anemia and ECT response.

4 Discussion

This study provides the systematic evaluation of the relationship between complete blood cell parameters and ECT efficacy in adolescents, aiming to identify easily accessible biomarkers for predicting ECT response and optimizing treatment selection for adolescent MDD patients to achieve personalized intervention. Our results demonstrate a significant association between anemia at admission and poor ECT response, with non-responders showing lower hemoglobin levels, reduced RBC counts, and elevated WBC counts. Hemoglobin emerged as a superior predictor of ECT efficacy compared to other blood cell parameters. Notably, patients with anemia experienced a higher incidence of post-ECT adverse effects, including memory impairment, headaches, and haziness. Furthermore, the predictive value of anemia appears to vary across subgroups, showing particularly strong associations in female patients and those with psychotic depression subtypes.

Anemia is defined as a condition characterized by hemoglobin concentration and/or RBC count below normal levels, insufficient to meet an individual’s physiological needs (22). A large cross-sectional study of 11,876 Japanese participants revealed a significant association between self-reported history of depression and history of iron-deficiency anemia (23), with evidence suggesting this relationship may be bidirectional (24, 25). Research involving 1,156 elderly participants demonstrated that the risk of anemia increases with depression severity (26). Additionally, anemia may contribute to the development of depression. In another study involving 223 patients with acute coronary syndrome, the presence of anemia at admission was found to increase the risk of developing depression three weeks after hospitalization (27), consistent with our current findings. In adolescent MDD patients, we observed that anemia independently correlated with reduced response rates to ECT treatment.

How might admission anemia affect ECT response? One possible explanation involves a direct cerebral mechanism related to impaired oxygen delivery. Anemia compromises cerebral oxygen metabolism, which is crucial for neuronal function (26, 28, 29). This is particularly critical for brain regions with high metabolic demands and established roles in MDD, such as the prefrontal cortex (responsible for executive function and emotion regulation), the hippocampus (critical for memory and stress response), and the temporal lobe (30–32). We hypothesize that a brain already experiencing anemic hypoxia may have a diminished capacity to support the substantial metabolic demands required for ECT-induced neuroplasticity. This could potentially weaken the treatment response and increase susceptibility to ECT-related adverse effects, particularly cognitive side effects such as memory impairment. Additionally, systemic effects of anemia, including fatigue and reduced physiological resilience (33–35), may further lower the tolerance threshold for somatic side effects like headaches. This aligns with our study findings, which showed a higher incidence of post-ECT memory loss and headaches reported in the anemia group. Beyond this direct cerebral effect, inflammation may constitute a shared pathological basis linking anemia to treatment resistance. Chronic inflammation is a recognized factor contributing to both the pathophysiology of depression and anemia of inflammation (36, 37). Proinflammatory cytokines can disrupt neuronal activity, alter neuronal excitability, and elevate seizure thresholds (38, 39). This may necessitate higher stimulation intensities to achieve adequate seizure outcomes. Furthermore, inflammation impairs neurotrophic signaling and suppresses neurogenesis (40, 41), thereby interfering with neural plasticity changes that underlie sustained antidepressant effects. Our finding of higher baseline WBC counts in ECT non-responders provides preliminary clinical support for the role of an inflammatory state in mediating poor outcomes. Therefore, from a clinical perspective, these insights suggest that proactively identifying and correcting anemia before ECT could be a strategic approach to potentially enhance treatment efficacy while reducing treatment-related morbidity.

Our study revealed an intriguing finding regarding the differential predictive value of anemia across subgroups. Female patients demonstrated greater sensitivity to anemia, which correlated with poorer ECT response, while no significant association was observed in males. This sexual dimorphism may be explained by sex hormones’ known influence on neuroinflammation and neuroendocrine systems (42–44), with hormonal fluctuations potentially amplifying depression susceptibility in young women (45–48), thereby accentuating anemia’s impact on ECT outcomes. Besides, the predictive power of anemia was particularly pronounced in patients with psychotic depression. Existing research indicates significantly reduced striatal dopamine transporter availability in psychotic depression (49, 50), suggesting impaired dopaminergic neurotransmission. Anemia, particularly iron-deficiency anemia, may exacerbate this pathological process, as iron is a critical cofactor for tyrosine hydroxylase, the rate-limiting enzyme in dopamine biosynthesis (51, 52). This dual pathology could worsen psychotic symptoms and diminish ECT efficacy.

Several limitations warrant consideration: First, we only assessed hemoglobin levels at admission without tracking dynamic changes during hospitalization, which might provide more accurate correlation data. Second, the absence of vitamin and mineral measurements prevented determination of anemia etiology. Third, although we adjusted for several confounders, unexamined factors like diet, iron metabolism, inflammatory markers (e.g., CRP, interleukins), and socioeconomic status may influence outcomes. Fourth, the retrospective design precludes causal inferences between anemia and ECT response. Future prospective cohort studies are needed to directly investigate whether correcting anemia prior to ECT initiation improves clinical outcomes and reduces treatment-related side effects. Furthermore, the clinical utility of hemoglobin as a standalone predictor may be limited by its moderate specificity (59.6%). Future research should focus on developing multi-parameter models that integrate hemoglobin with other biomarkers, such as inflammatory markers, and clinical features. Exploring optimal diagnostic thresholds to balance sensitivity and specificity is also warranted. Finally, moving beyond traditional diagnostic boundaries, subsequent investigations should prioritize developing sex-specific prediction models to enable refined clinical risk assessment. This study provides proof-of-concept for the role of hematological factors in predicting ECT response, laying the foundation for developing more accurate predictive algorithms.

5 Conclusion

Our study demonstrates a significant association between admission anemia and poorer ECT response in adolescent MDD patients. Baseline hemoglobin screening may serve as a practical biomarker to identify high-risk individuals, enabling optimized treatment strategies and enhanced management of post-ECT adverse effects. These findings highlight the need for personalized interventions, particularly in female patients and those with psychotic depression, where anemia correction prior to ECT may improve clinical outcomes.

Data availability statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Ethics statement

The studies involving humans were approved by the Ethics Committee of University the First Affiliated Hospital of Chongqing Medical University. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required from the participants or the participants’ legal guardians/next of kin in accordance with the national legislation and institutional requirements.

Author contributions

DG: Writing – review & editing, Formal Analysis, Conceptualization, Writing – original draft. HX: Investigation, Writing – review & editing, Data curation, Formal Analysis. JG: Writing – review & editing, Software, Investigation. YW: Writing – review & editing, Investigation. YC: Writing – review & editing, Conceptualization, Visualization. SH: Writing – review & editing, Supervision. LK: Resources, Supervision, Conceptualization, Funding acquisition, Writing – review & editing.

Funding

The author(s) declared that financial support was received for this work and/or its publication. This study was supported by the First Affiliated Hospital of Chongqing Medical University “Discipline Peak Plan” scientific and technological achievement transformation project: Research and application of early warning system for adolescent depression and suicide self-injury risk based on artificial intelligence technology (cyyy-xkdfjh-cgzh-202304, 2024-2026).

Acknowledgments

We acknowledge all participants for their help in facilitating this research.

Conflict of interest

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

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The author(s) declared that generative AI was used in the creation of this manuscript. This study employed AI tools solely for text polishing. After using the tool, the authors reviewed and edited the content as necessary and take full responsibility for the published material.

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