title: Resting-state connectivity biomarkers define neurophysiological subtypes of depression.
abstract: Biomarkers have transformed modern medicine but remain largely elusive in psychiatry, partly because there is a weak correspondence between diagnostic labels and their neurobiological substrates. Like other neuropsychiatric disorders, depression is not a unitary disease, but rather a heterogeneous syndrome that encompasses varied, co-occurring symptoms and divergent responses to treatment. By using functional magnetic resonance imaging (fMRI) in a large multisite sample (n = 1,188), we show here that patients with depression can be subdivided into four neurophysiological subtypes ('biotypes') defined by distinct patterns of dysfunctional connectivity in limbic and frontostriatal networks. Clustering patients on this basis enabled the development of diagnostic classifiers (biomarkers) with high (82-93%) sensitivity and specificity for depression subtypes in multisite validation (n = 711) and out-of-sample replication (n = 477) data sets. These biotypes cannot be differentiated solely on the basis of clinical features, but they are associated with differing clinical-symptom profiles. They also predict responsiveness to transcranial magnetic stimulation therapy (n = 154). Our results define novel subtypes of depression that transcend current diagnostic boundaries and may be useful for identifying the individuals who are most likely to benefit from targeted neurostimulation therapies.
authors.affiliation: Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York, USA.|Department of Psychiatry, Weill Cornell Medical College, New York, New York, USA.|Sackler Institute for Developmental Psychobiology, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Drysdale
authors.affiliation: Department of Bioengineering and Center for Mind, Brain and Computation, Stanford University, Stanford, California, USA.|Department of Statistics, Columbia University Medical Center, New York, New York, USA.
authors.forename: Logan
authors.initials: L
authors.lastname: Grosenick
authors.affiliation: Department of Psychiatry, Toronto Western Hospital, Toronto, Canada.
authors.forename: Jonathan
authors.identifier: 0000-0002-5140-174X
authors.initials: J
authors.lastname: Downar
authors.affiliation: Department of Psychiatry, Toronto Western Hospital, Toronto, Canada.
authors.forename: Katharine
authors.initials: K
authors.lastname: Dunlop
authors.affiliation: Department of Psychiatry, Toronto Western Hospital, Toronto, Canada.
authors.forename: Farrokh
authors.initials: F
authors.lastname: Mansouri
authors.affiliation: Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Meng
authors.affiliation: Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Fetcho
authors.affiliation: Department of Psychiatry, Columbia University Medical Center, New York, New York, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Zebley
authors.affiliation: Center for Neuromodulation in Depression and Stress and Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Desmond J
authors.initials: DJ
authors.lastname: Oathes
authors.affiliation: Department of Psychiatry and Behavioral Science, Stanford University, Stanford, California, USA.|Veteran Affairs Palo Alto Health Care System, Stanford University, Stanford, California, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Etkin
authors.affiliation: Department of Psychiatry and Behavioral Science, Stanford University, Stanford, California, USA.
authors.forename: Alan F
authors.initials: AF
authors.lastname: Schatzberg
authors.affiliation: Department of Psychiatry and Behavioral Science, Stanford University, Stanford, California, USA.
authors.forename: Keith
authors.initials: K
authors.lastname: Sudheimer
authors.affiliation: Department of Psychiatry and Behavioral Science, Stanford University, Stanford, California, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Keller
authors.affiliation: Department of Psychiatry, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Helen S
authors.initials: HS
authors.lastname: Mayberg
authors.affiliation: Department of Psychiatry, Weill Cornell Medical College, New York, New York, USA.|Institute of Geriatric Psychiatry, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Faith M
authors.initials: FM
authors.lastname: Gunning
authors.affiliation: Department of Psychiatry, Weill Cornell Medical College, New York, New York, USA.|Institute of Geriatric Psychiatry, Weill Cornell Medical College, New York, New York, USA.
authors.forename: George S
authors.initials: GS
authors.lastname: Alexopoulos
authors.affiliation: Berenson-Allen Center for Noninvasive Brain Stimulation and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Fox
authors.affiliation: Berenson-Allen Center for Noninvasive Brain Stimulation and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Pascual-Leone
authors.affiliation: Department of Radiology, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Henning U
authors.identifier: 0000-0003-2811-2074
authors.initials: HU
authors.lastname: Voss
authors.affiliation: Department of Psychology, Yale University, New Haven, Connecticut, USA.
authors.forename: B J
authors.initials: BJ
authors.lastname: Casey
authors.affiliation: Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York, USA.|Department of Psychiatry, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Dubin
authors.affiliation: Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York, USA.|Department of Psychiatry, Weill Cornell Medical College, New York, New York, USA.|Sackler Institute for Developmental Psychobiology, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Conor
authors.initials: C
authors.lastname: Liston
mesh_terms: D000328:Adult; D001921:Brain / Q000503:physiopathology*; D016000:Cluster Analysis; D003865:Major Depressive Disorder / Q000145:classification / Q000503:physiopathology*; D005260:Female; D005625:Frontal Lobe / Q000503:physiopathology; D059907:Functional Neuroimaging; D006801:Humans; D008032:Limbic System / Q000503:physiopathology; D008279:Magnetic Resonance Imaging; D008297:Male; D009434:Neural Pathways / Q000503:physiopathology; D066328:Ventral Striatum / Q000503:physiopathology