Common and divergent neuroimaging features in major depression, posttraumatic stress disorder, and their comorbidity

Abstract

Posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) are common stress-related psychiatric disorders. Genetic and neurobiology research has supported the viewpoint that PTSD and MDD may possess common and disorder-specific underlying mechanisms. In this systematic review, we summarize evidence for the similarities and differences in brain functional and structural features of MDD, PTSD, and their comorbidity, as well as the effects of extensively used therapies in patients with comorbid PTSD and MDD (PTSD + MDD). These functional magnetic resonance imaging (MRI) studies highlight the (i) shared hypoactivation in the prefrontal cortex during cognitive and emotional processing in MDD and PTSD; (ii) higher activation in fear processing regions including amygdala, hippocampus, and insula in PTSD compared to MDD; and (iii) distinct functional deficits in brain regions involved in fear and reward processing in patients with PTSD + MDD relative to those with PTSD alone. These structural MRI studies suggested that PTSD and MDD share features of reduced volume in focal frontal areas. The treatment effects in patients with PTSD + MDD may correlate with the normalization trend of structural alterations. Neuroimaging predictors of repetitive transcranial magnetic stimulation response in patients with PTSD + MDD may differ from the mono-diagnostic groups. In summary, neuroimaging studies to date have provided limited information about the shared and disorder-specific features in MDD and PTSD. Further research is essential to pave the way for developing improved diagnostic markers and eventually targeted treatment approaches for the shared and distinct brain alterations presented in patients with MDD and PTSD.

Keywords

posttraumatic stress disorder / major depressive disorder / comorbidity / transdiagnostic / disorder-specific

Supplementary data

Supplementary data is available at Psychoradiology Journal online.

Author contributions

Jing Jiang (Data curation, Formal analysis, Investigation, Visualization, Writing - original draft), Stefania Ferraro (Visualization, Writing - original draft, Writing - review & editing), Youjin Zhao (Formal analysis, Funding acquisition, Writing - original draft), Baolin Wu (Data curation, Formal analysis, Visualization), Jinping Lin (Data curation, Formal analysis), Taolin Chen (Funding acquisition, Visualization, Writing - review & editing), Jin Gao (Conceptualization, Supervision, Writing - review & editing), and Lei Li (Conceptualization, Funding acquisition, Validation, Writing - original draft, Writing - review & editing)

Conflict of interests

None declared.

Acknowledgments

The authors thank all authors of the included studies, and especially thank Dr. John A Sweeney for his kind help and suggestions during the preparation of this paper. This study was supported by the National Natural Science Foundation of China (Grant Nos. 82302159 and 82001795), Post-Doctor Research Project of West China Hospital of Sichuan University (2021HXBH025), and Sichuan Province Science and Technology Program (2022YFS0069, 2021YFS0242, and 2023YFS0076).

References

[1] Ahmadi N, Moss L, Hauser P, et al. (2018) Clinical outcome of maintenance electroconvulsive therapy in comorbid posttraumatic stress disorder and major depressive disorder. J Psychiatr Res 105:132-6.

[2] Ahmadi N, Moss L, Simon E, et al. (2016) Efficacy and long-term clinical outcome of comorbid posttraumatic stress disorder and major depressive disorder after electroconvulsive therapy. Depress Anxiety 33:640-7.

[3] Akhtar A, Pilkhwal Sah S. (2021) Advances in the pharmacotherapeutic management of post-traumatic stress disorder. Expert Opin Pharmacother 22:1919-30.

[4] Albert KM, Potter GG, Boyd BD, et al. (2019) Brain network functional connectivity and cognitive performance in major depressive disorder. J Psychiatr Res 110:51-6.

[5] Albott CS, Lee S, Cullen KR, et al. (2021) Characterization of comorbid posttraumatic stress disorder and major depressive disorder using ketamine as an experimental medicine probe. J Psychiatr Brain Sci 6:e210012.

[6] Albott CS, Lim KO, Erbes C, et al. (2022) Neurocognitive effects of repeated ketamine infusions in comorbid posttraumatic stress disorder and major depressive disorder. J Affect Disord 308: 289-97.

[7] Albott CS, Lim KO, Forbes MK, et al. (2018) Efficacy, safety, and durability of repeated ketamine infusions for comorbid posttraumatic stress disorder and treatment-resistant depression. J Clin Psychiatry 79:17m11634.

[8] Artin H, Bentley S, Mehaffey E, et al. (2022) Effects of intranasal (S)-ketamine on veterans with co-morbid treatment-resistant depression and PTSD: a retrospective case series. EClinMed 48:101439.

[9] Averill CL, Averill LA, Akiki TJ, et al. (2024) Findings of PTSD-specific deficits in default mode network strength following a mild experimental stressor. NPP-Digit Psychiatry Neurosci 2:9.

[10] Averill CL, Satodiya RM, ScottJC, et al. (2017) Posttraumatic stress disorder and depression symptom severities are differentially associated with hippocampal subfield volume loss in combat veterans. Chronic Stress 1:2470547017744538.

[11] Baeken C, Marinazzo D, Everaert H, et al. (2015) The impact of accelerated HF-rTMS on the subgenual anterior cingulate cortex in refractory unipolar major depression: insights from 18FDG PET brain imaging. Brain Stim 8:808-15.

[12] Bao W, Gao Y, Cao L, et al. (2021) Alterations in large-scale functional networks in adult posttraumatic stress disorder: a systematic review and meta-analysis of resting-state functional connectivity studies. Neurosci Biobehav Rev 131:1027-36.

[13] Barredo J, Bellone JA, Edwards M, et al. (2019) White matter integrity and functional predictors of response to repetitive transcranial magnetic stimulation for posttraumatic stress disorder and major depression. Depress Anxiety 36:1047-57.

[14] Barredo J, Berlow Y, Swearingen HR, et al. (2021) Multimodal elements of suicidality reduction after transcranial magnetic stimulation. Neuromodulation 24:930-7.

[15] Bora E, Fornito A, Pantelis C, et al. (2012) Gray matter abnormalities in major depressive disorder: a meta-analysis of voxel based morphometry studies. J Affect Disord 138:9-18.

[16] Brambilla P (2003) Brain anatomy and development in autism: review of structural MRI studies. Brain Res Bull 61:557-69.

[17] Bromis K, Calem M, Reinders AATS, et al. (2018) Meta-analysis of 89 structural MRI studies in posttraumatic stress disorder and comparison with major depressive disorder. Am J Psychiatry 175:98998.

[18] Bryant RA, Andrew E, Korgaonkar MS. (2021) Distinct neural mechanisms of emotional processing in prolonged grief disorder. Psychol Med 51:587-95.

[19] Callens L, Sienaert P (2024) The role of electroconvulsive therapy in posttraumatic stress disorder: a systematic review. J Ect

[20] Chiba H, Oe M, Uchimura N (2016) Patients with posttraumatic stress disorder with comorbid major depressive disorder require a higher dose of psychotropic drugs. Kurume Med J 62:23-8.

[21] Ciocchi S, Herry C, Grenier F, et al. (2010) Encoding of conditioned fear in central amygdala inhibitory circuits. Nature 468:277-82.

[22] Cook IA, Abrams M, Leuchter AF (2016) Trigeminal nerve stimulation for comorbid posttraumatic stress disorder and major depressive disorder. Neuromodulation 19:299-305.

[23] Cui L, Li S, Wang S, et al. (2024) Major depressive disorder: hypothesis, mechanism, prevention and treatment. Sig Transduct Target Ther 9:30.

[24] Dai D, Lacadie CM, Holmes SE, et al. (2020) Ketamine normalizes the structural alterations of inferior frontal gyrus in depression. Chronic Stress 4:2470547020980681.

[25] Dell'osso L, Carmassi C, Mucci F, et al. (2016) Depression, serotonin and tryptophan. CPD 22:949-54.

[26] Derakhshanian S, Zhou M, Rath A, et al. (2021) Role of ketamine in the treatment of psychiatric disorders. Health Psychol Res 9:25091.

[27] Dold M, Bartova L, Kautzky A, et al. (2017) The impact of comorbid post-traumatic stress disorder in patients with major depressive disorder on clinical features, pharmacological treatment strate-gies, and treatment outcomes—results from a cross-sectional European multicenter study. Eur Neuropsychopharmacol 27:625-32.

[28] Dunlop BW, Wong A (2019) The hypothalamic-pituitary-adrenal axis in PTSD: pathophysiology and treatment interventions. Prog Neuropsychopharmacol Biol Psychiatry 89:361-79.

[29] Feder A, Parides MK, Murrough JW, et al. (2014) Efficacy of intravenous ketamine for treatment of chronic posttraumatic stress disorder: a randomized clinical trial. JAMA Psychiatry 71:681-8.

[30] Flory JD, Yehuda R (2015) Comorbidity between post-traumatic stress disorder and major depressive disorder: alternative explanations and treatment considerations. Dialog Clin Neurosc 17: 141-50.

[31] Gill T, Watling SE, Richardson JD, et al. (2022) Imaging of astrocytes in posttraumatic stress disorder: a PET study with the monoamine oxidase B radioligand [(11)C]SL25.1188. Eur Neuropsychopharmacol 54:54-61.]

[32] Godard J, Baruch P, Grondin S, et al. (2012) Psychosocial and neurocognitive functioning in unipolar and bipolar depression: a 12month prospective study. Psychiatry Res 196:145-53.

[33] Gong Q Hu X, Pettersson-Yeo W, et al. (2017) Network-level dysconnectivity in drug-naïve first-episode psychosis: dissociating transdiagnostic and diagnosis-specific alterations. Neuropsychopharmacol 42:933-40.

[34] Gong Q, Puthusseryppady V, Dai J, et al. (2019a) Dysconnectivity of the medio-dorsal thalamic nucleus in drug-naïve first episode schizophrenia: diagnosis-specific or trans-diagnostic effect? Transl Psychiatry 9:9.

[35] Gong Q, Scarpazza C, Dai J, et al. (2019b) A transdiagnostic neuroanatomical signature of psychiatric illness. Neuropsychopharmacol. 44:869-75.

[36] Harnett NG, Goodman AM, Knight DC (2020) PTSD-related neuroimaging abnormalities in brain function, structure, and biochemistry. Exp Neurol 330:113331.

[37] Henigsberg N, Bajs M, Hrabac P, et al. (2011) Changes in brain metabolites measured with magnetic resonance spectroscopy in antidepressant responders with comorbid major depression and posttraumatic stress disorder. Coll Antropol 35:145-8.

[38] Hidalgo RB, Davidson JR (2000) Selective serotonin reuptake inhibitors in post-traumatic stress disorder. J Psychopharmacol 14:70-6.

[39] Holmes SE, Finnema SJ, Naganawa M, et al. (2022) Imaging the effect of ketamine on synaptic density (SV2A) in the living brain. Mol Psychiatry 27:2273-81.

[40] Hung C-I, Wang S-J, Liu C-Y, et al. (2011) Comorbidities and factors related to discontinuation of pharmacotherapy among outpatients with major depressive disorder. Compr Psychiatry 52:370-7.

[41] Huntley JH, Rezvani Habibabadi R, Vaishnavi S, et al. (2023) Transcranial magnetic stimulation and its imaging features in patients with depression, post-traumatic stress disorder, and traumatic brain injury. Acad Radiol 30:103-12.

[42] Jaffe AE, Tao R, Page SC, et al. (2022) Decoding shared versus divergent transcriptomic signatures across cortico-amygdala circuitry in PTSD and depressive disorders. Am J Psychiatry 179:673-686.

[43] Janiri D, Moser DA, Doucet GE, et al. (2020) Shared neural phenotypes for mood and anxiety disorders: a meta-analysis of 226 task-related functional imaging studies. JAMA Psychiatry 77:1729.

[44] Jeffreys M, Capehart B, Friedman MJ (2012) Pharmacotherapy for posttraumatic stress disorder: review with clinical applications. JRRD 49:703-15.

[45] Jenkins LM, Barba A, Campbell M, et al. (2016) Shared white matter alterations across emotional disorders: a voxel-based metaanalysis of fractional anisotropy. NeuroImage Clin 12:1022-34.

[46] Johnston JN, Kadriu B, Kraus C, et al. (2024) Ketamine in neuropsychiatric disorders: an update. Neuropsychopharmacol 49:23-40.

[47] Kaplan MJ, Klinetob NA (2000) Childhood emotional trauma and chronic posttraumatic stress disorder in adult outpatients with treatment-resistant depression. J Nerv Ment Dis 188: 596-601.

[48] Keller M, Mendoza-Quiñones R, Cabrera Muñoz A, et al. (2022) Transdiagnostic alterations in neural emotion regulation circuitsneural substrates of cognitive reappraisal in patients with depression and post-traumatic stress disorder. BMC Psychiatry 22:173.

[49] Kemp AH, Felmingham K, Das P, et al. (2007) Influence of comorbid depression on fear in posttraumatic stress disorder: an fMRI study. Psychiatry Res Neuroimag 155:265-9.

[50] Kennis M, Rademaker AR, Van Rooij SJH, et al. (2013) Altered functional connectivity in posttraumatic stress disorder with versus without comorbid major depressive disorder: a resting state fMRI study. F1000Res 2:289.

[51] Kessler RC, Chiu WT, Demler O, et al. (2005) Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 62:617-27.

[52] Kito S, Hasegawa T, Koga Y (2011) Neuroanatomical correlates of therapeutic efficacy of low-frequency right prefrontal transcranial magnetic stimulation in treatment-resistant depression. Psychiatry Clin Neurosci 65:175-82.

[53] Kito S, Hasegawa T, Koga Y (2012) Cerebral blood flow in the ventromedial prefrontal cortex correlates with treatment response to low-frequency right prefrontal repetitive transcranial magnetic stimulation in the treatment of depression. Psychiatry Clin Neurosci 66:138-45.

[54] Kline AC, Cooper AA, Rytwinski NK, et al. (2021) The effect of concurrent depression on PTSD outcomes in trauma-focused psychotherapy: a meta-analysis of randomized controlled trials. Behavior Therapy 52:250-66.

[55] Kochunov P, Hong LE, Dennis EL, et al. (2022) ENIGMA-DTI: translating reproducible white matter deficits into personalized vulnerability metrics in cross-diagnostic psychiatric research. Hum Brain Mapp 43:194-206.

[56] Koopowitz S-M, Zar HJ, Stein DJ, et al. (2023) PTSD and comorbid MDD is associated with activation of the right frontoparietal network. Psychiatry Res Neuroimaging 331:111630.

[57] Kostaras P, Bergiannaki J-D, Psarros C, et al. (2017) Posttraumatic stress disorder in outpatients with depression: still a missed diagnosis. J Trauma Dissociation 18:233-47.

[58] Kritzer MD, Mischel NA, Young JR, et al. (2022) Ketamine for treatment of mood disorders and suicidality: a narrative review of recent progress. Ann Clin Psychiatry 34:33-43.

[59] Kroes MCW, Rugg MD, Whalley MG, et al. (2011) Structural brain abnormalities common to posttraumatic stress disorder and depression. J Psychiatry Neurosci 36:256-65.

[60] Lanius RA, Frewen PA, Girotti M, et al. (2007) Neural correlates of trauma script-imagery in posttraumatic stress disorder with and without comorbid major depression: a functional MRI investigation. Psychiatry Res Neuroimag 155:45-56.

[61] Li N, Lee B, Liu R-J, et al. (2010) mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 329:959-64.

[62] Liston C, Chen AC, Zebley BD, et al. (2014) Default mode network mechanisms of transcranial magnetic stimulation in depression. Biol Psychiatry 76:517-26.

[63] Mahan AL, Ressler KJ (2012) Fear conditioning, synaptic plasticity and the amygdala: implications for posttraumatic stress disorder. Trends Neurosci 35:24-35.

[64] Marwood L, Wise T, Perkins AM, et al. (2018) Meta-analyses of the neural mechanisms and predictors of response to psychotherapy in depression and anxiety. Neurosci Biobehav Rev 95:61-72.

[65] Mcteague LM, Huemer J, Carreon DM, et al. (2017) Identification of common neural circuit disruptions in cognitive control across psychiatric disorders. Am J Psychiatry 174:676-85.

[66] Millan MJ, Agid Y, Brüne M, et al. (2012) Cognitive dysfunction in psychiatric disorders: characteristics, causes and the quest for improved therapy. Nat Reu Drug Discov 11:141-68.

[67] Moustafa AA, Phillips J, Kéri S, et al. (2016) On the complexity of brain disorders: a symptom-based approach. Front Comput Neurosci 10:16.

[68] Musazzi L, Treccani G, Mallei A, et al. (2013) The action of antidepressants on the glutamate system: regulation of glutamate release and glutamate receptors. Biol Psychiatry 73:1180-8.

[69] Ney LJ, Akhurst J, Bruno R, et al. (2021) Dopamine, endocannabinoids and their interaction in fear extinction and negative affect in PTSD. Prog Neuropsychopharmacol Biol Psychiatry 105:110118.

[70] Nijdam MJ, Gersons BP, Olff M (2013) The role of major depression in neurocognitive functioning in patients with posttraumatic stress disorder. Eur J Psychotraumatology 2:4.

[71] Nixon RD, Nearmy DM (2011) Treatment of comorbid posttraumatic stress disorder and major depressive disorder: a pilot study. J Trauma Stress 24:451-5.

[72] O'doherty DCM, Chitty KM, Saddiqui S, et al. (2015) A systematic review and meta-analysis of magnetic resonance imaging measurement of structural volumes in posttraumatic stress disorder. Psychiatry Res Neuroimag 232:1-33.

[73] O'donnell ML, Creamer M, Pattison P (2004) Posttraumatic stress disorder and depression following trauma: understanding comorbidity. Am J Psychiatry 161:1390-6.

[74] Pariante CM, Miller AH (2001) Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment. Biol Psychiatry 49:391-404.

[75] Philip NS, Barredo J, Van 'T Wout-Frank M, et al. (2018) Network mechanisms of clinical response to transcranial magnetic stimulation in posttraumatic stress disorder and major depressive disorder. Biol Psychiatry 83:263-72.

[76] Philip NS, Doherty RA, Faucher C, et al. (2022) Transcranial magnetic stimulation for posttraumatic stress disorder and major depression: comparing commonly used clinical protocols. J Trauma Stress 35:101-8.

[77] Philip NS, Ridout SJ, Albright SE, et al. (2016) 5-Hz transcranial magnetic stimulation for comorbid posttraumatic stress disorder and major depression. J Trauma Stress 29:93-6.

[78] Popoli M, Yan Z, Mcewen BS, et al. (2011) The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission. Nat Rev Neurosci 13:22-37.

[79] Pukay-Martin ND, Pontoski KE, Maxwell MA, et al. (2012) The influence of depressive symptoms on suicidal ideation among U.S. Vietnam-era and Afghanistan/Iraq-era veterans with posttraumatic stress disorder. J Trauma Stress 25:578-82.

[80] Rakesh G, Logue MW, Clarke-Rubright E, et al. (2023) Network centrality and modularity of structural covariance networks in posttraumatic stress disorder: a multisite ENIGMA-PGC Study. Brain Connectivity 13:211-25.

[81] Rytwinski NK, Scur MD, Feeny NC, et al. (2013) The co-occurrence of major depressive disorder among individuals with posttraumatic stress disorder: a meta-analysis. J Trauma Stress 26:299-309.

[82] Satterthwaite TD, Cook PA, Bruce SE, et al. (2016) Dimensional depression severity in women with major depression and post-traumatic stress disorder correlates with fronto-amygdalar hypoconnectivty. Mol Psychiatry 21:894-902.

[83] Schulze L, Schulze A, Renneberg B, et al. (2019) Neural correlates of affective disturbances: a comparative meta-analysis of negative affect processing in borderline personality disorder, major depressive disorder, and posttraumatic stress disorder. Biol Psychiatry Cogn Neurosci Neuroimag 4:220-32.

[84] Seitz KI, Sicorello M, Schmitz M, et al. (2024) Childhood maltreatment and amygdala response to interpersonal threat in a transdiagnostic adult sample: the role of trait dissociation. Biol Psychiatry Cogn Neurosci Neuroimag 9:626-34.

[85] Seitz KI, Ueltzhöffer K, Rademacher L, et al. (2023) Your smile won't affect me: association between childhood maternal antipathy and adult neural reward function in a transdiagnostic sample. Transl Psychiatry 13:70.

[86] Serra-Blasco M, Radua J, Soriano-Mas C, et al. (2021) Structural brain correlates in major depression, anxiety disorders and posttraumatic stress disorder: a voxel-based morphometry metaanalysis. Neurosci Biobehav Rev 129:269-81.

[87] Shen LH, Liao MH, Tseng YC (2012) Recent advances in imaging of dopaminergic neurons for evaluation of neuropsychiatric disorders. J Biomed Biotechnol 2012:1.

[88] Shepherd AM, Matheson SL, Laurens KR, et al. (2012) Systematic meta-analysis of insula volume in schizophrenia. Biol Psychiatry 72:775-84.

[89] Shou H, Yang Z, Satterthwaite TD, et al. (2017) Cognitive behavioral therapy increases amygdala connectivity with the cognitive control network in both MDD and PTSD. NeuroImage Clin 14:464-70.

[90] Smoller JW (2016) The genetics of stress-related disorders: PTSD, depression, and anxiety disorders. Neuropsychopharmacol 41:297319.

[91] Southwick SM, Paige S, Morgan CA 3rd, et al. (1999) Neurotransmitter alterations in PTSD: catecholamines and serotonin. Semin Clin Neuropsychiatry 4:242-8.

[92] Suo X, Lei D, Li L, et al. (2018) Psychoradiological patterns of smallworld properties and a systematic review of connectome studies of patients with 6 major psychiatric disorders. J Psychiatry Neurosci 43:416.

[93] Thomas JL, Wilk JE, Riviere LA, et al. (2010) Prevalence of mental health problems and functional impairment among active component and National Guard soldiers 3 and 12 months following combat in Iraq. Arch Gen Psychiatry 67:614-23.

[94] Valencia N, Seeger FR, Seitz KI, et al. (2024) Childhood maltreatment and transdiagnostic connectivity of the default-mode network: the importance of duration of exposure. J Psychiatr Res 177:23948.

[95] Van Rooij SJH, Rademaker AR, Kennis M, et al. (2015) Neural correlates of trauma-unrelated emotional processing in war veterans with PTSD. Psychol Med 45:575-87.

[96] Wang Z, He D, Yang L, et al. (2024) Similarities and differences between post-traumatic stress disorder and major depressive disorder: evidence from task-evoked functional magnetic resonance imaging meta-analysis. J Affect Disord 361:712-9.

[97] Watts BV, Groft A (2010) Retrospective evaluation of the dexamethasone suppression test as a predictor of response to electroconvulsive therapy in patients with comorbid major depressive disorder and posttraumatic stress disorder. J Ect 26:213-7.

[98] Whalley MG, Rugg MD, Smith APR, et al. (2009) Incidental retrieval of emotional contexts in post-traumatic stress disorder and depression: an fMRI study. Brain Cogn 69:98-107.

[99] Wilkes S, Ona C, Yang M, et al. (2020) Impacts of rTMS on refractory depression and comorbid PTSD symptoms at a military treatment facility. Mil Med 185:e1420-7.

[100] Yang Z, Gu S, Honnorat N, et al. (2018a) Network changes associated with transdiagnostic depressive symptom improvement follow-ing cognitive behavioral therapy in MDD and PTSD. Mol Psychiatry 23:2314-23.

[101] Yang Z, Oathes DJ, Linn KA, et al. (2018b) Cognitive behavioral therapy is associated with enhanced cognitive control network activity in major depression and posttraumatic stress disorder. Biol Psychiatry Cogn Neurosci Neuroimag 3:311-9.

[102] Yehuda R, Flory JD, Bierer LM, et al. (2015) Lower methylation of glucocorticoid receptor gene promoter 1F in peripheral blood of veterans with posttraumatic stress disorder. Biol Psychiatry 77: 356-64.

[103] Yuan M, Pantazatos SP, Zhu H, et al. (2019) Altered amygdala subregion-related circuits in treatment-naïve post-traumatic stress disorder comorbid with major depressive disorder. Eur Neuropsychopharmacol 29:1092-101.

[104] Zannas AS, Binder EB (2014) Gene-environment interactions at the FKBP5 locus: sensitive periods, mechanisms and pleiotropism. Genes Brain Behav 13:25-37.

[105] Zarate CA, Singh JB, Carlson PJ, et al. (2006) A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 63:856-64.

[106] Zhang F, Rao S, Cao H, et al. (2022) Genetic evidence suggests posttraumatic stress disorder as a subtype of major depressive disorder. J Clin Invest 132:e145942.

[107] Zhu X, Helpman L, Papini S, et al. (2017) Altered resting state functional connectivity of fear and reward circuitry in comorbid PTSD and major depression. Depress Anxiety 34: 641-50.

[108] Zhuo C, Lin X, Wang C, et al. (2020a) Unified and disease specific alterations to brain structure in patients across six categories of mental disorders who experience own-thought auditory verbal hallucinations: a pilot study. Brain Res Bull 160: 33-9.

[109] Zhuo C, Wang C, Song X, et al. (2020b) A unified model of shared brain structural alterations in patients with different mental disorders who experience own-thought auditory verbal hallucinations-a pilot study. Brain Behav 10:e01614.

[110] Zilcha-Mano S, Zhu X, Suarez-Jimenez B, et al. (2020) Diagnostic and predictive neuroimaging biomarkers for posttraumatic stress disorder. Biol Psychiatry Cogn Neurosci Neuroimag 5: 688-96.