Chronic stress and depressive-like behaviors in basic neuroscience research have been associated with impairments of neuroplasticity, such as neuronal atrophy and synaptic loss in the medial prefrontal cortex (mPFC) and hippocampus. The current review presents a novel integrative model of neuroplasticity as a multi-domain neurobiological, cognitive, and psychological construct relevant in depression and other related disorders of negative affect (e.g., anxiety). We delineate a working conceptual model in which synaptic plasticity deficits described in animal models are integrated and conceptually linked with human patient findings from cognitive science and clinical psychology. We review relevant reports including neuroimaging findings (e.g., decreased functional connectivity in prefrontal-limbic circuits), cognitive deficits (e.g., executive function and memory impairments), affective information processing patterns (e.g., rigid, negative biases in attention, memory, interpretations, and self-associations), and patient-reported symptoms (perseverative, inflexible thought patterns; inflexible and maladaptive behaviors). Finally, we incorporate discussion of integrative research methods capable of building additional direct empirical support, including using rapid-acting treatments (e.g., ketamine) as a means to test this integrative model by attempting to simultaneously reverse these deficits across levels of analysis.
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Chisholm D, Sweeny K, Sheehan P, Rasmussen B, Smit F, Cuijpers P, et al. Scaling-up treatment of depression and anxiety: a global return on investment analysis. Lancet Psychiatry. 2016;3:415–24.
Wang PS, Lane M, Olfson M, Pincus HA, Wells KB, Kessler RC. Twelve-month use of mental health services in the United States: results from the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62:629–40.
Abdallah CG, Sanacora G, Duman RS, Krystal JH. Ketamine and rapid-acting antidepressants: a window into a new neurobiology for mood disorder therapeutics. Annu Rev Med. 2015;66:509–23.
Duman RS, Aghajanian GK, Sanacora G, Krystal JH. Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat Med. 2016;22:238–49.
Duman RS, Aghajanian GK. Synaptic dysfunction in depression: potential therapeutic targets. Science. 2012;338:68–72.
Kashdan TB, Rottenberg J. Psychological flexibility as a fundamental aspect of health. Clin Psychol Rev. 2010;30:865–78.
Joormann J. Cognitive inhibition and emotion regulation in depression. Curr Dir Psychol Sci. 2010;19:161–6.
Disner S, Beevers C, Haigh EAP, Beck AT. Neural mechanisms of the cognitive model of depression. Nat Rev Neurosci. 2011;12:467–77.
Beck AT, Bredemeier K. A unified model of depression: integrating clinical, cognitive, biological, and evolutionary perspectives. Clin Psychol Sci. 2016;4:596–619.
Moda-Sava RN, Murdock MH, Parekh PK, Fetcho RN, Huang BS, Huynh TN, et al. Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation. Science. 2019;364:eaat8078.
Murrough JW, Iosifescu DV, Chang LC, Al Jurdi RK, Green CM, Perez AM, et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry. 2013;170:1134–42.
Xu Y, Hackett M, Carter G, Loo C, Galvez V, Glozier N, et al. Effects of low-dose and very low-dose dose ketamine among patients with major depression: a systematic review and meta-analysis. Int J Neuropsychopharmacol. 2015;19:pyv124.
Beurel E, Nemeroff CB. Interaction of stress, corticotropin-releasing factor, arginine vasopressin and behaviour. Curr Top Behav Neurosci. 2014;18:67–80.
Luscher B, Fuchs T. GABAergic control of depression-related brain states. Adv Pharmacol. 2015;73:97–144.
Waters RP, Rivalan M, Bangasser DA, Deussing JM, Ising M, Wood SK, et al. Evidence for the role of corticotropin-releasing factor in major depressive disorder. Neurosci Biobehav Rev. 2015;58:63–78.
Fee C, Banasr M, Sibille E. Somatostatin-positive gamma-aminobutyric acid interneuron deficits in depression: cortical microcircuit and therapeutic perspectives. Biol Psychiatry. 2017;82:549–59.
Wohleb ES, Franklin T, Iwata M, Duman RS. Integrating neuroimmune systems in the neurobiology of depression. Nat Rev Neurosci. 2016;17:497–511.
McEwen BS, Nasca C, Gray JD. Stress effects on neuronal structure: hippocampus, amygdala, and prefrontal cortex. Neuropsychopharmacology. 2016;41:3–23.
Anacker C, Hen R. Adult hippocampal neurogenesis and cognitive flexibility—linking memory and mood. Nat Rev Neurosci. 2017;18:335–46.
Koo JW, Chaudhury D, Han MH, Nestler EJ. Role of mesolimbic brain-derived neurotrophic factor in depression. Biol Psychiatry. 2019;86:738–48.
Cathomas F, Murrough JW, Nestler EJ, Han MH, Russo SJ. Neurobiology of Resilience: interface between mind and body. Biol Psychiatry. 2019;86:410–20.
Duman RS, Sanacora G, Krystal JH. Altered connectivity in depression: GABA and glutamate neurotransmitter deficits and reversal by novel treatments. Neuron. 2019;102:75–90.
Arnone D. Functional MRI findings, pharmacological treatment in major depression and clinical response. Prog Neuropsychopharmacol Biol Psychiatry. 2019;91:28–37.
Castrén E. Is mood Chem? Nat Rev Neurosci. 2005;6:241–6.
Castren E, Hen R. Neuronal plasticity and antidepressant actions. Trends Neurosci. 2013;36:259–67.
Changeaux JP, Danchin A. Selective stabilisation of developing synapses as a mechanism for the specification of neuronal networks. Nature. 1976;264:705–12.
Wang Q, Timberlake MA 2nd, Prall K, Dwivedi Y. The recent progress in animal models of depression. Prog Neuropsychopharmacol Biol Psychiatry. 2017;77:99–109.
Ota K, Liu R, Voleti B, Maldonado-Aviles J, Duric V, Iwata M, et al. REDD1 is essential for stress-induced synaptic loss and depressive behavior. Nat Med. 2014;20:531–5.
Wohleb ES, Terwilliger R, Duman CH, Duman RS. Stress-induced neuronal colony stimulating factor 1 provokes microglia-mediated neuronal remodeling and depressive-like behavior. Biol Psychiatry. 2018;83:38–49.
Roozendaal B, McEwen BS, Chattarji S. Stress, memory and the amygdala. Nat Rev Neurosci. 2009;10:423–33.
Patel D, Anilkumar S, Chattarji S, Buwalda B. Repeated social stress leads to contrasting patterns of structural plasticity in the amygdala and hippocampus. Behav Brain Res. 2018;347:314–24.
Caddy C, Amit BH, McCloud TL, Rendell JM, Furukawa TA, McShane R, et al. Ketamine and other glutamate receptor modulators for depression in adults. Cochrane Database Syst Rev. 2015:CD011612.
McCloud TL, Caddy C, Jochim J, Rendell JM, Diamond PR, Shuttleworth C, et al. Ketamine and other glutamate receptor modulators for depression in bipolar disorder in adults. Cochrane Database Syst Rev. 2015:CD011611.
Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature. 2016;533:481–6.
Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010;329:959–64.
Liu RJ, Duman C, Kato T, Hare B, Lopresto D, Bang E, et al. GLYX-13 produces rapid antidepressant responses with key synaptic and behavioral effects distinct from ketamine. Neuropsychopharmacology. 2017;42:1231–42.
Burgdorf J, Zhang XL, Nicholson KL, Balster RL, Leander JD, Stanton PK, et al. GLYX-13, a NMDA receptor glycine-site functional partial agonist, induces antidepressant-like effects without ketamine-like side effects. Neuropsychopharmacology. 2013;38:729–42.
Newport DJ, Carpenter LL, McDonald WM, Potash JB, Tohen M, Nemeroff CB, et al. Ketamine and other NMDA antagonists: early clinical trials and possible mechanisms in depression. Am J Psychiatry. 2015;172:950–66.
Abdallah C, Averill L, Gueorguieva R, Goktas S, Purohit P, Ranganathan M, et al. Rapamycin, an immunosuppressant and mTORC1 inhibitor, triples the antidepressant response rate to ketamine at two weeks following treatment. 2018. https://doi.org/10.1101/500959.
Sen S, Duman R, Sanacora G. Serum brain-derived neurotrophic factor, depression, and antidepressant medications: meta-analyses and implications. Biol Psychiatry. 2008;64:527–32.
Kang HJ, Voleti B, Hajszan T, Rajkowska G, Stockmeier CA, Licznerski P, et al. Decreased expression of synapse-related genes and loss of synapses in major depressive disorder. Nat Med. 2012;18:1413–7.
Price RB, Eldreth DA, Mohlman J. Deficient prefrontal attentional control in late-life generalized anxiety disorder: an fMRI investigation. Transl Psych. 2011;1:e46.
Price RB, Allen KB, Silk JS, Ladouceur CD, Ryan ND, Dahl RE, et al. Vigilance in the laboratory predicts avoidance in the real world: a dimensional analysis of neural, behavioral, and ecological momentary data in anxious youth. Dev Cogn Neurosci. 2016;19:128–36.
Siegle GJ, Thompson W, Carter CS, Steinhauer SR, Thase ME. Increased amygdala and decreased dorsolateral prefrontal BOLD responses in unipolar depression: related and independent features. Biol Psychiatry. 2007;61:198–209.
Gotlib IH, Joormann J. Cognition and depression: current status and future directions. Annu Rev Clin Psychol. 2010;6:285–312.
Dozois D, Beck A. Cognitive schemas, beliefs and assumptions. In: Dobson K, Dozois D, editors. Risk factors in depression. Oxford, England: Elsevier/Academic Press; 2008, p. 121–43.
de Raedt R, Koster EHW. Understanding vulnerability for depression from a cognitive neuroscience perspective: a reappraisal of attentional factors and a new conceptual framework. Cogn Affect Behav Neurosci. 2010;10:50–70.
Stange JP, Connolly SL, Burke TA, Hamilton JL, Hamlat EJ, Abramson LY, et al. Inflexible cognition predicts first onset of major depressive episodes in adolescence. Depress Anxiety. 2016;33:1005–12.
Schmaal L, Veltman DJ, van Erp TG, Samann PG, Frodl T, Jahanshad N, et al. Subcortical brain alterations in major depressive disorder: findings from the ENIGMA Major Depressive Disorder working group. Mol Psychiatry. 2016;21:806–12.
Schmaal L, Hibar DP, Samann 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.
Chen G, Guo Y, Zhu H, Kuang W, Bi F, Ai H, et al. Intrinsic disruption of white matter microarchitecture in first-episode, drug-naive major depressive disorder: a voxel-based meta-analysis of diffusion tensor imaging. Prog Neuropsychopharmacol Biol Psychiatry. 2017;76:179–87.
Park HJ, Friston K. Structural and functional brain networks: from connectionsto cognition. Science. 2013;342:1238411.
Sporns O, Chialvo DR, Kaiser M, Hilgetag CC. Organization, development and function of complex brain networks. Trends Cogn Sci. 2004;8:418–25.
Kaiser RH, Andrews-Hanna JR, Wager TD, Pizzagalli DA. Large-Scale network dysfunction in major depressive disorder: a meta-analysis of resting-state functional connectivity. JAMA Psychiatry. 2015;72:603–11.
Abdallah CG, Averill LA, Collins KA, Geha P, Schwartz J, Averill C, et al. Ketamine treatment and global brain connectivity in major depression. Neuropsychopharmacology. 2017;42:1210–9.
Hirshfeld-Becker DR, Gabrieli JDE, Shapero BG, Biederman J, Whitfield-Gabrieli S, Chai XJ. Intrinsic functional brain connectivity predicts onset of major depression disorder in adolescence: a pilot study. Brain Connect. 2019;9:388–98.
Jiang X, Shen Y, Yao J, Zhang L, Xu L, Feng R, et al. Connectome analysis of functional and structural hemispheric brain networks in major depressive disorder. Transl Psychiatry. 2019;9:136.
Greicius MD, Flores BH, Menon V, Glover GH, Solvason HB, Kenna H, et al. Resting-state functional connectivity in major depression: abnormally increased contributions from subgenual cingulate cortex and thalamus. Biol Psychiatry. 2007;62:429–37.
Rive MM, van Rooijen G, Veltman DJ, Phillips ML, Schene AH, Ruhe HG. Neural correlates of dysfunctional emotion regulation in major depressive disorder. A systematic review of neuroimaging studies. Neurosci Biobehav Rev. 2013;37:2529–53.
Carballedo A, Scheuerecker J, Meisenzahl E, Schoepf V, Bokde A, Moller HJ, et al. Functional connectivity of emotional processing in depression. J Affect Disord. 2011;134:272–9.
Anand A, Li Y, Wang Y, Wu J, Gao S, Bukhari L, et al. Activity and connectivity of brain mood regulating circuit in depression: a functional magnetic resonance study. Biol Psychiatry. 2005;57:1079–88.
Ochsner KN, Ray RD, Cooper JC, Robertson ER, Chopra S, Gabrieli JD, et al. For better or for worse: neural systems supporting the cognitive down- and up-regulation of negative emotion. Neuroimage. 2004;23:483–99.
Zilverstand A, Parvaz MA, Goldstein RZ. Neuroimaging cognitive reappraisal in clinical populations to define neural targets for enhancing emotion regulation. A systematic review. Neuroimage. 2017;151:105–16.
Pico-Perez M, Radua J, Steward T, Menchon JM, Soriano-Mas C. Emotion regulation in mood and anxiety disorders: a meta-analysis of fMRI cognitive reappraisal studies. Prog Neuropsychopharmacol Biol Psychiatry. 2017;79:96–104.
Johnstone T, van Reekum CM, Urry HL, Kalin NH, Davidson RJ. Failure to regulate: counterproductive recruitment of top-down prefrontal-subcortical circuitry in major depression. J Neurosci. 2007;27:8877–84.
Thompson SM, Kallarackal AJ, Kvarta MD, Van Dyke AM, LeGates TA, Cai X. An excitatory synapse hypothesis of depression. Trends Neurosci. 2015;38:279–94.
Koechlin E. Prefrontal executive function and adaptive behavior in complex environments. Curr Opin Neurobiol. 2016;37:1–6.
Wagner S, Muller C, Helmreich I, Huss M, Tadic A. A meta-analysis of cognitive functions in children and adolescents with major depressive disorder. Eur Child Adolesc Psychiatry. 2015;24:5–19.
Wagner S, Doering B, Helmreich I, Lieb K, Tadic A. A meta-analysis of executive dysfunctions in unipolar major depressive disorder without psychotic symptoms and their changes during antidepressant treatment. Acta Psychiatr Scandinavica. 2012;125:281–92.
McClintock SM, Husain MM, Greer TL, Cullum CM. Association between depression severity and neurocognitive function in major depressive disorder: a review and synthesis. Neuropsychology. 2010;24:9–34.
Roca M, Vives M, Lopez-Navarro E, Garcia-Campayo J, Gili M. Cognitive impairments and depression: a critical review. Actas Esp Psiquiatr. 2015;43:187–93.
Smith EE, Jonides J. Storage and executive processes in the frontal lobes. Science. 1999;283:1657–61.
Fuster JM. The prefrontal cortex. 3rd edn. Philadelphia, PA: Lippincott-Raven; 1997.
Murrough JW, Iacoviello B, Neumeister A, Charney DS, Iosifescu DV. Cognitive dysfunction in depression: neurocircuitry and new therapeutic strategies. Neurobiol Learn Mem. 2011;96:553–63.
Motter JN, Pimontel MA, Rindskopf D, Devanand DP, Doraiswamy PM, Sneed JR. Computerized cognitive training and functional recovery in major depressive disorder: a meta-analysis. J Affect Disord. 2016;189:184–91.
Siegle GJ, Price RB, Jones N, Ghinassi F, Painter T, Thase ME. You gotta work at it: pupillary indices of task focus are prognostic for response to a neurocognitive intervention for depression. Clin Psychol Sci. 2014;2:455–71.
Zhou FC, Wang YY, Zheng W, Zhang Q, Ungvari GS, Ng CH,et al. Prospective memory deficits in patients with depression: a meta-analysis. J Affect Disord. 2017;220:79–85.
Van Vreeswijk MF, De Wilde EJ. Autobiographical memory specificity, psychopathology, depressed mood and the use of the autobiographical memory test: a meta analysis. Behav Res Ther. 2004;42:731–43.
Pollock LR, Williams JM. Effective problem solving in suicide attempters depends on specific autobiographical recall. Suicide Life Threat Behav. 2001;31:386–96.
Williams JM, Ellis NC, Tyers C, Healy H, Rose G, MacLeod AK. The specificity of autobiographical memory and imageability of the future. Mem Cogn. 1996;24:116–25.
McEwen BS, Sapolsky RM. Stress and cognitive function. Curr Opin Neurobiol. 1995;5:205–16.
Mathews A, MacLeod C. Cognitive vulnerability to emotional disorders. Annu Rev Clin Psychol. 2005;1:167–95.
Peckham AD, McHugh RK, Otto MW. A meta-analysis of the magnitude of biased attention in depression. Depress Anxiety. 2010;27:1135–42.
Gilboa-Schechtman E, Erhard-Weiss D, Jeczemien P. Interpersonal deficits meet cognitive biases: memory for facial expressions in depressed and anxious men and women. Psychiatry Res. 2002;113:279–93.
Ridout N, Astell AJ, Reid IC, Glen T, O’Carroll RE. Memory bias for emotional facial expressions in major depression. Cogn Emot. 2003;17:101–22.
Hirsch CR, Meeten F, Krahe C, Reeder C. Resolving ambiguity in emotional disorders: the nature and role of interpretation biases. Annu Rev Clin Psychol. 2016;12:281–305.
Milders M, Bell S, Platt J, Serrano R, Runcie O. Stable expression recognition abnormalities in unipolar depression. Psychiatry Res. 2010;179:38–42.
Persad SM, Polivy J. Differences between depressed and nondepressed individuals in the recognition of and response to facial emotional cues. J Abnorm Psychol. 1993;102:358–68.
van Randenborgh A, Pawelzik M, Quirin M, Kuhl J. Bad roots to grow: deficient implicit self-evaluations in chronic depression with an early onset. J Clin Psychol. 2016;72:580–90.
Franck E, De Raedt R, De Houwer J. Implicit but not explicit self-esteem predicts future depressive symptomatology. Behav Res Ther. 2007;45:2448–55.
Phillips WJ, Hine DW, Thorsteinsson EB. Implicit cognition and depression: a meta-analysis. Clin Psychol Rev. 2010;30:691–709.
Nock MK, Park JM, Finn CT, Deliberto TL, Dour HJ, Banaji MR. Measuring the suicidal mind: implicit cognition predicts suicidal behavior. Psychol Sci. 2010;21:511–7.
Cha CB, Najmi S, Park JM, Finn CT, Nock MK. Attentional bias toward suicide-related stimuli predicts suicidal behavior. J Abnorm Psychol. 2010;119:616–22.
Barch DM, Pagliaccio D, Luking K. Mechanisms underlying motivational deficits in psychopathology: similarities and differences in depression and schizophrenia. Curr Top Behav Neurosci. 2016;27:411–49.
Chen C, Takahashi T, Nakagawa S, Inoue T, Kusumi I. Reinforcement learning in depression: a review of computational research. Neurosci Biobehav Rev. 2015;55:247–67.
Dombrovski AY, Szanto K, Clark L, Aizenstein HJ, Chase HW, Reynolds CF 3rd, et al. Corticostriatothalamic reward prediction error signals and executive control in late-life depression. Psychol Med. 2015;45:1413–24.
Dombrovski AY, Szanto K, Clark L, Reynolds CF, Siegle GJ. Reward signals, attempted suicide, and impulsivity in late-life depression. JAMA Psychiatry. 2013;70:1020–30.
Gradin VB, Kumar P, Waiter G, Ahearn T, Stickle C, Milders M, et al. Expected value and prediction error abnormalities in depression and schizophrenia. Brain. 2011;134:1751–64.
Kumar P, Waiter G, Ahearn T, Milders M, Reid I, Steele JD. Abnormal temporal difference reward-learning signals in major depression. Brain. 2008;131:2084–93.
Dombrovski AY, Hallquist MN. The decision neuroscience perspective on suicidal behavior: evidence and hypotheses. Curr Opin Psychiatry. 2017;30:7–14.
Berridge KC. Motivation concepts in behavioral neuroscience. Physiol Behav. 2004;81:179–209.
McGaugh JL. The amygdala modulates the consolidation of memories of emotionally arousing experiences. Annu Rev Neurosci. 2004;27:1–28.
Cahill L, Alkire MT. Epinephrine enhancement of human memory consolidation: interaction with arousal at encoding. Neurobiol Learn Mem. 2003;79:194–8.
Beevers CG, Clasen PC, Enock PM, Schnyer DM. Attention bias modification for major depressive disorder: effects on attention bias, resting state connectivity, and symptom change. J Abnorm Psychol. 2015;124:463–75.
White LK, Sequeira S, Britton JC, Brotman MA, Gold AL, Berman E, et al. Complementary features of attention bias modification therapy and cognitive-behavioral therapy in pediatric anxiety disorders. Am J Psychiatry. 2017;174:775–84.
Mathews A, MacLeod C. Cognitive approaches to emotion and emotional disorders. Annu Rev Psychol. 1994;45:25–50.
MacLeod C. Cognitive bias modification procedures in the management of mental disorders. Curr Opin Psychiatry. 2012;25:114–20.
Jones EB, Sharpe L. Cognitive bias modification: a review of meta-analyses. J Affect Disord. 2017;223:175–83.
Harmer CJ, Goodwin GM, Cowen PJ. Why do antidepressants take so long to work? A cognitive neuropsychological model of antidepressant drug action. Br J Psychiatry. 2009;195:102–8.
Association AP. Diagnostic and statistical manual of mental disorders. Arlington, VA: American Psychiatric Publishing; 2013.
Nolen-Hoeksema S, Morrow J, Fredrickson BL. Response styles and the duration of episodes of depressed mood. J Abnorm Psychol. 1993;102:20–8.
McEvoy PM, Mahoney AEJ, Moulds ML. Are worry, rumination, and post-event processing one and the same? Development of the repetitive thinking questionnaire. J Anxiety Disord. 2010;24:509–19.
Beck JG. Cognitive therapy: basics and beyond. New York, NY: The Guilford Press; 1995.
Beck AT, Dozois DJ. Cognitive therapy: current status and future directions. Annu Rev Med. 2011;62:397–409.
Teasdale JD, Segal ZV, Williams JMG, Ridgeway VA, Soulsby JM, Lau MA. Prevention of relapse/recurrence in major depression by mindfulness-based cognitive therapy. J Consult Clin Psychol. 2000;68:615–23.
Segal ZV, Walsh KM. Mindfulness-based cognitive therapy for residual depressive symptoms and relapse prophylaxis. Curr Opin Psychiatry. 2016;29:7–12.
Segal ZV, Teasdale JD, Williams JMG. Mindfulness-based cognitive therapy: theoretical rationale and empirical status. In: Folette SC, Linehan MM (eds.) Mindfulness and acceptance: Expanding the cognitive-behavioral tradition. New York, NY: Guilford Press; 2004.
Davidson J, Turnbull CD. Diagnostic significance of vegetative symptoms in depression. Br J Psychiatry. 1986;148:442–6.
Dimidjian S, Barrera M Jr., Martell C, Munoz RF, Lewinsohn PM. The origins and current status of behavioral activation treatments for depression. Annu Rev Clin Psychol. 2011;7:1–38.
Ratcliffe M. Experiences of Depression: a study in phenomenology. Oxford, UK: Oxford University Press; 2015.
Martell CR, Dimidjian S, Herman-Dunn R. Behavioral activation for depression: a clinician’s guide. New York: The Guilford Press; 2010.
Dimidjian S, Hollon SD, Dobson KS, Schmaling KB, Kohlenberg RJ, Addis ME, et al. Randomized trial of behavioral activation, cognitive therapy, and antidepressant medication in the acute treatment of adults with major depression. J Consult Clin Psychol. 2006;74:658–70.
Murrough JW, Collins KA, Fields J, DeWilde KE, Phillips ML, Mathew SJ, et al. Regulation of neural responses to emotion perception by ketamine in individuals with treatment-resistant major depressive disorder. Transl Psychiatry. 2015;5:e509.
Gartner M, Aust S, Bajbouj M, Fan Y, Wingenfeld K, Otte C, et al. Functional connectivity between prefrontal cortex and subgenual cingulate predicts antidepressant effects of ketamine. Eur Neuropsychopharmacol. 2019;29:501–8.
Li CT, Chen MH, Lin WC, Hong CJ, Yang BH, Liu RS, et al. The effects of low-dose ketamine on the prefrontal cortex and amygdala in treatment-resistant depression: A randomized controlled study. Hum Brain Mapp. 2016;37:1080–90.
Ionescu DF, Felicione JM, Gosai A, Cusin C, Shin P, Shapero BG, et al. Ketamine-Associated Brain Changes: a review of the neuroimaging literature. Harv Rev Psychiatry. 2018;26:320–39.
Downey D, Dutta A, McKie S, Dawson GR, Dourish CT, Craig K, et al. Comparing the actions of lanicemine and ketamine in depression: key role of the anterior cingulate. Eur Neuropsychopharmacol. 2016;26:994–1003.
Reed JL, Nugent AC, Furey ML, Szczepanik JE, Evans JW, Zarate CA, Jr. Ketamine normalizes brain activity during emotionally valenced attentional processing in depression. Neuroimage Clin. 2018;20:92–101.
Evans JW, Szczepanik J, Brutsche N, Park LT, Nugent AC, Zarate CA Jr. Default mode connectivity in major depressive disorder measured up to 10 days after ketamine administration. Biol Psychiatry. 2018;84:582–90.
Jett JD, Boley AM, Girotti M, Shah A, Lodge DJ, Morilak DA. Antidepressant-like cognitive and behavioral effects of acute ketamine administration associated with plasticity in the ventral hippocampus to medial prefrontal cortex pathway. Psychopharmacology. 2015;232:3123–33.
Nikiforuk A, Popik P. Ketamine prevents stress-induced cognitive inflexibility in rats. Psychoneuroendocrinology. 2014;40:119–22.
Shiroma PR, Albott CS, Johns B, Thuras P, Wels J, Lim KO. Neurocognitive performance and serial intravenous subanesthetic ketamine in treatment-resistant depression. Int J Neuropsychopharmacol. 2014;17:1805–13.
Permoda-Osip A, Kisielewski J, Bartkowska-Sniatkowska A, Rybakowski JK. Single ketamine infusion and neurocognitive performance in bipolar depression. Pharmacopsychiatry. 2015;48:78–9.
Price RB, Iosifescu DV, Murrough JW, Chang LC, Al Jurdi RK, Iqbal SZ, et al. Effects of ketamine on explicit and implicit suicidal cognition: a randomized controlled trial in treatment-resistant depression. Depress Anxiety. 2014;31:335–43.
Price RB, Nock MK, Charney DS, Mathew SJ. Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression. Biol Psychiatry. 2009;66:522–6.
Price RB, Kuckertz JM, Siegle GJ, Ladouceur CD, Silk JS, Ryan ND, et al. Empirical recommendations for improving the stability of the dot-probe task in clinical research. Psychol Assess. 2015;27:365–76.
Price RB, Brown V, Siegle GJ. Computational modeling applied to the dot-probe task yields improved reliability and mechanistic insights. Biol Psychiatry. 2019;85:606–12.
Rodebaugh TL, Scullin RB, Langer JK, Dixon DJ, Huppert JD, Bernstein A, et al. Unreliability as a threat to understanding psychopathology: the cautionary tale of attentional bias. J Abnorm Psychol. 2016;125:840–51.
Auxéméry Y. Post-traumatic psychiatric disorders: PTSD is not the only diagnosis. Presse Med. 2018;47:423–30.
Williams LM. Precision psychiatry: a neural circuit taxonomy for depression and anxiety. Lancet Psychiatry. 2016;3:472–80.
Feder A, Parides MK, Murrough JW, Perez AM, Morgan JE, Saxena S, et al. Efficacy of intravenous ketamine for treatment of chronic posttraumatic stress disorder: a randomized clinical trial. JAMA Psychiatry. 2014;71:681–8.
Glue P, Medlicott NJ, Harland S, Neehoff S, Anderson-Fahey B, Le Nedelec M, et al. Ketamine’s dose-related effects on anxiety symptoms in patients with treatment refractory anxiety disorders. J Psychopharmacol. 2017;31:1302–5.
Price RB, Gates K, Kraynak TE, Thase ME, Siegle GJ. Data-driven subgroups in depression derived from directed functional connectivity paths at rest. Neuropsychopharmacology. 2017;42:2623–32.
Price RB, Lane S, Gates K, Kraynak TE, Horner MS, Thase ME, et al. Parsing heterogeneity in the brain connectivity of depressed and healthy adults during positive mood. Biol Psychiatry. 2017;81:347–57.
Langenecker SA, Mickey BJ, Eichhammer P, Sen S, Elverman KH, Kennedy SE, et al. Cognitive control as a 5-HT1A-Based domain that is disrupted in major depressive disorder. Front Psychol. 2019;10:691.
Price RB, Rosen D, Siegle GJ, Ladouceur CD, Tang K, Allen KB, et al. From anxious youth to depressed adolescents: prospective prediction of 2-year depression symptoms via attentional bias measures. J Abnorm Psychol. 2015;125:267–78.
Fried EI, Nesse RM. Depression is not a consistent syndrome: an investigation of unique symptom patterns in the STAR*D study. J Affect Disord. 2014;172C:96–102.
Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science. 2003;301:805–9.
Hoogendam JM, Ramakers GM, Di Lazzaro V. Physiology of repetitive transcranial magnetic stimulation of the human brain. Brain Stimul. 2010;3:95–118.
Dukart J, Regen F, Kherif F, Colla M, Bajbouj M, Heuser I, et al. Electroconvulsive therapy-induced brain plasticity determines therapeutic outcome in mood disorders. Proc Natl Acad Sci USA. 2014;111:1156–61.
Cassilhas RC, Tufik S, de Mello MT. Physical exercise, neuroplasticity, spatial learning and memory. Cell Mol Life Sci. 2016;73:975–83.
Wilkinson S, Holtzheimer PE, Gao S, Kirwin D, Price R. Leveraging neuroplasticity to enhance adaptive learning: the potential for synergistic somatic-behavioral treatment combinations to improve clinical outcomes in depression. Biol Psychiatry. 2019;85:454–65.
Cullen KR, Westlund MK, Klimes-Dougan B, Mueller BA, Houri A, Eberly LE, et al. Abnormal amygdala resting-state functional connectivity in adolescent depression. JAMA Psychiatry. 2014;71:1138–47.
Young KD, Zotev V, Phillips R, Misaki M, Drevets WC, Bodurka J. Amygdala real-time functional magnetic resonance imaging neurofeedback for major depressive disorder: a review. Psychiatry Clin Neurosci. 2018;72:466–81.
Young KD, Siegle GJ, Misaki M, Zotev V, Phillips R, Drevets WC, et al. Altered task-based and resting-state amygdala functional connectivity following real-time fMRI amygdala neurofeedback training in major depressive disorder. Neuroimage Clin. 2018;17:691–703.
Dell’osso B, Camuri G, Castellano F, Vecchi V, Benedetti M, Bortolussi S, et al. Meta-review of metanalytic studies with repetitive transcranial magnetic stimulation (rTMS) for the treatment of major depression. Clin Pr Epidemiol Ment Health. 2011;7:167–77.
Derryberry D, Reed MA. Anxiety-related attentional biases and their regulation by attentional control. J Abnorm Psychol. 2002;111:225–36.
Hsu KJ, Beard C, Rifkin L, Dillon DG, Pizzagalli DA, Bjorgvinsson T. Transdiagnostic mechanisms in depression and anxiety: the role of rumination and attentional control. J Affect Disord. 2015;188:22–7.
Sumner JA. The mechanisms underlying overgeneral autobiographical memory: an evaluative review of evidence for the CaR-FA-X model. Clin Psychol Rev. 2012;32:34–48.
Hitchcock C, Werner-Seidler A, Blackwell SE, Dalgleish T. Autobiographical episodic memory-based training for the treatment of mood, anxiety and stress-related disorders: a systematic review and meta-analysis. Clin Psychol Rev. 2017;52:92–107.
Clarke PJ, Notebaert L, Macleod C. Absence of evidence or evidence of absence: reflecting on therapeutic implementations of attentional bias modification. BMC Psychiatry. 2014;14:8.
Franklin JC, Fox KR, Franklin CR, Kleiman EM, Ribeiro JD, Jaroszewski AC, et al. A brief mobile app reduces nonsuicidal and suicidal self-injury: evidence from three randomized controlled trials. J Consult Clin Psychol. 2016;84:544–57.
This project was supported in part by National Institute of Mental Health grant number R01MH113857 (RBP).
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The authors declare that they have no conflict of interest.
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Price, R.B., Duman, R. Neuroplasticity in cognitive and psychological mechanisms of depression: an integrative model. Mol Psychiatry 25, 530–543 (2020). https://doi.org/10.1038/s41380-019-0615-x
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