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• W2896620498 abstract "Major depressive disorder (MDD) with psychotic features or “psychotic depression” is a pernicious mood disorder with substantial morbidity and mortality. This disorder contrasts with schizophrenia spectrum and other psychotic disorders in that psychotic symptoms attenuate with remission from depressive symptoms. Although there are effective acute interventions for psychotic depression, less is known about longer term continuation and maintenance pharmacologic treatment with agents that can have a profound side effect burden [[1]Flint A.J. Meyers B.S. Rothschild A.J. Whyte E.M. Mulsant B.H. Rudorfer M.V. et al.Sustaining remission of psychotic depression: rationale, design and methodology of STOP-PD II.BMC Psychiatry. 2013; 1338https://doi.org/10.1186/1471-244x-13-38Crossref PubMed Scopus (0) Google Scholar]. The neurobiology of psychotic depression is understudied and poorly understood. Notably, there are few prior neuroimaging studies to guide research design and clinical practice [[2]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: 849-860https://doi.org/10.1038/npp.2014.259Crossref PubMed Scopus (24) Google Scholar]. These knowledge deficits highlight common challenges faced in psychiatric clinical practice and interventional study design. Resting-state functional magnetic resonance imaging provides an efficient and noninvasive methodology for examining brain networks [3Dunlop B.W. Rajendra J.K. Craighead W.E. Kelley M.E. McGrath C.L. Choi K.S. et al.Functional connectivity of the Subcallosal Cingulate Cortex and differential outcomes to treatment with cognitive-behavioral therapy or antidepressant medication for major depressive disorder.Am J Psychiatry. 2017; 174: 533-545https://doi.org/10.1176/appi.ajp.2016.16050518Crossref PubMed Scopus (125) Google Scholar, 4Fischer A.S. Keller C.J. Etkin A. The clinical applicability of functional connectivity in depression: Pathways toward more targeted intervention.Biol Psychiatry Cogn Neurosci Neuroimaging. 2016; 1: 262-270https://doi.org/10.1016/j.bpsc.2016.02.004Summary Full Text Full Text PDF PubMed Scopus (24) Google Scholar, 5Mulders P.C. van Eijndhoven P.F. Schene A.H. Beckmann C.F. Tendolkar I. Resting-state functional connectivity in major depressive disorder: a review.Neurosci Biobehav Rev. 2015; 56: 330-344https://doi.org/10.1016/j.neubiorev.2015.07.014Crossref PubMed Scopus (330) Google Scholar]. This tool examines the temporal coherence of the blood-oxygen-level-dependent signal among brain regions while a subject is quiescent and not focused on a task [[4]Fischer A.S. Keller C.J. Etkin A. The clinical applicability of functional connectivity in depression: Pathways toward more targeted intervention.Biol Psychiatry Cogn Neurosci Neuroimaging. 2016; 1: 262-270https://doi.org/10.1016/j.bpsc.2016.02.004Summary Full Text Full Text PDF PubMed Scopus (24) Google Scholar,[5]Mulders P.C. van Eijndhoven P.F. Schene A.H. Beckmann C.F. Tendolkar I. Resting-state functional connectivity in major depressive disorder: a review.Neurosci Biobehav Rev. 2015; 56: 330-344https://doi.org/10.1016/j.neubiorev.2015.07.014Crossref PubMed Scopus (330) Google Scholar]. Recently, there has been much work and interest focused on resting-state functional magnetic resonance with the hope of developing reliable biomarkers for research and clinical practice [3Dunlop B.W. Rajendra J.K. Craighead W.E. Kelley M.E. McGrath C.L. Choi K.S. et al.Functional connectivity of the Subcallosal Cingulate Cortex and differential outcomes to treatment with cognitive-behavioral therapy or antidepressant medication for major depressive disorder.Am J Psychiatry. 2017; 174: 533-545https://doi.org/10.1176/appi.ajp.2016.16050518Crossref PubMed Scopus (125) Google Scholar, 4Fischer A.S. Keller C.J. Etkin A. The clinical applicability of functional connectivity in depression: Pathways toward more targeted intervention.Biol Psychiatry Cogn Neurosci Neuroimaging. 2016; 1: 262-270https://doi.org/10.1016/j.bpsc.2016.02.004Summary Full Text Full Text PDF PubMed Scopus (24) Google Scholar, 5Mulders P.C. van Eijndhoven P.F. Schene A.H. Beckmann C.F. Tendolkar I. Resting-state functional connectivity in major depressive disorder: a review.Neurosci Biobehav Rev. 2015; 56: 330-344https://doi.org/10.1016/j.neubiorev.2015.07.014Crossref PubMed Scopus (330) Google Scholar, 6Chen L. Wang Y. Niu C. Zhong S. Hu H. Chen P. et al.Common and distinct abnormal frontal-limbic system structural and functional patterns in patients with major depression and bipolar disorder.Neuroimage Clin. 2018; 20: 42-50https://doi.org/10.1016/j.nicl.2018.07.002Crossref PubMed Scopus (30) Google Scholar, 7Drysdale A.T. Grosenick L. Downar J. Dunlop K. Mansouri F. Meng Y. et al.Resting-state connectivity biomarkers define neurophysiological subtypes of depression.Nat Med. 2017; 23: 28-38https://doi.org/10.1038/nm.4246Crossref PubMed Scopus (771) Google Scholar]. Resting-state functional magnetic resonance imaging is an indirect measure of brain function with numerous potential confounds and uncertain neurobiological underpinnings [[4]Fischer A.S. Keller C.J. Etkin A. The clinical applicability of functional connectivity in depression: Pathways toward more targeted intervention.Biol Psychiatry Cogn Neurosci Neuroimaging. 2016; 1: 262-270https://doi.org/10.1016/j.bpsc.2016.02.004Summary Full Text Full Text PDF PubMed Scopus (24) Google Scholar,[5]Mulders P.C. van Eijndhoven P.F. Schene A.H. Beckmann C.F. Tendolkar I. Resting-state functional connectivity in major depressive disorder: a review.Neurosci Biobehav Rev. 2015; 56: 330-344https://doi.org/10.1016/j.neubiorev.2015.07.014Crossref PubMed Scopus (330) Google Scholar]. Resting-state functional magnetic resonance imaging studies have great promise despite the realization of limitations and this approach is arguably a leading candidate among biomarkers in the search for tools to optimize clinical practice and interventional studies in psychiatry. One prior resting-state functional connectivity study examined 39 healthy participants, 39 patients with active MDD, and 22 patients with active MDD with psychotic features. Patients with psychotic depression had reduced hypothalamic and subgenual cortex connectivity. Notably this is the only prior resting-state functional magnetic resonance imaging study examining psychotic depression [[2]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: 849-860https://doi.org/10.1038/npp.2014.259Crossref PubMed Scopus (24) Google Scholar]. In EBioMedicine, Voineskos, Neufeld and colleagues examined resting-state functional connectivity of patients with psychotic depression and healthy controls within a primary and replication sample. Patients in this study were enrolled in a randomized controlled trial, and all patients reached remission and were taking both sertraline and olanzapine at the time of scanning. Depressed patients in the primary sample had decreased between-network functional connectivity in the default mode network (DMN) and bilateral insular, somatosensory/motor, and auditory cortices with the greatest peak of decreased connectivity within the right planum polare compared to healthy control subjects. Notably, the replication sample of patients with remitted psychotic depression had a similar pattern of functional connectivity. This suggests that the lack of increased DMN associated functional connectivity and attenuated between-network connectivity may be neurobiological correlates of remitted psychotic depression ([[8]Neufeld N.H. Mulsant B.H. Dickie E.W. Meyers B.S. Alexopoulos G.S. Rothschild A.J. et al.(In Press). Resting state functional connectivity in patients with remitted psychotic depression: A multi-centre STOP-PD study.EBioMedicine. 2018; https://doi.org/10.1016/j.ebiom.2018.09.025Summary Full Text Full Text PDF PubMed Scopus (5) Google Scholar] (In Press)). The DMN is a collection of widespread brain regions demonstrating functional connectivity while an individual is awake but at rest. This network facilitates unprompted, internal thoughts and emotions [[4]Fischer A.S. Keller C.J. Etkin A. The clinical applicability of functional connectivity in depression: Pathways toward more targeted intervention.Biol Psychiatry Cogn Neurosci Neuroimaging. 2016; 1: 262-270https://doi.org/10.1016/j.bpsc.2016.02.004Summary Full Text Full Text PDF PubMed Scopus (24) Google Scholar]. The DMN has been widely studied in unipolar depression and psychiatric disorder in general. Emerging evidence consistently suggests that patients with unipolar, nonpsychotic MDD and psychotic disorders such as schizophrenia have aberrant intra and internetwork patterns of connectivity [[5]Mulders P.C. van Eijndhoven P.F. Schene A.H. Beckmann C.F. Tendolkar I. Resting-state functional connectivity in major depressive disorder: a review.Neurosci Biobehav Rev. 2015; 56: 330-344https://doi.org/10.1016/j.neubiorev.2015.07.014Crossref PubMed Scopus (330) Google Scholar,[9]Looijestijn J. Blom J.D. Aleman A. Hoek H.W. Goekoop R. An integrated network model of psychotic symptoms.Neurosci Biobehav Rev. 2015; 59: 238-250https://doi.org/10.1016/j.neubiorev.2015.09.016Crossref PubMed Scopus (37) Google Scholar]. Abnormalities in subgenual cortex and DMN functional connectivity are a consistent finding in studies of nonpsychotic depression. Further, DMN, hyperactivity and hyperconnectivity may be associated with psychotic symptoms and a reflection of decreased gamma-Aminobutyric acid neurotransmission [[9]Looijestijn J. Blom J.D. Aleman A. Hoek H.W. Goekoop R. An integrated network model of psychotic symptoms.Neurosci Biobehav Rev. 2015; 59: 238-250https://doi.org/10.1016/j.neubiorev.2015.09.016Crossref PubMed Scopus (37) Google Scholar]. Given that the present study by Voineskos and colleagues is the first of its kind and cross-sectional, it is unclear if the demonstrated pattern of a lack of DMN hyperconnectivity to other brain regions is a trait biomarker of psychotic depression or a reflection of dynamic brain changes associated with remission from psychotic depression ([[8]Neufeld N.H. Mulsant B.H. Dickie E.W. Meyers B.S. Alexopoulos G.S. Rothschild A.J. et al.(In Press). Resting state functional connectivity in patients with remitted psychotic depression: A multi-centre STOP-PD study.EBioMedicine. 2018; https://doi.org/10.1016/j.ebiom.2018.09.025Summary Full Text Full Text PDF PubMed Scopus (5) Google Scholar] (In Press)). Regardless, this important work establishes a benchmark for future longitudinal studies of psychotic depression. This work also underscores the scientific imperative for a broader integration of neuroimaging into interventional studies in psychiatry to advance clinical neuroscience and psychiatric practice. Further work with resting-state functional magnetic resonance imaging holds the prospect for enhanced classification and diagnostic practices in psychiatric research and practice ([3Dunlop B.W. Rajendra J.K. Craighead W.E. Kelley M.E. McGrath C.L. Choi K.S. et al.Functional connectivity of the Subcallosal Cingulate Cortex and differential outcomes to treatment with cognitive-behavioral therapy or antidepressant medication for major depressive disorder.Am J Psychiatry. 2017; 174: 533-545https://doi.org/10.1176/appi.ajp.2016.16050518Crossref PubMed Scopus (125) Google Scholar, 4Fischer A.S. Keller C.J. Etkin A. The clinical applicability of functional connectivity in depression: Pathways toward more targeted intervention.Biol Psychiatry Cogn Neurosci Neuroimaging. 2016; 1: 262-270https://doi.org/10.1016/j.bpsc.2016.02.004Summary Full Text Full Text PDF PubMed Scopus (24) Google Scholar, 5Mulders P.C. van Eijndhoven P.F. Schene A.H. Beckmann C.F. Tendolkar I. Resting-state functional connectivity in major depressive disorder: a review.Neurosci Biobehav Rev. 2015; 56: 330-344https://doi.org/10.1016/j.neubiorev.2015.07.014Crossref PubMed Scopus (330) Google Scholar,[7]Drysdale A.T. Grosenick L. Downar J. Dunlop K. Mansouri F. Meng Y. et al.Resting-state connectivity biomarkers define neurophysiological subtypes of depression.Nat Med. 2017; 23: 28-38https://doi.org/10.1038/nm.4246Crossref PubMed Scopus (771) Google Scholar]). Clinical diagnoses such as MDD with psychotic features have substantial heterogeneity that contributes to poor outcomes and uncertainty in treatment approaches. Resting state functional connectivity studies such as the effort by Voineskos and colleagues hold promise for understanding the neurobiology of psychiatric disorders and honing treatment approaches ([[8]Neufeld N.H. Mulsant B.H. Dickie E.W. Meyers B.S. Alexopoulos G.S. Rothschild A.J. et al.(In Press). Resting state functional connectivity in patients with remitted psychotic depression: A multi-centre STOP-PD study.EBioMedicine. 2018; https://doi.org/10.1016/j.ebiom.2018.09.025Summary Full Text Full Text PDF PubMed Scopus (5) Google Scholar] (In Press)). However, one current challenge and unfortunate irony is the widespread heterogeneity of reported findings in neuroimaging literature. This limitation is not insurmountable however and solutions are exemplified by the efforts of this multicenter team. Large collaborations, data sharing, replication studies, and longitudinal efforts are important considerations [[10]Data Sharing and the future of science Nat Commun. 2018; 9: 2817https://doi.org/10.1038/s41467-018-05227-zCrossref PubMed Scopus (17) Google Scholar]. Multimodal work assimilating neuroimaging findings with risk genes, epigenetic markers, refined clinical characterization, and measures of environment will likely be key factors to unlock the mysteries of psychiatric heterogeneity. The study by Voineskos and colleagues is an important step in this process and has provided exciting new insights regarding the neurobiology of psychotic depression([[8]Neufeld N.H. Mulsant B.H. Dickie E.W. Meyers B.S. Alexopoulos G.S. Rothschild A.J. et al.(In Press). Resting state functional connectivity in patients with remitted psychotic depression: A multi-centre STOP-PD study.EBioMedicine. 2018; https://doi.org/10.1016/j.ebiom.2018.09.025Summary Full Text Full Text PDF PubMed Scopus (5) Google Scholar] (In Press)). The author declares no conflict of interest. The author is supported by NIMH grant R01MH113700 . Resting state functional connectivity in patients with remitted psychotic depression: A multi-centre STOP-PD studyRemission from psychotic depression is consistently associated with an absence of increased DMN-related functional connectivity and presence of decreased between-network functional connectivity. Future research will evaluate this abnormal DMN-related functional connectivity as a potential biomarker for treatment trajectories. Full-Text PDF Open Access" @default.
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• W2896620498 title "Indexing the neurobiology of psychotic depression with resting state connectivity: Insights from the STOP-PD study" @default.
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