Abstract
Major depressive disorder with psychotic features (psychotic depression) is a severe disorder. Compared with other psychotic disorders such as schizophrenia, relatively few studies on the neurobiology of psychotic depression have been pursued. Neuroimaging studies investigating psychotic depression have provided evidence for distributed structural brain abnormalities implicating the insular cortex and limbic system. We examined structural brain networks in participants (N = 245) using magnetic resonance imaging. This sample included healthy controls (n = 159) and the largest cross-sectional sample of patients with remitted psychotic depression (n = 86) collected to date. All patients participated in the Study of Pharmacotherapy of Psychotic Depression II randomized controlled trial. We used a novel, whole-brain, data-driven parcellation technique—non-negative matrix factorization—and applied it to cortical thickness data to derive structural covariance networks. We compared patients with remitted psychotic depression to healthy controls and found that patients had significantly thinner cortex in five structural covariance networks (insular-limbic, occipito-temporal, temporal, parahippocampal-limbic, and inferior fronto-temporal), confirming our hypothesis that affected brain networks would incorporate cortico-limbic regions. We also found that cross-sectional depression and severity scores at the time of scanning were associated with the insular-limbic network. Furthermore, the insular-limbic network predicted future severity scores that were collected at the time of recurrence of psychotic depression or sustained remission. Overall, decreased cortical thickness was found in five structural brain networks in patients with remitted psychotic depression and brain-behavior relationships were observed, particularly between the insular-limbic network and illness severity.
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References
Jääskeläinen E, Juola T, Korpela H, Lehtiniemi H, Nietola M, Korkeila J, et al. Epidemiology of psychotic depression—systematic review and meta-analysis. Psychol Med. 2018;48:905–18.
American Psychiatric Association. Diagnostic and statistical manual of mental disorders (DSM-5®). Arlington: American Psychiatric Publishing; 2013.
Fleming SK, Blasey C, Schatzberg AF. Neuropsychological correlates of psychotic features in major depressive disorders: a review and meta-analysis. J Psychiatr Res. 2004;38:27–35.
Coryell W, Pfohl B, Zimmerman M. The clinical and neuroendocrine features of psychotic depression. J Nerv Ment Dis. 1984;172:521–8.
Lykouras E, Malliaras D, Christodouiou GN, Moussas G, Christodoulou D. Delusional depression: phenomenology and response to treatment. Psychopathology. 1986;19:157–64.
Frances A, Brown RP, Kocsis JH, Mann JJ. Psychotic depression: a separate entity? Am J Psychiatry. 1981;138:831–3.
Glassman AH, Roose SP. Delusional depression. A distinct clinical entity? Arch Gen Psychiatry. 1981;38:424–7.
Nelson JC, Bowers MB Jr. Delusional unipolar depression: description and drug response. Arch Gen Psychiatry. 1978;35:1321–8.
Charney DS, Nelson JC. Delusional and nondelusional unipolar depression: further evidence for distinct subtypes. Am J Psychiatry. 1981;138:328–33.
Coryell W, Leon A, Winokur G, Endicott J, Keller M, Akiskal H, et al. Importance of psychotic features to long-term course in major depressive disorder. Am J Psychiatry. 1996;153:483–9.
Maj M, Pirozzi R, Magliano L, Fiorillo A, Bartoli L. Phenomenology and prognostic significance of delusions in major depressive disorder: a 10-year prospective follow-up study. J Clin Psychiatry. 2007;68:1411–7.
Ohayon MM, Schatzberg AF. Prevalence of depressive episodes with psychotic features in the general population. Am J Psychiatry. 2002;159:1855–61.
Rothschild AJ. Psychotic depression and suicide. Acta Psychiatr Scand. 2018;137:364–5.
Zalpuri I, Rothschild AJ. Does psychosis increase the risk of suicide in patients with major depression? A systematic review. J Affect Disord. 2016;198:23–31.
Gournellis R, Tournikioti K, Touloumi G, Thomadakis C, Michalopoulou PG, Christodoulou C, et al. Psychotic (delusional) depression and suicidal attempts: a systematic review and meta-analysis. Acta Psychiatr Scand. 2018;137:18–29.
Rothschild AJ. Clinical manual for diagnosis and treatment of psychotic depression. Arlington: American Psychiatric Publishing; 2009.
Nelson JC, Davis JM. DST studies in psychotic depression: a meta-analysis. Am J Psychiatry. 1997;154:1497–503.
Anton RF. Urinary free cortisol in psychotic depression. Biol Psychiatry. 1987;22:24–34.
Owashi T, Otsubo T, Oshima A, Nakagome K, Higuchi T, Kamijima K. Longitudinal neuroendocrine changes assessed by dexamethasone/CRH and growth hormone releasing hormone tests in psychotic depression. Psychoneuroendocrinology. 2008;33:152–61.
Coryell W, Fiedorowicz J, Zimmerman M, Young E. HPA-axis hyperactivity and mortality in psychotic depressive disorder: preliminary findings. Psychoneuroendocrinology. 2008;33:654–8.
Meltzer HY, Cho HW, Carroll BJ. Serum dopamine-β-hydroxylase activity in the affective psychoses and schizophrenia: decreased activity in unipolar psychotically depressed patients. Arch Gen Psychiatry. 1976;33:585–91.
Mód L, Rihmer Z, Magyar I, Arató M, Alföldi A, Bagdy G. Serum DBH activity in psychotic vs. nonpsychotic unipolar and bipolar depression. Psychiatry Res. 1986;19:331–3.
Cubells JF, Price LH, Meyers BS, Anderson GM, Zabetian CP, Alexopoulos GS, et al. Genotype-controlled analysis of plasma dopamine β-hydroxylase activity in psychotic unipolar major depression. Biol Psychiatry. 2002;51:358–64.
Thase ME, Kupfer DJ, Ulrich RF. Electroencephalographic sleep in psychotic depression. A valid subtype? Arch Gen Psychiatry. 1986;43:886–93.
Rothschild AJ, Benes F, Hebben N, Woods B, Luciana M, Bakanas E, et al. Relationships between brain CT scan findings and cortisol in psychotic and nonpsychotic depressed patients. Biol Psychiatry. 1989;26:565–75.
Busatto GF. Structural and functional neuroimaging studies in major depressive disorder with psychotic features: a critical review. Schizophr Bull. 2013;39:776–86.
O’Connor S, Agius M. A systematic review of structural and functional MRI differences between psychotic and nonpsychotic depression. Psychiatr Danub. 2015;27:S235–S239.
Sommer IEC, Vd Veer AJ, Wijkstra J, Boks MPM, Kahn RS. Comparing language lateralization in psychotic mania and psychotic depression to schizophrenia; a functional MRI study. Schizophr Res. 2007;89:364–5.
Kelley R, Garrett A, Cohen J, Gomez R, Lembke A, Keller J, et al. Altered brain function underlying verbal memory encoding and retrieval in psychotic major depression. Psychiatry Res. 2013;211:119–26.
Garrett A, Kelly R, Gomez R, Keller J, Schatzberg AF, Reiss AL. Aberrant brain activation during a working memory task in psychotic major depression. Am J Psychiatry. 2011;168:173–82.
Neufeld NH, Mulsant BH, Dickie EW, Meyers BS, Alexopoulos GS, Rothschild AJ, et al. Resting state functional connectivity in patients with remitted psychotic depression: a multi-centre STOP-PD study. EBioMedicine. 2018;36:446–53.
Sudheimer K, Keller J, Gomez R, Tennakoon L, Reiss A, Garrett A, et al. Decreased hypothalamic functional connectivity with subgenual cortex in psychotic major depression. Neuropsychopharmacology . 2015;40:849–60.
Oudega ML, van der Werf YD, Dols A, Wattjes MP, Barkhof F, Bouckaert F, et al. Exploring resting state connectivity in patients with psychotic depression. PLoS ONE. 2019;14:e0209908.
Simpson S, Baldwin RC, Jackson A, Burns A. The differentiation of DSM-III-R psychotic depression in later life from nonpsychotic depression: comparisons of brain changes measured by multispectral analysis of magnetic resonance brain images, neuropsychological findings, and clinical features. Biol Psychiatry. 1999;45:193–204.
Salokangas RKR, Cannon T, Van Erp T, Ilonen T, Taiminen T, Karlsson H, et al. Structural magnetic resonance imaging in patients with first-episode schizophrenia, psychotic and severe non-psychotic depression and healthy controls. Br J Psychiatry. 2002;181:s58–s65.
Keller J, Shen L, Gomez RG, Garrett A, Solvason HB, Reiss A, et al. Hippocampal and amygdalar volumes in psychotic and nonpsychotic unipolar depression. Am J Psychiatry. 2008;165:872–80.
Vassilopoulou K, Papathanasiou M, Michopoulos I, Boufidou F, Oulis P, Kelekis N, et al. A magnetic resonance imaging study of hippocampal, amygdala and subgenual prefrontal cortex volumes in major depression subtypes: melancholic versus psychotic depression. J Affect Disord. 2013;146:197–204.
Kim DK, Kim BL, Sohn SE, Lim SW, Na DG, Paik CH, et al. Candidate neuroanatomic substrates of psychosis in old-aged depression. Prog Neuropsychopharmacol Biol Psychiatry. 1999;23:793–807.
Coryell W, Nopoulos P, Drevets W, Wilson T, Andreasen NC. Subgenual prefrontal cortex volumes in major depressive disorder and schizophrenia: diagnostic specificity and prognostic implications. Am J Psychiatry. 2005;162:1706–12.
Wheeler AL, Voineskos AN. A review of structural neuroimaging in schizophrenia: from connectivity to connectomics. Front Hum Neurosci. 2014;8:1–18.
Behdinan T, Foussias G, Wheeler AL, Stefanik L, Felsky D, Remington G, et al. Neuroimaging predictors of functional outcomes in schizophrenia at baseline and 6-month follow-up. Schizophr Res. 2015;169:69–75.
Wheeler AL, Wessa M, Szeszko PR, Foussias G, Chakravarty MM, Lerch JP, et al. Further neuroimaging evidence for the deficit subtype of schizophrenia: a cortical connectomics analysis. JAMA Psychiatry. 2015;72:446–55.
Xu L, Groth KM, Pearlson G, Schretlen DJ, Calhoun VD. Source-based morphometry: the use of independent component analysis to identify gray matter differences with application to schizophrenia. Hum Brain Mapp. 2009;30:711–24.
Wannan CMJ, Cropley VL, Chakravarty MM, Bousman C, Ganella EP, Bruggemann JM, et al. Evidence for network-based cortical thickness reductions in schizophrenia. Am J Psychiatry. 2019;176:552–63.
Sotiras A, Resnick SM, Davatzikos C. Finding imaging patterns of structural covariance via non-negative matrix factorization. Neuroimage. 2015;108:1–16.
Sotiras A, Toledo JB, Gur RE, Gur RC, Satterthwaite TD, Davatzikos C. Patterns of coordinated cortical remodeling during adolescence and their associations with functional specialization and evolutionary expansion. Proc Natl Acad Sci USA. 2017;114:3527–32.
Pehlivanova M, Wolf DH, Sotiras A, Kaczkurkin A, Moore TM, Ciric R, et al. Diminished cortical thickness is associated with impulsive choice in adolescence. J Neurosci. 2018;38:2471–81.
Kaczkurkin AN, Park SS, Sotiras A, Moore TM, Calkins ME, Cieslak M, et al. Evidence for dissociable linkage of dimensions of psychopathology to brain structure in youths. Am J Psychiatry. 2019;176:1000–9.
Jirsaraie RJ, Kaczkurkin AN, Rush S, Piiwia K, Adebimpe A, Bassett DS, et al. Accelerated cortical thinning within structural brain networks is associated with irritability in youth. Neuropsychopharmacology. 2019;44:2254–62.
Kaczkurkin AN, Sotiras A, Baller EB, Barzilay R, Calkins ME, Chand GB, et al. Neurostructural heterogeneity in youth with internalizing symptoms. Biol Psychiatry. 2020;87:473–82.
Cui Z, Li H, Xia CH, Larsen B, Adebimpe A, Baum GL, et al. Individual variation in functional topography of association networks in youth. Neuron. 2020;106:1–14.
Croarkin PE. Indexing the neurobiology of psychotic depression with resting state connectivity: Insights from the STOP-PD study. EBioMedicine. 2018;37:32–33.
Suh JS, Schneider MA, Minuzzi L, MacQueen GM, Strother SC, Kennedy SH, et al. Cortical thickness in major depressive disorder: a systematic review and meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry. 2019;88:287–302.
Flint AJ, Meyers BS, Rothschild AJ, Whyte EM, Alexopoulos GS, Rudorfer MV, et al. Effect of continuing olanzapine vs placebo on relapse among patients with psychotic depression in remission: the STOP-PD II Randomized Clinical Trial. JAMA. 2019;322:622–31.
Flint AJ, Meyers BS, Rothschild AJ, Whyte EM, Mulsant BH, Rudorfer MV, et al. Sustaining remission of psychotic depression: rationale, design and methodology of STOP-PD II. BMC Psychiatry. 2013;13:1–12.
Jorm AF, Jacomb PA. The Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE): socio-demographic correlates, reliability, validity and some norms. Psychol Med. 1989;19:1015–22.
Folstein MF, Folstein SE, McHugh PR. Mini-mental state’: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189–98.
Miller MD, Paradis CF, Houck PR, Mazumdar S, Stack JA, Rifai AH, et al. Rating chronic medical illness burden in geropsychiatric practice and research: application of the Cumulative Illness Rating Scale. Psychiatry Res. 1992;41:237–48.
Rosen AFG, Roalf DR, Ruparel K, Blake J, Seelaus K, Villa LP, et al. Quantitative assessment of structural image quality. Neuroimage. 2018;169:407–18.
Dale AM, Fischl B, Sereno MI. Cortical surface-based analysis. I. Segmentation and surface reconstruction. Neuroimage. 1999;9:179–94.
Fischl B, Dale AM. Measuring the thickness of the human cerebral cortex from magnetic resonance images. Proc Natl Acad Sci USA. 2000;97:11050–5.
Fischl B, Sereno MI, Tootell RB, Dale AM. High-resolution intersubject averaging and a coordinate system for the cortical surface. Hum Brain Mapp. 1999;8:272–84.
Yang Z, Oja E. Linear and nonlinear projective nonnegative matrix factorization. IEEE Trans Neural Netw. 2010;21:734–49.
Goodkind M, Eickhoff SB, Oathes DJ, Jiang Y, Chang A, Jones-Hagata LB, et al. Identification of a common neurobiological substrate for mental illness. JAMA Psychiatry. 2015;72:305–15.
Schmaal L, Hibar DP, Sämann PG, Hall GB, Baune BT, Jahanshad N, et al. Cortical abnormalities in adults and adolescents with major depression based on brain scans from 20 cohorts worldwide in the ENIGMA Major Depressive Disorder Working Group. Mol Psychiatry. 2017;22:900–9.
Bijanki KR, Hodis B, Brumm MC, Harlynn EL, McCormick LM. Hippocampal and left subcallosal anterior cingulate atrophy in psychotic depression. PLoS ONE. 2014;9:e110770.
Redlich R, Opel N, Bürger C, Dohm K, Grotegerd D, Förster K, et al. The limbic system in youth depression: brain structural and functional alterations in adolescent in-patients with severe depression. Neuropsychopharmacology. 2018;43:546–54.
Stickel S, Wagels L, Wudarczyk O, Jaffee S, Habel U, Schneider F, et al. Neural correlates of depression in women across the reproductive lifespan—an fMRI review. J Affect Disord. 2019;246:556–70.
Sexton CE, Mackay CE, Ebmeier KP. A systematic review and meta-analysis of magnetic resonance imaging studies in late-life depression. Am J Geriatr Psychiatry. 2013;21:184–95.
García-Cabezas MÁ, Zikopoulos B, Barbas H. The Structural Model: a theory linking connections, plasticity, pathology, development and evolution of the cerebral cortex. Brain Struct Funct. 2019;224:985–1008.
Ghaziri J, Tucholka A, Girard G, Houde J-C, Boucher O, Gilbert G, et al. The corticocortical structural connectivity of the human insula. Cereb Cortex. 2017;27:1216–28.
Adams RA, Stephan KE, Brown HR, Frith CD, Friston KJ. The computational anatomy of psychosis. Front Psychiatry. 2013;4:1–26.
Sterzer P, Adams RA, Fletcher P, Frith C, Lawrie SM, Muckli L, et al. The predictive coding account of psychosis. Biol Psychiatry. 2018;84:634–43.
Eggart M, Lange A, Binser MJ, Queri S, Müller-Oerlinghausen B. Major depressive disorder is associated with impaired interoceptive accuracy: a systematic review. Brain Sci. 2019;9:1–17.
Preuschoff K, Quartz SR, Bossaerts P. Human insula activation reflects risk prediction errors as well as risk. J Neurosci. 2008;28:2745–52.
Catani M, Dell’acqua F, Thiebaut, de Schotten M. A revised limbic system model for memory, emotion and behaviour. Neurosci Biobehav Rev. 2013;37:1724–37.
Benarroch EE. The central autonomic network: functional organization, dysfunction, and perspective. Mayo Clin Proc. 1993;68:988–1001.
Thayer JF, Lane RD. A model of neurovisceral integration in emotion regulation and dysregulation. J Affect Disord. 2000;61:201–16.
Hagemann D, Waldstein SR, Thayer JF. Central and autonomic nervous system integration in emotion. Brain Cogn. 2003;52:79–87.
Beissner F, Meissner K, Bär K-J, Napadow V. The autonomic brain: an activation likelihood estimation meta-analysis for central processing of autonomic function. J Neurosci. 2013;33:10503–11.
LeDoux JE, Brown R. A higher-order theory of emotional consciousness. Proc Natl Acad Sci USA. 2017;114:E2016–E2025.
Iwabuchi SJ, Raschke F, Auer DP, Liddle PF, Lankappa ST, Palaniyappan L. Targeted transcranial theta-burst stimulation alters fronto-insular network and prefrontal GABA. Neuroimage. 2017;146:395–403.
Lee E-H, Han P-L. Reciprocal interactions across and within multiple levels of monoamine and cortico-limbic systems in stress-induced depression: a systematic review. Neurosci Biobehav Rev. 2019;101:13–31.
Mottolese R, Redouté J, Costes N, Le Bars D, Sirigu A. Switching brain serotonin with oxytocin. Proc Natl Acad Sci USA. 2014;111:8637–42.
Hawco C, Viviano JD, Chavez S, Dickie EW, Calarco N, Kochunov P. et al. A longitudinal human phantom reliability study of multi-center T1-weighted, DTI, and resting state fMRI data. Psychiatry Res Neuroimaging. 2018;282:134–42.
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Conceptualization: NHN, ANK, AS, BHM, EWD, AJF, BSM, GSA, AJR, EMW, LM, JN, MJH, CD, TDS, and ANV; methodology: NHN, ANK, AS, EWD, CD, TDS, and ANV; formal analysis: NHN and ANK; resources: TDS and ANV; writing—original draft: NHN; writing—review and editing: NHN, ANK, AS, BHM, EWD, AJF, BSM, GSA, AJR, EMW, LM, JN, MJH, CD, TDS, and ANV; visualizations: NHN, ANK, and TDS; supervision: TDS and ANV.
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Neufeld, N.H., Kaczkurkin, A.N., Sotiras, A. et al. Structural brain networks in remitted psychotic depression. Neuropsychopharmacol. 45, 1223–1231 (2020). https://doi.org/10.1038/s41386-020-0646-7
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DOI: https://doi.org/10.1038/s41386-020-0646-7
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