Overview of mechanisms of adult major depressive disorder comorbid attention deficit hyperactivity disorder and the prospects of transcranial direct current stimulation

doi:10.3969/j.issn.1674-8115.2026.01.013

Abstract

Abstract:

In recent years, the comorbidity of major depressive disorder (MDD) and attention deficit hyperactivity disorder (ADHD) has received increasing attention. In adult patients, MDD comorbid with ADHD usually implies high treatment costs, poor drug response, and an unfavorable disease prognosis. However, there are certain limitations in current drug therapies. As executive dysfunction is a key shared feature of MDD and ADHD, it is of great importance to explore the potential mechanisms of this comorbidity in terms of neuroimaging and to seek more effective treatment methods from the perspective of executive function. Research in recent years has shown that transcranial direct current stimulation (tDCS), a non-invasive physical therapy capable of regulating the activity of specific brain regions, can effectively improve relevant symptoms of MDD and adult ADHD. This article aims to review the treatment dilemmas faced by adult patients with MDD comorbid with ADHD, summarize the possible mechanisms underlying this comorbidity from multiple dimensions, such as brain structure and functional networks related to executive function, and simultaneously explore the application prospects of tDCS in the treatment of adult MDD comorbid with ADHD.

Key words: major depressive disorder (MDD), adult, attention deficit hyperactivity disorder (ADHD), executive function, neural mechanism, transcranial direct current stimulation (tDCS)

CLC Number:

R749.4

Xie Yixia, Wang Fan, Liu Xirui, Chen Ningning, Zhang Wenxuan, Wu Jialin, Ma Ting, Hong Wu. Overview of mechanisms of adult major depressive disorder comorbid attention deficit hyperactivity disorder and the prospects of transcranial direct current stimulation[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2026, 46(1): 107-114.

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References 64

[1]	Hartman C A, Larsson H, Vos M, et al. Anxiety, mood, and substance use disorders in adult men and women with and without attention-deficit/hyperactivity disorder: a substantive and methodological overview[J]. Neurosci Biobehav Rev, 2023, 151: 105209.
[2]	Song P G, Zha M M, Yang Q W, et al. The prevalence of adult attention-deficit hyperactivity disorder: a global systematic review and meta-analysis[J]. J Glob Health, 2021, 11: 04009.
[3]	Gill A, Aldosoky W, Ong M B H, et al. A narrative review on mental stress and cardiovascular disease: evidence, mechanisms, and potential interventions[J]. Heart Mind, 2023, 7(2): 62-69.
[4]	Jackson A C, Rogerson M C, Murphy B M. An integrated perspective for understanding the psychosocial impact of acute cardiovascular events[J]. Heart Mind, 2023, 7(3): 137-147.
[5]	Schein J, Childress A, Gagnon-Sanschagrin P, et al. Treatment patterns among patients with attention-deficit/hyperactivity disorder and comorbid anxiety and/or depression in the United States: a retrospective claims analysis[J]. Adv Ther, 2023, 40(5): 2265-2281.
[6]	Schiweck C, Arteaga-Henriquez G, Aichholzer M, et al. Comorbidity of ADHD and adult bipolar disorder: a systematic review and meta-analysis[J]. Neurosci Biobehav Rev, 2021, 124: 100-123.
[7]	Mayer J S, Bernhard A, Fann N, et al. Cognitive mechanisms underlying depressive disorders in ADHD: a systematic review[J]. Neurosci Biobehav Rev, 2021, 121: 307-345.
[8]	Li Z C, Li D, He Y, et al. Cross-disorder analysis of shared genetic components between cortical structures and major psychiatric disorders[J]. Schizophr Bull, 2022, 48(5): 1145-1154.
[9]	Mcintyre R S, Cha D S, Soczynska J K, et al. Cognitive deficits and functional outcomes in major depressive disorder: determinants, substrates, and treatment interventions[J]. Depress Anxiety, 2013, 30(6): 515-527.
[10]	Broletti M C, Efthymiou C, Murray A L, et al. Investigating the mediating role of executive function in the relationship between ADHD and DCD symptoms and depression in adults[J]. J Autism Dev Disord, 2024, 54(12): 4684-4696.
[11]	Hawkey E J, Tillman R, Luby J L, et al. Preschool executive function predicts childhood resting-state functional connectivity and attention-deficit/hyperactivity disorder and depression[J]. Biol Psychiatry Cogn Neurosci Neuroimaging, 2018, 3(11): 927-936.
[12]	唐睿, 宋洪文, 孔卓, 等. 经颅直流电刺激治疗常见神经精神疾病的临床应用专家共识 [J]. 中华精神科杂志, 2022, 55(5): 327-382.
	Tang R, Song H W, Kong Z, et al. Chinese experts′consensus on clinical application of transcranial direct current stimulation in the treatment of common neurological diseases and mental disorders [J]. Chinese Journal of Psychiatry, 2022, 55(5): 327-382.
[13]	Jha M K, Mathew S J. Pharmacotherapies for treatment-resistant depression: how antipsychotics fit in the rapidly evolving therapeutic landscape[J]. Am J Psychiatry, 2023, 180(3): 190-199.
[14]	Jiang J, Li L, Lin J P, et al. A voxel-based meta-analysis comparing medication-naive patients of major depression with treated longer-term ill cases[J]. Neurosci Biobehav Rev, 2023, 144: 104991.
[15]	Greven C U, Bralten J, Mennes M, et al. Developmentally stable whole-brain volume reductions and developmentally sensitive caudate and putamen volume alterations in those with attention-deficit/hyperactivity disorder and their unaffected siblings[J]. JAMA Psychiatry, 2015, 72(5): 490-499.
[16]	Westwood S J, Radua J, Rubia K. Noninvasive brain stimulation in children and adults with attention-deficit/hyperactivity disorder: a systematic review and meta-analysis[J]. J Psychiatry Neurosci, 2021, 46(1): E14-E33.
[17]	Onnink A M, Zwiers M P, Hoogman M, et al. Brain alterations in adult ADHD: effects of gender, treatment and comorbid depression[J]. Eur Neuropsychopharmacol, 2014, 24(3): 397-409.
[18]	Das D, Cherbuin N, Anstey K J, et al. Regional brain volumes and ADHD symptoms in middle-aged adults: the PATH through life study[J]. J Atten Disord, 2017, 21(13): 1073-1086.
[19]	Patel Y, Parker N, Shin J, et al. Virtual histology of cortical thickness reveals shared neurobiology across six psychiatric disorders[J]. Biol Psychiatry, 2020, 87(9): S239-S240.
[20]	Claeys E H I, Mantingh T, Morrens M, et al. Resting-state fMRI in depressive and (hypo)manic mood states in bipolar disorders: a systematic review[J]. Prog Neuropsychopharmacol Biol Psychiatry, 2022, 113: 110465.
[21]	Grimm S, Beck J, Schuepbach D, et al. Imbalance between left and right dorsolateral prefrontal cortex in major depression is linked to negative emotional judgment: an fMRI study in severe major depressive disorder[J]. Biol Psychiatry, 2008, 63(4): 369-376.
[22]	Zhou N, Yuan Z, Zhou H Y, et al. Using dynamic graph convolutional network to identify individuals with major depression disorder[J]. J Affect Disord, 2025, 371: 188-195.
[23]	Runia N, YüCel D E, Lok A, et al. The neurobiology of treatment-resistant depression: a systematic review of neuroimaging studies[J]. Neurosci Biobehav Rev, 2022, 132: 433-448.
[24]	Rajaprakash M, Leppert M L. Attention-deficit/hyperactivity disorder[J]. Pediatr Rev, 2022, 43(3): 135-147.
[25]	Agoalikum E, Klugah-Brown B, Wu H Z, et al. Structural differences among children, adolescents, and adults with attention-deficit/hyperactivity disorder and abnormal Granger causality of the right pallidum and whole-brain[J]. Front Hum Neurosci, 2023, 17: 1076873.
[26]	Mu C G, Dang X L, Luo X J. Mendelian randomization analyses reveal causal relationships between brain functional networks and risk of psychiatric disorders[J]. Nat Hum Behav, 2024, 8(7): 1417-1428.
[27]	Luo L K, Chen L Z, Wang Y X, et al. Patterns of brain dynamic functional connectivity are linked with attention-deficit/hyperactivity disorder-related behavioral and cognitive dimensions[J]. Psychol Med, 2023, 53(14): 6666-6677.
[28]	Pan P M, Sato J R, Salum G A, et al. Ventral striatum functional connectivity as a predictor of adolescent depressive disorder in a longitudinal community-based sample[J]. Am J Psychiatry, 2017, 174(11): 1112-1119.
[29]	Grimm O, Van Rooij D, Hoogman M, et al. Transdiagnostic neuroimaging of reward system phenotypes in ADHD and comorbid disorders[J]. Neurosci Biobehav Rev, 2021, 128: 165-181.
[30]	Barber A D, Sarpal D K, John M, et al. Age-normative pathways of striatal connectivity related to clinical symptoms in the general population[J]. Biol Psychiatry, 2019, 85(11): 966-976.
[31]	Dakwar-Kawar O, Mairon N, Hochman S, et al. Transcranial random noise stimulation combined with cognitive training for treating ADHD: a randomized, sham-controlled clinical trial[J]. Transl Psychiatry, 2023, 13(1): 271.
[32]	Faraone S V, Bellgrove M A, Brikell I, et al. Attention-deficit/hyperactivity disorder[J]. Nat Rev Dis Primers, 2024, 10: 11.
[33]	Nejati V, Majidinezhad M, Nitsche M. The role of the dorsolateral and ventromedial prefrontal cortex in emotion regulation in females with major depressive disorder (MDD): a tDCS study[J]. J Psychiatr Res, 2022, 148: 149-158.
[34]	Friedman N P, Robbins T W. The role of prefrontal cortex in cognitive control and executive function[J]. Neuropsychopharmacology, 2022, 47(1): 72-89.
[35]	Cao W Y, Liao H Y, Cai S N, et al. Increased functional interaction within frontoparietal network during working memory task in major depressive disorder[J]. Hum Brain Mapp, 2021, 42(16): 5217-5229.
[36]	Salehinejad M A, Ghanavati E, Rashid M H A, et al. Hot and cold executive functions in the brain: a prefrontal-cingular network[J]. Brain Neurosci Adv, 2021, 5: 23982128211007769.
[37]	Baller E B, Kaczkurkin A N, Sotiras A, et al. Neurocognitive and functional heterogeneity in depressed youth[J]. Neuropsychopharmacology, 2021, 46(4): 783-790.
[38]	Mencarelli L, Romanella S M, Di Lorenzo G, et al. Neural correlates of N-back task performance and proposal for corresponding neuromodulation targets in psychiatric and neurodevelopmental disorders[J]. Psychiatry Clin Neurosci, 2022, 76(10): 512-524.
[39]	Tan W J, Liu Z N, Xi C, et al. Decreased integration of the frontoparietal network during a working memory task in major depressive disorder[J]. Aust N Z J Psychiatry, 2021, 55(6): 577-587.
[40]	Piani M C, Maggioni E, Delvecchio G, et al. Sustained attention alterations in major depressive disorder: a review of fMRI studies employing Go/No-Go and CPT tasks[J]. J Affect Disord, 2022, 303: 98-113.
[41]	Rafi H, Murray R, Delavari F, et al. Neural basis of internal attention in adults with pure and comorbid ADHD[J]. J Atten Disord, 2023, 27(4): 423-436.
[42]	Menon V. 20 years of the default mode network: a review and synthesis[J]. Neuron, 2023, 111(16): 2469-2487.
[43]	Wang X L, Cheng B C, Roberts N, et al. Shared and distinct brain fMRI response during performance of working memory tasks in adult patients with schizophrenia and major depressive disorder[J]. Hum Brain Mapp, 2021, 42(16): 5458-5476.
[44]	Liu R, Qi H, Guan L, et al. Functional connectivity of the default mode network subsystems in patients with major depressive episodes with mixed features[J]. Gen Psychiatr, 2022, 35(6): e100929.
[45]	Metin B, Damla Kayaalp S, Farhad S, et al. Task-based modulation of functional connectivity of dorsal attention network in adult-ADHD[J]. Neurosci Lett, 2024, 842: 137998.
[46]	Bi R, Dong W X, Zheng Z X, et al. Altered motivation of effortful decision-making for self and others in subthreshold depression[J]. Depress Anxiety, 2022, 39(8/9): 633-645.
[47]	Gao Y J, Guo X, Zhong Y, et al. Decreased dorsal attention network homogeneity as a potential neuroimaging biomarker for major depressive disorder[J]. J Affect Disord, 2023, 332: 136-142.
[48]	Borsini A, Wallis A S J, Zunszain P, et al. Characterizing anhedonia: a systematic review of neuroimaging across the subtypes of reward processing deficits in depression[J]. Cogn Affect Behav Neurosci, 2020, 20(4): 816-841.
[49]	Wang Y P, Ma L L, Wang J L, et al. The neural and genetic underpinnings of different developmental trajectories of attention-deficit/hyperactivity symptoms in children and adolescents[J]. BMC Med, 2024, 22(1): 223.
[50]	Wilbertz G, Delgado M R, Tebartz Van Elst L, et al. Neural response during anticipation of monetary loss is elevated in adult attention deficit hyperactivity disorder[J]. World J Biol Psychiatry, 2017, 18(4): 268-278.
[51]	Vetter N C, Buse J, Backhausen L L, et al. Anterior insula hyperactivation in ADHD when faced with distracting negative stimuli[J]. Hum Brain Mapp, 2018, 39(7): 2972-2986.
[52]	Chen L, Fukuda A M, Jiang S X, et al. Treating depression with repetitive transcranial magnetic stimulation: a clinician′s guide[J]. Am J Psychiatry, 2025, 182(6): 525-541.
[53]	许毅, 李达, 谭立文, 等. 重复经颅磁刺激治疗专家共识 [J]. 转化医学杂志, 2018, 7(1): 4-9.
	Xu Y, Li D, Tan L W, et al. Chinese experts consensus on repetitive transcranial magnetic stimulation [J]. Translational Medicine Journal, 2018, 7(1): 4-9.
[54]	石敏, 郑文艳, 陶丹红, 等. 重复经颅磁刺激联合抗抑郁药对抑郁症患者的疗效及注意功能的影响 [J]. 全科医学临床与教育, 2025, 23(6): 510-513.
	Shi M, Zheng W Y, Tao D H, et al. Effect of repetitive transcranial magnetic stimulation combined with sertraline on adolescent depression [J]. Chinese Journal of Practical Medicine, 2025, 23(6): 510-513.
[55]	郭艳雪, 韩冰, 吕政, 等. 10Hz重复经颅磁刺激对脑卒中患者不同负荷言语和空间工作记忆的影响 [J]. 中国康复医学杂志, 2024, 39(10): 1468-1473.
	Guo Y X, Han B, Lü Z, et al. Effects of 10Hz repetitive transcranial magnetic stimulation on verbal and spatial working memories with different loads in stroke patients [J]. Chinese Journal of Rehabilitation Medicine, 2024, 39(10): 1468-1473.
[56]	姜霖霖, 牛陵川, 王愉乐, 等. 高频重复经颅磁刺激对脑梗死后抑郁患者的影响 [J]. 康复学报, 2021, 31(6): 455-460.
	Jiang L L, Niu L C, Wang Y L, et al. Effect of high-frequency repetitive transcranial magnetic stimulation on depression after cerebral infarction [J]. Rehabilitation Journal, 2021, 31(6): 455-460.
[57]	薛青, 戚小红, 高乐虹, 等. 采用视听整合测试评估经颅磁刺激治疗注意缺陷多动障碍的效果 [J]. 中国医药导报, 2017, 14(29): 69-71+79.
	Xue Q, Qi X H, Gao L H, et al. A study of rTMS treatment for ADHD patients evaluated by integrated visual and auditory continuous performance test[J]. China Medical Herald, 2017, 14(29): 69-71+79.
[58]	Mauche N, Ulke C, Huang J, et al. Treatment of adult attention-deficit hyperactivity disorder (ADHD) with transcranial direct current stimulation (tDCS): study protocol for a parallel, randomized, double-blinded, sham-controlled, multicenter trial (stim-ADHD)[J]. Eur Arch Psychiatry Clin Neurosci, 2024, 274(1): 71-82.
[59]	Chan M M Y, Yau S S Y, Han Y M Y. The neurobiology of prefrontal transcranial direct current stimulation (tDCS) in promoting brain plasticity: a systematic review and meta-analyses of human and rodent studies[J]. Neurosci Biobehav Rev, 2021, 125: 392-416.
[60]	Huang H J, Chen Y M, Kong S Q, et al. Targeting right orbitofrontal cortex (OFC) with transcranial direct current stimulation (tDCS) can improve cognitive executive function in a major depressive episode, but not depressive mood: a double-blind randomized controlled pilot trial[J]. J Psychiatr Res, 2023, 168: 108-117.
[61]	Salehinejad M A, Nejati V, Mosayebi-Samani M, et al. Transcranial direct current stimulation in ADHD: a systematic review of efficacy, safety, and protocol-induced electrical field modeling results[J]. Neurosci Bull, 2020, 36(10): 1191-1212.
[62]	Lu H L, Zhang Y J, Qiu H K, et al. A new perspective for evaluating the efficacy of tACS and tDCS in improving executive functions: a combined tES and fNIRS study[J]. Hum Brain Mapp, 2024, 45(1): e26559.
[63]	Antonenko D, Fromm A E, Thams F, et al. Microstructural and functional plasticity following repeated brain stimulation during cognitive training in older adults[J]. Nat Commun, 2023, 14(1): 3184.
[64]	Silva J B S, Franceschi G L A, De Carvalho C F. Transcranial direct current stimulation: new perspectives in the rehabilitation of children and adolescents[M]// Dias N M, Cardoso C de O. Neuropsychological Interventions for Children - Volume 2. Cham: Springer Nature Switzerland, 2024: 193-209.